ACTA PHARMACOLOGICA SINICA
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2024
·
IF 6.9
Zhang Chen-chun,Li Yuan,Jiang Chang-you,Le Qiu-min,Liu Xing,Ma Lan,Wang Fei-fei
The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H 2 O 2 inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H 2 O 2 -induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H 2 O 2 -treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H 2 O 2 -induced apoptosis of N2a cells.
研究领域:
细胞生物学
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分子生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2019
·Vol. 20
·期 3
·487
·
IF 4.183
Xuexia Li,Xiubo Du,Jiazuan Ni
Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn2+is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn2+on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn2+via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 104M−1). Zn2+accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn2+-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn2+-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn2+-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn2+-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn2+can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn2+dyshomeostasis and the etiology of Alzheimer’s disease.Keywords:tau-R3;Zn2+;aggregation;neurotoxicity
研究领域:
神经科学
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分子生物学
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病理学
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DOI
PubMed
高影响因子
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
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2017
·Vol. 72
·期 6
·1635-1645
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IF 5.071
Dai Chongshan,Ciccotosto Giuseppe D.,Cappai Roberto,Wang Yang,Tang Shusheng,Xiao Xilong,Velkov Tony
Background: Neurotoxicity is an adverse effect patients experience during colistin therapy. The development of effective neuroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy. The present study investigates the neuroprotective effect of the synergistic tetracycline antibiotic minocycline against colistin-induced neurotoxicity.Methods: The impact of minocycline pretreatment on colistin-induced apoptosis, caspase activation, oxidative stress and mitochondrial dysfunction were investigated using cultured mouse neuroblastoma-2a (N2a) and primary cortical neuronal cells.Results: Colistin-induced neurotoxicity in mouse N2a and primary cortical cells gives rise to the generation of reactive oxygen species (ROS) and subsequent cell death via apoptosis. Pretreatment of the neuronal cells with minocycline at 5, 10 and 20 μM for 2 h prior to colistin (200 μM) exposure (24 h), had an neuroprotective effect by significantly decreasing intracellular ROS production and by upregulating the activities of the anti-ROS enzymes superoxide dismutase and catalase. Minocycline pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation and subsequent apoptosis. Immunohistochemical imaging studies revealed colistin accumulates within the dendrite projections and cell body of primary cortical neuronal cells.Conclusions: To our knowledge, this is first study demonstrating the protective effect of minocycline on colistin-induced neurotoxicity by scavenging of ROS and suppression of apoptosis. Our study highlights that co-administration of minocycline kills two birds with one stone: in addition to its synergistic antimicrobial activity, minocycline could potentially ameliorate unwanted neurotoxicity in patients undergoing polymyxin therapy.
研究领域:
药理学
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神经科学
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毒理学
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抗菌化疗
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 9
·2201-2213
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IF 4.109
Qi Xiong,Xiang Tian,Congyue Xu,Baomiao Ma,Wei Liu,Binlian Sun,Qin Ru,Xiji Shu
PM 2.5 exposure has been demonstrated to correlate with neurological disorders recently. Ferroptosis is recognized as a newly found programmed form of cell death associated with neurodegenerative diseases, while glutathione peroxidase 4 (GPX4) is a key regulator of ferroptosis. However, the relationship between PM 2.5 -induced neurotoxicity and ferroptosis is still unclear. The current study aims to investigate if ferroptosis is involved in neurotoxicity post PM 2.5 exposure and its underlying mechanism. The PM 2.5 -treated neuronal Neuro-2a (N2A) and SH-SY5Y cells were applied to the current study. The results showed that PM 2.5 significantly increased the neuronal cell death, yet the ferroptosis antagonist Ferrostain-1 (Fer-1) markedly decreased the cell death induced by PM 2.5 . Western blot further confirmed that ferroptosis was triggered post PM 2.5 treatment in N2A cells by decreasing expressions of GPX4 and ferritin heavy chain (FTH), as well as enhancing expressions of ferritin light chain (FTL) and transferrin receptor protein (TFRC). Meanwhile, PM 2.5 treatment augmented neuronal oxidative damage and mitochondrial dysfunction. The bioinformatic analysis indicated that CREB could be the regulator of GPX4, and our results showed that ERK/CREB pathway was down-regulated in N2A cells post PM 2.5 treatment. The addition of ERK1/2 agonist post PM 2.5 treatment significantly inhibit ferroptosis via increasing the expression of GPX4. Taken together, the present study demonstrated that PM 2.5 -induced ferroptosis via inhibiting ERK/CREB pathway, and these findings will advance our knowledge of PM 2.5 -induced cytotoxicity in the nervous system.
研究领域:
神经科学
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毒理学
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细胞生物学
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环境健康
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DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2024
·
IF 4.8
Lu Wang,Yingjuan Wei,Zhenzhou Sun,Wenya Tai,Hui Li,Yaling Yin,Lin‐Hua Jiang,Jian‐Zhi Wang
Background Oxidative stress is a well‐known pathological factor driving neuronal loss and age‐related neurodegenerative diseases. Melatonin, coenzyme Q10 and lecithin are three common nutrients with an antioxidative capacity. Here, we examined the effectiveness of them administrated individually and in combination in protecting against oxidative stress‐induced neuronal death in vitro, and neurodegenerative conditions such as Alzheimer's disease and associated deficits in vivo. Methods Mouse neuroblastoma Neuro‐2a (N2a) cells were exposed with H 2 O 2 for 6 h, and subsequently treated with melatonin, coenzyme Q10, and lecithin alone or in combination for further 24 h. Cell viability was assessed using the CCK ‐8 assay. Eight‐week‐old male mice were intraperitoneally injected with D‐(+)‐galactose for 10 weeks and administrated with melatonin, coenzyme Q10 , lecithin, or in combination for 5 weeks starting from the sixth week, followed by behavioral tests to assess the effectiveness in mitigating neurological deficits, and biochemical assays to explore the underlying mechanisms. Results Exposure to H 2 O 2 significantly reduced the viability of N2a cells and increased oxidative stress and tau phosphorylation, all of which were alleviated by treatment with melatonin, coenzyme Q10, lecithin alone, and, most noticeably, by combined treatment. Administration of mice with D‐(+)‐galactose‐induced oxidative stress and tau phosphorylation, brain aging, impairments in learning and memory, anxiety‐ and depression‐like behaviors, and such detrimental effects were mitigated by melatonin, coenzyme Q10, lecithin alone, and, most consistently, by combined treatment. Conclusions These results suggest that targeting oxidative stress via supplementation of antioxidant nutrients, particularly in combination, is a better strategy to alleviate oxidative stress‐mediated neuronal loss and brain dysfunction due to age‐related neurodegenerative conditions.
研究领域:
神经科学
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药理学
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细胞生物学
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衰老研究
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产品关联
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
·
2018
·
IF 4.936
Pan Liu,Xiao Chen,Haizhe Zhou,Liqun Wang,Zaijun Zhang,Xiaohu Ren,Feiqi Zhu,Yi Guo,Xinfeng Huang,Jianjun Liu,Peter S. Spencer,Xifei Yang
Alzheimer’s disease (AD), the most common neurodegenerative disease, has no effective treatment. Dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid isolated from the root of Menispermum dauricum DC, reportedly has neuroprotective effects in cerebral ischemia. Here, we investigated the effects of DAU on N2a cells stably transfected with Swedish mutant amyloid precursor protein (N2a/APP), an AD-like cell model. ELISA and Western blot analysis revealed that DAU inhibited APP processing and reduced Aβ accumulation. In addition, DAU ameliorated tau hyperphosphorylation via PP2A, p35/25, and CDK5 pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by DAU was also validated in HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis revealed 85 differentially expressed proteins in the lysates between the wild-type N2a cells (N2a/WT) and the N2a/APP cells in the presence or absence of DAU; these were classified into 6 main categories according to their functions: endoplasmic reticulum (ER) stress-associated proteins, oxidative stress-associated proteins, cytoskeleton proteins, molecular chaperones, mitochondrial respiration and metabolism-related proteins, and signaling proteins. Taken together, we demonstrated that DAU treatment reduces AD-like pathology, thereby suggesting that DAU has potential therapeutic utility in AD.
研究领域:
神经科学
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药理学
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细胞生物学
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蛋白质组学
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DOI
PubMed
高影响因子
JOURNAL OF ALZHEIMERS DISEASE
·
2018
·Vol. 64
·期 1
·309-322
·
IF 3.476
Du Yehong,Fu Min,Wang Yu Tian,Dong Zhifang
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the deposition of amyloid-β peptides (Aβ). Aβ accumulation leads to the formation of neurofibrillary tangles, inflammation, axonal injury, synapse loss, and neuronal apoptosis. Thus, reducing Aβ levels should exert a neuroprotective effect against AD. Ginsenoside Rf, an extract from Panax notoginseng, has potent anti-fatigue, anti-nociception, anti-oxidation, and anti-inflammation properties. However, it is unclear whether ginsenoside Rf is effective in the treatment of AD. Here, we reported that ginsenoside Rf could significantly attenuate Aβ-induced apoptosis in N2A cells, as reflected by a dramatic increase in mitochondrial membrane potential and decrease in Ca2 + concentration, reactive oxygen species, and active caspase-3 expression. Meanwhile, ginsenoside Rf could alleviate the Aβ-induced inflammation reaction, such as the decrease of interferon-gamma (IFN-γ) and active caspase-1 expression and the increase of interleukin-13. Furthermore, we also found that Rf is able to accelerate Aβ clearance and subsequently reduces Aβ level in N2A cells stably transfected with human Swedish mutant APP695 (N2A-APP). More importantly, daily Rf treatment (20 mg/kg, i.p.) throughout the experiment dramatically improved spatial learning and memory in Aβ42-induced mouse model of AD. Taken together, these results indicate that ginsenoside Rf may decrease Aβ-induced neurotoxicity and memory decline via anti-inflammatory response during AD development, suggesting that Rf may be a potential therapeutic agent for treating AD.
研究领域:
神经科学
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药理学
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分子生物学
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2016
·Vol. 55
·期 1
·421-434
·
IF 5.397
Dai Chongshan,Ciccotosto Giuseppe D.,Cappai Roberto,Tang Shusheng,Li Daowen,Xie Sanlei,Xiao Xilong,Velkov Tony
Neurotoxicity is an unwanted side-effect seen in patients receiving therapy with the “last-line” polymyxin antibiotics. This is the first study to show that colistin-induced neurotoxicity in neuroblastoma-2a (N2a) cells gives rise to an inflammatory response involving the IL-1β/p-IκB-α/NF-κB pathway. Pretreatment with curcumin at 5, 10, and 20 μM for 2 h prior to colistin (200 μM) exposure for 24 h, produced an anti-inflammatory effect by significantly down-regulating the expression of the pro-inflammatory mediators cyclooxygenase-2 (COX-2), phosphorylation of the inhibitor of nuclear factor-kappa B (NF-κB) (p-IκB)-α, and concomitantly NF-κB levels. Moreover, curcumin significantly decreased intracellular reactive oxygen species (ROS) production and increased the activities of the anti-ROS enzymes superoxide dismutase, catalase, and the intracellular levels of glutathione. Curcumin pretreatment also protected the cells from colistin-induced mitochondrial dysfunction, caspase activation, and subsequent apoptosis. Overall, our findings demonstrate for the first time, a potential role for curcumin for treating polymyxin-induced neurotoxicity through the modulation of NF-κB signaling and its potent anti-oxidative and anti-apoptotic effects.
研究领域:
药理学
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神经科学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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