Oxidative stress, redox regulation and diseases of cellular differentiation

Abstract

Background Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers. Scope of review We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects. Primary conclusions Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development. General Significance The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies.

Hydrogen peroxide (H2O2) controls axon pathfinding during zebrafish development

“…Our results reveal a new link between two key regulatory pathways, Hedgehog and redox signalling. Shh signalling has a central role in multiple aspects of embryonic development and in various human pathologies, such as degenerative diseases, cancer and autoimmunity (reviews in Briscoe and Therond (2013), Carney and Ingham (2013) and Petrova and Joyner (2014)), in which the balance between oxidants and anti-oxidants is often perturbed (van der Vliet and JanssenHeininger, 2014; Ye et al, 2014). Our results not only uncover the link between H 2 O 2 and Hedgehog signalling in the context of axon growth but also suggest a new strategy to target pathological actions of Hedgehog signalling by the pharmacological modulation of H 2 O 2 levels.…”

MicroRNA-mediated regulation of glutathione and methionine metabolism and its relevance for liver disease

“…Another level of regulation of GSH homeostasis is provided by glutathione S-transferase (GST), that along with other antioxidant enzymes provides the cell with protection against a range of harmful electrophiles produced during oxidative damage to membranes [12]. In humans, GST includes 22 family members, classified according to their structure as cytosolic, mitochondrial and membrane associated.…”

Ameliorative effect of gallic acid on methotrexate-induced hepatotoxicity and nephrotoxicity in rat

“…8,9 In the regulation of oxidative processes, cellular systems have been equipped with several antioxidant defense mechanisms, and there are several phytochemicals of plant origin with inherent antioxidant properties that are capable of boosting cellular enzymic and nonenzymic antioxidant indices thus making them excellent scavengers of free radicals. 10 The chemoprotective properties of plant extracts have been extensively studied and are attributed to the presence of flavonoids, anthocyanins and phenolic compounds. 11 Gallic acid (GA) (3,4,5-trihydroxybenzoic acid) ( Figure 1B) is a naturally occurring phenolic compound present in green tea, gall nut, grapes, red wine, hops, oak bark etc.…”