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Translational ​Stroke Research



  • The Role of ICP Monitoring in Minimally Invasive Surgery for the Management of Intracerebral Hemorrhage


    Intracerebral hemorrhage (ICH) is the second major stroke type, with high incidence, high disability rate, and high mortality. At present, there is no effective and reliable treatment for ICH. As a result, most patients have a poor prognosis. Minimally invasive surgery (MIS) is the fastest treatment method to remove hematoma, which is characterized by less trauma and easy operation. Some studies have confirmed the safety of MIS, but there are still no reports showing that it can significantly improve the functional outcome of ICH patients. Intracranial pressure (ICP) monitoring is considered to be an important part of successful treatment in traumatic brain diseases. By monitoring ICP in real time, keeping stable ICP could help patients with craniocerebral injury get a good prognosis. In the course of MIS treatment of ICH patients, keeping ICP stable may also promote patient recovery. In this review, we will take ICP monitoring as the starting point for an in-depth discussion.


    REF: Zhang G, Li Y, Chen D, et al. The Role of ICP Monitoring in Minimally Invasive Surgery for the Management of Intracerebral Hemorrhage. Transl Stroke Res. Published online December 29, 2023. doi:10.1007/s12975-023-01219-4 PMID: 38157144

  • Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH

    Parkin抑制USP 30促进线粒体自噬调节MFN2泛素化减轻SAH后早期脑损伤

    Subarachnoid hemorrhage (SAH) is a type of stroke with a high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells and inflammatory responses caused by high extracellular ATP lead to poor outcomes. USP30 is a deubiquitinating enzyme that inhibits mitophagy, resulting in a failure to remove damaged mitochondria in a timely manner after SAH; nevertheless, the pathway through which USP30 inhibits mitophagy is unknown. This study evaluated the neuroprotective role and possible molecular basis by which inhibiting USP30 to attenuate SAH-induced EBI by promoting neuronal mitophagy. We used an in vitro model of hemoglobin exposure and an in vivo model of intravascular perforation. Increased expression of USP30 was found after SAH in vivo and in vitro, and USP30 inhibition expression in SAH mice treated with MF094 resulted in significant improvement of neurological injury and inflammatory response and mediated good outcomes, suggesting a neuroprotective effect of USP30 inhibition. In cultured neurons, inhibition of USP30 promoted ubiquitination modification of mitochondrial fusion protein 2 (MFN2) by E3 ubiquitin ligase (Parkin), separating damaged mitochondria from the healthy mitochondrial network and prompting mitophagy, causing early clearance of damaged intracellular mitochondria, and reducing the onset of apoptosis. The high extracellular ATP environment was meliorated, reversing the conversion of microglia to a pro-inflammatory phenotype and reducing inflammatory injury. USP30 inhibition had no autophagy-promoting effect on structurally and functionally sound mitochondria and did not inhibit normal intracellular ATP production. The findings suggest that USP30 inhibition has a neuroprotective effect after SAH by promoting early mitophagy after SAH to clear damaged mitochondria.


    REF: Liu Y, Yao C, Sheng B, et al. Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH. Transl Stroke Res. Published online December 26, 2023. doi:10.1007/s12975-023-01228-3 PMID: 38147294

  • Therapeutic Potential of Intravenous miR-21 Mimic after Stroke Following STAIR Criteria


    The microRNA-21 (miR-21) levels in the brain are crucial in determining post-stroke brain damage and recovery. The miR-21 exerts neuroprotection by targeting mRNAs that translate proteins that mediate brain damage. We currently determined the efficacy and efficiency of intravenously administered miR-21 mimic after focal cerebral ischemia in mice. Adult male mice were intravenously administered with either control mimic or miR-21 mimic at 5 min/2 h after reperfusion following 1 h transient middle cerebral artery occlusion to determine the therapeutic window of miR-21 mimic. Adult female, type-2 diabetic male, aged male, and aged female mice were administered with control/miR-21 mimic at 5 min after reperfusion following 35 min/1 h transient middle cerebral artery occlusion. Early administration of miR-21 mimic significantly reduced brain damage and promoted long-term recovery after stroke. Further, miR-21 mimic is more effective in males than in females subjected to stroke. However, delayed treatment with miR-21 mimic is not efficacious, and type-2 diabetic subjects show no improvement with miR-21 mimic treatment.


    REF: Chelluboina B, Jeong S, Davis CK, Mehta SL, Vemuganti R. Therapeutic Potential of Intravenous miR-21 Mimic after Stroke Following STAIR Criteria. Transl Stroke Res. Published online December 22, 2023. doi:10.1007/s12975-023-01223-8 PMID: 38129636

  • The Drainage Dysfunction of Meningeal Lymphatic Vessels Is Correlated with the Recurrence of Chronic Subdural Hematoma: a Prospective Study


    Meningeal lymphatic vessels (mLVs) were recently discovered to be involved in the waste drainage process in the brain, which has also been associated with a variety of neurological diseases. This research paper hypothesizes that the drainage function of mLVs may be affected after chronic subdural hematoma (CSDH) and the alterations of mLVs' drainage may predict CSDH recurrence. In this prospective observational study, unenhanced 3D T2-fluid-attenuated inversion recovery (3D T2-FLAIR) MRI data were collected from CSDH patients and healthy participants for analysis. Patients with CSDH who underwent surgery received MRI scans before and after surgery, whereas healthy controls and patients with CSDH who received pharmaceutical treatment received only one MRI scan at enrollment. The signal unit ratio (SUR) of mLVs were then measured according to the MRI data and calculated to define mLVs' drainage function. Finally, the relationship between mLVs' drainage function and CSDH recurrence was analyzed accordingly. Thirty-four participants were enrolled in this study, including 27 CSDH patients and 7 controls. The SUR of mLVs in all CSDH patients changed significantly before and after surgery. Moreover, the drainage function of the mLVs ipsilateral to hematoma (mLVs-IH) in CSDH patients was significantly lower than that in the controls (p < 0.05). Last, a higher improvement rate of the drainage function of the mLVs-IH is correlated to a lower risk of recurrence (p < 0.05). This study revealed the mLVs' drainage dysfunction after CSDH through non-invasive MRI. Furthermore, the drainage function of mLVs is an independent predictive factor of CSDH recurrence.


    REF: Zhang J, Yu L, Wang X, et al. The Drainage Dysfunction of Meningeal Lymphatic Vessels Is Correlated with the Recurrence of Chronic Subdural Hematoma: a Prospective Study. Transl Stroke Res. Published online December 22, 2023. doi:10.1007/s12975-023-01227-4 PMID: 38133745

  • Crosstalk Between Matrix Metalloproteinases and Their Inducer EMMPRIN/CD147: a Promising Therapeutic Target for Intracerebral Hemorrhage

    基质金属蛋白酶与其诱导因子EMMPRIN/CD 147的相互作用:脑出血治疗的新靶点

    Intracerebral hemorrhage (ICH) is characterized by the disruption of cerebrovascular integrity, resulting in hematoma enlargement, edema formation, and physical damage in the brain parenchyma. Primary ICH also leads to secondary brain injury contributed by oxidative stress, dysregulated immune responses, and proteolysis. In this context, matrix metalloproteinases (MMPs) represent a ubiquitous superfamily of structurally related zinc-dependent endopeptidases capable of degrading all components of the extracellular matrix. They disrupt the blood-brain barrier and promote neuroinflammation. Importantly, several MMP members are upregulated following ICH, and members may have different functions at specific periods in ICH. Hence, the modulation and function of MMPs are more complex than expected. Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that induces the production of MMPs. In this review, we systematically discuss the biology and functions of MMPs and EMMPRIN/CD147 in ICH and the complex crosstalk between them.


    REF: Liu Y, Qi L, Li Z, Yong VW, Xue M. Crosstalk Between Matrix Metalloproteinases and Their Inducer EMMPRIN/CD147: a Promising Therapeutic Target for Intracerebral Hemorrhage. Transl Stroke Res. Published online December 15, 2023. doi:10.1007/s12975-023-01225-6 PMID: 38100014

  • Methylated MFGE8 Promotes Early Brain Injury After Subarachnoid Hemorrhage and Inhibiting Autophagy of Nerve Cell


    Spontaneous subarachnoid hemorrhage (SAH) is a relatively common clinical hemorrhagic stroke crisis. The important role of early brain injury (EBI) and autophagy in SAH has been increasingly recognized in recent years. This study aims to investigate the function and the undergoing mechanism of MFGE8 in EBI after SAH. High expression of DNMT1 and P2X7R and low expression of MFGE8 were observed in SAH mice. • Activation of autophagy reduces EBI after SAH in mice. • DNMT1/MFGE8 reduces autophagy in EBI after SAH in both mouse and cell models. • DNMT1 targets the MFGE8 promoter to upregulate its methylation level. • MFGE8 inhibits P2X7R to activate PI3k/AKT/mTOR pathway and autophagy, thus inhibiting EBI after SAH.


    REF: Zou L, Xu S, Wang C, Wu P, Xu C, Shi H. Methylated MFGE8 Promotes Early Brain Injury After Subarachnoid Hemorrhage and Inhibiting Autophagy of Nerve Cell. Transl Stroke Res. Published online December 14, 2023. doi:10.1007/s12975-023-01217-6 PMID: 38095841

  • Prevalence and Predictors of Hemorrhagic Foci on Long-term Follow-up MRI of Recent Single Subcortical Infarcts


    Hemorrhagic foci surrounding the lacune in the long-term evolution of recent single subcortical infarcts (RSSIs) remains largely unexplored. We aimed to determine the prevalence, characteristics, and predictors of hemorrhagic foci in patients with RSSI. From a prospective, longitudinal study of RSSIs, we recruited patients who underwent multimodal MRI assessments both at baseline and approximately one year after the stroke onset. Hemorrhagic foci were identified using susceptibility-weighted imaging (SWI). Among 101 patients with RSSI, nearly half (n = 45, 44.6%) had hemorrhagic foci within the index RSSI lesions on follow-up SWI. RSSIs with hemorrhagic foci formation were associated with a longer time to follow-up imaging (median 449 versus 401 days, P = 0.005) and higher likelihood of being located in the anterior circulation compared to those without hemorrhagic foci (88.9% versus 64.3%, P = 0.003). Hemorrhagic foci were also associated with larger lesion size (P < 0.001), a higher proportion of cavitation formation (P = 0.003), higher baseline NIHSS scores (P = 0.004), and poorer functional outcomes (P = 0.001). In the subset of RSSIs in the lenticulostriate artery (LSA) territory, after adjustment for covariates, larger initial lesion volume (OR 1.80, 95% CI 1.13-2.87; P = 0.014) and greater decreases in LSA total length (OR 0.59, 95% CI 0.36-0.96; P = 0.035) were independently associated with hemorrhagic foci formation. The extent of ischemia in the initial infarct is predictive of the presence of hemorrhagic residues. Our findings contribute to the current understanding of the mechanisms underlying the evolution of RSSIs.


    REF: Jiang S, Shang WZ, Cui JY, et al. Prevalence and Predictors of Hemorrhagic Foci on Long-term Follow-up MRI of Recent Single Subcortical Infarcts. Transl Stroke Res. Published online December 14, 2023. doi:10.1007/s12975-023-01224-7 PMID: 38095840

  • Platelet Analysis in the Thrombus Plus Serum BNP for Detecting Clot-Related Atrial Fibrillation. Results From the ITACAT Multicentric Registry


    Occult atrial fibrillation (AF) is a common cause of cryptogenic stroke. This study aimed to investigate the utility of surrogate markers within the clot (clot markers), in combination with serum biomarkers, to identify AF-associated clots in patients who underwent mechanical thrombectomy. Each retrieved thrombus was analyzed to identify fibrin, red blood cells, platelets - CD61 staining (PLT) and T-CD4 lymphocyte/macrophage/monocyte (CD4) profile. Serum biomarkers such as D-dimer, lipoprotein (A), and brain natriuretic peptide (BNP) were also assessed in the acute phase of the stroke. Patients with stroke-related AF and large artery atherosclerosis (LAA) stroke were compared by matched case-control design to identify markers associated with AF clot profile. The predictive abilities of clot markers and serum biomarkers to detect AF clot were tested in patients with cryptogenic stroke. In patients with AF clot, the PLT percentage was higher (66.64% vs. 55.43%, OR = 1.03); CD4 percentage was lower (3.84% vs. 7.95%, OR = 0.95); and BNP marker was higher (2114 pg/ml vs. 276 pg/ml, OR = 1.04) compared to LAA clot. PLT was independently associated to AF-clot (OR, 1.04) but demonstrated moderate ability to identify AF-clot cases (C-test 0.668, p = 0.018). The combination of PLT with BNP significantly improved AF-clot prediction (C-test 0.847, p < 0.001). The clot composition of patients with cryptogenic stroke and AF detection showed four-fold higher PLT and BNP pattern of risk than patients with cryptogenic stroke without AF detection (38.5% vs. 8.7%) (OR = 1.40). Integrating intra-thrombus platelet with serum BNP offers a promising approach for detecting AF-associated clots in patients with cryptogenic stroke.

    隐匿性心房颤动(AF)是隐源性卒中的常见原因。本研究旨在探讨血栓内替代标记物(血栓标记物)与血清生物标记物相结合,在接受机械血栓切除术的患者中识别房颤相关血栓的实用性。对每一个回收的血栓进行分析,以确定纤维蛋白、红细胞、血小板CD61染色(PLT)和T-CD4淋巴细胞/巨噬细胞/单核细胞(CD4)图谱。中风急性期的血清生物标志物,如D-二聚体、脂蛋白(A)和脑利钠肽(BNP)也被评估。采用配对病例对照设计对卒中相关房颤和大动脉粥样硬化(LAA)卒中患者进行比较,以确定与房颤凝块特征相关的标志物。在隐源性卒中患者中测试血栓标志物和血清生物标志物检测房颤血栓的预测能力。房颤血栓患者的PLT百分比高于LAA血栓患者(66.64%vs.55.43%,OR=1.03),CD4百分比低于LAA血栓患者(3.84%vs.7.95%,OR=0.95),BNP标志物高于LAA血栓患者(2114 pg/ml vs.276 pg/ml,OR=1.04)。PLT与房颤血栓独立相关(OR1.04),但对房颤血栓的识别能力中等(C检验0.668,p=0.018)。血小板和脑钠素的结合显著改善了房颤-血栓的预测(C-检验0.847,p<0.001)。伴房颤的隐源性卒中患者的血栓成分显示PLT和BNP模式的风险是未检出房颤的隐源性卒中患者的四倍(38.5%vs.8.7%)(OR=1.40)。血栓内血小板与血清BNP的结合为检测不明原因卒中患者的房颤相关血栓提供了一种有前景的方法。

    REF: Pagola J, Juega J, Dorado L, et al. Platelet Analysis in the Thrombus Plus Serum BNP for Detecting Clot-Related Atrial Fibrillation. Results From the ITACAT Multicentric Registry. Transl Stroke Res. Published online December 13, 2023. doi:10.1007/s12975-023-01220-x PMID: 38091189

  • Time Dimension Influences Severity of Stroke and Heightened Immune Response in Mice


    Ischemic stroke is caused by obstructed cerebral blood flow, which results in neurological injury and poor outcomes. Pro-inflammatory signaling from both residential and infiltrating immune cells potentiates cerebral injury and worsens patient outcomes after stroke. While the occurrence of a stroke exhibits a time-of-day-dependent pattern, it remains unclear whether disrupted circadian rhythms modulate post-stroke immunity. In this study, we hypothesized that stroke timing differentially affects immune activation in mice. Following middle cerebral artery occlusion (MCAO), circadian genes BMAL1, CLOCK, Cry1, and Cry2 elevated at ZT06, with a significant difference between ZT06 and ZT18. Conversely, expression of the negative limb circadian clock gene, Per1, decreased at ZT06 and ZT18 in stroke mice compared to sham. Paralleling these circadian gene expression changes, we observed a significant increase in TNF-α and a decrease in IL-10 expression at 48 h post-MCAO, when the procedure was performed at ZT06 (MCAO-ZT6), which corresponds to a deep sleep period, as compared to when the stroke was induced at ZT12 (MCAO-ZT12), ZT18 (MCAO-ZT18), or ZT0 (MCAO-ZT12). Similarly, increased pro-inflammatory, decreased anti-inflammatory monocytes, and increased NLRP3 were observed in blood, while changes in the expression of CD11b and Iba1 were noted within brain tissue at 48 h of MCAO-ZT06, as compared to MCAO-ZT18. Consistent with the increased immune response, infarct volume and sensorimotor deficits were greater in MCAO-ZT06 mice compared to MCAO-ZT18 mice at 48 h. Finally, we found reduced weight and length of the spleen while splenocytes showed significant time-dependent changes in Tregs, Bregs, and monocytes in MCAO-ZT06 mice. Taken together, this study demonstrates that circulating and splenic immune responses following ischemic stroke exhibit a circadian expression pattern which may contribute to time-of-day-dependent stroke outcomes.


    REF: Kamat PK, Khan MB, Siddiqui S, et al. Time Dimension Influences Severity of Stroke and Heightened Immune Response in Mice. Transl Stroke Res. Published online December 13, 2023. doi:10.1007/s12975-023-01226-5 PMID: 38091188

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