NEUROCHEMICAL RESEARCH
·
2022
·Vol. 48
·期 2
·570-578
·
IF 4.414
Guo Shenglong,Lei Qi,Guo Hena,Yang Qian,Xue Yanli,Chen Ruili
Ferroptosis and neuroinflammation play a crucial role in the pathogenesis of Alzheimer’s disease (AD), and Edaravone (EDA) has been demonstrated to have anti-inflammatory, antioxidant and neuroprotective effects in neurodegenerative diseases. However, the relationship between EDA and ferroptosis in AD is unidentified. This research aimed to elucidate the mechanism of EDA in AD with Aβ 1-42-induced HT22 cells as in vitro cell model. The results showed that EDA could significantly reduce Aβ 1-42 -induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-α, IL-1β and IL-6, prevent the activation of TLR4/NF-κB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in Aβ 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.
研究领域:
神经科学
·
药理学
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细胞生物学
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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
RSC Advances
·
2018
·Vol. 8
·期 31
·17389-17398
·
IF 2.936
Yunquan Zheng,Qisheng Pan,Liuda Mo,Wenyi Zhang,Yunjian Duan,Chengqun Chen,Haijun Chen,Yanghao Guo,Xianai Shi,Jianmin Yang
Alzheimer's disease (AD) is an extremely complex disease, characterized by several pathological features including oxidative stress and amyloid-β (Aβ) aggregation. Blockage of Aβ-induced injury has emerged as a potential therapeutic approach for AD. Our previous efforts resulted in the discovery of Monascus pigment rubropunctatin derivative FZU-H with potential neuroprotective effects. This novel lead compound significantly diminishes toxicity induced by Aβ(1-42) in Neuro-2A cells. Our further mechanism investigation revealed that FZU-H inhibited Aβ(1-42)-induced caspase-3 protein activation and the loss of mitochondrial membrane potential. In addition, treatment of FZU-H was proven to attenuate Aβ(1-42)-induced cell redox imbalance and Tau hyperphosphorylation which caused by okadaic acid in Neuro-2A cells. These results indicated that FZU-H shows promising neuroprotective effects for AD.
研究领域:
神经科学
·
药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2019
·Vol. 458
·期 1
·71-78
·
IF 2.884
Ba Fang,Zhou Yuxin,Zhou Jie,Chen Xueyun
Repetitive transcranial magnetic stimulation (rTMS) is a technique protecting neurons against diverse neurodegenerative disorders by delivering magnetic stimuli into the brain through the intact scalp. In the current study, the protection effect of rTMS on Parkinson’s disease (PD) and the associated mechanism driving the treatment were explored. The PD symptoms were induced using 6-OHDA in mice, and the effect of rTMS of two frequencies (1 Hz and 10 Hz) on the cognitive behaviors and neuron viability was detected. Afterwards, the level of Aβ 1–42 and activity of MKK7-ERK-Fos-APP axis under the administration of rTMS were recorded as well. The intracranial injection of 6-OHDA impaired the cognitive behaviors of the mice in the test of Morris water maze as well as reducing the viability and number of neurons in PD mice. After the treatment of rTMS of both frequencies, the cognitive function of mice was improved and the neuron viability and number were restored in mice brain tissues. The administration of rTMS also increased the cerebrospinal fluid (CSF) level of Aβ 1–42 in PD mice, which was accompanied by the suppressed levels of p-MKK7, p-ERK1/2, p–c-Fos, and APP. Moreover, the effect of rTMS on mice nerve system was all exerted in a frequency-dependent manner. In conclusion, the findings outlined in the current study affirmed the protection effect of rTMS against PD. The anti-PD function of rTMS was associated with the suppression of MKK7-ERK-Fos-APP axis, which subsequently resulted in the increased CSF Aβ 1–42 level and decreased brain Aβ 1–42 level.
研究领域:
神经科学
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药理学
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神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2023
·
IF 11.4
Dingbang Huang,Lixuan Chen,Qiuyi Ji,Yang Xiang,Qin Zhou,Kaiju Chen,Xiaoshun Zhang,Fei Zou,Xingmei Zhang,Zaihua Zhao,Tao Wang,Gang Zheng,Xiaojing Meng
Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ 1-42 -treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ 1-42 , and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ 1-42 -treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.
研究领域:
神经科学
·
毒理学
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神经退行性疾病
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2019
·
IF 3.448
Lingfeng Wang,Zhijun Pu,Mingxin Li,Kaixuan Wang,Lijuan Deng,Wei Chen
Aims Dauricine has been found that has significant neuroprotective effect on Alzheimer's disease (AD), but the mechanism is unclear, so we further investigated the possible mechanism of dauricine on AD. Main methods Cell counting kit-8 (CCK8) was applied to measure the cytotoxicity of dauricine on SH-SY5Y cells that overexpress the Swedish mutant form of human β-amyloid precursor protein (APPsw) and control cells (Neo). We used the Cu 2+ to induce oxidative damage on APPsw cells, then tested the effect of dauricine on the damage and relative factors including reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and superoxide dismutase (SOD) activity. The secretion level of amyloid beta 1–42(Aβ 1 – 42 ), protein expression of apoptosis-related factors and the components of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were determined by western blotting. Aβ 1 – 42 -transgenic Caenorhabditis elegans GMC101 , a model of AD, was applied to evaluate the neuroprotective effect of dauricine through the behavioral experiment and relative anti-oxidative tests. Key findings In vitro, dauricine decreased the secretion level of Aβ 1 – 42 , significantly reduced the level of Cu 2+ -induced ROS, and restored MMP and SOD activity in APPsw cells. Meanwhile, dauricine could suppress the activation of caspase-3 and to upregulate the expression of Bcl-2. Dauricine also regulated the proteins levels of Nrf2, and Kelch-like ECH-associated protein 1 (Keap1) that is necessary for the activation of Nrf2 in APPsw cell. As oxidative stress induced by Aβ or paraquat (PQ), dauricine showed protective effects in the survival experiment of GMC101 worms. Significance Those data revealed that dauricine has the pharmacological activity of anti-oxidative and anti-apoptosis, and shows the potential therapeutic value for 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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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROSCIENCE
·
2023
·
IF 3.3
Lu-Lu Lin,Gui-Jun Song,Hui Zhang,Yan Yin,Shi-Meng Xin,Li Ding,Yu Li
Alzheimer's disease (AD) is a serious neurodegenerative disease characterized by amyloid-β (Aβ) aggregation and neuroinflammation. G-protein-coupled receptor 34 (Gpr34) was found highly expressed in the hippocampus of APP/PS1 mice. However, its role in AD remains unclear. Herein, the role of Gpr34 as well as its molecular mechanism was explored. Data in GSE85162 were analyzed and the differently expressed genes in the hippocampus tissues of APP/PS1 mouse model of AD were subjected to GO, KEGG and GSEA enrichment analyses. APP/PS1 mice were used as an animal model of AD and the cognitive impairment was evaluated by a water maze test. The level of Gpr34 in hippocampus and BV-2 cells as well as the activation of ERK/NF-κB signal was determined by quantitative real-time PCR, western blot or immunofluorescence. Our results showed that, in BV-2 cells exposed to Aβ 1-42 , Gpr34 knockdown decreased the levels of TNF-α, IL-1β, IL-6 and iNOS and suppressed the activation of ERK/NF-κB signal. Moreover, the Gpr34-overexpression-induced activation of ERK/NF-κB signal and up-regulated levels of TNF-α, IL-1β, IL-6 and iNOS were abolished by FR180204, an ERK inhibitor. On the other hand, the in vivo study showed that Gpr34 knockdown ameliorated the cognitive impairment in APP/PS1 mice, decreased the levels of TNF-α, IL-1β and IL-6, the activation of microglia and ERK/NF-κB signal. In conclusion, Gpr34 knockdown relieved cognitive deficits in APP/PS1 mice and suppressed neuroinflammation and microglial activation, maybe via the ERK/NF-κB signal. It is indicated that the high level of Grp34 in hippocampus may contribute to the pathogenesis of AD.
研究领域:
神经科学
·
分子生物学
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ARCHIV DER PHARMAZIE
·
2024
·Vol. 357
·期 5
·2300693
·
IF 4.3
Jingfang Zhai,Canhua Hao,Xiaojing Wang,Yuexing Cao,Yinbo Pan,Min Zhou,Jie Sun,Chuanyou Li
Aβ 1−42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC 50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aβ 1−42 and protect nerve cells, and it can also penetrate the blood–brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl 3 -induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.
研究领域:
药理学
·
神经科学
·
药物设计
·
生物化学
✓ 已验证
DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Yanwen Wang,Miao Cai,Yue Lou,Siran Zhang,Xiaoli Liu
To elucidate the potential molecular mechanisms of ZBTB20-AS1 on ZBTB20 and GSK-3β/Tau signaling pathway in the pathogenesis of Alzheimer's disease (AD), SH-SY5Y cells were obtained for in vitro experiments and AD models were constructed using β-Amyloid 1–42. CCK8 assay was implemented for determining cell viability . Flow cytometry was used for cell apoptosis detection. Dual-luciferase reporter and RNA-RNA pull down assay was employed for elucidating molecular interactions . Immunohistochemistry, RT-qPCR and western blotting were performed for measuring gene expression. The results showed that expression of LncRNA ZBTB20-AS1 was significantly upregulated, while ZBTB20 was downregulated in SH-SY5Y-AD cells. ZBTB20 was the target gene of LncRNA ZBTB20-AS1. Overexpression of ZBTB20 or knockdown of LncRNA ZBTB20-AS1 inhibited SH-SY5Y-AD cells apoptosis and suppressed GSK3β/Tau pathway, and knockdown of ZBTB20-AS1 increased cell viability and decreased apoptosis. In conclusion, overexpression of ZBTB20-AS1 inhibited ZBTB20 expression and promoted GSK-3β expression and Tau phosphorylation, contributing to the development of AD.
研究领域:
神经科学
·
分子生物学
·
细胞生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2021
·
IF 7.376
Wen-Qiao Qiu,Wei Ai,Feng-Dan Zhu,Yue Zhang,Min-Song Guo,Betty Yuen-Kwan Law,Jian-Ming Wu,Vincent Kam-Wai Wong,Yong Tang,Lu Yu,Qi Chen,Chong-Lin Yu,Jian Liu,Da-Lian Qin,Xiao-Gang Zhou,An-Guo Wu
Activation of the NLRP3 inflammasome and its mediated neuroinflammation are implicated in neurodegenerative diseases, while mitophagy negatively regulates NLRP3 inflammasome activation. SHP-2, a protein-tyrosine phosphatase, is critical for NLRP3 inflammasome regulation and inflammatory responses. In this study, we investigated whether triterpenoid saponins in Radix Polygalae inhibit the NLRP3 inflammasome via mitophagy induction. First, we isolated the active fraction (polygala saponins (PSS)) and identified 17 saponins by ultra-performance liquid chromatography coupled with diode-array detection and tandem quadrupole time-of-flight mass spectrometry (UHPLC-DAD-Q/TOF-MS). In microglial BV-2 cells, PSS induced mitophagy as evidenced by increased co-localization of LC3 and mitochondria, as well as an increased number of autophagic vacuoles surrounding the mitochondria. Furthermore, the mechanistic study found that PSS activated the AMPK/mTOR and PINK1/parkin signaling pathways via the upregulation of SHP-2. In Aβ(1-42)-, A53T-α-synuclein-, or Q74-induced BV-2 cells, PSS significantly inhibited NLRP3 inflammasome activation, which was attenuated by bafilomycin A1 (an autophagy inhibitor) and SHP099 (an SHP-2 inhibitor). In addition, the co-localization of LC3 and ASC revealed that PSS promoted the autophagic degradation of the NLRP3 inflammasome. Moreover, PSS decreased apoptosis in conditioned medium-induced PC-12 cells. In APP/PS1 mice, PSS improved cognitive function, ameliorated Aβ pathology, and inhibited neuronal death. Collectively, the present study, for the first time, shows that PSS inhibit the NLRP3 inflammasome via SHP-2-mediated mitophagy in vitro and in vivo, which strongly suggests the therapeutic potential of PSS in various neurodegenerative diseases.
研究领域:
神经科学
·
药理学
·
分子生物学
·
神经退行性疾病
✓ 已验证
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2021
·
IF 5.194
Min Wang,Longji Fang,Tongtong Liu,Xuejie Chen,Yan Zheng,Yilong Zhang,Shiming Chen,Zeng Li
The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase , anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC 50 = 3.08 ± 0.29 μM) and exhibited good anti-neuroinflammatory activity (IC 50 = 2.91 ± 0.47 μM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 μM concentration. Furthermore, possessing significant self-mediated Aβ 1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8 . In the bi-directional transport assay, a8 exhibited a blood–brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.
研究领域:
神经科学
·
药理学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2020
·
IF 5.162
Shuaishuai Xing,Ying Chen,Baichen Xiong,Weixuan Lu,Qi Li,Yuanyuan Wang,Mengxia Jiao,Feng Feng,Yao Chen,Wenyuan Liu,Haopeng Sun
In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schrödinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513–4169 displayed the highest inhibitory activity and selectivity against BChE ( ee AChE IC 50 > 10 μM, eq BChE IC 50 = 3.73 ± 1.90 μM). Molecular dynamic (MD) simulation validated the binding pattern of 2513–4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513–4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513–4169 against toxic Aβ 1 – 42 . In vivo behavioral study further confirmed the great efficacy of 2513–4169 on reversing Aβ 1 – 42 -induced cognitive impairment of mice and clearing the toxic Aβ 1 – 42 in brains. Moreover, 2513–4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513–4169 is a promising lead compound for future optimization to discover anti-AD treating agents.
研究领域:
神经科学
·
药理学
·
药物发现
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
APPLIED BIOCHEMISTRY AND MICROBIOLOGY
·
2023
·Vol. 58
·期 1
·S138
·
IF 0.8
Zhang Q.,Li J.,Sun Y.,Song S.,Li X.,Chen G.
Abstract Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. Neuritic plaques containing amyloid-β protein (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein constitute major neuropathological hallmarks of AD. The neurotoxicity of aggregated Aβ has been implicated as a critical cause in the pathogenesis of AD. The aim of this study was to exam the use of neoagarohexaose (NAH) in the potential treatment of AD effects, using SH-SY5Y neuronal cell line exposed to β-amyloid protein (Aβ 1-42 ). The present study was designed to explore the neuroprotective effects of NAH on neuroblastoma SH-SY5Y cells as a function of dosage. The cells were exposed to Aβ 1-42 with or without NAH (26.7, 53.4, and 106.8 μM) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used for detecting the viability of treated cells. In treated cells, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) were determined using their manufacturer kits. Flow cytometry analysis was used to assess apoptosis, changes in intracellular calcium concentration, and the mitochondrial membrane potential (MMP) after treatment. Additionally, changes in the mechanism of Aβ 1-42 aggregation in the presence of NAH were explored using thioflavin T (ThT) and Congo red (CR) assays. The results showed that incubation with NAH prior to Aβ 1-42 exposure increased cell survival and prevented reactive oxygen species generation. Moreover, NAH decreased the apoptotic rate, inhibited MMP depolarization, reversed the change in intracellular calcium concentration, enhanced the activities of SOD and GSH-Px, and decreased the level of MDA. In addition, the results showed that NAH, which reduced the absorption of the amyloid indicator ThT and CR dyes, was a potent inhibitor of Aβ fibrillogenesis. In conclusion, NAH protects SH-SH5Y cells from Aβ-induced damage by reducing oxidative stress and weakens the spontaneous amyloid formation of Aβ fibrils in vitro and can inhibit the amyloidization of amyloid β protein (Aβ). This study shows that NAH may be a promising anti-AD drug candidate for AD treatment.
研究领域:
神经科学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）