SENSORS AND ACTUATORS B-CHEMICAL
·
2018
·
IF 5.667
Li Zou,Xinghui Li,Tingting Li,Liansheng Ling
We have constructed a novel colorimetric sensing platform for quantitative detection of acetylcholinesterase (AChE) activity and its inhibitor (donepezil) in rat blood, which integrates the signal amplification of DNAzyme and hybridization chain reaction (HCR) with the assembly of gold nanoparticles (AuNPs). Herein, in the presence of AChE and its substrate acetylthiocholine (ATCh), the sensing system exhibits a dramatic decrease in absorbance at 522 nm, where AChE hydrolyzes ATCh into thiocholine, the resulting thiols capture Cu 2+ from DNAzyme, and then the substrate strand of DNAzyme acts as an initiator to trigger HCR process. The HCR products can induce the assembly of AuNPs via DNA hybridization, accompanying by a sharp color-change from red to blue. When donepezil is added, the enzymatic activity of AChE is suppressed, resulting in an increase in the absorbance at 522 nm. Under optimal conditions, the colorimetric sensing platform shows sensitive responses to AChE and donepezil in the range of 0.02–1.5 mU mL −1 and 0.5–100 nM, respectively. The detection limits of AChE and donepezil are as low as 5 μU mL −1 and 0.5 nM, respectively. Owing to high sensitivity of the proposed method, various nonspecific interactions can be eliminated with a sufficient dilution, indicating that our strategy has great potential for practical application in neurobiology and pharmacology fields.
研究领域:
生物化学
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分子诊断
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药物筛选
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DOI
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2024
·
IF 3.7
Jiannan Zheng,Guode Zhao,Zixia Hu,Chenyang Jia,Weiwei Li,Ying Peng,Jiang Zheng
Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer’s disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP. The structure of 6-O-desmethyl DNP (M1), the oxidative metabolite of DNP, was characterized by chemical synthesis, LC–MS/MS, and nuclear magnetic resonance. A reactive quinone methide resulting from the metabolism of DNP was captured by glutathione (GSH) fortified in liver microsomal incubations after exposure to DNP, and the resulting GSH conjugate (M2) was detected in the bile of rats receiving DNP. Recombinant human P450 enzyme incubation studies demonstrated that CYP3A4 was the principal enzyme responsible for the production of M1 and M2. The generation of M2 declined in rat primary hepatocytes pretreated with ketoconazole, an inhibitor of CYP3A4, which also decreased the vulnerability of rat primary hepatocytes to DNP-caused cytotoxicity. These findings suggest that the quinone methide metabolite may contribute to the cytotoxicity and hepatotoxicity caused by the DNP.
研究领域:
药理学
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毒理学
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医学
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DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2022
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IF 6.978
Ze Qiang Zhao,Ling Liang,Liu Fu Hu,Yu Ting He,Li Yue Jing,Yue Liu,Bo Zhi Chen,Xin Dong Guo
To alleviate the dilemma of drug administration in Alzheimer’s disease (AD) patients, it is of great significance to develop a new drug delivery system. In this study, a subcutaneously implanted microneedle (MN) device with a swellable gelatin methacryloyl (GelMA) needle body and a dissolvable polyvinyl alcohol (PVA) backing layer was designed. The backing layer quickly dissolved once the MN was introduced into the subcutaneous, and the hydrogel needles were implanted in the subcutaneous to enable prolonged drug release. Compared with oral administration, the MN system offers the benefits of a high administration rate, a fast onset of effect, and a longer duration of action. By detecting the concentration of acetylcholine (ACH) and Aβ 1–42, it was found that MN administration exhibited a stronger therapeutic effect. The biological safety of the MN system was also assessed, and no obvious signs of hemolysis, cytotoxicity, and inflammatory reaction were observed. Together, these findings suggested that the MN system is a convenient, efficient, and safe method of delivering donepezil hydrochloride (DPH) and may provide AD patients with a novel medicine administration option.
研究领域:
药学
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神经科学
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生物医学工程
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药物递送系统
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DOI
PubMed
高影响因子
LUMINESCENCE
·
2020
·Vol. 36
·期 1
·35-44
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IF 1.855
Hui Guo,Jiawen Xie,Tancong Liao,Xun Tuo
Donepezil (DNP) is one of approved drugs to treat Alzheimer's disease (AD). However, the potential effect of DNP on DNA is still unclear. Therefore, the interaction of DNP with calf thymus DNA (DNA) was studied in vitro using spectroscopic and molecular docking methods. Steady-state and transient fluorescence experiments showed that there was a clear binding interaction between DNP and DNA, resulting from DNP fluorescence being quenched using DNA. DNP and DNA have one binding site between them, and the binding constant (K b ) was 0.78 × 10 4 L·mol −1 at 298 K. In this binding process, hydrophobic force was the main interaction force, because enthalpy change (ΔH) and entropy change (ΔS) of DNP–DNA were 67.92 kJ·mol −1 and 302.96 J·mol −1 ·K −1 , respectively. DNP bound to DNA in a groove-binding mode, which was verified using a competition displacement study and other typical spectroscopic methods. Fourier transform infrared (FTIR) spectrum results showed that DNP interacted with guanine (G) and cytosine (C) bases of DNA. The molecular docking results further supported the results of spectroscopic experiments, and suggested that both Pi-Sigma force and Pi-Alkyl force were the major hydrophobic force functioning between DNP and DNA.
研究领域:
生物化学
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药物研究
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Brain Sciences
·
2026
·Vol. 16
·期 8
·816
·
IF 3.4
Haodong Wang,Yajun Wang,Zhengyang Lv,Yueting Deng,Chao Pan,Yuping Li,Zikai Zhou
HighlightsWhat are the main findings?5xFAD mice show reduced hippocampal theta–low gamma coupling and elevated theta–high gamma coupling.Donepezil preferentially enhances theta–low gamma coupling, with limited normalization of theta–high gamma coupling.What are the implications of the main findings?Theta–low gamma coupling may serve as a treatment-responsive readout of cholinergic modulation in AD models.Persistent theta–high gamma elevation may reflect a stable AD-related hippocampal network abnormality.Background/Objectives: Alzheimer’s disease (AD) is associated with progressive hippocampal circuit dysfunction, but electrophysiological measures of state-dependent abnormalities and treatment responsiveness remain incompletely characterized. We examined hippocampal theta–gamma coupling in 5xFAD mice across behavioral states and after donepezil. Methods: Local field potentials were recorded from CA1 in freely behaving wild-type (WT) and 5xFAD mice during home-cage activity, open-field exploration, and Y-maze testing. Power spectral density and theta–gamma phase–amplitude coupling (PAC) were quantified at the animal level at baseline and after seven days of donepezil. Results: Untreated 5xFAD mice showed reduced theta–low-gamma coupling during home-cage and open-field activity, but not Y-maze exploration, and elevated theta–high-gamma coupling in all three contexts. Donepezil increased theta–low-gamma coupling during open-field and Y-maze exploration and produced a partial numerical shift toward WT levels in the home cage. For theta–high-gamma coupling, the treated group did not differ significantly from either comparator. Untreated 5xFAD mice also showed reduced center exploration and distance traveled in the open field, while Y-maze spontaneous alternation was unchanged. Theta–high-gamma coupling correlated positively with open-field center time in WT mice only. Conclusions: Hippocampal theta–gamma coupling shows frequency- and context-dependent abnormalities in 5xFAD mice. Theta–low-gamma coupling is sensitive to short-term cholinergic modulation during exploration, whereas donepezil’s effect on theta–high-gamma coupling remains inconclusive. Animal-level PAC may provide a candidate functional readout, but longitudinal and cross-model validation is required before biomarker claims are justified.
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产品关联
DOI
高影响因子
MOLECULES
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2021
·Vol. 26
·期 5
·1303
·
IF 4.412
Yingda Zang,Ke Liu,Weiping Wang,Chuangjun Li,Jie Ma,Jingzhi Yang,Xinyi Chen,Xiaoliang Wang,Dongming Zhang
The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F–donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63–4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol-5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen–glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore,6bdcould cross the blood–brain barrier in vitro. More importantly, compared to edaravone,6bdhad stronger free-radical scavenging activity. Molecular docking studies revealed that6bdcould interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate6bdas a leading structure worthy of further investigation.Keywords:Alzheimer’s disease;Claulansine F–donepezil hybrids;AChE inhibitory activity;free-radical scavenging activity;neuroprotective effects
研究领域:
药理学
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神经科学
✓ 已验证
DOI
PubMed
高影响因子
ACS Omega
·
2021
·
IF 3.512
Lin-Xi Wan,Shi-Xing Miao,Zhen-Xiang He,Xiaohuan Li,Xian-Li Zhou,Feng Gao
Palladium/BuAd2P efficiently catalyzed the direct α-arylation of ketone in the anti-Alzheimer’s disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue (12) shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against H2O2-induced damage in SH-SY5Y cells. Docking results of compound 12 also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).
研究领域:
药物化学
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神经科学
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有机合成
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DOI
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2026
·
IF 5.3
Wei Li,Yan Guo,Xiaoli Wang,Chunyan Yang,Jiang Zhu,Zhongcheng Cao
Alzheimer’s disease (AD) still lacks therapies that definitively halt its progression. Dual AChE/MAO-B inhibitors offer a promising strategy to address both symptoms and pathology. Here, we designed and synthesised a series of donepezil-safinamide hybrids. The optimised compound 28c was identified as a potent inhibitor of AChE (IC50 = 1.70 μM) and MAO-B (IC50 = 0.18 μM). Mechanistic studies indicated that 28c acts as a reversible mixed-type inhibitor of AChE and a competitive reversible inhibitor of MAO-B. Molecular docking and molecular dynamic simulations revealed that 28c could strongly and stably bind to MAO-B and AChE mainly through van der Waals interactions. Moreover, compound 28c demonstrated effective blood-brain barrier penetration, exhibited suitable stability in mouse plasma and brain homogenate, and showed a favourable safety profile both in vitro and in vivo. Furthermore, 28c could attenuate AD-related symptoms and exert hippocampal neuroprotection effect in vivo, highlighting its promise as an anti-AD candidate.
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2025
·
IF 2.2
Jiale Liu,Kai Liu,Xinyuan Cui,Yujie Ji,Zhaoqi Ding,Zenghui Chang,Junshuo Zhang,Xinyi Wang,Yuanyuan Liu
Donepezil (DNP) is often combined with nimodipine (NMD) for the treatment of Alzheimer's disease (AD). However, its underlying mechanisms remain poorly understood. This study integrated pharmacodynamics, microbiomics, and fecal metabolomics analysis to explore the therapeutic potential and mechanism of DNP + NMD in AD. The results showed that DNP + NMD significantly reduced the contents of serum inflammatory cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) as well as the contents of nitric oxide synthase (NOS), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE) in the hippocampus, alleviated neuronal damage in hippocampal tissues and effectively improved cognitive deficits of AD rats. Furthermore, DNP + NMD greatly increased the relative abundance of beneficial bacteria ( Lactobacillus and Prevotellaceae_ Prevotella ) and decreased the relative abundance of harmful bacteria ( Ruminococcus and Akkermansia ). Fecal metabolomic analyses indicated that DNP + NMD regulated 28 fecal differential metabolite levels mainly through six key pathways, including linoleic acid metabolism, arachidonic acid metabolism, unsaturated fatty acid biosynthesis, steroid hormone biosynthesis, saturated fatty acid biosynthesis, primary bile acid biosynthesis, pantothenic acid biosynthesis, and coenzyme A biosynthesis pathway. Moreover, Spearman's correlation analysis revealed significant associations between affected metabolites and specific gut microbes. In general, our research sheds light that DNP + NMD exerts a neuroprotective effect against AD by ameliorating the gut microbiota and fecal metabolic disorders, uncovering novel mechanistic insights and therapeutic targets for AD intervention.
研究领域:
神经病学
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药理学
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微生物学
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代谢组学
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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
JOURNAL OF MOLECULAR STRUCTURE
·
2023
·
IF 3.8
Junjie Wang,Hui Zhou,Yang Li,Yeshu Mu,Jinghua Li,Chen Hong,Wen Luo
A novel series of benzo[ cd ]indol-2(1 H )-one-donepezil (BIO-DPZ) hybrids (5a-m, 6a-k) was designed, synthesized and evaluated as cholinesterase inhibitors and living cell imaging agents. These compounds were potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Compound 6a exhibited the strongest inhibitory activity against AChE with an IC 50 value of 0.16 μM. Compound 6i had the strongest inhibition of BuChE with an IC 50 value of 5.37 μM. Kinetic and molecular modeling studies showed that 6a bound both catalytic active site and peripheral anionic site of AChE. Compounds 6a and 6i both showed lower SH-SY5Y, HepG2 and HL-7702 cytotoxicity than the mitoxantrone. Promisingly, the most active compound, 6a, was successfully used in living SH-SY5Y cell imaging and had predictable lipophilicity and blood-brain-barrier permeation properties. These hybrids should undergo further systematic study in the treatment of Alzheimer's disease.
研究领域:
药理学
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神经科学
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药物化学
✓ 已验证
DOI
高影响因子
Journal of Biological Engineering
·
2023
·Vol. 17
·期 1
·1-20
·
IF 5.6
Liu Tiemei,Zhang Qiang,Li Hongru,Cui Xiaoqian,Qi Zhiping,Yang Xiaoyu
Background Spinal cord injury (SCI) is a serious injury with high mortality and disability rates, and there is no effective treatment at present. It has been reported that some treatments, such as drug intervention and stem cell transplantation have positive effects in promoting neurological recovery. Although those treatments are effective for nerve regeneration, many drawbacks, such as low stem cell survival rates and side effects caused by systemic medication, have limited their development. In recent years, injectable hydrogel materials have been widely used in tissue engineering due to their good biocompatibility, biodegradability, controllable properties, and low invasiveness. The treatment strategy of injectable hydrogels combined with stem cells or drugs has made some progress in SCI repair, showing the potential to overcome the drawbacks of traditional drugs and stem cell therapy.
Methods In this study, a novel injectable electroactive hydrogel (NGP) based on sodium hyaluronate oxide (SAO) and polyaniline-grafted gelatine (NH2-Gel-PANI) was developed as a material in which to load neural stem cells (NSCs) and donepezil (DPL) to facilitate nerve regeneration after SCI. To evaluate the potential of the prepared NGP hydrogel in SCI repair applications, the surface morphology, self-repairing properties, electrical conductivity and cytocompatibility of the resulting hydrogel were analysed. Meanwhile, we evaluated the neural repair ability of NGP hydrogels loaded with DPL and NSCs using a rat model of spinal cord injury.
Results The NGP hydrogel has a suitable pore size, good biocompatibility, excellent conductivity, and injectable and self-repairing properties, and its degradation rate matches the repair cycle of spinal cord injury. In addition, DPL could be released continuously and slowly from the NGP hydrogel; thus, the NGP hydrogel could serve as an excellent carrier for drugs and cells. The results of in vitro cell experiments showed that the NGP hydrogel had good cytocompatibility and could significantly promote the neuronal differentiation and axon growth of NSCs, and loading the hydrogel with DPL could significantly enhance this effect. More importantly, the NGP hydrogel loaded with DPL showed a significant inhibitory effect on astrocytic differentiation of NSCs in vitro. Animal experiments showed that the combination of NGP hydrogel, DPL, and NSCs had the best therapeutic effect on the recovery of motor function and nerve conduction function in rats. NGP hydrogel loaded with NSCs and DPL not only significantly increased the myelin sheath area, number of new neurons and axon area but also minimized the area of the cystic cavity and glial scar and promoted neural circuit reconstruction.Conclusion sThe DPL- and NSC-laden electroactive hydrogel developed in this study is an ideal biomaterial for the treatment of traumatic spinal cord injury.
研究领域:
生物医学工程
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神经科学
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组织工程
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药学
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干细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ALZHEIMERS DISEASE
·
2025
·
IF 3.1
Yujie Ji,Xinyuan Cui,Zhaoqi Ding,Xinyi Wang,Yibing Wang,Yichun Zhang,Zeyang Yuan,Zenghui Chang,Kai Liu,Yuanyuan Liu
BackgroundWith the aging population, the number of Alzheimer's disease (AD) patients has been increasing annually, creating an urgent need for AD therapeutic drugs. Donepezil combined with nimodipine (DN) has demonstrated therapeutic potential in the treatment of AD, but its mechanism of action remains unclear.ObjectiveTo reveal the mechanism of DN in the treatment of AD rats.MethodsThe AD rat model was established and evaluated by behavioral experiments and pathology. The therapeutic mechanism of DN in AD treatment was investigated through lipidomics and hippocampal metabolomics analyses based on ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF/MS).ResultsThe learning and memory ability of AD rats can be improved after DN treatment. Significant changes were observed in 40 serum lipid metabolites and 19 hippocampal metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, sphingolipid metabolism, amino acid metabolism, unsaturated fatty acid metabolism and other processes in AD rats.ConclusionsDN could improve cognitive function and nerve damage in AD rats. It may plays a therapeutic role in AD rats by regulating cholinergic damage, Ca2+ overload, oxidative stress, neuroinflammation, and energy deficiency caused by metabolic disorders, which has practical significance for further research and clinical application of DN.
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DOI
PubMed
高影响因子
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