Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin

Reisman, Scott A.; Lee, Chun‐Yue I.; Meyer, Colin; Proksch, Joel W.; Ward, Keith W.

doi:10.1007/s00403-013-1433-7

Cited by 49 publications

(45 citation statements)

References 24 publications

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“…Three different activators for the transcription factor Nrf2 were used: the synthetic acetylenic tricyclic bis(cyanoenone) TBE-31 54 , the triterpenoid RTA-408 (RTA) 55 , and the naturally occurring isothiocyanate sulforaphane (SFN) 56 . The concentration of each compound was optimized based on the potency in inducing NAD(P)H:quinone oxidoreductase 1 (NQO1), a prototypic Nrf2 target gene, without causing any cytotoxicity, using a quantitative bioassay 57 .…”

Section: Methodsmentioning

confidence: 99%

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

Bartolomé

Esteras

Martín-Requero

et al. 2017

Sci Rep

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Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y). We found that p62 deficiency is associated with inhibited complex I mitochondrial respiration due to lack of NADH for the electron transport chain. This deficiency was also associated with increased levels of NADPH reflecting a higher activation of pentose phosphate pathway as this is accompanied with higher cytosolic reduced glutathione (GSH) levels. Complex I inhibition resulted in lower mitochondrial membrane potential and higher cytosolic ROS production. Pharmacological activation of transcription factor Nrf2 increased mitochondrial NADH levels and restored mitochondrial membrane potential in p62-deficient cells. Our results suggest that the phenotype is caused by a loss-of-function effect, because similar alterations were found both in the mutant fibroblasts and the p62 KD model. These findings highlight the implication of energy metabolism in pathophysiological events associated with p62 deficiency.

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Section: Methodsmentioning

confidence: 99%

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

Bartolomé

Esteras

Martín-Requero

et al. 2017

Sci Rep

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“…Vatiquinone is also an antioxidant that has been shown to be benefi cial in open-label trials [ 158 ] and is now in a randomized double-blind trial for pediatric Leigh syndrome patients. RTA-308 is also an antioxidant and anti-infl ammatory agent that acts by increasing Nrf2 activity that in turn enhances the expression of prooxidant genes and represses infl ammatory genes in animal models [ 159 ]. It is currently in a safety/effi cacy trial to assess workload during exercise training in mitochondrial myopathy patients.…”

Section: Clinical Approachesmentioning

confidence: 98%

Development of Treatments and Therapies to Target Mitochondrial Dysfunction

Helliwell

2016

Mitochondrial Dysfunction in Neurodegenerative Disorders

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Mitochondrial diseases affect 1:10,000 people worldwide, with a further 1:6,000 at risk of developing symptoms, and can be caused by mutations in the nuclear genome or by mutations within/deletion of mitochondrial DNA (mtDNA). There is currently no therapy for patients with these diseases. In addition, mitochondrial dysfunction can be considered contributory or causal for other neurological diseases, such that therapies that improve mitochondrial function may have widereaching benefi ts. This chapter summarizes cell-and animal-based attempts to fi nd a therapy by modulating major mitochondrial pathways including mitochondrial biogenesis, fi ssion, fusion and altering metabolic intermediates, mitophagy and the mammalian target of rapamycin (mTOR) pathway. Clinical trials currently in progress include drugs that are direct or indirect antioxidants, a mitogenesis activator, an antiapoptotic compound and a compound that improves electron transport chain effi ciency.

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“…It binds to promoter regions known as elements of antioxidant response (ARE) that transcribed genes of cytoprotective proteins and antioxidants like glutatión S-transferase (GST), quinone reductase NAD(P)H (NQO1), UDPglucuronosyltransferases (UGT), epoxide hydrolase (EPHX), c glutamylcysteine ligase (GCL), heme oxygenase-1 (HO-1), glutathione reductase the (GR), thioredoxin reductase (TrxR), catalase (CAT) and superoxide dismutase (SOD). Nrf2 also promotes gene transcription nonenzymatic antioxidant proteins as thioredoxin and ferritin [59].…”

Section: Skinmentioning

confidence: 99%

Possible Role of Nrf2 in Oxidative and Inflammatory Processes During Menopause

Mendoza¹,

Zamarripa²,

Hernández³

et al. 2016

A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2

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The increase in life expectancy leads to the possibility of development chronic diseases, from special physiological conditions as occurs in the menopause, which is defined as the permanent cessation of ovulation, marked by the end of menstruation. It has been related to decreased ovarian function that occurs around an age of 45 years. This event involves the reduction in estrogen production and may contribute to the development of chronic-degenerative diseases. Many diseases developed during menopause have been associated with oxidative stress, such as osteoporosis, hot flushes, cognitive impairment, insulin resistance, dry skin, obesity, and cardiovascular events. The knowledge about the participation of Nrf2 in diseases that occur during menopause is very limited. Here, only diseases such as osteoporosis, cardiovascular diseases and dry skin, which are present during menopause and its later stages have been described. The Nrf2 pathway involves the participation of PI3K/Akt, MAPK, and eNOS, which act as mediators for cytoprotection and antioxidation. Compounds such as equol, fitoestrogens, alkyl cathecols, or curcumin could be offered as options to antioxidant treatment, added the fact that they are present in fruits and vegetables which are rich in vitamins, minerals and calcium, thus including all the required nutrients for an adequate nutrition.

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Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin

Cited by 49 publications

References 24 publications

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

Pathogenic p62/SQSTM1 mutations impair energy metabolism through limitation of mitochondrial substrates

Development of Treatments and Therapies to Target Mitochondrial Dysfunction

Possible Role of Nrf2 in Oxidative and Inflammatory Processes During Menopause

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