An Essential Role of NRF2 in Diabetic Wound Healing

Long, Min; Vega, Montserrat Rojo de la; Wen, Qing; Bharara, Manish; Jiang, Tao; Zhang, Rui; Zhou, Shiwen; Wong, Pak Kin; Wondrak, Georg T.; Wang, Cong-Yi; Zhang, Donna D.

doi:10.2337/db15-0564

Cited by 170 publications

(157 citation statements)

References 56 publications

(55 reference statements)

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“…2B). Previous reports indicate that absence of NRF2 promotes MMP9 activity (Long et al, 2016). We observe an increase in NRF2 expression on cigarette smoke exposure and inhibition of its expression on vitamin E treatment on cells exposed to CSC (Fig.…”

Section: Csc Induces Nrf2 Overexpression In Keratinocytes In Vitrosupporting

confidence: 54%

How Does Chronic Cigarette Smoke Exposure Affect Human Skin? A Global Proteomics Study in Primary Human Keratinocytes

Rajagopalan

Nanjappa

Raja

et al. 2016

OMICS: A Journal of Integrative Biology

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Cigarette smoking has been associated with multiple negative effects on human skin. Long-term physiological effects of cigarette smoke are through chronic and not acute exposure. Molecular alterations due to chronic exposure to cigarette smoke remain unclear. Primary human skin keratinocytes chronically exposed to cigarette smoke condensate (CSC) showed a decreased wound-healing capacity with an increased expression of NRF2 and MMP9. Using quantitative proteomics, we identified 4728 proteins, of which 105 proteins were overexpressed (≥2-fold) and 41 proteins were downregulated (≤2-fold) in primary skin keratinocytes chronically exposed to CSC. We observed an alteration in the expression of several proteins involved in maintenance of epithelial barrier integrity, including keratin 80 (5.3 fold, p value 2.5 × 10), cystatin A (3.6-fold, p value 3.2 × 10), and periplakin (2.4-fold, p value 1.2 × 10). Increased expression of proteins associated with skin hydration, including caspase 14 (2.2-fold, p value 4.7 × 10) and filaggrin (3.6-fold, p value 5.4 × 10), was also observed. In addition, we report differential expression of several proteins, including adipogenesis regulatory factor (2.5-fold, p value 1.3 × 10) and histone H1.0 (2.5-fold, p value 6.3 × 10) that have not been reported earlier. Bioinformatics analyses demonstrated that proteins differentially expressed in response to CSC are largely related to oxidative stress, maintenance of skin integrity, and anti-inflammatory responses. Importantly, treatment with vitamin E, a widely used antioxidant, could partially rescue adverse effects of CSC exposure in primary skin keratinocytes. The utility of antioxidant-based new dermatological formulations in delaying or preventing skin aging and oxidative damages caused by chronic cigarette smoke exposure warrants further clinical investigations and multi-omics research.

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Section: Csc Induces Nrf2 Overexpression In Keratinocytes In Vitrosupporting

confidence: 54%

How Does Chronic Cigarette Smoke Exposure Affect Human Skin? A Global Proteomics Study in Primary Human Keratinocytes

Rajagopalan

Nanjappa

Raja

et al. 2016

OMICS: A Journal of Integrative Biology

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“…Moreover, mice lacking Nrf2 demonstrated a slowed wound-healing process, due to the deprivation of efficient antioxidant activity [34]. Environmental challenges, such as UV irradiation, toxic chemicals, and mechanical wounding, result in increased reactive oxygen species (ROS), inflammation, skin aging, and cancer development [46].…”

Section: Discussionmentioning

confidence: 99%

A Novel Peptide, Nicotinyl–Isoleucine–Valine–Histidine (NA–IVH), Promotes Antioxidant Gene Expression and Wound Healing in HaCaT Cells

et al. 2018

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Nicotinamide (NA), a water-soluble vitamin B3, has been shown to exert cellular-protective effects against reactive oxygen species (ROS). In order to improve the cellular-protective effects of NA, we synthesized a novel compound, nicotinyl–isoleucine–valine–histidine (NA–IVH), by combining NA with jellyfish peptides’ IVH. In the present study, we examined the cellular-protective effects of the novel synthetic nicotinyl-peptide, NA–IVH. We found that NA–IVH enhances the radical scavenging activity with a robust increase of the nuclear factor (erythroid-derived 2)-like factor (Nrf2) expression in human HaCaT keratinocytes. In addition, NA–IVH protected the cells from hydrogen peroxide (H2O2)-induced cell death. Interestingly, NA–IVH exhibited an improved wound-healing effect in a high glucose condition, possibly through the regulation of reactive oxygen species (ROS). Collectively, our results imply that a novel nicotinyl-peptide, NA–IVH, has a wound-healing effect in a hyperglycemic condition, possibly by modulating excessive ROS.

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“…Compelling evidence for the importance of the Nrf2 pathway for disease prevention and control of tissue damage associated with inflammation comes from numerous studies with mice lacking the Nrf2 gene (reviewed in (Senger et al, 2016)). Also, consistent with folklore use of BL for diabetic complications, Nrf2 has been implicated in protection from diabetic pathology (de Haan, 2011; Evans and Goldfine, 2016; Li et al, 2012; Long et al, 2016). Consequently, in studies described here, we investigated regulation of the Nrf2 pathway by BL in human microvascular endothelial cells, which are pivotal “gatekeepers” of inflammation (Dejana, 2004; Granger DN, 2010) and closely involved in diabetic complications (Avogaro et al, 2011; Brownlee, 2005).…”

Section: Introductionmentioning

confidence: 67%

Anti-inflammatory activity of Barleria lupulina: Identification of active compounds that activate the Nrf2 cell defense pathway, organize cortical actin, reduce stress fibers, and improve cell junctions in microvascular endothelial cells

Senger

Hoang

Kim

et al. 2016

Journal of Ethnopharmacology

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Ethnopharmacological relevance Hot aqueous extracts of the plant Barleria lupulina (BL) are used for treating inflammatory conditions and diabetic vascular complications. Aim of the Study The goal was to identify active compounds in hot aqueous extracts of BL (HAE-BL) that are consistent with a role in reducing inflammation and reducing the vascular pathology associated with diabetes. In particular, we examined activation of the Nrf2 cell defense pathway because our initial findings indicated that HAE-BL activates Nrf2, and because Nrf2 is known to suppress inflammation. Activation of Nrf2 by HAE-BL has not been described previously. Materials and Methods Human endothelial cells, real-time PCR, western blotting, cytoskeletal analyses, and assay-guided fractionation with HPLC were used to identify specific compounds in HAE-BL that activate the Nrf2 cell defense pathway and reduce markers of inflammation in vitro. Results HAE-BL potently activated the Nrf2 cell defense pathway in endothelial cells consistent with its traditional use and reported success in reducing inflammation. Assay guided fractionation with HPLC identified three alkyl catechols: 4-ethylcatechol, 4-vinylcatechol, and 4-methylcatechol, that are each potent Nrf2 activators. In addition to activating Nrf2, HAE-BL and akyl catechols each profoundly improved organization of the endothelial cell actin cytoskeleton, reduced actin stress fibers, organized cell-cell junctions, and induced expression of mRNA encoding claudiin-5 that is important for formation of endothelial tight junctions and reducing vascular leak. Conclusions HAE-BL contains important alkyl catechols that potently activate the Nrf2 cell defense pathway, improve organization of the endothelial cell cytoskeleton, and organize tight cell junctions. All of these properties are consistent with a role in reducing inflammation and reducing vascular leak. Because activation of the Nrf2 cell defense pathway also prevents cancers, neuro-degeneration, age-related macular degeneration, and also reduces the severity of chronic obstructive pulmonary disorder and multiple sclerosis, HAE-BL warrants additional consideration for these other serious disorders.

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An Essential Role of NRF2 in Diabetic Wound Healing

Cited by 170 publications

References 56 publications

How Does Chronic Cigarette Smoke Exposure Affect Human Skin? A Global Proteomics Study in Primary Human Keratinocytes

How Does Chronic Cigarette Smoke Exposure Affect Human Skin? A Global Proteomics Study in Primary Human Keratinocytes

A Novel Peptide, Nicotinyl–Isoleucine–Valine–Histidine (NA–IVH), Promotes Antioxidant Gene Expression and Wound Healing in HaCaT Cells

Anti-inflammatory activity of Barleria lupulina: Identification of active compounds that activate the Nrf2 cell defense pathway, organize cortical actin, reduce stress fibers, and improve cell junctions in microvascular endothelial cells

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