Abstract
In the paradigm of drug administration, determining the correct dosage of a therapeutic is often a challenge. Several drugs have been noted to demonstrate contradictory effects per se at high and low doses. This duality in function of a drug at different concentrations is known as hormesis. Therefore, it becomes necessary to study these biphasic functions in order to understand the mechanistic basis of their effects. In this article, we focus on different molecules and pathways associated with diseases that possess a duality in their function and thus prove to be the seat of hormesis. In particular, we have highlighted the pathways and factors involved in the progression of cancer and how the biphasic behavior of the molecules involved can alter the manifestations of cancer. Because of the pragmatic role that it exhibits, the imminent need is to draw attention to the concept of hormesis. Herein, we also discuss different stressors that trigger hormesis and how stress-mediated responses increase the overall adaptive response of an individual to stress stimulus. We talk about common pathways through which cancer progresses (such as nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1), sirtuin-forkhead box O (SIRT-FOXO) and others), analyzing how diverse molecules associated with these pathways conform to hormesis.
Highlights
For several decades, it was believed that drug dosage follows a linear pattern, generating enormous ignorance in the knowledge of the responses in the low-dose zone [1]
Such a biphasic response brings into light an immensely significant concept called “hormesis”, which refers to a phenomenon that is designated by a “low-dose stimulation and high-dose inhibition” [3]
In order to determine how the beneficial role of hormesis might be extrapolated in mitigating malefic consequences of cellular insults, it becomes pertinent to recognize the different cellular/molecular systems and intervening pathways that ensure a biphasic relationship in generating adaptive responses to a stressor stimulus [30]
Summary
It was believed that drug dosage follows a linear pattern, generating enormous ignorance in the knowledge of the responses in the low-dose zone [1]. Small episodes of mild ischemia referred to as ischemic preconditioning (IPC) have been reported to shield the brain from future severe depletion of blood and, oxygen [10] In another adaptive biphasic response, mild caloric restriction (CR) in diverse animals was found to be associated with protection against different forms of cancer [18,19,20]. While extreme dietary (calorie) restriction could manifest into malnutrition, mild restriction, on the contrary, evokes an adaptive response that defends an individual from cancer and other progressive degenerative pathologies, such as neuro-degenerative and geriatric diseases [21] This takes us to another subcategory of hormesis, ‘mitohormesis’, wherein subjecting an individual to sub-lethal volumes of mitochondrial reactive oxygen species (mtROS) increases the lifespan [22,23]. The top three pathways that contribute to the mode of action of the essential oil were: (1) interferon signaling, (2) N-glycan biosynthesis and (3) ERK5 signaling [16]
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