TOXICOLOGY LETTERS
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2023
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IF 3.5
Yizhou Zhong,Bingli Zhang,Yuji Huang,Jiaxin Du,Boxuan Liang,Zhiming Li,Rongyi Ye,Bo Wang,Hongyi Xian,Xifei Yang,Weifeng Rong,Xiang Guo,Xingfen Yang,Zhenlie Huang
1,2-Dichloroethane (1,2-DCE) is a pervasive environmental pollutant found in ambient and residential air, as well as ground and drinking water . Brain edema is the primary pathological consequence of 1,2-DCE overexposure. We found that microRNA (miRNA)-29b dysregulation after 1,2-DCE exposure can aggravate brain edema by suppressing aquaporin 4 (AQP4). Moreover, circular RNAs (circRNAs) can regulate the expression of downstream target genes through miRNA , and affect protein function. However, circRNAs’ role in 1,2-DCE-induced brain edema via miR-29b-3p/AQP4 axis remains unclear. To address the mechanism’s bottleneck, we explored the circRNA-miRNA-mRNA network underlying 1,2-DCE-driven astrocyte swelling in SVG p12 cells by circRNA sequencing, electron microscopy and isotope 3 H labeling combined with the 3-O-methylglucose uptake method. The results showed that 25 and 50 mM 1,2-DCE motivated astrocyte swelling, characterized by increased water content, enlarged cell vacuoles, and mitochondrial swelling. This was accompanied by miR-29b-3p downregulation and AQP4 upregulation. We verified that AQP4 were negatively regulated by miR-29b-3p in 1,2-DCE-induced astrocyte swelling. Also, circRNA sequencing highlighted that circBCL11B was upregulated by 1,2-DCE. This was manifested as circBCL11B overexpression playing an endogenous competitive role via upregulating AQP4 by binding to miR-29b-3p, thus leading to astrocyte swelling. Conversely, circBCL11B knockdown reversed the 1,2-DCE-motivated AQP4 upregulation and alleviated the cell swelling. Finally, we demonstrated that the circBCL11B was targeted to miR-29b-3p by fluorescence in situ hybridization and dual-luciferase reporter assay. In conclusion, our findings indicate that circBCL11B acts as a competing endogenous RNA to facilitate 1,2-DCE-caused astrocyte swelling via miR-29b-3p/AQP4 axis. These observations provide new insight into the epigenetic mechanisms underlying 1,2-DCE-induced brain edema.
研究领域:
毒理学
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神经科学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
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2020
·Vol. 26
·期 12
·1288-1302
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IF 4.074
Meng Gao,Weitian Lu,Yue Shu,Zhengyu Yang,Shanquan Sun,Jin Xu,Shengwei Gan,Shujuan Zhu,Guoping Qiu,Fei Zhuo,Shiye Xu,Yiying Wang,Junhong Chen,Xuan Wu,Juan Huang
Background Specific highly polarized aquaporin-4 (AQP4) expression is reported to play a crucial role in blood-brain barrier (BBB) integrity and brain water transport balance. The upregulation of polymerase δ-interacting protein 2 (Poldip2) was involved in aggravating BBB disruption following ischemic stroke. This study aimed to investigate whether Poldip2-mediated BBB disruption and cerebral edema formation in mouse bacterial meningitis (BM) model occur via induction of AQP4 polarity loss. Methods and Results Mouse BM model was induced by injecting mice with group B hemolytic streptococci via posterior cistern. Recombinant human Poldip2 (rh-Poldip2) was administered intranasally at 1 hour after BM induction. Small interfering ribonucleic acid (siRNA) targeting Poldip2 was administered by intracerebroventricular (i.c.v) injection at 48 hours before BM induction. A specific inhibitor of matrix metalloproteinases (MMPs), UK383367, was administered intravenously at 0.5 hour before BM induction. Western blotting, immunofluorescence staining, quantitative real-time PCR, neurobehavioral test, brain water content test, Evans blue (EB) permeability assay, transmission electron microscopy (TEM), and gelatin zymography were carried out. The results showed that Poldip2 was upregulated and AQP4 polarity was lost in mouse BM model. Both Poldip2 siRNA and UK383367 improved neurobehavioral outcomes, alleviated brain edema, preserved the integrity of BBB, and relieved the loss of AQP4 polarity in BM model. Rh-Poldip2 upregulated the expression of MMPs and glial fibrillary acidic protein (GFAP) and downregulated the expression of β-dystroglycan (β-DG), zonula occludens-1 (ZO-1), occludin, and claudin-5; whereas Poldip2 siRNA downregulated the expression of MMPs and GFAP, and upregulated β-DG, ZO-1, occludin, and claudin-5. Similarly, UK383367 downregulated the expression of GFAP and upregulated the expression of β-DG, ZO-1, occludin, and claudin-5. Conclusion Poldip2 inhibition alleviated brain edema and preserved the integrity of BBB partially by relieving the loss of AQP4 polarity via MMPs/β-DG pathway.
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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传染病学
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产品关联
DOI
PubMed
高影响因子
Translational Stroke Research
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2023
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IF 6.9
Chen Yan-Yan,Gong Zhi-Cheng,Zhang Mei-Mei,Huang Zhao-Hui
Abstract Failure to achieve target-specific delivery to ischemic brain sites has hampered the clinical efficacy of newly developed therapies for ischemic stroke. Emodin, an active ingredient isolated from traditional Chinese medicine, has been indicated to alleviate ischemic stroke; however, the underlying mechanism remains unclear. In this study, we aimed to achieve brain-targeted delivery of emodin to maximize its therapeutic efficacy and elucidate the mechanisms by which emodin alleviates ischemic stroke. A polyethylene glycol (PEG)/cyclic Arg-Gly-Asp (cRGD)-modified liposome was used to encapsulate emodin. TTC, HE, Nissl staining, and immunofluorescence staining were employed to evaluate the therapeutic efficacy of brain-targeting emodin in MCAO and OGD/R models. Inflammatory cytokine levels were determined using ELISA. Immunoprecipitation, immunoblotting, and RT-qPCR were utilized for clarifying the changes in key downstream signaling. Lentivirus-mediated gene restoration was employed to verify the core effector of emodin for relieving ischemic stroke. Encapsulating emodin in a PEG/cRGD-modified liposome enhanced its accumulation in the infarct region and substantially raised its therapeutic efficacy. Furthermore, we demonstrated that AQP4, the most abundant water transporter subunit expressed in astrocytes, plays a crucial role in mediating the mechanisms by which emodin inhibits astrocyte swelling, neuroinflammatory blood–brain barrier (BBB) breakdown in vivo and in vitro, and brain edema in general. Our study unveiled the critical target of emodin responsible for alleviating ischemic stroke and a localizable drug delivery vehicle in the therapeutic strategy for ischemic stroke and other brain injuries. Graphical Abstract
研究领域:
神经科学
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药理学
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药物递送系统
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中风研究
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DOI
PubMed
高影响因子
RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY
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2018
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IF 1.792
Bo Wang,Wenyang Li,Hongyu Jin,Xinshi Nie,Hui Shen,Erran Li,Wei Wang
Chronic intermittent hypoxia (CIH) is one of the main features of obstructive sleep apnea (OSA), which is also commonly associated with neurocognitive impairments. The present study aimed to elucidate the beneficial effect of curcumin on CIH-induced brain injuries. Male balb/c mice (6 ∼ 8 weeks) were exposed to normoxia or a pattern of CIH (8 h/day, cycles of 180 s each, hypoxia: 5% O 2 for 50 s, reoxygenation: 21% O 2 for 50 s) for 10 weeks, along with daily curcumin treatment (50, 100, or 200 mg/kg, intragastrically) or its vehicle. The results showed that CIH induced significant brain edema, as well as neuronal apoptosis and astrogliosis in the cerebral cortex, brainstem, and cerebellum regions of brain. In addition, increased astrocytic AQP4 expression and activation of p38 MAPK pathway were observed after CIH exposure. Curcumin dose-dependently mitigated the brain edema and relevant cell alterations, showing a neuroprotective effect in CIH-induced brain injury. Together, these results suggest curcumin ameliorates the CIH-induced brain injuries, including brain edema, neuronal death and astrogliosis. The beneficial role of curcumin is mediated partially by regulating AQP4 and p38 MAPK pathway.
研究领域:
神经科学
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药理学
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睡眠医学
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2026
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IF 12.2
Jiahui Xie,Yueran Ren,Minlin Lai,Jiayu Liang,Jingru Liang,Yifeng Zheng,Huidi Wang,Jiafeng Zhang,Boxin Zhao,Wei Song,Jia Yin
Clinical and animal data show peripheral-central crosstalk: microbial tryptophan metabolism regulate cognition under CCH. • This study highlights microbial tryptophan metabolism, especially ILA, as a promising therapeutic target for cognition. • This study identifies the ILA–AHR–AQP4 pathway as a key mediator of glymphatic restoration, which improves cognition. Microbial tryptophan metabolites regulate cognitive function, but their role in vascular cognitive impairment (VCI) induced by chronic cerebral hypoperfusion (CCH) remains poorly understood. In the CCH cohort, we observed gut microbiota dysbiosis and reduced levels of microbial tryptophan metabolites, including indole-3-lactic acid (ILA), in cognitively impaired CCH patients, with these metabolites serving as protective factors. In mice with bilateral carotid artery stenosis, gut microbiota dysbiosis and ILA reduction preceded cognitive decline and were accompanied by astrocytic aryl hydrocarbon receptor (AHR) inactivation, aquaporin-4 (AQP4) depolarization, and glymphatic dysfunction. Fecal microbiota transplantation (FMT) reconstituted the gut microbiota and salvaged cognition. The cognitive improvement following FMT depended on the restoration of the glymphatic system. Tryptophan supplementation increased cerebral ILA concentrations, activated astrocytic AHR, and polarized AQP4, thereby rescuing glymphatic function and enabling cognitive recovery. Notably, ILA supplementation alone was sufficient to restore AQP4 polarization and cognitive function. Mechanistically, we identified dioxin-responsive elements within the promoters of the AQP4 polarization-associated genes alpha-syntrophin ( Snta1 ) and dystroglycan 1 ( Dag1 ). ILA supplementation activated AHR in astrocytes and upregulated the expression of these genes, whereas AHR-specific antagonist pretreatment inhibited the upregulation of Snta1 and Dag1 induced by ILA. These findings demonstrate an ILA–AHR–AQP4 axis linking microbial tryptophan metabolism to the glymphatic system, which is important for cognitive restoration and indicates a novel therapeutic insight for VCI associated with CCH. Given the exploratory nature of the clinical cohorts, the findings warrant validation in larger independent cohorts. (Trial registration: ClinicalTrials. gov. ID number: NCT04688138). Download: Download high-res image (318KB) Download: Download full-size image
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DOI
高影响因子
Journal of Neuroinflammation
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2024
·Vol. 21
·期 1
·1-17
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IF 9.3
Zhao Lina,Zhang Zhen,Wang Pei,Zhang Nannan,shen Hao,Wu Hening,Wei Zhiyong,Yang Fei,Wang Yunying,Yu Zhijie,Li Haibo,Hu Zhanfei,Zhai Hongyan,Wang Zhiwei,Su Fuhong,Xie Keliang,Li Yun
Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE.
研究领域:
神经科学
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微生物学
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分子生物学
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病理生理学
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DOI
高影响因子
MOLECULAR NEUROBIOLOGY
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2024
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IF 4.6
Wang Zhenhua,Li Yuan,Wang Zhixu,Liao Yuhui,Ye Qingqing,Tang Shilong,Wei Ting,Xiao Pengyu,Huang Juan,Lu Weitian
Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood–brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH.
研究领域:
神经科学
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药理学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2026
·Vol. 51
·期 1
·73
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IF 4.5
Zhou Juan,Li Haipeng,Wen Ying,He Lingli,He Yangli,Meng Heng
Neuromyelitis optica spectrum disorder (NMOSD) is a rare but serious inflammatory demyelinating disease. A key characteristic of NMOSD is the presence of a pathogenic autoantibody in serum called aquaporin-4 immunoglobulin G (AQP4-IgG). This study investigates the mechanism of astrocyte-derived small extracellular vesicles (EVs) carrying mitochondrial DNA (mtDNA) to promote AQP4-IgG-induced microglial activation in neuromyelitis optica (NMO) via the toll-like receptor 9 (TLR9)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-kappa B (NF-κB) pathway. Serum IgG was isolated from NMOSD patients (AQP4-IgG) and healthy controls (Con-IgG). Astrocytes were treated with AQP4-IgG or Con-IgG. EVs were isolated via ultracentrifugation, characterized, and examined for internalization. Microglia were exposed to EVs, and mtDNA levels were assessed. An NMO mouse model was established, with neurological damage, mouse behaviors, tissue damage, and microglial characterization evaluated using modified neurological severity score, open-field test, rotarod test, luxol fast blue staining, and flow cytometry. Inflammatory cytokines, TLR9, MyD88, p65, IκBα, p-p65, and p-IκBα in BV2 cells and spinal cord tissues were analyzed via ELISA, RT-qPCR, and western blot. AQP4-IgG-induced astrocyte-derived EVs increased Iba1-high-expressing and CD86/tumor necrosis factor-α-high-expressing cells, reduced CD206/transforming growth factor-β-high-expressing cells, and boosted inflammatory responses. AQP4-IgG-induced EVs carried mtDNA to activate microglia via the TLR9/MyD88/NF-κB pathway. TLR9/MyD88/NF-κB pathway inhibition reversed AQP4-IgG-induced EVs’ promotion on microglial activation. In vivo, AQP4-IgG-induced EVs-mtDNA exacerbated microglial activation and NMO through the TLR9/MyD88/NF-κB pathway. AQP4-IgG-induced EVs carried mtDNA to upregulate TLR9, further activating the MyD88/NF-κB pathway, thereby promoting microglial activation and transition toward pro-inflammatory gene-high-expressing cells to drive NMO progression.
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产品关联
DOI
PubMed
高影响因子
Alexandria Engineering Journal
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2024
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IF 6.2
Huiyuan Peng,Weihua Guo,Jinsong Wang,Weili Xia,Yu Xiong,Wenhua Xu,Weibo Dai,Feng Zheng
Addressing the devastating and often irreversible effects of stroke necessitates innovative therapeutic strategies that go beyond the limitations of current treatments. This study heralds a promising interdisciplinary approach by employing LAP/PDA composite nanomaterials integrated into silk fibroin-based hydrogels. These engineered materials not only demonstrated significantly enhanced mechanical properties, but also showed excellent biocompatibility when co-cultured with human mesenchymal stem cells (hMSCs). Importantly, the application of these composite hydrogels in stroke models yielded remarkable therapeutic outcomes. The results indicated a substantial reduction in cerebral infarction volumes, improved survival rates of transplanted hMSCs, and increased neurogenesis, underlining their transformative potential in stroke management. Molecular markers such as AQP4, α-DG, and β-DG were also explored, revealing modulated astrocyte activation and cellular signaling pathways. In summary, the composite LAP/PDA nanomaterials, in conjunction with hMSCs and Brain-Derived Neurotrophic Factor (BDNF), unveil a compelling and multifaceted approach for addressing the unmet needs in stroke treatment, thereby opening new avenues in regenerative medicine and tissue engineering.
研究领域:
神经科学
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再生医学
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组织工程
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纳米技术
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干细胞生物学
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DOI
高影响因子
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