ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Li Zhang,Zhennan Mao,Weibin Li,Siyu Chi,Hemei Cheng,Zijun Wang,Caixia Wang,Zhihong Liu
The blood–brain barrier (BBB) presents a major challenge in the theranostics of brain diseases by impeding the delivery of drugs to the brain. Currently the most common strategy for transferring substances across the BBB is receptor-mediated transcytosis, which is restricted by several key factors, including insufficient endocytosis by brain microvessel endothelial cells (BMECs) due to underexpressed pinocytotic vesicles, lysosomal retention, and limited exocytosis to the brain parenchyma. We report a hybrid cell membrane (HCM)-coated and 2-methacryloyloxyethyl phosphorylcholine (MPC)-modified nanocarrier to promote drug delivery across the BBB by modulating the transcytosis process. The HCM incorporates a brain metastatic tumor cell membrane for recognition of BMECs and a GFP-293-S cell membrane expressing Spike protein to facilitate membrane fusion between the nanocarrier and BMECs, thereby bypassing vesicle-dependent endocytosis and enhancing cellular uptake. Membrane fusion reduces the chance of lysosomal retention, and MPC modification enhances exocytosis into the brain parenchyma via the interaction of MPC with transporters expressed on the abluminal endothelial membrane. The nanocarrier achieves significantly improved delivery of CuS, a photothermal agent, to the brain and thus enables highly efficient therapy of brain glioma.
研究领域:
药学
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神经科学
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产品关联
DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2017
·Vol. 8
·期 1
·83-96
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IF 3.094
Pan Linmei,Zhou Jing,Ju Feng,Zhu Huaxu
Alpha-asarone is a bioactive component of Acorus tatarincuii Schott with low bioavailability, which is often used for treatments of various brain diseases in clinical setting. This study was to formulate biodegradable methoxy polyethylene glycol-polylactic acid (mPEG-PLA) nanoparticles (NPs) surface-modified by lactoferrin (Lf), for delivering α-asarone into the brain following intranasal administration. Alpha-asarone NPs were prepared by premix membrane emulsification. The relative parameters were optimized by a Box-Behnken experimental design. The particle size, zeta potential, and dispersibility index of NPs and Lf-NPs were characterized. Their ex vivo permeation, pharmacokinetics, distribution in the brain and other tissue, brain targeting, and toxicity were investigated. Following intranasal administration, Lf-NPs had a better permeability and no significant poor bioavailability compared to NPs; the area under curve from 0 to 12 h of α-asarone in Lf-NPs of the olfactory bulb, hippocampus, olfactory bundles, and thalamus were 2.14-, 4.17-, 3.62-, and 1.96-fold of those in NP group, respectively. Lactoferrin could enhance the efficacy of brain targeting with NPs and reduce its liver accumulation. Toxicity of NPs on nasal mucosal cilia and epithelial cells was also decreased by Lf. To summarize, these results demonstrate that Lf-NPs of α-asarone have potential as a carrier for nose-to-brain delivery of α-asarone for brain diseases.
研究领域:
药剂学
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神经科学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
INFLAMMATION
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2023
·
IF 5.1
Han Ruili,Liu Lei,Wang Yuying,Wu Ruolin,Yang Ying,Zhao Yuanlin,Jian Lele,Yuan Yuan,Zhang Lijun,Gu Yu,Gao Changjun,Ye Jing
The microglia overactivation-induced neuroinflammation is a significant cause of the brain injury after intracerebral hemorrhage (ICH). Iron homeostasis is crucial for microglia activation, but the mechanism and causality still need further study. This study aimed to explore the roles and mechanism of the mitochondrial iron transporter SLC25A28 in microglia activation after ICH. Intrastriatal injection of autologous blood was used to establish ICH model, and the neuroinflammation, iron metabolism and brain injuries were assessed in wildtype or microglia-specific SLC25A28 knockout mice after ICH. Mitochondria iron levels and microglial function were determined in SLC25A28 overexpressed or deleted microglia. The extracellular acidification rate (ECAR), lactate production, and glycolytic enzyme levels were used to determine aerobic glycolysis. The results showed that ICH stimulated mitochondrial iron overload, and synchronously upregulated the SLC25A28 expression. In vitro , SLC25A28 overexpression increased mitochondrial iron levels in microglia. Interestingly, microglial SLC25A28 deficiency ameliorated neuroinflammation, brain edema, blood–brain barrier injury and ethological alterations in mice after ICH. Mechanically, SLC25A28 deficiency inhibited microglial activation by restricting the aerobic glycolysis. Moreover, zinc protoporphyrin could reduce SLC25A28 expression and mitigated brain injury. SLC25A28 plays crucial roles in mitochondrial iron homeostasis and microglia activation after ICH, and it might be a potential therapeutic target for ICH.
研究领域:
神经科学
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分子生物学
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神经病学
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产品关联
DOI
PubMed
高影响因子
Materials Today Nano
·
2023
·
IF 10.3
Dong Zhang,Jianglong Kong,Xueying Huang,Jie Zeng,Qiaohui Du,Tao Yang,Hui Yue,Qing Bao,Yao Miao,Yajing Xu,Honglin Jiang,Fang Lei,Mingying Yang,Yi Wang,Chuanbin Mao
Targeted brain tumor therapy by nanoparticles (NPs) remains a daunting challenge due to the difficulty for NPs to go through the blood-brain barriers (BBB) and blood-brain tumor barriers (BBTB). In addition, Dactolisib (Dac) is an effective dual PI3K/mTOR inhibitor for cancer treatment. It was the first PI3K inhibitor to enter clinical trials but exhibited toxicity to normal tissues if not delivered to tumor sites by a tumor-targeting carrier. To explore Dac for glioblastoma (GBM) therapy while avoiding its toxicity, we developed a new brain tumor-targeting drug delivery system self-assembled from zein, a cell membrane-penetrating amphiphilic protein originally present in corn. Specifically, the amphiphilicity of zein drove it to self-assemble into NPs that encapsulated Dac with high efficiency. RVG29, a 29-mer brain-targeting peptide, was chemically conjugated to zein constituting the NPs, forming Dac-encapsulated NPs (zein-RVG-Dac_NPs). In vitro assays were conducted to verify the capability of the NPs in penetrating BBB/BBTB, targeting GBM cancer cells and killing them. ELISA was employed to assess the expression of nicotinic acetylcholine receptors (nAChR) on the cancer cells to understand the mechanism of cancer cell membrane penetration by the NPs. The NPs were intravenously injected into orthotopic GBM mice models to demonstrate the brain tumor targeting as well as the effective GBM therapy due to the targeted delivery of Dac to brain tumors. The treated tumors were immunohistochemically analyzed to verify the tumor destruction. To confirm the biosafety of the NPs in treating GBM, we also histopathologically evaluated the major normal organs and chemically analyzed the blood biomarkers. We found that a combination of zein and RVG29 facilitated the zein-RVG-Dac_NPs to cross the BBB/BBTB and became uptaken by the GBM cells through the nAChR-mediated pathways, enabling the NPs to cross BBB/BBTB and deliver Dac selectively to GBM cells. Hence, administration of the NPs through tail veins significantly increased the accumulation of Dac in the orthotopic brain tumor of mice and effectively inhibited tumor growth. Neither toxicity nor adverse effects in the major organs were found due to the excellent biocompatibility of zein and the targeted delivery of Dac into brain tumor cells. Hence, integrating a cancer cell-penetrating natural protein (zein) and a brain-targeting peptide (RVG29) can form NPs that can effectively penetrate BBB/BBTB and then enter brain tumor cells to release Dac, leading to highly effective targeted brain cancer therapy. Such NPs can be extended to the development of therapeutics for treating different brain diseases due to their unique combination of biocompatibility and brain-targeting capability.
研究领域:
神经科学
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药学
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癌症研究
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纳米技术
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药物递送系统
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产品关联
DOI
高影响因子
IBRO Neuroscience Reports
·
2024
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IF 2
Min Wei,Yi Liu,Dongsheng Li,Xingdong Wang,Xiaodong Wang,Yuping Li,Zhengcun Yan,Hengzhu Zhang
Background Following recent research advancements, an increasing level of evidence had been published to indicate that celastrol exerted a therapeutic effect on a range of nervous system diseases. This study therefore aimed to investigate the potential involvement of celastrol on ferroptosis and the blood-brain barrier disruption in intracerebral haemorrhage. Methods We established a rat intracerebral haemorrhage and adrenal pheochromocytoma cell (PC12) OxyHb models using an ACSL4 overexpression vector. Ferroptosis-related indices were assessed using corresponding assay kits, and immunofluorescence and flow cytometry were used to measure reactive oxygen species (ROS) levels. Additionally, quantitative PCR (qPCR) and western blot analyses were conducted to evaluate the expression of key proteins and elucidate the role of celastrol in intracerebral haemorrhage (ICH). Results Celastrol significantly improved neurological function scores, blood-brain barrier integrity, and brain water content in rats with ICH. Moreover, subsequent analysis of ferroptosis-related markers, such as Fe2+, ROS, MDA, and SOD, suggested that celastrol exerted a protective effect against the oxidative damage induced by ferroptosis in ICH rats and cells. Furthermore, Western blotting indicated that celastrol attenuated ferroptosis by modulating the expression levels of key proteins, including acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and anti-transferrin receptor 1 (TFR1) both in vitro and in vivo. ACSL4 overexpression attenuated the neuroprotective effects of celastrol on ICH in vitro. Molecular docking analysis revealed that celastrol interacted with ACSL4 via the GLU107, GLN109, ASN111, and LYS357 binding sites. Conclusions Celastrol exerted antioxidant properties and aids in neurological recovery after stroke by suppressing ACSL4 expression during ferroptosis. As such, this drug represented a promising pharmaceutical candidate for the treatment of ICH.
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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产品关联
DOI
PubMed
高影响因子
MATERIALS TECHNOLOGY
·
2024
·
IF 2.9
Xin Tian,Taoxiang Shi,Shiyang Fu,Zheda Liu,Yalan You,Keke Chen,Anqi Yao,Chengguang Zhu,Minhui Zeng,Wenfang Tang,Xiaojun Tao,Xiangling He
In this study, we grafted cholesterol with pullulan to synthesize hydrophobic pullulan(CHP). Three CHP polymers (CHP1, CHP2, and CHP3), with different degrees of substitution were designed by changing the feed ratio of cholesterol to pullulan. The 1H-NMR results showed that the hydrophobic substitutability of CHP1, CHP2, and CHP3 were calculated to be 8.26%, 5.67%, and 3.52%, respectively. The sizes of CHP1 NPs, CHP2 NPs, and CHP3 NPs were (118±7.9), (123±4.7) and (158±9.3) nm, respectively. The CHP NPs embedded with VCR and adsorbed Tween 80 (CHPT@VCR NPs). The results of microscale thermal imaging (MST) testing indicated the CHP-1 NPs with the highest degree of cholesterol substitution possessed the highest adsorption capacity for Tween 80. In vitro pharmacological studies were conducted in SJ-GBM2 cells, the results showed that the tumor cells inhibition rate and the cellular uptake rate of CHPT@VCR-1 NPs were the highest compared with CHPT@VCR-2 NPs and CHPT@VCR-3 NPs.
研究领域:
药剂学
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肿瘤学
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DOI
高影响因子
MATERIALS & DESIGN
·
2023
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IF 8.4
Jingyu Wang,Yongrou Zhang,Zuyue Lei,Junqi Wang,Yangming Zhao,Taolin Sun,Zhenyu Jiang,Licheng Zhou,Zejia Liu,Yiping Liu,Bao Yang,Liqun Tang
In surgical training and experimental research, brain tissues immersed in cerebrospinal fluid often exhibit complex deformation and strain rate effects that can compromise their reliability and stability. Therefore, it is essential to develop a high-fidelity human brain tissue simulant material that serves as a physical surrogate model to understand its mechanical behavior, such as traumatic brain injury (TBI). However, the existing simulant materials have failed to meet the required mechanical properties. This study presents a composite hydrogel consisting of both a rigid polysaccharides network (Sodium alginate and Pectin) and a flexible polyacrylamide network, exhibiting brain tissue-like mechanical properties under various solution environments and strain rates. The results show that nonlinear mechanical behavior and good similarity under various external environments (artificial cerebrospinal fluid, normal saline, deionized water, and air environments) and different strain rates (0.001 s −1 ,900 s −1 ,1700 s −1 ). By analyzing the experimental data and theoretical analysis, we examine the effects of complex environments on the mechanical behavior of composite hydrogel and porcine brain tissue. Given that the properties of human brain tissue resemble those of porcine brain tissue, our work has significant reference value in realizing surgical training and advancing related research in biomedical engineering.
研究领域:
生物医学工程
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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
高影响因子
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
·
2025
·
IF 5
Yue-Xin Ning,Ji-Ru Cai,Ting-Ting Wang,Yi-Han Wang,Yu Cui,Hui-Sheng Chen
Background Endovascular treatment (EVT) alone was not demonstrated to be non-inferior to intravenous alteplase bridging EVT in acute large vessel occlusion (LVO) stroke. Using cerebral ischemia/reperfusion (I/R) injury model, intravenous tenecteplase (TNK) was administrated after ischemia followed by reperfusion at various time points. Objectives To investigate whether intravenous TNK bridging EVT vs EVT alone could improve I/R injury, and this effect may be associated with the time from TNK to reperfusion. Methods Rats received intravenous TNK (1.4 mg/kg) or vehicle (sterile water) 1.0 hour after middle cerebral artery occlusion (MCAO), followed by reperfusion after 0.5 or 1.0 hour following TNK. Neurological deficit scores, infarct volume, and brain edema were measured at 24 hours after MCAO. Microthrombi were determined by immunofluorescence staining for CD31 + /fibrinogen + and CD31 + /thrombocyte + . Inflammatory cell infiltration in the ischemic brain region was determined by flow cytometry. Results Compared with vehicle, TNK significantly reduced neurological deficit scores, brain infarction, neuro-inflammation, and blood-brain barrier (BBB) disruption, and significantly reduced intravascular fibrin and platelet deposition, and brain inflammatory cell infiltration in penumbra of I/R rats. Furthermore, a better beneficial trend was found in TNK bridging reperfusion at 0.5 hour after TNK compared with TNK bridging reperfusion at 1.0 hour after TNK. Conclusions Our results demonstrate that intravenous TNK bridging reperfusion produced neuroprotective action through dissolving microvascular thrombus and alleviating inflammatory cell infiltration to improve microcirculation, with the result of maintaining BBB integrity and inhibiting neuroinflammation, and the neuroprotective benefit may be associated with the time from TNK to reperfusion.
研究领域:
神经科学
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药理学
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实验性卒中研究
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DOI
PubMed
高影响因子
Materials Today Bio
·
2025
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IF 10.2
Chenjie Xia,Changhui Hu,Rui Xu,Feihong Zhuo,Mengfei Yang,Yinjia Li,Zixuan Shan,Cheng Xu,Yutong Wang,Zhipeng Chen
Ischemic stroke is a neurological disease characterized by high morbidity and mortality. A key pathological mechanism involves rapid restoration of blood oxygen in the infarcted area, which triggers oxidative stress and inflammatory responses leading to neuronal damage. The complex etiology of the disease poses challenges to single-target pharmacotherapy, necessitating the development of multi-targeted combination drug treatments. Reports showed that water- and lipid-soluble components of Danshen, exert synergistic neuroprotective effects. However, the disparate physicochemical properties of these compounds lead to differential release kinetics, hampering the therapeutic efficacy. Furthermore, the blood-brain barrier (BBB) presents a formidable obstacle to the penetration of water-soluble constituents. Here, we developed a novel biomimetic drug delivery system utilizing hollow polydopamine coated with red blood cell membranes. Water-soluble (W) and lipid-soluble (L) components of Danshen were loaded at distinct membrane regions to facilitate synchronized release profile. Additionally, borneol was used to modify the membrane to enhance the BBB penetration capacity. Mechanism study revealed that W and L possess synergistic effect through inhibiting NF-κB and TNF-α pathways. In summary, this delivery system enables concurrent loading and efficient brain delivery of multiple constituents, thereby promoting neurological recovery and presenting a promising therapeutic strategy for ischemic stroke.
研究领域:
神经病学
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药剂学
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药理学
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生物医学工程
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH
·
2025
·
IF 2.6
Naizhu Wang,Jingkun Wu,Zhaofei Song,Hongbin Wang,Yan Zhao
Hypertension in the brain may lead to hypertensive intracerebral hemorrhage (HICH), a devastating disease. This study, grounded on bioinformatics insights, aims to investigate the functions of Selectin E (SELE) and forkhead box P1 (FOXP1) in the progression of HICH. Increased SELE expression was detected in the striatum of a mouse model of HICH generated via angiotensin II and L-NAME treatments. Knockdown of SELE alleviated hemorrhage, neutrophil infiltration, and blood–brain barrier (BBB) rupture in the mouse brain. FOXP1, poorly expressed in the HICH mice, was found to repress SELE transcription by binding to its promoter region. Overexpression of FOXP1 resulted in analogous alleviating effects in the HICH mice; however, the effects were abrogated by the additional SELE overexpression. In vitro , human brain microvascular endothelial cells (HBMECs) were treated with thrombin to generate a cellular model of ICH, followed by co-culture with HL-60 cell-derived neutrophils. The FOXP1 overexpression reduced the adhesion of neutrophils, and it alleviated HBMEC apoptosis and permeability while enhancing angiogenesis. Still, these effects were counteracted by the SELE upregulation. In conclusion, this study demonstrates that SELE upregulation upon FOXP1 loss is associated with neutrophil infiltration and BBB rupture in HICH.
研究领域:
神经病学
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分子生物学
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心血管疾病
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免疫学
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生物信息学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Luyao Liu,Ruikun Wang,Weijuan Gao,Xianming Hou,Xiaofei Jin,Yanmeng Zhao,Xiaohong Zhou,Yi Zhang
Ethnopharmacological relevance Cerebral ischemia-reperfusion (I/R) injury is a common complication of ischemic stroke, with autophagy and pyroptosis playing key roles. Huangqi and Danggui (HQDG) are a commonly used drug pair of Chinese traditional medicine for clinical treatment of ischemic stroke. Aim of the study The study aims to investigate the interaction between autophagy and pyroptosis regulated by HQDG through the AMPK/mTOR signaling pathway during cerebral I/R injury. Materials and methods Model of middle-cerebral artery occlusion/reperfusion (MCAO/R) in SD rats was established using the Longa suture method. The components of traditional Chinese medicine were detected by liquid chromatography coupled to quadrupole orbitrap high resolution mass spectrometry (LC/MS). Neurological deficits were evaluated by neurological function score. Changes of cerebral blood flow were detected by a laser speckle blood flow imaging instrument. The volume of cerebral infarction was observed by 2,3,5-Chlorotriphenyltetrazolium (TTC) staining. The permeability of the blood-brain barrier was measured by Evans blue test. Neurovascular unit and autophagosomes in brain tissue were assessed by transmission electron microscopy. Neuronal pyroptosis was detected by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL)/Caspase-1 staining. The expression of autophagy related proteins, pyroptosis related proteins, and AMPK/mTOR pathway related proteins were detected by Western blot. Results After cerebral I/R injury, autophagy and pyroptosis, were characterized by increased number of autophagosomes and pyroptosis cells, upregulated expression of Beclin 1, LC3-II/LC3-I, NLRP3, cleaved Caspase-1, IL-1beta, IL-18 proteins, and downregulated expression of P62 proteins. HQDG significantly improved neurological function, reduced the volume of cerebral infarction, increased cerebral blood flow, improved blood-brain barrier permeability and the function of neurovascular units. Autophagy was further activated and pyroptosis was significantly inhibited by HQDG, which promoted increased number of autophagosomes, enhanced expression of Beclin 1, LC3-II/LC3-I proteins, reduced expression of P62, NLRP3, cleaved Caspase-1, IL-1beta, and IL-18 proteins, and downregulated the number of pyroptosis cells. On the other hand, after administering 3-Methyladenine (3-MA) to inhibit autophagy, the above effects of HQDG were significantly inhibited. Besides, HQDG promoted AMPK phosphorylation, and weakened mTOR phosphorylation. However, after the administration of AMPK inhibitor Compound C, HQDG caused increase in Beclin 1 and LC3-II/LC3-I, reduced P62 and NLRP3, and cleaved Caspase-1 protein expression, whereas cerebral blood flow decreased. Conclusion HQDG alleviated pyroptosis by promoting autophagy via AMPK/mTOR signaling pathway after middle-cerebral artery occlusion/reperfusion in rats, showing its potential for treatment of cerebral I/R injury in humans.
研究领域:
药理学
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神经科学
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中医药
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL BIOLOGY AND TOXICOLOGY
·
2024
·Vol. 40
·期 1
·1-28
·
IF 5.3
Liu Yuhan,Qin Yanling,Zhang Yanning
Uremic encephalopathy (UE) poses a significant challenge in neurology, leading to the need to investigate the involvement of non-coding RNA (ncRNA) in its development. This study employed ncRNA-seq and RNA-seq approaches to identify fundamental ncRNAs, specifically circRNA and miRNA, in the pathogenesis of UE using a mouse model. In vitro and in vivo experiments were conducted to explore the circRNA-PTPN4/miR-301a-3p/FOXO3 axis and its effects on blood–brain barrier (BBB) function and cognitive abilities. The research revealed that circRNA-PTPN4 binds to and inhibits miR-301a-3p, leading to an increase in FOXO3 expression. This upregulation results in alterations in the transcriptional regulation of ZO-1, affecting the permeability of human brain microvascular endothelial cells (HBMECs). The axis also influences the growth, proliferation, and migration of HBMECs. Mice with UE exhibited cognitive deficits, which were reversed by overexpression of circRNA-PTPN4, whereas silencing FOXO3 exacerbated these deficits. Furthermore, the uremic mice showed neuronal loss, inflammation, and dysfunction in the BBB, with the expression of circRNA-PTPN4 demonstrating therapeutic effects. In conclusion, circRNA-PTPN4 plays a role in promoting FOXO3 expression by sequestering miR-301a-3p, ultimately leading to the upregulation of ZO-1 expression and restoration of BBB function in mice with UE. This process contributes to the restoration of cognitive abilities. Graphical Abstract 1. The circRNA-PTPN4/miR-301a-3p/FOXO3 axis is identified as a key regulator of blood–brain barrier integrity and cognitive function in uremic encephalopathy. 2. circRNA-PTPN4 sequestration of miR-301a-3p enhances FOXO3 expression, leading to upregulation of ZO-1 and improved endothelial permeability. 3. Overexpression of circRNA-PTPN4 in uremic mice restores cognitive abilities and reduces neuronal loss and inflammatory infiltration.
研究领域:
神经学
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分子生物学
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非编码RNA
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认知科学
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病理生理学
✓ 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）