UNASSIGNED: We have been conducting a collaborative study on the thresholds of mutagens. In our previous examinations of cell activity and cell proliferation as endpoints, both displayed hormesis. This time, we conducted experiments to determine thresholds using the micronucleus test as an endpoint.
UNASSIGNED: The micronucleus test was conducted using Chinese hamster CHL/IU cells and mouse lymphoid L5178Y cells. Additionally, we conducted preliminary investigations into the gene expression using human TK6 cells.
UNASSIGNED: When adhesive CHL/IU cells were treated with mitomycin C (MMC), and the hormetic response was examined, hormesis was not observed clearly. When L5178Y cells were treated with methyl methanesulfonate (EMS), AF-2, MMC, and colchicine, all of them exhibited an adaptive response. Additionally, cross-adaptive responses using AF-2 and MMC or EMS and MMC were conducted, both combinations showed a cross-adaptive response. When the gene expression patterns of six genes were investigated by RT-PCR after treatment with MMC, EMS, and H2O2 using TK6 cells, two genes, GADD45 A and P21, were induced in a dose- and time-dependent manner.
UNASSIGNED: Adaptive responses arise from preconditioning. As hormesis is inherently linked to preconditioning, adaptive responses observed in this study strongly suggest that hormesis was induced, hence existence of thresholds.

UNASSIGNED: Observational data indicate that diets rich in fruits and vegetables have a positive effect on inflammatory status, improve metabolic resilience and may protect against the development of non-communicable diseases. Nevertheless, experimental evidence demonstrating a causal relationship between nutrient intake (especially whole foods) and changes in metabolic health is scarce. This study investigated the pleiotropic effects of sulforaphane from broccoli sprouts, compared to pea sprouts, on biomarkers of endothelial function, inflammation and metabolic stress in healthy participants subjected to a standardized caloric challenge.
UNASSIGNED: In this double-blind, crossover, randomized, placebo-controlled trial 12 healthy participants were administered 16 g broccoli sprouts, or pea sprouts (placebo) followed by the standardized high-caloric drink PhenFlex given to disturb healthy homeostasis. Levels of inflammatory biomarkers and metabolic parameters were measured in plasma before and 2 h after the caloric overload.
UNASSIGNED: Administration of broccoli sprouts promoted an increase in levels of CCL-2 induced by caloric load (p = 0.017). Other biomarkers (sICAM-1, sVCAM-1, hs-CRP, and IL-10) individually showed insignificant tendencies toward increase with administration of sulforaphane. Combining all studied biomarkers into the systemic low-grade inflammation score further confirmed upregulation of the inflammatory activity (p = 0.087) after sulforaphane. No significant effects on biomarkers of metabolic stress were detected.
UNASSIGNED: This study has demonstrated that sulforaphane facilitated development of a mild pro-inflammatory state during the caloric challenge, which could be suggestive of the onset of the hormetic response induced by this phytonutrient. The use of integrative outcomes measures such as the systemic low-grade inflammation score can be viewed as a more robust approach to study the subtle and pleiotropic effects of phytonutrients.Clinical trial registration:www.clinicaltrials.gov, identifier NCT05146804.

The present paper identifies a critical factor that leads to false negative results (i.e., failing to indicate efficacy when beneficial results did occur) in randomized human drug trials. The paper demonstrates that human performance can only be enhanced by a maximum of 30-60% as described by the hormetic dose response which defines the limits of biological plasticity. However, human epidemiological/clinical trials typically contain such extensive variability that often requires responses greater than 2-3 times control group responses to show statistical significance. Thus, many potentially beneficial agents may be missed because the clinical trial fails to recognize and take into consideration the limits of biological plasticity. The paper proposes that this hormesis-biological plasticity-clinical trial conundrum can be addressed successfully via the use of a weight-of-evidence methodology similar to that used by regulatory agencies such as EPA in environmental assessment of chemical toxicity.

A previous study found that the characteristic parameter σ2(k∙ECx) (the concentration ECx and slope k of the concentrationresponse curve (CRC) at the effect x %) can predict the acute combined toxicity of multiple mixtures with S-shaped CRCs. In this paper, the competence of σ2(k∙ECx) to predict the long-term toxicity of multiple mixtures with J-shaped CRCs was explored using the Aliivibrio fischeri as the test organism. The combined toxicity was evaluated by the independent action (IA) model and the effect ratio (ERx) model. The stepwise method was used to divide J-shaped CRC into ML and MR (SL and SR). The results showed that the σ2(k∙ECx) and ERx of each segment was in good agreement with the exponential function. A new type of mixture was added to the original type A and type B, whose rules of interaction were opposite to those of type B (named opposite B, OB). This paper improves the understanding and analysis of the J-shaped CRCs in environmental risk assessment.

Dietary polyphenols, which are present in Aronia melanocarpa, have been associated with various beneficial effects on human health including antioxidant, antiviral, and anti-inflammatory activities. We aimed to investigate the immunomodulatory effects of aronia juice polyphenols in a randomized placebo-controlled human intervention study and cell culture experiments. A total of 40 females were asked to consume either 200 mL of aronia juice or a placebo drink for six weeks and were investigated again after a washout period of another six weeks. We observed that only half of the participants tolerated the aronia juice well (Vt) and the other half reported complaints (Vc). The placebo (P) was generally tolerated with one exception (p = 0.003). Plasma polyphenol levels increased significantly in Vt after the intervention (p = 0.024) but did neither in P nor in Vc. Regulatory T cell (Treg) frequencies remained constant in Vt and P during the intervention, whereas Tregs decreased in Vc (p = 0.018). In cell culture, inhibiting effects of ferulic acid (p = 0.0005) and catechin (p = 0.0393) on the differentiation of Tregs were observed as well as reduced activation of CD4-T cells in ferulic acid (p = 0.0072) and aronia juice (p = 0.0163) treated cells. Interestingly, a CD4+CD25-FoxP3+ cell population emerged in vitro in response to aronia juice, but not when testing individual polyphenols. In conclusion, our data strengthen possible individual hormetic effects, the importance of the food matrix for bioactivity, and the need for further investigations on possible impacts of specific physiological features such as the gut microbiota in the context of personalized nutrition.

Highlights Home-based hydrotherapy leads to fewer missed kindergarten-days in total. In the application group, more fever days could be registered. Hydrotherapy, according to the hormesis principle by Sebastian Kneipp, aims to reduce infections of the lower respiratory tract. Parents participation motivated by increase in applicable health knowledge for their children. Objectives: This study investigates the effect of cold-water hydrotherapy stimulation according to the hormesis principle by Sebastian Kneipp on the number of missing kindergarten-days, fever days, and respiratory tract infections in children aged 3-6 years. Study design: A nonrandomized, controlled, explorative, mixed-methods clinical study. Intervention: The hydrotherapeutic intervention treated children aged 3-6 years with Kneipp arm affusions over 6 weeks. The control group received no intervention. Number of missed kindergarten-days, fever days, and respiratory tract infections were assessed by means of a digital diary. Through a self-developed structured questionnaire, sociodemographic data of both groups were compared and reason for participation in the study was recorded and qualitatively evaluated. Results: Twenty children participants and their parents in the intervention group and 18 in the control group were evaluated. The intervention was conducted at home by the parents. Statistical analysis revealed no significant differences between the groups but still showed intermediate effect sizes (indicating an underpowered study). These effect sizes point to a potentially lower proportion of children in the application group versus the control group with missed kindergarten-days in total (d = 0.67), days missed due to fever (d = 0.29), and infections of the lower respiratory tract (d = 0.60). In a future study, these parameters will thus serve as promising factors for evaluation. Parent\'s stated reasons for participation interest were to improve health, increase their own health knowledge, and because of their interest in alternative therapies and to support research. Conclusions: Cold-water hydrotherapy stimulation, according to the hormesis principle by Sebastian Kneipp, did reduce the number of days absent in kindergarten in total in the intervention group and lower respiratory tract infections occurred less frequently. Parent\' participation interest demonstrated a desire to increase health literacy and implement this with their own children. Due to the small sample size, the results should be interpreted cautiously. Clinical Trial Registration Number: German Register of Clinical Trials (DRKS): ID 00017562.

METHODS: Galactose, a ubiquitous monosaccharide with incompletely understood physiology is often exploited for inducing oxidative-stress mediated aging in animals. Recent research demonstrates that galactose can conserve cellular function during periods of starvation and prevent/alleviate cognitive deficits in a rat model of sporadic Alzheimer\'s disease. The present aim is to examine the acute effects of oral galactose on the redox regulatory network (RRN).
RESULTS: Rat plasma and hippocampal RRNs are analyzed upon acute orogastric gavage of galactose (200 mg kg-1 ). No systemic RRN disbalance is observed; however, a mild pro-oxidative shift accompanied by a paradoxical increment in tissue reductive capacity suggesting overcompensation of endogenous antioxidant systems is observed in the hippocampus. Galactose-induced increment of reductive capacity is accompanied by inflation of the hippocampal pool of nicotinamide adenine dinucleotide phosphates indicating ROS detoxification through disinhibition of the oxidative pentose phosphate pathway flux, reduced neuronal activity, and upregulation of Leloir pathway gatekeeper enzyme galactokinase-1.
CONCLUSIONS: Based on the observed findings, and in the context of previous work on galactose, a hormetic hypothesis of galactose is proposed suggesting that the protective effects may be inseparable from its pro-oxidative action at the biochemical level.

UNASSIGNED: We previously showed that hormetic responses can be established in cell activity tests using human and murine adherent cells. This time, we examined whether hormetic responses can be established in cell proliferation tests using suspended human and murine lymphoid cells.
UNASSIGNED: Human lymphoblastoid cells (TK6) and mouse lymphoma cells (L5178Y) were cultured in multi-well culture plates and treated with mitomycin C, ethyl methansulfonate, hygromycin B, aclarubicin or colchicine at various dose levels and the number of cells was measured at varied times using a flow cytometer.
UNASSIGNED: When the ratio of the number of cells treated with a test chemical to those in the negative control was plotted, the dose-response relationship typically showed a reverse U-shaped curve, indicating the occurrence of hormesis and existence of thresholds in cell toxicity. The hormetic responses depended largely on the test chemical, dose level and exposure time. When examining responses over the course of time, a J-shaped or fallen S-shaped curve was also observed.
UNASSIGNED: The dose-response relationship showed a reverse U-shaped curve, a hallmark of hormesis, at least some time points for all chemicals tested here, indicating that chemical hormesis can be established in in vitro cell proliferation tests.

The goal is to study the method of photodynamic therapy, which has become widespread in recent decades. This method of treatment has gained popularity in the treatment of both oncological and non-oncological inflammatory diseases in dentistry and other medical fields. We can conclude that the complex action of Rada Dent and Tskaltubo water (inhalation of Tskaltubo water and its use as rinses) leads to a gradual reduction and eventual eradication of the inflammatory process in the case of periodontitis. This can be explained by the unique properties that are characteristic of \"Rada Dent\" and Tskaltubo water. As we have seen, the above biochemical indicators are the determinants of periodontitis in patients with periodontitis, they are markers of the degree of periodontitis and we have clearly seen the complex action. High efficiency of \"Rada Dent\" and radon in the water of Tskaltubo - normalization of the action of oral enzymes, slowing down the inflammatory processes in the oral cavity and finally eradication. It is these unique properties that have become triggering the treatment and inhibit the initial stage of periodontitis.

Hormesis is a biphasic dose-response relationship featured by low-dose stimulation and high-dose inhibition. Although the hormetic phenomenon has been extensively studied over the past decades, there is little information regarding the influence of energy source on the occurrence of hormesis, especially the time-dependent one. In this study, to explore the role of cultivation system\'s energy source in time-dependent hormesis, the toxic dose-responses of Aliivibrio fischeri (A. fischeri) bioluminescence to Sulfadoxine (SDX) during 24 h were determined in four cultivation systems with different energy source conditions. The results indicated that the time-dependent hormetic effects were induced by SDX in all cultivation systems: SDX triggered hormetic phenomenon on the bioluminescence at each growth stage over 24 h in the cultivation systems with sufficient and insufficient energy source; due to the diauxic growth of A. fischeri under multiple energy source conditions, the hormetic effects of SDX gradually disappeared after the preferred energy source was used up. It was speculated that the inhibitory action of SDX was derived from its interaction with DHPS to impede the synthesis of proteins, and SDX bound with AC to upregulate the quorum sensing (QS) system to exhibit the stimulatory action. Comparing the time-dependent hormesis in each cultivation system, it was obtained that the energy source could impact the hourly maximum stimulatory rate, the EC50 of SDX, and the time point that hormesis occurred, which might result from the influence of energy source on the stimulatory and inhibitory actions of SDX through regulating the metabolic system (individual level) and QS system (group level) of bacteria. This study clarifies the importance of energy source for hormesis occurrence, which may further promote the development of hormesis.