The present paper provides the first integrative assessment of the capacity of dietary, endogenous and other agents to induce hormetic dose responses in oocytes, their supportive cells such as granulosa cells, blastocyst formation and early stage embryo development with the goal of improving fertility and reproductive success. The analysis showed that numerous agents enhance oocyte maturation and blastocyst/embryonic development in an hormetic fashion. These findings indicate that numerous agents improve oocyte related biological functioning under normal conditions as well as enhancing its capacity to prevent damage from numerous chemical toxins and related stressor agents, including heat and age-related processes in pre-post conditioning and concurrent exposures. The present assessment suggests that hormetic based lifestyles and dietary interventions may offer the potential to enhance healthy reproductive performance with applications to animal husbandry and human biology. The present findings also significantly extend the generality of the hormesis dose response concept to multiple fundamental biological processes (i.e., oocyte maturation, fertilization and blastocyst/embryo development).

Isometric exercise is a non-pharmacologic intervention to improve muscle hemodynamic responses and blood pressure in humans. However, the effects of intensity, duration, and muscle mass factors of isometric exercise on local muscle hemodynamic responses and systemic blood pressure regulation have not been studied. The purpose of this study was to assess whether various modes of isometric exercise could induce various levels of muscle hemodynamic responses that are related to the blood pressure changes. Near-infrared spectroscopy was used to assess muscle hemodynamic responses after 4 isometric exercise protocols in 20 healthy adults. One-way analysis of variance (ANOVA) with repeated measures was used to assess the effect of factors of isometric exercise on oxyhemoglobin, deoxy-hemoglobin, blood volume, and oxygenation. For oxygenation, the lowest mean was recorded for the unilateral isometric handgrip exercise at 30% of MVC for 2 min (-0.317 ± 0.379 μM) while the highest mean was observed for the isometric wall squat (1.496 ± 0.498 μM, P < 0.05). Additionally, both the bilateral isometric handgrip exercise at 30% MVC for 1 min (1.340 ± 0.711 μM, P < 0.05) and the unilateral isometric handgrip exercise at 20% MVC for 3 min (0.798 ± 0.324 μM, P < 0.05) are significantly higher than 30% of MVC for 2 min. Blood pressure showed an inverse trend with oxygenation changes of the forearm muscle. The study indicates that the duration and muscle mass of isometric exercise are more effective on oxygenation responses and systematic blood pressure regulation, and suggests that the local muscle oxygenation factor following isometric contractions may mediate systematic blood pressure regulation.

Empirical evidence has shown that light therapy (LT) can reduce depression symptoms by stimulating circadian rhythms. However, there is skepticism and inconclusive results, along with confusion regarding dosing. The purpose of this study is to quantify light as a stimulus for the circadian system and create a dose-response relationship that can help reduce maladies among adolescents and young adults (AYAs). This will provide a reference for light exposure and neural response, which are crucial in the neuropsychological mechanism of light intervention. The study also aims to provide guidance for clinical application.
The latest quantitative model of CLA (circadian light) and CSt,f (circadian stimulus) was adopted to quantify light dose for circadian phototransduction in youth depression-related light therapy. Articles published up to 2023 through Web of Science, Cochrane Library, Medline (OVID), CINAHL, APA PsycINFO, Embase, and Scholars were retrieved. A meta-analysis of 31 articles (1,031 subjects) was performed using Stata17.0, CMA3.0 (comprehensive meta-analysis version 3.0) software, and Python 3.9 platform for light therapy efficacy comparison and dose-response quantification.
Under various circadian stimulus conditions (0.1 < CSt,f < 0.7) of light therapy (LT), malady reductions among AYAs were observed (pooled SMD = -1.59, 95%CI = -1.86 to -1.32; z = -11.654, p = 0.000; I2 = 92.8%), with temporal pattern (p = 0.044) and co-medication (p = 0.000) suggested as main heterogeneity sources. For the efficacy advantage of LT with a higher circadian stimulus that is assumed to be influenced by visualization, co-medication, disease severity, and time pattern, sets of meta-analysis among random-controlled trials (RCTs) found evidence for significant efficacy of circadian-active bright light therapy (BLT) over circadian-inactive dim red light (SMD = -0.65, 95% CI = -0.96 to -0.34; z = -4.101, p = 0.000; I2 = 84.9%) or circadian-active dimmer white light (SMD = -0.37, 95% CI = -0.68 to -0.06; z = -2.318, p = 0.02; I2 = 33.8%), whereas green-blue, circadian-active BLT showed no significant superiority over circadian-inactive red/amber light controls (SMD = -0.21, 95% CI = -0.45 to 0.04; z = -2.318, p = 0.099; I2 = 0%). Overall, circadian-active BLT showed a greater likelihood of clinical response than dim light controls, with increased superiority observed with co-medication. For pre-to-post-treatment amelioration and corresponding dose-response relationship, cumulative duration was found more influential than other categorical (co-medication, severity, study design) or continuous (CSt,f) variables. Dose-response fitting indicated that the therapeutic effect would reach saturation among co-medicated patients at 32-42 days (900-1,000 min) and 58-59 days (1,100-1,500 min) among non-medicated AYAs. When exerting high circadian stimulus of light therapy (0.6 < CSt,f < 0.7), there was a significantly greater effect size in 1,000-1,500 min of accumulative duration than <1,000 or >1,500 min of duration, indicating a threshold for practical guidance.
The results have been based on limited samples and influenced by a small sample effect. The placebo effect could not be ignored.
Although the superiority of LT with higher circadian stimulus over dimmer light controls remains unproven, greater response potentials of circadian-active BLT have been noticed among AYAs, taking co-medication, disease severity, time pattern, and visual characteristics into consideration. The dose-response relationship with quantified circadian stimulus and temporal pattern had been elaborated under various conditions to support clinical depression treatment and LT device application in the post-pandemic era.

Quercetin is a polyphenol present in numerous fruits and vegetables and therefore widely consumed by humans with average daily dietary intakes of 10-20 mg/day. It is also a popular dietary supplement of 250-1000 mg/day. However, despite the widespread consumer interest in quercetin, due to its possible chemopreventive properties, the extensively studied quercetin presents a highly diverse and complex array of biological effects. Consequently, the present paper provides the first assessment of quercetin-induced hormetic concentration/dose responses, their quantitative features and mechanistic foundations, and their biological, biomedical, clinical, and public health implications. The findings indicate that quercetin-induced hormetic dose responses are widespread, being independent of biological model, cell type, and endpoint. These findings have the potential to enlighten future experimental studies with quercetin especially with respect to study design parameters and may also affect the appraisal of possible public health benefits and risks associated with highly diverse consumer consumption practices.

Background: Gastric cancer stands as a primary cause of cancer-related deaths worldwide, making the discovery of new therapeutic agents essential for enhancing treatment outcomes. Curcumin, a polyphenolic compound found in turmeric (Curcuma longa), has demonstrated potential in multiple cancer types due to its anti-cancer characteristics. This research aimed to examine the impact of curcumin on gastric cancer cell growth, migration, and invasion, as well as its influence on the phosphoinositide 3-kinase (PI3K) signaling cascade. Methods: Gastric cancer cell lines were exposed to varying curcumin concentrations, followed by assessments of cell viability, migration, and invasion. Furthermore, gene and protein expression levels associated with the PI3K signaling cascade were evaluated using reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Results: The findings revealed a dose-dependent decrease in cell viability, migration, and invasion in gastric cancer cells treated with curcumin. Additionally, curcumin administration led to the downregulation of key genes and proteins within the PI3K signaling process, such as PI3K, Akt, and mTOR. Conclusion: These findings propose that curcumin may exercise its anti-cancer effects on gastric cancer cells, partly by suppressing the PI3K signaling pathway. This study\'s outcomes support curcumin\'s potential as a therapeutic agent for gastric cancer and encourage further exploration of its underlying molecular mechanisms and in vivo effectiveness.

UNASSIGNED: The local hemodynamic response after cupping therapy has been considered as a contributing factor for improving muscle tissue health; however, the effects of cupping pressure and duration on the spatial hemodynamic response have not been investigated.
UNASSIGNED: The objective of this study was to investigate the hemodynamic response inside and outside the cupping cup under various pressures and durations of cupping therapy.
UNASSIGNED: A 3-way factorial design with repeated measures was used to investigate the main and interaction effects of the location (areas inside and outside the cup), pressure (-225 and -300 mmHg) and duration (5 and 10 min) on the hemodynamic response of the biceps muscle. A functional near-infrared spectroscopy was used to assess hemodynamic changes in 18 participants.
UNASSIGNED: A significant three-way interaction of the location, pressure, and duration factors was observed in oxyhemoglobin (p= 0.023), deoxy-hemoglobin (p= 0.013), and blood volume (p= 0.013). A significant increase was observed in oxyhemoglobin, blood volume, and oxygenation compared to pre-cupping (p< 0.05) in the area outside the cup.
UNASSIGNED: Our findings indicate that an appropriate combination of cupping pressure and duration can effectively affect the spatial hemodynamic response of the biceps.

The diverse biological effects of polyamines (putrescine, spermidine and spermine) were reviewed in the context of hormesis in an integrative manner for the first time. The findings illustrate that each of these polyamines commonly induces hormetic dose responses in a wide range of biological models and types of cells for multiple endpoints in numerous plant species and animal models. Plant research emphasized preconditioning experimental studies in which the respective polyamines conferred some protection against the damaging effects of a broad range of environmental stressors such as drought, salinity, cold/heat, heavy metals and UV-damage in an hormetic manner. Polyamine-based animal hormesis studies emphasized biomedical endpoints such as longevity and neuroprotection. These findings have important biological and biomedical implications and should guide experimental designs of low dose investigations.

Moringa oleifera, a traditional Indian herb, is widely known for its capacity to induce antioxidant, anti-inflammatory and other chemoprotective effects in a broad range of biomedical models. These perspectives have led to an extensive number of studies using various moringa extracts to evaluate its capacity to protect biological systems from oxidative stress and to explore whether it could be used to slow the onset of numerous age-related conditions and diseases. Moringa extracts have also been applied to prevent damage to plants from oxidative and saline stresses, following hormetic dose–response patterns. The present paper provides the first integrated and mechanistically based assessment showing that moringa extracts commonly induce hormetic dose responses and that many, perhaps most, of the beneficial effects of moringa are due to its capacity to act as an hormetic agent.

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.

BACKGROUND: Effects of ketone supplements as well as relevant dose-response relationships and time effects on blood β-hydroxybutyrate (BHB), glucose and insulin are controversial.
OBJECTIVE: This study aimed to summarize the existing evidence and synthesize the results, and demonstrate underlying dose-response relationships as well as sustained time effects.
METHODS: Medline, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant randomized crossover/parallel studies published until 25th November 2022. Three-level meta-analysis compared the acute effects of exogenous ketone supplementation and placebo in regulating blood parameters, with Hedge\'s g used as measure of effect size. Effects of potential moderators were explored through multilevel regression models. Dose-response and time-effect models were established via fractional polynomial regression.
RESULTS: The meta-analysis with 327 data points from 30 studies (408 participants) indicated that exogenous ketones led to a significant increase in blood BHB (Hedge\'s g = 1.4994, 95% CI [1.2648, 1.7340]), reduction in glucose (Hedge\'s g = -0.3796, 95% CI [-0.4550, -0.3041]), and elevation in insulin of non-athlete healthy population (Hedge\'s g = 0.1214, 95%CI [0.0582, 0.3011]), as well as insignificant change in insulin of obesity and prediabetes. Nonlinear dose-response relationship between ketone dosage and blood parameter change was observed in some time intervals for BHB (30-60 min; >120 min) and insulin (30-60 min; 90-120 min), with linear relationship observed for glucose (>120 min). Nonlinear associations between time and blood parameter change were found in BHB (>550 mg/kg) and glucose (450-550 mg/kg), with linear relationship observed in BHB (≤250 mg/kg) and insulin (350-550 mg/kg).
CONCLUSIONS: Dose-response relationships and sustained time effects were observed in BHB, glucose and insulin following ketone supplementation. Glucose-lowering effect without increasing insulin load among population of obesity and prediabetes was of remarkable clinical implication.
UNASSIGNED: PROSPERO (CRD42022360620).