Metformin-enhances resilience via hormesis.

The present paper demonstrates that metformin (MF) induced a broad spectrum of hormetic biphasic dose responses in a wide range of experimental studies, affecting multiple organ systems, cell types, and endpoints enhancing resilience to chemical stresses in preconditioning and co-current exposure protocols. Detailed mechanistic evaluations indicate that MF-induced hormetic-adaptive responses are mediated often via the activation of adenosine monophosphate-activated kinase (AMPK) protein and its subsequent upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). Hormesis-induced protective responses by MF are largely mediated via a vast and highly integrated anti-inflammatory molecular network that enhances longevity and delays the onset and slows the progression of neurodegenerative and other chronic diseases.

Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations.

Novel mechanistic insights are discussed herein that link a single, nontoxic, low-dose radiotherapy (LDRT) treatment (0.5-1.0 Gy) to (1) beneficial subcellular effects mediated by the activation of nuclear factor erythroid 2-related transcription factor (Nrf2) and to (2) favorable clinical outcomes for COVID-19 pneumonia patients displaying symptoms of acute respiratory distress syndrome (ARDS).

Thresholds for carcinogens.

Current regulatory cancer risk assessment principles and practices assume a linear dose-response relationship-the linear no-threshold (LNT) model-that theoretically estimates cancer risks occurring following low doses of carcinogens by linearly extrapolating downward from experimentally determined risks at high doses. The two-year rodent bioassays serve as experimental vehicles to determine the high-dose cancer risks in animals and then to predict, by extrapolation, the number of carcinogen-induced tumors (tumor incidence) that will arise during the lifespans of humans who are exposed to environmental carcinogens at doses typically orders of magnitude below those applied in the rodent assays. An integrated toxicological analysis is conducted herein to reconsider an alternative and once-promising approach, tumor latency, for estimating carcinogen-induced cancer risks at low doses.

The hormetic dose-response mechanism: Nrf2 activation.

A generalized mechanism for hormetic dose responses is proposed that is based on the redox-activated transcription factor (TF), Nrf2, and its upregulation of an integrative system of endogenous anti-oxidant and anti-inflammatory adaptive responses. Nrf2 can be activated by numerous oxidative stressors (e.g.

The phytoprotective agent sulforaphane prevents inflammatory degenerative diseases and age-related pathologies via Nrf2-mediated hormesis.

In numerous experimental models, sulforaphane (SFN) is shown herein to induce hormetic dose responses that are not only common but display endpoints of biomedical and clinical relevance. These hormetic responses are mediated via the activation of nuclear factor erythroid- derived 2 (Nrf2) antioxidant response elements (AREs) and, as such, are characteristically biphasic, well integrated, concentration/dose dependent, and specific with regard to the targeted cell type and the temporal profile of response. In experimental disease models, the SFN-induced hormetic activation of Nrf2 was shown to effectively reduce the occurrence and severity of a wide range of human-related pathologies, including Parkinson's disease, Alzheimer's disease, stroke, age-related ocular damage, chemically induced brain damage, and renal nephropathy, amongst others, while also enhancing stem cell proliferation.

Re-analysis of herbal extracts data reveals that inflammatory processes are mediated by hormetic mechanisms.

Using data from Schink et al. (2018), a large number of herbal extracts were assessed for their capacity to induce pro- and anti-inflammatory effects based on TLR4 expression normalized for cell viability in two immune cell models (i.e.

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.

Two decades (1998-2018) of research Progress on Hormesis: advancing biological understanding and enabling novel applications.

This commentary briefly summarizes the extraordinary resurgence of hormesis within the biological, biomedical, toxicological and risk assessment domains over the past two decades. It places this resurgence within the context of challenging the scientific validity of the threshold and linear dose responses. It argues that conducting research on mechanisms that actuate and regulate the stimulatory response features of hormesis will provide the knowledge needed to develop potentially transformational applications aimed at protecting and enhancing biological resiliency as well as treating/curing a multitude of diverse medical conditions.

Estimating the range of the maximum hormetic stimulatory response.

An ever-expanding hormetic database (HDB) was used to demonstrate that the median maximal hormetic stimulatory response (MHSR) of biphasic dose-response relationships increases in value with an increase in the number of stimulatory doses/concentrations that are administered below the estimated threshold/ZEP (zero equivalent point - i.e., the dose where the response crosses the control group value).

Hormesis mediates dose-sensitive shifts in macrophage activation patterns.

The activation or polarization of macrophages to pro- or anti-inflammatory states evolved as an adaptation to protect against a spectrum of biological threats. Such an adaptation engages pro-oxidative mechanisms and enables macrophages to neutralize and kill threatening organisms (e.g.

Enhancing and Extending Biological Performance and Resilience.

Human performance, endurance, and resilience have biological limits that are genetically and epigenetically predetermined but perhaps not yet optimized. There are few systematic, rigorous studies on how to raise these limits and reach the true maxima. Achieving this goal might accelerate translation of the theoretical concepts of conditioning, hormesis, and stress adaptation into technological advancements.

Mechanisms and Effects of Transcranial Direct Current Stimulation.

The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety.