Self-assembled metal-phenolic nanocomplexes comprised of green tea catechin for tumor-specific ferroptosis.

Ferroptosis, a newly discovered form of regulated cell death, has garnered significant attention in the field of tumor therapy. However, the presence of overexpressed glutathione (GSH) and insufficient levels of H2O2 in the tumor microenvironment (TME) hinders the occurrence of ferroptosis. In response to these challenges, here we have constructed the self-assembled nanocomplexes (FeE NPs) utilizing epigallocatechin-3-gallate (EGCG) from green tea polyphenols and metal ions (Fe3+) as components. After grafting PEG, the nanocomplexes (FeE@PEG NPs) exhibit good biocompatibility and synergistically enhanced tumor-inhibitory properties. FeE@PEG NPs can be disassembled by H2O2 in the TME, leading to the rapid release of Fe3+ and EGCG. The released Fe3+ produces large amounts of toxic •OH by the Fenton reactions while having minimal impact on normal cells. The generated •OH effectively induces lipid peroxidation, which leads to ferroptosis in tumor cells. Meanwhile, the released EGCG can autoxidize to produce H2O2, which further promotes the production of •OH radicals and increases lipid peroxide levels. Moreover, EGCG also depletes the high levels of intracellular GSH, leading to an intracellular redox imbalance and triggering ferroptosis. This study provides new insights into advancing anticancer ferroptosis through rational material design, offering promising avenues for future research.

Clinical features, surgical treatment, and long-term outcomes of moyamoya disease in a single institution of Fujian, Southeast China: A retrospective study.

At present, detailed demographic and clinical data of moyamoya disease (MMD) in the population of Southeast China are lacking. Therefore, this study aimed to evaluate the epidemiological and clinical features of MMD in Southeast China. Our cohort included 170 patients diagnosed with MMD over the preceding 5 years. Clinical characteristics were obtained through a retrospective chart review, while follow-up information and outcomes were obtained through clinical visits and imaging. The median age at symptom onset was 49 years (range 4-73), with a peak in the age distribution observed at 41 to 60 years. The female-to-male ratio was 1.125 (90/80), and the ratio of the ischemic type to the hemorrhagic type was 2.33 (119/50). The most common initial symptom was an ischemic event. The 5-year Kaplan-Meier risk of stroke was 4.9% for all patients treated with surgical revascularization. Of all patients, 83.9% were able to live independently with no significant disability, and 89.8% showed improved cerebral hemodynamics. Our study provided detailed demographic and clinical data on Southeastern Chinese patients with MMD, which was consistent with findings in other parts of China. Raising clinical awareness of MMD in primary hospitals is important to facilitate early diagnosis and timely treatment of MMD patients.

Schisandrin B Protects against Ischemic Brain Damage by Regulating PI3K/AKT Signaling in Rats.

OBJECTIVE: To explore the effect and mechanism of schisandrin B (Sch B) in the treatment of cerebral ischemia in rats. METHODS: The cerebral ischemia models were induced by middle cerebral artery occlusion (MCAO) and reperfusion. Sprague-Dawley rats were divided into 6 groups using a random number table, including sham, MCAO, MCAO+Sch B (50 mg/kg), MCAO+Sch B (100 mg/kg), MCAO+Sch B (100 mg/kg)+LY294002, and MCAO+Sch B (100 mg/kg)+wortmannin groups. The effects of Sch B on pathological indicators, including neurological deficit scores, cerebral infarct volume, and brain edema, were subsequently studied. Tissue apoptosis was identified by terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining. The protein expressions involved in apoptosis, inflammation response and oxidative stress were examined by immunofluorescent staining, biochemical analysis and Western blot analysis, respectively. The effect of Sch B on phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling was also explored. RESULTS: Sch B treatment decreased neurological deficit scores, cerebral water content, and infarct volume in MCAO rats (P<0.05 or P<0.01). Neuronal nuclei and TUNEL staining indicated that Sch B also reduced apoptosis in brain tissues, as well as the Bax/Bcl-2 ratio and caspase-3 expression (P<0.01). Sch B regulated the production of myeloperoxidase, malondialdehyde, nitric oxide and superoxide dismutase, as well as the release of cytokine interleukin (IL)-1 ß and IL-18, in MCAO rats (P<0.05 or P<0.01). Sch B promoted the phosphorylation of PI3K and AKT. Blocking the PI3K/AKT signaling pathway with LY294002 or wortmannin reduced the protective effect of Sch B against cerebral ischemia (P<0.05 or P<0.01). CONCLUSIONS: Sch B reduced apoptosis, inflammatory response, and oxidative stress of MCAO rats by modulating the PI3K/AKT pathway. Sch B had a potential for treating cerebral ischemia.

GLP-1R knockdown abrogates the protective effects of liraglutide on ischaemic stroke via inhibition of M2 polarisation and activation of NLRP3 inflammasome by reducing Nrf2 activation.

Liraglutide has been recently discovered to penetrate the blood-brain barrier to exert neuroprotective effects. However, relevant mechanisms of the protective effects of liraglutide on ischaemic stroke remain to be elucidated. This study examined the mechanism of GLP-1R in regulating the protective effect of liraglutide against ischaemic stroke. Middle cerebral artery occlusion (MCAO) male Sprague-Dawley rat model with/without GLP-1R or Nrf2 knockdown was established and subjected to liraglutide treatment. Then neurological deficit and brain oedema of rats was evaluated and brain tissues were subjected to TTC, Nissl, TUNEL and immunofluorescence staining. Rat primary microglial cells firstly underwent lipopolysaccharide (LPS) treatment, then GLP-1R or Nrf2 knockdown treatment, and finally Liraglutide treatment to research the NLRP3 activation. As a result, Liraglutide protected rats' brain tissues after MCAO, which attenuated brain oedema, infarct volume, neurological deficit score, neuronal apoptosis and Iba1 expression but enhanced live neurons. However, GLP-1R knockdown abrogated these protective effects of liraglutide on MCAO rats. According to in vitro experiments, Liraglutide promoted M2 polarisation, activated Nrf2 and inhibited NLRP3 activation in LPS-induced microglial cells, but GLP-1R or Nrf2 knockdown reversed these effects of Liraglutide on LPS-induced microglial cells. Further, Nrf2 knockdown counteracted the protection of liraglutide on MCAO rats, whereas sulforaphane (agonist of Nrf2) counteracted the effect of Nrf2 knockdown on liraglutide-treated MCAO rats. Collectively, GLP-1R knockdown abrogated the protection of liraglutide on MCAO rats by activating NLRP3 via inactivating Nrf2.

Assessment of bypass patency using transcranial Doppler sonography: correlations with computerized tomography angiography findings in patients with moyamoya disease.

To explore the utility of transcranial Doppler (TCD) findings when assessing bypass patency in patients with Moyamoya disease (MMD). Computed tomography angiography (CTA) and TCD sonography (TCDS) were performed before and after surgery to evaluate bypass patency. The peak systolic flow velocity (PSV) of the superficial temporal artery (STA) and the pulsatility index (PI) were compared between the groups that achieved patency and not, and receiver operating characteristic (ROC) curve analyses were used to define the TCDS criteria revealing patency. This study included 35 hemispheres (15 women; mean age 47 years) with Moyamoya disease who underwent STA-middle carotid artery bypass in our institution between January 2022 and October 2022. The PSV first increased on postoperative days 4-5 and then decreased on postoperative days 6-7 and 7-8. Patients with transient neurological diseases (TNDs), compared to those without, evidenced a significantly lower PSV value (P < 0.05). Compared with the non-patency group, the PSV was higher (P < 0.001) in the patency group. The cutoff values reflecting patency with good sensitivity and specificity were PSV > 49.00; PSV ratio (postoperative/preoperative) > 1.218; PSV ratio (operation side/contralateral side) > 1.082; and PSV ratio (adjusted) > 1.202. In the patency group, the PSV and PI significantly increased (P < 0.001) and decreased (P < 0.001) respectively. Bypass patency can be noninvasively and accurately evaluated via TCDS, affording an objective basis for assessment of the effect of revascularization surgery on patients with MMD.

Multifunctional Hollow MnO2 @Porphyrin@Bromelain Nanoplatform for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) has been showing great potential in cancer treatment. However, the efficacy of PDT is always limited by the intrinsic hypoxic tumor microenvironment (TME) and the low accumulation efficiency of photosensitizers in tumors. To address the issue, a multifunctional hollow multilayer nanoplatform (H-MnO2 @TPyP@Bro) comprising manganese dioxide, porphyrin (TPyP) and bromelain (Bro), is developed for enhanced photodynamic therapy. MnO2 catalyzes the intracellular hydrogen peroxide (H2 O2 ) to produce oxygen (O2 ), reversing the hypoxic TME in vivo. The generated O2 is converted into singlet oxygen (1 O2 ) by the TPyP shell under near-infrared light, which can inhibit tumor proliferation. Meanwhile, the Bro can digest collagen in the extracellular matrix around the tumor, and can promote the accumulation of H-MnO2 @TPyP@Bro in the deeper tumor tissue, further improving the therapeutic effect of PDT. In addition, MnO2 can react with the overexpressed glutathione in TME to release Mn2+ . Consequently, Mn2+ not only induces chemo-dynamic therapy based on Fenton reaction by converting H2 O2 into hydroxyl radicals, but also activates the Mn2+ -based magnetic resonance imaging. Therefore, the developed H-MnO2 @TPyP@Bro nanoplatform can effectively modulate the unfavorable TME and overcome the limitations of conventional PDT for cancer diagnostic and therapeutic.

Research progress on postoperative transient neurological dysfunction in pediatric and adult patients with moyamoya disease after revascularization surgery.

Moyamoya disease (MMD) is characterized by occlusion of the internal carotid artery (ICA) and its terminal branches, leading to compromised cerebral perfusion. Surgical revascularization is an effective therapy to improve cerebral hemodynamic. Transient neurological dysfunction (TND) usually occurs early after surgery and resolved within a few weeks without permanent neurologic deficit. In this article, we have reviewed the clinical features, mechanisms, and factors about TND in both pediatric and adult MMD patient.

A procedurally activatable nanoplatform for chemo/chemodynamic synergistic therapy.

Responsive nano-drug delivery systems, especially multi-responsive systems, based on the complex characteristics of the tumor microenvironment (TME), such as acidic pH, hypoxia, and hydrogen peroxide (H2O2) overexpression, could enhance the biological activity of the drugs and reduce the side effects. In this study, a H2O2/glutathione (GSH) procedurally activatable nanoplatform (Cu9S5-PEG/DOX NSs) was prepared as a vector of drugs released by responsive morphologic transformation and the co-activated Fenton agent for tumor-specific synergistic therapy. After endocytosis into tumor cells, Cu9S5-PEG/DOX NSs were initially oxidized by over-expressed H2O2 and transformed from nanosheets to nanoflowers, leading to the release of doxorubicin (DOX). Subsequently, Cu9S5 nanoflowers (Cu9S5 NFs) reacted with the local GSH, liberated a large number of copper ions, and induced GSH depletion. The released DOX promoted the generation of intracellular H2O2 through cascade reactions, which were further utilized to facilitate the release of DOX and generate toxic hydroxyl radicals (˙OH) via a copper-based Fenton-like reaction. Cu9S5-PEG/DOX NSs sequentially activated by H2O2 and GSH in tumor cells exhibited relatively high cytotoxicity, whereas normal cells were still alive. This nanoplatform, as a procedurally activatable delivery system, may have excellent potential for tumor-specific synergistic therapy.

Schisandrin B Inhibits NLRP3 Inflammasome Pathway and Attenuates Early Brain Injury in Rats of Subarachnoid Hemorrhage.

OBJECTIVE: To determine whether Schisandrin B (Sch B) attenuates early brain injury (EBI) in rats with subarachnoid hemorrhage (SAH). METHODS: Sprague-Dawley rats were divided into sham (sham operation), SAH, SAH+vehicle, and SAH+Sch B groups using a random number table. Rats underwent SAH by endovascular perforation and received Sch B (100 mg/kg) or normal saline after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evan's blue extravasation, and terminal transferase-mediated dUTP nick end-labeling (TUNEL) staining were carried out 24 h after SAH. Immunofluorescent staining was performed to detect the expressions of ionized calcium binding adapter molecule 1 (Iba-1) and myeloperoxidase (MPO) in the rat brain, while the expressions of B-cell lymphoma 2 (Bcl-2), Bax, Caspase-3, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis-associated specklike protein containing the caspase-1 activator domain (ASC), Caspase-1, interleukin (IL)-1ß, and IL-18 in the rat brains were detected by Western blot. RESULTS: Compared with the SAH group, Sch B significantly improved the neurological function, reduced brain water content, Evan's blue content, and apoptotic cells number in the brain of rats (P<0.05 or P<0.01). Moreover, Sch B decreased SAH-induced expressions of Iba-1 and MPO (P<0.01). SAH caused the elevated expressions of Bax, Caspase-3, NLRP3, ASC, Caspase-1, IL-1ß, and IL-18 in the rat brain (P<0.01), all of which were inhibited by Sch B (P<0.01). In addition, Sch B increased the Bcl-2 expression (P<0.01). CONCLUSION: Sch B attenuated SAH-induced EBI, which might be associated with the inhibition of neuroinflammation, neuronal apoptosis, and the NLRP3 inflammatory signaling pathway.

LncRNA CEBPA-AS1 alleviates cerebral ischemia-reperfusion injury by sponging miR-340-5p regulating APPL1/LKB1/AMPK pathway.

Long non-coding RNAs (lncRNAs) regulate neurological damage in cerebral ischemia-reperfusion injury (CIRI). This study aimed to investigate the biological roles of lncRNA CEBPA-AS1 in CIRI. Middle cerebral artery occlusion and ischemia-reperfusion injury (MCAO/IR) rat model and oxygen-glucose deprivation and reoxygenation (OGD/R) cell lines were generated; the expression of CEBPA-AS1 was evaluated by qRT-PCR. The effects of CEBPA-AS1 on cell apoptosis and nerve damage were examined. The downstream microRNA (miRNA) and mRNA of CEBPA-AS1 were predicted and verified. We found that overexpression of CEBPA-AS1 could attenuate MCAO/IR-induced nerve damage and neuronal apoptosis in the rat model. Knockdown of CEBPA-AS1 aggravated cell apoptosis and enhanced the production of LDH and MDA in the OGD/R cells. Upon examining the molecular mechanisms, we found that CEBPA-AS1 stimulated APPL1 expression by combining with miR-340-5p, thereby regulating the APPL1/LKB1/AMPK pathway. In the rescue experiments, CEBPA-AS1 overexpression was found to attenuate OGD/R-induced cell apoptosis and MCAO/IR induced nerve damage, while miR-340-5p reversed these effects of CEBPA-AS1. In conclusion, CEBPA-AS1 could decrease CIRI by sponging miR-340-5, regulating the APPL1/LKB1/AMPK pathway.

GLP-1R Agonist Liraglutide Attenuates Inflammatory Reaction and Neuronal Apoptosis and Reduces Early Brain Injury After Subarachnoid Hemorrhage in Rats.

Liraglutide, one of the glucagon-like peptide 1 receptor (GLP-1R) agonists, has been demonstrated to protect brain damage produced by ischemic stroke. However, it remains unknown whether liraglutide attenuates early brain injury after subarachnoid hemorrhage. The present study was performed to explore the effect of liraglutide on early brain injury after subarachnoid hemorrhage in rats, and further investigate the potential mechanisms. Sprague-Dawley rats underwent subarachnoid hemorrhage (SAH) by endovascular perforation, then received subcutaneous injection with liraglutide (50 or 100 µg/kg) or vehicle after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, and Evans Blue extravasation were measured 24 h after SAH. Immunofluorescent staining was performed to detect the extent of microglial activation in rat brain 24 h after SAH. TUNEL staining was performed to evaluate neuronal apoptosis in rat brain of SAH. Expression of GLP-1R, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), Bcl-2, Bax, and cleaved caspase-3 in rat brain were determined by western blot. Expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in rat brain was assessed by ELISA. Neurological dysfunction, brain water content, Evans Blue extravasation, microglial activation, and neuronal apoptosis were significantly reduced by GLP-1R agonist liraglutide. Expression of GLP-1R in rat brain was decreased after SAH, which is significantly elevated by liraglutide. Expression of inflammatory mediates like COX-2, iNOS, TNF-α, and IL-1ß was increased after SAH, which were significantly inhibited by liraglutide. Furthermore, SAH caused the elevated expression of pro-apoptotic factors Bax and cleaved caspase-3 in rat brain, both of which were inhibited by liraglutide. In addition, liraglutide reversed the expression of anti-apoptotic protein Bcl-2. Our results demonstrated that liraglutide reduces early brain injury and attenuates inflammatory reaction and neuronal apoptosis in rats of SAH. Liraglutide provides neuroprotection against SAH, which might be associated with the inhibition of inflammation and apoptosis.

Use of siphon irrigation during burr-hole craniostomy to evacuate chronic subdural hematoma: A retrospective cohort comparison study.

Burr-hole craniostomy (BHC) is a widely accepted treatment for chronic subdural hematomas (CSDHs). This study adopted siphon irrigation to evacuate CSDHs and investigated its efficacy and safety as compared with the traditional irrigation used in BHC.A retrospective cohort study was conducted at a center between January 2017 and December 2018. The data of 171 patients who underwent burr-hole craniostomy for CSDH were collected and analyzed. A total of 68 patients underwent siphon irrigation (siphon group) and 103 patients were treated by a traditional method (control group). A follow-up was conducted 6 months after the surgery.No significant difference was observed in the baseline characteristics and preoperative computed tomography (CT) features of the 2 groups (P > .05). The postoperative CT features of the siphon group, which included the volume of hematoma evacuation (P = .034), hematoma evacuation rate (P < .001), recovery rate of the midline shift (P = .017), and occurrence of pneumocephalus (P = .037) were significantly different and better than those of the control group. The length of hospital stay after surgery of the siphon group was significantly shorter than that of the control group (P = .015). The Markwalder score of the siphon group was significantly superior to that of the control group on postoperative day 1 (P = .006). Although the recurrence rate in the siphon group (2/68, 2.5%) was lower than that in the control group (11/103, 8.9%), no statistically significant difference was observed between them (P = .069). Moreover, no significant differences were observed in terms of complications and mortality rate between the 2 groups.There was no significant difference in the recurrence rate between the groups that underwent siphon irrigation and traditional irrigation. However, in comparison, siphon irrigation can better improve postoperative CT features, promote early recovery of neurological dysfunction after surgery, and shorten the length of hospital stay. This indicates that siphon irrigation may be a better therapeutic option in BHC for CSDH.

Baicalin Reduces Early Brain Injury after Subarachnoid Hemorrhage in Rats.

OBJECTIVE: To evaluate the effect of baicalin on subarachnoid hemorrhage (SAH) in rats and explore the potential mechanisms. METHODS: Sprague-Dawley rats underwent experimental SAH and received treatment with baicalin at 10 or 50 mg/kg after 2 and 12 h of SAH. Neurological scores, brain water content, Evans-blue extravasation, and levels of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), myeloperoxidase (MPO), and malondialdehyde (MDA) were measured 24 h after SAH. Expression of nuclear factor erythroid-related factor 2 (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), matrix metalloproteinase-9 (MMP-9), aquaporin 4 (AQP4), occludin, and zonulaoccludens-1 (ZO-1) were detected in the brain by Western blot. Heme oxygenase-1 (HO-1) was detected by quantitative polymerase chain reaction, and tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were assessed by enzyme-linked immunosorbent assay. RESULTS: Baicalin attenuated EBI 24 h after SAH in rats (P<0.05). Baicalin elevated neurological scores, GSH-Px, SOD, and increased the expression of Nrf2, NQO1, HO-1, occludin, and ZO-1 in SAH rats (P<0.05 or P<0.01). Baicalin reduced MPO, MDA, and the expression of MMP-9, AQP4, TNF-α, and IL-1ß (P<0.05 or P<0.01). CONCLUSION: Baicalin reduced SAH-induced EBI, partially via activation of the Nrf2/HO-1 pathway and inhibition of MMP-9 and AQP4.

Propofol Reduces Inflammatory Brain Injury after Subarachnoid Hemorrhage: Involvement of PI3K/Akt Pathway.

BACKGROUND: Our previous study showed that propofol, one of the widely used anesthetic agents, can attenuate subarachnoid hemorrhage (SAH)-induced early brain injury (EBI) via inhibiting inflammatory and oxidative reaction. However, it is perplexing whether propofol attenuates inflammatory and oxidative reaction through modulating PI3K/Akt pathway. The present study investigated whether PI3K/Akt pathway is involved in propofol's anti-inflammation, antioxidation, and neuroprotection against SAH-induced EBI. MATERIALS AND METHODS: Adult Sprague-Dawley rats underwent SAH and received treatment with propofol or vehicle after 2 and 12 hours of SAH. LY294002 was injected intracerebroventricularly to selectively inhibit PI3K/Akt signaling. Mortality, SAH grading, neurological scores, brain water content, evans blue extravasation, myeloperoxidase, malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured 24 hours after SAH. Immunoreactivity of p-Akt, t-Akt, nuclear factor- kappa B (NF-κB) p65, nuclear factor erythroid-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase (NQO1), and cyclooxygenase-2 (COX-2) in rat brain was determined by western blot. Tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in rat brain were examined by ELISA. RESULTS: Propofol significantly reduces neurological dysfunction, BBB permeability, brain edema, inflammation, and oxidative stress, all of which were reversed by LY294002. Propofol significantly upregulates the immunoreactivity of p-Akt, Nrf2, and NQO1, all of which were abolished by LY294002. Propofol significantly downregulates the overexpression of NF-κB p65, COX-2, TNF-α, and IL-1ß, all of which were inhibited by LY294002. CONCLUSION: These results suggest that propofol attenuates SAH-induced EBI by inhibiting inflammatory reaction and oxidative stress, which might be associated with the activation of PI3K/Akt signaling pathway.

Resveratrol downregulates the TLR4 signaling pathway to reduce brain damage in a rat model of focal cerebral ischemia.

Previous studies have demonstrated that inflammation and disruption of the blood-brain barrier (BBB) are important pathological processes during focal cerebral ischemia. Therefore, the present study evaluated the neuroprotective effects of resveratrol against brain damage, inflammation and BBB disruption in rats with focal cerebral ischemia and assessed the potential underlying molecular mechanisms. Sprague-Dawley rats underwent cerebral ischemia/reperfusion (IR) and then received intraperitoneal resveratrol (10 and 100 mg/kg) 2 h following the onset of ischemia. Following 24 h of ischemia, neurological deficit scores, cerebral infarctions, morphological characteristics, cerebral water content, myeloperoxidase (MPO) activity and Evans blue extravasation were assessed. Additionally, the protein expression levels of Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB p65 were detected using western blot analyses, the mRNA expression levels of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) were examined by reverse-transcription polymerase chain reaction, and tumor necrosis factor (TNF)-α and interleukin (IL)-1ß blood levels were determined by ELISA. Resveratrol significantly reduced neurological deficit scores, cerebral infarct sizes, neuronal injury, MPO activity and EB content. Cerebral ischemia increased the expression levels of TLR4, NF-κB p65, COX-2, MMP-9, TNF-α and IL-1ß, but all of these factors were reduced by resveratrol. In conclusion, the present data suggest that resveratrol reduces inflammation, BBB disruption and brain damage in rats following focal cerebral ischemia. Additionally, the neuroprotective effects of resveratrol against cerebral ischemia may be associated with downregulation of the TLR4 pathway.

Uneven cerebral hemodynamic change as a cause of neurological deterioration in the acute stage after direct revascularization for moyamoya disease: cerebral hyperperfusion and remote ischemia caused by the 'watershed shift'.

Superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is the standard surgical treatment for moyamoya disease (MMD). The main potential complications of this treatment are cerebral hyperperfusion (CHP) syndrome and ischemia, and their managements are contradictory to each other. We retrospectively investigated the incidence of the simultaneous manifestation of CHP and infarction after surgery for MMD. Of the 162 consecutive direct revascularization surgeries performed for MMD, we encountered two adult cases (1.2%) manifesting the simultaneous occurrence of symptomatic CHP and remote infarction in the acute stage. A 47-year-old man initially presenting with infarction developed CHP syndrome (aphasia) 2 days after left STA-MCA anastomosis, as assessed by quantitative single-photon emission computed tomography (SPECT). Although lowering blood pressure ameliorated his symptoms, he developed cerebral infarction at a remote area in the acute stage. Another 63-year-old man, who initially had progressing stroke, presented with aphasia due to focal CHP in the left temporal lobe associated with acute infarction at the tip of the left frontal lobe 1 day after left STA-MCA anastomosis, when SPECT showed a paradoxical decrease in cerebral blood flow (CBF) in the left frontal lobe despite a marked increase in CBF at the site of anastomosis. Symptoms were ameliorated in both patients with the normalization of CBF, and there were no further cerebrovascular events during the follow-up period. CHP and cerebral infarction may occur simultaneously not only due to blood pressure lowering against CHP, but also to the 'watershed shift' phenomenon, which needs to be elucidated in future studies.

miR-204 suppresses the development and progression of human glioblastoma by targeting ATF2.

In human cancers, miRNAs are important regulators of multiple cellular processes, and aberrant miRNA expression has been observed, and their alterations contribute to multiple cancer development and progression. Till now, little has been known about the role of miR-204 in human glioblastoma (GBM). In the present study, we used in-vitro assays to investigate the mechanisms of miR-204 in GBM cell lines and 60 cases of GBM tissues. Here, we found that miR-204 expression is downregulated in both GBM cell lines A172, U87 and U251 cells and GBM tissues as compared with NHA cells and normal tissues (all p<0.001). In addition, the ectopic expression of miR-204 suppressed A172 and U87 cell proliferation, migration and invasion. Meanwhile, miR-204 over-expression extremely inhibited the protein expression of ATF2. Notably, the enforced expression of ATF2 in A172 and U87 cells with the over-expression of miR-204 attenuated the inhibitory effects of miR-204 on proliferation, migration and invasion. In conclusion, our findings suggest that miR-204 suppressed cell proliferation, migration and invasion through inhibition of ATF2, thus, miR-204 may function as a useful drug target in the treatment and diagnosis of GBM.

5-LOX Inhibitor Zileuton Reduces Inflammatory Reaction and Ischemic Brain Damage Through the Activation of PI3K/Akt Signaling Pathway.

Previous studies from our laboratories showed that an anti-inflammatory drug, 5-lipoxygenase inhibitor zileuton, attenuates ischemic brain damage via inhibiting inflammatory reaction. However, it was elusive whether zileuton attenuates inflammatory reaction and ischemic brain damage through the modulation of PI3K/Akt signaling pathway. In the present study, we, for the first time, investigated whether PI3K/Akt pathway was involved in zileuton's anti-inflammatory and neuroprotective properties against brain damage following experimental ischemic stroke. Adult male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO), then received treatment with zileuton or vehicle after the onset of ischemia. LY294002 was injected intracerebroventricularly to inhibit the activation of PI3K/Akt signaling pathway selectively. Neurological deficit scores, cerebral infarct volume, morphological characteristic and cerebral water content were assessed 24 h after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expression of p-Akt, t-Akt and COX-2 in ischemic brain were determined by western blot. NF-κB p65 immuno-positive cells in ischemic brain were detected 24 h after cerebral ischemia. The content of TNF-α in blood was examined by ELISA. 5-LOX inhibitor zileuton significantly reduces neurological deficit scores, cerebral infarct volume, cerebral water content, ischemic neuronal injury and the enzymatic activity of MPO, all of which were abolished by LY294002 administration. Zileuton significantly up-regulates the expression of p-Akt, which was inhibited by LY294002 administration. Zileuton significantly down-regulates the over-expression of NF-κB p65 and COX-2, and attenuates the release of TNF-α, all of which were disminished by LY294002 administration. These results suggest that zileuton attenuates ischemic brain damage by inhibiting inflammatory reaction through the activation of PI3K/Akt signaling pathway.

Propofol Attenuates Early Brain Injury After Subarachnoid Hemorrhage in Rats.

Our previous studies demonstrated that propofol protects rat brain against focal cerebral ischemia. However, whether propofol attenuates early brain injury after subarachnoid hemorrhage in rats remains unknown until now. The present study was performed to evaluate the effect of propofol on early brain injury after subarachnoid hemorrhage in rats and further explore the potential mechanisms. Sprague-Dawley rats underwent subarachnoid hemorrhage (SAH) by endovascular perforation then received treatment with propofol (10 or 50 mg/kg) or vehicle after 2 and 12 h of SAH. SAH grading, neurological scores, brain water content, Evans blue extravasation, the myeloperoxidase activity, and malondialdehyde (MDA) content were measured 24 h after SAH. Expression of nuclear factor erythroid-related factor 2 (Nrf2), nuclear factor-kappa B (NF-κB) p65, and aquaporin 4 (AQP4) expression in rat brain were detected by Western blot. Expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) were determined by reverse transcription-polymerase chain reaction (RT-PCR). Expressions of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were assessed by ELISA. Neurological scores, brain water content, Evans blue extravasation, the myeloperoxidase activity, and MDA content were significantly reduced by propofol. Furthermore, expression of Nrf2 in rat brain was upregulated by propofol, and expression of NF-κB p65, AQP4, COX-2, MMP-9, TNF-α, and IL-1ß in rat brain were attenuated by propofol. Our results demonstrated that propofol improves neurological scores, reduces brain edema, blood-brain barrier (BBB) permeability, inflammatory reaction, and lipid peroxidation in rats of SAH. Propofol exerts neuroprotection against SAH-induced early brain injury, which might be associated with the inhibition of inflammation and lipid peroxidation.

Repetitive ischemic preconditioning attenuates inflammatory reaction and brain damage after focal cerebral ischemia in rats: involvement of PI3K/Akt and ERK1/2 signaling pathway.

Ischemic preconditioning (IPC) has been demonstrated to provide a neuroprotection against brain damage produced by focal cerebral ischemia. However, it is elusive whether ischemic preconditioning attenuates ischemic brain damage through modulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. In the present study, we first explored the best scheme of repetitive ischemic preconditioning (RIPC) to protect rat brain against ischemic damage and then further investigated the underlying mechanisms in RIPC's neuroprotection. Adult male Sprague-Dawley rats underwent ischemic preconditioning or (and) middle cerebral artery occlusion (MCAO). LY294002 or (and) PD98059 were injected intracerebroventricularly to selectively inhibit the activation of PI3K/Akt or ERK1/2. Neurological deficit scores, cerebral infarct volume, and morphological characteristic were detected at corresponding time after cerebral ischemia. The enzymatic activity of myeloperoxidase (MPO) was measured 24 h after cerebral ischemia. Expressions of p-Akt, t-Akt, p-ERK1/2, t-ERK1/2, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in ischemic brain were determined by Western blot. The release of tumor necrosis factor-α (TNF-α) in blood was examined by ELISA. In the various schemes of RIPC, IPC2 × 5 min causes less neuronal damage in the cortex and subcortex of ischemic brain and provides an obvious alleviation of cerebral infarction and neurological deficit after lethal ischemia. IPC2 × 5 min significantly reduces cerebral infarct volume, neurological deficit scores, and MPO activity; all of which were diminished by LY294002 or (and) PD98059. IPC2 × 5 min significantly upregulates the expressions of p-Akt and p-ERK1/2, which were inhibited by LY294002 or (and) PD98059. IPC2 × 5 min significantly downregulates the expressions of NF-κB p65 and COX-2 and attenuates the release of TNF-α; all of which were abolished by LY294002 or (and) PD98059. IPC2 × 5 min is the best scheme of RIPC to protect rat brain against cerebral ischemia. IPC2 × 5 min attenuates brain damage in rats subjected to lethal ischemia, and this neuroprotection is associated with inhibition of neuroinflammation through modulating PI3K/Akt and ERK1/2 signaling pathway.