CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Tao Peng,Xu Lu,Yang Jin,Xicheng Yang,Qian Liu,Chen Chen,Wanting Zhou,Yuting Guo,Yu Zhang,Yankun Gao,Hongjuan Zhang,Hongliang He,Lina Chen
It is effective through uncoupling postsynaptic density protein-95 (PSD95) and neuronal nitric oxide synthase (nNOS) for treating ischemic stroke with high disability, mortality and recurrence rate. However, there are no reliable uncouplers for PSD95-nNOS in clinical practice, and the established screening models for discovering PSD95-nNOS uncouplers have high costs and interference. In this study, epoxy functional fluorescent magnetic mesoporous silica (EFMMS) was synthesized by combining carbon dots (CDs), magnetic mesoporous silica and epoxy functionalization. Ni-EFMMS was further constructed by loading nickel ions to simultaneously purify and covalently immobilize His-tagged neuronal nitric oxide synthase (His-nNOS) and then couple with green fluorescent proteins (GFP) labeled PSD95, finally fabricating nano-biosensor (PSD95-nNOS/Ni-EFMMS). The nanomaterial was well constructed and characterized, and it distinctly constituted stable ratio fluorescence between CDs and GFP-PSD95. The ratio fluorescence intensity of PSD95-nNOS/Ni-EFMMS remained stable even after separately mixing with metal ions, amino acids and natural impurities, and the loss of ratio fluorescence intensity was less than 20% even at pH 4 or 10. PSD95-nNOS/Ni-EFMMS still kept the ratio fluorescence intensity above 90% after being recycled for seven times. Three compounds (gnetol, baicalein and emodin-8- O -β- D -glucoside) with strong uncoupling efficiency were screened from fourteen natural active ingredients. Furthermore, the theoretical feasibility of uncoupling was verified by molecular docking. In general, this study provides a novel “one-stone-four-birds strategy” to fabricate magnetic mesoporous nano-ratio fluorescence sensor for efficiently and accurately discovering PSD95-nNOS uncoupling active substances.
研究领域:
神经生物学
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药物化学
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生物传感技术
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产品关联
DOI
高影响因子
Journal of Materials Chemistry B
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2018
·Vol. 6
·期 10
·1531-1542
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IF 4.776
Jiaojiao Huang,Chenghong Sun,Dandan Yao,Chong-Zhi Wang,Lei Zhang,Yu Zhang,Lina Chen,Chun-Su Yuan
In the search for novel efficient nNOS–PSD-95 (nitric oxide synthase–postsynaptic density protein-95) uncouplers from natural products for stroke treatment, highly selective surface molecular imprinted polymers based on sandwich structured magnetic mesoporous silica (Fe3O4@nSiO2@mSiO2@MIPs, MMS@MIPs) were designed and optimized as artificial antibodies. The resultant polymers exhibited satisfactory adsorption performance and excellent recyclability, and were successfully utilized as sorbents to capture candidate uncouplers from natural products. Furthermore, the biological activity and the functional mechanism of the obtained candidates were investigated in vivo and in vitro. Consequently, coptisine, chelerythrine and nitidine chloride presented both potent neuroprotective effects on glutamate-injured PC12 cells and uncoupling activity targeting nNOS–PSD-95 in vitro. Simultaneously, they effectively ameliorated neurological deficit and reduced infarct volume of MCAO/R (middle cerebral artery occlusion and reperfusion) rats. Therefore, coptisine, chelerythrine and nitidine chloride were considered the most promising nNOS–PSD-95 uncouplers for further preclinical studies of ischemic stroke treatment.
研究领域:
药理学
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材料科学
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神经科学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
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2020
·Vol. 10
·期 13
·7671-7681
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IF 3.119
Linli Pan,Yingying Ding,Xiaoting Ni,Chong-Zhi Wang,Bo Jiang,Yu Zhang,Nan Jiang,Yulin Tang,Lina Chen,Chun-Su Yuan
Novel and highly selective molecularly imprinted polymers based on the surface of metal–organic frameworks, NH2-MIL-101(Cr) (MIL@MIPS), were successfully fabricated to capture neuronal nitric oxide synthase–postsynaptic density protein-95 (nNOS–PSD-95) uncouplers from Sanhuang Xiexin Decoction (SXD) for stroke treatment. The resultant polymers were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis, and X-ray diffraction. The performance tests revealed that MIL@MIPs had a large binding capacity, fast kinetics, and excellent selectivity. Then the obtained polymers were satisfactorily applied to solid-phase extraction coupled with high-performance liquid chromatography to selectively capture nNOS–PSD-95 uncouplers from SXD. Furthermore, the biological activities of components obtained from SXD were evaluated in vivo and in vitro. As a consequence, the components showed a potent neuroprotective effect from the MTS assay and uncoupling activity from the co-immunoprecipitation experiment. In addition, the anti-ischemic stroke assay in vivo was further investigated to determine the effect of reducing infarct size and ameliorating neurological deficit by the active components. Therefore, this present study contributes a valuable new method and new tendency to selectively capture active components for stroke treatment from SXD and other natural medicines.
研究领域:
药学
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材料科学
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神经科学
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中医
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2025
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IF 8.4
Chen Yu-qi,Ye Jun-rui,Wang Sha-sha,Peng Ye,Zhou Run,Yuan Ruo-lan,Wang Wen-fei,Chu Shi-feng,Zhang Zhao,Chen Nai-hong
Selective serotonin reuptake inhibitors (SSRIs) are characterized by delayed therapeutic onset largely due to their reliance on the desensitization of 5-HT 1A autoreceptors (5-HT 1A R auto s) within the dorsal raphe nucleus (DRN). It has been shown that dissociation of serotonin transporter (SERT) and neuronal nitric oxide synthase (nNOS) interaction selectively modulates 5-HT 1A R auto s, thereby facilitating fast-onset antidepressant responses. Targeting the atypical disk large/ZO-1 (PDZ) domain has been implicated in the SERT-nNOS interaction. In this study, we established a drug screening system based on mBRET combined with biological tests to find SERT-nNOS interaction blockers (SNIBs). During screening the compound libraries, 9 top candidates were found to be capable of binding to the PDZ domain of nNOS. We then identified esflurbiprofen as a promising fast-onset antidepressant candidate. Pharmacodynamic studies revealed that esflurbiprofen effectively penetrated the DRN following systemic administration. Esflurbiprofen (10, 20, 40 mg/kg, i.p., once every 4 days) dose-dependently ameliorated depressive-like behaviors in mice subjected to chronic social defeat stress (CSDS) and chronic restraint stress (CRS). In rs-fMRI analysis, we found that esflurbiprofen enhanced the functional connectivity of emotion-related neural networks in CSDS mice. We further demonstrated that esflurbiprofen disrupted the SERT-nNOS complex in the DRN, augmented membrane-associated SERT, and reduced the concentration of 5-HT in the extracellular space of the DRN. This cascade subsequently enhanced serotonergic neuronal firing through the inhibition of negative feedback mediated by 5-HT 1A R auto s, culminating in an augmented release of 5-HT from serotonergic neurons projecting to the prefrontal cortex and hippocampus. These results highlight the potential of esflurbiprofen to induce rapid antidepressant effects by targeting the SERT-nNOS interaction within the DRN.
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2018
·
IF 2.831
Dandan Yao,Lei Zhang,Jiaojiao Huang,Chenghong Sun,Yu Zhang,Xiaoli Gu,Chong-Zhi Wang,Fei Li,Lina Chen,Chun-Su Yuan
In this work, surface magnetic molecularly imprinted polymers (SMMIPs) were synthesized and used as artificial receptors in the dispersive magnetic solid phase extraction (DMSPE) for capturing potential neuronal nitric oxide synthase–post synaptic density protein-95 (nNOS–PSD-95) uncouplers, which is known as neuroprotection against stroke. Factors that affected selective separation and adsorption of the artificial receptors, such as the amount of template, the types of functional monomer and porogen solvents, and the molar ratio of template/functional monomer/cross-linker were optimized. The artificial receptors were also characterized using fourier transformed infrared, scanning electron microscope, thermal gravimetric analysis and physical property measurement systems. Multiple interactions between template and SMMIPs led to larger binding capacities, faster binding kinetics, quicker separation abilities and more efficient selectivity than the surface magnetic nonimprinted polymers (SMNIPs). The SMMIPs were successfully applied to capture potential nNOS–PSD-95 uncouplers from complex samples, and eight compounds were seized and confirmed rapidly when combined with HPLC and MS. The detection of the new nNOS–PSD-95 uncouplers ranged from 0.001 to 1.500 mg/mL with correlation coefficients of 0.9990–0.9995. The LOD and LOQ were 0.10–0.68 μg/mL and 0.47–2.11 μg/mL, respectively. The neuroprotective effect and co-immunoprecipitation test in vitro revealed that Emodin-1- O -β- d -glucoside, Rhaponticin, Gnetol and 2,3,5,4′-Tetrahydroxystilbene-2- O -β- d -glucoside have neuroprotective and uncoupling activities, and that they may be the new uncouplers of nNOS–PSD-95
研究领域:
药理学
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分析化学
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神经科学
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DOI
PubMed
高影响因子
Frontiers in Behavioral Neuroscience
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2021
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IF 3.558
Yin Ying,Qian Shiyu,Chen Yifan,Sun Yan,Li Yuqiao,Yu Yongfei,Li Jianqing,Wu Zhangjie,Yu Xinlang,Ge Rui,Han Jia,Sun Dongdong,Wu Haoxin,Liu Lanying,Xue Wenda,Wang Wei
Previous studies have demonstrated that Yueju-Ganmaidazao (YG) decoction induces rapid antidepressant-like effects, and the antidepressant response is mostly dependent on the suppression of nitric oxide-cyclic guanosine monophosphate signaling in male mice. This study aimed to investigate the sex difference mediated by calcium/calmodulin-dependent protein kinase II (CaMKII)-neuronal nitric oxide synthase (nNOS) signaling involved in the antidepressant-like effect of YG in mice. We found that the immobility times in the tail suspension test (TST) were found to be decreased after the single injection of YG in male and female mice with the same dosage. Additionally, chronic administration for 4 days of subthreshold dosage of YG and escitalopram (ES) also significantly decreased the immobility time in mice of both sexes. Chronic subthreshold dosage of YG and ES in LPS-treated mice and in chronic unpredictable stress (CUS) mice both decreased the immobility time, which was increased by stress. Meanwhile, in CUS-treated mice, sucrose preference test, forced swimming test, and open field test were applied to further confirm the antidepressant-like effects of YG and ES. Moreover, CUS significantly decreased the expression of nNOS and CaMKII, and both YG and ES could enhance the expression in the hippocampus of female mice, which was opposite to that in male mice, while endothelial nitric oxide synthase expression was not affected by stress or drug treatment neither in male mice nor in female mice. Finally, subthreshold dosage of YG combined with 7-nitroindazole (nNOS inhibitor) induced the antidepressant-like effects both in female and in male mice, while the single use of YG or 7-NI did not display any effect. However, pretreatment with KN-93 (CaMKII inhibitor) only blocked the antidepressant-like effect of high-dosage YG in female mice. Meanwhile, in CUS mice, chronic stress caused NR1 overexpression and inhibited cAMP response element binding protein action, which were both reversed by YG and ES in male and female mice, implying that YG and ES produced the same antidepressant-like effect in mice of both sexes. The study revealed that chronic treatment with a subthreshold dose of YG also produced antidepressant-like effects in female mice, and these effects depended on the regulation of the CaMKII-nNOS signaling pathway.
研究领域:
药理学
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神经科学
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行为科学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-15
·
IF 9.429
Ding Yingying,Jin Yang,Peng Tao,Gao Yankun,Zang Yang,He Hongliang,Li Fei,Zhang Yu,Zhang Hongjuan,Chen Lina
Background Disruption of the postsynaptic density protein-95 (PSD95)—neuronal nitric oxide synthase (nNOS) coupling is an effective way to treat ischemic stroke, however, it still faces some challenges, especially lack of satisfactory PSD95-nNOS uncouplers and the efficient high throughput screening model to discover them. Results Herein, the multifunctional metal–organic framework (MMOF) nanoparticles as a new screening system were innovatively fabricated via layer-by-layer self-assembly in which His-tagged nNOS was selectively immobilized on the surface of magnetic MOF, and then PSD95 with green fluorescent protein (GFP-PSD95) was specifically bound on it. It was found that MMOF nanoparticles not only exhibited the superior performances including the high loading efficiency, reusability, and anti-interference ability, but also possessed the good fluorescent sensitivity to detect the coupled GFP-PSD95. After MMOF nanoparticles interacted with the uncouplers, they would be rapidly separated from uncoupled GFP-PSD95 by magnet, and the fluorescent intensities could be determined to assay the uncoupling efficiency at high throughput level. Conclusions In conclusion, MMOF nanoparticles were successfully fabricated and applied to screen the natural actives as potential PSD95-nNOS uncouplers. Taken together, our newly developed method provided a new material as a platform for efficiently discovering PSD95-nNOS uncouplers for stoke treatment. Graphical Abstract
研究领域:
药理学
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神经科学
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材料科学
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产品关联
DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2023
·Vol. 29
·期 4
·1000-1011
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IF 5.5
Di Zhang,Bei Jing,Zhen-ni Chen,Xin Li,Hui-mei Shi,Ya-chun Zheng,Shi-quan Chang,Li Gao,Guo-ping Zhao
Introduction Sciatica causes intense pain. No satisfactory therapeutic drugs exist to treat sciatica. This study aimed to probe the potential mechanism of ferulic acid in sciatica treatment. Methods Thirty-two SD rats were randomly divided into 4 groups: sham operation, chronic constriction injury (CCI), mecobalamin, and ferulic acid. We conducted RNA sequencing, behavioral tests, ELISA, PCR, western blotting, and immunofluorescence analysis. TAK-242 and JSH23 were administered to RSC96 and GMI-R1 cells to explore whether ferulic acid can inhibit apoptosis and alleviate inflammation. Results RNA sequencing showed that TLR4/NF-κB pathway is involved in the mechanism of sciatica. CCI induced cold and mechanical hyperalgesia; destroyed the sciatic nerve structure; increased IL-1β, IL-6, TNF-α, IL-8, and TGF-β protein levels and IL-1β, IL-6, TNF-α, TGF-β, TLR4, and IBA-1 mRNA levels; and decreased IL-10 and INF-γ protein levels and IL-4 mRNA levels. Immunohistochemistry showed that IBA-1, CD32, IL-1β, iNOS, nNOS, COX2, and TLR4 expression was increased while S100β and Arg-1 decreased. CCI increased TLR4, IBA-1, IL-1β, iNOS, Myd88, p-NF-κB, and p-p38MAPK protein levels. Treatment with mecobalamin and ferulic acid reversed these trends. Lipopolysaccharide (LPS) induced RSC96 cell apoptosis by reducing Bcl-2 and Bcl-xl protein and mRNA levels and increasing Bax and Bad mRNA and IL-1β, TLR4, Myd88, p-NF-κB, and p-p38MAPK protein levels, while ferulic acid inhibited cell apoptosis by decreasing IL-1β, TLR4, Myd88, p-NF-κB, and p-p38MAPK levels and increasing Bcl-2 and Bcl-xl levels. In GMI-R1 cells, Ferulic acid attenuated LPS-induced M1 polarization by decreasing the M1 polarization markers IL-1β, IL-6, iNOS, and CD32 and increasing the M2 polarization markers CD206, IL-4, IL-10 and Arg-1. After LPS treatment, IL-1β, iNOS, TLR4, Myd88, p-p38MAPK, and p-NF-κB levels were obviously increased, and Arg-1 expression was reduced, while ferulic acid reversed these changes. Conclusion Ferulic acid can promote injured sciatic nerve repair by reducing neuronal cell apoptosis and inflammatory infiltration though the TLR4/NF-κB pathway.
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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细胞生物学
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炎症研究
✓ 已验证
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）