Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes

Gold-quercetin nanoparticles prevent metabolic endotoxemia-induced kidney injury by regulating TLR4/NF-kB signaling and Nrf2 pathway in high fat diet fed mice

“…55 In the present study, a significant increase in Nrf2 activation, NQO1, and HO-1 and reduction in SOD1 and SOD2 levels were observed in HFDinduced kidney tissue, demonstrating that Nrf2-related genes were activated and associated with kidney injury. Moreover, Nrf2 pathway was also enhanced in LPS-exposed podocytes in vitro, resulting in the upregulation of HO-1 and NQO1 expression.…”

Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

“…Furthermore, relatively weak immunostaining is observed for the phosphorylated (activated) form of NRF2 and for two key upstream regulators of NRF2 activation, PKC-δ and RACK1, in tissue sections from female Krt16 -/- mice compared to control (Supplemental Figure 1). Similar to the situation already reported for males (Kerns et al, 2016), therefore, female Krt16 -/- paw skin shows clear signs of oxidative stress secondary to hypoactive NRF2 signaling ahead of lesion onset. Again, and as previously reported for male Krt16 -/- mice (Kerns et al, 2016), the presence of copious amount of NRF2 protein offers an ideal opportunity for preventive therapy via topical SF in female Krt16 -/- mice.…”

“…Similar to the situation already reported for males (Kerns et al, 2016), therefore, female Krt16 -/- paw skin shows clear signs of oxidative stress secondary to hypoactive NRF2 signaling ahead of lesion onset. Again, and as previously reported for male Krt16 -/- mice (Kerns et al, 2016), the presence of copious amount of NRF2 protein offers an ideal opportunity for preventive therapy via topical SF in female Krt16 -/- mice. Such a therapeutic approach for PC, regardless of the sex of the individual, is buttressed by the finding of elevated, but hypoactive NRF2 in the lesional plantar epidermis of both male and female PC patients (Supplemental Figure 2) (Kerns et al, 2016).…”

“…We recently reported that the PC-like PPK lesions arising in the paw skin of Krt16 -/- mice are preceded by profound oxidative stress that results from impaired synthesis of the antioxidant glutathione secondary to hypo-functional nuclear factor erythroid-derived 2 related factor 2 (NRF2) (Kerns et al, 2016). The latter, a basic leucine zipper (bZIP) transcription factor that plays essential and pleiotropic roles in cellular responses to stress and maintenance of redox balance (Wang et al, 2013), is expressed at elevated levels but is hypo-phosphorylated and dysfunctional in Krt16 -/- paw skin and in biopsies of PPK lesions in individuals with PC (Kerns et al, 2016).…”

“…The latter, a basic leucine zipper (bZIP) transcription factor that plays essential and pleiotropic roles in cellular responses to stress and maintenance of redox balance (Wang et al, 2013), is expressed at elevated levels but is hypo-phosphorylated and dysfunctional in Krt16 -/- paw skin and in biopsies of PPK lesions in individuals with PC (Kerns et al, 2016). Topical treatment with sulforaphane (SF), a small molecule activator of NRF2 (Zhang et al, 1992), leads to restoration of the redox balance and prevention of PPK development in Krt16 -/- paw skin (Kerns et al, 2016). Though it yielded novel insight into the pathophysiology of PC-associated PPK with significant implications for therapy, this previous study was restricted to male mice.…”