BIOORGANIC CHEMISTRY
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2022
·
IF 5.307
Yuanyuan Liu,Chu Han,Rongji Dai,Bo Li
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the extracellular amyloid plaques in the brain. Recent studies have shown that ferroptosis , a recently identified cell death pathway associated with the accumulation of lipid hydroperoxides, is closely related to the occurrence and exacerbation of AD. The application of ferroptosis inhibitors can alleviate the development of AD in both cellular and animal models. Herein, a series of dual-functional hydroxylated chalcone derivatives by integrating the heterocyclic dimethylaminopyrimidine in the core structure were designed and synthesized beyond our previous research to optimize their inhibition activities towards Aβ protein aggregation and ferroptosis simultaneously. The inhibitory ability of the novel synthesized chalcone derivatives were greatly improved. The results indicated that the introduction of the dimethylaminopyrimidine structure provided improved effect on Aβ protein aggregation inhibitory activity in both solution and cellular models. Trihydroxy chalcone derivative A-N-5 provided the best inhibition activities against Aβ protein aggregation in cellular models. The trihydroxy compound A-N-5 did not show cytotoxicity at the concentration lower than 100 µM (with IC 50 > 1 mM), but had a significant effect on promoting cell proliferation. Results indicated that compound A-N-5 could potentially promote neuronal cell growth in the damaged brain tissue. The compound could also inhibit ferroptosis induced by RSL or erastin and reduce the lipid peroxidation levels induced by Aβ 1-42 protein aggregation. Molecular docking was also conducted to explain the better inhibitory effect of novel compounds to inhibit Aβ protein aggregation compared to the previous designed molecules without incorporation of the dimethylaminopyrimidine. In summary, the trihydroxy compound A-N-5 showed the best inhibition activities against Aβ aggregation as well as ferroptosis with low cytotoxicity as a promising molecular skeleton candidate for further development of lead compound for in vivo test to treat AD.
研究领域:
神经科学
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药物化学
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分子生物学
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DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Xiaolei Song,Chenchen Wang,Qin Ding,Peng Li,Shihao Sun,Wei Wei,Juan Zhang,Rongli Sun,Lihong Yin,Songqin Liu,Yuepu Pu
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. The vicious circle between amyloid-β peptide (Aβ) overgeneration and microglial dysfunction is an important pathological event that promotes AD progression. However, therapeutic strategies toward only Aβ or microglial modulation still have many problems. Herein, inspired by the Aβ transportation, an Aβ-derived peptide (CKLVFFAED) engineered biomimetic nanodelivery system (MK@PC-R NPs) is reported for realizing BBB penetration and reprogram neuron and microglia in AD lesion sites. This hollow mesoporous Prussian blue-based MK@PC-R NPs carrying curcumin and miRNA-124 can down-regulate β secretase expression, thereby inhibiting Aβ production and reducing Aβ-induced neurotoxicity. Meanwhile, MK@PC-R NPs with excellent antioxidant and anti-inflammatory properties could normalize the microglial phenotype and promote Aβ degradation, providing neuroprotection. As expected, after treatment with MK@PC-R NPs, the Aβ burdens, neuron damages, neuroinflammation, and memory deficits of transgenic AD mice (APP/PS1 mice) are significantly attenuated. Overall, this biomimetic nanodelivery system with anti-Aβ and anti-inflammatory properties provides a promising strategy for the multi-target therapy of early AD.
研究领域:
神经科学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
NEUROSCIENCE LETTERS
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2023
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IF 2.5
Rong Wei,Jun-Qiu He,Wen-Hua Chen,Kin Yip Tam
Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (Aβ) plaques and neurogenic fibrillary tangles. These features are thought to play important pathogenic roles, including neuronal dysfunction and apoptosis in the disease progression. Herein, we systematically evaluated a previously reported dual-target isoquinoline inhibitor ( 9S ) for cholinesterase and Aβ aggregation in in vitro and in vivo models of AD. 9S exhibited neuroprotective effects in Aβ-induced and PHF6-induced PC12 cell models as well as in an okadaic acid-induced SH-SY5Y cell model, which were due to attenuated neuronal apoptosis through modulations of GSK-3β phosphorylation and reactive oxygen species. One-month administration of 9S to triple transgenic AD (3 × Tg-AD) female mice (aged 6 months) led to significant improvement in cognitive deficits. Whereas similar treatment regimens for older 3 × Tg-AD female mice (aged 10 months) showed negligible neuroprotective effects. These findings suggest the importance of therapeutic intervention at the early stage of the disease.
研究领域:
神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2021
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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
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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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DOI
PubMed
高影响因子
BMC NEUROSCIENCE
·
2026
·Vol. 27
·期 1
·8
·
IF 3.3
Yu Lujie,Zhao Mingxin,Zhang Wenjing,Lv Zhigan,Zhao Keqi,Li Huailiang,Qi Yunjie,Peng Xin,Zheng Ziliang,Zhang Weiwei
Inflammation and oxidative stress are critical pathological hallmarks of Alzheimer’s disease (AD). Hydrogen therapy shows promise due to its selective hydroxyl radical (∙OH) scavenging capacity, yet conventional hydrogen delivery fails to effectively accumulate in the brain due to low solubility and rapid diffusion. Here, we report ultra-small palladium hydride (PdH) nanosheets as a dual-functional nanomedicine for AD treatment. The PdH nanosheets exhibit high hydrogen-releasing efficiency via autocatalysis, enabling in situ ∙OH scavenging in the brain. Concurrently, their near-infrared (NIR) photothermal effect, degrading amyloid-β (Aβ) aggregates and transiently enhancing blood-brain barrier (BBB) permeability for improved drug delivery. In AD mice, intravenous PdH treatment combined with NIR irradiation significantly reduced escape latency in the Morris water maze, paralleling reductions in brain Aβ plaques and ROS levels. This study establishes a synergistic strategy of nanoscale hydrogen delivery and photothermal therapy, addressing the dual challenges of BBB penetration and multi-pathology intervention in AD.
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DOI
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Yunfei Tang,Mengmeng Xiao,Tongtong Duo,Xiaowan Zhang,Ziyue Chen,Wei Wei
The abnormal expression of monoamine oxidase B (MAO-B) and the soluble oligomer (Aβo) formed by β-amyloid deposition play key roles in the pathogenesis of Alzheimer’s disease. However, the simultaneous detection of MAO-B and Aβo remains a huge challenge. Herein, a bimetallic core–shell probe ZIF-8 embedding rhodamine 6G (Au/Rh6G/Pd@ZIF-8) with peroxidase-like activity is designed to detect MAO-B and Aβo simultaneously. MAO-B catalyzes the substrate phenethylamine (PEA) to produce H2O2, which oxidizes thiamine with the catalysis of Au/Rh6G/Pd@ZIF-8 to produce a fluorescent product that emits a strong fluorescence at 440 nm. When Aβo is present in the system, due to the specific coordination between Aβo and Zn2+, the intact ZIF-8 structure collapses, leading to Rh6G release and fluorescence recovery. The simultaneous determination of MAO-B and Aβo by Au/Rh6G/Pd@ZIF-8 is realized. The results showed that the designed biosensor had high specificity and sensitivity, a wide detection range, and a low detection limit for MAO-B and Aβo simultaneous detection. Fluorescence signals for MAO-B and Aβo detection did not interfere with each other because they are excited separately, which provides more valuable data for the diagnosis of Alzheimer’s disease.
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产品关联
DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
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2020
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IF 4.364
Zhao Yueyang,Long Zhimin,Ding Ya,Jiang Tingting,Liu Jiajun,Li Yimin,Liu Yuanjie,Peng Xuehua,Wang Kejian,Feng Min,He Guiqiong
Dihydroartemisinin (DHA) is an active metabolite of sesquiterpene trioxane lactone extracted from Artemisia annua, which is used to treat malaria worldwide. DHA can activate autophagy, which is the main mechanism to remove the damaged cell components and recover the harmful or useless substances from eukaryotic cells and maintain cell viability through the autophagy lysosomal degradation system. Autophagy activation and autophagy flux correction are playing an important neuroprotective role in the central nervous system, as they accelerate the removal of toxic protein aggregates intracellularly and extracellularly to prevent neurodegenerative processes, such as Alzheimer’s disease (AD). In this study, we explored whether this mechanism can mediate the neuroprotective effect of DHA on the AD model in vitro and in vivo. Three months of DHA treatment improved the memory and cognitive impairment, reduced the deposition of amyloid β plaque, reduced the levels of Aβ40 and Aβ42, and ameliorated excessive neuron apoptosis in APP/PS1 mice brain. In addition, DHA treatment increased the level of LC3 II/I and decreased the expression of p62. After Bafilomycin A1 and Chloroquine (CQ) blocked the fusion of autophagy and lysosome, as well as the degradation of autolysosomes (ALs), DHA treatment increased the level of LC3 II/I and decreased the expression of p62. These results suggest that DHA treatment can correct autophagic flux, improve autophagy dysfunction, inhibit abnormal death of neurons, promote the clearance of amyloid-β peptide (Aβ) fibrils, and have a multi-target effect on the neuropathological process, memory and cognitive deficits of 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
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Xiaoyu Fu,Jing Han,Yu Xia,Wei Wang,Ya Wen,Boning Zhang,Xue Zhang,Xinyu Wang,Shengnan Han,Chenggang Zhang
Alzheimer's disease (AD) incidence is rising with no effective treatments. Eleutheroside B (EB) has neuroprotective potential, but its therapeutic effects and mechanisms in AD are unclear. This study investigated EB's effects on AD pathologies and elucidated its underlying mechanisms using a transgenic Caenorhabditis elegans ( C. elegans ) model. We found that EB could ameliorate cognitive impairment, locomotor dysfunction, and shortened lifespan induced by amyloid-β(Aβ) and Tau aggregation in C. elegans , and reduce the relative expression levels of Aβ, Tau, and phosphorylated Tau (p-Tau) proteins. EB significantly improved the health status and anti-aging capacity of the worms, as evidenced by prolonged healthspan, elevated pharyngeal pumping rate and body bend frequency, and increased body length and width. Notably, EB exhibited no observable toxicity even at high-dose administration. Furthermore, EB activated key antioxidant transcription factors skn-1 , daf-16 , and hsf-1 ; it also increased the expression levels of antioxidant enzymes superoxide dismutase-3(SOD-3) and glutathione S-transferase 4(GST-4), decreased reactive oxygen species (ROS) levels, and elevated the expression of heat shock proteins Hsp-4 and Hsp-6. EB also reduced the accumulation of p62/SQST-1 protein, promoted the colocalization of lgg-1::GFP with lysosomes, and increased the relative mRNA expression of autophagy-related genes aak-2 , unc-51 , bec-1 , vps-34 , and lgg-1 . After targeted knockdown of these genes, the protective effects of EB against AD-related pathologies were abolished. Our findings demonstrate that EB exhibits anti-aging properties and potential for ameliorating AD, which is likely mediated via antioxidative activities and autophagy induction.
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产品关联
DOI
PubMed
高影响因子
Metabolites
·
2022
·Vol. 12
·期 9
·841
·
IF 5.581
Simeng Zhang,Yuchan Deng,Annan Zhang,Lili Yan,Zhichao Zhang,Jing Wei,Qiang Zhang
The transitional expression and aggregation of amyloid β (Aβ) are the most important causative factors leading to the deterioration of Alzheimer’s disease (AD), a commonly occurring metabolic disease among older people. Antioxidant agents such as vitamin C (Vc) have shown potential effects against AD and aging. We applied an liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method and differential metabolites strategy to explore the metabolic disorders and Vc restoration in a human Aβ transgenic (Punc-54::Aβ1–42) nematode model CL2006. We combined the LC-MS/MS investigation with the KEGG and HMDB databases and the CFM-ID machine-learning model to identify and qualify the metabolites with important physiological roles. The differential metabolites responding to Aβ activation and Vc treatment were filtered out and submitted to enrichment analysis. The enrichment showed that Aβ mainly caused abnormal biosynthesis and metabolism pathways of phenylalanine, tyrosine and tryptophan biosynthesis, as well as arginine and proline metabolism. Vc reversed the abnormally changed metabolites tryptophan, anthranilate, indole and indole-3-acetaldehyde. Vc restoration affected the tryptophan metabolism and the biosynthesis of phenylalanine, tyrosine and tryptophan. Our findings provide supporting evidence for understanding the metabolic abnormalities in neurodegenerative diseases and the repairing effect of drug interventions.Keywords:Alzheimer’s disease;dementia;neurodegenerative disease;aging;Aβ;metabolism;amino acid;ascorbic acid
研究领域:
神经科学
·
代谢组学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INDUSTRIAL AND ENGINEERING CHEMISTRY
·
2025
·
IF 6
Jingwen Xu,Yijie Li,Ning Guo,Guangwen Luo,Le Wang,Jiaqi Wang,Jiayi Gao,Wanyang Qin,Lishan Yao,Guoliang Li
Oxidative stress and amyloid- β ( Aβ ) deposition are closely linked to the occurrence and progression of Alzheimer’s disease (AD). Herein, a strategy for alleviating AD by simultaneously inhibiting Aβ aggregation and scavenging excess ROS was proposed. An antioxidant amphiphilic polymer, DSe-Cys-(PEG) 2 , containing diselenide linkages was synthesized to load hydrophilic Schisandrin B (Sch B), which has antioxidant and heat shock response-promoting properties. DSe-Cys-(PEG) 2 self-assembled with Sch B to form nanosized M@Sch B micelles, demonstrating significant scavenging effects on H 2 O 2 , Fe 3+ , ·DPPH, ·ABTS + , and improvement the aging-related phenotypes in Caenorhabditis elegans ( C. elegans ) CL4176, including a 33.33% increase in maximum lifespan, a 51.08% enhancement in locomotion ability, a 38.10% rise in body bending frequency, delayed egg-laying, and paralysis prevention compared to the control group. Furthermore, M@Sch B significantly retarded aging by reducing lipofuscin accumulation and decreasing ROS accumulation by enhancing antioxidases activity and reducing malondialdehyde content. M@Sch B upregulated the expression of anti-aging genes daf-16 , antioxidant stress genes ( skn-1 , sod-3 ), and key heat shock factors ( hsf-1 , hsp-16.2 ), while downregulating aging genes ( daf-2 , age-1 ) and Aβ mRNA expression based on the synergistic antioxidant effect of M and Sch B. M@Sch B can simultaneously mitigates multiple AD-related factors, including synergistic antioxidant effects and inhibition of Aβ aggregation, which are of great significance for delaying aging and treating AD.
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产品关联
DOI
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2022
·Vol. 40
·期 15
·1821-1830
·
IF 5.56
Xin Lu,Yijun Liu,Nan Qin,Chenxi Du,Yanyu Hu,Yao Chen,Haopeng Sun
Comprehensive Summary The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). We have identified tryptophan-tetrahydroisoquinoline derivatives as selective micro-nanomolar butyrylcholinesterase (BChE) inhibitors. Molecular docking was applied for the rational design and binding mode analysis. They were defined according to their target inhibitory activity, low cytotoxicity, predicted permeability through the blood-brain barrier (BBB), and in vivo cognitive improvement. Additionally, the preferred compound showed ability to decrease self-induced Aβ 1-42 aggregation and Aβ 1-42 induced SH-SY5Y cell injury. Altogether, these factors indicated their potential as unique lead compounds for AD treatment.
研究领域:
神经科学
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药物化学
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分子生物学
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产品关联
DOI
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 2
·177
·
IF 5.5
Jun Li,Dongqing Huang,Wanchen Liao,Yulin Wang,Yibiao Liu,Ping Luan
Background: The excessive accumulation of Aβ plays a critical role in the development of Alzheimer’s disease. However, the therapeutic potential of drugs like curcumin is often limited by low biocompatibility and BBB permeability. In this study, we developed a nanomaterial, BP-PEG-Tar@Cur, which was designed to enhance the biocompatibility of (curcumin) Cur, target Aβ, and augment BBB permeability through near-infrared (NIR) photothermal effects.Methods: Soluble Aβ, ThT fluorescence, and Aβ depolymerization fluorescence experiments were conducted to evaluate the ability of BP-PEG-Tar@Cur to inhibit Aβ aggregation and dissociate Aβ fibrils. Cell uptake assays were performed to confirm the targeting ability of BP-PEG-Tar@Cur towards Aβ. In vitro mitochondrial ROS clearance and in vivo detection of inflammatory factors were used to assess the anti-inflammatory and antioxidant properties of the nanodrug. Water maze behavioral experiments were conducted to evaluate the effect of BP-PEG-Tar@Cur on spatial memory, learning ability, and behavioral disorders in AD mice.Results: The nanodrug effectively inhibited Aβ aggregation and dissociated Aβ fibrils in vitro. BP-PEG-Tar@Cur demonstrated efficiency in curbing ROS overproduction in mitochondria and dampening the activation of microglia and astrocytes triggered by Aβ aggregation. Water maze behavioral experiments revealed that BP-PEG-Tar@Cur enhanced spatial memory, learning ability, and alleviated behavioral disorders in AD mice.Conclusions: Collectively, these findings demonstrate that BP-PEG-Tar@Cur has the potential to be an effective targeted drug for inhibiting Aβ aggregation and improving cognitive impairment in AD mice.
研究领域:
神经科学
·
药理学
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纳米医学
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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）