Overexpression of Heme Oxygenase-1 Protects Dopaminergic Neurons against 1-Methyl-4-Phenylpyridinium-Induced Neurotoxicity

Hung, Shih-Ya; Liou, Houng‐Chi; Kang, Kai-Hsiang; Wu, Ruey‐Meei; Wen, Chun-Chiang; Fu, Wen‐Mei

doi:10.1124/mol.108.048611

Cited by 122 publications

(85 citation statements)

References 37 publications

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“…It is established that expression levels or the activity of HO-1 and GPx are involved in the elimination or inactivation of ROS [35], and that this effect is mediated by activation of NRF2 [36]. Although normal tissues express extremely low basal levels of HO-1 protein [37,38], diabetic rats receiving antioxidant treatment have significantly increased HO-1 protein levels compared with normal controls [39]. Together, our data suggest that the expression of HO-1 protein may be a key factor in preventing mice from developing renal lesions in DN.…”

Section: Discussionmentioning

confidence: 99%

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

Yang¹,

Ka²,

et al. 2013

Diabetologia

101

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Aims/hypothesis Chronic inflammatory processes have been increasingly shown to be involved in the pathogenesis of diabetes and diabetic nephropathy. Recently, we demonstrated that a lectin-like domain of thrombomodulin (THBD), which is known as THBD domain 1 (THBDD1) and which acts independently of protein C activation, neutralised an inflammatory response in a mouse model of sepsis. Here, therapeutic effects of gene therapy with adeno-associated virus (AAV)-carried THBDD1 (AAV-THBDD1 ) were tested in a mouse model of type 2 diabetic nephropathy.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

Yang¹,

Ka²,

et al. 2013

Diabetologia

101

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“…For example, CO exerts cytoprotective effects through its potent anti-inflammatory, anti-apoptotic, and vasodilatory properties. 4,18) Bile pigments biliverdin and bilirubin are peroxy radical scavengers. 5) However, some studies suggested that HO-1 induction might not always be beneficial and the release of redox-active iron from heme might enhance oxidative stress.…”

Section: )mentioning

confidence: 99%

“…18) We examined the effects of EPS on HO-1 expression using the human neuroblastoma cell line SH-SY5Y, which is a model of neuronal cells. SH-SY5Y cells were treated with EPS at 10, 50, and 100 µM for 24 h. EPS at those concentrations had no effect on cell viability (data not shown).…”

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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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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“…It has been widely reported that HO-1 plays a crucial role in maintaining redox homeostasis during cellular stress (11)(12)(13). Increased HO-1 expression contributes to promoting the degradation of heme into carbon monoxide and biliverdin, the latter being the immediate precursor of the powerful antioxidant molecule bilirubin (14).…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner

Jin¹

2011

Mol Med Report

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Abstract. Parkinson's disease (PD) is a progressive neurodegenerative disorder with selective loss of dopaminergic neurons in the substantia nigra. Evidence suggests that oxidative stress is involved in the pathogenesis of PD. Sulforaphane (SF), a naturally occurring isothiocyanate, has been shown to protect against oxidative stress by inducing the expression of various NF-E2-related factor-2 (Nrf2) responsive genes. Previous studies have shown that SF protects dopaminergic neurons against PD-related neurotoxin 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. However, the molecular mechanisms by which SF protects against 6-OHDA-induced cytotoxicity are poorly elucidated. In this study, we found that pretreatment with SF significantly reduced 6-OHDAinduced caspase-3 activation and subsequent cell death. SF also increased heme oxygenase-1 (HO-1) expression, which conferred protection against 6-OHDA-induced cytotoxicity. Furthermore, SF induced the translocation of Nrf2 into the nucleus and activated PI3K/Akt, a pathway that is involved in SF-induced Nrf2 nuclear translocation, HO-1 expression and cytoprotection. These results suggest that SF inhibits 6-OHDA-induced cytotoxicity through increasing HO-1 expression in a PI3K/Akt-dependent manner.

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Overexpression of Heme Oxygenase-1 Protects Dopaminergic Neurons against 1-Methyl-4-Phenylpyridinium-Induced Neurotoxicity

Cited by 122 publications

References 37 publications

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

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

Sulforaphane protects against 6-hydroxydopamine-induced cytotoxicity by increasing expression of heme oxygenase-1 in a PI3K/Akt-dependent manner

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