Table 2.

Role of ROS in diseases of cellular differentiation

Disease	Pathology related to differentiation	Potential differentiation therapy	Regulation of cell differentiation by ROS	Remarks
Acute myeloid leukemia	Loss of granulocyte or monocyte differentiation	Inducing leukemic cell differentiation	Excessive ROS production or oxidative DNA damage is frequently observed in hematopoietic malignancies [69–71]; Altered ROS levels stimulate leukemogenesis through regulation of redox-sensitive transcription factors (e.g. Nrf2, Bach1, NFκB, AP-1, and HIF1α) [72]; Either suppression of high ROS or amplification of existing ROS levels may be of clinical benefit in treatment of AML [73].	Despite many encouraging results, the only successful clinical application of differentiation therapy is all-trans retinoic acid for acute promyelocytic leukemia. Differentiation therapy targeting redox homeostasis is likely to provide opportunities for improved pharmacological intervention.
Neuroblastoma	Neuroblastoma differentiation block	Inducing neuroblastoma differentiation	Hypoxic tumor cells are highly tumorigenic and poorly differentiated; Hypoxia leads to neuroblastoma dedifferentiation by down-regulation of neuronal marker genes and up-regulation of genes expressed in neuronal crest sympathetic progenitors through activation of Notch signaling in a HIF dependent way [74]; Increased ROS levels by pro-oxidants (e.g. buthionine sulfoximine or diethyl maleate) activate protein kinase C-δ through oxidative modification at the amino-terminal regulatory domain causing neuroblastoma apoptosis [75].	In neuroblastoma, hypoxia and ROS have been linked with either progression or spontaneous regression. A better understanding of the opposing mechanisms would likely be informative.
Atherosclerosis	Foam cell differentiation	Inhibiting monocyte-to- macrophage/foam cell differentiation	Intensive monocyte recruitment, macrophage differentiation and lipid- laden foam cells formation and death, are hallmarks of atherosclerosis. ROS play a critical role in most of these processes and contribute to the pathophysiology of atherosclerosis [76]; Oxidative stress induced thiol oxidation and protein S-glutathionylation accelerate atherogenesis [77].	Studies aimed at identifying the intracellular targets of ROS involved in redox signaling in macrophages and at elucidating the redox signaling mechanisms that control differentiation, may lead to the development of novel preventive and therapeutic strategies for atherosclerosis.
Bone loss-associated disorders (e.g. osteoporosis, rheumatoid arthritis, Paget’s disease, periodontal disease, osteosarcoma and cancer bone metastasis)	Osteoclast differentiation	Inhibiting osteoclast differentiation	ROS produced by NOX2 or mitochondria stimulate M-CSF or RANKL-induced osteoclastogenesis through activation of redox-sensitive signaling pathways (e.g. NFκB, MAPK, PI3K/Akt) [78–80]; Decreased ROS levels by antioxidants (e.g. NAC or GSH), Nox2 inhibitors or overexpression of GPx, prevent osteoclastogenesis [80, 81]; Keap1/Nrf2 regulates osteoclast differentiation through modulating ROS by expression of cytoprotective enzymes [82]; FoxO activation decreases osteoclast numbers and bone resorption through both cell autonomous and indirect mechanisms [83].	Pharmaceutical inhibition of osteoclast differentiation is one therapeutic strategy to mitigate the extent of bone loss-associated disorders. Several chemical-, natural product-, and biological- based inhibitors are now in clinical trials [84].
Degenerative fibrotic disease: Multisystemic diseases (e.g. systemic sclerosis, chronic graft versus host disease, and nephrogenic systemic fibrosis); Organ-specific diseases (e.g. cardiac fibrosis, idiopathic pulmonary fibrosis, intestinal fibrosis, liver cirrhosis, progressive kidney disease, macular degeneration, and benign prostatic hyperplasia)	Myofibroblast differentiation	Inhibiting or reversing fibroblast-to-myofibroblast differentiation	TGFβ is the foremost inducer of fibroblast-to-myofibroblast differentiation in diverse tissues. It induces a pro-oxidant shift in redox homeostasis via the induction of NOX4- induced ROS, which activates downstream signaling pathways (e.g. Smad2/3, MAPK, PI3K/Akt) [85]. Fibroblast-to-myofibroblast differentiation can be inhibited and reversed by restoring redox homeostasis using NOX4 inhibitors or antioxidants as well as enhancing NO signaling via activation of soluble guanylyl cyclases or inhibition of phosphodiesterases [86].	Despite the considerable morbidity and mortality, there are currently no effective treatments and no approved antifibrotic therapies. Redox signaling plays a fundamental and integral role in the molecular pathogenesis of fibrosis and represents a potential therapeutic target for the treatment of different fibrotic disorders.
Neurological disorders: Acute brain injury (e.g. traumatic brain injury (TBI), and stroke); Chronic neurodegenerative diseases (e.g. Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis)	Loss of neurons and glial cells	Transplantation of stem cell- differentiated neuroblasts or inducing endogenous neurogenesis [87–90]	ROS mediate neurogenesis through activation of redox sensitive signaling pathways (e.g. PI3K/Akt, p38 and ERK), and transcription factors (e.g. NFκB, AP-1 and NFAT) [91]; Oxidative imbalance is increasingly related to neurodevelopmental disorders [92, 93]; Controlling intracellular redox proteins might provide potential therapeutic targets, e.g. Prx6 and GSTP in cerebrospinal fluid could be potential targets for therapeutic interventions in the TBI patients [94, 95].	A detailed understanding of the redox regulation of neurogenesis is critical for guiding efforts to restore function and ameliorate the devastating effects of acute cerebral injury and chronic neurodegenerative disease.
Obesity	Adipocyte differentiation	Inhibiting adipocyte differentiation	ROS promote adipogenesis through activation of redox-sensitive signaling pathways (e.g. insulin/IGF, and ERK, by inhibiting PTP1B activities), and transcription factors (e.g. C/EBPβ, and PPARγ) [96–98]; Nrf2 and oxidative stress play critical roles in adipocyte differentiation and function [99]; NAC or NOX inhibitors suppress ROS levels, inhibit adipocyte differentiation and fat accumulation, and improve symptoms of obesity-associated metabolic syndromes [100–102].	More studies are needed to understand the precise roles of ROS and redox signaling mechanisms in the pathogenesis of obesity and related metabolic disorders.
Type 2 diabetes	Beta-cell dedifferentiation	Restoring beta-cell differentiation	Type 2 diabetes results from insulin resistance and insulin deficiency and is traditionally thought to be caused by beta-cell dysfunction and enhanced beta-cell apoptosis. Recent work indicates that loss of FoxO1 causes beta-cell dysfunction and diabetes by triggering the loss of beta- cell identity/beta-cell dedifferentiation [103, 104].	The exact mechanisms of beta-cell dedifferentiation remain to be worked out, which may help to develop a new class of type 2 diabetes therapies based on the prevention or reversal of beta-cell dedifferentiation.

Only selected diseases are presented to best serve the focus of this chapter. Details of some of the diseases are discussed in the text.