Colistin-Induced Apoptosis of Neuroblastoma-2a Cells Involves the Generation of Reactive Oxygen Species, Mitochondrial Dysfunction, and Autophagy

Dai, Chongshan; Tang, Shusheng; Velkov, Tony; Xiao, Xilong

doi:10.1007/s12035-015-9396-7

Cited by 46 publications

(60 citation statements)

References 49 publications

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“…Associated with colistin therapy, nephrotoxicity and neurotoxicity remain poorly characterized adverse effects. In terms of the relationship of colistininduced neurotoxicity and p53, Dai et al reported that the gene expression of p53, Bax, and caspase-8 significantly increased in the model of colistin-induced neurotoxicity using the mouse neuroblastoma 2a (N2a) cell line (all P values of Ͻ 0.01) (7). A recent study has shown that p53 plays a pathological role in the progression of colistin-induced apoptosis in PC-12 cells (27).…”

Section: Discussionmentioning

confidence: 99%

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p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

Zhang

Xie

Chen

et al. 2016

Antimicrob Agents Chemother

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Colistin is used as a last-line treatment option against multidrug-resistant (MDR) Gram-negative bacteria, which can cause life-threatening infections (1-3). However, its clinical use is limited by potential nephrotoxicity and neurotoxicity (4, 5), the mechanisms of which are still unknown. It has been discovered in a mouse model and neuroblastoma 2a cells that autophagy is involved in colistin-induced nephrotoxicity (6, 7). Apoptosis and autophagy are two common forms of cell death (8, 9). Apoptosis is a prevalent form of programmed cell death (PCD) in multicellular organisms, which is the culmination of coordinately regulated intrinsic and extrinsic pathways involving major protein families, including the Bcl-2 family and caspases (10). Autophagy is a catabolic process of degradation and recycling of dysfunctional cellular components by lysosomal systems (11-13). Autophagy participates in organelle turnover and in the bioenergetic management of starvation stresses, pathogen infection, and hypoxia in order to maintain cellular homeostasis (14,15). A number of stimuli can induce autophagy, apoptosis, or both, and recent studies suggest that autophagy delays or promotes apoptosis under certain conditions (16,17). For example, treatment of cells with pemetrexed and simvastatin promoted autophagy and inhibited apoptosis (16), while oridonin phosphate induced autophagy and enhanced apoptotic cell death (17). However, the precise mechanisms that determine autophagy, apoptosis, and their interaction remain to be elucidated.A number of studies in tumor cells (e.g., hepatocellular carcinoma and OVCAR-3 cancer cells) have shown that the p53 tumor suppressor protein, which is an important cellular stress sensor, can trigger cell cycle arrest and apoptosis and also regulate autophagy (18)(19)(20). Activation of p53 in response to a death stimulus leads to the transcription of genes involved in apoptosis, including PUMA (p53 upregulated modulator of apoptosis), AMPK (AMPactivated protein kinase), and Bax in the nucleus. These in turn activate the intrinsic mitochondrial apoptotic pathway in the cytoplasm via inhibition of the antiapoptotic proteins Bcl-2 and Bcl-X L (19,20). In addition, p53 appears to play a dual role in the control of autophagy. At basal levels, p53 has an inhibitory effect, and its activation initiates the autophagic process (21,22). Thus, p53-induced autophagy may either constitute a physiological cellular defense response (23) or contribute to cell death (24). The cellular localization of p53 appears to determine whether a cell will undergo autophagy or apoptosis. Nuclear p53 induces and regulates autophagy, while cytoplasmic p53 inhibits autophagy (22,25).

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Section: Discussionmentioning

confidence: 99%

“…However, its clinical use is limited by potential nephrotoxicity and neurotoxicity (4,5), the mechanisms of which are still unknown. It has been discovered in a mouse model and neuroblastoma 2a cells that autophagy is involved in colistin-induced nephrotoxicity (6,7). Apoptosis and autophagy are two common forms of cell death (8,9).…”

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confidence: 99%

p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

Zhang

Xie

Chen

et al. 2016

Antimicrob Agents Chemother

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“…All reactions were conducted in triplicate. β-actin was used as an internal control, and fold change in gene expression was calculated using the threshold cycle method (2 −ΔΔ CT ) [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

Curcumin Attenuates on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Modulation of the Nrf2/HO-1 and TGF-β1/Smad3 Pathway

et al. 2018

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This study aimed to investigate the protective effect of curcumin against carbon tetrachloride (CCl4)-induced acute liver injury in a mouse model, and to explain the underlying mechanism. Curcumin at doses of 50, 100 and 200 mg/kg/day were administered orally once daily for seven days prior to CCl4 exposure. At 24 h, curcumin-attenuated CCl4 induced elevated serum transaminase activities and histopathological damage in the mouse’s liver. Curcumin pre-treatment at 50, 100 and 200 mg/kg significantly ameliorated CCl4-induced oxidative stress, characterized by decreased malondialdehyde (MDA) formations, and increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) content, followed by a decrease in caspase-9 and -3 activities. Curcumin pre-treatment significantly decreased CCl4-induced inflammation. Furthermore, curcumin pre-treatment significantly down-regulated the expression of TGF-β1 and Smad3 mRNAs (both p < 0.01), and up-regulated the expression of nuclear-factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both p < 0.01) in the liver. Inhibition of HO-1 attenuated the protective effect of curcumin on CCl4-induced acute liver injury. Given these outcomes, curcumin could protect against CCl4-induced acute liver injury by inhibiting oxidative stress and inflammation, which may partly involve the activation of Nrf2/HO-1 and inhibition of TGF-β1/Smad3 pathways.

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“…Cell viability was examined by using MTT method according to the previous study [ 49 ]. In brief, cells were (2–5 × 10 4 ) seed into 96-well plates.…”

Section: Methodsmentioning

confidence: 99%

GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways

Dai

Yang

et al. 2017

Molecules

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Olaquindox, a quinoxaline 1,4-dioxide derivative, is widely used as a feed additive in many countries. The potential genotoxicity of olaquindox, hence, is of concern. However, the proper mechanism of toxicity was unclear. The aim of the present study was to investigate the effect of growth arrest and DNA damage 45 alpha (GADD45a) on olaquindox-induced DNA damage and cell cycle arrest in HepG2 cells. The results showed that olaquindox could induce reactive oxygen species (ROS)-mediated DNA damage and S-phase arrest, where increases of GADD45a, cyclin A, Cdk 2, p21 and p53 protein expression, decrease of cyclin D1 and the activation of phosphorylation-c-Jun N-terminal kinases (p-JNK), phosphorylation-p38 (p-p38) and phosphorylation-extracellular signal-regulated kinases (p-ERK) were involved. However, GADD45a knockdown cells treated with olaquindox could significantly decrease cell viability, exacerbate DNA damage and increase S-phase arrest, associated with the marked activation of p-JNK, p-p38, but not p-ERK. Furthermore, SP600125 and SB203580 aggravated olaquindox-induced DNA damage and S-phase arrest, suppressed the expression of GADD45a. Taken together, these findings revealed that GADD45a played a protective role in olaquindox treatment and JNK/p38 pathways may partly contribute to GADD45a regulated olaquindox-induced DNA damage and S-phase arrest. Our findings increase the understanding on the molecular mechanisms of olaquindox.

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Colistin-Induced Apoptosis of Neuroblastoma-2a Cells Involves the Generation of Reactive Oxygen Species, Mitochondrial Dysfunction, and Autophagy

Cited by 46 publications

References 49 publications

p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

p53 Mediates Colistin-Induced Autophagy and Apoptosis in PC-12 Cells

Curcumin Attenuates on Carbon Tetrachloride-Induced Acute Liver Injury in Mice via Modulation of the Nrf2/HO-1 and TGF-β1/Smad3 Pathway

GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways

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