11 results on '"Zhang, Shijun"'
Search Results
2. Organic Anion Transporter 1 Deficiency Accelerates Learning and Memory Impairment in tg2576 Mice by Damaging Dendritic Spine Morphology and Activity
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Wu, Xinlin, Zhang, Jianqing, Liu, Heng, Mian, Yansheng, Liang, Birong, Xie, Hongbo, Zhang, Shijun, Sun, Baoguo, and Zhou, Houming
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- 2015
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3. A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer's Disease Transgenic Mice.
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Kuwar, Ram, Rolfe, Andrew, Di, Long, Blevins, Hallie, Xu, Yiming, Sun, Xuehan, Bloom, George S., Zhang, Shijun, and Sun, Dong
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NLRP3 protein ,COGNITIVE ability ,INFLAMMASOMES ,ALZHEIMER'S disease ,TRANSGENIC mice ,SMALL molecules - Abstract
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns. Among the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the pathogenesis of AD.Objective: We recently developed a novel class of small molecule inhibitors that selectively target the NLRP3 inflammasome. One of the lead compounds, JC124, has shown therapeutic efficacy in a transgenic animal model of AD. In this study we tested the preventative efficacy of JC124 in another strain of transgenic AD mice.Methods: In this study, 5-month-old female APP/PS1 and matched wild type mice were treated orally with JC124 for 3 months. After completion of treatment, cognitive functions and AD pathologies, as well as protein expression levels of synaptic proteins, were assessed.Results: We found that inhibition of NLRP3 inflammasome with JC124 significantly decreased multiple AD pathologies in APP/PS1 mice, including amyloid-β (Aβ) load, neuroinflammation, and neuronal cell cycle re-entry, accompanied by preserved synaptic plasticity with higher expression of pre- and post-synaptic proteins, increased hippocampal neurogenesis, and improved cognitive functions.Conclusion: Our study demonstrates the importance of the NLRP3 inflammasome in AD pathological development, and pharmacological inhibition of NLRP3 inflammasome with small molecule inhibitors represents a potential therapy for AD. [ABSTRACT FROM AUTHOR]- Published
- 2021
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4. Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease.
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Saathoff, John M., Liu, Kai, Chojnacki, Jeremy E., He, Liu, Chen, Qun, Lesnefsky, Edward J., and Zhang, Shijun
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NEUROPROTECTIVE agents ,ALZHEIMER'S disease ,MITOCHONDRIA ,ENDOPLASMIC reticulum ,TETRACYCLINE - Abstract
We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer's disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca
2+ levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca2+ level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca2+ in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action. [ABSTRACT FROM AUTHOR]- Published
- 2016
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5. Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer's Disease.
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Liu, Kai, Chojnacki, Jeremy E, Wade, Emily E, Saathoff, John M, Lesnefsky, Edward J, Chen, Qun, and Zhang, Shijun
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CALCIUM metabolism ,PROTEIN metabolism ,ALZHEIMER'S disease ,ANIMAL experimentation ,APOPTOSIS ,BIOLOGICAL transport ,BRAIN ,CELL lines ,CHOLESTEROL ,CYTOPLASM ,MICE ,MOLECULAR structure ,PEPTIDES ,RESEARCH funding ,NEUROPROTECTIVE agents ,CURCUMIN ,PHARMACODYNAMICS ,PHYSIOLOGY - Abstract
Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer's disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aβ species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD. [ABSTRACT FROM AUTHOR]
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- 2015
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6. Development of bivalent compounds as potential neuroprotectants for Alzheimer's disease.
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He, Liu, Jiang, Yuqi, Green, Jakob, Blevins, Hallie, and Zhang, Shijun
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ALZHEIMER'S disease , *NEUROPROTECTIVE agents , *DRUG design , *REACTIVE oxygen species , *CHOLESTEROL - Abstract
In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC 50 of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer's disease. [ABSTRACT FROM AUTHOR]
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- 2019
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7. Design and characterization of bivalent compounds as potential neuroprotectants for Alzheimer’s disease: Impact of the spacer on biological activity.
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He, Liu, Boice, Ashley, Liu, Kai, Yan, Xing, Jiang, Yuqi, and Zhang, Shijun
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PIPERAZINE , *CHELATING agents , *CHEMICAL synthesis , *NEUROPROTECTIVE agents , *GENETICS of Alzheimer's disease - Abstract
In our continuing efforts to develop bivalent compounds as potential neuroprotectants for Alzheimer’s disease, a series of bivalent compounds that contain cholesterylamine and an extended spacer were synthesized and biologically characterized. Our results demonstrated that incorporation of a piperazine ring into the spacer composition significantly improved the protective potency in MC65 cell models. Our results also suggested that the optimal spacer length for such bivalent compounds ranges from 17 to 21 atoms, and further spacer extension beyond 21 atoms results no further optimization. Notably, incorporation of a piperazine ring into the spacer diminished the biometal chelating capacity for these bivalent compounds, thus suggesting structural flexibility of these compounds in interactions with metals. Collectively, the results provided valuable guidance to develop new bivalent compounds as neuroprotectants for Alzheimer’s disease. [ABSTRACT FROM AUTHOR]
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- 2018
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8. Catechol-containing compounds are a broad class of protein aggregation inhibitors: Redox state is a key determinant of the inhibitory activities.
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Velander, Paul, Wu, Ling, Hildreth, Sherry B., Vogelaar, Nancy J., Mukhopadhyay, Biswarup, Helm, Richard F., Zhang, Shijun, and Xu, Bin
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CATECHOL-O-methyltransferase , *CATECHOL , *QUINONE , *SMALL molecules , *LABORATORY rats , *ALZHEIMER'S disease , *PROTEINS , *TYPE 2 diabetes - Abstract
A range of neurodegenerative and related aging diseases, such as Alzheimer's disease and type 2 diabetes, are linked to toxic protein aggregation. Yet the mechanisms of protein aggregation inhibition by small molecule inhibitors remain poorly understood, in part because most protein targets of aggregation assembly are partially unfolded or intrinsically disordered, which hinders detailed structural characterization of protein-inhibitor complexes and structural-based inhibitor design. Herein we employed a parallel small molecule library-screening approach to identify inhibitors against three prototype amyloidogenic proteins in neurodegeneration and related proteinopathies: amylin, Aβ and tau. One remarkable class of inhibitors identified from these screens against different amyloidogenic proteins was catechol-containing compounds and redox-related quinones/anthraquinones. Secondary assays validated most of the identified inhibitors. In vivo efficacy evaluation of a selected catechol-containing compound, rosmarinic acid, demonstrated its strong mitigating effects of amylin amyloid deposition and related diabetic pathology in transgenic HIP rats. Further systematic investigation of selected class of inhibitors under aerobic and anaerobic conditions revealed that the redox state of the broad class of catechol-containing compounds is a key determinant of the amyloid inhibitor activities. The molecular insights we gained not only explain why a large number of catechol-containing polyphenolic natural compounds, often enriched in healthy diet, have anti-neurodegeneration and anti-aging activities, but also could guide the rational design of therapeutic or nutraceutical strategies to target a broad range of neurodegenerative and related aging diseases. [Display omitted] • Parallel drug library screening identified catechol-containing compounds as a broad class of amyloid inhibitors. • Multiple secondary assays validated most of the identified inhibitors, including in vivo efficacy of rosmarinic acid. • Aerobic but not anaerobic conditions significantly enhanced anti-amyloid activities of the catechol-containing compounds. • Reducing biochemical agents blocked or diminished amyloid remodeling/inhibition activities of catechol-containing inhibitors. • Explain why catechol-containing compounds, enriched in healthy diet, have anti-neurodegeneration and anti-aging effects. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer’s disease.
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Chojnacki, Jeremy E., Liu, Kai, Saathoff, John M., and Zhang, Shijun
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LIGAND analysis , *CURCUMIN , *ALZHEIMER'S disease treatment , *DIOSGENIN , *DISEASE progression , *DRUG synthesis - Abstract
In an effort to combat the multifaceted nature of Alzheimer’s disease (AD) progression, a series of multifunctional, bivalent compounds containing curcumin and diosgenin were designed, synthesized, and biologically characterized. Screening results in MC65 neuroblastoma cells established that compound 38 with a spacer length of 17 atoms exhibited the highest protective potency with an EC 50 of 111.7 ± 9.0 nM. A reduction in protective activity was observed as spacer length was increased up to 28 atoms and there is a clear structural preference for attachment to the methylene carbon between the two carbonyl moieties of curcumin. Further study suggested that antioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formation may contribute to the neuroprotective outcomes. Additionally, compound 38 was found to bind directly to Aβ, similar to curcumin, but did not form complexes with the common biometals Cu, Fe, and Zn. Altogether, these results give strong evidence to support the bivalent design strategy in developing novel compounds with multifunctional ability for the treatment of AD. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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10. Structural understanding of 5-(4-hydroxy-phenyl)-N-(2-(5-methoxy-1H-indol-3-yl)-ethyl)-3-oxopentanamide as a neuroprotectant for Alzheimer's disease.
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Saathoff, John, Green, Jakob, Jiang, Yuqi, Xu, Yiming, Kellogg, Glen E., and Zhang, Shijun
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ALZHEIMER'S disease , *METHOXY compounds , *CYCLIC compounds , *NEUROPROTECTIVE agents , *LEAD compounds - Abstract
[Display omitted] In our continuing efforts to develop novel neuroprotectants for Alzheimer's disease (AD), a series of analogs based on a lead compound that was recently shown to target the mitochondrial complex I were designed, synthesized and biologically characterized to understand the structure features that are important for neuroprotective activities. The results from a cellular AD model highlighted the important roles of the 4-OH on the phenyl ring and the 5-OCH 3 on the indole ring of the lead compound. The results also demonstrated that the β-keto moiety can be modified to retain or improve the neuroprotective activity. Docking studies of selected analogs to the FMN site of mitochondrial complex I also supported the observed neuroprotective activities. Collectively, the results provide further information to guide optimization and development of analogs based on this chemical scaffold as neuroprotectants with a novel mechanism of action for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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11. A comparison of the location in membranes of curcumin and curcumin-derived bivalent compounds with potential neuroprotective capacity for Alzheimer's disease.
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Ausili, Alessio, Gómez-Murcia, Victoria, Candel, Adela M., Beltrán, Andrea, Torrecillas, Alejandro, He, Liu, Jiang, Yuqi, Zhang, Shijun, Teruel, José A., and Gómez-Fernández, Juan C.
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CURCUMIN , *ALZHEIMER'S disease , *NEUROPROTECTIVE agents , *FLUORESCENCE quenching , *MOLECULAR dynamics - Abstract
[Display omitted] • Curcumin adopts a carpet disposition in the membrane. • The curcumin moiety of bivalent compounds is found in a more polar environment than pure curcumin. • Curcumin and bivalent compounds show a poor miscibility with phospholipids. Curcumin and two bivalent compounds, namely 17MD and 21MO, both obtained by conjugation of curcumin with a steroid molecule that acts as a membrane anchor, were comparatively studied. When incorporated into 1,2-dipalmitoyl- sn -glycero-3-phosphocholine the compounds showed a very limited solubility in the model membranes. Curcumin and the two bivalent compounds were also incorporated in membranes of 1-palmitoyl-2-oleoyl- sn -glycero-3-phosphocholine and quenching the fluorescence of pure curcumin or of the curcumin moiety in the bivalent compounds by acrylamide it was seen that curcumin was accessible to this water soluble quencher but the molecule was somehow located in a hydrophobic environment. This was confirmed by quenching with doxyl-phosphatidylcholines, indicating that the curcumin moieties of 17MD and 21MO were in a more polar environment than pure curcumin itself. 1H NOESY MAS-NMR analysis supports this notion by showing that the orientation of curcumin was parallel to the plane of the membrane surface close to C2 and C3 of the fatty acyl chains, while the curcumin moiety of 17MD and 21MO positioned close to the polar part of the membrane with the steroid moiety in the centre of the membrane. Molecular dynamics studies were in close agreement with the experimental results with respect to the likely proximity of the protons studied by NMR and show that 17MD and 21MO have a clear tendency to aggregate in a fluid membrane. The anchorage of the bivalent compounds to the membrane leaving the curcumin moiety near the polar part may be very important to facilitate the bioactivity of the curcumin moiety when used as anti-Alzheimer drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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