Effect of hemopexin treatment on outcome after intracerebral hemorrhage in mice

Chen-Roetling, Jing; Yang, Lixue; Cao, Yang; Yan, Zhe; Lu, Xiangping; Regan, Raymond F.

doi:10.1016/j.brainres.2021.147507

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…We chose the dose of HPX (5 µg, 5 μl) for intraventricular injection in the rat model based on previous study [30]. Our results were consistent with previous studies that reported HPX could alleviate cognitive dysfunction after focal cerebral ischemiareperfusion injury in rats [37]. As a receptor protein for heme-HPX complexes, CD91 is not expressed by the cerebral endothelium.…”

Section: Discussionsupporting

confidence: 79%

Free-heme induces neuroinflammation and cognitive impairment by microglial activation via the TLR4/MyD88/NF-kB signaling pathway

Wei,

Zhang,

Cheng

et al. 2023

Preprint

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Background: Red blood cells (RBCs) transfusion is related to perioperative neurocognitive disorders. The toxic effect of free-heme has been identified in many pathologies. However, the underlying mechanisms of RBCs transfusion or free-heme in cognitive impairment have not been clearly explored. Therefore, this research was conducted to determine the mechanism of heme-induced neuroinflammation and cognitive impairment. Methods: Rats were received intraperitoneal injection of hemin alone or combined with intracerebroventricular injection of Hemopexin (HPX), and MWM test was conducted to measure cognitive function. The elimination condition of heme-HPX complexes was evaluated by flow cytometry for CD91+ cells. The microglial inflammatory response in rat brain and BV2 cells was observed by immunofluorescence staining of Iba-1 and ELISA analysis of TNF-α, IL-1β and IL-6. Furthermore, neuronal apoptosis in HT22 cells alone and in HT22 + BV2 coculture system was detected by flow cytometry and immunofluorescence staining. Finally, western blot was conducted to detect TLR4/MyD88/NF-kB proteins in rat brain and BV2 cells treated with hemin or combined with pathway inhibitors. Additionally, the M1 surface marker CD86 was observed in BV2 cells to further confirm neuroinflammation. Results: Intraperitoneal injection of hemin induced cognitive impairment, increase of CD91+ cells, up-regulation of TNF-α and IL-1β, down-regulation of IL-6, activation of microglia, and activation of the TLR4/MyD88/NF-kB signaling pathway in rat brain. Significantly, intracerebroventricular injection of HPX reduced the above effects. Hemin induced boost of TNF-α, IL-1β and IL-6 in BV2 cells, as well as apoptosis in HT22 cells. Notably, when HT22 cells were cocultured with BV2 cells, apoptosis was significantly increased. Hemin also induced activation of the TLR4/MyD88/NF-kB signaling pathway and increased the M1 surface marker CD86 in BV2 cells, and inhibiting this pathway reduced the inflammatory responses. Conclusions: Free-heme induces cognitive impairment, and the underlying mechanism may involve neuronal apoptosis and microglial inflammation via the TLR4/MyD88/NF-kB signaling pathway. HPX may have potential therapeutic effects.

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Section: Discussionsupporting

confidence: 79%

Free-heme induces neuroinflammation and cognitive impairment by microglial activation via the TLR4/MyD88/NF-kB signaling pathway

Wei,

Zhang,

Cheng

et al. 2023

Preprint

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“…With the development of medical knowledge, the ICH incidence showed an increasing trend worldwide ( van Asch et al, 2010 ; Wu and Anderson, 2020 ), resulting from the spiraling increment of older adults; the application of anticoagulants, antiplatelets, and thrombolytics; and other issues ( Carpenter et al, 2016 ; Wu et al, 2019 ). Although significant progress in potential treatment after ICH models has been developed in preclinical research ( Bentz et al, 2010 ; Xiong et al, 2014 ; Alharbi et al, 2016 ; Chen-Roetling et al, 2021 ), the lack of available evidence-based therapeutic strategies still limits the improvement of ICH prognosis in the clinical setting, where only active first-stage rehabilitation and general rehabilitation may lead to a modification of the outcomes ( Saulle and Schambra, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage

Yang

Fan

Mazhar

et al. 2022

Front. Cell. Neurosci.

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Intracerebral hemorrhage (ICH), a common lethal subtype of stroke accounting for nearly 10–15% of the total stroke disease and affecting two million people worldwide, has a high mortality and disability rate and, thus, a major socioeconomic burden. However, there is no effective treatment available currently. The role of mesenchymal stem cells (MSCs) in regenerative medicine is well known owing to the simplicity of acquisition from various sources, low immunogenicity, adaptation to the autogenic and allogeneic systems, immunomodulation, self-recovery by secreting extracellular vesicles (EVs), regenerative repair, and antioxidative stress. MSC therapy provides an increasingly attractive therapeutic approach for ICH. Recently, the functions of MSCs such as neuroprotection, anti-inflammation, and improvement in synaptic plasticity have been widely researched in human and rodent models of ICH. MSC transplantation has been proven to improve ICH-induced injury, including the damage of nerve cells and oligodendrocytes, the activation of microglia and astrocytes, and the destruction of blood vessels. The improvement and recovery of neurological functions in rodent ICH models were demonstrated via the mechanisms such as neurogenesis, angiogenesis, anti-inflammation, anti-apoptosis, and synaptic plasticity. Here, we discuss the pathological mechanisms following ICH and the therapeutic mechanisms of MSC-based therapy to unravel new cues for future therapeutic strategies. Furthermore, some potential strategies for enhancing the therapeutic function of MSC transplantation have also been suggested.

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“…However, photoreceptors and ganglion cells also have the potential to express HP and HPX locally in the retina [ 25 ]. In the intracerebral hemorrhage (ICH) model, the deletion of HPX aggravates brain injury and intraperitoneal treatment of hemopexin can reduce the early-stage blood–brain barrier (BBB) disruption and cell death [ 27 , 28 ]. In addition, the genetic deletion of HP in young mice can reduce brain damage, improve neurological function, but show aggravated outcomes in aged HP KO mice after ICH [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Retinal Proteomic Analysis in a Mouse Model of Endotoxin-Induced Uveitis Using Data-Independent Acquisition-Based Mass Spectrometry

Zhang

et al. 2022

IJMS

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Uveitis is a group of sight-threatening ocular inflammatory diseases, potentially leading to permanent vision loss in patients. However, it remains largely unknown how uveitis causes retinal malfunction and vision loss. Endotoxin-induced uveitis (EIU) in rodents is a good animal model to study uveitis and associated acute retinal inflammation. To understand the pathogenic mechanism of uveitis and screen potential targets for treatment, we analyzed the retinal proteomic profile of the EIU mouse model using a data-independent acquisition-based mass spectrometry (SWATH-MS). After systemic LPS administration, we observed activation of microglial cells accompanied with the elevation of pro-inflammatory mediators and visual function declines. In total, we observed 79 upregulated and 90 downregulated differentially expressed proteins (DEPs). Among the DEPs, we found that histone family members (histone H1, H2A, H2B) and blood proteins including haptoglobin (HP), hemopexin (HPX), and fibrinogen gamma chain (FGG) were dramatically increased in EIU groups relative to those in control groups. We identified phototransduction and synaptic vesicle cycle as the top two significant KEGG pathways. Moreover, canonical pathway analysis on DEPs using Ingenuity Pathway Analysis revealed top three most significant enriched pathways related to acute phase response signaling, synaptogenesis signaling, and eif2 signaling. We further confirmed upregulation of several DEPs associated with the acute phase response signaling including HP, HPX, and FGG in LPS-treated retinas by qPCR and Western blot. In summary, this study serves as the first report to detect retinal proteome changes in the EIU model. The study provides several potential candidates for exploring the mechanism and novel therapeutic targets for uveitis and other retinal inflammatory diseases.

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Effect of hemopexin treatment on outcome after intracerebral hemorrhage in mice

Cited by 9 publications

References 40 publications

Free-heme induces neuroinflammation and cognitive impairment by microglial activation via the TLR4/MyD88/NF-kB signaling pathway

Free-heme induces neuroinflammation and cognitive impairment by microglial activation via the TLR4/MyD88/NF-kB signaling pathway

Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage

Retinal Proteomic Analysis in a Mouse Model of Endotoxin-Induced Uveitis Using Data-Independent Acquisition-Based Mass Spectrometry

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