Subchronic exposure to di-(2-ethylhexyl) phthalate (DEHP) elicits blood-brain barrier dysfunction and neuroinflammation in male C57BL/6J mice.

BACKGROUND: Exposure to di-(2-ethylhexyl) phthalate (DEHP) can cause neurotoxicity but the mechanism is not clear. Blood brain barrier (BBB) is one of the most important tissues to protect the brain. However, whether DEHP can disrupt the BBB or not remains unclear. The objective of this study is to investigate the potential effects of subchronic DEHP exposure on BBB integrity and discuss the role of BBB in DEHP inducible neurotoxicity with an emphasis on neuroinflammatory responses. Male adult C57BL/6J mice were orally administered with vehicle or 200 or 750 mg/kg/day DEHP for 90 days. Subchronic exposure to high-dose DEHP increased water intake but decreased body weight and brain weight. The concentrations of DEHP metabolites increased in serum from all DEHP-exposed groups while increased in brain only from the high-dose group. DEHP induced neurobehavioural alterations and damaged hippocampal neurons. DEHP increased BBB permeability by Evans blue (EB) extravasation and decreased tight junction proteins (ZO-1, occludin, and claudin-5) while presenting a neuroinflammatory feature characterized by the upregulated inflammatory mediators TNF-α and the NLRP3/caspase-1/IL-1ß inflammasome pathway. Our data provide new insights into neurotoxicity caused by subchronic DEHP exposure, which is probably involved in BBB dysfunction and neuroinflammatory responses.

The Critical Role of Erythrolysis and Microglia/Macrophages in Clot Resolution After Intracerebral Hemorrhage: A Review of the Mechanisms and Potential Therapeutic Targets.

Intracerebral hemorrhage (ICH) is a common cerebrovascular disorder with high morbidity and mortality. Secondary brain injury after ICH, which is initiated by multiple hemolytic products during erythrolysis, has been identified as a critical factor accounting for the poor prognosis of ICH patients. Clot resolution and hematoma clearance occur immediately after ICH via erythrolysis and erythrophagocytosis. During this process, erythrolysis after ICH results in the release of hemoglobin and products of degradation along with rapid morphological changes in red blood cells (RBCs). Phagocytosis of deformed erythrocytes and products of degradation by microglia/macrophages accelerates hematoma clearance, which turns out to be neuroprotective. Thus, a better understanding of the mechanism of erythrolysis and the role of microglia/macrophages after ICH is urgently needed. In this review, the current research progresses on the underlying mechanism of erythrolysis and erythrophagocytosis, as well as several useful tools for the quantification of erythrolysis-induced brain injury, are summarized, providing potential intervention targets and possible treatment strategies for ICH patients.

Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment.

Aim: The complement cascade is activated and may play an important pathophysiologic role in brain injury after experimental intracerebral hemorrhage (ICH). However, the exact mechanism of specific complement components has not been well studied. This study determined the role of complement C1q/C3-CR3 signaling in brain injury after ICH in mice. The effect of minocycline on C1q/C3-CR3 signaling-induced brain damage was also examined. Methods: There were three parts to the study. First, the natural time course of C1q and CR3 expression was determined within 7 days after ICH. Second, mice had an ICH with CR3 agonists, LA-1 or vehicle. Behavioral score, neuronal cell death, hematoma volume, and oxidative stress response were assessed at 7 days after ICH. Third, the effect of minocycline on C1q/C3-CR3 signaling and brain damage was examined. Results: There were increased numbers of C1q-positive and CR3-positive cells after ICH. Almost all perihematomal C1q-positive and CR3-positive cells were microglia/macrophages. CR3 agonist LA-1 aggravated neurological dysfunction, neuronal cell death, and oxidative stress response on day 7 after ICH, as well as enhancing the expression of the CD163/HO-1 pathway and accelerating hematoma resolution. Minocycline treatment exerted neuroprotective effects on brain injury following ICH, partly due to the inhibition of C1q/C3-CR3 signaling, and that could be reversed by LA-1. Conclusions: The complement C1q/C3-CR3 signaling is upregulated after ICH. The activation of C1q/C3-CR3 signaling by LA-1 aggravates brain injury following ICH. The neuroprotection of minocycline, at least partly, is involved with the repression of the C1q/C3-CR3 signaling pathway.

Neutrophil to lymphocyte ratio predicting poor outcome after aneurysmal subarachnoid hemorrhage: A retrospective study and updated meta-analysis.

Background: The relationship between neutrophil to lymphocyte ratio (NLR) and poor outcome of aneurysmal subarachnoid hemorrhage (aSAH) is controversial. We aim to evaluate the relationship between NLR on admission and the poor outcome after aSAH. Method: Part I: Retrospective analysis of aSAH patients in our center. Baseline characteristics of patients were collected and compared. Multivariate analysis was used to evaluate parameters independently related to poor outcome. Receiver operating characteristic (ROC) curve analysis was used to determine the best cut-off value of NLR. Part II: Systematic review and meta-analysis of relevant literature. Related literature was selected through the database. The pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to evaluate the correlation between NLR and outcome measures. Results: Part I: A total of 240 patients with aSAH were enrolled, and 52 patients had a poor outcome. Patients with poor outcome at 3 months had a higher admission NLR, Hunt & Hess score, Barrow Neurological Institute (BNI) scale score, Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and proportion of hypertension history. After adjustment, NLR at admission remained an independent predictor of poor outcome in aSAH patients (OR 0.76, 95% CI 0.69-0.83; P < 0.001). The best cut-off value of NLR in ROC analysis is 12.03 (area under the curve 0.805, 95% CI 0.735 - 0.875; P < 0.001). Part II: A total of 16 literature were included. Pooled results showed that elevated NLR was significantly associated with poor outcome (OR 1.31, 95% CI 1.14-1.49; P < 0.0001) and delayed cerebral ischemia (DCI) occurrence (OR 1.32, 95% CI 1.11-1.56; P = 0.002). The results are more reliable in large sample sizes, low NLR cut-off value, multicenter, or prospective studies. Conclusion: Elevated NLR is an independent predictor of poor outcome and DCI occurrence in aSAH.

Influence of Nurse-Led Health Education on Self-Management Ability, Satisfaction, and Compliance of Elderly Patients with Chronic Obstructive Pulmonary Disease Based on Knowledge, Belief, and Practice Model.

Objective: Knowledge, belief, and behavior model (knowledge-attitude-practice (KAP)) is known as a cognitive model. Health education is important to the prognosis of patients, including chronic obstructive pulmonary disease (COPD) patients. However, the investigation regarding health education based on the KAP model is few. Thus, this work is aimed at analyzing the influence of nurse-led health education on self-management ability, satisfaction, and compliance of elderly patients with COPD based on knowledge, belief, and practice model. Methods: 60 elderly patients with COPD cured in our hospital from January 2019 to April 2021 were enrolled for the study. The patients were randomly assigned to control group (n = 30) and study group (n = 30). The former group received routine nursing, and the latter group accepted health education based on "knowledge, belief, and practice" model. Finally, the scores of nursing satisfaction, KAP score, compliance rate, self-management level, pulmonary function, and life quality were compared in the two groups. Results: The nursing satisfaction of the study group (100.00%) was higher than that (83.33%) of the control group (P < 0.05). The scores of knowledge, attitude, and behavior were remarkably higher in the study group than in the control group after nursing (P < 0.05). Moreover, KAP scores also significantly increased in the study group after nursing. The compliance rate of the study group (93.33%) was higher than that of the control group (66.67%) (P < 0.05). After nursing, the scores of symptom management, daily life management, emotion management, information management, and management efficiency were higher in the study group than in the control group (P < 0.05). In addition, pulmonary functions were improved in the two groups following nursing. Compared with the control groups, the 6 min walking distance, FEV1%, and FEV1/FVC% were higher in the study group (P < 0.05). After nursing, the scores of life quality were reduced in the two groups. The scores of physiological function, psychological function, social function, and health self-cognition were lower in the study group than in the control group (P < 0.05). Conclusion: Based on the model of knowledge, belief, and practice, nurse-led health education can successfully enhance the self-management ability, satisfaction, and compliance of elderly COPD patients.

Organic-Inorganic Double-Gel System Thermally Insulating and Hydrophobic Polyimide Aerogel.

Aerogel materials are used in various fields, but there is a shortage of aerogel materials with an excellent combination of mechanical properties, thermal stability, and easy preparation. In this study, polyimide aerogel materials with superior mechanical properties, thermal stability, and low thermal conductivity were prepared by forming a double-gel system in the liquid phase. The amino-modified gel, prepared by coating SiO2 nano-microspheres with GO through a modified sol-gel method (SiO2@GO-NH2), was subsequently homogeneously dispersed with PAA wet gel in water to form a double-gel system. The construction of a double-gel system enabled the PI aerogel to shape a unique honeycomb porous structure and a multi-layered interface of PI/SiO2/GO. The final obtained PI aerogel possessed effective thermal conductivity (0.0309 W/m·K) and a high specific modulus (46.19 m2/s2). In addition, the high thermal stability (543.80 °C in Ar atmosphere) and the ability to retain properties under heat treatment proved its durability in high thermal environments. The hydrophobicity (131.55°) proves its resistance to water from the environment. The excellent performance of this PI aerogel and its durability in thermal working environments make it possible to be applied in varied industrial and research fields, such as construction and energy, where heat and thermal insulation are required.

Inhibition of Mer exacerbates early brain injury by regulating microglia/macrophage phenotype after subarachnoid hemorrhage in mice.

BACKGROUND: Polarization of microglia/macrophages toward the pro-inflammatory phenotype is a crucial contributor to neuroinflammation after subarachnoid hemorrhage (SAH). Mer belongs to the TAM receptor tyrosine kinases family, which is known to play a significant role in the resolution of inflammation. However, the effect and mechanism of Mer after SAH remain unclear. In this study, we explored the effect of Mer on modulating the microglia/macrophage phenotype and neuroinflammation and possible potential mechanism after SAH. METHOD: Endovascular perforation model of SAH was performed. There are 3 parts in this study. Firstly, the time course of Mer expression was determined within 72 hours after SAH. Secondly, the effect of Mer downregulation on brain water content, neurological function, and microglial polarization was evaluated at 24 h after SAH. Thirdly, the neuroprotective effects of pharmacological Mer agonist were assessed. RESULT: The expression of Mer increased after SAH, and was prominently localized in microglia/macrophages. Treatment with Mer siRNA increased pro-inflammatory phenotype and decreased anti-inflammatory phenotype of microglia/macrophage, thus resulted in exacerbation of neurological deficits and brain edema after SAH. Mechanistically, the downregulation of Mer inhibited the downstream anti-inflammatory signals, SOCS1/SOCS3, by decreasing phosphorylated STATs. CONCLUSION: Mer is involved in the microglia/macrophage polarization and inflammation resolution after SAH, and that mechanism, at least in part, may contribute to the involvement of the STATs/SOCSs pathway.

Sex-Associated Differences in Neurovascular Dysfunction During Ischemic Stroke.

Neurovascular units (NVUs) are basic functional units in the central nervous system and include neurons, astrocytes and vascular compartments. Ischemic stroke triggers not only neuronal damage, but also dissonance of intercellular crosstalk within the NVU. Stroke is sexually dimorphic, but the sex-associated differences involved in stroke-induced neurovascular dysfunction are studied in a limited extend. Preclinical studies have found that in rodent models of stroke, females have less neuronal loss, stronger repairing potential of astrocytes and more stable vascular conjunction; these properties are highly related to the cerebroprotective effects of female hormones. However, in humans, these research findings may be applicable only to premenopausal stroke patients. Women who have had a stroke usually have poorer outcomes compared to men, and because stoke is age-related, hormone replacement therapy for postmenopausal women may exacerbate stroke symptoms, which contradicts the findings of most preclinical studies. This stark contrast between clinical and laboratory findings suggests that understanding of neurovascular differences between the sexes is limited. Actually, apart from gonadal hormones, differences in neuroinflammation as well as genetics and epigenetics promote the sexual dimorphism of NVU functions. In this review, we summarize the confirmed sex-associated differences in NVUs during ischemic stroke and the possible contributing mechanisms. We also describe the gap between clinical and preclinical studies in terms of sexual dimorphism.

Probenecid-Blocked Pannexin-1 Channel Protects Against Early Brain Injury via Inhibiting Neuronal AIM2 Inflammasome Activation After Subarachnoid Hemorrhage.

Aim: Previous studies have proved that inhibiting inflammasome activation provides neuroprotection against early brain injury (EBI) after subarachnoid hemorrhage (SAH), which is mainly focused on the microglial inflammatory response, but the potential role of neuronal inflammasome activation in EBI has not been clearly identified. This study examined whether the pannexin-1 channel inhibitor probenecid could reduce EBI after SAH by inhibiting neuronal AIM2 inflammasome activation. Methods: There are in vivo and in vitro parts in this study. First, adult male SD rats were subjected to the endovascular perforation mode of SAH. The time course of pannexin-1 and AIM2 expressions were determined after SAH in 72 h. Brain water content, neurological function, AIM2 inflammasome activation, and inflammatory response were evaluated at 24 h after SAH in sham, SAH, and SAH + probenecid groups. In the in vitro part, HT22 cell treated with hemin was applied to mimic SAH. The expression of AIM2 inflammasome was detected by immunofluorescence staining. Neuronal death and mitochondrial dysfunction were determined by the LDH assay kit and JC-1 staining. Results: The pannexin-1 and AIM2 protein levels were upregulated after SAH. Pannexin-1 channel inhibitor probenecid attenuated brain edema and improved neurological dysfunction by reducing AIM2 inflammasome activation and reactive oxygen species (ROS) generation after SAH in rats. Treating HT22 cells with hemin for 12 h resulted in AIM2 and caspase-1 upregulation and increased mitochondrial dysfunction and neuronal cell death. Probenecid significantly attenuated the hemin-induced AIM2 inflammasome activation and neuronal death. Conclusions: AIM2 inflammasome is activated in neurons after SAH. Pharmacological inhibition of the pannexin-1 channel by probenecid attenuated SAH-induced AIM2 inflammasome activation and EBI in vivo and hemin-induced AIM2 inflammasome activation and neuronal death in vitro.

Changes of FSTL1 and MMP-9 levels in patients with acute cerebral infarction and its relationship with hemorrhagic transformation.

BACKGROUND: hemorrhagic transformation is a serious complication of acute ischemic stroke, which may lead to poor prognosis and delayed use of anticoagulant therapy. METHODS: 125 patients with cerebral infarction from December 2019 to December 2020 in the Second Affiliated Hospital of Zhejiang University were selected. All patients did not receive intravascular therapy, intravenous thrombolysis and other reperfusion treatment; and the relevant laboratory data were collected within 24 h after admission. At the same time, 15 healthy subjects were selected as the research objects for prospective analysis. Hemorrhagic transformation (HT) was defined as a condition in which computed tomography (CT) did not indicate bleeding at admission, but follow-up magnetic resonance imaging (MRI) or CT showed hemorrhage. The patients were divided into HT group (n = 50) and non-HT group (n = 75) according to whether there was HT after admission. The concentrations of FSTL1 and MMP-9 in peripheral blood of the two groups were detected. RESULTS: The concentrations of FSTL1 and MMP-9 in acute cerebral infarction (ACI) group were significantly higher than those in control group. However the HT group had a higher concentration of FSTL1 and MMP-9 than the non-HT group. The serum FSTL1 and MMP-9 were independent risk factors for hemorrhagic transformation. The area under the ROC curve of FSTL1 and MMP-9 in diagnosis of HT was 0.809 and 0.856 respectively, and their combined value was 0.923. CONCLUSION: The high levels of FSTL1 and MMP-9 had strong correlation with HT in ACI patients.

Neutrophil Extracellular Traps may be a Potential Target for Treating Early Brain Injury in Subarachnoid Hemorrhage.

Neuroinflammation is closely associated with poor prognosis in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to investigate the role of neutrophil extracellular traps (NETs), which are important regulators of sterile inflammation, in SAH. In this study, markers of NET formation, quantified by the level of citrullinated histone H3 (CitH3), were significantly increased after SAH and correlated with SAH severity. CitH3 peaked at 12 h in peripheral blood and at 24 h in the brain. Administration of the peptidyl arginine deiminase 4 (PAD4) selective antagonist GSK484 substantially attenuated SAH-induced brain edema and neuronal injury. Moreover, the benefit of NET inhibition was also confirmed by DNAse I treatment and neutrophil depletion. Mechanistically, NETs markedly exacerbated microglial inflammation in vitro. NET formation aggravated neuroinflammation by promoting microglial activation and increased the levels of TNF-α, IL-1ß, and IL-6, while inhibiting NETs demonstrated anti-inflammatory effects by decreasing the levels of these proinflammatory factors. Moreover, neurogenic pulmonary edema (NPE), a severe nonneurological complication after SAH, is associated with a high level of NET formation. However, GSK484 effectively inhibited the formation of NETs in the lungs of NPE mice, thereby preventing the diffusion of neutrophilic infiltration and attenuating the swelling of the alveolar interstitium. In conclusion, NETs promoted neuroinflammation after SAH, while pharmacological inhibition of PAD4-NETs could reduce the inflammatory damage caused by SAH. These results supported the idea that NETs might be potential therapeutic targets for SAH.

Autophagy protein NRBF2 attenuates endoplasmic reticulum stress-associated neuroinflammation and oxidative stress via promoting autophagosome maturation by interacting with Rab7 after SAH.

BACKGROUND: Neuroinflammation and oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study is the first to show that activation of autophagy protein nuclear receptor binding factor 2 (NRBF2) could reduce endoplasmic reticulum stress (ERS)-associated inflammation and oxidative stress after SAH. METHODS: Male C57BL/6J mice were subjected to endovascular perforation to establish a model of SAH. NRBF2 overexpression adeno-associated virus (AAV), NRBF2 small interfering RNAs (siRNA), lysosomal inhibitor-chloroquine (CQ), and late endosome GTPase Rab7 receptor antagonist-CID1067700 (CID) were used to investigate the role of NRBF2 in EBI after SAH. Neurological tests, brain water content, western blotting and immunofluorescence staining were evaluated. RESULTS: Our study found that the level of NRBF2 was increased after SAH and peaked at 24 h after SAH. In addition, we found that the overexpression of NRBF2 significantly improved neurobehavioral scores and reduced ERS, oxidative stress, and neuroinflammation in SAH, whereas the inhibition of NRBF2 exacerbated these phenotypes. In terms of mechanism, NRBF2 overexpression significantly promoted autophagosome maturation, with the downregulation of CHOP, Romo-1, TXNIP, NLRP3, TNF-α, and IL-1ß expression through interaction with Rab7. The protective effect of NRBF2 on ERS-associated neuroinflammation and oxidative stress after SAH was eliminated by treatment with CQ. Meanwhile, it was also reversed by intraperitoneal injection of CID. Moreover, the MIT domain of NRBF2 was identified as a critical binding site that interacts with Rab7 and thereby promotes autophagosome maturation. CONCLUSION: Our data provide evidence that the autophagy protein NRBF2 has a protective effect on endoplasmic reticulum stress-associated neuroinflammation and oxidative stress by promoting autophagosome maturation through interactions with Rab7 after SAH.

AXL kinase-mediated astrocytic phagocytosis modulates outcomes of traumatic brain injury.

BACKGROUND: Complex changes in the brain microenvironment following traumatic brain injury (TBI) can cause neurological impairments for which there are few efficacious therapeutic interventions. The reactivity of astrocytes is one of the keys to microenvironmental changes, such as neuroinflammation, but its role and the molecular mechanisms that underpin it remain unclear. METHODS: Male C57BL/6J mice were subjected to the controlled cortical impact (CCI) to develop a TBI model. The specific ligand of AXL receptor tyrosine kinase (AXL), recombinant mouse growth arrest-specific 6 (rmGas6) was intracerebroventricularly administered, and selective AXL antagonist R428 was intraperitoneally applied at 30 min post-modeling separately. Post-TBI assessments included neurobehavioral assessments, transmission electron microscopy, immunohistochemistry, and western blotting. Real-time polymerase chain reaction (RT-PCR), siRNA transfection, and flow cytometry were performed for mechanism assessments in primary cultured astrocytes. RESULTS: AXL is upregulated mainly in astrocytes after TBI and promotes astrocytes switching to a phenotype that exhibits the capability of ingesting degenerated neurons or debris. As a result, this astrocytic transformation promotes the limitation of neuroinflammation and recovery of neurological dysfunction. Pharmacological inhibition of AXL in astrocytes significantly decreased astrocytic phagocytosis both in vivo and in primary astrocyte cultures, in contrast to the effect of treatment with the rmGas6. AXL activates the signal transducer and activator of the transcription 1 (STAT1) pathway thereby further upregulating ATP-binding cassette transporter 1 (ABCA1). Moreover, the supernatant from GAS6-depleted BV2 cells induced limited enhancement of astrocytic phagocytosis in vitro. CONCLUSION: Our work establishes the role of AXL in the transformation of astrocytes to a phagocytic phenotype via the AXL/STAT1/ABCA1 pathway which contributes to the separation of healthy brain tissue from injury-induced cell debris, further ameliorating neuroinflammation and neurological impairments after TBI. Collectively, our findings provide a potential therapeutic target for TBI.

Two Co(II) coordination polymers: magnetic properties and application values against chronic subdural hematoma.

In this current experiment, by applying the mixed-ligand synthesis method, two coordination polymers (CPs) containing Co(II) were created triumphantly with reaction between 1,3-bis(1-imidazoly)benzene (mbib) and Co(II) salts with the aid of diverse carboxylic ligands, and their chemical formulae are [Co3(opda)3(mbib)4(H2O)4]·2H2O (1, H2opda is 1,2-phenylenediacetic acid) and [Co(mpda)(mbib)]·H2O (2, H2mpda is 1,3-phenylenediacetic acid). The two compounds' magnetic performances suggest that between the adjacent metal ions, there present the antiferromagnetic coupling. The evaluation of their treatment activity against chronic subdural hematoma was carried out and the relevant mechanism was studied simultaneously. Firstly, before the treatment of compound, the chronic subdural hematoma was generated. Furthermore, the enzyme-linked immunosorbent assay detection kit was implemented and in hematoma capsule, the anti-inflammatory cytokines level and pro-inflammatory cytokines level was detected. Additionally, the cytotoxicity of compounds 1 and 2 on the normal human cells was determined with Cell Counting Kit-8 assay. Above all, we proved compound 1 decreased the pro-inflammatory cytokines content and increased the anti-inflammatory cytokines content in the hematoma capsule, which is much stronger than that of compound 2. Both compounds 1 and 2 showed no cytotoxicity on the normal human cells.

Metformin Alleviates Neuroinflammation Following Intracerebral Hemorrhage in Mice by Regulating Microglia/Macrophage Phenotype in a Gut Microbiota-Dependent Manner.

The gut microbiota plays a key role in regulating intracerebral hemorrhage (ICH)-induced neuroinflammation. The anti-neuroinflammatory effects of metformin (Met) have been reported in many central nervous system (CNS) diseases. However, whether Met regulates neuroinflammation through the gut microbiota in ICH-induced brain injury remains unknown. We found that Met treatment substantially alleviated neurological dysfunction and reduced neuroinflammation by inhibiting pro-inflammatory polarization of microglia/macrophages in mice with ICH. Moreover, Met treatment altered the microbiota composition and improved intestinal barrier function. The expression of lipopolysaccharide-binding protein (LBP), a biomarker of intestinal barrier damage, was also significantly reduced by Met treatment. Neuroinflammation was also potently ameliorated after the transplantation of fecal microbiota from Met-treated ICH mice. The neuroprotective effects of fecal microbiota transplantation (FMT) were similar to those of oral Met treatment. However, suppression of the gut microbiota negated the neuroprotective effects of Met in ICH mice. Therefore, Met is a promising therapeutic agent for neuroinflammation owing to ICH-induced imbalance of the gut microbiota.

Wogonin Accelerates Hematoma Clearance and Improves Neurological Outcome via the PPAR-γ Pathway After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a cerebrovascular disease with high mortality and morbidity for which effective treatments are currently lacking. Wogonin is a major flavonoid compound isolated from Scutellaria radix. Accumulating evidence suggests that wogonin plays a crucial role in anti-inflammatory and anti-oxidative stress. Treatment of microglia with nuclear receptor agonists augments the expression of phagocytosis-related genes. However, the neuroprotective effects of wogonin in ICH remain obscure. In this study, we elucidated an innovative mechanism by which wogonin acts to enhance phagocytosis in a murine model of ICH. Wogonin promoted hematoma clearance and improved neurological recovery after ICH by upregulating the expression of Axl, MerTK, CD36, and LAMP2 in perihematomal microglia and BV2 cells. Treatment of a murine model of ICH with wogonin stimulated microglial phagocytosis in vitro. Further, we demonstrated that wogonin dramatically attenuated inflammatory and oxidative stress responses in a murine model of ICH by reducing the expression of pro-inflammatory cytokines and pro-oxidant enzymes such as TNF-α, IL-1ß, and inducible nitric oxide synthase (iNOS) after ICH. The effects of wogonin were abolished by administration of the PPAR-γ inhibitor GW9662. In conclusion, our data suggest that wogonin facilitates hematoma clearance and neurobehavioral recovery by targeting PPAR-γ.

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage.

BACKGROUND: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. METHODS: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. RESULTS: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1ß, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro. CONCLUSION: Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.

Leucine-Rich Glioma Inactivated 1 Promotes Oligodendrocyte Differentiation and Myelination via TSC-mTOR Signaling.

Leucine-rich glioma inactivated 1 (Lgi1), a putative tumor suppressor, is tightly associated with autosomal dominant lateral temporal lobe epilepsy (ADLTE). It has been shown that Lgi1 regulates the myelination of Schwann cells in the peripheral nervous system (PNS). However, the function and underlying mechanisms for Lgi1 regulation of oligodendrocyte differentiation and myelination in the central nervous system (CNS) remain elusive. In addition, whether Lgi1 is required for myelin maintenance is unknown. Here, we show that Lgi1 is necessary and sufficient for the differentiation of oligodendrocyte precursor cells and is also required for the maintenance of myelinated fibers. The hypomyelination in Lgi1-/- mice attributes to the inhibition of the biosynthesis of lipids and proteins in oligodendrocytes (OLs). Moreover, we found that Lgi1 deficiency leads to a decrease in expression of tuberous sclerosis complex 1 (TSC1) and activates mammalian target of rapamycin signaling. Together, the present work establishes that Lgi1 is a regulator of oligodendrocyte development and myelination in CNS.

Accuracy of magnetic resonance venography in diagnosing cerebral venous sinus thrombosis.

OBJECTIVES: The non-specific clinical manifestations and lack of effective diagnostic techniques have made cerebral venous sinus thrombosis (CVST) difficult to recognize and easy to misdiagnose. Several studies have suggested that different types of magnetic resonance venography (MRV) have advantages in diagnosing CVST. We conducted this meta-analysis to assess the accuracy of MRV in identifying CVST. MATERIAL AND METHODS: We searched the Embase, PubMed, and Chinese Biomedical (CBM) databases comprehensively to retrieve eligible articles up to Mar 31, 2018. The methodological quality of each article was evaluated individually. The summary diagnostic accuracy of MRV for CVST was obtained from pooled analysis with random-effects models. Sensitivity analysis, subgroup analysis, and meta-regression were used to explore the sources of heterogeneity. A trim and fill analysis was conducted to correct the funnel plot asymmetry. RESULTS: The meta-analysis synthesized 12 articles containing 27 cohorts with a total of 1933 cases. The pooled sensitivity and specificity were 0.86 (95% CI: 0.83, 0.89) and 0.94 (95% CI: 0.93, 0.95), respectively. The pooled diagnostic odds ratio (DOR) was 75.24 (95% CI: 38.33, 147.72). The area under the curve (AUC) was 0.9472 (95% CI: 0.9229, 0.9715). Subgroup analysis and meta-regression analysis revealed the technical types of MRV and the methods of counting cases contributing to the heterogeneity. The trim and fill method confirmed that publication bias has little effect on our results. CONCLUSIONS: MRV has excellent diagnostic performance and is accurate in confirming CVST.

Phosphodiesterase-4 inhibition confers a neuroprotective efficacy against early brain injury following experimental subarachnoid hemorrhage in rats by attenuating neuronal apoptosis through the SIRT1/Akt pathway.

Phosphodiesterase-4 (PDE4) plays a fundamental role in a range of central nervous system (CNS) insults, however, the role of PDE4 in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The current study was designed to investigate the role of PDE4 in EBI after SAH and explore the potential mechanism. The SAH model in Sprague-Dawley rat was established by endovascular perforation process. Rats were randomly divided into: sham group, SAH?+?vehicle group, SAH?+?rolipram (PDE4 inhibitor) group, SAH?+?rolipram?+?sirtinol (SIRT1 inhibitor) group and SAH?+?rolipram+MK2206 (Akt inhibitor) group. Mortality, SAH grades, neurological function, brain edema, immunofluorescence staining and western blotting were performed. Double fluorescence labeling staining indicated that PDE4 was located predominately in neurons after SAH. Rolipram reduced brain edema, improved neurological function in the rat model of SAH. Moreover, rolipram increased the expression of Sirtuin1 (SIRT1) and up-regulated the phosphorylation of Akt, which was accompanied by the reduction of neuronal apoptosis. Administration of sirtinol inhibited the phosphorylation of Akt. Moreover, all the beneficial effects of rolipram against SAH were abolished by both sirtinol and MK2206. These data indicated that PDE4 inhibition by rolipram protected rats against EBI after SAH via suppressing neuronal apoptosis through the SIRT1/Akt pathway. Rolipram might be an important therapeutic drug for SAH.