Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells

Yama, Kaori; Sato, Keisuke; Abe, Natsuki; Murao, Yu; Tatsunami, Ryosuke; Tampo, Yoshiko

doi:10.1016/j.redox.2014.12.002

Cited by 35 publications

(25 citation statements)

References 55 publications

(68 reference statements)

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“…Our study of bovine aortic endothelial cells revealed that LY294002, an inhibitor of phosphatidylinositol 3-kinase, 30) abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. 21) In contrast, in the case of Schwann cells, it was unlikely that the action of EPS was associated with the kinase because LY294002 had no influence on EPS-stimulated GSH synthesis (data not shown). On the other hand, Nrf2 was degraded by the ubiquitin-proteasome system and proteasome inhibitors enhanced HO-1 mRNA and protein accumulation.…”

Section: )mentioning

confidence: 90%

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Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Yama

Sato

Murao

et al. 2016

Biological & Pharmaceutical Bulletin

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Heme oxygenase (HO)-1 has potent antioxidant and anti-inflammatory functions. Recent studies have shown that the upregulation of HO-1 is beneficial to counteract neuroinflammation, making HO-1 a new therapeutic target for neurological diseases. We have reported that epalrestat (EPS), which is currently used for the treatment of diabetic neuropathy, increases HO-1 levels through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in bovine aortic endothelial cells. In this study, we tested the hypothesis that EPS upregulates HO-1 via Nrf2 activation in the component cells of the nervous system, by using rat Schwann cells and human SH-SY5Y cells. Treatment of Schwann cells with EPS at near-plasma concentration led to a dramatic increase in HO-1 levels. Nrf2 knockdown by small interfering RNA (siRNA) suppressed the EPS-induced HO-1 expression. EPS did not promote the intracellular accumulation of free ferrous ion and reactive oxygen species, by increasing ferritin via Nrf2 during HO-1 induction. Moreover, EPS stimulated the expression of superoxide dismutase 1 and catalase, which also are Nrf2 target gene products. It also markedly increased HO-1 levels in SH-SY5Y cells through the activation of Nrf2. We demonstrated for the first time that EPS upregulates HO-1, superoxide dismutase, and catalase by activating Nrf2. We suggest that EPS has the potential to prevent several neurological diseases. Key words epalrestat; heme oxygenase (HO)-1; superoxide dismutase (SOD); catalaseHeme oxygenase (HO)-1 is a stress-responsive enzyme that has anti-inflammatory, antioxidant, and cytoprotective functions. Expectations are high that the regulation and amplification of HO-1 by pharmacological approaches would lead to the discovery of novel drugs for the treatment of a variety of diseases.1) HO-1 has emerged as an anti-inflammatory therapeutic target.2) In particular, targeting HO-1 in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, has been reported.3) As HO-1 expression is involved in neuropathological changes, its regulation is essential for the development of new therapeutic approaches.3) However, such metalloporphyrins as cobalt protoporphyrin IX, which are prototypical inducers of HO-1 and commonly used in experimental cell culture and animal models, are not applicable to clinical interventions because of their high toxicity.2) It is expected that the upregulation of HO-1 by currently available pharmacological agents, whose safety and pharmacokinetics have already been confirmed clinically, would be useful for the treatment of a variety of diseases.The biochemical activities of heme degradation products and their metabolic derivatives contribute to the cytoprotective function of HO-1. HO-1 catalyzes the degradation of heme to produce ferrous iron, carbon monoxide, and biliverdin, the latter of which is subsequently converted into bilirubin. Carbon monoxide is involved in inflammation regulation.4) Bilirubin and biliverdin, which can scavenge peroxyl radicals, are cytoprotec...

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Section: )mentioning

confidence: 90%

“…In our previous reports, we have described that EPS activates Nrf2 in rat Schwann cells and bovine aortic endothelial cells. 10,21) Schwann cells, the myelin forming cells in the peripheral nervous system, are crucial for the proper function and maintenance of peripheral nerves.…”

Section: Effect Of Eps On Ho-1 Levels and Nrf2 In Sh-sy5y Cellsmentioning

confidence: 99%

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Yama

Sato

Murao

et al. 2016

Biological & Pharmaceutical Bulletin

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“…Rice is widely consumed around the world and rice-derived peptides are reported to have various biological effects such as anti-microbial activity, (8,9) anti-oxidative activity (10,11) and dipeptidyl peptidase-IV-inhibitory activity. (12,13) Compounds that have so far been reported to increase intracellular glutathione levels include silymarin, (14) cyanohydroxybutene, (15) α-naphthoflavone, (16) apocynin, (17) epalrestat, (18,19) ribose-cysteine, (20) β-carotene, (21) noradrenaline, (22) and lactacystin. (23) In a previous study, we demonstrated that rice-derived peptides (RP), obtained from commercial rice proteins using a commercial protease from Aspergillus oryzae , inhibit dipeptidyl peptidase-IV.…”

Section: Introductionmentioning

confidence: 99%

Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice

Kawakami

Moritani

Uraji³

et al. 2017

J. Clin. Biochem. Nutr.

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Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We found that rice peptides increased intracellular glutathione levels in human hepatoblastoma HepG2 cells. Acetaminophen is a commonly used analgesic. However, an overdose of acetaminophen causes severe hepatotoxicity via depletion of hepatic glutathione. Here, we investigated the protective effects of rice peptides on acetaminophen-induced hepatotoxicity in mice. ICR mice were orally administered rice peptides (0, 100 or 500 mg/kg) for seven days, followed by the induction of hepatotoxicity via intraperitoneal injection of acetaminophen (700 mg/kg). Pretreatment with rice peptides significantly prevented increases in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels and protected against hepatic glutathione depletion. The expression of γ-glutamylcysteine synthetase, a key regulatory enzyme in the synthesis of glutathione, was decreased by treatment with acetaminophen, albeit rice peptides treatment recovered its expression compared to that achieved treatment with acetaminophen. In addition, histopathological evaluation of the livers also revealed that rice peptides prevented acetaminophen-induced centrilobular necrosis. These results suggest that rice peptides increased intracellular glutathione levels and could protect against acetaminophen-induced hepatotoxicity in mice.

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“…Four plant-based polyphenols -fisetin, rhamnetin, pyrogallin and purpurogallin-4-carboxylic acid -are active in the Keap1-Nrf2 cellular reporter assay, but only two of them -fisetin and pyrogallin -boost PMM2 enzymatic activity. Several reports indicate that epalrestat activates NRF2 in cultured cells (Yama et al, 2016;Yama et al, 2015). Using quantitative RT-PCR, we showed that epalrestat treatment of pmm-2 F125L/F125L homozygote worms modestly upregulates SKN-1 transcripts.…”

Section: Discussionmentioning

confidence: 63%

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG

Iyer¹,

Murthy²,

Parton³

et al. 2019

Preprint

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Phosphomannomutase 2 deficiency, or PMM2-CDG, is the most common congenital disorder of glycosylation affecting over 1,000 patients globally. There are no approved drugs that treat the symptoms or root cause of PMM2-CDG. In order to identify clinically actionable compounds that boost human PMM2 enzyme function, we performed a multi-species drug repurposing screen using a first-ever worm model of PMM2-CDG followed by PMM2 enzyme functional studies in PMM2-CDG patient fibroblasts.Drug repurposing candidates from this study, and drug repurposing candidates from a previously published study using yeast models of PMM2-CDG, were tested for their effect on human PMM2 enzyme activity in PMM2-CDG fibroblasts. Of the 20 repurposing candidates discovered in the wormbased phenotypic screen, 12 are plant-based polyphenols. Insights from structure-activity relationships revealed epalrestat, the only antidiabetic aldose reductase inhibitor approved for use in humans, as a firstin-class PMM2 enzyme activator. Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains range from 30% to 400% over baseline depending on genotype.Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations. We demonstrate that epalrestat is the first small molecule activator of PMM2 enzyme activity with the potential to treat peripheral neuropathy and correct the underlying enzyme deficiency in a majority of pediatric and adult PMM2-CDG patients.Keywords: Phosphomannomutase 2 deficiency, drug repurposing, PMM2-CDG, congenital disorder of glycosylation, aldose reductase inhibitor, epalrestat conserved process that occurs in all animal cells throughout development and adulthood (Chang et al, 2018). PMM2-CDG is a multi-system, multi-organ disease because a minimal level of glycosylation is required at all times in all cells of the body, with cell types or organs more or less vulnerable to the complex sequelae of hypoglycosylation. Although a clear genotype-phenotype relationship is obscured by genetic and possibly environmental modifiers, as the residual level of PMM2 enzymatic activity increases the number and severity of organ systems affected decreases. For example, patients homozygous for a mutation in the promoter of PMM2 do not get PMM2-CDG or even a mild form of PMM2-CDG but instead have hyperinsulinemic hypoglycemia and polycystic kidney disease because this mutation impairs binding by a kidney-and pancreas-specific transcription factor to a chromatin loop in the promoter of PMM2 (Cabezas et al, 2017). As another example, hypoglycosylation of the calcium channel CACNA1A caused a gain-of-function channelopathy that in turn leads to an i...

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Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells

Cited by 35 publications

References 55 publications

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Epalrestat Upregulates Heme Oxygenase-1, Superoxide Dismutase, and Catalase in Cells of the Nervous System

Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice

Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG

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