Antioxidants
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2021
·Vol. 10
·期 4
·529
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IF 6.313
Hao Wu,Xi Liu,Ze-Yu Gao,Ming Lin,Xin Zhao,Yi Sun,Xiao-Ping Pu
Neuroinflammation, oxidative stress, and mitochondrial dysfunction are all important pathogenic mechanisms underlying motor dysfunction and dopaminergic neuronal damage observed in patients with Parkinson’s disease (PD). However, despite extensive efforts, targeting inflammation and oxidative stress using various approaches has not led to meaningful clinical outcomes, and mitochondrial enhancers have also failed to convincingly achieve disease-modifying effects. We tested our hypothesis that treatment approaches in PD should simultaneously reduce neuroinflammation, oxidative stress, and improve alterations in neuronal energy metabolism using the flavonoid icaritin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Using matrix-assisted laser desorption/ionization–mass spectrometry imaging (MALDI-MSI), coupled with biochemical analyses and behavioral tests, we demonstrate that icaritin improves PD by attenuating the the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activity and stabilizing mitochondrial function, based on our extensive analyses showing the inhibition of NLRP3 inflammasome, reduction of NLRP3-mediated IL-1β secretion, and improvements in the levels of antioxidant molecules. Our data also indicated that icaritin stabilized the levels of proteins related to mitochondrial function, such as voltage-dependent anion channel (VDAC) and ATP synthase subunit beta (ATP5B), as well as those of molecules related to energy metabolism, such as ATP and ADP, ultimately improving mitochondrial dysfunction. By employing molecular docking, we also discovered that icaritin can interact with NLRP3, VDAC, ATP5B, and several blood–brain barrier (BBB)-related proteins. These data provide insights into the promising therapeutic potential of icaritin in PD.Keywords:icaritin;Parkinson’s disease;1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;inflammation;oxidative stress;mitochondrial disfunction
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
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产品关联
DOI
PubMed
高影响因子
Sensors and Actuators Reports
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2022
·
IF 0
Chuyue Tang,Zhuo Zou,Taotao Liang,Chengsong Yuan,Jiechang Gao,Kanglai Tang,Chang Ming Li
Dopamine plays a critical role in some fatal diseases including Parkinson's disease, schizophrenia, Tourette syndrome and HIV infection studies but its detection sensitivity demands further improvement. Aptamer-based biosensor has good selectivity to detect biologically active substances; however, it is very challenging to achieve high sensitivities for practical applications. Here an electrochemical biosensor is constructed by hollow carbon spheres, aptamer and methylene blue (MB) to monitor dopamine released from Parkinson's disease model (SH-SY5Y) cells with a low detection limit, wide detection range, high sensitivity and good selectivity for much better performance than reported aptamer sensors. Investigation discovers that MB intercalation in aptamers can offer two sites to absorb two dopamine through π-π interaction instead of one DA absorption on an aptamer alone, thereby doubling the detection sensitivity. The sensor was further used to monitor dopamine released from SH-SY5Y cells, clearly confirming the effect of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine on dopamine synthesis in SH-SY5Y cells and demonstrating the great potential of the sensor in real-time detect dopamine released from living cells. This work renders a new avenue to amplify the detection sensitivity by intercalating redox small molecule to increase the aptamer reaction sites while bridging the interfacial electron transfer.
研究领域:
分析化学
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神经科学
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生物医学工程
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DOI
CELLULAR SIGNALLING
·
2024
·
IF 4.4
Wentao Hu,Menghan Wang,Guifang Sun,Limin Zhang,Hong Lu
Parkinson's disease (PD) is a gradually debilitating neurodegenerative syndrome. Here, we analyzed GSE7621 chip data obtained from the Gene Expression Omnibus (GEO) database to explore the pathogenesis of PD. Early B Cell Factor 3 (EBF3), a member of the highly evolutionarily conserved EBF-transcription factor family, is involved in neuronal development. EBF3 expression is low in the substantia nigra of patients with PD. However, whether EBF3 is implicated in dopaminergic neuron death during PD has not yet been investigated. Therefore, we aimed to reveal the potential anti-apoptotic effect and molecular mechanism of EBF3 in PD. We established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model in vivo and a 1-methyl-4-phenylpyridine (MPP + )-induced SH-SY5Y cell model in vitro . EBF3 was downregulated in the substantia nigra of PD mice and SH-SY5Y cells treated with MPP + , and the m6A methylation modification level was low. Fat mass and obesity-associated protein (FTO) siRNA upregulated m6A methylation modification of EBF3 and extended the EBF3 mRNA half-life. Functionally, as demonstrated by the results of the open-field test, pole test and gait analysis, EBF3 overexpression ameliorated MPTP-induced behavioral disorder. Further, EBF3 overexpression suppressed neuronal apoptosis in vivo , as evidenced by decreased TUNEL + cells, and the increased activation of caspase-3 and caspase-9. Similar results were obtained in vitro , as reflected by increased cell viability, decreased LDH activity and restored mitochondrial function, collectively protecting SH-SY5Y cells from MPP + -induced apoptosis. Mechanistically, the results of luciferase reporter, ch-IP and DNA pull-down assays confirmed that, as a transcription factor, EBF3 bound to the promoter of CNTNAP4 (a protein associated with neuronal differentiation) and directly regulated CNTNAP4 transcription. Strikingly, CNTNAP4 knockdown markedly abolished the effect of EBF3 on cell apoptosis, thus aggravating PD. In conclusion, the low level of m6A methylation modification may contribute to the low expression of EBF3 during PD. Additionally, EBF3 attenuates PD by activating CNTNAP4 transcription, suggesting that EBF3 may be a novel therapeutic target in PD.
研究领域:
神经科学
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分子生物学
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转化医学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Qing Zheng,Hanghang Liu,Hao Zhang,Yaobao Han,Jiaxin Yuan,Tingting Wang,Yifan Gao,Zhen Li
Mitochondrial dysfunction of neurons is the core pathogenesis of incurable Parkinson's disease (PD). It is crucial to ameliorate the mitochondrial dysfunction of neurons for boosting the therapy of PD. Herein, the remarkable promotion of mitochondrial biogenesis to ameliorate mitochondrial dysfunction of neurons and improve the treatment of PD by using mitochondria-targeted biomimetic nanoparticles, which are Cu 2- x Se-based nanoparticles functionalized with curcumin and wrapped with DSPE-PEG 2000 -TPP-modified macrophage membrane (denoted as CSCCT NPs), is reported. These nanoparticles can efficiently target mitochondria of damaged neurons in an inflammatory environment, and mediate the signaling pathway of NAD + /SIRT1/PGC-1 α /PPAR γ /NRF1/TFAM to alleviate 1-methyl-4-phenylpyridinium (MPP + )-induced neuronal toxicity. They can reduce the mitochondrial reactive oxygen species, restore mitochondrial membrane potential (MMP), protect the integrity of mitochondrial respiratory chain, and ameliorate mitochondrial dysfunction via promoting mitochondrial biogenesis, which synergistically improve the motor disorders and anxiety behavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. This study demonstrates that targeting mitochondrial biogenesis to ameliorate mitochondrial dysfunction has a great potential in the treatment of PD and mitochondria-related diseases.
研究领域:
神经科学
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纳米技术
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药理学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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