ACS Nano
·
2020
·
IF 14.588
Patryk Szwargulski,Maximilian Wilmes,Ehsan Javidi,Florian Thieben,Matthias Graeser,Martin Koch,Cordula Gruettner,Gerhard Adam,Christian Gerloff,Tim Magnus,Tobias Knopp,Peter Ludewig
Magnetic particle imaging (MPI) is an innovative radiation-free tomographic imaging method providing excellent temporal resolution, contrast, sensitivity, and safety. Mobile human MPI prototypes suitable for continuous bedside monitoring of whole-brain perfusion have been developed. However, for the clinical translation of MPI, a crucial gap in knowledge still remains: while MPI can visualize the reduction in blood flow and tissue perfusion in cerebral ischemia, it is unclear whether MPI works in intracranial hemorrhage. Our objective was to investigate the capability of MPI to detect intracranial hemorrhage in a murine model. Intracranial hemorrhage was induced through the injection of collagenase into the striatum of C57BL/6 mice. After the intravenous infusion of a long-circulating MPI-tailored tracer consisting of superparamagnetic iron oxides, we detected the intracranial hemorrhage in less than 3 min and could monitor hematoma expansion in real time. Multicontrast MPI can distinguish tracers based on their physical characteristics, core size, temperature, and viscosity. By employing in vivo multicontrast MPI, we were able to differentiate areas of liquid and coagulated blood within the hematoma, which could provide valuable information in surgical decision making. Multicontrast MPI also enabled simultaneous imaging of hemorrhage and cerebral perfusion, which is essential in the care of critically ill patients with increased intracranial pressure. We conclude that MPI can be used for real-time diagnosis of intracranial hemorrhage. This work is an essential step toward achieving the clinical translation of MPI for point-of-care monitoring of different stroke subtypes.
研究领域:
医学影像学
·
神经科学
·
分子影像学
✓ 已验证
DOI
PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2024
·
IF 5.9
Yecheng Wang,Caiyun Huang,Xiaoying Wang,Rong Cheng,Xue Li,Jiahao Wang,Lu Zhang,Fuhao Li,Hao Wang,Xinyu Li,Yi Li,Yiqing Xia,Jian Cheng,Xiaofan Pan,Jia Jia,Guo-dong Xiao
Aims: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. Results: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophage, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream AMP-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I or AMPK abolished the therapeutic effects of succinate following ICH. Innovation and Conclusion: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate. Key words: succinate; uncoupling protein 2; microglia; neuroinflammation; intracerebral hemorrhage
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2021
·
IF 4.432
Xin Guo,Pingping Cao,Xiongfeng Lian,Meng Hu,Jingyi Zhao,Wenjing Shen,Haili Wang,Hailong Yu,Yingzhu Chen
Phillyrin, a natural plant extract, has significant antioxidant and anti-apoptotic effects. However, its effect on intracerebral hemorrhage (ICH) remains unclear. In this study, we investigated a potential role for phillyrin in the regulation of the oxidative stress and apoptosis induced by ICH. A model of ICH was induced by collagenase IV (0.2 U in 1 μl sterile normal saline) in male C57BL/6J (B6) mice and different doses of phillyrin (5, 15, or 30 mg/kg) were intraperitoneally (i.p.) injected at 30 min, 6 h, and 22 h after modeling. We found that phillyrin significantly reduced neural function and lesion volume, improved injury of white and grey matter around the lesion, decreased apoptosis and oxidative stress, increased the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase 1(HO-1), NADPH quinone oxidoreductase 1 (NQO1) and Superoxide Dismutase-1(SOD-1) in vitro and in vivo , and protected neurons from the stimulation of hemin by promoting Nrf2 nuclear translocation. Treatment with ML385 (Nrf2 inhibitor) completely reversed the protective effects of phillyrin in vivo after ICH injury. Based on our findings, we conclude that phillyrin treatment alleviates ICH injury-induced apoptosis and oxidative stress via activation of the Nrf2 signaling pathway, highlighting a potential role for phillyrin as an ICH therapeutic.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INFLAMMATION
·
2023
·
IF 5.1
Han Ruili,Liu Lei,Wang Yuying,Wu Ruolin,Yang Ying,Zhao Yuanlin,Jian Lele,Yuan Yuan,Zhang Lijun,Gu Yu,Gao Changjun,Ye Jing
The microglia overactivation-induced neuroinflammation is a significant cause of the brain injury after intracerebral hemorrhage (ICH). Iron homeostasis is crucial for microglia activation, but the mechanism and causality still need further study. This study aimed to explore the roles and mechanism of the mitochondrial iron transporter SLC25A28 in microglia activation after ICH. Intrastriatal injection of autologous blood was used to establish ICH model, and the neuroinflammation, iron metabolism and brain injuries were assessed in wildtype or microglia-specific SLC25A28 knockout mice after ICH. Mitochondria iron levels and microglial function were determined in SLC25A28 overexpressed or deleted microglia. The extracellular acidification rate (ECAR), lactate production, and glycolytic enzyme levels were used to determine aerobic glycolysis. The results showed that ICH stimulated mitochondrial iron overload, and synchronously upregulated the SLC25A28 expression. In vitro , SLC25A28 overexpression increased mitochondrial iron levels in microglia. Interestingly, microglial SLC25A28 deficiency ameliorated neuroinflammation, brain edema, blood–brain barrier injury and ethological alterations in mice after ICH. Mechanically, SLC25A28 deficiency inhibited microglial activation by restricting the aerobic glycolysis. Moreover, zinc protoporphyrin could reduce SLC25A28 expression and mitigated brain injury. SLC25A28 plays crucial roles in mitochondrial iron homeostasis and microglia activation after ICH, and it might be a potential therapeutic target for ICH.
研究领域:
神经科学
·
分子生物学
·
神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Medicine
·
2021
·
IF 5.093
Zhang Xinyi,Wang Li,Fu Wenhui,Feng Yue,Zeng Chengrun,Zhou Liu,Zhang Tao,Xu Tingting,Cao Jianpeng,Li Zibo,Chen Yue
18F-Labeled blood pool agents (BPAs) have attracted great attention for identifying bleeding sites. However, many BPAs are not sufficiently evaluated partially due to the limitations of labeling methods. In our previous work, we noticed that 18F-PEG1-vinyl sulfone (18F-VS) could efficiently label red blood cells (RBCs) ex vivo and in situ. However, its application as BPA is not fully evaluated. In this study, we systematically explored the feasibility of using 18F-VS-labeled RBCs as a positron emission tomography (PET) BPA for intra-abdominal bleeding diagnosis. In brief, we first optimized the labeling conditions, which lead to an 80% labeling yield of RBCs after incubating with 18F-VS in phosphate-buffered saline (PBS) at 37°C for 20 min. 18F-VS-labeled RBCs were found to be stable in vitro, which could simplify its transportation/storage for in vivo applications. In normal rat PET study, the cardiovascular system could be clearly imaged up to 5 h post injection (p.i.). An intra-abdominal hemorrhage rat model demonstrated that the 18F-VS-labeled RBCs clearly showed the dynamic changes of extravascular radioactivity due to intra-abdominal hemorrhage. Validation in the model of gastrointestinal bleeding clearly demonstrated the great potential of using 18F-VS-labeled RBCs as a BPA, which could be further evaluated in future studies.
研究领域:
医学影像学
·
核医学
·
放射化学
✓ 已验证
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
·
药理学
·
昼夜节律生物学
·
神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8509
·
IF 13.3
Tao Liu,Peng Ma,Fengya Jing,Yinghua Tao,Jinfang Lu,Dandan Wei,Liuxin Yang,Feiling Feng,Yonghua Li,Hongbin Yuan,Tianzhu Zhang
Background: The development of hemostatic materials for non-compressible intra-abdominal hemorrhage in complex pre-hospital emergency settings remains a formidable challenge. Methods: A novel injectable hydrogel based on mussel-inspired nanocomposite microspheres was designed. The biocompatible hydrogel was formed by hydrating gelatin methacryloyl (GelMA) cryogel microspheres—reinforced with polydopamine (PDA)-intercalated nanoclay—with sterile saline, offering the dual benefits of convenient storage of microspheres and precise delivery to deep bleeding points via injection. Results: The cryogel microspheres, featuring rapid water and blood absorption within 1 second, exhibited outstanding procoagulant capabilities in both in vitro and in vivo experiments, showing potential as hemostatic agents for open wounds. Notably, the on-demand formulated hydrogel effectively controlled severe bleeding within 2 minutes post-injection in rat liver volumetric defect and partial resection models, demonstrating significantly enhanced applicability compared to bulk hemostatic agents for irregular wounds. Additionally, ultrasound-guided application in a porcine liver rupture model confirmed that the hydrogel rapidly filled and sealed deep wounds, interacted with blood components to form stable, large clots adhering to the wound surface, and thus established durable hemostasis. Conclusion: This study presents a promising injectable hemostatic material for pre-hospital emergency hemorrhage control.
研究领域:
生物医学工程
·
创伤医学
·
再生医学
·
纳米医学
·
止血学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Guanghao Wu,Zhenya Liu,Changwen Mu,Da Song,Jiaxin Wang,Xiangxi Meng,Ziyuan Li,Hong Qing,Yuping Dong,Hai-Yan Xie,Dai-Wen Pang
The intrinsic features and functions of platelets and mesenchymal stem cells (MSCs) indicate their great potential in the treatment of intracerebral hemorrhage (ICH). However, neither of them can completely overcome ICH because of the stealth process and the complex pathology of ICH. Here, we fabricate hybrid cells for versatile and highly efficient ICH therapy by fusing MSCs with platelets and loading with lysophosphatidic acid-modified PbS quantum dots (LPA-QDs). The obtained LPA-QDs@FCs (FCs = fusion cells) not only inherit the capabilities of both platelets and MSCs but also exhibit clearly enhanced proliferation activated by LPA. After systemic administration, many proliferating LPA-QDs@FCs rapidly accumulate in ICH areas for responding to the vascular damage and inflammation and then efficiently prevent both the primary and secondary injuries of ICH but with no obvious side effects. Moreover, the treatment process can be tracked by near-infrared II fluorescence imaging with highly spatiotemporal resolution, providing a promising solution for ICH therapy.
研究领域:
神经科学
·
干细胞生物学
·
纳米技术
·
生物医学工程
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2019
·
IF 3.103
Bin Chen,Zhenghong Chen,Mingjian Liu,Xiaorong Gao,Yijun Cheng,Yongxu Wei,Zhebao Wu,Derong Cui,Hanbing Shang
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke because it has few viable therapeutic options to intervene against primary or second brain injury. Recently, evidence has suggested that ferroptosis, a nonapoptotic form of cell death, is involved in ICH. In this study, we examined whether ICH-induced neuron death is partly ferroptotic in humans and assessed its temporal and spatial characteristics in mice. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) was used to examine the role of ferroptosis after ICH. Fold changes in ferroptosis-related gene expression, intracellular iron levels, malondialdehyde (MDA) levels, and both protein levels and cellular localization of cyclooxygenase-2 (COX-2) were measured to monitor ferroptosis. Transmission electron microscopy (TEM) was also performed to examine the ultrastructure of cells after ICH. We found that the expression level of prostaglandin-endoperoxide synthase (PTGS2) was increased in both in vitro and in vivo ICH models; by comparison, expression level of RPL8 was increased in human brain tissue. In mice, iron and MDA levels were significantly increased 3 h after ICH; COX-2 levels were increased at 12 h after ICH and peaked at 3 days after ICH; COX-2 colocalized with NeuN (a neuronal biomarker); and TEM showed that shrunken mitochondria were found at 3 h, 3 days, and 7 days after ICH. Moreover, ICH-induced neurological deficits, memory impairment and brain atrophy were reduced by Fer-1 treatment. Our results demonstrated that neuronal ferroptosis occurs during the acute phase of ICH in brain areas distant from the hematoma and that inhibition of ferroptosis by Fer-1 exerted a long-term cerebroprotective effect.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Gu Lingui,Sun Mingjiang,Li Ruihao,Zhang Xingyu,Tao Yihao,Yuan Ye,Luo Xu,Xie Zongyi
Neuroinflammation has been proven to exert an important effect on brain injury after intracerebral hemorrhage (ICH). Previous studies reported that Didymin possessed anti-inflammatory properties after acute hepatic injury, hyperglycemia-induced endothelial dysfunction, and death. However, the role of Didymin in microglial pyroptosis and neuroinflammation after ICH is unclear. The current study aimed to investigate the effect of Didymin on neuroinflammation mediated by microglial pyroptosis in mouse models of ICH and shed some light on the underlying mechanisms. In this study, we observed that Didymin treatment remarkably improved neurobehavioral performance and decreased BBB disruption and brain water content. Microglial activation and neutrophil infiltration in the peri-hematoma tissue after ICH were strikingly mitigated by Didymin as well. At the molecular level, administration of Didymin significantly unregulated the expression of Rkip and downregulated the expression of pyroptotic molecules and inflammatory cytokines such as Nlrp3 inflammasome, GSDMD, caspase-1, and mature IL-1β, TNF-α, and MPO after ICH. Besides, Didymin treatment decreased the number of Caspase-1-positive microglia and GSDMD-positive microglia after ICH. Inversely, Locostatin, an Rkip-specific inhibitor, significantly abolished the anti-pyroptosis and anti-neuroinflammation effects of Didymin. Moreover, Rkip binding with Asc could interrupt the activation and assembly of the inflammasome. Mechanistically, inhibition of Caspase-1 by VX-765 attenuated brain injury and suppressed microglial pyroptosis and neuroinflammation by downregulation of GSDMD, mature IL-1β, TNF-α, and MPO based on Locostatin-treated ICH. Taken together, Didymin alleviated microglial pyroptosis and neuroinflammation, at least in part through the Asc/Caspase-1/GSDMD pathway via upregulating Rkip expression after ICH. Therefore, Didymin may be a potential agent to attenuate neuroinflammation via its anti-pyroptosis effect after ICH.
研究领域:
神经科学
·
药理学
·
炎症
·
神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Neuroinflammation
·
2017
·Vol. 14
·期 1
·1-18
·
IF 5.102
Zhao Hengli,Pan Pengyu,Yang Yang,Ge Hongfei,Chen Weixiang,Qu Jie,Shi Jiantao,Cui Gaoyu,Liu Xin,Feng Hua,Chen Yujie
Background Emerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H2S) as a gasotransmitter for NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-associated neuroinflammation in the central nervous system. However, the effects of H2S on neuroinflammation after intracerebral haemorrhage (ICH), especially on the NLRP3 inflammasome, remain unknown.Methods We employed a Sprague–Dawley rat of collagenase-induced ICH in the present study. The time course of H2S content and the spatial expression of cystathionine-β-synthase (CBS) after ICH, the effects of endogenous and exogenous H2S after ICH, the effects of endogenous and exogenous H2S on NLRP3 inflammasome activation under P2X7 receptor (P2X7R) overexpression after ICH, and the involvement of the P2X7R in the mechanism by which microglia-derived H2S prevented NLRP3 inflammasome activation were investigated.Results We found ICH induced significant downregulation of endogenous H2S production in the brain, which may be the result of decreasing in CBS, the predominant cerebral H2S-generating enzyme. Administration of S-adenosyl-l-methionine (SAM), a CBS-specific agonist, or sodium hydrosulfide (NaHS), a classical exogenous H2S donor, not only restored brain and plasma H2S content but also attenuated brain oedema, microglial accumulation and neurological deficits at 1 day post-ICH by inhibiting the P2X7R/NLRP3 inflammasome cascade. Endogenous H2S production, which was derived mainly by microglia and above treatments, was verified by adenovirus-overexpressed P2X7R and in vitro primary microglia studies.Conclusion sThese results indicated endogenous H2S synthesis was impaired after ICH, which plays a pivotal role in the P2X7R/NLRP3 inflammasome-associated neuroinflammatory response in the pathogenesis of secondary brain injury. Maintaining appropriate H2S concentrations in the central nervous system may represent a potential therapeutic strategy for managing post-ICH secondary brain injury and associated neurological deficits.
研究领域:
神经科学
·
药理学
·
炎症
·
神经病学
✓ 已验证
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Taoyang Yuan,Tianyou Wang,Jianhua Zhang,Shun Shi,Zhipeng Gu,Yiwen Li,Jianguo Xu
Poor prognosis is often expected after the treatment of intracerebral haemorrhage (ICH) when the approach lacks effective neuroprotective interventions. Minocycline (Mino) is a promising clinical neuroprotective candidate for acute ICH therapy that mainly inhibits activation of microglia/macrophages. However, to address iron neurotoxicity, ferroptosis, and oxidative stress-induced multiple neuroinjury mechanisms, the neuroprotective effect of minocycline still urgently needs to be enhanced. To address this issue, procyanidins (PACs), typical natural polyphenols, is used to improve the neuroprotective effect of Mino by constructing PACs-Mino nanoparticles (NPs) using 3-aminophenylboronic acid as the crosslinker. The yielding NPs possessed improved antioxidant and iron-removing capacities in vitro. More importantly, PACs-Mino NPs exerted excellent therapeutic effects on ICH, showing improved neuroprotective activity and resulting in neurobehavioral recovery, in an in vitro cellular model and an in vivo ICH rat model. This study can provide a general strategy that uses natural polyphenols to boost the performance of drugs for ICH treatment, and the results may be further extended to other injuries of the central nervous system, such as brain injury and spinal cord injury.
研究领域:
神经科学
·
药理学
·
纳米技术
·
神经病学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）