查找使用阿拉丁产品的科研文献

Sulfur dioxide derivatives aggravated ovalbumin-induced asthma through targeting TRPV1 and tight junctions

Zhou Liping,Lao Zishan,Fan Xinsheng,Hao Mengyang,Yang Yubing

This study aimed to investigate the effects of sulfur dioxide (SO2) derivatives on asthma induced by ovalbumin (OVA). Sprague Dawley rats were sensitized to and challenged with OVA and SO2 derivatives (NaHSO3 and Na2SO3, 1:3 M/M) to establish 28-day (short-term) and 42-day (long-term) asthma models. Exposure to SO2 derivatives aggravated asthma and hence, promoted lung injury in OVA-induced asthma. In addition, it upregulated the protein expression of TRPV1 and downregulated the expression of tight junctions (TJs). These changes were dose-dependent and were more pronounced in the presence of a high concentration of SO2 derivatives. In vitro, SO2 derivatives also increased the calcium influx and TRPV1 protein expression, and decreased TJ expression. Besides, no significant difference in the TJ expression was found between the WT and TRPV1−/- mice. The underlying mechanism might be related to regulating the effects of TRPV1 and TJs.

PEA prevented early BBB disruption after cerebral ischaemic/reperfusion (I/R) injury through regulation of ROCK/MLC signaling

Dequan Kong,Baoying Xie,Yuhang Li,Yaping Xu

Palmitoylethanolamide (PEA) offers a strong protection against BBB disruption and neurological deficits after cerebral ischaemic/reperfusion (I/R) injury. To date, these BBB protective effects of PEA are mainly attributed to PPARα-mediated actions. However, whether PEA protects against BBB disruption through direct regulation of cytoskeletal microfilaments remains unknown. Here, we identified PEA as a Rho-associated protein kinase (ROCK2) inhibitor (IC 50  = 38.4 ± 4.8 μM). In vitro data suggested that PEA reduced the activation of ROCK/MLC signaling and stress fiber formation within microvascular endothelial cells (ECs) after oxygen-glucose deprivation (OGD), and consequently attenuated early (0–4 h) EC barrier disruption. These actions of PEA could not be blocked by the PPARα antagonist GW6471. In summary, the present study described a previously unexplored role of PEA as a ROCK2 inhibitor, and propose a PPARα-independent mechanism for pharmacological effects of PEA.

Immune cell targeting-mediated cytomimetic drug delivery system for BBB-penetrating and precise therapy of in situ glioma

Xiu Wang,Baoqin Song,Mengru Wu,Lijing Qin,Wanjun Liang

Gliomas are a group of highly malignant tumors that are prone to recurrence after surgery. Due to the limitation of the blood-brain barrier (BBB), most antitumor drugs cannot cross it. Therefore, improving the delivery efficiency of antitumor drugs in their treatment remains a significant challenge. Herein, we report a unique cellular biomimetic drug delivery system (CTP@RAW) that benefits from the exceptional immune homing and long-term tracking ability of RAW 264.7 cells to specifically penetrate BBB and target tumor sites. The drug (TMZ) is encapsulated in RAW264.7 to avoid being cleared or degraded by the blood, improve bioavailability and reduce systemic toxicity. And that, owning to polydopamine (PDA) coating on the quantum dots-drug nanoparticles, which can endogenously and controllably release TMZ in response to certain tumor microenvironment (high GSH and low pH). This delivery system can also achieve precise localization and real-time visualization of tumors via fluorescence imaging. The released drugs effectively inhibit tumor growth by regulating cytokine expression levels, including GFAP, Ki67, Caspase-3, and TNF-α. Our study demonstrates that this drug delivery system can cross BBB, improve drug delivery efficiency, and has excellent potential for visualization and precision treatment of in situ gliomas.

Cross-and-Capture: A Dual-Ligand PAMAM Nanocarrier for Sequential BBB Penetration and Ischemic Lesion Retention of Breviscapine

The clinical management of ischemic stroke is severely constrained by the blood–brain barrier (BBB), which restricts therapeutic drug access to the brain parenchyma, and the rapid systemic clearance of neuroprotective agents such as breviscapine (Bre). To overcome this dual challenge, we engineered a dual-targeting nanocarrier, L57&PGP-PEG-PAMAM, designed to sequentially traverse the BBB and anchor within the ischemic inflammatory microenvironment. This construct employs a PEGylated fifth-generation polyamidoamine (PAMAM) dendrimer scaffold functionalized with two distinct peptides: L57, which mediates transcytosis via LRP1 receptors on the BBB, and PGP, which targets CXCR2 receptors overexpressed on infiltrating neutrophils at the lesion. The resulting nano particles exhibited a hydrodynamic diameter of 140.2 ± 0.6 nm (zeta potential: 9.32 mV) and encapsulated Bre with a loading capacity of 20.12% and encapsulation efficiency of 71.78%, displaying sustained release (54.6% over 72 h). Crucially, in vivo fluorescence imaging confirmed markedly superior brain accumulation relative to non-targeted and PEGylated-only controls, while in a rat MCAO model, the formulation reduced infarct volume to 21.7 ± 6.4%, improved neurological scores to 1.52 ± 0.28, and suppressed pro-inflammatory IL-15/IL-27 levels—collectively outperforming free Bre. This work establishes a robust “cross-and-capture” strategy that effectively decouples BBB penetration from lesion-specific retention for ischemic stroke therapy.

Establishment of an Ultrasound Responsive Microfluidic Chip of BBB-Glioblastoma model for Studying Sonodynamic Therapy-enhanced Nanodrug Delivery

Liyang Wu,Bingcheng Lin,Huadong Fan,Yihong Li

Glioblastoma (GB), the most common primary malignant brain tumor, faces limited treatment efficacy due to Blood-Brain-Barrier (BBB) restricting drug delivery. Sonodynamic therapy (SDT) presents a promising non-invasive alternative, using ultrasound for deep tissue penetration to transiently open the BBB and activate sonosensitizers for localized GB destruction. However, mechanistic understanding and optimization of SDT are hindered by the lack of integrated platforms capable of quantitatively elucidating the relationships between ultrasound-controlled BBB dynamics, drug delivery kinetics, and SDT efficacy. To address this, we developed a physiologically relevant BBB-GB organ-on-a-chip model integrating human cerebral microvascular endothelial cells (HCMECs), primary astrocytes (ACs), and U87-MG cells within a Matrigel-embedded microfluidic chip. This model recapitulated key BBB features, confirmed by continuous ZO-1 tight junction expression and size-selective permeability (FITC-dextran assay). Crucially, the ultrasound-opened barrier retained selective permeability, favoring nanocarriers like our tumor-targeting SFN@RB@SPM nanomicelles while effectively excluding free small molecules (Rose Bengal) and other nanoparticle types (Exo-RB), thereby mimicking the discriminative function of the biological BBB. low-intensity ultrasound (1 MHz, 1 W/cm2, 30 seconds) induced transient, reversible BBB opening, with full functional and structural recovery within 24 hours. Utilizing this controlled opening, our self-assembled tumor-targeting nanomicelles (SFN@RB@SPM) exhibited significantly enhanced BBB permeability. Real-time monitoring revealed efficient, selective uptake of SFN@RB@SPM by U87-MG cells. Sequential ultrasound application—first to open the BBB for nanomicelles delivery and second to activate SDT—synergistically amplified intracellular reactive oxygen species (ROS) generation and induced near-complete U87-MG cell death. These effects were unachievable with either ultrasound or nanomicelles alone. This integrated BBB-GB organ-on-a-chip platform enables simultaneous quantification of ultrasound-regulated BBB permeability, multi-cellular interactions, tumor-targeted nanodrug delivery dynamics, and SDT therapeutic efficacy. It thus provides a powerful in vitro tool for elucidating SDT mechanisms and accelerating the development of novel glioma therapies.

Regulation of pathological BBB restoration via nanostructured ROS-responsive glycolipid-like copolymer entrapping siVEGF for glioblastoma targeted therapeutics

Wen Lijuan,Peng Yu,Wang Kai,Huang Zhihua,He Shiying,Xiong Ruiwen,Wu Longping,Zhang Fengtian,Hu Fuqiang

Glioblastoma (GBM) is one of the malignant brain tumors with high mortality and no curative treatments. Abnormally elevated vascular endothelial growth factor (VEGF) in GBM seriously disrupts the blood brain barrier (BBB) with an increased permeability, resulting in poor outcome and prognosis. RNAi interference has shown strong potential to inhibit VEGF expression, thus it is necessary to development an effective and safe gene delivery system possessing the ability to cross the BBB and target GBM cells. This study aims to explore the anti-GBM effect of angiopep-2 (Ap) peptide modified reactive oxygen species (ROS) cleavable thioketal (TK) linked glycolipid-like nanocarrier (CSTKSA) delivering anti-VEGF siRNA (R), termed as Ap-CSTKSA/R complexes. Ap functionalized modification produced an enhanced cellular uptake and a stronger bio-distribution of Ap-CSTKSA/R complexes in U87 MG cells and brain tumor tissues, respectively. Ap-CSTKSA/R complexes exhibited great superiority in GBM growth inhibition and finally translated into the longest survival period mainly via receptor-mediated targeting delivery, VEGF gene silencing accompanied with remarkable angiogenesis inhibition, and suppressed expression of caveolin-1 which is involved in BBB functional regulation in the occurrence and treatment of GBM. The study indicated that Ap functionalization on ROS-responsive glycolipid-like copolymer exhibits a promising and effective gene delivery platform for GBM targeted treatment.

Luteolin-Loaded TGN/RAP12 Dual-Peptide Functionalized Nanoparticles: Synergistic Enhancement of BBB Penetration and Microglia Targeting in Alzheimer’s Disease

Shumeng Liu,Yue Xing,Yue Na,Hao Wu,Chi Liu,Zhigang Wang,Ning Zhang,Xiuhong Wu,Fang Geng

Luteolin (Ltn), a natural flavonoid, effectively inhibits microglial activation in Alzheimer’s disease (AD) with promising therapeutic potential, but its efficacy is severely limited by the blood–brain barrier (BBB). To overcome this obstacle, this study prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)—designated as TGN/RAP12-RBC-NPs@Ltn—which were coated with red blood cell membranes (RBCm) functionalized with two peptides, TGN (TGNYKALHPHN) and RAP12 (EAKIEKHNHYQK). The results demonstrated that TGN significantly enhanced BBB permeability, while RAP12 enabled effective targeting and delivery of TGN/RAP12-RBC-NPs@Ltn to microglial mitochondria in the brain. In addition, the presence of RBCm significantly inhibited the phagocytosis of NPs by macrophages, exerting a notable role in immune evasion. Meanwhile, the study confirmed that encapsulating Ltn within NPs significantly enhanced cognitive function in APP/PS1 mice, modulated the expression of key mitochondrial metabolic enzymes—pyruvate dehydrogenase (PDH) and its phosphorylated forms (pS232PDH, pS293PDH, pS300PDH)—in microglia, thereby ameliorating mitochondrial dysfunction and effectively regulating the neuroinflammatory environment in the mouse brain, and ultimately contributed to therapeutic efficacy. From this, it could be seen that TGN/RAP12-RBC-NPs@Ltn could significantly enhance the therapeutic effect of Ltn on AD, providing an effective treatment strategy for delaying the progression of AD.

Rapid antiepileptic activity identification of isopimpinellin using a multi-model of epilepsy based on behavior-biomarker-BBB screening pipeline

Xin Gao,Xinjia Li,Yuanteng Zheng,Lijie Xia,Haonan Li,Yuqing Li,Attila Sik,Kechun Liu,Meng Jin

Background Epilepsy is a common neurological disorder that manifests as sudden abnormal electrical discharges and convulsions, affecting more than 70 million people worldwide. Current antiepileptic drugs (AEDs) can inhibit seizures, while long-term use has side effects. In addition, one-third of patients do not respond to the available AEDs. In recent years, traditional Chinese medicines (TCMs), which have multi-target and multi-pathway actions with low side effects, have offered a promising alternative for treating epilepsy. Purpose This study aims to develop a multi-tiered screening strategy combining behavioral, biomarker, blood-brain barrier (BBB) permeability, and computational approaches to identify optimal antiepileptic compounds from TCMs. Methods A TCMs library was initially screened based on pentylenetetrazol (PTZ)-induced seizures and biomarkers ( c-fos and c-jun ), which was followed by further screening using parallel artificial membrane permeation assay (PAMPA). Then, a multi-indicator in silico approach, including cluster analysis, Lipinski's Rule of 5, and clinical drug similarity assessment, was employed to discover hit compounds. Mouse epilepsy models confirmed the antiepileptic candidates. Finally, the underlying mechanism was investigated through proteomics and further verified by analyzing the key targets CSF1/CSF1R, microglial activation, and target intervention studies. Results Overall, 11 antiepileptic candidates were identified from a total of 730 TCMs, yielding a hit rate of 1.5%. ISOP exhibited the desirable BBB permeability and the optimal antiepileptic activity via multi-indicator in silico analysis. Accordingly, ISOP mitigated seizures in zebrafish and mice, including delayed seizures by 2-3 times, inhibited neuronal discharges by 60-70%, and reduced Mouse Racine's score by 3 points. A total of 27 differentially expressed proteins (DEPs) were revealed, which were enriched in the inflammatory response, among other functions. By suppressing CSF1, ISOP led to the downregulation of CSF1R, thus inhibiting microglial activation, ultimately exerting antiepileptic effects. Conclusion A rapid antiepileptic drug screening strategy was generated for the first time, integrating BBB permeability early in the screening process. By using this screening pipeline, ISOP was identified, which represents a novel CSF1R-targeting candidate for the treatment of epilepsy.

Paclitaxel-loaded dextran nanoparticles decorated with RVG29 peptide for targeted chemotherapy of glioma: an in vivo study

Hailing Han,Ying Zhang,Shunzi Jin,Ping Chen,Shi Liu,Zhigang Xie,Xiabin Jing,Zhanfeng Wang

Gliomas are the most common malignant brain tumors and notorious due to the blood–brain barrier (BBB). In this study, an RVG peptide is used as a targeting ligand to construct multi-targeting micelles (RVG–Dex–PTX) towards the brain (passing the BBB) and brain glioma. In vivo imaging and fluorescence imaging were carried out. The results showed that Cy5-labeled M(RVG, PTX) can cross the BBB and reach the intracranial C6 glioma, prolonging the median mean survival time. Specifically, the elevated RVG29 could enhance the uptake of the micelles by C6 glioma cells and thus enhance the PTX efficacy. In conclusion, RVG29 is a promising targeting peptide for the BBB and intracranial tumors, and the M(RVG, PTX) micelles prepared from dextran, PTX, and RVG29 are a potential formulation for C6 glioma treatment.

Synthesis of 1,3,5-triphenyl-1,2,4-triazole derivatives and their neuroprotection by anti-oxidative stress and anti-inflammation and protecting BBB

Yang Wang,Ruiqi Su,Jianwen Chen,Xuan Liu,Jingning Luo,Yaoqiang Lao,Ping Huang,Jinguo Shi,Caibao Jiang,Liping Liao,Jingxia Zhang

Acute ischemic stroke (AIS) is a serious cardiovascular and cerebrovascular disease; Oxidative stress and neuroinflammation are important factors which destroy blood-brain barrier (BBB) in AIS. In the study, a series of 1,3,5-triphenyl-1,2,4-triazole derivatives were designed and synthesized; the optimal compound 9 was obtained by screening their anti-oxidant and anti-inflammatory effects; the neuroprotection effect of compound 9 was evaluated with a rat middle cerebral artery occlusion (MCAO) model. Subsequently, the mechanism of neuroprotection were explored via Western blot. The results prompt compound 9 maybe exert anti-AIS neuroprotection by inhibiting oxidative stress and neuroinflammation inhibition by inhibiting Keap1, COX-2 and iNOS. At the same time, it can protect BBB by reducing glycocalyx degradation and matrix metallopeptidase-9 levels. Its LD 50  > 1000 mg/kg on mice and hERG channel inhibition IC 50  > 30 μM, which lower acute toxicity and hERG channel inhibition would make compound 9 a promising stroke treatment candidate.

Integration of Sonosensitive Nanomicelles and Ultrasound for Enhanced BBB Penetration and Targeted Therapy against Glioblastoma: Intravenous Injection vs. Intranasal Dripping

Yandai Lin,Wei Wang,Fengqi Xuan,Zhe Liu

The blood brain barrier (BBB) is pivotal to protect brain from external interferences and to maintain homeostasis for normal physiological processes. However, it also becomes a vital obstacle for drug delivery across BBB and undermines efficiency of brain tumor therapies. In this study, an amphiphilic peptide with cell-penetrating sequence and hydrophilic targeting terminal (RGD) was self-assembled with encapsulation of Rose Bengal (RB) to generate the functionalized nanomicelles (PRN). With active target capacity, the integration of PRN and medical ultrasound was applied to enhance BBB penetration and achieve consecutive glioblastoma-targeted sonodynamic therapy. The temporary BBB opening and penetration enhancement have been validated in vitro and in vivo under US irradiation, and the efficacious tumor growth inhibition and lesion elimination were evidenced by a mechanism of in situ ROS-induced tumor cell apoptosis. Meanwhile, therapeutic efficacies by both intravenous injection and intranasal dripping of PRN were investigated, and a rationale of immune-actuation and multilateral cell death were proposed for this therapeutic modality of drug-device-field integration (DDFI). This research has provided an advanced glioblastoma treatment by different administrations and delivery pathways across BBB, and outlook an inspiring vision with a cutting-edge DDFI modality for broader applications of disease-oriented treatments.

NDP-MSH binding melanocortin-1 receptor ameliorates neuroinflammation and BBB disruption through CREB/Nr4a1/NF-κB pathway after intracerebral hemorrhage in mice

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.