NEUROSCIENCE
·
2019
·
IF 3.244
Sen Shang,Lin Liu,Xingjuan Wu,Fan Fan,Erling Hu,Leilei Wang,Yan Ding,Yali Zhang,Xiaoyun Lu
The intense and prolonged inflammatory response after ischemic stroke significantly contributes to the secondary neural injury. PI3Kγ, which is involved in the regulation of vascular permeability, chemotactic leukocyte migration and microglia activation, is a key target for intervention in the inflammatory response. In this study, we identified the protective effect of the PI3Kγ inhibitor AS605240 against stroke-related injury in the mouse model of transient intraluminal middle cerebral artery occlusion (tMCAO). The results showed that administration of AS605240 could improve the neurological function score, reduce the infarct size and decrease astrocyte activation in the tMCAO mice after injury. The inhibitory effect of AS605240 on microglia activation is relatively clear. Therefore, in this study, the effects of AS605240 on astrocytes were studied in cell cultures. IL-6 and its soluble receptor were used to construct the astrocyte activation model. AS605240 treatment significantly reduced the astrocyte activation markers and the morphological changes of cells. We also identified 13 inflammatory factors whose expression was significantly upregulated by IL-6/sIL-6R and significantly inhibited by AS605240 at the protein level, and seven of those factors were verified at the mRNA level. These results indicated that specific inhibition of PI3Kγ could reduce astrocyte activation induced by inflammation, which might aid the repair and remodeling of neurons in the later stage after ischemic stroke.
研究领域:
神经科学
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药理学
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免疫学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2023
·Vol. 59
·期 3
·204-213
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IF 2.1
Liu Xu-Ying,Li Qiu-Shi,Yang Wen-Hai,Qiu Yue,Zhang Fei-Fei,Mei Xiu-Hui,Yuan Qi-Wen,Sui Ru-Bo
Cerebral ischemia/reperfusion (CI/R) usually causes neuroinflammation within the central nervous system, further prompting irreversible cerebral dysfunction. Perilipin 2 (Plin2), a lipid droplet protein, has been reported to exacerbate the pathological process in different diseases, including inflammatory responses. However, the role and mechanism of Plin2 in CI/R injury are unclear. In this study, the rat models of transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R) were established to mimic I/R injury, and we found that Plin2 was highly expressed in the ischemic penumbra of tMCAO/R rats. The siRNA-mediated knockdown of Plin2 significantly decreased neurological deficit scores and reduced infarct areas in rats induced by I/R. Detailed investigation showed that Plin2 deficiency alleviated inflammation of tMCAO/R rats as evidenced by reduced secretion of proinflammatory factors and the blockade of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. In vitro experiments showed that Plin2 expression was upregulated in mouse microglia subjected to oxygen–glucose deprivation/reoxygenation (OGD/R). Plin2 knockdown inhibited OGD/R-induced microglia activation and the accumulation of inflammation-related factors. Taken together, this study demonstrates that lipid droplet protein Plin2 contributes to the pathologic process of CI/R damage by impacting inflammatory response and NLRP3 inflammasome activation. Thus, Plin2 may provide a new therapeutic direction for CI/R injury.
研究领域:
神经科学
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免疫学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
NEUROSCIENCE
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2024
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IF 2.9
Xinyue Zhang,Xiao Wang,Le Yin,Dan Wang,Hong Jiao,Xiaodan Liu,Jiaolin Zheng
HECT domain and Ankyrin repeat-containing E3 ubiquitin protein ligase 1 (HACE1) is an E3 ubiquitin ligase involving oxidative stress, an important contributor in cerebral ischemia–reperfusion injury (CIRI). It was proposed to be associated with the PI3K/AKT pathway and Nrf2 nuclear translocation, which are important players of oxidative stress. Therefore, we supposed that HACE1 might affect CIRI by regulating the PI3K/AKT/Nrf2 pathway. Here, we used the transient middle cerebral artery occlusion-reperfusion (tMCAO/R) model to induce CIRI in rats and found lower HACE1 expression in ischemic rats compared with the control. To explore the exact role of HACE1, the lentivirus vector carrying the HACE1 sequence was administrated to rats by intracerebroventricular injection (1 × 10 9 TU/mL, 9 μL) one week before tMCAO/R operation. HACE1 overexpression alleviated tMCAO/R-induced brain damage in rats. Further studies revealed that it reduced oxidative stress via activating the PI3K/AKT/Nrf2 pathway, thereby inhibiting neuronal apoptosis in the ischemic penumbra of rats with CIRI. Then, differentiated PC12 cells were cultured in oxygen-glucose deprivation-reoxygenation (OGD/R) conditions (OGD: 1 % O 2 , 94 % N2, and 5 % CO 2 ; R: normal atmosphere) to simulate CIRI in vitro . Similarly, HACE1 overexpression inhibited neuronal apoptosis caused by OGD/R treatment. The PI3K inhibitor LY294002 reversed the inhibitory effects of HACE1 overexpression on oxidative stress in OGD/R-injured cells, accompanied by the inactivated AKT/Nrf2 pathway. Altogether, our results suggest that HACE1 protects against oxidative stress-induced neuronal apoptosis in CIRI by activating the PI3K/AKT/Nrf2 pathway, providing a new insight into the CIRI treatment.
研究领域:
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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药理学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
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IF 6.7
Ji Liu,Ying Han,Zhiyun Wu,Manli Chen,Wenwen Wu,Zijun Zhao,Jinjin Yuan,Zhijian Zheng,Qiang Lin,Nan Liu,Hongbin Chen
Background Perilladehyde, an extract of perillae in the Labiatae family, can produce significant anti-inflammatory and antioxidant effects. Although literature evidences the favorable effect of perillaldehyde on ischemic stroke, the exact mechanism remains blurred. Purpose This study attempted to explore the impact of perillaldehyde on cerebral ischemia-reperfusion injury and the related action mechanism. Methods The rat tMCAO and neuronal OGD/R models were established to simulate cerebral ischemia-reperfusion injury. Lentiviruses were used to interfere with the expression of Nrf2 and Trx2 in neurons. The effects and action mechanisms of perillaldehyde were explored by various experimental methods, including chromatin immunoprecipitation assay, Western Blot, flow cytometry, dual-luciferase reporter gene assay, transmission electron microscopy, MRI, RNA-seq, and immunofluorescence staining. Results Perillaldehyde pretreatment effectively mitigated the tMCAO-induced brain injury in rats by reducing cerebral infarction, improving neuromotor function, and attenuating cell apoptosis in the ischemic penumbra. In vitro, perillaldehyde pretreatment alleviated cell death and excessive oxidative stress, preserved the mitochondrial membrane integrity, enhanced mitochondrial energy metabolism, and facilitated the restoration of mitochondrial ultrastructure after OGD/R. The mechanism probe revealed that perillaldehyde activated the Nrf2/Keap1/Trx2 signaling axis, thus promoting the transcription of Trx2 and improving mitochondrial structure and function. The aforementioned impacts of perillaldehyde were somewhat counteracted by disrupting the expression of Nrf2 and Trx2, suggesting that the neuroprotection of perillaldehyde partially involves the activation of the Nrf2/Keap1/Trx2 axis. Conclusions This study firstly demonstrates the existence of the Nrf2/Keap1/Trx2 signaling axis in cerebral ischemia-reperfusion injury and evidences that perillaldehyde pretreatment can promote the restoration of neuronal mitochondrial structure and function by activating the Nrf2/Keap1/Trx2 axis after cerebral ischemia-reperfusion injury. These findings signify that perillaldehyde holds great promises for clinical management of ischemic stroke.
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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医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Yu Shan,Yang Jinghui,Zhang Rui,Guo Qian,Wang Lu
Systemic inflammatory stimulus is a risk factor for the incidence of ischemic stroke and contributes to poorer clinical outcomes. Solute carrier 15A3 (SLC15A3) is a peptide/histidine transporter that is implicated in regulating inflammatory responses. However, whether SLC15A3 affects the progression of ischemic stroke associated with systemic inflammation is unclear. The transient middle cerebral artery occlusion (tMCAO) mice with LPS administration (LPS/tMCAO) were prepared as an in vivo model, and LPS-induced BV2 cells under oxygen–glucose deprivation (OGD) exposure were utilized as an in vitro model. We found that SLC15A3 was highly expressed in the ischemic penumbra of LPS/tMCAO mice, and its inhibition reduced infarct area, attenuated neurological deficit, recovered motor function, and mitigated apoptotic neurons. Knockdown of SLC15A3 suppressed the proinflammatory M1-type markers and promoted the levels of M2-associated genes. The in vitro results confirmed that SLC15A3 overexpression promoted microglia polarizing towards M1 subtypes, while SLC15A3 inhibition exerted an opposite effect. In addition, we demonstrated that the p65 signaling pathway and HIF1α were activated by LPS/OGD. Luciferase reporter assay showed that inhibiting p65 using its specific inhibitor BAY 11–7082 or silencing HIF1α using siRNAs reduced the transcriptional activity of SLC15A3 in LPS/OGD-induced BV2 cells. Results in NIH 3T3 cells also confirmed that p65 and HIF1α directly bound to the SLC15A3 promoter to activate SLC15A3 transcription. In conclusion, this work shows that SLC15A3 , transcriptionally activated by p65 and HIF1α, contributes to poor outcomes in ischemic stroke associated with systemic inflammation by promoting microglial cells polarizing towards M1 types.
研究领域:
神经科学
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免疫学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2021
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IF 9.229
Yan Cheng,Airong Cheng,Yanlong Jia,Lin Yang,Yan Ning,Liang Xu,Yazhi Zhong,Zerui Zhuang,Jitian Guan,Xiaolei Zhang,Yan Lin,Teng Zhou,Xiusong Fan,Jianwu Li,Peng Liu,Gen Yan,Renhua Wu
Stroke is the second leading cause of death globally and the most common cause of severe disability. Several barriers need to be addressed more effectively to treat stroke, including efficient delivery of therapeutic agents, rapid release at the infarct site, precise imaging of the infarct site, and drug distribution monitoring. The present study aimed to develop a bio-responsive theranostic nanoplatform with signal-amplifying capability to deliver rapamycin (RAPA) to ischemic brain tissues and visually monitor drug distribution. A pH-sensitive theranostic RAPA-loaded nanoparticle system was designed since ischemic tissues have a low-pH microenvironment compared with normal tissues. The nanoparticles demonstrated good stability and biocompatibility and could efficiently load rapamycin, followed by its rapid release in acidic environments, thereby improving therapeutic accuracy. The nano-drug-delivery system also exhibited acid-enhanced magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging signal properties, enabling accurate multimodal imaging with minimal background noise, thus improving drug tracing and diagnostic accuracy. Finally, in vivo experiments confirmed that the nanoparticles preferentially aggregated in the ischemic hemisphere and exerted a neuroprotective effect in rats with transient middle cerebral artery occlusion (tMCAO). These pH-sensitive multifunctional theranostic nanoparticles could serve as a potential nanoplatform for drug tracing as well as the treatment and even diagnosis of acute ischemic stroke. Moreover, they could be a universal solution to achieve accurate in vivo imaging and treatment of other diseases.
研究领域:
药学
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神经科学
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纳米技术
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医学成像
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Cellular & Molecular Immunology
·
2025
·
IF 19.8
Bai Ying,Ren Hui,Leng Shuo,Yuan Mengqin,Jiang YiXin,Zhang Shenyang,Wang Yu,Ju Minzi,Wang Zhi,Xi Wen,Xu Lian,Zheng Bingjing,Li Daxing,Huo Xinchen,Zhu Tianhao,Zhang Beicheng,Shen Ling,Zhang Yuan,Jiang Wei,Zhang John H.,Han Bing,Yao Honghong
Splenic sympathetic activity critically modulates peripheral immunity after ischemic stroke, thus intervention in spleen sympathetic activity represents a promising therapeutic strategy for stroke. However, the mechanisms underlying spleen-brain-immune axis communication remain poorly understood. Here, we utilized a surgical denervation protocol to perform splenic sympathetic denervation (SDN), which significantly attenuated brain injury following stroke. Through single-cell RNA sequencing, we identified a novel GZMK + CD8 + CD27 + CCR7 + T-cell subset in patients with acute ischemic stroke (AIS), which we designated stroke-associated T (Tsa) cells. The expansion of Tsa cells was positively correlated with the severity of clinical symptoms and was driven by the splenic sympathetic nervous system. Stroke-induced sympathetic activation triggers the release of splenic norepinephrine (NE), which preferentially signals through ADRB2 on Tsa cells to promote their mobilization. Additionally, ischemic injury induces endothelial cell-specific expression of CCL19, which chemoattracts Tsa cells into the brain parenchyma via their cognate CCR7 receptor, exacerbating neuroinflammatory injury and neurological deficits in a transient middle cerebral artery occlusion (tMCAO) mouse model. We developed a CCR7-targeting peptide to disrupt this chemotactic axis and reduce T-cell infiltration, thereby mitigating brain injury. Our findings highlight SDN as a promising therapeutic strategy to attenuate ischemia‒reperfusion injury and suggest its potential as an adjunctive therapy for reperfusion treatment in AIS patients.
研究领域:
神经科学
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免疫学
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卒中研究
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神经免疫学
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分子生物学
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细胞生物学
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生物医学研究
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药理学
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系统生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2022
·Vol. 10
·期 24
·7103-7116
·
IF 7.59
Wuxuan Wang,Zheng Zhang,Yi Liu,Lingqi Kong,Wenyu Li,Wei Hu,Yucai Wang,Xinfeng Liu
Potent antioxidative drugs are urgently needed to treat ischemia-reperfusion (I/R) induced reactive oxygen species (ROS)-mediated cerebrovascular and neural injury during ischemia strokes. However, current antioxidative agents have limited application in such disease due to low blood–brain barrier (BBB) penetration. We herein designed a “neutrophil piggybacking” strategy based on albumin opsonized nanoparticles co-encapsulated with antioxidases catalase (CAT) and superoxide dismutase 1 (SOD1). The system utilized the natural potential of neutrophils to target inflamed tissues to deliver antioxidases to injured sites in the brain. In addition, the system was integrated with a selenium (Se)-containing crosslinker to inhibit ferroptosis. We showed that the nanoparticles opsonized in the hybrid form rather than with an albumin-shell structure exhibited enhanced neutrophil targeting and efficient BBB penetration in vitro and in vivo. We further showed that the neutrophil-mediated delivery of antioxidases effectively reduced oxidative damage and apoptosis of neurons in brain tissue in a transient middle cerebral artery occlusion (tMCAO) mouse model. Moreover, the successful delivery of Se with the nanoparticles increased the expression of glutathione peroxidase 4 (GPX4) and effectively inhibited neuronal ferroptosis, achieving a satisfactory neuroprotective effect in I/R injury mice. Our study demonstrated that the rationally designed nanomedicines using the “neutrophil piggybacking” strategy can efficiently penetrate the BBB, greatly expanding the application of nanomedicines in the treatment of central nervous system (CNS) diseases.
研究领域:
神经科学
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纳米医学
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药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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