BIOMATERIALS
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2024
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IF 12.8
Jiani Huang,Fei Wu,Wenzhao Cao,Yuhan Chen,Qiong Yao,Peili Cen,Jing Wang,Lu Hong,Xiaohui Zhang,Rui Zhou,Chentao Jin,Mei Tian,Hong Zhang,Yan Zhong
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder globally, with no effective treatment available yet. A crucial pathological hallmark of AD is the accumulation of hyperphosphorylated tau protein, which is deteriorated by reactive oxygen species (ROS) and neuroinflammation in AD progression. Thus, alleviation of ROS and inflammation has become a potential therapeutic strategy in many studies. Herein, we reported ultrasmall coordination polymer nanoparticles formed by ferric ions and gallic acid (Fe-GA CPNs), which owned antioxidant and anti-inflammation properties for AD therapeutics. The facilely prepared Fe-GA CPNs exhibited remarkable superoxide dismutase, peroxidase enzyme activity, and ROS eliminating ability with great water solubility, compared with gallic acid. We demonstrated that Fe-GA CPNs effectively relieved oxidative stress, ameliorated inflammation by downregulating TLR4/NF-κB and modulating microglial polarization towards anti-inflammation phenotype, and reduced hyperphosphorylated tau protein levels. Furthermore, Fe-GA CPNs treatment significantly improved cognitive function in tauopathy-induced AD rats, and achieved a neuroprotective effect against AD pathology. This study highlights the potential of coordination polymer nanoparticles as promising therapeutic candidates for AD and other tau-related neurodegenerative diseases.
研究领域:
神经退行性疾病
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纳米技术
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药理学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2019
·
IF 3.414
Xiao-wen Jiang,Wen-wu Liu,Yu-ting Wu,Qiong Wu,Hong-yuan Lu,Zi-hua Xu,Hui-yuan Gao,Qing-chun Zhao
Ethnopharmacological relevance Alzheimer's disease (AD) is a frequently occurring disease of the elderly, and “deficiency” is the root of AD. Most famous experts of traditional Chinese medicine believe that the disease is based on deficiency, and the deficiency of kidney essence is the basis. Notopterygium incisum (Qiang huo) is beneficial to bladder, liver, and kidneys. It is used to treat liver and kidney deficiency, language difficulties, and mental coma. Qiang huo yu feng tang has been used to treat liver and kidney deficiency, unclear language and mental paralysis in many traditional Chinese medicine books and records. In modern times, it has been used to treat AD and exhibited favourable efficacy. Aim of the study This study attempts to investigate the effects of furocoumarins from Notopterygium incisum (NRE) on the Aβ cascade, tau pathology and inflammatory pathology of AD. Materials and methods In this study, we reported a detailed protocol for stabilizing HEK APPswe293T cells with lentivirus for the first time. This cell line can secrete high concentration of Aβ. In addition, we treated N2a cells with AKT/PKC specific inhibitors (wortmannin/GF-109203X) and established a tau pathological cell model (AKT/PKC N2a) by activating GSK3β and triggering hyperphosphorylation of tau. The Aβ levels and the expression of phosphorylated tau were detected by ELISA and Western blot . The cognitive ability of NRE on APP/PS1 mice was detected using a Morris water maze (MWM) assay and Aβ contents were also evaluated. Results In HEK APPswe293T cells, NRE (10, 20, 40 μg/mL) significantly inhibited the secretion and production of Aβ in dose dependent manner. In addition, NRE also suppressed the expression of phosphorylated tau in wortmannin/GF-109203X treated N2a cells. Furthermore, NRE ameliorated the cognitive impairment of APP/PS1 mice, and the contents of Aβ, IL-1β and TNF-α were significantly depressed in hippocampus and cortex. Conclusion In conclusion, our results demonstrated that NRE has a potential anti-AD effect via the inhibition of the Aβ cascade, tau pathology and neuroinflammation in vitro and in vivo.
研究领域:
药理学
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神经科学
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传统中医
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分子生物学
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DOI
PubMed
高影响因子
PSYCHOPHARMACOLOGY
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2026
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IF 3.3
Chen Shuting,Zhao Kexuan,Shi Zhidan,Zhang Chu,Wu Hao,Tian Meng,Sun Yi,He Ling
Rationale Tau protein hyperphosphorylation and neuroinflammation playimportant roles in the onset and progression of Alzheimer's disease (AD). SIRT1has been implicated in the regulation of synaptic plasticity, cognitive function, andmemory, and is associated with the modulation of autophagy-and inflammation-related signaling pathways, including AMPK/mTOR/ULK1 and NF-κB. Resveratrol(RSV) has been reported to ameliorate cognitive impairment in AD models,primarily in the context of Aβ–related pathology; however, its potential effects andunderlying mechanisms in Tau-driven pathology remain incompletely understood. Objectives To investigate the effect of RSV on cognitive impairment in mice withTau mutation-induced Alzheimer's disease, and to explore its effects on autophagyand neuroinflammation. Methods Tauopathy models were established using AAV-P301L-Tau. Cognitivefunction was assessed via behavioral tests; Hippocampal injury was evaluatedAccepted manuscriptACCEPTED MANUSCRIPTusing HE and Nissl staining, while autophagy was assessed byimmunofluorescence staining. Mechanisms were examined using Western blot,qRT-PCR, and CCK-8 assays. Results RSV treatment was associated with attenuation of neuronal damage,reduction of p-Tau accumulation, and improvement of cognitive impairment in ADmice. Consistent trends were observed in vitro, where RSV treatment wasassociated with increased cell viability and modulation of autophagy-relatedmarkers in AAV-P301L-Tau-induced BV2 cells. In addition, RSV administration wasaccompanied by coordinated changes in signaling components related to SIRT1,AMPK/mTOR/ULK1, and NF-κB pathways, along with reduced expression ofinflammatory mediators. Conclusions RSV treatment was associated with coordinated modulation ofsignaling components related to the AMPK/mTOR/ULK1 and NF-κB pathways,together with improvements in cognitive performance in AD mice. These findingssupport the potential therapeutic relevance of RSV in Tau-drivenneurodegenerative pathology, while further studies are required to clarify theunderlying mechanisms.
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Tao Long,Xue Chen,Yue Zhang,Yu-Jia Zhou,Yan-Ni He,Yun-Fei Zhu,Hai-Jun Fu,Lu Yu,Chong-Lin Yu,Betty Yuen-Kwan Law,Jian-Ming Wu,Da-Lian Qin,An-Guo Wu,Xiao-Gang Zhou
Enhancing the clearance of proteins associated with Alzheimer's disease (AD) emerges as a promising approach for AD therapeutics. This study explores the potential of Radix Stellariae , a traditional Chinese medicine, in treating AD. Utilizing transgenic C. elegans models of AD, we demonstrated that a 75% ethanol extract of Radix Stellariae (RSE) (at 50 µg/mL) effectively diminishes Aβ and Tau protein expression, and alleviates their induced impairments including paralysis, behavioral dysfunction, neurotoxicity, and ROS accumulation. Additionally, RSE enhances the stress resistance of C. elegans . Further investigations revealed that RSE promotes autophagy, a critical cellular process for protein degradation, in these models. We found that inhibiting autophagy-related genes negated the neuroprotective effects of RSE, suggesting a central role for autophagy in the actions of RSE. In PC-12 cells, we observed that RSE not only inhibited Aβ fibril formation but also promoted the degradation of AD-related proteins and reduced their cytotoxicity. Mechanistically, RSE was found to induce autophagy via modulating PI3K/AKT/mTOR and AMPK/mTOR signaling pathways. Importantly, inhibiting autophagy counteracted the beneficial effects of RSE on the clearance of AD-associated proteins. Moreover, we identified Dichotomine B, a β-carboline alkaloid, as a key active constituent of RSE in mitigating AD pathology in C. elegans at concentrations ranging from 50 to 1000 µM. Collectively, our study presents novel discoveries that RSE alleviates AD pathology and toxicity primarily by inducing autophagy, both in vivo and in vitro. These findings open up new avenues for exploring the therapeutic potential of RSE and its active component, Dichotomine B, in treating neurodegenerative diseases like AD.
研究领域:
神经科学
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药理学
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中药学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biosensors-Basel
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2025
·Vol. 15
·期 12
·784
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IF 5.6
Jiao Wang,Keyu Yao,Jiahua Li,Duo Wai-Chi Wong,James Chung-Wai Cheung
Early diagnosis of Alzheimer’s disease (AD) remains challenging due to the extremely low concentration of relevant biomarkers and the limited sensitivity of conventional detection techniques. In this study, we present a carbon nanotube field-effect transistor (CNT-FET) immunosensor for label-free detection of phosphorylated tau at threonine 217 (p-tau217). The device employs a Y2O3/HfO2dielectric layer and gold nanoparticles (AuNPs) to improve biofunctionalization, with anti-p-tau217 antibodies immobilized on the CNT channels. In phosphate-buffered saline (PBS), the sensor exhibited a linear response over a concentration range of 3 fM to 30 pM (R2= 0.973) and achieved a limit of detection (LOD) of 1.66 fM. The device demonstrated high selectivity, with a normalized signal response (NSR) for p-tau217 that was 5–6 times higher than for human serum albumin (HSA) and p-tau231, even at 1000-fold higher concentrations of these interferents. The sensor exhibited reproducibility with a relative standard deviation (RSD) of 4.8% (n= 9) and storage stability with only a 10% decrease in signal after 7 days at 4 °C. Mechanistic analysis indicated that the net positive charge and structural flexibility of the p-tau217 peptide led to a reduction in drain current upon binding, consistent with electrostatic gating effects in p-type CNT-FETs. Current limitations include the absence of standardized p-tau217 reference materials. Future work will focus on validation with clinical samples. This CNT-FET platform enables rapid, minimally invasive detection of p-tau217 and holds strong potential for integration into clinical workflows to facilitate early AD diagnosis.
研究领域:
神经科学
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生物传感器
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纳米技术
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生物医学工程
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早期诊断
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即时检测
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2021
·
IF 8.128
Xin Lin,E Shuang,Xuwei Chen
A multifunctional metal–organic framework (MOF) hybrid Zr-FeTCPP-MOF is fabricated with 2-aminoterephthalic acid (NH 2 -BDC) and Fe (III) meso -Tetra (4-carboxyphenyl) porphine chloride (FeTCPPCl) participating in the coordination to Zr 6 clusters via one-pot hydrothermal method. The adsorption of phosphoproteins on the surface of Zr-FeTCPP-MOF hybrid cause the chances on the absorbance (Abs), fluorescence (FL) and resonance light scattering (RLS) signals of Zr-FeTCPP-MOF/3,3′,5,5′-Tetramethylbenzidine (TMB) system, and an array sensing platform is successfully built for sensitive identification of protein phosphorylation based on the three-dimensional spectral changes of MOF/TMB sensing system induced by the variations on the structure, size, and phosphorylation site of phosphoproteins. This array sensing system is robust in recognizing different phosphoprotein species, and shows high sensitivity in discriminating similar phosphoproteins of different phosphorylation distribution, i.e., caseins (α-, β- and κ-cas). The detection limit of this array sensing platform to individual phosphoprotein is low down to 5 nM. The practical application of this MOF/TMB-base sensing system is substantially demonstrated by identifying tau peptides with different phosphorylation distribution, and distinguishing cancer cells of abnormal phosphorylations from normal cells. This work proves the reliability, sensitivity, and practicality of the MOF/TMB-base sensing system platform for the diagnosis of phosphorylation-related diseases in clinical trials.
研究领域:
生物化学
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分析化学
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医学诊断
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产品关联
DOI
PubMed
高影响因子
Environment & Health
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2026
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IF 6.3
Shiyin Zhong,Qiongli Zhou,Jirui Yang,Zhimin Zhang,Xueting Chai,Jinghao Luo,Xin Zhang,Jingjing Liu,Yangzong Yixi,Lei Shi,Xuhong Chang,Hui Wang
Manganese (Mn) is an essential trace element, but increasing industrial and agricultural use has led to elevated levels of environmental Mn levels. Chronic overexposure to Mn can cause a Parkinson’s-like neurodegenerative disorder; however, the underlying mechanisms remain incompletely understood. This study combined in vitro and in vivo models to investigate the role of the cGAS–STING/NLRP3 axis in regulating the p38 MAPK/NF–κB pathway in the process of Mn-induced Tau aggregation leading to neurotoxicity. Our results demonstrated that MnCl2 exposure significantly activated both the cGAS–STING/NLRP3 signaling axis and the p38 MAPK/NF–κB pathway, accompanied by increased Tau expression. Genetic ablation of cGAS, STING, or NLRP3 attenuated Mn-induced Tau upregulation, indicating that the cGAS–STING/NLRP3 signaling axis mediates Tau expression. RNA-seq analysis further revealed that the decreased Tau expression in knockout cells is associated with the MAPK/NF–κB signaling pathway. Pharmacological inhibition of p38 MAPK or NF–κB markedly downregulated cGAS–STING signaling, inflammatory cytokine release, and phosphorylated Tau (p-Tau) levels. Moreover, we observed colocalization and interaction among p-p38, p-p65, and p-Tau. Overall, these findings reveal that Mn activates the cGAS–STING/NLRP3 signaling axis regulated by the p38 MAPK/NF–κB pathway, driving pathological Tau aggregation.
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DOI
高影响因子
Frontiers in Aging Neuroscience
·
2025
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IF 4.5
Che Chen,Qianfeng Shao,Sheng Zhou
Objective Explore the potential mechanism of Mahuang Fuzi Xixin Decoction (MFXD) in the treatment of Alzheimer’s disease (AD) using network pharmacology, molecular docking approaches, and test its efficacy by in vitro experiments. Methods Active components of MFXD were screened from TCMSP, BATMAN-TCM, and TCMID, with corresponding targets obtained from SwissTargetPrediction and TCMSP. AD-related differential genes were retrieved from GEO. Intersection targets were identified via Venn diagrams, followed by GO/KEGG enrichment analyses, PPI network construction, and molecular docking. In vitro validation experiments were carried out using PC12 cells induced by Aβ 25–35 to simulate the pathological state of AD. For the detection of cell viability, the CCK-8 assay was employed to evaluate the protective effect of MFXD and its active components on damaged PC12 cells. Western blot analysis was used to determine the protein expression levels of key molecules involved in AD-related signaling pathways, including phosphorylated p-NF-κB p65, NF-κB p65, p-GSK-3β, GSK-3β, MMP-9, p-Tau, and Tau. Additionally, the ELISA was utilized to measure the secretion level of TNF-α in the supernatant of Aβ 25–35 -induced PC12 cells, so as to assess the anti-inflammatory effect of MFXD. Results Thirty-seven active components and 230 targets of MFXD were identified, along with 4913 AD-related differentially expressed genes from GEO dataset GSE122063 , yielding 47 intersection targets. GO annotation enriched these targets in processes like reactive oxygen species metabolism, components like extracellular matrix, and functions like neurotransmitter binding; several pathways were enriched in the KEGG analysis, such as TNF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway. The intersection target PPI network identified MMP9, EGFR, FOS as core targets. Molecular docking results indicated that quercetin binds to the three core targets (MMP9, EGFR, FOS), while luteolin binds preferentially to EGFR and MMP9. In vitro , Aβ 25–35 -induced PC12 cells treated with quercetin/luteolin had concentration-dependent viability increases (all P < 0.001); 15% MFXD-containing serum restored viability to ≥ 95% (P < 0.001 vs. AD model, comparable to DHCL). Western blot showed AD model had elevated p-NF-κB p65/NF-κB p65, MMP9/β-actin, p-Tau/Tau and reduced p-GSK-3β/GSK-3β (all P < 0.05); MFXD reversed these (all P < 0.05), while DHCL only inhibited p-NF-κB p65/NF-κB p65. ELISA showed MFXD and DHCL both reduced AD model’s TNF-α (all P < 0.001). Conclusion MFXD potentially exerts anti-AD effects through a multi-component, multi-target, multi-pathway approach. Its key active components (quercetin, luteolin) may act by modulating the core target MMP9. Also, MFXD can simultaneously regulate several pathways, such as the TNF signaling pathway, Calcium signaling pathway, and NF-κB signaling pathway, and target Tau protein-related pathology by restoring the phosphorylation level of GSK-3β to suppress abnormal hyperphosphorylation of Tau, and thereby alleviating pathological damage in AD.
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2019
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IF 3.861
Hanbo Pan,Hongda Qiu,Ke Zhang,Panpan Zhang,Weida Liang,Mengxiang Yang,Chenye Mou,Miaoman Lin,Ming He,Xiao Xiao,Difan Zhang,Haixing Wang,Fufeng Liu,Yongmei Li,Haixiao Jin,Xiaojun Yan,Hongze Liang,Wei Cui
Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and impaired cognitive functions. Fascaplysin is a β-carboline alkaloid isolated from marine sponge Fascaplysinopsis bergquist in 1988. Previous studies have shown that fascaplysin might act on acetylcholinesterase and β-amyloid (Aβ) to produce anti-AD properties. In this study, a series of fascaplysin derivatives were synthesized. The cholinesterase inhibition activities, the neuronal protective effects, and the toxicities of these compounds were evaluated in vitro. Compounds 2a and 2b, the two most powerful compounds in vitro, were further selected to evaluate their cognitive-enhancing effects in animals. Both 2a and 2b could ameliorate cognitive dysfunction induced by scopolamine or Aβ oligomers without affecting locomotor functions in mice. We also found that 2a and 2b could prevent cholinergic dysfunctions, decrease pro-inflammatory cytokine expression, and inhibit Aβ-induced tau hyperphosphorylation in vivo. Most importantly, pharmacodynamics studies suggested that 2b could penetrate the blood–brain barrier and be retained in the central nervous system. All these results suggested that fascaplysin derivatives are potent multitarget agents against AD and might be clinical useful for AD treatment.
研究领域:
神经科学
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药理学
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药物化学
✓ 已验证
DOI
PubMed
高影响因子
JCI Insight
·
2021
·
IF 8.315
Kewei Liu,Juan Zhu,Yuan Chang,Zhenzhou Lin,Zhu Shi,Xing Li,Xing Chen,Chuman Lin,Suyue Pan,Kaibin Huang
Status epilepticus (SE) is a neurological emergency usually accompanied by acute cerebral edema and long-term cognitive impairment, and is characterized by neurodegeneration and aberrant hyperphosphorylated tau protein (p-tau) aggregation. The glia-lymphatic (glymphatic) system plays a central role in facilitating the clearance of metabolic waste from the brain, but its relationship with cerebral edema and cognitive dysfunction after SE is unclear. We hypothesized that cerebral edema after SE might impair glymphatic system function through compression, thus leading to impaired removal of metabolic waste, and ultimately affecting long-term cognitive function. Our results showed that glymphatic system function was temporarily impaired, as evidenced by 2-photon imaging, MRI enhancement, imaging of brain sections, and astrocytic water channel aquaporin 4 (AQP4) protein polarization. The severity of cerebral edema on MRI correlated well with glymphatic system dysfunction within 8 days following SE. Moreover, when cerebral edema was alleviated by glibenclamide treatment or genetic deletion of Trpm4 , post-SE glymphatic system function recovered earlier, along with fewer p-tau–deposited neurons and neuronal degeneration and better cognitive function. These findings suggest that SE-induced cerebral edema may cause glymphatic system dysfunction and render the post-SE brain vulnerable to p-tau aggregation and neurocognitive impairment.
研究领域:
神经科学
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神经病学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
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2022
·
IF 5.702
Xiang-Yu Zheng,Hai-Chen Zhang,Yu-Dan Lv,Feng-Yan Jin,Xiu-Juan Wu,Jie Zhu,Yang Ruan
Background Patients with Alzheimer's disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)-a drug for treating seizures-on learning and memory and the neuropathological features of AD. Methods We crossbred APP23 mice with microtubule-associated protein tau (MAPT) transgenic mice to generate APP23/MAPT mice. These mice were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months. Results Low doses of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/β, thus rescuing neurons from synaptic dystrophy and apoptosis. Low doses of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid β-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid β-peptide (Aβ) by reducing the expression of β-site APP-cleaving enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement ability in mice, and did not alleviate cognitive decline in AD mice. Conclusion Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. A low concentration of LEV may help ameliorate abnormalities of AD; however, a high LEV concentration did not induce similar results.
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PLoS One
·
2016
·Vol. 11
·期 4
·e0152371
·
IF 3.057
Wei Jiang,Tao Luo,Sheng Li,Yue Zhou,Xiu-Yin Shen,Feng He,Jie Xu,Hua-Qiao Wang
Increasing evidence shows that oxidative stress and the hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer’s disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3β (PI3K/Akt/GSK3β) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3β, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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