EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Li-ying Guo,Ting Wang,Hou-xu Ma,Shihao Chen,Zhi-yong Chang,Fei Li
Alzheimer's disease (AD) and osteoporosis (OP) are both serious degenerative diseases, with the potential for concurrent occurrence in clinical settings, and they share certain pathological correlations. Osthole (OST) and notopterol (NOT) are the main active ingredients in traditional Chinese medicine, Angelica pubescens and Notopterygium incisum , respectively, and they exhibit neuroprotective and osteoprotective effects. However, whether the combination of OST and NOT produces a synergistic effect against AD and/or OP remains unclear. The aim of this study was to investigate whether the combination of OST and NOT could produce synergistic anti-AD and/or OP effects using the previously constructed zebrafish AD/OP comorbidity model. Active compounds with anti-AD and OP effects were screened from Angelica pubescens and Notopterygium incisum through network pharmacology, identifying OST and NOT, respectively. Then, the AlCl 3 -induced (Aluminum chloride, AlCl 3 ) AD combined with OP zebrafish model, in conjunction with the Chou-Talalay synergy evaluation model, was employed to assess whether the OST and NOT combination produced synergistic effects against AD and/or OP. Furthermore, a CuSO 4 -induced (Copper sulfate, CuSO 4 ) inflammation zebrafish model was used to investigate whether the combination of OST and NOT produced synergistic anti-inflammatory effects, thereby resulting in synergistic anti-AD and/or OP effects. The results demonstrated that the OST-NOT combined treatment produced a synergistic anti-AD and OP effect. Moreover, the combined treatment of OST and NOT significantly inhibited nitric oxide (NO) and reactive oxygen species (ROS) release more effectively than OST or NOT alone, indicating a synergistic anti-inflammatory effect of the OST and NOT combined treatment.
研究领域:
药理学
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神经科学
·
骨骼生物学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2020
·
IF 4.831
Jianan Guo,Zhisheng Mi,Xiaoying Jiang,Changjun Zhang,Zili Guo,Linzi Li,Jinping Gu,Tao Zhou,Renren Bai,Yuanyuan Xie
A series of active hybrids combining 3-hydroxypyridin-4(1 H )-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (pFe 3+ = 14.8–19.2) and showed favorable monoamine oxidase B (MAO-B) inhibitory effects compared to the reference drug Pargyline (IC 50 = 86.9 nM). Among them, compound 11 g displayed the best MAO-B inhibitory activity with an IC 50 value of 99.3 nM. Molecular docking analysis showed that compound 11 g could enter the entrance cavity and substrate cavity of MAO-B. Furthermore, the compound 11 g had an excellent antioxidant effect and was capable of protecting from the amyloid- β 1-42 (A β 1-42 ) induced PC12 cell damage. In silico tools were applied for predicting the blood–brain barrier (BBB) penetration and compound 11 g was proved to overcome the brain exposure challenge. In the mice behavioral study, compound 11 g significantly ameliorated cognitive impairment induced by Scopolamine. More importantly, compound 11 g displayed favorable pharmacokinetic profiles in a rat model. In summary, compound 11 g , with both anti-MAO-B and iron-chelating ability, was proved to be a promising potential anti-AD agent for further optimization.
研究领域:
神经科学
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药物化学
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生物化学
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2020
·
IF 4.902
Yao Qi,Lin Guo,Yibing Jiang,Yijie Shi,Haijuan Sui,Liang Zhao
It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer’s disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD.
研究领域:
神经科学
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药理学
·
分子生物学
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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
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毒理学
·
神经退行性疾病
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DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2026
·
IF 5.5
Duoduo Ren,Xuejun Chai,Chenyao Xiang,Yongkang Zhao,Penghao Sun,Mengli Wang,Jing Li,Jiayue Wu,Chenju Yi,Shulin Chen,Enyao Li,Shanting Zhao
This study aimed to clarify the neuroprotective effect of Acer truncatum Bunge seed oil (ASO) and its interactions with the gut microbiota in transgenic mice with 5 × Familial Alzheimer's disease (5 × FAD). The AD-transgenic mice were fed with standard diet supplemented with 4% ASO from one to six months of age. The result show that ASO intervention can alleviate learning and memory impairment, enhance motor coordination and endurance, and reduce Aβ deposition in the brains. It also inhibit the proliferation of microglia and astrocytes, decrease the levels of IL-1β, IL-6, and TNF-α in the hippocampus and serum. Then, ASO could increase the Chao1 index and Shannon index, alter the gut microbiota composition, specifically, enhance the growth of gut bacteria correlated with the production of SCFAs, including Ruminococcaceae, Butyricicoccus, Sutterella and others, particularly those related to butyrate production. Additionally, ASO can increase the concentrations of SCFAs in fresh feces and serum, particularly butyric acid. ASO could primarily modulate the biosynthesis of unsaturated fatty acids, glycerophospholipid metabolism, and sphingolipids metabolism in serum. At the same time, Fecal microbiota transplantation (FMT) could reduce Aβ deposition, enhance learning and memory. Finally, Supplementation of sodium Buty also mitigate learning and memory impairments. This study highlights the gut microbiota might be a potential therapeutic target for AD and provides a scientific foundation for developing novel pharmaceuticals or nutraceuticals.
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 6
·2804
·
IF 4.9
Danni Chen,Opeyemi B. Fasina,Jiahui Lin,Jiayuan Zeng,Majid Manzoor,Hiroshi Ohno,Lan Xiang,Jianhua Qi
In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities fromGentiana rigescensFranch and conducted continuous structure–activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood–brain barrier (BBB). At the cell level, TBG096 exerts NGF-mimic activity by regulation of heat-shock cognate protein 70 (Hsc70) and downstream proteins. Subsequently, high-fat diet (HFD)-induced Alzheimer disease (AD) mouse models were used to evaluate the anti-AD efficacy of the compound. TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg/kg, respectively. In order to elucidate the mechanism of action of the compound against AD, the RNA-sequence analysis of transcriptomics, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot analysis were performed using animal samples. TBG096 significantly increased the expression of the Wnt gene family (Wnt10b,Wnt5a, andWnt1) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively. At the same time, it reduced the activity of microglia, astrocyte cells, and expression of inducible nitric oxide synthase (INOS) in the brain. Moreover, this compound significantly increased phosphorylated-adenosine 5′-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and β-amyloid (Aβ) at the protein level. These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70/HK2/PKM2/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway.
研究领域:
药理学
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神经科学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Junjie Li,Liming Liu,Syed Jalil Shah,Ying Tang,Shanliang Jiang,Guangyuan Mu,Quanru Man,Zhongxing Zhao,Zhenxia Zhao
Metal-organic frameworks (MOFs) modification and composite to chase high adsorption capacity and desorption efficiency for volatile organic compounds (VOCs) capture are a great challenge work. Seeking a suitable strategy to simultaneously promote the adsorption capacity and regeneration efficiency of MOFs is a significant practical challenge in this context. Herein, novel heat-conducting MOFs (HKUST-1) composite films were prepared for efficient and synchronous improvement of adsorption affinity and desorption efficiency. In our case, bulk Boron nitride (BN) was exfoliated into BN nano-sheets (BNNS), which were then spread as flakes on PVDF nanofibers to form a conductive network (BNNS/PVDF film, which was abbreviated as B/P film). With the aid of citric acid (CA) modification, HKUST-1 crystals were dispersed-grown on modified B/P (mB/P) film, resulting in the formation of a hierarchical pore structure in HK-mB/P film with a relatively high MOFs loading amount (45.8 wt%) and surface area (448 m 2 /g). Performance evaluation experiments showed that the toluene adsorption and desorption rates of the HK-mB 0.4 /P 0.6 film were 5.5 and 5.3 times higher than those of the powder HKUST-1, respectively. The fast adsorption rate could be ascribed to the constructed heat-conducting network and porous stacked nanofibers. Furthermore, its adsorption capacity for toluene was significantly increased up to 4.69 mmol/g at low pressure ( P / P 0 = 0.01), which was approximately-two times higher than that of pure HKUST-1. This merit was mainly attributed to the newly formed interface between HKUST-1 and mBNNS, which could strengthen the adsorption affinity for toluene by the generated unsaturated metal sites of (BNNS-CA-O|Cu|O-ligand) and π-π attraction of B-N bonds. Besides, the HK-mB 0.4 /P 0.6 film also displayed good cycling performance, with only a 3–4 % decrease in activity observed after five consecutive cycles.
研究领域:
材料科学
·
环境工程
·
化学工程
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DOI
高影响因子
CHINESE SCIENCE BULLETIN
·
2014
·Vol. 59
·期 27
·3449-3456
·
IF 1.365
Lei Ying,Liu Yu,Song Huiming,Sun Bo
Dendroclimatological techniques were employed to investigate the relationship between Chinese Pinus ( Pinus tabulaeformis Carr.) growth and climatic variability in the Mt. Yishan region of Shandong Province, China, over the past 253 years. Using regression analysis, the wetness index (WI) was reconstructed for the Mt. Yishan area for the period 1755–2007 AD based on tree-ring widths; predictor variables accounted for 40 % of the variance. The reconstructed time-series displayed an increasing trend after the late 1960s. Both the estimated and the observed WI for May–August were better correlated with precipitation than temperature during the period 1958–2007 AD, indicating that the contribution of precipitation to the WI was larger than temperature in the study area. The reconstructed WI was compared with the dryness/wetness index of China and land areas that were affected by droughts and floods using the agricultural statistics for Shandong Province. In addition, the WI time-series corresponded well with the peanut yield in Shandong Province at high frequency, which may be reasonable in the context of agriculture in Shandong. The 3-, 5- to 6- and 9- to 10-year periodicities detected in the time-series suggested that the reconstructed WI in the Mt. Yishan area may be related to large-scale climate variations.
研究领域:
树轮气候学
·
气候学
·
环境科学
·
农业科学
·
古气候学
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DOI
高影响因子
Journal of Pharmaceutical Analysis
·
2026
·
IF 11.2
Guifeng Zhang,Hongjiang Li,Wei Zhang,Dan Pu,Longxing Wang,Xiaofei Han,Ju Wu
Mannan-oligosaccharides (MOS), as indigestible functional prebiotic, support intestinal health. Here, we engineered MOS to undergo linoleic acid (LA)-mediated self-assembly with quercetin, forming lipid bilayer nanoparticles (MOS-LA/LA-Q NPs). These nanoparticles achieved a high quercetin encapsulation efficiency (92.4%) and demonstrated superior stability in aqueous solution at 4 °C. The MOS outer layer effectively protected the quercetin core from gastrointestinal stress. Triggered by microbial enzymes, the system enabled a sustained quercetin release, up to 60% over 48 h, representing a novel microbe-specific delivery mechanism. In an Alzheimer’s disease (AD) mice models induced by AlCl 3 /D-galactose, MOS-LA/LA-Q NPs significantly enhanced gut microbiota diversity, restored gut microbiota balance, suppressed pathogenic bacteria, and regulated metabolites short-chain fatty acid (SCFA) and lactic acid levels. Compared with free quercetin, these nanoparticles (NPs) alleviated cognitive deficits, reduced inflammation and oxidative stress in both the colon and brain, improved gut-brain barrier integrity, and restored gut-brain function more significantly. Mechanistically, these effects were associated with modulation of the kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathways, reducing tau phosphorylation and Aβ amyloid levels, thus demonstrating superior neuroprotection. This study proposes a novel strategy for addressing the complex pathology of AD through multi-target intervention, highlighting the potential of MOS-based NPs to enhance quercetin’s therapeutic efficacy.
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DOI
高影响因子
Frontiers in Pharmacology
·
2018
·
IF 3.831
Huang Xianfeng,Wang Jing,Chen Xiao,Liu Pan,Wang Shujin,Song Fangchen,Zhang Zaijun,Zhu Feiqi,Huang Xinfeng,Liu Jianjun,Song Guoqiang,Spencer Peter S.,Yang Xifei
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop (Humulus lupulus L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysates of N2a/APP cells in the presence or absence of Xn. Generally, these 51 differential proteins could be classified into seven main categories according to their functions, including: endoplasmic reticulum (ER) stress-associated proteins; oxidative stress-associated proteins; proteasome-associated proteins; ATPase and metabolism-associated proteins; cytoskeleton-associated proteins; molecular chaperones-associated proteins, and others. We used Western-blot analysis to validate Xn-associated changes of some key proteins in several biological/pathogenic processes. Taken together, we show that Xn reduces AD-related changes in stably transfected N2a/APP cells. The underlying mechanisms involve modulation of multiple pathogenic pathways, including those involved in ER stress, oxidative stress, proteasome molecular systems, and the neuronal cytoskeleton. These results suggest Xn may have potential for the treatment of AD and/or neuropathologically related neurodegenerative diseases.
研究领域:
神经科学
·
分子生物学
·
药理学
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2022
·
IF 3.841
Aihong Yang,Wenjing Liu,Xiangyu Li,Wanru Wu,Xiaodi Kou,Rui Shen
More and more evidence suggested that bio-metals including iron, zinc and copper play an important role in Alzheimer's disease (AD). Metal chelation agents may play an important role through promoting the metal homeostasis for AD treatment. In this study, UA (usnic acid), a natural product with antioxidant activity and metal chelation sites was selected as a lead compound. Different types of tertiary amine groups were introduced to synthesize four UA derivatives 1–4 as metal chelators and cholinesterase inhibitors since tertiary amine moiety was the key pharmacophore to inhibit cholinesterase. And the related activities such as antioxidant, anti-cholinesterase and metal chelation were evaluated. Results showed that 1–4 displayed excellent anti-oxidant activity, with lowest IC 50 of 0.433 µM for ·OH scavenging ability and 8.808 µM for ·O 2 − scavenging ability. The mechanisms of anti-oxidant activities were furtherly studied by cyclic voltammetry. Besides, 1–4 also showed good anti-cholinesterase activities with lowest IC 50 of 0.269 µM for acetylcholinesterase (AChE) and 0.361 µM for butyrylcholinesterase (BuChE). The results of molecular docking with AChE and BuChE were consistent with the experimental results. 1–4 displayed obvious chelating abilities with Cu(II) and Fe(III) by UV–vis spectra analysis and the metal complexes also showed good anti-AD activities. Interestingly, single crystal of Cu(II) complex of the hydrolyzed mono-substituted ligand was obtained which further substantiated the metal binding ability and provided clues to the anti-AD activities of the metal complex. Meanwhile, hydrolysis ratio of 4 was also tested by HPLC. Finally, BBB permeability of 1–4 was acceptable by ADMET prediction. Overall, these findings demonstrated that compounds 1–4 might be considered as potential candidates in the anti-AD therapy.
研究领域:
药理学
·
药物化学
·
神经科学
·
无机化学
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产品关联
DOI
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2020
·
IF 3.073
Xiaoying Jiang,Jianan Guo,Yangjing Lv,Chuansheng Yao,Changjun Zhang,Zhisheng Mi,Yuan Shi,Jinping Gu,Tao Zhou,Renren Bai,Yuanyuan Xie
A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe 3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC 50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid- β 1-42 (A β 1-42 ) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.
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DOI
PubMed
高影响因子
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