Taurine induces hormesis in multiple biological models: May have transformative implications for overall societal health.

This paper represents the first integrative assessment and documentation of taurine-induced hormetic effects in the biological and biomedical areas, their dose response features, mechanistic frameworks, and possible public health, therapeutic and commercial applications. Taurine-induced hormetic effects are documented in a wide range of experimental models, cell types and for numerous biological endpoints, with most of these experimental findings being reported within the past five years. It is suggested that the concept of hormesis may have a transformative effect on taurine research and its public health and therapeutic applications.

RUTIN, a widely consumed flavonoid, that commonly induces hormetic effects.

Rutin is a flavonoid present in numerous fruits and vegetables and therefore widely consumed by humans. It is also a popular dietary supplement of 250-500 mg/day. There is considerable consumer interest in rutin due to numerous reports in the biomedical literature of its multi-system chemo-preventive properties. The present paper provides the first assessment of rutin-induced hormetic concentration/dose responses, their quantitative features and mechanistic basis, along with their biological, biomedical, clinical, and public health implications. The findings indicate that rutin-induced hormetic dose responses are widespread, being reported in numerous biological models and cell types for a wide range of endpoints. Of critical importance is that the optimal hormetic findings shown in in vitro systems are currently not achievable for human populations due to low gastrointestinal tract bioavailability. These findings have the potential to strengthen future experimental studies with rutin, particularly concerning study design parameters.

Flavonoids commonly induce hormetic responses.

The present paper provides a new perspective of previously published findings by Siwak (Food Chem 141:1227-1241, 2013) which showed that 15 structurally diverse flavonoids reduced toxicity (i.e., enhanced cell viability) from hypochlorite using the MTT assay within a pre-conditioning experimental protocol, with each agent showing a similar biphasic concentration response relationship. We use this Commentary to point out that each of the concentration response relationships are consistent with the hormetic dose response. The paper of Siwak (Food Chem 141:1227-1241, 2013) is unique in that it provides a comparison of a relatively large number of agents using the identical experimental protocol.

Tetracycline and sulfadiazine toxicity in human liver cells Huh-7.

As typical antibiotics, tetracycline (TC) and sulfadiazine (SDZ) enter the human body through the food chain. Therefore, it is necessary to understand their individual and combined toxicity. In this study, the effects of TC, SDZ, and their mixture on cell viability, cell membrane damage, liver cell damage, and oxidative damage were evaluated in in vitro assays with human liver cells Huh-7. The results showed cytotoxicity of TC, SDZ, and their mixture, which induced oxidative stress and caused membrane and cell damage. The effect of antibiotics on Huh-7 cells increased with increasing concentration, except for lactate dehydrogenase (LDH) activity that commonly showed a threshold concentration response and cell viability, which commonly showed a biphasic trend, suggesting the possibility of hormetic responses where proper doses are included. The toxicity of TC was commonly higher than that of SDZ when applied at the same concentration. These findings shed light on the individual and joint effects of these major antibiotics on liver cells, providing a scientific basis for the evaluation of antibiotic toxicity and associated risks.

Hormesis determines lifespan.

This paper addresses how long lifespan can be extended via multiple interventions, such as dietary supplements [e.g., curcumin, resveratrol, sulforaphane, complex phytochemical mixtures (e.g., Moringa, Rhodiola)], pharmaceutical agents (e.g., metformin), caloric restriction, intermittent fasting, exercise and other activities. This evaluation was framed within the context of hormesis, a biphasic dose response with specific quantitative features describing the limits of biological/phenotypic plasticity for integrative biological endpoints (e.g., cell proliferation, memory, fecundity, growth, tissue repair, stem cell population expansion/differentiation, longevity). Evaluation of several hundred lifespan extending agents using yeast, nematode (Caenorhabditis elegans), multiple insect and other invertebrate and vertebrate models (e.g., fish, rodents), revealed they responded in a manner [average (mean/median) and maximum lifespans] consistent with the quantitative features [i.e., 30-60% greater at maximum (Hormesis Rule)] of the hormetic dose response. These lifespan extension features were independent of biological model, inducing agent, endpoints measured and mechanism. These findings indicate that hormesis describes the capacity to extend life via numerous agents and activities and that the magnitude of lifespan extension is modest, in the percentage, not fold, range. These findings have important implications for human aging, genetic diseases/environmental stresses and lifespan extension, as well as public health practices and long-term societal resource planning.

Quercetin induces its chemoprotective effects via hormesis.

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.

Polyamines and hormesis: Making sense of a dose response dichotomy.

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 induces its beneficial effect via hormesis.

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 dose­response 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.

Hormesis, biological plasticity, and implications for clinical trial research.

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.

Naringin commonly acts via hormesis.

The present paper provides the first integrative assessment of the capacity of naringin and its metabolite, naringenin, to induce hormetic dose responses within a broad range of experimental biomedical models. The findings indicate that these agents commonly induced protective effects that are typically mediated via hormetic mechanisms leading to biphasic dose-response relationships. The maximum protective effects are generally modest, 30-60 % greater than control group values. The range of experimental findings with these agents has been reported for models with various neurodegenerative diseases, nucleus pulpous cells (NPCs) located within intravertebral discs, several types of stem cells (i.e., bone marrow, amniotic fluid, periodontal, endothelial) as well as cardiac cells. These agents also were effective within preconditioning protocols protecting against environmental toxins such as ultraviolet radiation (UV), cadmium, and paraquat. The mechanism(s) by which the hormetic responses mediates these biphasic dose responses is complex but commonly involves the activation of nuclear factor erythroid 2-related factor (Nrf2), an increasingly recognized regulator of cellular resistance to oxidants. Nrf2 appears to play a role in controlling the basal and induced expression of an array of antioxidant response element-dependent genes to regulate oxidant exposure's physiological and pathophysiological outcomes. Hence its importance in the assessment of toxicologic and adaptive potential is likely to be significant.

Protective effects of alpha lipoic acid (ALA) are mediated by hormetic mechanisms.

The endogenous and dietary agent, alpha lipoic acid (ALA), is evaluated for its capacity to induce a broad spectrum of adaptive responses via hormetic dose responses and their underlying mechanisms. ALA was shown to induce hormetic effects in a wide range of experimental models within in vitro and in vivo experimental settings which included direct exposure and pre- and post-conditioning experimental protocols. The hormetic effects occur in a broad range of organ systems, including the brain, heart, kidney and other tissues, with possible public health and clinical/therapeutic applications linked to reducing the onset and progression of neurogenerative diseases and also in the preservation of sperm health and functionality during cryopreservation. This paper provides the first integrated assessment of ALA-induced hormetic dose responses. Underlying mechanisms that mediated the occurrence of ALA-induced hormetic effects involved the induction of low levels of ROS that activate key cell signaling antioxidant (e.g. Nrf2) pathways.

Rhodiola rosea and salidroside commonly induce hormesis, with particular focus on longevity and neuroprotection.

The biological effects of Rhodiola rosea extracts and one of its major constituents, salidroside, were evaluated for their capacity to induce hormesis/hormetic effects. The findings indicate that the Rhodiola rosea extracts and salidroside commonly induce hormetic dose responses within a broad range of biological models, cell types and across a broad range of endpoints, with particular emphasis on longevity and neuroprotective endpoints. This paper represents the first integrative documentation and assessment of Rhodiola rosea extracts and salidroside induction of hormetic effects. These findings have important biomedical applications and should have an important impact with respect to critical study design, dose selection and other experimental features.

Boron enhances adaptive responses and biological performance via hormetic mechanisms.

Boron is shown in the present review to induce hormetic dose responses in a broad range of biological models, organ systems and endpoints. Of particular importance is that numerous hormetic findings have been reported with whole animal studies, with extensive dose response evaluations with the optimal dosing being similar across multiple organ systems. These findings appear to be underappreciated and suggest that boron may have clinically significant systemic effects beyond that of its putative and more subtle essentiality functions. The re-exploration of boron's bioactivity as seen through hormetic mechanisms may also underscore the value of this approach to the assessment of micronutrient effects in human health and disease.

Lithium and hormesis: Enhancement of adaptive responses and biological performance via hormetic mechanisms.

Biomedical and consumer interest in the health-promoting properties of pure single entities of known or unknown chemical constituents and mixtures has never been greater. Since its "rediscovery" in the 1950s, lithium is an example of such a constituent that represents an array of scientific and public health challenges and medical potentials that may now be understood best when seen through the lens of the dose-response paradigm known as hormesis. The present paper represents the first review of the capacity of lithium to induce hormetic dose responses in a broad range of biological models, organ systems, and endpoints. Of significance is that the numerous hormetic findings occur with extensive concentration/dose response evaluations with the optimal dosing being similar across multiple organ systems. The particular focus of these hormetic dose-response findings was targeted to research with a broad spectrum of stem cell types and neuroprotective effects. These findings suggest that lithium may have critically valuable systemic effects with respect to those therapeutically treated with lithium as well as for exposures that may be achieved via dietary intervention.

Nitric oxide and hormesis.

This present paper provides an assessment of the occurrence of nitric oxide (NO)-induced hormetic-biphasic dose/concentration relationships in biomedical research. A substantial reporting of such NO-induced hormetic effects was identified with particular focus on wound healing, tumor promotion, and sperm biology, including mechanistic assessment and potential for translational applications. Numerous other NO-induced hormetic effects have been reported, but require more development prior to translational applications. The extensive documentation of NO-induced biphasic responses, across numerous organs (e.g., bone, cardiovascular, immune, intestine, and neuronal) and cell types, suggests that NO-induced biological activities are substantially mediated via hormetic processes. These observations are particularly important because broad areas of NO biology are constrained by the quantitative features of the hormetic response. This determines the amplitude and width of the low dose stimulation, affecting numerous biomedical implications, study design features (e.g., number of doses, dose spacing, sample sizes, statistical power), and the potential success of clinical trials.

An open source pipeline for quantitative immunohistochemistry image analysis of inflammatory skin disease using artificial intelligence.

BACKGROUND: The application of artificial intelligence (AI) to whole slide images has the potential to improve research reliability and ultimately diagnostic efficiency and service capacity. Image annotation plays a key role in AI and digital pathology. However, the work-streams required for tissue-specific (skin) and immunostain-specific annotation has not been extensively studied compared with the development of AI algorithms. OBJECTIVES: The objective of this study is to develop a common workflow for annotating whole slide images of biopsies from inflammatory skin disease immunostained with a variety of epidermal and dermal markers prior to the development of the AI-assisted analysis pipeline. METHODS: A total of 45 slides containing 3-5 sections each were scanned using Aperio AT2 slide scanner (Leica Biosystems). These slides were annotated by hand using a commonly used image analysis tool which resulted in more than 4000 images blocks. We used deep learning (DL) methodology to first sequentially segment (epidermis and upper dermis), with the exclusion of common artefacts and second to quantify the immunostained signal in those two compartments of skin biopsies and the ratio of positive cells. RESULTS: We validated two DL models using 10-fold validation runs and by comparing to ground truth manually annotated data. The models achieved an average (global) accuracy of 95.0% for the segmentation of epidermis and dermis and 86.1% for the segmentation of positive/negative cells. CONCLUSIONS: The application of two DL models in sequence facilitates accurate segmentation of epidermal and dermal structures, exclusion of common artefacts and enables the quantitative analysis of the immunostained signal. However, inaccurate annotation of the slides for training the DL model can decrease the accuracy of the output. Our open source code will facilitate further external validation across different immunostaining platforms and slide scanners.

Hormesis mediates platelet-rich plasma and wound healing.

Platelet-rich plasma (PRP) has become an accepted and general wound healing approach with an extremely wide range of applications. Despite considerable diversity in the composition of platelet-rich plasma products that are applied in specific wound healing usage, it is widely recognised that such diverse platelet-rich plasma complex mixtures routinely display hormetic-like biphasic concentrations that are independent of the tissue treated and endpoints measured. The present paper is the first to place the area of platelet-rich plasma-biomedical research and applications within an hormetic framework. The platelet-rich plasma area is also unique as it represents the application of the hormetic concept to the issue of complex biological mixtures.

Genome-wide association study reveals novel genomic regions governing agronomic and grain quality traits and superior allelic combinations for Basmati rice improvement.

Background: Basmati is a speciality segment in the rice genepool characterised by explicit grain quality. For the want of suitable populations, genome-wide association study (GWAS) in Basmati rice has not been attempted. Materials: To address this gap, we have performed a GWAS on a panel of 172 elite Basmati multiparent population comprising of potential restorers and maintainers. Phenotypic data was generated for various agronomic and grain quality traits across seven different environments during two consecutive crop seasons. Based on the observed phenotypic variation, three agronomic traits namely, days to fifty per cent flowering, plant height and panicle length, and three grain quality traits namely, kernel length before cooking, length breadth ratio and kernel length after cooking were subjected to GWAS. Genotyped with 80K SNP array, the population was subjected to principal component analysis to stratify the underlying substructure and subjected to the association analysis using Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK) model. Results: We identified 32 unique MTAs including 11 robust MTAs for the agronomic traits and 25 unique MTAs including two robust MTAs for the grain quality traits. Six out of 13 robust MTAs were novel. By genome annotation, six candidate genes associated with the robust MTAs were identified. Further analysis of the allelic combinations of the robust MTAs enabled the identification of superior allelic combinations in the population. This information was utilized in selecting 77 elite Basmati rice genotypes from the panel. Conclusion: This is the first ever GWAS study in Basmati rice which could generate valuable information usable for further breeding through marker assisted selection, including enhancing of heterosis.

Hormesis: wound healing and fibroblasts.

Hormetic dose responses are reported here to occur commonly in the dermal wound healing process, with the particular focus on cell viability, proliferation, migration and collagen deposition of human and murine fibroblasts with in vitro studies. Hormetic responses were induced by a wide range of substances, including endogenous agents, pharmaceutical preparations, plant-derived extracts including many well-known dietary supplements, as well as physical stressor agents such as low-level laser treatments. Detailed mechanistic studies have identified common signaling pathways and their cross-pathway communications that mediate the hormetic dose responses. These findings complement and extend a similar comprehensive assessment concerning the occurrence of hormetic dose responses in keratinocytes. These findings demonstrate the generality of the hormetic dose response for key wound healing endpoints, suggesting that the hormesis concept has a fundamental role in wound healing, with respect to guiding strategies for experimental evaluation as well as therapeutic applications.

Hormesis: Wound healing and keratinocytes.

Hormetic dose responses (i.e., a biphasic dose/concentration response characterized by a low dose stimulation and a high dose inhibition) are shown herein to be commonly reported in the dermal wound healing process, with the particular focus on cell viability, proliferation, and migration of human keratinocytes in in vitro studies. Hormetic responses are induced by a wide range of substances, including endogenous agents, numerous drug and nanoparticle preparations and especially plant derived extracts, including many well-known dietary supplements as well as physical stressor agents, such as low-level laser treatments. Detailed mechanistic studies have identified common signaling pathways and their cross-pathway communications that mediate the hormetic dose responses. These findings suggest that the concept of hormesis plays a fundamental role in wound healing, with important potential implications for agent screening and evaluation, as well as clinical strategies.