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The specific protective mechanism of mitophagy and Nrf2 in brain injury has not been fully clarified. This study aimed to reveal the effect of Nrf2 on hydraulic shock brain injury in mice, and explore its possible mechanism. Twenty-four Nrf2 knockout (Nrf2-/-) and wild-type mice (WT) of C57BL/6J were randomly divided into two groups: control group (C) and brain injury group (TBI). Hematoxylin-eosin staining (HE) assay was used for the histomorphological observation. The apoptotic state of brain tissue was detected by TUNEL. Mechanical damage in vitro models of glial cells were prepared. The wild-type (WT) and Nrf2 knockout (KO) mice were constructed to investigate the changes of mitophagy and apoptosis-related indicators by Western blotting. The experimental results showed that 24 h after TBI, the tissue structure was highly porous, the cells were highly edema, the neuronal space increased significantly, the neuron degeneration, and the cell vacuolation was obvious. Meanwhile, the number of apoptotic cells and the apoptosis rate of glial cells increased significantly. After injury, the relative expression of Parkin, Pink, Beclin and LC-3II proteins were significantly decreased in all mice. The protein expressions of Caspase3 and Caspase12 were significantly increased. However, in the TBI group, KO mice were more impaired than WT mice. In conclusion, Nrf2 plays a protective role by promoting mitophagy to inhibit apoptosis in the process of brain injury caused by hydraulic shock in mice, which provides a new idea for the effective treatment of brain injury.

Objective: Aneurysms occurring in the ophthalmic segment (C6) of the internal carotid artery (ICA) have complex anatomy. This poses a challenge for the use of traditional open surgery, which is gradually being replaced by endovascular treatment (EVT). However, multiple aneurysm (MA) EVT, especially in MAs occurring ipsilaterally, has not been specifically described or discussed. The present study aimed to propose a more concise clinical classification standard for ipsilateral C6 ICA MAs and report on the clinical experience with EVT., Methods: The cases of 18 patients with ipsilateral C6 ICA MAs treated with EVT were retrospectively reviewed. The treatment results and procedure-related complications were recorded, and clinical and angiographic follow-ups were performed at least six months after surgery., Results: A total of 38 ipsilateral C6 ICA aneurysms were treated during the study period and classified into four main types and six total subtypes based on anatomical features. There was a failure to coil through the stent in one aneurysm, while the remaining 37 were successfully treated using various EVT methods. Of these, 36 were completely concluded. One aneurysm had a size reduction, and one had no changes during the angiographic follow-up. All Tubridge flow diverter stents were patent. All patients achieved satisfactory clinical outcomes and were independent at the final follow-up., Conclusion: EVT may be safe and feasible for the treatment of C6 ICA MAs. Traditional stent-assisted coiling methods, the Willis covered stent, and the double-layered low-profile visualized intraluminal support stent all achieved favorable results. The flow diverter stent is also considered a safe and efficient option for selected aneurysms, but the visual deficit risk should be considered. The present study introduces a new EVT classification option based on the anatomical features of an aneurysm., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Microglial activation and subsequent inflammatory responses are critical processes in aggravating secondary brain injury after intracerebral hemorrhage (ICH). Pterostilbene (3', 5'-dimethoxy-resveratrol) features antioxidant and anti-inflammation properties and has been proven neuroprotective. In this study, we aimed to explore whether Pterostilbene could attenuate neuroinflammation after experimental ICH, as well as underlying molecular mechanisms. Here, a collagenase-induced ICH in mice was followed by intraperitoneal injection of Pterostilbene (10 mg/kg) or vehicle once daily. PTE-treated mice performed significantly better than vehicle-treated controls in the neurological behavior test after ICH. Furthermore, our results showed that Pterostilbene reduced lesion volume and neural apoptosis, and alleviated blood-brain barrier (BBB) damage and brain edema. RNA sequencing and subsequent experiments showed that ICH-induced neuroinflammation and microglial proinflammatory activities were markedly suppressed by Pterostilbene treatment. With regard to the mechanisms, we identified that the anti-inflammatory effects of Pterostilbene relied on remodeling mitochondrial dynamics in microglia. Concretely, Pterostilbene reversed the downregulation of OPA1, promoted mitochondrial fusion, restored normal mitochondrial morphology, and reduced mitochondrial fragmentation and superoxide in microglia after OxyHb treatment. Moreover, conditionally deleting microglial OPA1 in mice largely countered the effects of Pterostilbene on alleviating microglial inflammation, BBB damage, brain edema and neurological impairment following ICH. In summary, we provided the first evidence that Pterostilbene is a promising agent for alleviating neuroinflammation and brain injury after ICH in mice, and uncovered a novel regulatory relationship between Pterostilbene and OPA1-mediated mitochondrial fusion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Hu, Wang, Cheng, Yu, Li, Luo, Zhang, Wu and Zhang.)

Background: Aquaporin 4 (AQP4), usually expressed at astrocytes end-feet, is a main component of the lymph-lymphatic system and promotes paravascular cerebrospinal fluid-interstitial fluid exchange. Moreover, angiotensin II type 1 (AT 1 ) receptor affects amyloid β (Aβ) levels. This study aimed to detect the effect of AT 1 receptor deficiency on the blood-brain barrier (BBB) of traumatic brain injury (TBI) mice and the effect on Aβ level and glial lymphatic circulation., Methods: TBI model was built using AT 1 receptor knockout mice (AT 1 -KO) and C57BL/6 mice (wild type, WT). BBB integrity was detected by Evans blue extravasation. The expression of the astrocytic water channel AQP4 and astrocyte activation were evaluated with immunofluorescence. The expressions of amyloid precursor protein (APP), junction protein zonula occludens protein-1 (ZO-1) and occludin in mice brain were detected by Western blot (WB). Aβ levels were assayed by enzyme-linked immunosorbent assay (ELISA)., Results: AT 1 receptor deficiency defended BBB integrity and rescued occludin and ZO-1 decrease in mice brain induced by TBI. AT 1 -KO mice had less increase of APP expression and Aβ 1-42, Aβ 1-40 levels compared to WT mice under TBI. Moreover, AT 1 receptor deficiency was found to significantly inhibit AQP4 depolarization after TBI., Conclusion: T 1 receptor deficiency attenuated TBI-induced impairments of BBB by rescuing tight junction proteins and inhibited AQP4 polarization, thus improving the function of glymphatic system to enhance interstitial Aβ clearance in TBI mice brain.

Several reports suggest that hydrogen sulfide (H 2 S) exerts multiple biological and physiological effects on the pathogenesis of traumatic brain injury (TBI). However, the exact molecular mechanism involved in this effect is not yet fully known. In this study, we found that H 2 S alleviated TBI-induced motor and spatial memory deficits, brain pathology, and brain edema. Moreover, sodium hydrosulfide (NaHS), an H 2 S donor, treatment markedly increased the expression of Bcl-2, while inhibited the expression of Bax and Cleaved caspase-3 in TBI-challenged rats. Tunnel staining also demonstrated these results. Treatment with NaHS significantly reduced the glutamate and glutaminase 2 (GLS-2) protein levels, and glutamate-mediated oxidative stress in TBI-challenged rats. Furthermore, we demonstrated that H 2 S treatment inhibited glutamate-mediated oxidative stress through the p53/GLS-2 pathway. Therefore, our results suggested that H 2 S protects brain injury induced by TBI through modulation of the glutamate-mediated oxidative stress in the p53/GLS-2 pathway-dependent manner.

Background: The glymphatic pathway has been shown to be impaired in traumatic brain injury (TBI). Omega-3 polysaturated fatty acids (Omega-3, PUFAs) are involved in the clearance of amyloid-ß through the glymphatic system and this effect is Aquaporin-4 (AQP4) dependent. We hypothesize that Omega-3 PUFAs can alleviate neurological impairment in TBI by protecting the glymphatic pathway. Methods: We pretreated mice with Omega-3 PUFAs rich fish oil and introduced TBI in the mice. Neurological functions were assessed through the modified neurological severity score (mNSS) system and Rota-rod test. Aß42 levels and radioisotope clearance were examined to determine the function of glymphatic system. AQP4 protein and mRNA expressions and its polarity were examined in fish oil treated TBI mice or control mice. Finally, the integrity of blood-brain barrier was determined by Evans blue extravasation and measurement of tight junction proteins (ZO-1 and Occludin) levels. Results: TBI surgery induced significant neurological functional impairment, Omega-3 PUFAs attenuated TBI-induced neurological impairment, as evidenced by reduced mNSS, improved performance in the Rota-rod test. Furthermore, Omega-3 PUFAs improved glymphatic clearance after induction of TBI in mice, reduced Aß42 accumulation, partially restored the clearance of both 3 H-mannitol and 14 C-Inulin. Omega-3 PUFAs also suppressed AQP4 expression and partially prevented loss of AQP4 polarity in mice undergoing TBI. Finally, Omega-3 PUFAs protected mice from TBI induced blood-brain barrier disruption. Conclusion: Omaga-3 PUFAs attenuate neurological function by partially restoring the AQP4 dependent glymphatic system in mice with TBI., (Copyright © 2020 Zhang, Wan, Yang, Wang, Chen, Chen, Liu, Zhang, Wu, Han and Fan.)

Background: Circular RNAs (circRNAs) play an important role in the tumorigenesis of glioma. Our study indicated that low hsa_circ_0008225 expression was associated with poor overall survival in patients with glioma. However, the relevant mechanism of hsa_circ_0008225 in glioma tumorigenesis remains unclear., Methods: Two datasets (GSE86202 and GSE92322) were downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed circRNAs (DEcircRNAs) between glioma tissues and matched normal tissues were screened using R language., Results: A total of 79 overlapping DEcircRNAs were identified by comparison of glioma and matched normal tissues. In addition, low hsa_circ_0008225 expression was associated with poor overall survival in patients with glioma. Overexpression of hsa_circ_0008225 markedly inhibited the proliferation, migration and invasion of SHG44 cells via inducing apoptosis. Mechanically, overexpression of hsa_circ_0008225 increased the expression of miR-890 targeted gene ZMYND11 via acting as a competitive 'sponge' of miR-890., Conclusion: Our results suggested that hsa_circ_0008225 functions as a tumor inhibitor in glioma by sponging miR-890 and then promoting the function of ZMYND11. Therefore, hsa_circ_0008225 could be a potential prognostic biomarker for the treatment of glioma., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The aim of the present study was to was investigate the treatment efficacy of hyperbaric oxygen (HBO) combined with nimodipine on diffuse brain injury. AA total of 80 patients with diffuse brain injury were randomly divided into four groups: Group A, conventional treatment; Group B, conventional treatment + nimodipine; Group C, conventional treatment + HBO therapy and Group D, conventional treatment + nimodipine + HBO therapy. The Glasgow Coma Scale (GCS) score and serum tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels were assessed before treatment and at 8, 24, 48 and 72 h after treatment. The bilateral middle cerebral arterial blood flow velocity (VmMCA) was measured by transcranial Doppler ultrasound. The results indicated that serum TNF-α and IL-1β were significantly decreased in all groups at 24, 48 and 72 h after treatment, compared with 8 h after treatment (P<0.05), with Group D exhibiting the largest decrease. The serum TNF-α, IL-1β and VmMCA peaked at 8 h and gradually decreased over the treatment period. VmMCA was decreased in Group B and D compared with Group A and C, and the decrease rate was higher in Group D compared with Group B (P<0.05). GCS scores were significantly increased in all groups at 24, 48 and 72 h after treatment compared with 8 h after treatment (P<0.05), with Group D exhibiting the largest increase. Serum TNF-α and IL-1β levels were positively correlated with VmMCA (P<0.05) and negatively correlated with GCS (P<0.05). Punctate hemorrhage was observed in all groups on CT before treatment, with a value of 66±3 HU. Punctate hemorrhage was observed to decrease over time in CT images, and CT values were significantly decreased in all groups at 8, 24, 48 and 72 h compared with before treatment (P<0.05). CT values were significantly lower in group D compared with groups A, B and C (P<0.05) at all time points. Serum TNF-α and IL-1β levels were positively correlated with CT value (P<0.05). In conclusion, HBO combined with nimodipine exhibited increased efficacy in the treatment of brain injury compared with either treatment alone.

Background/aims: Traumatic brain injury (TBI) is a complex neurological injury in young adults lacking effective treatment. Emerging evidences suggest that inflammation contributes to the secondary brain injury following TBI, including breakdown of the blood brain barrier (BBB), subsequent edema and neurological deterioration. High mobility group box-1 (HMGB1) has been identified as a key cytokine in the inflammation reaction following TBI. Here, we investigated the therapeutic efficacy of HMGB1 A-box fragment, an antagonist competing with full-length HMGB1 for receptor binding, against TBI., Methods: TBI was induced by controlled cortical impact (CCI) in adult male mice. HMGB1 A-box fragment was given intravenously at 2 mg/kg/day for 3 days after CCI. HMGB1 A-box-treated CCI mice were compared with saline-treated CCI mice and sham mice in terms of BBB disruption evaluated by Evan's blue extravasation, brain edema by brain water content, cell death by propidium iodide staining, inflammation by Western blot and ELISA assay for cytokine productions, as well as neurological functions by the modified Neurological Severity Score, wire grip and beam walking tests., Results: HMGB1 A-box reversed brain damages in the mice following TBI. It significantly reduced brain edema by protecting integrity of the BBB, ameliorated cell degeneration, and decreased expression of pro-inflammatory cytokines released in injured brain after TBI. These cellular and molecular effects were accompanied by improved behavioral performance in TBI mice. Notably, HMGB1 A-box blocked IL-1β-induced HMGB1 release, and preferentially attenuated TLR4, Myd88 and P65 in astrocyte cultures., Conclusion: Our data suggest that HMGB1 is involved in CCI-induced TBI, which can be inhibited by HMGB1 A-box fragment. Therefore, HMGB1 A-box fragment may have therapeutic potential for the secondary brain damages in TBI., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Glioblastoma multiforme (GBM) is a highly malignant cancer in the brain with a median survival time of approximately one year. However, the mechanisms underlying GBM development and occurrence are poorly understood. Recently, miRNAs were reported to play important roles in GBM. We performed microRNA profiling by comparing the human GBM cell line T98G and control cell line HCN1A. MicroRNA assays, PCR and Western blot analysis were performed to detect the expressions of microRNAs, mRNAs and proteins of target genes, respectively. Cell migration and invasion assays were conducted. A murine in situ xenograft tumor model was used to evaluate tumor growth in vivo. Glioblastoma tissues were examined to investigate the clinical relevance of our findings. MiR-302d and miR-16 levels were found to be decreased in T98G cells. MiR-302d and miR-16 inhibited the expressions of p65 and FGF2, respectively, by binding to the 3'-UTR of their mRNAs. Over-expression of miR-302d and miR-16 inhibited T98G cell migration and invasion in vitro, and tumorigenesis in the xenograft tumor mouse model in vivo, by suppressing p65 and FGF2. Negative correlations between miR-302d and p65 and between miR-16 and FGF2 were observed in patient glioblastoma tissues. MiR-302d and miR-16 inhibit tumorigenesis by down-regulating p65 and FGF2, which potentially contributes to the treatment of glioblastoma with clinical relevance.

Intracranial hemorrhage (ICH) is a common subtype of stroke with high morbidity and mortality. However, few studies have examined the effects of diabetes on the recovery from ICH-induced brain injury. Therefore, we examined the effects of diabetes on protein levels of aquaporins, neuronal loss, angiogenesis, blood brain barrier (BBB) integrity, and neurological deficits following intra-DH collagenase-induced ICH in the hippocampus. We found that diabetic rats exhibited enhanced AQP9 expression in the hippocampus relative to non-diabetic rats, which was associated with increased behavioral deficits. Additionally, ICH induced neovascularization, proliferation of brain microvascular endothelial cells, and hippocampal neuronal loss. However, ICH-induced neovascularization and proliferation of brain microvascular endothelial cells was severely impaired in diabetic rats. Furthermore, ICH-induced hippocampal neuronal loss was exaggerated in diabetic rats. Finally, ICH impaired BBB integrity in the ipsilateral hemisphere, which was increased in diabetic rats. Taken together, the attenuated brain angiogenesis, increased hippocampal neuronal loss, and impaired BBB integrity in diabetic rats after ICH were associated with enhanced AQP9 expression. This may suggest that AQP9 is one of the underlying mechanisms that can mitigate the recovery from ICH in diabetic populations., (Copyright © 2016. Published by Elsevier B.V.)

Cerebral aneurysm is a bulging of the artery inside the brain that results from a weakened or thin area of the artery wall. Ruptured cerebral aneurysm could lead to serious brain damage or even death, thus the proper treatment is essential. Compared with the conventional microsurgical clipping approach, the endovascular coiling treatment has many advantages, however, with a major disadvantage of high recurrence rate. One way to lower the recurrence rate, which has been tried since one decade ago, is to modify the coil to be bioactive and releasing biological molecules to stimulate tissue ingrowth and aneurysm healing. We have identified three candidates including osteopontin (OPN), IL-10 and matrix metallopeptidase 9 (MMP-9) from previous studies and generated platinum coils coated with these proteins in the carrier of poly-DL-lactic glycolic acid (PLGA). We were interested to know whether coils coated with OPN, IL-10 and MMP-9 were able to promote aneurysm healing and we have tested it in the rat carotid aneurysm model. We found that OPN and IL-10 coated coils had shown significant improvement in tissue ingrowth while MMP-9 coated coils failed to enhance tissue ingrowth compared with the control group. Our studies suggested the possible application of OPN and IL-10 coated coils in aneurysm treatment to overcome the recurrence., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Resveratrol is a naturally occurring phytoalexin found in red grapes, and believed to have neuroprotective, anti-oxidant, and anti-inflammatory effects. But little is known about its effect on the neural impairments induced by microglial over-activation, which leads to neuroinflammation and multiple pathophysiological damages. In this study, we aimed to investigate the protective effects of resveratrol on the impairments of neural development by microglial over-activation insult. The results indicated that resveratrol inhibited the lipopolysaccharide (LPS)-dependent release of cytokines from activated microglia and LPS-dependent changes in NF-κB signaling pathway. Conditioned medium (CM) from activated microglia treated by resveratrol directly protected primary cultured hippocampal neurons against LPS-CM-induced neuronal death, and restored the inhibitory effects of LPS-CM on dendrite sprouting and outgrowth. Finally, neurons cultured in CM from LPS-stimulated microglia treated by resveratrol exhibited increased spine density compared to those without resveratrol treatment. Our findings support that resveratrol inhibits microglial over-activation and alleviates neuronal injuries induced by microglial activation. Our study suggests the use of resveratrol as an alternative intervention approach that could prevent further neuronal insults.

Human glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Fibroblast growth factor-2 (FGF2) belongs to the FGF superfamily and functions as a potential oncoprotein in GBM. FGF2 has low molecular weight (18K) and high molecular weight (HMW) isoforms. Nuclear accumulation of HMW-FGF2 strongly promotes glioblastoma cell proliferation, yet mechanism governing such cellular distribution remains unexplored. We investigated the mechanisms regulating FGF2 cellular localization in T98G human brain glioblastoma cells. We found HMW-FGF2, but not 18K-FGF2, is primarily located in the nucleus and interacts with nuclear transport protein Karyopherin-β2/Transportin (Kapβ2). SiRNA-directed Kapβ2 knockdown significantly reduced HMW-FGF2's nuclear translocation. Moreover, inhibiting Ran GTPase activity also resulted in decreased HMW-FGF2 nuclear accumulation. Proliferation of T98G cells is greatly enhanced with transfections HMW-FGF2. Decreased PTEN expression and activated Akt signaling were observed upon HMW-FGF2 overexpression and might mediate pro-survival effect of FGF2. Interestingly, addition of nuclear localization signal (NLS) to 18K-FGF2 forced its nuclear import and dramatically increased cell proliferation and Akt activation. These findings demonstrated for the first time the molecular mechanisms for FGF2's nuclear import, which promotes GBM cell proliferation and survival, providing novel insights to the development of GBM treatments.

Subarachnoid hemorrhage (SAH) is a life-threatening disease that causes high morbidity and mortality. Pirfenidone is a SAH drug that prevents secondary bleeding and cerebral infarction. To improve its therapeutic efficacy, this study aimed to employ a functionalized graphene oxide nanosheet (FGO) as a drug carrier loading pirfenidone to treat SAH. The graphene oxide nanosheet was introduced with transcription activator peptide (Tat), followed by functionalization with methoxy polyethylene glycol (mPEG) and loading with pirfenidone. The pirfenidone-loaded FGO (pirfenidone-FGO) exhibits better treatment efficacy than the single pirfenidone due to more effective loading and controlled release of the drug in tissue. The introduction of Tat and mPEG onto GO nanosheet contributes to the ability to cross the blood-brain barrier and the stability in blood circulation of the drug. At lower pH values, the highly efficient release of the drug from the pirfenidone-FGO exerts effective treatment to acidic inflammatory lesion after severe SAH. Besides its treatment function, FGO is also shown as a strong near infrared absorbing material which can be applied in photoacoustic imaging, allowing rapid real-time monitoring with deep resolution of brain tissues after SAH. The treatment efficacy of pirfenidone-FGO for central nervous system injuries is further demonstrated by hematoxylin and eosin staining of coronal brain slices, as well as measurements of brain water content and blood-brain barrier permeability. Our study supports the potential of FGO in clinical application in treatment of SAH., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In this study, we examined the effectiveness of percutaneous injected fibrin glue as a treatment for frontal sinus cerebrospinal fluid (CSF) rhinorrhea in a series of 4 cases. All 4 patients had fracture in the posterior wall of the frontal sinus. The anterior wall of the frontal sinus was punctured following high-resolution computed tomography imaging. In 3 out of 4 patients with defective skull due to prior frontal craniotomy, direct percutaneous puncture of the frontal sinus was used. Fibrin glue was injected to close the fistula and to seal the rhinorrhea. Surgery procedures lasted for 15-35 minutes (average 27.6 min). Rhinorrhea was stopped in all patients after the surgery, with no recurrence at a 10-month follow-up visit. In 1 case, the glue was expelled by coughing at 2 days after the surgery but was completely stopped with no recurrence after a second attempt. One patient with no recurrence at a 10-month follow-up died of tumor relapse at 12 months. In summary, fibrin glue could be used as a novel treatment for frontal sinus CSF rhinorrhea.