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@#[摘 要] 白喉毒素（DT）及其衍生物可通过受体介导的胞吞转运作用穿越血脑屏障（BBB），并将毒素或药物靶向递送至肿瘤细胞，是有前景的靶向治疗脑胶质瘤的策略之一。目前，用于靶向治疗脑胶质瘤研究的DT衍生物主要有CRM107、DT389-EGF、CRM197、DTAT/DTAT13/DTATEGF和DTEGF13。其中，CRM107和DT389-EGF已经进入临床Ⅱ期试验，其余衍生物尚处于临床前研究阶段。根据现有研究进展，CRM107和CRM197是最有希望在脑胶质瘤治疗中取得突破的两种衍生物，但关键在于降低其毒副作用和提高靶向性。因此，明晰DT及其衍生物在靶向治疗脑胶质瘤的关键作用机制及应用现状，可为促进开发高效低毒的脑胶质瘤治疗药物提供新的思路。
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Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota-gut-brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ
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Blood-brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (
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Post-traumatic stress disorder (PTSD) is a psychiatric disease that seriously affects brain function. Currently, selective serotonin reuptake inhibitors (SSRIs) are used to treat PTSD clinically but have decreased efficiency and increased side effects. In this study, nasal cannabidiol inclusion complex temperature-sensitive hydrogels (CBD TSGs) were prepared and evaluated to treat PTSD. Mice model of PTSD was established with conditional fear box. CBD TSGs could significantly improve the spontaneous behavior, exploratory spirit and alleviate tension in open field box, relieve anxiety and tension in elevated plus maze, and reduce the freezing time. Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex, amygdala, and hippocampus CA1. CBD TSGs could reduce the level of tumor necrosis factor-
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Ischemic stroke is a cerebrovascular disease normally caused by interrupted blood supply to the brain. Ischemia would initiate the cascade reaction consisted of multiple biochemical events in the damaged areas of the brain, where the ischemic cascade eventually leads to cell death and brain infarction. Extensive researches focusing on different stages of the cascade reaction have been conducted with the aim of curing ischemic stroke. However, traditional treatment methods based on antithrombotic therapy and neuroprotective therapy are greatly limited for their poor safety and treatment efficacy. Nanomedicine provides new possibilities for treating stroke as they could improve the pharmacokinetic behavior of drugs
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As one of the most important components of caveolae, caveolin-1 is involved in caveolae-mediated endocytosis and transcytosis pathways, and also plays a role in regulating the cell membrane cholesterol homeostasis and mediating signal transduction. In recent years, the relationship between the expression level of caveolin-1 in the tumor microenvironment and the prognostic effect of tumor treatment and drug treatment resistance has also been widely explored. In addition, the interplay between caveolin-1 and nano-drugs is bidirectional. Caveolin-1 could determine the intracellular biofate of specific nano-drugs, preventing from lysosomal degradation, and facilitate them penetrate into deeper site of tumors by transcytosis; while some nanocarriers could also affect caveolin-1 levels in tumor cells, thereby changing certain biophysical function of cells. This article reviews the role of caveolin-1 in tumor prognosis, chemotherapeutic drug resistance, antibody drug sensitivity, and nano-drug delivery, providing a reference for the further application of caveolin-1 in nano-drug delivery systems.
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As a typical human pathogenic fungus,
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Background The interaction of the receptor for advanced glycation end product (RAGE) on blood-brain-barrier(BBB) with amyloid β (Aβ) plays an important role in the occurrence and development of AD. RP1 is a RAGEspecific binding peptide, which was discovered in our previous experiments, and it has been proved to beeffective on AD cell model, however, its effects on BBB tight junctions (TJs) and on Aβ transport into the brain isunclear.Methods Immunofluorescence experiment was used to identify whether RP1 bound with RAGE specifically.BEnd3-immortalized mouse brain microvascular endothelial cells were used to construct a BBB model. TEER andFD40 tests were used to confirm the stability of the BBB model, and the colocalization of the RP1 and RAGE onthe surface bEnd3 cells was observed with confocal microscopy.Results We confirmed that RP1 can bind to RAGE specifically in vitro. Functional analyses indicated that RP1 caneffectively alleviate the destroy of TJs of BBB and the decrease of permeability of BBB caused by Aβ. Furthermore,RP1 can competitively inhibit the interaction of Aβ with the RAGE in vitro, and effectively inhibit Aβ transport intothe brain.Conclusion RP1 can inhibit BBB damage induced by Aβ and block RAGE-Aβ interaction effectively, and RP1 canbe a candidate of RAGE inhibitors contributing to AD treatment
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ProBiotic-4 is a probiotic preparation composed of , , , and . This study aims to investigate the effects of ProBiotic-4 on the microbiota-gut-brain axis and cognitive deficits, and to explore the underlying molecular mechanism using senescence-accelerated mouse prone 8 (SAMP8) mice. ProBiotic-4 was orally administered to 9-month-old SAMP8 mice for 12 weeks. We observed that ProBiotic-4 significantly improved the memory deficits, cerebral neuronal and synaptic injuries, glial activation, and microbiota composition in the feces and brains of aged SAMP8 mice. ProBiotic-4 substantially attenuated aging-related disruption of the intestinal barrier and blood-brain barrier, decreased interleukin-6 and tumor necrosis factor- at both mRNA and protein levels, reduced plasma and cerebral lipopolysaccharide (LPS) concentration, toll-like receptor 4 (TLR4) expression, and nuclear factor-B (NF-B) nuclear translocation in the brain. In addition, not only did ProBiotic-4 significantly decreased the levels of -H2AX, 8-hydroxydesoxyguanosine, and retinoic-acid-inducible gene-I (RIG-I), it also abrogated RIG-I multimerization in the brain. These findings suggest that targeting gut microbiota with probiotics may have a therapeutic potential for the deficits of the microbiota-gut-brain axis and cognitive function in aging, and that its mechanism is associated with inhibition of both TLR4-and RIG-I-mediated NF-B signaling pathway and inflammatory responses.
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@#[Abstract] Objective: To investigate the influences of human lung adenocarcinoma PC-9 cells on tight junction proteins of blood brain barrier (BBB) under CXCR4/SDF-1 axis by establishing a model of BBB in vitro. Methods: The immortalized mouse brain microvascular endothelial Bends cells were used to establish a model of BBB in vitro by monolayer culture; Subsequently, transendothelial electric resistance (TEER) and fluorescein sodium permeability experiment were used to detect the function of in vitro BBB model and observe the effect of PC-9 cells on the function of BBB model, respectively. Western blotting was used to detect the effect of PC-9 cells on function of BBB model and expressions of endothelial tight junction proteins under the treatment of single or combined AMD3100 and SDF-1 (1 μg/ml AMD3100,100 ng/ml SDF-1, AMD3100+SDF-1). Transwell assay was used to detect the influence of CXCR4/SDF-1 axis on the ability of PC-9 cells transmigrating the cell layer of BBB model. Results: Monolayer culture of Bends cells can form tightly connected BBB withhighTEER,which reached (182.13±5.19) Ω.cm2 at the 96 h; in the meanwhile, fluorescein sodium permeability experiment showed that BBB had significantly lower permeability than that of control group ([40.31±2.43]% vs [150.10±3.17]%, P<0.05). The TEER of BBB decreased to (46.7±4.35) Ω·cm2 after coculture with PC-9 cells for 24 h, and at the same time the sodium fluorescein permeability of BBB significantly increased than that of pre-treatment ([136.32±4.93]% vs [50.24±6.21]%, P<0.05). PC-9 cells up-regulated the expressions of tight junction proteins of Bends cells under the treatment of AMD3100 (P<0.05). The number of PC-9 cells transmigrating the BBB inAMD3100 treatment group was significantly lower than that of CON group (43±2 vs 81±2, P<0.05). Conclusion: AMD3100 can reduce the ability of PC-9 cells destroying the tight junction of the BBB model established in vitro by Bends cells.
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Blood-brain barrier (BBB) breakdown and the associated microvascular hyperpermeability are hallmark features of several neurological disorders, including traumatic brain injury (TBI). However, there is no viable therapeutic strategy to rescue BBB function. Tissue inhibitor of metalloproteinase-1 (TIMP1) has been considered to be beneficial for vascular integrity, but the molecular mechanisms underlying the functions of TIMP1 remain elusive. Here, we report that TIMP1 executes a protective role on neuroprotective function ameliorating BBB disruption in mice with experimental TBI. In human brain microvessel endothelial cells (HBMECs) exposed to hypoxia and inflammation injury, the recombinant TIMP1 (rTIMP1) treatment maintained integrity of junctional proteins and trans-endothelial tightness. Mechanistically, TIMP1 interacts with CD63/integrin 1 complex and activates downstream FAK signaling, leading to attenuation of RhoA activation and F-actin depolymerization for endothelial cells structure stabilization. Notably, these effects depend on CD63/integrin 1 complex, instead of the MMP-inhibitory function. Together, our results identified a novel MMP-independent function of TIMP1 in regulating endothelial barrier integrity. Therapeutic interventions targeting TIMP1 and its downstream signaling may be beneficial to protect BBB function following brain injury and neurological disorders.
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BACKGROUND: Human urine-derived stem cells are newly discovered adult stem cells, characterized by rich sources, simple extraction, good proliferative ability and multi-directional differentiation potential. In recent years, human urine-derived stem cells have been used for the repair of neurological functions in urinary diseases, such as stress urinary incontinence and vesicoureteral reflux. OBJECTIVE: To explore the biological characteristics of human urine-derived stem cells and to study their repairing effect in a rat model of spinal cord injury. METHODS: Cell phenotypes of human urine-derived stem cells were detected using flow cytometry, and the immunohistochemical staining was used to identify neuron-like cells differentiated from human urine-derived mesenchymal stem cells. Then, an animal model of spinal cord injury at T9 segment was made by Allen method, and after modeling 24 Sprague-Dawley rats were assigned into spinal cord injury group or cell treatment group (n=12/group). In the cell treatment group, the model rats were injected 2 μL of 1.0×1011/L human urine-derived stem cells, while in the spinal cord injury group, the rats were administered the same volume of L-DMEM containing 10% fetal bovine serum. Basso, Beattie and Bresnahan scores were valued at 1, 10, 20, and 30 days after modeling. Spinal cord samples from all the rats were taken out at 30 days after modeling, and Luxol Fast Blue staining, microglia/macrophages staining and glial fibrillary acidic protein staining were used to value the injured area of the spinal cord and the fluorescence intensity of glial fibrillary acidic protein. RESULTS AND CONCLUSION: (1) Flow cytometry showed high expression on CD29 and CD90, and low expression on CD45 in human urine-derived mesenchymal stem cells. Moreover, human urine-derived mesenchymal stem cells could be induced to differentiating into neuron-like cells in vitro. (2) Basso, Beattie and Bresnahan scores showed no significant difference between the two groups at 1 and 10 days after modeling (P > 0.05), while, at 20 and 30 days after modeling, the scores in the cell treatment group were significantly higher than those in the spinal cord injury group (P < 0.05). (3) Luxol Fast Blue staining showed that the injured area of the spinal cord in the cell treatment group was markedly less than that in the spinal cord injury group (P < 0.05), and the glial fibrillary acidic protein showed lower fluorescence intensity in the cell treatment group than the spinal cord injury group (P < 0.05). To conclude, human urine-derived stem cells can differentiate into neuron-like cells and have therapeutic effects in the rat model of spinal cord injury.
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Nowadays, nanotechnology is revolutionizing the approaches to different fields from manufacture to health. Carbon nanotubes (CNTs) as promising candidates in nanomedicine have great potentials in developing novel entities for central nervous system pathologies, due to their excellent physicochemical properties and ability to interface with neurons and neuronal circuits. However, most of the studies mainly focused on the drug delivery and bioimaging applications of CNTs, while neglect their application prospects as therapeutic drugs themselves. At present, the relevant reviews are not available yet. Herein we summarized the latest advances on the biomedical and therapeutic applications of CNTs and for neurological diseases treatments as inherent therapeutic drugs. The biological mechanisms of CNTs-mediated bio-medical effects and potential toxicity of CNTs were also intensely discussed. It is expected that CNTs will exploit further neurological applications on disease therapy in the near future.
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Paeonol has neuroprotective function, which could be useful for improving central nervous system disorder. The purpose of this study was to characterize the functional mechanism involved in brain transport of paeonol through blood-brain barrier (BBB). Brain transport of paeonol was characterized by internal carotid artery perfusion (ICAP), carotid artery single injection technique (brain uptake index, BUI) and intravenous (IV) injection technique in vivo. The transport mechanism of paeonol was examined using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) as an in vitro model of BBB. Brain volume of distribution (V(D)) of [³H]paeonol in rat brain was about 6-fold higher than that of [¹⁴C]sucrose, the vascular space marker of BBB. The uptake of [³H]paeonol was concentration-dependent. Brain volume of distribution of paeonol and BUI as in vivo and inhibition of analog as in vitro studies presented significant reduction effect in the presence of unlabeled lipophilic compounds such as paeonol, imperatorin, diphenhydramine, pyrilamine, tramadol and ALC during the uptake of [³H]paeonol. In addition, the uptake significantly decreased and increased at the acidic and alkaline pH in both extracellular and intracellular study, respectively. In the presence of metabolic inhibitor, the uptake reduced significantly but not affected by sodium free or membrane potential disruption. Similarly, paeonol uptake was not affected on OCTN2 or rPMAT siRNA transfection BBB cells. Interestingly. Paeonol is actively transported from the blood to brain across the BBB by a carrier mediated transporter system.
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Animals , Rats , Blood-Brain Barrier , Brain , Carotid Arteries , Carotid Artery, Internal , Central Nervous System , Diphenhydramine , Endothelial Cells , Hydrogen-Ion Concentration , In Vitro Techniques , Membrane Potentials , Perfusion , Pyrilamine , RNA, Small Interfering , Sodium , Tramadol , TransfectionABSTRACT
Objective: To evaluate the effect of two-photon in vivo imaging on detecting the blood brain barrier (BBB) injury in the ultra-early stage of cerebral ischemic stroke. Methods: Twelve clean grade C57BL/6 healthy male mice aged 8-12 weeks were randomly divided into Sham group and middle cerebral artery occlusion (MCAO) group,which were sham operated or middle cerebral artery occluded,respectively. After 60 min of ischemia,MCAO mice were treated with reperfusion for 30-60 min after the suture being removed. The vessels and the neutrophils of mice in the two groups were labeled intravenously with Alexa-Fluora-488 conjugated dextran and rhodamine 6G,respectively. The integrity of BBB was detected by intravenous injection of tetramethylrhodamine-5-maleimide (TMR). Before and after the stroke,the real-time changes of the fluorescence intensity of the inside and outside cerebral vessels of mice in the MCAO group were observed by two-photon fluorescence microscopy. Results: The fluorescence intensity of TMR in the external cerebrovascular of mice in the MACO group was significantly increased within 30-60 min after stroke (P=0.000),suggesting there existed tracer leakage. Compared with the Sham group,the movement of neutrophils in the blood vessels of mice in the MACO group was significantly slowed down (P=0.000). Conclusion: Two-photon in vivo imaging can be used to detect the BBB injury in the ultra-early stage of cerebral ischemic stroke,which provides a certain reference value for clinical application.
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The sigma-1 receptor (R) is a unique intracellular protein. R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology. Moreover, R PET tracers can be used for target validation and quantification in diagnosis. Herein, we describe the radiosynthesis, PET/CT imaging of novel R C-labeled radioligands based on 6-hydroxypyridazinone, [C]HCC0923 and [C]HCC0929. Two radioligands have high affinities to R, with good selectivity. In mice PET/CT imaging, both radioligands showed appropriate kinetics and distributions. Additionally, the specific interactions of two radioligands were reduced by compounds and (self-blocking). Of the two, [C]HCC0929 was further investigated in positive ligands blocking studies, using classic R agonist SA 4503 and R antagonist PD 144418. Both R ligands could extensively decreased the uptake of [C]HCC0929 in mice brain. Besides, the biodistribution of major brain regions and organs of mice were determined . These studies demonstrated that two radioligands, especially [C]HCC0929, possessed ideal imaging properties and might be valuable tools for non-invasive quantification of R in brain.
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Dbait is a small double-stranded DNA molecule that has been utilized as a radiosensitizer to enhance the sensitivity of glioma to radiotherapy (RT). However, there is no effective drug delivery system to effectively overcome the blood-brain barrier (BBB). The aim of this study was to develop a gene delivery system by using the BBB and glioma dual-targeting and microenvironment-responsive micelles (ch-K(s-s)R8-An) to deliver Dbait into glioma for RT. Angiopep-2 can target the low-density lipoprotein receptor-related protein-1 (LRP1) that is overexpressed on brain capillary endothelial cells (BCECs) and glioma cells. In particular, due to upregulated matrix metalloproteinase 2 (MMP-2) in the tumor microenvironment, we utilized MMP-2-responsive peptides as the enzymatically degradable linkers to conjugate angiopep-2. The results showed that ch-K(s-s)R8-An micelles maintained a reasonable size (80-160 nm) with a moderate distribution and a decreased mean diameter from the cross-linking as well as exhibited low critical micelle concentration (CMC) with positive surface charge, ranging from 15 to 40 mV. The ch-K5(s-s)R8-An/pEGFP showed high gene transfection efficiency , improved uptake in glioma cells and good biocompatibility and . In addition, the combination of ch-K5(s-s)R8-An/Dbait with RT significantly inhibited the growth of U251 cells . Thus, ch-K5(s-s)R8-An/Dbait may prove to be a promising gene delivery system to target glioma and enhance the efficacy of RT on U251 cells.
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Objective To compare the therapeutic effects of orthotopic injection and tail vein injection of human amniotic mesenchymal stem cells(hAMSCs)on histological restoration and neurological functions of rats with spinal cord injury. Methods Transected spinal cord injury model in rats was established by transplanting DAPI prelabelled hAMSCs one week after injury.BBB scores were used to evaluate the hindlimb movement of rats. The histological patterns.and morphology of medullary sheath of spinal cord were observed. Results BBB scores in the orthotopic injection group and tail vein injection group were increased gradually from one to six week after hAM-SCs transplantation and reached 6.5 ± 0.5 and 7.12 ± 1.61 respectively 6 weeks after cell transplantation,higher than that of the control group(both P < 0.01). However,there was no statistical significance between the two groups.Histological results indicated that the repair of injured tissue in the orthotopic injection group and tail vein injection group were both better than that in the control group,and there were more vesica and loosened layers forming in the injured spinal cord of rats in the PBS control group as compared with the orthotopic and tail vein transplantation group. Conclusion hAMSCs transplantation through tail vein injection could promote histological restoration and neurological regeneration of rats with spinal cord injury,which has the similar therapeutic effects with hAMSCs orthotopic transplantation.
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The blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB) prevent drug and nano-drug delivery systems from entering the brain. However, ligand-mediated nano-drug delivery systems have significantly enhanced the therapeutic treatment of glioma. In this study we investigated the mechanism especially the integrity of liposomes and lipid disks while traversing the BBB and BBTB both and . Fluorophores (DiO, DiI and DiD) were loaded into liposomes and lipid disks to form Förster resonance energy transfer (FRET) nano-drug delivery systems. Using brain capillary endothelial cells as a BBB model, we show that liposomes and disks are present in the cytoplasm as their intact forms and traverse the BBB with a ratio of 0.68‰ and 1.67‰, respectively. Using human umbilical vein endothelial cells as BBTB model, liposomes and disks remained intact and traversed the BBTB with a ratio of 2.31‰ and 8.32‰ at 3 h. imaging and immunohistochemical results revealed that liposomes and disks could traverse the BBB and BBTB as intact forms. In conclusion, these observations explain in part the mechanism by which nano-drug delivery systems increase the therapeutic treatment of glioma.