Role of HO-1 in the Arsenite-Induced Neurotoxicity in Primary Cultured Cortical Neurons

Teng, Y. C.; Tai, Y. I.; Lee, Y. H.; Lin, Anya Maan Yuh

doi:10.1007/s12035-013-8492-9

Cited by 22 publications

(18 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Arsenic ( As ) has been identified as inducer of heme oxygenase (HO)-1expression in many cells and tissues (Teng et al 2013; Li et al 2013). Consistent with these reports, we demonstrated that the induction of HO-1 protein expression was dose- and time-dependent in HK-2 cells after As exposure.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

2015

View full text Add to dashboard Cite

Our recent study demonstrated that sodium arsenite at a clinically relevant dose induced nephrotoxicity in human renal proximal tubular epithelial cell line HK-2, which could be inhibited by natural product 2,3,5,6-Tetramethylpyrazine (TMP) with antioxidant activity. The present study demonstrated that arsenic exposure resulted in protein and enzymatic induction of heme oxygenase-1 (HO-1) in dose- and time-dependent manners in HK-2 cells. Blocking HO-1enzymatic activity by Zinc protoporphyrin (ZnPP) augmented arsenic-induced apoptosis, ROS production and mitochondrial dysfunction, suggesting a critical role for HO-1 as a renal protectant in this procession. On the other hand, TMP, upstream of HO-1, inhibited arsenic-induced ROS production and ROS-dependent HO-1 expression. TMP also prevented mitochondria dysfunction and suppressed activation of the intrinsic apoptotic pathway in HK-2 cells. Our results revealed that the regulation of arsenic-induced HO-1 expression was performed through multiple ROS-dependent signal pathways and the corresponding transcription factors, including p38 MAPK and JNK (but not ERK), AP-1, Nrf2 and NF-κB. TMP inhibited arsenic-induced activations of JNK, p38 MAPK, ERK, AP-1 and Nrf2 and block HO-1 protein expression. The present study, furthermore, demonstrated arsenic-induced expression of Arsenic response protein 2 (ARS2) that was regulated by p38 MAPK, ERK and NF-κB. To our knowledge, this is the first report showing that ARS2 involved in arsenic-induced nephrotoxicity while TMP pretreatment prevented such an up-regulation of ARS2 in HK-2 cells. Given ARS2 and HO-1 sharing the similar regulation mechanism, we speculated that ARS2 might also mediate cell survival in this procession. In summary, our study highlighted a role of HO-1 in the protection against arsenic-induced cytotoxicity downstream from the primary targets of TMP and further indicated that TMP may be used as a potential therapeutic agent in the treatment of arsenic-induced nephrotoxicity.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Several studies have shown that the induction of HO-1 by As is ROS dependent (Fan et al 2010; Teng et al 2013). Our previous data have demonstrated that As exposure elevated ROS production in HK-2 cells (Gong et al 2014).…”

Section: Resultsmentioning

confidence: 99%

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

2015

View full text Add to dashboard Cite

show abstract

“…However, HO-1 was recently reported as a harmful gene that mediated oxidative stress and apoptosis, particularly in neurons [18,[70][71][72]. The upregulation of HO-1 is a key event in the cascade leading to excessive mitochondrial iron deposition in oxidative challenged astroglia and promotes mitochondrial oxidation [23,24,26,27,34,73].…”

Section: Discussionmentioning

confidence: 99%

“…However, whether HO-1 is harmful or helpful in AD has been debated for a long time in this research field [16]. HO activity has been shown to be neuroprotective or anti-oxidative stress in various models of neural injury and disease [17,18]. The overexpression of HO-1 in neurons appears to be relatively resistant to glutamate, H 2 O 2 and other damage, such as amyloid-␤-mediated oxidative damage in vitro and in vivo [19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

Wang

Yang

Peng

et al. 2014

JAD

View full text Add to dashboard Cite

The stress protein heme oxygenase-1 (HO-1) is upregulated and co-localizes to pathological features, including tauopathies in the brains of individuals with Alzheimer's disease. However, the relationship between HO-1 and Alzheimer's disease remains unclear. In our previous research, the long-term overexpression of HO-1 was shown to promote tau aggregation by inducing tau phosphorylation in the mouse brain. In this study, we found that the long-term overexpression of HO-1 led to cognitive decline in transgenic mice, as determined by the water maze test, and that HO-1 can affect two pathways for tauopathy. Through one pathway, HO-1 promotes the expression of CDK5 by accumulating reactive oxygen species, which are produced by HO-1 downstream products of iron in neuro2a cell lines and mouse brain. Through the second pathway, HO-1 induces tau truncation at D421 in vivo and in vitro. Clearly, there is a HO-1-dependent mechanism responsible for tau protein phosphorylation and tau truncation in vivo and in vitro. Taken together, our results suggest that HO-1 plays an important role in the disease process of tauopathies in AD.

show abstract

“…In support of this notion, arsenics have been shown to induce oxidative stress, including free radical formation, glutathione depletion, lipid peroxidation, and mitochondrial impairment [5][6][7][8][9][10][11][12]. Antioxidative strategies have been suggested for arsenics-induced neurotoxicity [13][14][15][16][17][18][19][20][21]. Indeed, melatonin with antioxidative activities via direct scavenging free radicals, chelating metals, and enhancing antioxidative defensive enzymes has been used as a neuroprotective agent for decades [17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Ameliorates Arsenite-Induced Neurotoxicity: Involvement of Autophagy and Mitochondria

Teng¹,

Tai²,

Huang

et al. 2015

Mol Neurobiol

Self Cite

View full text Add to dashboard Cite

In the present study, the neuroprotective effect of melatonin on arsenite-induced neurotoxicity was investigated in rat primary cultured cortical neurons. Incubation of melatonin prevented arsenite-induced neuronal cell loss in a concentration-dependent manner. Furthermore, melatonin significantly attenuated arsenite-induced elevation in microtubule-associated protein light chain 3 (LC3)-II levels, a biomarker of autophagy. Our fluorescent staining assay showed that melatonin decreased arsenite-induced elevation of co-localized fluorescent puncta of monodansylcadaverine (a specific marker of autophagic vacuoles) and lysotracker red (a specific marker of lysosomes), indicating that melatonin is capable of inhibiting arsenite-induced autophagy and autolysosome formation. Because 3-methyladenine (an autophagic inhibitor) attenuated the arsenite-reduced α-synuclein levels (a protein essential for the neurite outgrowth and synaptic plasticity), melatonin via inhibiting autophagy attenuated the arsenite-reduced α-synuclein levels. At the same time, melatonin ameliorated the arsenite-induced reduction in growth associated protein 43 (a hallmark protein of neurite outgrowth) and discontinuous neurites of rat primary cultured cortical neurons. In addition, melatonin was found to prevent arsenite-induced decreases in cytochrome c oxidase levels (a biomarker of mitochondrial mass) and elevation in co-localized fluorescent puncta of autolysosomes and cytochrome c oxidase. Moreover, melatonin prevented arsenite-induced reduction in peroxisome proliferator-activated receptor gamma co-activator 1 α, a transcriptional co-activator of mitochondrial biosynthesis. Taken together, melatonin may exert its neuroprotective action via inhibiting arsenite-induced autophagy and enhancing mitochondrial biogenesis and thus restoring α-synuclein levels, neuronal integrity, and mitochondrial mass in rat primary cultured cortical neurons.

show abstract

Role of HO-1 in the Arsenite-Induced Neurotoxicity in Primary Cultured Cortical Neurons

Cited by 22 publications

References 34 publications

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-κB, AP-1 and MAPK pathways in human proximal tubular cells

Overexpression of Heme Oxygenase 1 Causes Cognitive Decline and Affects Pathways for Tauopathy in Mice

Melatonin Ameliorates Arsenite-Induced Neurotoxicity: Involvement of Autophagy and Mitochondria

Contact Info

Product

Resources

About