BIOMATERIALS
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2018
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IF 8.806
Jing Sun,Chunfang Wei,Yanan Liu,Wenjie Xie,Mengmeng Xu,Hui Zhou,Jie Liu
Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis. Controlled release , target ability, and multi-channel synergistic treatment are key factors associated with the success of AD drugs. Herein, we report a novel mesoporous nano-selenium (MSe) release delivery system (MSe-Res/Fc-β-CD/Bor) based on the borneol (Bor) target, β-cyclodextrin nanovalves (Fc-β-CD) with loaded resveratrol (Res). Previous experiments have shown that MSe-Res/Fc-β-CD/Bor first releases Bor by interacting with blood or intracellular esterases , allowing the nanosystem to pass through the blood-brain barrier (BBB). Subsequently, the Fc-β-CD is opened by the redox (H 2 O 2 ) response to the release of Res at the lesion site. We demonstrated that MSe-Res/Fc-β-CD/Bor inhibited aggregation of β-amyloid proteins (Aβ), mitigated oxidative stress , and suppressed tau hyperphosphorylation , while protecting nerve cells and successfully improving memory impairment in APP/PS1 mice. Interestingly, compared with rivastigmine (Riv) positive drugs alone, the MSe/Fc-β-CD/Bor loaded with Riv had a better pharmacokinetic index. These results indicate that MSe-Res/Fc-β-CD/Bor could be a prospective drug for treating AD.
研究领域:
神经学
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药学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
Journal of Functional Foods
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2021
·
IF 4.451
Tao Zhou,Yan Liu,Qiulian Wang,Qingquan Dou,Xukai Li,Yinping Pan,Lingzheng Meng,Tian Xue
Increasing evidence suggested that the gut microbiome-brain axis plays a critical role in regulating cognitive functions. In this study, we aimed to investigate the dietary treatment effect of Spirulina platensis on learning deficits in high fat diet (HFD) fed mice and clarify the potential mechanisms via investigating the gut microbiome-brain axis. Dietary administration of 1% and 2% Spirulina platensis for 16 weeks significantly improved the spatial learning and memory performance of the HFD-fed mice in both Barnes Maze test and Morris water maze test. The Aβ accumulation, tau-hyperphosphorylation, and neuroinflammation in the hippocampus were significantly inhibited by Spirulina platensis . Spirulina platensis also abrogated HFD induced gut microbial dysbiosis and unbalance of gut microbial metabolites indicating its modulating effect on the gut-brain axis. This study provides further evidence for the application of Spirulina platensis as functional supplement for treatment of Alzheimer’s disease.
研究领域:
神经科学
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微生物学
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营养学
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药理学
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DOI
高影响因子
ACS Chemical Neuroscience
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2020
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IF 4.486
Yaojun Ju,Harapriya Chakravarty,Kin Yip Tam
Alzheimer’s disease (AD) is a complex neurodegenerative disorder affecting millions of people worldwide. The underlying pathologic mechanisms of AD are unclear. Over the decades, the development of single target agent did not lead to any successful treatment for AD. A multitarget agent that could tackle more than one AD phenotype may be helpful as a treatment strategy. Cholinesterases (ChEs) including acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), are currently the drug targets with approved treatments. Moreover, amyloid beta (Aβ) deposition is a hallmark of AD that receives considerable attention. Herein, 9Q, a previously reported dual target inhibitor dealing with cholinergic dysfunction and amyloid deposition for AD treatment, has undergone thorough investigations. In vitro studies revealed that 9Q exhibited over 80% inhibition of ChE activity at 100 μM and more than 30% inhibition of Aβ aggregation at 1 mM concentration. Moreover 9Q was able to penetrate the blood–brain barrier (BBB) and enhance the cerebral acetylcholine level in triple transgenic AD (3xTg-AD) mice. Following one month treatment with 9Q, the amyloid burden and the cognitive deficits in 3xTg-AD mice were significantly ameliorated. It was observed that 9Q treatment mitigated synapse dysfunction, decreased amyloidogenic APP processing, and reduced the tau pathology in 3xTg-AD mice. Taken together, our results suggested that dual inhibition of cholinesterases and Aβ aggregation could be a promising approach in AD treatment.
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
Acta Pharmaceutica Sinica B
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2019
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IF 5.808
Fangfang Li,Zongliang Liu,Heyuan Sun,Chunmei Li,Wenyan Wang,Liang Ye,Chunhong Yan,Jingwei Tian,Hongbo Wang
Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, blood–brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.
研究领域:
肿瘤学
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药理学
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分子生物学
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神经科学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2019
·
IF 4.784
Fei Gao,Jing Zhao,Ping Liu,Dongsheng Ji,Litao Zhang,Mengxiao Zhang,Yuqin Li,Yuliang Xiao
The purpose of this study was to ascertain the effect of selenium-chondroitin sulfate nanoparticles ( [email protected] ) on multi-target-directed therapy for the treatment of Alzheimer's disease (AD). [email protected] nanoparticles were successfully synthesized, and their therapeutic effects were studied in in vitro AD models. [email protected] effectively inhibited amyloid-β (Aβ) aggregation and protected SH-SY5Y cells from Aβ 1–42 -induced cytotoxicity. Moreover, [email protected] significantly decreased okadaic acid-induced actin cytoskeleton instability in SH-SY5Y cells. In addition, [email protected] decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased the levels of glutathione peroxidase (GSH-Px). The Western blot results indicated that [email protected] attenuated the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of GSK-3β. In summary, this study demonstrated that [email protected] could inhibit the aggregation of Aβ, reduce damage to the cytoskeleton, mitigate oxidative stress and attenuate the hyperphosphorylation of tau protein. [email protected] might be a potent multi-functional agent for the treatment of AD and thus warrants further research and evaluation.
研究领域:
神经科学
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药学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
RSC Advances
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2018
·Vol. 8
·期 31
·17389-17398
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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
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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
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
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2020
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IF 3.292
Zuntao Wu,Lin Bai,Runqi Tu,Lijie Zhang,Yue Ba,Huizhen Zhang,Xing Li,Xuemin Cheng,Wenjie Li,Hui Huang
Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (proBDNF) increased, while that of mature BDNF (mBDNF), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of BACE1 protein and tau phosphorylation level in PFC and hippocampus increased, APP mRNAs in PFC and prolonged induction of BACE1 in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.
研究领域:
神经毒理学
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神经科学
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分子生物学
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行为科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Kun Hu,Shaojun Wu,Jiaxin Xu,Yongzhen Zhang,Yanan Zhang,Xinyuan Wu,Jie Miao,Yongxu Yao,Susu Zhu,Guangtong Chen,Jie Ren
Alzheimer’s disease (AD), one of the neurodegenerative disorders, is highly correlated with the abnormal hyperphosphorylation of Tau and aggregation of β-amyloid (Aβ). Oxidative stress, neuroinflammation, and abnormal autophagy are key drivers of AD and how they contribute to neuropathology remains largely unknown. The flavonoid compound pongamol is reported to possess a variety of pharmacological activities, such as antioxidant, antibacterial, and anti-inflammatory. This study investigated the neuroprotective effect and its mechanisms of pongamol in lipopolysaccharide (LPS)-induced BV2 cells, d-galactose/sodium nitrite/aluminum chloride (d-gal/NaNO2/AlCl3)-induced AD mice, and Caenorhabditis elegans models. Our research revealed that pongamol reduced the release of inflammatory factors IL-1β, TNF-α, COX-2, and iNOS in LPS-induced BV2 cells. Pongamol also protected neurons and significantly restored memory function, inhibited Tau phosphorylation, downregulated Aβ aggregation, and increased oxidoreductase activity in the hippocampus of AD mice. In addition, pongamol reversed the nuclear transfer of NF-κB and increased the levels of Beclin 1 and LC3 II/LC3 I. Most importantly, the anti-inflammatory and promoter autophagy effects of pongamol may be related to the regulation of the Akt/mTOR signaling pathway. In summary, these results showed that pongamol has a potential neuroprotective effect, which greatly enriched the research on the pharmacological activity of pongamol for improving 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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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Zhang Liding,Cao Kai,Xie Jun,Liang Xiaohan,Gong Hui,Luo Qingming,Luo Haiming
Amyloid-β (Aβ) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aβ aggregation and scavenging of ROS may be a promising therapeutic strategy to alleviate Alzheimer’s disease pathology. Based on the previously developed antibody 1F12 that targets all forms of Aβ 42 , we developed an Aβ 42 and ROS dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying the brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aβ-rich regions. Combined with peripheral and central nervous system treatments, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aβ 42 misfolding, accelerating Aβ 42 clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aβ clearance exhibited by this Aβ 42 and ROS dual-targeted strategy also reduced the burden of hyperphosphorylated tau, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings indicate that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that can facilitate multi-target treatment of AD.
研究领域:
神经科学
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纳米技术
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药学
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分子生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR LIQUIDS
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2024
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IF 5.3
Wan-Yi Ge,Wen-Pu Shi,Xue-Ting Wang,Huan Liang,Xu-Dong Deng,Liang-Liang Chen,Xiao-Qian Jin,Wei-Hong Guo,Da-Chuan Yin
Protein liquid–liquid phase separation (LLPS) is a significant process in biology and material sciences. Finding suitable conditions for protein LLPS is essential for its in-depth and systematic study. Here, we provide a mixed solution screening kit based on biomacromolecule crowding agents to find protein LLPS conditions. The screening kit consists of 96 chemical formulations, in which the biomacromolecule crowding agents are used as the key components. The aqueous solution of the target protein is mixed with each chemical agent in the kit and then placed in an incubator for some time. The LLPS conditions for the target protein can be found by examining the LLPS phenomena in the droplets. We used nine proteins as model target proteins—lysozyme, bovine serum albumin, bovine hemoglobin, ovalbumin, catalase, FUS, Aβ, Tau, and α-Synuclein—to evaluate the performance of the screening kit. We found that utilization of the screening kit is efficient and useful to find different conditions for LLPS of proteins. The screening results reveal two types of conditions: those that promote and those that inhibit LLPS. Both conditions are extremely valuable because those that promote LLPS can be used to do extensive studies on the LLPS processes of the proteins of interest, whereas those that inhibit LLPS can be utilized as leads for developing novel medications to treat LLPS-related disorders. Furthermore, novel applications for the kit were investigated by utilizing the screening products.
研究领域:
生物学
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材料科学
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生物物理学
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药学
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DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
·
IF 6.9
Yuanfang Sun,Qi Xia,Lijing Du,Yu Gan,Xiaopeng Ren,Gang Liu,Yongkuan Wang,Shikai Yan,Shasha Li,Xiuyun Zhang,Xue Xiao,Huizi Jin
Alzheimer's disease (AD) presents a significant challenge due to its prevalence and lack of cure, driving the quest for effective treatments. Anshen Bunao Syrup , a traditional Chinese medicine known for its neuroprotective properties, shows promise in addressing this need. However, understanding its precise mechanisms in AD remains elusive. This study aimed to investigate Anshen Bunao Syrup's therapeutic potential in AD treatment using a scopolamine-induced AD rat model. Assessments included novel-object recognition and Morris water maze tasks to evaluate spatial learning and memory, alongside Nissl staining and ELISA analyses for neuronal damage and biomarker levels. Results demonstrated that Anshen Bunao Syrup effectively mitigated cognitive dysfunction by inhibiting amyloid-β and phosphorylation Tau aggregation, thereby reducing neuronal damage. Metabolomics profiling of rats cortex revealed alterations in key metabolites implicated in tryptophan and fatty acid metabolism pathways, suggesting a role in the therapeutic effects of Anshen Bunao Syrup . Additionally, ELISA and correlation analyses indicated attenuation of oxidative stress and immune response through metabolic remodeling. In conclusion, this study provides compelling evidence for the neuroprotective effects of Anshen Bunao Syrup in AD models, shedding light on its potential as a therapeutic agent for AD prevention and treatment.
研究领域:
神经科学
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药理学
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中医药
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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
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Licong Yang,Yabin Wang,Zhiwei Li,Xiaohua Wu,Jingtao Mei,Guodong Zheng
The pathology of Alzheimer's disease (AD) is highly correlated with obesity-induced insulin resistance. Resveratrol (Res) is a natural phenol that demonstrates a neuroprotective effect, but the bioactivity of Res is low in vivo . Here, chitosan (CS) was cross-linked with sodium tripolyphosphate (TPP) to encapsulate low water solubility Res. Next, a brain-targeted peptide (TG: TGNYKALHPHNG) was modified on the surface of Res-loaded CS/TPP nanoparticles (TG-Res-CS/TPP-NPs) to specifically deliver Res to the brain. Morris water maze results indicated that cognitive impairments were ameliorated by TG-Res-CS/TPP-NPs in obesity-related AD mice. Obesity-related insulin resistance promotes Tau phosphorylation and Aβ aggregation in the brain. Administration of TG-Res-CS/TPP-NPs alleviated lipid deposition-induced insulin resistance and decreased the level of phosphorylated Tau and Aβ aggregation via the JNK/AKT/GSK3β pathway. Additionally, TG-Res-CS/TPP-NPs transported across blood-brain barrier which in turn increased glucose transporter expression levels, antioxidant enzyme activity and inhibited microglial cell activation . Thus, TG-Res-CS/TPP-NPs were more effective than Res-CS/TPP-NPs at regulating glucose homeostasis , oxidative stress and neuroinflammation in the brain. Moreover, inflammatory , lipid metabolism and oxidative stress-related gut microbiota including Helicobacter , Colidextribacter , Anaerotruncus , Parasutterella , Allobaculum , Alloprevotella , Alistipes , Bifidobacterium and Candidatus_Saccharimonas were also regulated by TG-Res-CS/TPP-NPs. This work indicates the potential use of TG-Res-CS/TPP-NPs for the delivery of Res.
研究领域:
药理学
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神经科学
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分子生物学
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生物技术
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）