Pivotal roles of p53 transcription-dependent and -independent pathways in manganese-induced mitochondrial dysfunction and neuronal apoptosis

Wan, Chunhua; Ma, Xa; Shi, Shangshi; Zhao, Jianya; Nie, Xiaobing; Han, Jingling; Xiao, Jing; Wang, Xiaoke; Jiang, Shengyang; Jiang, Junkang

doi:10.1016/j.taap.2014.10.013

Cited by 45 publications

(20 citation statements)

References 47 publications

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“…Mitochondria are the main sites for ROS production, and the structural or functional abnormalities destroy tissue homeostasis and induce tissue damage . However, the association between skin diseases and mitochondrial energy metabolism dysfunction is not known well.…”

Section: Discussionmentioning

confidence: 99%

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Hua

et al. 2019

Experimental Dermatology

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Hydrogen sulphide (H2S) is an important gasotransmitter with several physiological functions. However, the roles and the detailed mechanisms of H2S on skin wound healing are not known well. In the present study, 129S1/SvImJ mice were intraperitoneally injected with NaHS (50 μmol/kg/d) for 2 weeks. Then, a round wound of 6 mm diameter with depth into the dermis was made. The skin wound area, blood perfusion, superoxide production, malondialdehyde (MDA) levels, total antioxidant capacity (T‐AOC), expression of vascular endothelial growth factor (VEGF), dynamin‐related protein 1 (DRP1) and optic atrophy 1 (OPA1) were measured. After NaHS (50 μmol/L) pre‐administration for 4 hours, cell migration rate, DRP1, OPA1 and α–smooth muscle actin (α‐SMA) expression, superoxide production and mitochondrial membrane potential in primary skin fibroblasts were measured. Tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in human keratinocytes were also measured. The results showed that NaHS pretreatment significantly accelerated wound healing and improved blood flow in the wound after operation. NaHS increased VEGF expression in the wound and promoted tube formation in HUVECs. Meanwhile, NaHS attenuated reactive oxygen species (ROS) production, suppressed MDA level but restored T‐AOC in the wound. NaHS also promoted skin fibroblasts migration and α‐SMA expression after scratch. Moreover, NaHS alleviated ROS, increased mitochondrial membrane potential, decreased DRP1 but enhanced OPA1 expression in skin fibroblasts after scratch. NaHS also accelerated human keratinocytes migration after scratch. Taken together, exogenous H2S supplementary accelerated the skin wound healing, which might be related to oxidative stress inhibition and VEGF enhancement.

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Section: Discussionmentioning

confidence: 99%

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Hua

et al. 2019

Experimental Dermatology

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“…Transcription factors’ localization, such as NF-κB and NF - E2 - related factor 2 (Nrf2), is affected [43, 44]. Of particular interest, Mn-induced p53 phosphorylation, as well as upregulation of p53 levels, have been shown to be important events in cellular response to Mn exposure both in vivo and in vitro, possibly contributing to neuronal apoptosis [31, 45–47]. Endoplasmic reticulum (ER) stress is another factor that may lead to Mn-induced apoptosis [48].…”

Section: Introductionmentioning

confidence: 99%

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

Peres

Schettinger

Chen

et al. 2016

BMC Pharmacol Toxicol

291

183

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Manganese (Mn) is an essential heavy metal. However, Mn’s nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson’s disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

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“…Additionally, epigenetic mechanisms, such as DNA hypermethylation, have been suggested to account for ΔNp73 transcriptional repression (Lai et al, 2014). Mn exposure induces DNA damage via oxidative stress (Oikawa et al, 2006; Stephenson et al, 2013) and upregulates p53 (Wan et al, 2014). Furthermore, genotoxic stress has been shown to selectively degrade ΔNp73 via the antizyme AZ1 (Dulloo et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, caspase-3 has been shown to cleave p73 (Sayan et al, 2008). Mn exposure induces mitochondria-mediated apoptosis in neurons, which is partially facilitated by p53 (Wan et al, 2014), and ΔNp73 antagonizes the functional p53 by regulating the expression of anti-apoptotic molecules such as Bcl-xL and Mcl-1 (Basu and Haldar, 1998; Grob et al, 2001; Huttinger-Kirchhof et al, 2006; Melino et al, 2002). However, the cellular and molecular mechanisms underlying Mn-induced neurotoxicity still have not been delineated.…”

Section: Introductionmentioning

confidence: 99%

p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity

et al. 2017

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Chronic exposure to elevated levels of manganese (Mn) has been linked to a Parkinsonian-like movement disorder, resulting from dysfunction of the extrapyramidal motor system within the basal ganglia. However, the exact cellular and molecular mechanisms of Mn-induced neurotoxicity remain elusive. In this study, we treated C57/BL6J mice with 30 mg/kg Mn via oral gavage for 30 days. Interestingly, in nigral tissues of Mn-exposed mice, we found a significant downregulation of the truncated isoform of p73 protein at the N-terminus (ΔNp73). To further determine the functional role of Mn-induced p73 downregulation in Mn neurotoxicity, we examined the interrelationship between the effect of Mn on p73 gene expression and apoptotic cell death in an N27 dopaminergic neuronal model. Consistent with our animal study, a 300 μM Mn treatment significantly suppressed p73 mRNA expression in N27 dopaminergic cells. We further determined that protein levels of the ΔNp73 isoform was also reduced in Mn-treated N27 cells and primary striatal cultures. Furthermore, overexpression of ΔNp73 conferred modest cellular protection against Mn-induced neurotoxicity. Taken together, our results demonstrate that Mn exposure downregulates p73 gene expression resulting in enhanced susceptibility to apoptotic cell death. Thus, further characterization of the cellular mechanism underlying p73 gene downregulation will improve our understanding of the molecular underpinnings of Mn neurotoxicity.

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Pivotal roles of p53 transcription-dependent and -independent pathways in manganese-induced mitochondrial dysfunction and neuronal apoptosis

Cited by 45 publications

References 47 publications

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

Exogenous hydrogen sulphide supplement accelerates skin wound healing via oxidative stress inhibition and vascular endothelial growth factor enhancement

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity

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