Open Medicine
·
2023
·Vol. 18
·期 1
·
IF 2.1
Qi Duan,Junxia Wu
Dihydroartemisinin (DHA) has been found to inhibit the expression of von Willebrand factor (VWF), a marker of endothelial cell injury, but its mechanism in cerebral ischemia/reperfusion (I/R) injury remains obscure. In this study, I/R model was constructed through middle cerebral artery occlusion (MCAO) in rats, followed by DHA administration. The effect of DHA on rat cerebral I/R injury was investigated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin and eosin staining, TUNEL staining, and Western blot. Brain microvascular endothelial cells (BMVECs) isolated from newborn rats were exposed to oxygen–glucose deprivation/reoxygenation (OGD/R), and then treated with DHA. The results showed that MCAO treatment induced infarction, nerve cell apoptosis, and brain tissue impairment in rats, which was mitigated by DHA. OGD/R inhibited viability and accelerated apoptosis of BMVECs, which was alleviated by DHA. I/R procedures or OGD/R up-regulated expressions of VWF, ATG7, Beclin1, and LC3-II/LC3-I ratio, while down-regulating Occludin, Claudin-5, ZO-1, P62, SIRT1, and FOXO1 expressions in vivo and in vitro ; however, these effects of I/R procedures or OGD/R were offset by DHA. VWF overexpression reversed the above effects of DHA on OGD/R-induced BMVECs. In summary, DHA ameliorates cerebral I/R injury in rats by reducing VWF level and activating autophagy-mediated SIRT1/FOXO1 signaling pathway.
研究领域:
神经科学
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药理学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 12
·1572
·
IF 5.5
Xiaofeng Wang,Jue Wang,Xia Zhao,Langui Xie,Rui Yang,Chunmeng Sun,Jiasheng Tu,Huimin Sun
Background/Objectives : Polysorbate 80 (PS80), a complex surfactant mixture, is widely recognized for its ability to enhance drug permeation across the blood–brain barrier (BBB). While this effect is generally attributed to the combined actions of its components, the specific contribution and potential selectivity of individual minor components remain poorly understood. This study therefore aimed to isolate and compare the primary minor components of PS80 to determine whether they uniformly enhance BBB permeation or exhibit drug-specific functions. Methods : In this research, four primary minor components of PS80—polyoxyethylene sorbitan monooleate (PSM), polyoxyethylene isosorbide monooleate (PIM), polyoxyethylene sorbitan dioleate (PSD), and a polyethylene glycol/polyoxyethylene sorbitan/polyoxyethylene isosorbide mixture (PEG/PS/PI mixture)—were isolated using preparative liquid-phase chromatography. Drug-loaded formulations were then prepared using the solvent evaporation method incorporating five model drugs: 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR, MW = 1013.39 Da), donepezil (MW = 379.49 Da), nimodipine (MW = 418.44 Da), chlorogenic acid (MW = 354.31 Da), and paclitaxel (MW = 853.92 Da). The permeability of these formulations across the BBB was evaluated in BALB/c mice after intravenous administration. Brain distribution of the lipophilic dye DiR was assessed using fluorescence imaging, whereas brain homogenate concentrations of therapeutic drugs were quantified by UPLC-MS/MS. Results : Results revealed that the enhancement of brain delivery was dependent on both the specific minor component and the drug. The PEG/PS/PI mixture specially enhanced the brain homogenate concentration of donepezil to 11.8 ± 1.2 ng/mL, representing a 6.9-fold enhancement, while PIM micelles increased the delivery of DiR, donepezil, and nimodipine. In contrast, PSM and PSD micelles improved transport of only DiR and donepezil. The broad performance of PIM suggests a more flexible formulation—a hypothesis that warrants further validation. Conversely, none of the different minor components enhanced the delivery of chlorogenic acid or paclitaxel, underscoring the critical role of specific drug–component interactions. Conclusions : This component-resolved insight challenges the conventional perception of PS80 and provides a rational framework for engineering precision brain-targeted delivery systems by selecting functional minor components.
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PubMed
高影响因子
JOURNAL OF NEUROSCIENCE METHODS
·
2022
·
IF 2.987
Yao He,Yingqian Zhang,Wanxin Li,Qinxi Li,Bangcheng Zhao,Xun Tang,Daojun Chen,Ting Zhang,Tao Zhang,Zhihui Zhong
Background Blood-brain barrier (BBB) disruption is pivotal in the pathophysiological process of ischemic stroke and is often measured in rodent stroke studies. Traditionally, rodent BBB permeability increase is determined by measuring cerebral leakage of certain dyes such as Evans Blue or sodium fluorescein (NaFL). However, due to the special processing of samples for BBB permeability measurement, they cannot be used afterward for determining other essential parameters such as cerebral infarction volume. Therefore, using different batches of animals for assessing BBB permeability and infarction volume is typical. However, this would limit the stroke study’s statistical power and scientific value while hindering the implementation of procedures for high standard animal welfare. New method The rats subjected to middle cerebral artery occlusion (MCAO) were intraperitoneally injected with NaFL during the reperfusion phase. The brains were sliced and measured for BBB permeability using the small animal optical imaging system (IVIS® Lumia series III). Afterward, the same brain samples were either sliced or homogenized for tests that assessed infarction volume or other molecular changes. Results The sum fluorescence intensity of the ischemic brain slices under the IVIS® Lumia series Ⅲ showed a strong correlation with the infarction volume determined by 2,3,5-triphenyl tetrazolium chloride (TTC) staining (r = 0.7440, P = 0.0087). The fluorescence intensity of the whole ischemic brain was correlated with the NaFL concentration of brain tissue homogenates (r = 0.8653, P = 0.0026) and cerebral infarction volume (r = 0.7282, P = 0.0072). Comparison with existing methods The new method enables concurrent measurement of BBB permeability and infarction volume on the same batch of brain tissue samples without affecting most downstream biochemical assays. Conclusions By applying the new method, we could use the same batch of ischemic rodent brain tissue for multiple assays, including BBB permeability and infarction volume. Through this, we would reduce the animal numbers in each study and help to maximize the scientific and statistical potential of future rodent ischemic studies.
研究领域:
神经科学
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生物医学工程
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药理学
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DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2025
·Vol. 31
·期 2
·e70289
·
IF 5
Yunzhao Chen,Hexi Guo,Xinguo Sun,Shanjun Wang,Mingyu Zhao,Junjie Gong,Anqi He,Jing Li,Yuheng Liu,Zengguang Wang
Background Intracerebral hemorrhage (ICH) is a life-threatening cerebrovascular disorder with no specific pharmacological treatment. ICH causes significant behavioral deficits and cognitive impairments. Recent research suggests that circadian rhythm regulation could be a promising therapeutic strategy for ICH. Melatonin has been shown to alleviate glymphatic system (GS) dysfunction by regulating circadian rhythms, thereby improving depressive-like behaviors and postoperative sleep disorders in mice. However, its application in ICH treatment and specific mechanisms are not well understood. Methods ICH models were created in 8-to-10-week-old mice using collagenase injection. Circadian rhythm modulation was tested with melatonin and luzindole. Behavioral and cognitive impairments were assessed with the modified neurological severity score, corner test, and novel object recognition test. Brain water content was measured by the dry/wet weight method, and cerebral perfusion was assessed by cerebral blood flow measurements. GS function was evaluated using RITC-dextran and Evans blue assays. Immunofluorescence and western blotting were used to analyze GS function and BBB permeability. Results Melatonin restored GS transport after ICH, promoting hematoma and edema absorption, reducing BBB damage, and improving cognitive and behavioral outcomes. However, luzindole partially blocked these benefits and reversed the neuroprotective effects. Conclusion Melatonin and luzindole treatment affect GS function, BBB permeability, and cognitive-behavioral outcomes in mice with ICH. The underlying mechanism may involve the regulation of circadian rhythms.
研究领域:
神经科学
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药理学
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昼夜节律生物学
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神经病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2020
·
IF 7.727
Yanchao Liu,Yi Han,Ting Fang,Si-Min Chen,Xinyu Hu,Lijun Song,Hui Shen,Haiqing Dong,Yuan-Ying Jiang,Zui Zou,Yongyong Li,Mao-Mao An
As the gold standard treatment for invasive fungal infection , amphotericin B (AmB) is limited by its severe nephrotoxicity . It has been shown that AmB complex with albumin in vivo forms a sub-10 nm nanocomplex within kidney excretion size range and eventually induces the nephrotoxicity. This study presents an approach to take advantage of the “weakness” of such unique interaction between AmB and albumin to form AmB nanocomplex beyond the size range of kidney excretion. Herein, a novel strategy was developed by directly assembling molecular BSA into larger-sized nanostructures with the reconstructed intermolecular disulfide bond and hydrophobic interaction. The rich binding sites of AmB within BSA nanostructures enabled the efficient AmB loading and forming nanoparticle (AmB-NP) which exceeds the size range of kidney excretion (~ 60 nm). We found nanoassembly with BSA redirected biodistribution of AmB with a 2.8-fold reduction of drug accumulation in the kidney and significantly improved its renal impairment in mice. Furthermore, we found that nanoassembly with BSA significantly increased the biodistribution of AmB in brain and endowed it 100-folds increase in pharmacological effect against meningoencephalitis caused by common fungal pathogen Cryptococcus neoformans . Together, this study not merely overcomes the nephrotoxicity of AmB using its “weakness” by a nanoassembly method, and provides a new strategy for reducing toxicity of drugs with high albumin binding rate in vivo .
研究领域:
药理学
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纳米医学
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传染病学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2019
·Vol. 16
·期 1
·1-13
·
IF 5.7
Wu Xuan,Fu Siming,Liu Yun,Luo Hansheng,Li Feng,Wang Yiying,Gao Meng,Cheng Yuan,Xie Zongyi
Background Neuroinflammation and blood-brain barrier (BBB) disruption are two vital mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Recently, melanocortin-1 receptor (Mc1r) activation by Nle4-D-Phe7-α-MSH (NDP-MSH) was shown to play a neuroprotective role in an experimental autoimmune encephalomyelitis (EAE) mouse model. This study aimed to investigate whether NDP-MSH could alleviate neuroinflammation and BBB disruption after experimental ICH, as well as the potential mechanisms of its neuroprotective roles.Methods Two hundred and eighteen male C57BL/6 mice were subjected to autologous blood-injection ICH model. NDP-MSH, an agonist of Mc1r, was administered intraperitoneally injected at 1 h after ICH insult. To further explore the related protective mechanisms, Mc1r small interfering RNA (Mc1r siRNA) and nuclear receptor subfamily 4 group A member 1 (Nr4a1) siRNA were administered via intracerebroventricular (i.c.v) injection before ICH induction. Neurological test, BBB permeability, brain water content, immunofluorescence staining, and Western blot analysis were implemented.Results The Expression of Mc1r was significantly increased after ICH. Mc1r was mainly expressed in microglia, astrocytes, and endothelial cells following ICH. Treatment with NDP-MSH remarkably improved neurological function and reduced BBB disruption, brain water content, and the number of microglia in the peri-hematoma tissue after ICH. Meanwhile, the administration of NDP-MSH significantly reduced the expression of p-NF-κB p65, IL-1β, TNF-α, and MMP-9 and increased the expression of p-CREB, Nr4a1, ZO-1, occludin, and Lama5. Inversely, the knockdown of Mc1r or Nr4a1 abolished the neuroprotective effects of NDP-MSH.Conclusion sTaken together, NDP-MSH binding Mc1r attenuated neuroinflammation and BBB disruption and improved neurological deficits, at least in part through CREB/Nr4a1/NF-κB pathway after 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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DOI
PubMed
高影响因子
Biomaterials Advances
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2022
·
IF 0
Xianming Zhang,Qinghua Yu,Ping Zhou,Shiyu Yang,Jiashan Xia,Tao Deng,Chao Yu
The blood-brain barrier (BBB) is the major obstacle limiting the reach of therapeutic drugs into the brain. Herein, an aspirin-based anti-inflammatory replenisher (aspCD) was fabricated by carbonizing aspirin to deliver drugs into the brain visually. The as-prepared aspCD combined the BBB-penetrating and anti-inflammatory effects of aspirin with the fluorescent and drug-loading properties of carbon dots (CDs), thereby delivering therapeutic drugs into the brain and acting as imaging agent as well as anti-inflammatory replenisher. In vivo experiments of mice and zebrafish revealed that fluorescence aspCD could effectively penetrate BBB. In vitro and in vivo inflammatory models demonstrated that aspCD could be regarded as an excellent anti-inflammatory replenisher. In addition, as a functional carrier, aspCD was proved to be capable of loading drugs with different polarity. In summary, carbonization of active precursors (therapeutic drugs) into CDs could be a promising strategy to achieve the loading and visualization of drugs as well as the retainment of their biological activities.
研究领域:
神经科学
·
药学
·
材料科学
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产品关联
DOI
PubMed
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Kewei Liu,Yuqin Peng,Mingheng Xu,Kun Yuan,Yongchuan Li,Chuman Lin,Xiaolin Zhao,Juan Zhu,Yuan Chang,Zhenzhou Lin,Suyue Pan,Huanrong Ma,Xiaorui Wang,Kaibin Huang
Brain edema robustly increases mortality and hinders functional recovery after acute ischemic stroke. However, there are currently no effective therapies available for treating or preventing it. The unchecked opening of the transient receptor potential M4 (TRPM4) channel results in an excessive influx of Na + and water, which contributes significantly to the formation of brain edema after ischemic stroke. 9-phenanthrol (9-Phe), a potent TRPM4 inhibitor, has limited clinical applicability due to its potential cytotoxicity and poor solubility. A brain-targeting T7 (HAIYPRH)-modified lipid nanoparticle (LNP) encapsulated 9-Phe (9-Phe@T7-LNP) is designed and synthesized to improve the physicochemical properties and pharmacokinetic properties of 9-Phe for treating brain edema in vivo. These results demonstrated that 9-Phe@T7-LNP can penetrate the intact blood-brain barrier (BBB) in normal mice and target the brain parenchyma. Moreover, 9-Phe@T7-LNP effectively reduced infarct volume and brain edema, prevented neuronal loss and BBB disruption, improved survival, and facilitated neurological function recovery after transient middle cerebral artery occlusion in mice. Additionally, 9-Phe@T7-LNP scavenged oxygen-free radicals and prevented neuronal apoptosis in cultured neurons subjected to oxygen and glucose deprivation/reperfusion. In summary, these findings showed that 9-Phe@T7-LNP holds strong potential as a promising targeted therapy for brain edema after stroke, providing superior pharmacological neuroprotection against brain edema.
研究领域:
神经科学
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药理学
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纳米技术
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中风研究
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产品关联
DOI
高影响因子
NEUROSCIENCE
·
2024
·
IF 2.9
Tao Ye,Ning Zhang,Yunting He,Chunyan Chen,Qiqi Zha,Anbang Zhang,Xiuqi Sun,Xuemei Wu
Cerebral ischemia–reperfusion injury is frequently associated with neuroinflammation. The modulation of microglial polarization presents a promising approach for addressing cerebral ischemia–reperfusion injury. While electroacupuncture preconditioning has demonstrated efficacy in the management of ischemic stroke, the underlying therapeutic mechanisms remain inadequately understood. The investigation focused on elucidating the relationship between alterations in the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway and microglial polarization subsequent to EA pretreatment. Established a middle cerebral artery occlusion (MCAO) rat model following electroacupuncture (EA) treatment at the Baihui (GV 20) acupoint. Male Sprague-Dawley rats were randomly assigned to the sham, Ischemia/Reperfusion (I/R), I/R + EA groups (n = 6). The results of Nissl Staining and TUNEL Stainingl showed that the number of curative neurons increased significantly after pretreatment, indicating an improvement in neuron formation and an increase in the number of austenite. The level of apoptosis in brain tissue in the I/R group was significantly higher than that in the sham operation group. Electroacupuncture pretreatment can effectively inhibit apoptosis occurrence. In addition, electric acupuncture pretreatment protects rat blood–brain barrier integrity and mitochondrial function. After treatment, the number of M1-type microglia decreased, while the number of M2-type microglia increased. These results suggest that EA preconditioning may alleviate neurological deficits and neuronal apoptosis caused by cerebral I/R injury, while maintaining the integrity of the blood–brain barrier and promoting microglial polarization through the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway. Our findings establish a new molecular mechanism and theoretical foundation for electroacupuncture therapy of ischemic stroke.
研究领域:
神经科学
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免疫学
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药理学
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中医
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DOI
PubMed
高影响因子
JOURNAL OF DRUG TARGETING
·
2014
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IF 2.723
Ling Li,Jue Tuo,Yanqi Xie,Meihong Huang,Min Huang,Rongbiao Pi,Haiyan Hu
In recent years, specific transportation mechanisms on the blood–brain barrier (BBB) are extensively employed for brain-targeted drug delivery via colloidal nanocarriers. However, in this study, we purposed to exploit the sodium-dependent vitamin C transporter 2 (SVCT2)-mediated transportation on the blood–cerebrospinal fluid barrier to enhance central nervous system penetration of the highly hydrophilic ibuprofen (IBU) by synthesizing a SVCT2-targeted chemical delivery system (CDS), ibuprofen-C6-O-ascorbic acid (IAA). The physicochemical parameters of IAA were determined, and the transporter-mediated transportation mechanism of IAA was explored on a BBB monolayer mode. The overall brain targeting effect of IAA was assayed on mice by measuring the biodistribution of IBU after i.v. administration and calculating the pharmacokinetic parameters and targeting indexes. Results showed that lipophilicity and solubility of IAA was conspicuously improved compared with IBU. At the physiological pH, IAA was stable while in brain homogenates it was easily degraded. Transport studies on the BBB monolayer mode revealed that IAA displayed higher transepithelial permeability than IBU via SVCT2. The biodistribution study in vivo demonstrated that the overall targeting efficiency of IAA was 1.77-fold greater than that of the IBU. In conclusion, the synthetic IAA might be a promising brain-targeted CDS for smuggling small-molecule hydrophilic pharmaceuticals into the brain.
研究领域:
药理学
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神经科学
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药物化学
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产品关联
DOI
PubMed
高影响因子
Molecular Therapy-Methods & Clinical Development
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2019
·
IF 4.875
Zhilong Chen,Guoqing Fan,Anan Li,Jing Yuan,Tonghui Xu
The motor system controls muscle movement through lower motor neurons in the spinal cord and brainstem. Lower motor neurons are efferent neurons in the central nervous system (CNS) characterized by axonal projections that reach specific targets in the periphery. Lower motor neuron lesions result in the denervation and dysfunction of peripheral skeletal muscle. Great progress has been made to develop therapeutic strategies to transduce lower motor neurons with genes. However, the widespread distribution of lower motor neurons makes their specific, extensive, and efficient transduction a challenge. In this study, we demonstrated that, compared to the other tested recombinant adeno-associated virus (rAAV) serotypes, rAAV2-retro mediated the most efficient retrograde transduction of lower motor neurons in the spinal cord following intramuscular injection in neonatal mice. A single injection of rAAV2-retro in a single muscle enabled the efficient and extensive transduction of lower motor neurons in the spinal cord and brainstem rather than transducing only the lower motor neurons connected to the injected muscle. rAAV2-retro achieved the extensive transduction of lower motor neurons by the cerebrospinal fluid pathway. Our work suggests that gene delivery via the intramuscular injection of rAAV2-retro represents a promising tool in the development of gene therapy strategies for motor neuron diseases.
研究领域:
神经科学
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基因治疗
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 21
·11404
·
IF 4.9
Changxu Wu,Jinwu Zhang,Shisen Yang,Chunzi Peng,Maojie Lv,Jing Liang,Xiaoning Li,Liji Xie,Yingyi Wei,Hailan Chen,Jiakang He,Tingjun Hu,Zhixun Xie,Meiling Yu
Rutin is a flavonoid compound with potential for treating Alzheimer’s disease, preventing brain damage, mitigating cerebral ischemia–reperfusion injury, and exhibiting anti-glioblastoma activity. However, its efficacy is limited by its low solubility, poor bioavailability, and limited permeability across the blood–brain barrier (BBB). To enhance the bioavailability and brain-targeting ability of Rutin, transferrin-modified Rutin liposome (Tf-Rutin-Lip) was developed using liposomes as a delivery system. Rutin liposomes were prepared using the thin-film dispersion method, and the preparation conditions were optimized using the response surface methodology. Then, transferrin (Tf) was incorporated into the liposomes through covalent modification, yielding Tf-Rutin liposomes. The toxicity of these liposomes on bEnd.3 cells, as well as their impact on the tight junctions of these cells, was rigorously evaluated. Additionally, in vitro and in vivo experiments were conducted to validate the brain-targeting efficacy of the Tf-Rutin liposomes. A susceptible detection method was developed to characterize the pharmacokinetics of Tf-Rutin-Lip further. The optimized conditions for the preparation of Tf-Rutin-Lip were determined as follows: a lipid-to-cholesterol ratio of 4.63:1, a drug-to-lipid ratio of 1:45.84, a preparation temperature of 42.7 °C, a hydration volume of 20 mL, a sonication time of 10 min, a surfactant concentration of 80 mg/mL, a DSPE-MPEG-2000 concentration of 5%, and a DSPE-PEG2000-COOH to DSPE-MPEG-2000 molar ratio of 10%. The liposomes did not affect the cell activity of bEnd.3 cells at 24 h and did not disrupt the tight junction of the blood–brain barrier. Tf-modified liposomes were taken up by bEnd.3 cells, which, in turn, passed through the BBB, thus improving liposomal brain targeting. Furthermore, the results of pharmacokinetic experiments showed that the Cmax, AUC0-∞, AUC0-t, MRT0-∞, and t1/2of Tf-Rutin-Lip increased 1.99-fold, 2.77-fold, 2.58-fold, 1.26-fold, and 1.19-fold compared to those of free Rutin solution, respectively. These findings suggest that Tf-Rutin-Lip is brain-targeted and may enhance the efficacy of Rutin in the treatment of brain disorders.
研究领域:
药剂学
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神经科学
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药物递送系统
·
药理学
✓ 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）