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.

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.

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.

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.

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: 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.

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.

Low-dose radiation therapy (LDRT) for COVID-19 and its deadlier variants.

Coronavirus variants are gaining strongholds throughout the globe. Despite early signals that SARS-CoV-2 coronavirus case numbers are easing up in the United States and during the middle of a (not so easy) vaccination roll out, the country has passed a grim landmark of 600,000 deaths. We contend that these numbers would have been much lower if the medical community undertook serious investigations into the potential of low doses of radiation (LDRT) as a mainstream treatment modality for COVID-19 pneumonia. LDRT has been posited to manifest anti-infectious and anti-inflammatory properties at doses of 0.3-1.0 Gy via the activation of the Nrf-2 pathway. Although some researchers are conducting well-designed clinical trials on the potential of LDRT, the deep-rooted, blind, and flawed acceptance of the Linear No-Threshold (LNT) model for ionizing radiation has led to sidelining of this promising therapy and thus unimaginable numbers of deaths in the United States.

Comparison of conventional with Parker flex-tip tracheal tube for intubation through air-Q intubating laryngeal airway.

BACKGROUND AND AIMS: The problem of difficult and failed intubation led to increased development of equipment for airway management. A number of supraglottic airways have now been developed to facilitate the passage of tracheal tubes. Conventional PVC tracheal tubes are recommended for intubation through the air-Q ILA. No study has compared different PVC tubes for blind intubation through air-Q ILA. Thus, we undertook this prospective, randomised, single blind study to compare two PVC tracheal tubes with different designs viz. conventional PVC tracheal tube (TT) and Parker flex-tip TT with regards to success rate, ease of intubation and total time required for successful intubation through air-Q ILA. MATERIAL AND METHODS: One hundred patients of either sex, aged 18-60 years, belonging to American Society of Anesthesiologists (ASA) physical status class I and II scheduled for elective surgery under general anesthesia requiring endotracheal intubation were included in the study. Blind intubation using conventional PVC TT and Parker flex-tip tube was done in group A (n = 50) and group B (n = 50), respectively. RESULTS: The first attempt success rate in Parker flex-tip TT was significantly more as compared to conventional PVC TT (P = 0.002). Success rate of intubation was significantly more in Parker flex-tip TT as compared to conventional PVC TT (P = 0.004). The intubation was significantly easy in Parker flex-tip tube as compared to conventional PVC TT (P = 0.002). Total time of intubation was less in Parker flex-tip tube as compared to PVC TT (P = 0.043). CONCLUSION: Unique design of the Parker Flex-tip TT resulted in increase in success rate, first attempt success rate and ease of intubation in group B in present study.

Cytotoxicity models of Huntington's disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies.

This paper assesses in vivo cytotoxicity models of Huntington's disease (HD). Nearly 150 agents were found to be moderately to highly effective in mitigating the pathological sequelae of cytotoxic induction of HD features in multiple rodent models. Typically, rodents are treated with a prospective HD-protective agent before, during, or after the application of a chemical or transgenic process for inducing histopathological and behavioral symptoms of HD. Although transgenic and knockout rodent models (1) display relatively high construct and face validity, and (2) are ever more routinely employed to mimic genetic-to-phenotypic expression of HD features, toxicant models are also often employed, and have served as valuable test beds for the elucidation of biochemical processes and discovery of therapeutic targets in HD. Literature searches of the toxicant HD rodent models yielded nearly 150 agents that were moderately to highly effective in mitigating pathological sequelae in multiple mouse and rat HD models. Experimental models, study designs, and exposure protocols (e.g., pre- and post-conditioning) used in testing these agents were assessed, including dosing strategies, endpoints, and dose-response features. Hormetic-like biphasic dose responses, chemoprotective mechanisms, and the translational relevance of the preclinical studies and their therapeutic implications are critically analyzed in the present report. Notably, not one of the 150 agents that successfully delayed onset and progression of HD in the experimental models has been successfully translated to the treatment of humans in a clinical setting. Potential reasons for these translational failures are (1) the inadequacy of dose-response analyses and subsequent lack of useful dosing data; (2) effective rodent doses that are too high for safe human application; (3) key differences between the experimental models and humans in pharmacokinetic/pharmacodynamic features, ages and routes of agent administration; (4) lack of robust pharmacokinetic, mechanistic or systematic approaches to probe novel treatment strategies; and (5) inadequacies of the chemically induced HD model in rats to mimic accurately the complex genetic and developmental origin and progression of HD in humans. These deficiencies need to be urgently addressed if pharmaceutical agents for the treatment of HD are going to be successfully developed in experimental models and translated with fidelity to the clinic.

HORMESIS: A Fundamental Concept with Widespread Biological and Biomedical Applications.

Hormesis is a biphasic dose response with specific quantitative features for the amplitude and width of the stimulation. It is highly generalizable and independent of biological model, endpoint, inducing agent, level of biological organization and mechanism. Hormesis may be induced via a direct stimulation or by overcompensation to a disruption of homeostasis. The induction of hormesis by low-level stressor agents not only rapidly upregulates adaptive processes to repair damage but also protects the adapted system from damage due to a subsequent challenging dose (toxic) within a definable temporal window. The striking consistency of the amplitude of hormetic response suggests that hormesis provides a quantitative description of biological plasticity. Knowledge of hormesis has particular potential biomedical significance with respect to slowing or retarding both normal aging processes and the progression of severe neurological diseases.

What is hormesis and its relevance to healthy aging and longevity?

This paper provides a broad overview of hormesis, a specific type of biphasic dose response, its historical and scientific foundations as well as its biomedical applications, especially with respect to aging. Hormesis is a fundamental component of adaptability, neutralizing many endogenous and environmental challenges by toxic agents, thereby enhancing survival. Hormesis is highly conserved, broadly generalizable, and pleiotrophic, being independent of biological model, endpoint measured, inducing agent, level of biological organization and mechanism. The low dose stimulatory hormetic response has specific characteristics which defines both the quantitative features of biological plasticity and the potential for maximum biological performance, thereby estimating the limits to which numerous medical and pharmacological interventions may affect humans. The substantial degrading of some hormetic processes in the aged may profoundly reduce the capacity to respond effectively to numerous environmental/ischemic and other stressors leading to compromised health, disease and, ultimately, defining the bounds of longevity.

Malaria-related knowledge and prevention practices in four neighbourhoods in and around Mumbai, India: a cross-sectional study.

BACKGROUND: India accounts for the highest number of malaria cases outside of Africa. Eighty per cent of India's population lives in malaria-risk areas, with cases increasing in urban areas. Mumbai, India, one of the most populous cities in the world, has experienced such an increase. To be successful, many malaria control efforts require community participation, which in turn depends on individuals' knowledge and awareness of the disease. This study assessed the knowledge and prevention practices regarding malaria in residents of four different areas of Mumbai, India, around the time of a malaria outbreak and the start of a widespread awareness campaign. METHODS: A cross-sectional comparative study assessed malaria-related knowledge and prevention practices in four geographically and socio-demographically distinct areas of Mumbai, India. A structured interviewer-administered questionnaire was administered to a stratified random sample of 119 households between 16 December 2010 and 30 January 2011. Participant socio-demographic characteristics, malaria knowledge, malaria prevention practices, and household environmental factors were examined overall and compared across the four areas of Mumbai. RESULTS: Overall, respondents had excellent knowledge of the mosquito as the means of transmission of malaria, mosquito biting times and breeding sites, and fever as a symptom of malaria. However, many respondents also held misconceptions about malaria transmission and symptoms. Respondents generally knew that bed nets are an effective prevention strategy, but only 30% used them, and only 4% used insecticide-treated bed nets. Knowledge and prevention practices varied across the four areas of Mumbai. CONCLUSIONS: Although most residents know that bed nets are effective in preventing malaria, usage of bed nets is very low, and almost no residents use insecticide-treated bed nets. As the four areas of Mumbai differed in knowledge, prevention practices, and primary sources of information, malaria control campaigns should be tailored according to the knowledge gaps, practices, environments, resources, and preferences in different areas of the city, using the interpersonal and media channels most likely to reach the target audiences. Malaria control efforts involving bed nets should emphasize use of insecticide-treated bed nets.

Use of X-rays to treat shoulder tendonitis/bursitis: a historical assessment.

This article assesses the therapeutic efficacy of ionizing radiation for the treatment of shoulder tendonitis/bursitis in the USA over the period of its use (human 1936-1961; veterinary 1954-1974). Results from ~3,500 human cases were reported in the clinical case studies over 30 articles, and indicated a high treatment efficacy (>90 %) for patients. Radiotherapy was effective with a single treatment. The duration of treatment effectiveness was prolonged, usually lasting until the duration of the follow-up period (i.e., 1-5 years). Therapeutic effectiveness was reduced for conditions characterized as chronic. Similar findings were reported with race horses in the veterinary literature. These historical findings are consistent with clinical studies over the past several decades in Germany, which have used more rigorous study designs and a broader range of clinical evaluation parameters. Radiotherapy treatment was widely used in the mid twentieth century in the USA, but was abandoned following the discovery of anti-inflammatory drugs and the fear of radiation-induced cancer. That X-ray treatment could be an effective means of treating shoulder tendonitis/bursitis, as a treatment option, and is essentially unknown by the current medical community. This paper is the first comprehensive synthesis of the historical use of X-rays to treat shoulder tendonitis/bursitis and its efficacy in the USA.

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.

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.

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.

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.

How radiotherapy was historically used to treat pneumonia: could it be useful today?

X-ray therapy was used to treat pneumonia during the first half of the 20th century. Fifteen studies report that approximately 700 cases of bacterial (lobar and bronchopneumonia), sulfanilamide non-responsive, interstitial, and atypical pneumonia were effectively treated by low doses of X-rays, leading to disease resolution, based on clinical symptoms, objective disease biomarkers, and mortality incidence. The capacity of the X-ray treatment to reduce mortality was similar to serum therapy and sulfonamide treatment during the same time period. Studies with four experimental animal models (i.e., mice, guinea pig, cat, and dog) with bacterial and viral pneumonia supported the clinical findings. The mechanism by which the X-ray treatment acts upon pneumonia involves the induction of an anti-inflammatory phenotype that leads to a rapid reversal of clinical symptoms, facilitating disease resolution. The capacity of low doses of X-rays to suppress inflammatory responses is a significant new concept with widespread biomedical and therapeutic applications.