Current Opinion in Toxicology最新文献

Component-based approaches for cumulative risk assessment provide an important tool for informing public health policy. While current quantitative cumulative risk assessments focus narrowly on pesticides that share a mechanism of action, growing scientific evidence supports expansion of their application to encompass stressors that target a common disease. Case studies have demonstrated dose additive effects of chemicals with different mechanisms of action on liver steatosis, craniofacial malformations, and male reproductive tract developmental disruption. Evidence also suggests that nonchemical stressors such as noise or psychosocial stress can modify effects of chemicals. Focused research attention is required before nonchemical stressors can routinely be included in quantitative cumulative risk assessments.

Acute kidney damage and dysfunction is a significant medical problem that is brought about by disease or by drug-induced toxicity. Though this problem has long been recognized, our understanding of human kidney damage has relied heavily upon the use of animal models and the study of human kidneys after damage has already occurred. Recent advances in the field of stem cell research now make it possible to investigate the dynamic mechanisms of damage that occur in the kidneyin human renal cells derived from human pluripotent stem cells (hPSCs). In this review, we briefly summarize normal human kidney development and describe how this knowledge has been used to inform strategies for the directed differentiation of hPSCs to renal cell types and kidney organoids. We also review recent translational advances in the use of such platforms to investigate molecular and cellular mechanisms of nephrotoxicity and elucidation of modes of action of drug-induced kidney toxicity as mediated by specific drugs of concern. Finally, we discuss the prospects for the use of cell-based therapeutics to reverse extant kidney damage in vivo, and eventually, the goal of restoration of renal function with stem-cell-derived organs.

Biomarkers, defined as molecules in biological samples that are used as indicators of organ function, can assess exposure to potentially injurious chemicals, effects on organ function, or susceptibility to organ functional decline. The kidneys are frequently exposed to many drugs and chemicals and loss of kidney function is a frequent consequence of diseases such as diabetes. This review summarizes findings reported in 2021 and early-2022 from clinical and experimental animal studies on biomarkers, focusing on five topics: 1) Progression and severity of diabetic kidney disease; 2) acute kidney injury (AKI) and chronic kidney disease (CKD) severity and prognosis; 3) progression of AKI to CKD; 4) renal cell carcinoma (RCC) severity and prognosis; and 5) detection of exposure to environmental chemicals and nephrotoxic drugs.

This paper summarizes recent findings on the occurrence of hormesis in a wide range of adult stem cells, embryonic stem cells, and induced pluripotent stem cells and their derived cells. These areas of biomedical and toxicological research are quite new, with the strong majority of hormesis publications for most of these stem cells being published within the last five years. Hormetic responses were typically assessed for key biological priorities of stem cells, including cell proliferation, cell differentiation, cell migration, and enhanced resilience in highly inflammatory micro-environments. The quantitative features of the hormesis dose/concentration responses of all types of stem cells were similar with respect to amplitude and width of the stimulation. This was also the case with non-stem cells. Mechanistic pathways for hormetic dose responses were commonly reported and assessed for general patterns across inducing agents, culture conditions, and stem cell types. The use of hormetic strategies can enhance stem-cell performance on multiple key parameters in an integrated manner that has the potential to impact public health. For example, it can affect exercise that targets muscle stem cells (satellite cells) to prevent or decelerate down age-related fragility, medical applications (preconditioning of stem cells that target damaged tissues, for example, following stroke or heart attack), and the expression and timing of age-related degenerative processes and diseases.

The present review aims to discuss the role of bioactive compounds in the context of the hormetic-based lifestyle medicine. The dose–response relationships of nutritional hormetins and exercise are non-linear and individual variability was found on the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in human studies. Other molecular pathways, epigenetic mechanisms, bioactive metabolites of dietary factors, as well as oxygen concentration, are involved in the regulation of hormesis. Studies of the interactions among phytochemicals, other food components, endogenous and microbial metabolites should be performed in individuals with different health, nutritional, and training status. In conclusion, lifestyle medicine implies personalized training and dietary interventions to induce resilience and avoid both oxidative and reductive stress.

Whilst most body tissues have an intrinsic ability to withstand day-to-day stresses, even more intriguing (and of enormous clinical potential) is the striking adaptive responses to stress that drive increased ‘resilience’ against further insult. Numerous species are now known to exploit these ‘preconditioning’ (hormetic-like) responses to boost their resistance to a range of stressors (including ischemia, radiation and nutrient deprivation). Here, we review recent studies in model and less-traditional organisms that are accelerating our mechanistic understanding of these phenomena; we highlight cutting-edge research implicating a role for immune cells, altered cellular metabolism through to exosomes and epigenetics. Given the emerging complexity of tissue preconditioning, detailed mechanistic understanding will no doubt prove critical for the therapeutic activation of these remarkable responses.

Polyphenols have been found in both rodent and human studies to exhibit diverse bioactivities though the mechanisms of action underlying those beneficial functions remain to be fully elucidated. Polyphenols in animals are widely recognized as xenobiotics and known to induce adaptive responses. Essential related mechanisms include expressions of antioxidative and xenobiotic-metabolizing enzymes, and heat shock proteins. Additionally, hormesis has been recognized to be an adaptive mechanism by which mild stressors can potentiate the protective capacity of the host, while those at excessive levels are harmful or lethal. Interestingly, the hormesis-related early events in lipolysis induced by polyphenols have recently been identified. For example, both curcumin and (−)-epigallocatechin-3-gallate were found to markedly decrease the amount of triglycerides in differentiated Huh7 mouse hepatoma cells. Interestingly, oxidative and protein stresses induced by those polyphenols were also demonstrated to significantly contribute to their lipolysis effects. Moreover, the key response to lipolysis was identified as a marked decrease in intracellular ATP levels. Taken together, phytochemicals may partially exhibit their bioactivities through hormesis-related mechanisms, and this hypothesis may be supported by the fact that they often show side-effects when given at high doses.

In plants, radiation hormesis phenomenon occurs as enhanced growth, accelerated development, increased tolerance to stressors, or accumulation of compounds of interest in response to low-dose irradiation. This review summarizes the recent findings regarding radiation hormesis in plants in response to ionising or UV-radiation. While molecular mechanisms of UV-hormesis are clearer and involve sensing of UV-radiation by the specific photoreceptors, the precise molecular events underlying hormetic responses to ionising radiation are yet to be uncovered. Based on the available information, the scheme of possible pathways triggering radiation stimulation response in cells is discussed. It is argued that beneficial responses to low-dose ionising radiation may depend on the optimization of hydrogen peroxide (H₂O₂) levels and the interplay between the signalling pathways of reactive oxygen species (ROS) and phytohormones.

In recent years, evidence for plant hormesis has been rapidly accumulating. However, many dimensions of hormesis induced by low-dose stressors with various mechanisms underlying their effects on plant metabolism remain insufficiently studied. This prevents the widespread use of hormesis to increase the resistance and productivity in plants. This review provides an overview of the most important issues of plant hormesis induced by various low-dose stressors, which include (1) hormesis occurrence, (2) the mechanistic foundations of hormesis and their significance to preconditioning, and (3) hormetic transgenerational effects. In addition, the review examines the main gaps and directions in these issues of plant hormesis.