Advanced Science
·
2025
·
IF 14.1
Yanan Wang,Xutao Ma,Xinyuan Wang,Liru Liu,Xue Zhang,Qiuyue Wang,Yingfei Zhu,Huanhua Xu,Liangmin Yu,Zhiyu He
The scarcity of effective neuroprotective agents and the presence of blood-brain barrier (BBB)-mediated extremely inefficient intracerebral drug delivery are predominant obstacles to the treatment of cerebral ischemic stroke (CIS). Herein, ROS-responsive borneol-based amphiphilic polymeric NPs are constructed by using traditional Chinese medicine borneol as functional blocks that served as surface brain-targeting ligand, inner hydrophobic core for efficient drug loading of membrane-permeable calcium chelator BAPTA-AM, and neuroprotective structural component. In MCAO mice, the nanoformulation (polymer: 3.2 mg·kg −1 , BAPTA-AM: 400 µg·kg −1 ) reversibly opened the BBB and achieved high brain biodistribution up to 12.7%ID/g of the total administered dose after 3 h post single injection, effectively restoring intracellular Ca 2+ and redox homeostasis, improving cerebral histopathology, and inhibiting mitochondrial PI3K/Akt/Bcl-2/Bax/Cyto-C/Caspase-3,9 apoptosis pathway for rescuing dying neurons (reduced apoptosis cell from 59.5% to 7.9%). It also remodeled the inflammatory microenvironment in cerebral ischemic penumbra by inhibiting astrocyte over-activation, reprogramming microglia polarization toward an anti-inflammatory phenotype, and blocking NF-κB/TNF- α /IL-6 signaling pathways. These interventions eventually reduced the cerebral infarction area by 96.3%, significantly improved neurological function, and restored blood flow reperfusion from 66.2% to ≈100%, all while facilitating BBB repair and avoiding brain edema. This provides a potentially effective multiple-stage sequential treatment strategy for clinical CIS.
研究领域:
药学
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神经科学
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药物递送系统
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传统中药
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中风治疗
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产品关联
DOI
PubMed
高影响因子
npj Parkinsons Disease
·
2025
·Vol. 11
·期 1
·1-16
·
IF 8.2
Chen Wen,Wang Haobo,Ye Xiang,Hao Xingkai,Yan Fujie,Wu Jian,Li Danyang,Wang Yan,Xu Lizhou
Plant-derived extracellular vesicles (EVs) show health benefits. Gardenia jasminoides Ellis, known for its neuroprotective properties, lacks therapeutic investigation on gardenia-derived extracellular vesicles (GDEVs). This study investigated the value of GDEVs in Parkinson’s disease (PD) using rotenone (Rot)-induced Parkinsonism models in dopaminergic PC12 neuron cells and Caenorhabditis elegans . PD features apoptosis in dopaminergic neurons, while GDEVs alleviate PD by mitigating mitochondrial-mediated apoptosis. Specifically, GDEVs improve Rot-induced mitochondrial dysfunction to reduce cytochrome C release and apoptosis. Consequently, GDEVs reduce the risk of PD by lowering α-synuclein levels and regulating dopamine release. RNA sequencing and subsequent studies showed that GDEVs reduce p38 MAPK and p53 phosphorylation levels, and increase the Bcl-2/Bax ratio to prevent apoptosis in PC12 cells. In Caenorhabditis elegans , we verified that GDEVs reduce PD progression by increasing dopaminergic neurons using BZ555 mutants, and enhance dopamine release and motility. This study highlights the therapeutic potential of GDEVs in preventing neurodegenerative diseases.
研究领域:
神经科学
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植物学
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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
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神经退行性疾病
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生物医学研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yue Tang,Yueyue Kang,Xinru Zhang,Caiyi Cheng
Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is a major factor in the pathogenesis of dry age-related macular degeneration (AMD). Although the therapeutic effect of mesenchymal stem cell (MSC) exosomes on dry AMD has been preliminarily discussed, the underlying mechanism has yet to be reported. Here, we demonstrate that MSC exosomes, acting as a nanodrug, can effectively reduce the incidence of dry AMD by regulating Nrf2/Keap1 signaling pathway. In the in vitro study, MSC exosomes relieved the damage of ARPE-19 cells, suppressed the activity of lactate dehydrogenase (LDH), decreased the level of reactive oxygen species (ROS) and upregulated the activity of superoxide dismutase (SOD). In the in vivo study, MSC exosomes were administered via intravitreal injection. MSC exosomes effectively protected RPE layer, photoreceptor outer segment/inner segment (OS/IS) layer and outer nuclear layer (ONL) from NaIO 3 -induced damage. Western blotting results showed that the ratio of Bcl-2/Bax was increased after pre-administration of MSC exosomes in both in vitro and in vivo studies. Moreover, MSC exosomes were found to upregulate the expressions of Nrf2, P-Nrf2, Keap1 and HO-1, while the antioxidant effect of MSC exosomes was blocked by ML385 (a Nrf2 inhibitor). Besides, immunofluorescence results showed that MSC exosomes upregulated the expression of P-Nrf2 in the nucleus compared to the oxidant group. These results indicate that MSC exosomes protect RPE cells from oxidative damage by regulating Nrf2/Kepa1 signaling pathway. In conclusion, MSC exosomes are promising nanotherapeutics for the treatment of dry AMD.
研究领域:
眼科学
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干细胞生物学
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分子生物学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·Vol. 10
·期 14
·2207448
·
IF 15.1
Jiahui Yan,Jingwen Zhang,Yanan Wang,Hong Liu,Xueping Sun,Aixin Li,Pengfei Cui,Liangmin Yu,Xuefeng Yan,Zhiyu He
Pyroptosis, systemic inflammation, and mitochondrial apoptosis are the three primary contributors to sepsis's multiple organ failure, the ultimate cause of high clinical mortality. Currently, the drugs under development only target a single pathogenesis, which is obviously insufficient. In this study, an acid-responsive hollow mesoporous polydopamine (HMPDA) nanocarrier that is highly capable of carrying both the hydrophilic drug NAD + and the hydrophobic drug BAPTA-AM, with its outer layer being sealed by the inflammatory targeting peptide PEG-LSA, is developed. Once targeted to the region of inflammation, HMPDA begins depolymerization, releasing the drugs NAD + and BAPTA-AM. Depletion of polydopamine on excessive reactive oxygen species production, promotion of ATP production and anti-inflammation by NAD + replenishment, and chelation of BAPTA (generated by BA-AM hydrolysis) on overloaded Ca 2+ can comprehensively block the three stages of sepsis, i.e., precisely inhibit the activation of pyroptosis pathway (NF- κ B-NLRP3-ASC-Casp-1), inflammation pathway (IL-1 β , IL-6, and TNF- α ), and mitochondrial apoptosis pathway (Bcl-2/Bax-Cyt-C-Casp-9-Casp-3), thereby restoring intracellular homeostasis, saving the cells in a state of “critical survival,” further reducing LPS-induced systemic inflammation, finally restoring the organ functions. In conclusion, the synthesis of this agent provides a simple and effective synergistic drug delivery nanosystem, which demonstrates significant therapeutic potential in a model of LPS-induced sepsis.
研究领域:
药理学
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纳米技术
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免疫学
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细胞生物学
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治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Jindan Xiao,Liuming Xie,Bing Zheng,Wenjie Ma,Yi Chen,Jianhua Xie,Xiaobo Hu,Qiang Yu
Autophagy is pivotal for the management of intestinal homeostasis, modulation of intestinal immunity response and anti-microbial protection. Previous studies have documented the protective function of Polygonatum cyrtonema Saponin (PCS) against intestinal injury, but whether PCS modulated autophagy and its associated responses remained unknown. A model of dextran sodium sulfate (DSS)- elicited intestinal injury was employed to confirm this hypothesis. The results showed that PCS effectively relieved the typical symptoms of DSS-induced weight reduction, shortened colon length, and augmented disease activity index score, down-regulated organ indices, reduced hepatic oxidative stress, and inhibited excessive inflammatory mediators. Meanwhile, PCS intervention ameliorated the intestinal barrier dysfunction via promoting the differentiation of goblet cells and augmenting the expression of tight junction proteins (TJs). It also suppressed apoptosis in intestinal cells by altering the Bcl-2/Bax ratios and diminishing the expressions of Caspase-9 and Caspase-3. Additionally, PCS remarkably enhanced autophagy by modulating the PI3K/AKT/mTOR signal pathway. More importantly, the classical autophagy inducer rapamycin augmented the beneficial effects of PCS. In contrast, the autophagy inhibitor 3-methyladenine essentially eliminated the above effects, revealing a role for autophagy in the response. Further studies have demonstrated that PCS intervention improved the diversities of the intestinal flora, increased occupancy of beneficial bacteria in Lachnospiraceaeae and Akkermansia , which was closely associated with autophagy. Taken together, these findings demonstrated that PCS is a potential supplier of prebiotics by modulating immunity, repairing intestinal mucosal injury, regulating autophagy and intestinal flora, and autophagy is a key target for PCS-mediated intestinal barrier protection.
研究领域:
胃肠病学
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免疫学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
高影响因子
Environmental Science-Nano
·
2023
·Vol. 10
·期 12
·3389-3400
·
IF 7.3
Shuoli Ma,Wen-Xiong Wang
Marine hydrosphere is in grave danger if extreme weather conditions, such as high temperatures and heat waves, become the norm. The functional characteristics of nano Zn oxides (nZnO) might provide a “booster substance” that helps marine species to endure environmental stress. In the present study, physiological indicators and simulated severe environments were used to evaluate the antioxidative ability of nZnO in marine rabbitfish Siganus fuscescens, with an aim to help them resist extreme environmental stress. Rabbitfish were exposed to different diets with ZnSO4 and nZnO at the optimum requirement level (Zn content of 62.5 μg g−1), and then challenged with a low dissolved oxygen concentration and higher temperature. We demonstrated that dietary nZnO promoted the anti-oxidation defense system of the rabbitfish by improving the activities of the antioxidant enzymes, i.e., catalase (CAT), superoxide dismutase (SOD), and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio without tissue damage. Compound stressors reduced the median survival duration of the rabbitfish from 4.25 h to 2.5 h (dietary exposure) and 9 h to 5.75 h (dietary nZnO exposure) compared to single environmental stress. nZnO downregulated the HIF gene expression and increased the prolyl hydroxylase (PHD) activity in the liver of the rabbitfish. After 10 h of extreme environmental exposure, the gene expression results indicated that nZnO inhibited the NF-κB/IL-1β/IL-6 pathway and TNF-α/Bcl-2/Bax/caspase 9 pathway and activated the akt/mTOR/elovl5 and elovl8 pathway of the rabbitfish to maintain the resilience of the fish under the extreme environment. These results strongly suggested that nZnO may improve the anti-oxidation ability of fish to resist extreme environments.
研究领域:
海洋生物学
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环境科学
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水产养殖
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Yan Chen,Ming Zhang,Zhifang Liu,Ning Zhang,Qingpeng Wang
Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to the failure of tumor therapy. Here, a series of ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling the TME through suppressing JAK2/STAT3 signaling was developed. A candidate was screened out, which displayed potent antiproliferative and antimetastatic performance both in vitro and in vivo. It displayed superior pharmacokinetic properties compared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated apoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The JAK2/STAT3 and TGF-β1 signaling pathways were remarkably inhibited, and pro-death autophagy was subsequently promoted. The inflammatory and hypoxic TME was suppressed by downregulating COX-2, MMP9, and HIF-1α, which resulted in inhibited angiogenesis in tumors by inhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive TME was reversed by blocking the immune checkpoint PD-L1, further improving the density of CD3+ and CD8+ tumor-infiltrating lymphocytes, and promoting macrophage polarization from M2- to M1-type.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）