Frontiers in Aging Neuroscience
·
2024
·
IF 4.1
Yu Xingzhi,Tao Jie,Xiao Tian,Duan Xiaohua
Introduction: Gastrodia elata Blume is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing Gastrodia elata are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of Gastrodia elata, and, in recent years, this herb has also been used in the treatment of Alzheimer’s disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4′-methylenediphenol, a key active ingredient of Gastrodia elata, can mitigate amyloid-β (Aβ)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD.Methods: We investigated the effects of 4,4′-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4′-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action.Results: 4,4′-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4′-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased Aβ protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4′-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4′-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in Aβ toxicity; importantly, our results suggested that these effects of 4,4′-methylenediphenol were mediated, at least partly, via the activation of DAF-16.Conclusion: We have demonstrated that 4,4′-methylenediphenol can reduce Aβ-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of Gastrodia elata and its active ingredients.
研究领域:
神经科学
·
药理学
·
老年学
·
分子生物学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Qiaofeng Zhou,Xiying Guo,Tu Chen,Yumin Liu,Huimin Ji,Yixuan Sun,Xiaosong Yang,Changhan Ouyang,Xiufen Liu,Min Lei
Celastrol, the primary constituent of Tripterygium wilfordii , has demonstrated neuroprotective properties in rats with dementia by reducing inflammation. A high-fat diet and streptozotocin injection were utilized to establish a diabetic rat model, which was then employed to investigate the possible protective effect of celastrol against the development of diabetes-induced learning and memory deficits. Afterwards, the experimental animals received a dose of celastrol by gavage (4 mg/kg/d). An animal study showed that celastrol enhanced insulin sensitivity and glucose tolerance in diabetic rats. In the Morris water maze test, rats with diabetes performed poorly in terms of spatial learning and memory; treatment with celastrol improved these outcomes. Additionally, administration of celastrol downregulated the expression of inflammatory-related proteins (NF-κB, IKKα, TNF-α, IL-1β, and IL-6) and greatly reduced the generation of Aβ in the diabetic hippocampus tissue. Moreover, the insulin signaling pathway-related proteins PI3K, AKT, and GSK-3β were significantly upregulated in diabetic rats after celastrol was administered. Also, celastrol prevented damage to the brain structures and increased the synthesis of synaptic proteins like PSD-95 and SYT1. In conclusion, celastrol exerts a neuroprotective effect by modulating the insulin signaling system and reducing inflammatory responses, which helps to ameliorate the cognitive impairment associated with diabetes.
研究领域:
神经科学
·
药理学
·
糖尿病研究
·
神经保护
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Xi-Xi Li,Xiu-Yuan Lang,Teng-Teng Ren,Jun Wang,Rongfeng Lan,Xiao-Yan Qin
Ethnopharmacological relevance Tibetan ginseng named Wangla (tuber of Coeloglossum viride var. bracteatum ) is a traditional tonic that has Yang-strengthening and qi-enhancing, tranquilizing, intelligence-enhancing and longevity-enhancing properties. It has been used to treat impotence, spermatorrhea , anemia and insomnia. Therefore, its characteristic components and neuronal modulating effects were studied. Aim of the study: To investigate the elimination of Aβ-induced toxicity by CE and to elucidate the molecular mechanisms involving BDNF , FGF2 , and their related signaling axis, and the RIP1-driven inflammatory pathway. Materials and methods We established Aβ-induced toxicity models in cultured neurons and ICR mice , respectively. MWM and fear conditioning tests were performed for behavioral analysis of cognitive functions in mice. Western blot was used to investigate the levels of BDNF, FGF2, and their downstream effector TrkB/Akt/Bcl-2, as well as the RIP1-driven RIP1/RIP3/MLKL pathway. Immunofluorescence assay is used to examine the status of glial cells. Results CE abrogated Aβ toxicity and inhibited apoptosis in cultured neurons, mainly by regulating the BDNF, FGF2, and TrkB/Akt signaling pathways as well as RIP1-driven inflammation and necroptosis. Similarly, mice injected intracerebrally with Aβ exhibited cognitive deficits and had elevated oxidative stress and inflammatory factors detected in their serum and brain. However, CE-treated mice showed recovery of cognitive abilities and quelled levels of oxidative stress and inflammatory factors. Moreover, Aβ toxicity led to a reduction in BDNF, FGF2, and related signaling regulators in the hippocampus and prefrontal cortex, accompanied by activation of RIP1-driven inflammatory signaling pathways, and a reduction in TBK1 and Bcl-2. However, CE restored the levels of BDNF, FGF2, and TrkB/Akt signaling pathway, while inhibiting RIP1-induced RIP1/RIP3/MLKL pathway, thereby antagonizing apoptosis and maintaining neuronal activity. Conclusions CE effectively eliminated the toxicity of Aβ in cultured neurons and mouse models, which holds promise for drug development .
研究领域:
神经药理学
·
民族药理学
·
分子生物学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2022
·Vol. 48
·期 2
·570-578
·
IF 4.414
Guo Shenglong,Lei Qi,Guo Hena,Yang Qian,Xue Yanli,Chen Ruili
Ferroptosis and neuroinflammation play a crucial role in the pathogenesis of Alzheimer’s disease (AD), and Edaravone (EDA) has been demonstrated to have anti-inflammatory, antioxidant and neuroprotective effects in neurodegenerative diseases. However, the relationship between EDA and ferroptosis in AD is unidentified. This research aimed to elucidate the mechanism of EDA in AD with Aβ 1-42-induced HT22 cells as in vitro cell model. The results showed that EDA could significantly reduce Aβ 1-42 -induced apoptosis of HT22 cells and formation of pro-inflammatory factors TNF-α, IL-1β and IL-6, prevent the activation of TLR4/NF-κB /NLRP3 signaling pathway, and inhibit ferroptosis and lipid peroxidation. Taken together, EDA contributes to inhibiting neuroinflammatory injury and ferroptosis in Aβ 1-42-induced HT22 cells, and thus may be a potential candidate for the treatment of AD.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TALANTA
·
2017
·
IF 4.162
Ling-Feng Jiang,Bo-Cheng Chen,Ben Chen,Xue-Jian Li,Hai-Lin Liao,Hong-Miao Huang,Zhan-Jing Guo,Wen-Yan Zhang,Lin Wu
A sensitive and stable bioassay for the detection of Aβ oligomer (Aβo), a potentially promising candidate biomarker for Alzheimer's disease (AD) diagnosis, was developed using Fe 3 O 4 magnetic nanoparticles (MNPs) as the recognition and concentration elements and BaYF 5 :Yb,Er upconversion nanoparticles (UCNPs) as highly sensitive labels, conjugated with the Aβo aptamer (DNA1) and the complementary oligonucleotide of the Aβo aptamer (DNA2), respectively. The DNA1 hybridized with DNA2 to form the duplex structure on the surface of the MNPs/UCNPs nanocomposites probe. When the target Aβo was introduced, the aptamer DNA1 preferentially bound with Aβo and caused the dissociation of some complementary DNA2, liberating some UCNP-labeled complementary DNA2 and leading to a decreased upconversion fluorescent intensity on the surface of MNPs. The decreased fluorescence intensity of UCNPs was related to the concentration of Aβo in the range of 0.2–15 nM with a detection limit of 36 pM. The developed method then was successfully applied to measure Aβo in artificial cerebrospinal fluid. Benefiting from the magnetic separation and concentration effect of MNPs, the high sensitivity of UCNPs, as well as the selectivity and stability of the aptamer, the present strategy offered valuable information related to early diagnosis of AD process.
研究领域:
纳米技术
·
生物材料
·
神经科学
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2017
·
IF 3.883
Jing Sun,Wenjie Xie,Xufeng Zhu,Mengmeng Xu,Jie Liu
Functionalized nanomaterials, which have been applied widely to inhibit amyloid-β protein (Aβ) aggregation, show enormous potential in the field of prevention and treatment of Alzheimer’s disease (AD). A significant body of data has demonstrated that the morphology and size of nanomaterials have remarkable effects on their biological behaviors. In this work, we proposed and designed three kinds of brain-targeting sulfur nanoparticles (RVG@Met@SNPs) with novel morphologies (volute-like, tadpole-like, and sphere-like) and investigated the effect of different RVG@Met@SNPs on Aβ–Cu2+ complex aggregation and their corresponding neurotoxicity. Among them, the sphere-like nanoparticles (RVG@Met@SS) exhibited the most effective inhibitory activity, due to their unique mini size effect, and they reduced 61.6% the Aβ–Cu2+ complex aggregation and increased 92.4% SH-SY5Y cell viability in a dose of 10 μg/mL. In vitro and in vivo, the abilities of different morphologies of RVG@Met@SNPs to cross the blood–brain barrier (BBB) and target brain parenchymal cells were significantly different. Moreover, improvements in learning disability and cognitive loss were shown in the transgenic AD mice model using the Morris water maze test after multiple doses of RVG@Met@SNPs treatment. In general, the purpose of this research is to develop a biological application of sulfur nanoparticles and to provide a novel functionalized nanomaterial to treat AD.
研究领域:
纳米技术
·
神经科学
·
药学科学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Jinman Liu,Xue Zuo,Mingjun Huang,Jiansong Fang,Weirong Li,Qing Shi,Qi Wang,Yong Liang
This study aimed to investigate the potential effects of Gomisin B, a natural compound known for its inhibition of CYP3A4, on cognitive dysfunction in APP/PS1 transgenic mice with Alzheimer's disease (AD). Additionally, the study explored the combined effects of Gomisin B and Osthole (OST). The research involved male wild-type (WT) mice and 7-month-old APP/PS1 transgenic AD mice. The assessment of behavioral changes included the use of the open field test (OFT) and the Morris water maze (MWM). OST levels in brain tissue were quantified using LC-MS/MS, while levels of oxidative stress were measured through an assay kit. Neuronal apoptosis was studied using Nissl staining, RT-qPCR, and immunofluorescence. Amyloid plaque clearance was assessed using thioflavine-S (Th-S) staining, RT-qPCR, and ELISA. The results of the study revealed that Gomisin B led to a significant improvement in cognitive dysfunction in APP/PS1 mice. Moreover, the simultaneous administration of OST and Gomisin B demonstrated enhanced therapeutic effects. These effects were attributed to the inhibition of β-site APP-Cleaving Enzyme 1 (BACE1) and oxidative stress by Gomisin B, along with its anti-apoptotic properties. The combined use of OST and Gomisin B exhibited a synergistic impact, resulting in more pronounced anti-oxidant and anti-apoptotic effects. In summary, this study pioneers the exploration of Gomisin B's multifunctional anti-AD properties in APP/PS1 mice. The findings provide a solid groundwork for the development of anti-Alzheimer's drugs based on natural active ingredients.
研究领域:
神经科学
·
药理学
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2024
·
IF 10.7
Mengfei Chen,Zhenjun Zhu,Shujian Wu,Aohuan Huang,Zhiqing Xie,Jie Cai,Rong Huang,Shubo Yu,Ming Liu,Jumei Zhang,Yuchung Tse,Qingping Wu,Juan Wang,Yu Ding
Oxidative stress (OS) and disruption of proteostasis caused by aggregated proteins are the primary causes of cell death in various diseases. Selenopeptides have shown the potential to control OS and alleviate inflammatory damage, suggesting promising therapeutic applications. However, their potential function in inhibiting proteotoxicity is not yet fully understood. To address this gap in knowledge, this study aimed to investigate the effects and underlying mechanisms of the selenopeptide VPRKL(Se)M on amyloid β protein (Aβ) toxicity in transgenic Caenorhabditis elegans . The results revealed that supplementation with VPRKL(Se)M can alleviate Aβ-induced toxic effects in the transgenic C. elegans model. Moreover, the addition of VPRKL(Se)M inhibited the Aβ aggregates formation, reduced the reactive oxygen species (ROS) levels, and ameliorated the overall proteostasis. Importantly, we found that the inhibitory effects of VPRKL(Se)M on Aβ toxicity and activation of the unfolded protein are dependent on skinhead-1 (SKN-1). These findings suggested that VPRKL(Se)M is a potential bioactive agent for modulating SKN-1, which subsequently improves proteostasis and reduces OS. Collectively, the findings from the current study suggests VPRKL(Se)M may play a critical role in preventing protein disorder and related diseases.
研究领域:
神经科学
·
生物化学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yadan Zhang,Xiaoyu Zhang,Tianhan Kai,Lin Zhang,Anping Li
Plant-derived exosome-like nanovesicles (ELNs) are nano-sized vesicles extracted from edible plants. Lycium ruthenicum Murray (LRM) has been gaining increasing attention due to its nutritional and medicinal value, but the ELNs in LRM has not been reported. In this study, LRM-ELNs were obtained, and the proteins, lipids, microRNAs (miRNAs) and active components in LRM tissues and LRM-ELNs was analyzed by LC-MS/MS, LC-MS, high-throughput sequencing techniques, and physical and chemical analysis. LRM-ELNs can be uptaken by PC12 cells through macropinocytosis and caveolin-mediated endocytosis primarily. Transcriptomic and western blot experiments indicate that LRM-ELNs can inhibit Aβ-induced apoptosis in PC12 cells through the MAPK and PI3K/AKT signaling pathways, with miRNAs playing a crucial role. These results indicate that LRM-ELNs have the protection effect on PC12 cells and can be considered as dietary supplements for alleviating neurodegenerative diseases.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2017
·Vol. 42
·期 11
·3061-3072
·
IF 2.581
He Qidi,Huang Guan,Chen Yixin,Wang Xiaoqin,Huang Zhishu,Chen Zuanguang
Cerebral deposition of amyloid β-peptide (Aβ), a fundamental feature of Alzheimer’s disease (AD), damages the neurocytes and impairs the cognition functions and associative learning memory of AD patients. A series of novel 2-arylethenylquinoline derivatives were synthesized and evaluated in our previous study, which inhibited Aβ aggregation in vitro effectively at the concentration of 20 μmol/L and exhibited high antioxidant activity. In order to verify the capacity of anti-AD in vivo, the transgenic Caenorhabditis elegans ( C. elegans ) strain CL2355 expressing neural Aβ was employed as the AD model to investigate the neuroprotective activity of seven high-potential compounds (4a1, 4a2, 4b1, 4b2, 4c1, 4c2, 4c3) selected from those derivatives. Learning memory associated chemotaxis assay was performed to evaluate the neural repairment capacity. The underlying mechanism was investigated by mRNA analysis of Aβ gene and heat shock protein genes ( hsp-16.1 and hsp-16.2 ) and Western blot of Aβ. Our data indicated that among seven tested compound, 4b1 and 4c2 reduced Aβ-induced stress, suppressed the expression of neural Aβ monomers and toxic oligomers, and recovered the damaged associative learning memory in C. elegans AD model. These findings further confirmed their potentials to become valuable agents for AD therapy.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2020
·
IF 5.977
Chang Liu,Dingkun Lu,Xinrui You,Guoyue Shi,Jingjing Deng,Tianshu Zhou
Herein, a novel ratiometric fluorescent probe based on [email protected] /GMP ICP nanoparticles was developed for the detection of Aβ monomer in rat as a biomarker for Alzheimer’s disease (AD) by fully exploring the competitive coordination interaction and by taking advantage of excellent optical property of carbon dots sensitized lanthanide infinite coordination polymer (ICP) nanoparticles. The carbon dots (CDs) with abundant functional groups were encapsulated into Eu/GMP ICPs through self-adaptive chemistry , which could not only sensitize the red fluorescence of Eu/GMP ICPs effectively, but also act as an internal reference for self-correction. In the absence of Cu 2+ , the as-formed [email protected] /GMP ICPs exhibited the characteristic emission of CDs at 400 nm and strong emission of Eu 3+ at 592 nm, 615 nm, 650 nm and 694 nm. With the addition of Cu 2+ , the red fluorescence of Eu 3+ decreased due to the coordination interaction between CDs and Cu 2+ , thus destroyed the antenna effect. After the subsequent addition of Aβ monomer, the specific binding occurred between Cu 2+ and Aβ monomer, and then the red fluorescence of Eu 3+ restored again. During this process, the fluorescence of CDs remained unchanged, thus could be used as an internal reference to cancel out the environmental fluctuation and was more adaptive for the detection of Aβ monomer in biological fluids. The method demonstrated here was highly sensitive, free from the interference of other species in rat brain, the in vivo analysis of Aβ monomer in CSF and different brain regions from normal rats and Alzheimer’s rats could be realized, which was of great significance for better understanding the mechanism of AD and paving the way to understand the chemical essence involved in AD.
研究领域:
纳米技术
·
荧光光谱
·
生物标志物检测
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Jia Xi Ye,Jia Ying Wu,Liang Ai,Min Zhu,Yun Li,Dong Yin,Qihui Huang
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the significant involvement of amyloid-beta (Aβ) peptide in its pathogenesis. Geniposide, derived from the versatile medicinal of Gardenia jasminoides , is one of the active compounds studied extensively. The objective was to explore the impact of geniposide on Aβ 25-35 -induced damage in HT22 cells, specifically focusing on its modulation of PINK1/Parkin-mediated mitophagy. In our investigation, geniposide exhibited remarkable restorative effects by enhancing cell viability and preserving the mitochondrial membrane potential. Moreover, it effectively reduced and mitigated the oxidative stress and apoptosis rates induced by Aβ 25-35 . Notably, geniposide exhibited the capacity to enhance autophagic flux, upregulate LC3II and Beclin-1 expression, and downregulate the expression of p62. Furthermore, geniposide positively influenced the expression of PINK1 and Parkin proteins, with molecular docking substantiating a strong interaction between geniposide and PINK1/Parkin proteins. Intriguingly, the beneficial outcomes of geniposide on alleviating the pronounced apoptosis rates, the overproduction of reactive oxygen species, and diminished the PINK1 and Parkin expression induced by Aβ 25-35 were compromised by the mitophagy inhibitor cyclosporine A (CsA). Collectively, these findings suggested that geniposide potentially shields HT22 cells against neurodegenerative damage triggered by Aβ 25-35 through the activation of mitophagy. The insights contribute valuable references to the defensive consequences against neurological damage of geniposide, thereby highlighting its potential as a therapeutic intervention in AD.
研究领域:
神经科学
·
药理学
·
细胞生物学
·
分子生物学
·
神经退行性疾病
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）