A general model of hormesis in biological systems and its application to pest management

Hormesis, a phenomenon whereby exposure to high levels of stressors is inhibitory but low (mild, sublethal and subtoxic) doses are stimulatory, challenges decision-making in the management of cancer, neurodegenerative diseases, nutrition and ecotoxicology. In the latter, increasing amounts of a pesticide may lead to upsurges rather than declines of pests, ecological paradoxes that are difficult to predict. Using a novel re-formulation of the Ricker population equation, we show how interactions between intervention strengths and dose timings, dose–response functions and intrinsic factors can model such paradoxes and hormesis. A model with three critical parameters revealed hormetic biphasic dose and dose timing responses, either in a J-shape or an inverted U-shape, yielding a homeostatic change or a catastrophic shift and hormetic effects in many parameter regions. Such effects were enhanced by repeated pulses of low-level stimulations within one generation at different dose timings, thereby reducing threshold levels, maximum responses and inhibition. The model provides insights into the complex dynamics of such systems and a methodology for improved experimental design and analysis, with wide-reaching implications for understanding hormetic effects in ecology and in medical and veterinary treatment decision-making. We hypothesized that the dynamics of a discrete generation pest control system can be determined by various three parameter spaces, some of which reveal the conditions for occurrence of hormesis, and confirmed this by fitting our model to both hormetic data from the literature and to a non-hormetic dataset on pesticidal control of mirid bugs in cotton

Utilizing early cellular changes to explore biological responses to individual chemical and mixture exposures

Humans are continuously exposed to a vast number of chemicals, whether it be from the air we breathe, the water we drink, or the medications we take daily. Early cellular changes after exposure to chemical insult, both individual chemicals and mixtures (two or more chemicals) thereof, can offer a wealth of information about cellular adaptation (e.g., cell death or survival decision processes). From this understanding, better prediction models for chemical risk assessment, such as toxicity or carcinogenicity, can be elucidated. Further, these prediction models can greatly improve the large backlog of chemicals waiting to be evaluated for potential adverse effects. One approach to understand cellular changes and responses after chemical or mixture exposure is with toxicodynamics. From a toxicodynamic approach, a host of information can be determined, such as spatiotemporal interactions of chemical insult with biological targets, the corresponding disruption of intracellular pathways and bioenergetics, and downstream effects after exposure. Appropriately measuring these dynamic cellular changes is imperative. The recent advances in molecular biology, high-throughput in vitro screening assays, and numerous computational techniques have allowed toxicologists to collect large data sets on signaling pathways that are perturbed in response to chemical insults. From these early cellular perturbations, whether they be signaling proteins, biomolecules (e.g., ATP, hormones, NADH), or ions (e.g., Ca2+ or K+), in response to a wide range of doses, especially low concentrations, improved risk assessment prediction models for individual chemical and mixture exposures can be utilized by many fields, such as risk assessment for environmental toxicology and target molecule/pathway analysis for drug development and pharmacology

A critical role of the transcription factor Miz-1 in T cell activation and maturation

A functional immune system is important to protect the organism against various pathogens and to induce an adequate response to vaccinations. B and T lymphocytes are the main drivers of adaptive immunity. An important regulator of their development is the MYC-interacting zinc finger protein 1 (Miz-1). The transcription factor Miz-1 is highly necessary for adequate T cell development by restricting apoptosis during V(D)J recombination. However, the importance of Miz-1 in mature T cells is yet not fully understood. To provide new insights into the role of Miz-1 for T lymphocytes, mice possessing a conditional knockout of Miz-1 either in all hematopoietic cells (Vav-Cre x Miz-1fl/fl) or specifically in T cells (CD4 Cre x Miz-1fl/fl) were used. As the POZ domain of Miz-1 is necessary for its transcriptional activity, this domain was targeted by Cre-mediated deletion in both mouse models. Phenotypical analysis of these mice showed severe perturbations of the peripheral T cells, resulting in a reduction of mature T cells in several secondary lymphoid organs. Likewise, this decrease was observed in CD4+ as well as in CD8+ T cells. T cell activation experiments showed that Miz-1 controls proliferation as well as apoptosis of peripheral T cells. Miz-1 deficiency resulted in a faster proliferation but also an excessive induction of apoptosis. Furthermore, the process of apoptosis seems to be p53-independent and induced via the extrinsic apoptosis pathway. Flow cytometry experiments revealed that Miz-1 is a novel regulator of T cell aging, since young mice possessing a functional Miz-1 deletion exhibited similar distributions of T cell populations as old control mice. Due to Miz-1 deficiency, the numbers of naïve T cells dropped while frequencies of memory T cells were increased. Thus, Miz-1 is necessary to maintain the homeostasis of naïve and memory T cells in the course of aging

Neuroprotection: Rescue from Neuronal Death in the Brain

Dear Colleagues, The brain is vulnerable to injury. Following injury in the brain, apoptosis or necrosis may occur easily, leading to various functional disabilities. Neuronal death is associated with a number of neurological disorders including hypoxic ischemia, epileptic seizures, and neurodegenerative diseases. The brain subjected to injury is regarded to be responsible for the alterations in neurotransmission processes, resulting in functional changes. Oxidative stress produced by reactive oxygen species has been shown to be related to the death of neurons in traumatic injury, stroke, and neurodegenerative diseases. Therefore, scavenging or decreasing free radicals may be crucial for preventing neural tissues from harmful adversities in the brain. Neurotrophic factors, bioactive compounds, dietary nutrients, or cell engineering may ameliorate the pathological processes related to neuronal death or neurodegeneration and appear beneficial for improving neuroprotection. As a result of neuronal death or neuroprotection, the brain undergoes activity-dependent long-lasting changes in synaptic transmission, which is also known as functional plasticity. Neuroprotection implying the rescue from neuronal death is now becoming one of global health concerns. This Special Issue attempts to explore the recent advances in neuroprotection related to the brain. This Special Issue welcomes original research or review papers demonstrating the mechanisms of neuroprotection against brain injury using in vivo or in vitro models of animals as well as in clinical settings. The issues in a paper should be supported by sufficient data or evidence. Prof. Bae Hwan Lee Guest Edito

Impaired Mitochondrial Bioenergetics under Pathological Conditions

Mitochondria are the powerhouses of cells; however, mitochondrial dysfunction causes energy depletion and cell death in a variety of diseases. Altered oxidative phosphorylation and ion homeostasis are associated with ROS production resulting from the disassembly of respiratory supercomplexes and the disruption of electron transfer chains. In pathological conditions, the dysregulation of mitochondrial homeostasis promotes Ca2+ overload in the matrix and ROS accumulation, which induces the mitochondrial permeability transition pore formation responsible for mitochondrial morphological changes linked to membrane dynamics, and ultimately, cell death. Finally, studies on the impaired mitochondrial bioenergetics in pathology could provide molecular tools to counteract diseases associated with mitochondrial dysfunction