Steering lithium and potassium storage mechanism in covalent organic frameworks by incorporating transition metal single atoms.

Organic electrodes mainly consisting of C, O, H, and N are promising candidates for advanced batteries. However, the sluggish ionic and electronic conductivity limit the full play of their high theoretical capacities. Here, we integrate the idea of metal-support interaction in single-atom catalysts with π-d hybridization into the design of organic electrode materials for the applications of lithium (LIBs) and potassium-ion batteries (PIBs). Several types of transition metal single atoms (e.g., Co, Ni, Fe) with π-d hybridization are incorporated into the semiconducting covalent organic framework (COF) composite. Single atoms favorably modify the energy band structure and improve the electronic conductivity of COF. More importantly, the electronic interaction between single atoms and COF adjusts the binding affinity and modifies ion traffic between Li/K ions and the active organic units of COFs as evidenced by extensive in situ and ex situ characterizations and theoretical calculations. The corresponding LIB achieves a high reversible capacity of 1,023.0 mA h g-1 after 100 cycles at 100 mA g-1 and 501.1 mA h g-1 after 500 cycles at 1,000 mA g-1. The corresponding PIB delivers a high reversible capacity of 449.0 mA h g-1 at 100 mA g-1 after 150 cycles and stably cycled over 500 cycles at 1,000 mA g-1. This work provides a promising route to engineering organic electrodes.

Biochanin A Reduces Inflammatory Injury and Neuronal Apoptosis following Subarachnoid Hemorrhage via Suppression of the TLRs/TIRAP/MyD88/NF-κB Pathway.

Inflammatory injury and neuronal apoptosis participate in the period of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Suppression of inflammation has recently been shown to reduce neuronal death and neurobehavioral dysfunction post SAH. Biochanin A (BCA), a natural bioactive isoflavonoid, has been confirmed to emerge the anti-inflammatory pharmacological function. This original study was aimed at evaluating and identifying the neuroprotective role of BCA and the underlying molecular mechanism in an experimental Sprague-Dawley rat SAH model. Neurobehavioral function was evaluated via the modified water maze test and modified Garcia neurologic score system. Thus, we confirmed that BCA markedly decreased the activated level of TLRs/TIRAP/MyD88/NF-κB pathway and the production of cytokines. BCA also significantly ameliorated neuronal apoptosis which correlated with the improvement of neurobehavioral dysfunction post SAH. These results indicated that BCA may provide neuroprotection against EBI through the inhibition of inflammatory injury and neuronal apoptosis partially via the TLRs/TIRAP/MyD88/NF-κB signal pathway.

Rhein induces apoptosis and autophagy in human and rat glioma cells and mediates cell differentiation by ERK inhibition.

In this study, we investigated the anticancer potentials of Rhein, an anthraquinone derivative of most commonly used Chinese rhubarb on the rat F98 glioma cells. The experimental studies revealed that Rhein induced cell cycle arrest, caspase mediated apoptosis. It results in the formation of intracellular acidic vesicles in cytoplasm, leading to autophagy. Differentiation of viable cells towards elongation of matured astrocytes was proved by monitoring dramatic changes in morphological characteristics as well as identified from the elevation of glial fibrillary acidic protein (GFAP) expression. Rhein treatment did not alter the phosphorylated MAPKs activation including p-38, JNK and NF-κB, transcription unit whereas rhein significantly inhibited ERK1/2 activation in F98 glioma cells. PD98059, a specific inhibitor for ERK activation imitates rhein effects on morphology and expressions of GFAP but did not help to induce any apoptosis or autophagy. Collective data exhibited that potentials of rhein in anti-cancer property in ERK-independent apoptosis and autophagy in association with downregulated ERK-dependent differentiation process of glioma cell lines.

Roles of Pannexin-1 Channels in Inflammatory Response through the TLRs/NF-Kappa B Signaling Pathway Following Experimental Subarachnoid Hemorrhage in Rats.

Background: Accumulating evidence suggests that neuroinflammation plays a critical role in early brain injury after subarachnoid hemorrhage (SAH). Pannexin-1 channels, as a member of gap junction proteins located on the plasma membrane, releases ATP, ions, second messengers, neurotransmitters, and molecules up to 1 kD into the extracellular space, when activated. Previous studies identified that the opening of Pannexin-1 channels is essential for cellular migration, apoptosis and especially inflammation, but its effects on inflammatory response in SAH model have not been explored yet. Methods: Adult male Sprague-Dawley rats were divided into six groups: sham group (n = 20), SAH group (n = 20), SAH + LV-Scramble-ShRNA group (n = 20), SAH + LV-ShRNA-Panx1 group (n = 20), SAH + LV-NC group (n = 20), and SAH + LV-Panx1-EGFP group (n = 20). The rat SAH model was induced by injection of 0.3 ml fresh arterial, non-heparinized blood into the prechiasmatic cistern in 20 s. In SAH + LV-ShRNA-Panx1 group and SAH + LV-Panx1-EGFP group, lentivirus was administered via intracerebroventricular injection (i.c.v.) at 72 h before the induction of SAH. The Quantitative real-time polymerase chain reaction, electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting were performed to explore the potential interactive mechanism between Pannexin-1 channels and TLR2/TLR4/NF-κB-mediated signaling pathway. Cognitive and memory changes were investigated by the Morris water maze test. Results: Administration with LV-ShRNA-Panx1 markedly decreased the expression levels of TLR2/4/NF-κB pathway-related agents in the brain cortex and significantly ameliorated neurological cognitive and memory deficits in this SAH model. On the contrary, administration of LV-Panx1-EGFP elevated the expressions of TLR2/4/NF-κB pathway-related agents, which correlated with augmented neuronal apoptosis. Conclusion: Pannexin-1 channels may contribute to inflammatory response and neurobehavioral dysfunction through the TLR2/TLR4/NF-κB-mediated pathway signaling after SAH, suggesting a potential role of Pannexin-1 channels could be a potential therapeutic target for the treatment of SAH.

[Retracted] Retinoic acid­incorporated glycol chitosan nanoparticles inhibit the expression of Ezh2 in U118 and U138 human glioma cells.

We wish to retract our research article entitled "Retinoic acid-incorporated glycol chitosan nanoparticles inhibit Ezh2 expression in U118 and U138 human glioma cells" published in Molecular Medicine Reports 12: 6642-6648, 2015. An interested reader noted some anomalies in the presentation of Fig. 4 in our paper, calling into question the validity of the reported data. In examining our original article, we acknowledge that the data for RA (25 µm) did not show a higher density of cells compared with RA (10 µm), as shown in Fig. 4, and therefore Fig. 4 conveyed inaccurate information for the readers. Owing to the importance of these results, which bear significantly upon the conclusions that one may draw from this work, we have decided to withdraw our paper from Molecular Medicine Reports [the original article was published in Molecular Medicine Reports 12: 6642-6648, 2015; DOI: 10.3892/mmr.2015.4294.

Activation of the Protein Kinase B (Akt) Reduces Nur77-induced Apoptosis During Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rat.

Nur77 is a potent pro-apoptotic member of the orphan nuclear receptor superfamily. Our previous study revealed Nur77-mediated apoptosis is also involved in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). Previous researches show that Protein Kinase B (Akt) negatively regulates Nur77 DNA binding and apoptosis by phosphorylating Nur77. To determine whether activation of Akt is directly associated with Nur77 dependent apoptosis pathway, we hypothesized that insulin, an activator of Akt, may effectively ameliorate EBI by inhibiting Nur77 transcriptional activity. This study was designed to explore the neuroprotective effects of insulin in EBI after SAH. Adult male Sprague Dawley (SD) rats were randomly assigned to three groups: control, SAH, and SAH + insulin. 0.2 U/kg insulin was administered subcutaneous, starting 30 min after the SAH induced, 3 times/d. Insulin significantly activated Akt, increased the phosphorylation of Nur77 and alleviated increases in Bcl-2 and cyto C associated with SAH induction. Improvement of neurological deficit, alleviation of brain edema, and amelioration of EBI were obtained after treatment of insulin. TUNEL-positive cells were reduced markedly in brain cortex by insulin. Our studies indicate activation of Akt plays important roles in inhibiting the Nur77-dependent apoptotic pathway. These findings strongly support the hypothesis that insulin treatment can ameliorate EBI after experimentally induced SAH.

Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a devastating neurological injury with high morbidity and mortality that is mainly caused by early brain injury (EBI). Progranulin (PGRN) is known to be involved in various biological functions, such as anti-inflammation and tissue repair. This study aimed to investigate the change of PGRN in the brain after SAH and its role on EBI. METHODS: The levels of PGRN, myeloperoxidase (MPO), interleukin1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were detected in the cerebrospinal fluid (CSF) from SAH patients by enzyme-linked immunosorbent assay (ELISA). In addition, PGRN levels were also detected in the cerebral cortex after experimental SAH in rats by western blotting and immunohistochemistry (IHC). Recombinant human PGRN (r-PGRN) or an equal volume of phosphate-buffered saline (PBS) was administrated at 30 min after SAH. All rats were subsequently sacrificed at 24 h after SAH. Neurological score and brain water content were assessed. For mechanistic studies, the changes of MPO, matrix metalloproteinase-9 (MMP-9), zonula occludens 1 (ZO-1), Bcl-2, and cleaved caspase-3 were examined by western blotting and the levels of pro-inflammatory cytokines (IL-1ß and TNF-α) were determined by ELISA. In addition, neuronal apoptosis and blood brain barrier (BBB) permeability were examined. RESULTS: The levels of PGRN significantly decreased, and the levels of MPO, IL-1ß, and TNF-α were markedly elevated in the CSF from SAH patients. In rats, PGRN levels in the brain also decreased after SAH. Administration of r-PGRN decreased brain water content and improved neurological scores at 24 h after SAH. These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1. In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN. CONCLUSIONS: These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-κB signaling pathway.

Early brain injury (EBI) determines the unfavorable outcomes after subarachnoid hemorrhage (SAH). Fisetin, a natural flavonoid, has anti-inflammatory and neuroprotection properties in several brain injury models, but the role of fisetin on EBI following SAH remains unknown. Our study aimed to explore the effects of fisetin on EBI after SAH in rats. Adult male Sprague-Dawley rats were randomly divided into the sham and SAH groups, fisetin (25mg/kg or 50mg/kg) or equal volume of vehicle was given at 30min after SAH. Neurological scores and brain edema were assayed. The protein expression of toll-like receptor 4 (TLR 4), p65, ZO-1 and bcl-2 was examined by Western blot. TLR 4 and p65 were also assessed by immunohistochemistry (IHC). Enzyme-linked immunosorbent assay (ELISA) was performed to detect the production of pro-inflammatory cytokines. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling (TUNEL) was perform to assess neural cell apoptosis. High-dose (50mg/kg) fisetin significantly improved neurological function and reduced brain edema at both 24h and 72h after SAH. Remarkable reductions of TLR 4 expression and nuclear factor κB (NF-κB) translocation to nucleus were detected after fisetin treatment. In addition, fisetin significantly reduced the productions of pro-inflammatory cytokines, decreased neural cell apoptosis and increased the protein expression of ZO-1 and bcl-2. Our data provides the evidence for the first time that fisetin plays a protective role in EBI following SAH possibly by suppressing TLR 4/NF-κB mediated inflammatory pathway.

Retinoic acid­incorporated glycol chitosan nanoparticles inhibit the expression of Ezh2 in U118 and U138 human glioma cells.

At present, one of the most life threatening types of adult brain tumor is glioblastoma multiforme (GBM). The molecular mechanism underlying the progression of GBM remains to be fully elucidated. The modern method of clinical treatment has only improved the average survival rates of a newly diagnosed patients with GBM by ~15 months. Therefore, the discovery of novel molecules, which are involved in glioma inhibition is required. In the present study, U118 and U138 human glioma cells were transfected with all­trans retinoic acid (RA)-incorporated glycol chitosan (GC) nanoparticles.An MTT assay was used for the analysis of cell proliferation and flow cytometric analysis and ssDNA detection assays were performed for the determination of induction of cell apoptosis. Cell cycle distribution was analyzed by flow cytometry. Exposure of the U118 and U138 human glioma cells to the RA­incorporated GC nanoparticles for 24 h resulted in a concentration­dependent inhibition of cell proliferation. Among the range of experimental RA concentrations, the minimum effective treatment concentration was 10 µM, with a half maximal inhibitory concentration of 25 µM. The results also demonstrated that RA transfection resulted in the inhibition of cell proliferation, inhibition of the expression of Ezh2, and apoptosis through the mitochondrial signaling pathway by a decrease in membrane potential, the release of cytochrome c, and cell cycle arrest in the G0/G1 phase.

Establishment of swine-penetrating craniocerebral gunshot wound model.

BACKGROUND: Bullet-induced brain wounds are common among military personnel in war zones and among civilians with gun accidents or crime-related gun injuries. The goal of this study was to develop a nonfatal porcine model of penetrating craniocerebral gunshot wound (PCGW) by firing a projectile in live swine to induce PCGW in such a realistic manner as to reconstruct their physical characteristics. MATERIALS AND METHODS: We established a nonfatal porcine model of PCGW based on a custom-designed experimental gun that emulates the shooting of a 5.56-mm NATO standard rifle at 800 m (317 m/s; 200.9 J). Commercial swine (n = 20) were subjected to a ballistic wound to the bilateral frontal lobe, and four swine were used as controls. Surviving swine were used in subsequent first-aid, management, and monitoring experiments for neurosurgeons. Various physiological variables were measured continuously. After computed tomography (CT) scanning and three-dimensional CT reconstructions, all pigs underwent primary lifesaving emergency interventions, including emergency decompressive craniotomies and hemorrhage control. RESULTS: In our nonfatal porcine model of PCGW, injuries were comparable in their morphology to real gunshot wounds, as evidenced by analysis of wound characteristics and CT scan images. The survival rates of the pigs were 100% within 2 h, 95% within 6 h, 85% within 12 h, and 85% within 24 h (P < 0.01). Hemodynamics, hematology, blood routine biochemistry, coagulation, and other physiological parameters also exhibited significant changes in the PCGW pigs. CONCLUSIONS: This model makes possible the laboratory reproduction of real ballistic wounds in a live large animal model that is close to humans.

Expression of Cytoplasmic Gelsolin in Rat Brain After Experimental Subarachnoid Hemorrhage.

Convincing evidence indicates that apoptosis contributes to the unfavorable prognosis of subarachnoid hemorrhage (SAH), a significant cause of morbidity and case fatality throughout the world. Gelsolin (GSN) is a Ca(2+)-dependent actin filament severing, capping, and nucleating protein, as well as multifunctional regulator of cell structure and metabolism, including apoptosis. In the present study, we intended to investigate the expression pattern and cell distribution of GSN in rat brain after experimental SAH. GSN expression was examined in sham group and at 3, 6, 12 h, day 1 (1 day), 2, 3, 5, and 7 days after SAH by Western blot analysis as well as real-time polymerase chain reaction. Immunohistochemistry and immunofluorescence were performed to detect the localization of GSN. The level of GSN protein expression was significantly decreased in SAH group and reached a bottoming point on 1 day after SAH. GSN mRNA level was significantly decreased in SAH groups in comparison with the sham group, and reached a minimum value at 12 h after SAH. Immunohistochemistry showed that GSN was constitutively and obviously expressed in the cortex of the normal rat brain and significantly decreased in the rat cortex after SAH. In addition, immunofluorescence results revealed that GSN expression could be found in both neurons and microglias, as well as in glialfibrillary acidic protein-positive astrocytes. The decreased expression of GSN could mainly be found in neurons and astrocytes as well, and GSN-positive microglias showed different cell morphological characteristics. Interestingly, the protein and gene levels of GSN seemed to be constant in the rat hippocampus of sham and SAH groups. These findings suggested a potential role of GSN in the pathophysiology of the brain at the early stage of SAH.

Constriction and dysfunction of pial arterioles after regional hemorrhage in the subarachnoid space.

Increasing evidence indicates that poor outcomes after brain hemorrhage, especially after subarachnoid hemorrhage (SAH), can be attributed largely to dysfunction of the cerebral microcirculation. However, the cause of this dysfunction remains unclear. Here, we investigated changes in the cerebral microcirculation after regional hemorrhage in the subarachnoid space using the closed cranial window technique in mice. A single pial arteriole on the surface of the brain was punctured to induce a regional hemorrhage in the subarachnoid space. Physiological parameters were monitored during the procedure, and microvessel diameter was measured after hemorrhage. The vasoreactivity of the arterioles in response to hypercapnia as well as to topical application of the vasodilator acetylcholine (ACh) and S-nitroso-N-acetyl-penicillamine (SNAP) were assessed. The constriction of pial arterioles was detected without changes in other physiological parameters. Decreased reactivity of pial arterioles to all of the applied vasodilatory stimuli was observed after hemorrhage. Our results indicate that regional hemorrhage in the subarachnoid space can induce the vasospasm of microvessels and also reduce the vasoreactivity of pial arterioles.

Baincalein alleviates early brain injury after experimental subarachnoid hemorrhage in rats: possible involvement of TLR4/NF-κB-mediated inflammatory pathway.

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) largely contributes to unfavorable outcomes. Hence, effective therapeutic strategies targeting on EBI have recently become a major goal in the treatment of SAH patients. Baicalein is a flavonoid that has been shown to offer neuroprotection in kinds of brain injury models. This study investigated the effects of baicalein on EBI in rats following SAH. SAH was inducted in male Sprauge-Dawley rats by injection of fresh non-heparinized arterial blood into the prechiasmatic cistern. Baicalein (30 or 100 mg/kg) or vehicle were administrated 30 min after injury. Neurological deficit, brain edema, blood-brain barrier (BBB) permeability and neural cell apoptosis were assessed. To explore the further mechanisms, the change of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) signaling pathway and the levels of apoptosis associated proteins were also examined. Our study showed that treatment with baicalein (30 mg/kg) significantly improved neurological function at 24h after SAH and reduced brain edema at both 24h and 72 h after SAH. Baicalein also significantly reduced neural cell death, BBB permeability. These changes were associated with the remarkable reductions of TLR4 expression, IκB-α degradation, NF-κB translocation to nucleus, as well as the expressions of matrix metalloproteinase-9, tight junctions protein, interleukin-1ß and tumor necrosis factor- ɑ. These findings suggest that baicalein may ameliorate EBI after SAH potentially via inhibition of inflammation-related pathway.

Ghrelin alleviates early brain injury after subarachnoid hemorrhage via the PI3K/Akt signaling pathway.

Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). Although the neuroprotective effects of ghrelin have been demonstrated in several studies, whether ghrelin reduces EBI after SAH remains unknown. In this study, we hypothesized that treatment with ghrelin would attenuate EBI after SAH, and that this protection would be mediated, at least in part, by activation of the PI3K/Akt signaling pathway. Adult male Sprague-Dawley rats (n=100) were randomly divided into the following groups: control group (n=20), SAH group (n=20), SAH+vehicle group (n=20), SAH+ghrelin group (n=20) and SAH+ghrelin+LY294002 group (n=20). The rats were injected with autologous blood (0.3mL) into the prechiasmatic cistern to induce SAH. Ghrelin (80µg/kg, IP), or an equal volume of vehicle, was administered immediately after surgery. The PI3K inhibitor, LY294002, was applied to manipulate the proposed pathway. Mortality, neurological scores, brain edema, cell apoptosis, and the expression of p-Akt, and cleaved caspase-3 proteins were assayed after 24h SAH. Ghrelin significantly improved neurological function and reduced neuronal apoptosis and brain edema at 24h after SAH. The level of p-Akt, expressed mainly in neurons, was markedly up-regulated. Additionally, the level of cleaved caspase-3 was decreased by ghrelin treatment. The beneficial effects of ghrelin in SAH rats were partially suppressed by LY294002. These results demonstrate that ghrelin may reduce EBI after SAH, via a mechanism involving the PI3K/Akt signaling pathway.

Astaxanthin alleviates early brain injury following subarachnoid hemorrhage in rats: possible involvement of Akt/bad signaling.

Apoptosis has been proven to play a crucial role in early brain injury pathogenesis and to represent a target for the treatment of subarachnoid hemorrhage (SAH). Previously, we demonstrated that astaxanthin (ATX) administration markedly reduced neuronal apoptosis in the early period after SAH. However, the underlying molecular mechanisms remain obscure. In the present study, we tried to investigate whether ATX administration is associated with the phosphatidylinositol 3-kinase-Akt (PI3K/Akt) pathway, which can play an important role in the signaling of apoptosis. Our results showed that post-SAH treatment with ATX could cause a significant increase of phosphorylated Akt and Bad levels, along with a significant decrease of cleaved caspase-3 levels in the cortex after SAH. In addition to the reduced neuronal apoptosis, treatment with ATX could also significantly reduce secondary brain injury characterized by neurological dysfunction, cerebral edema and blood-brain barrier disruption. In contrast, the PI3K/Akt inhibitor, LY294002, could partially reverse the neuroprotection of ATX in the early period after SAH by downregulating ATX-induced activation of Akt/Bad and upregulating cleaved caspase-3 levels. These results provided the evidence that ATX could attenuate apoptosis in a rat SAH model, potentially, in part, through modulating the Akt/Bad pathway.

Astaxanthin offers neuroprotection and reduces neuroinflammation in experimental subarachnoid hemorrhage.

BACKGROUND: Neuroinflammation has been proven to play a crucial role in early brain injury pathogenesis and represents a target for treatment of subarachnoid hemorrhage (SAH). Astaxanthin (ATX), a dietary carotenoid, has been shown to have powerful anti-inflammation property in various models of tissue injury. However, the potential effects of ATX on neuroinflammation in SAH remain uninvestigated. The goal of this study was to investigate the protective effects of ATX on neuroinflammation in a rat prechiasmatic cistern SAH model. METHODS: Rats were randomly distributed into multiple groups undergoing the sham surgery or SAH procedures, and ATX (25 mg/kg or 75 mg/kg) or equal volume of vehicle was given by oral gavage at 30 min after SAH. All rats were sacrificed at 24 h after SAH. Neurologic scores, brain water content, blood-brain barrier permeability, and neuronal cell death were examined. Brain inflammation was evaluated by means of expression changes in myeloperoxidase, cytokines (interleukin-1ß, tumor necrosis factor-α), adhesion molecules (intercellular adhesion molecule-1), and nuclear factor kappa B DNA-binding activity. RESULTS: Our data indicated that post-SAH treatment with high dose of ATX could significantly downregulate the increased nuclear factor kappa B activity and the expression of inflammatory cytokines and intercellular adhesion molecule-1 in both messenger RNA transcription and protein synthesis. Moreover, these beneficial effects lead to the amelioration of the secondary brain injury cascades including cerebral edema, blood-brain barrier disruption, neurological dysfunction, and neuronal degeneration. CONCLUSIONS: These results indicate that ATX treatment is neuroprotective against SAH, possibly through suppression of cerebral inflammation.

Inhibition of c-Jun N-terminal kinase ameliorates early brain injury after subarachnoid hemorrhage through inhibition of a Nur77 dependent apoptosis pathway.

Nur77 is a potent pro-apoptotic member of the orphan nuclear receptor superfamily. Our previous study revealed Nur77-mediated apoptotic also involved in early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH). Previous researches show that c-Jun N-terminal kinase (JNK) positively regulates Nur77 nuclear export and apoptosis by phosphorylating Nur77. To determine whether activation of JNK is directly associated with Nur77 dependent apoptosis pathway. We hypothesized that SP600125, a chemical inhibitor of JNK, may effectively ameliorate EBI by inhibiting Nur77 phosphorylation and its transcriptional activity. Hence, in this study was designed to explore the neuroprotective effects of SP600125 in EBI after SAH. Adult male SD rats were randomly assigned to four groups: control; SAH + DMSO; SAH + SP10 and SAH + SP30, a dose of 10 and 30 mg/kg SP600125 was directly administered intraperitoneally 30 min before and 2 h after SAH induction. SP600125 markedly decreased expressions of p-JNK, p-Nur77, Bcl-2, cyto C, caspase-3 and inhibited apoptosis. Improvement of neurological deficit, alleviation of brain edema and amelioration of EBI were obtained after treatment of SP600125. Transferase-mediated dUTP nick end labeling-positive cells were reduced markedly in brain cortex by SP600125. Our studies indicate JNK plays important roles in Nur77 activation. These findings strongly support the hypothesis that SP600125 treatment can ameliorate EBI after experimentally induced SAH by inhibiting a Nur77-dependent apoptotic pathway.

Nuclear receptor nur77 promotes cerebral cell apoptosis and induces early brain injury after experimental subarachnoid hemorrhage in rats.

Nur77 is a potent proapoptotic member of the nuclear receptor superfamily that is expressed predominantly in brain tissue. It has been demonstrated that Nur77 mediates apoptosis in multiple organs. Nur77-mediated early brain injury (EBI) involves a conformational change in BCL-2 and triggers cytochrome C (cytoC) release resulting in cellular apoptosis. This study investigates whether Nur77 can promote cerebral cell apoptosis after experimentally induced subarachnoid hemorrhage (SAH) in rats. Sprague Dawley rats were randomly assigned to three groups: 1) untreated group, 2) treatment control group, and 3) SAH group. The experimental SAH group was divided into four subgroups, corresponding to 12 hr, 24 hr, 48 hr, and 72 hr after experimentally induced SAH. It remains unclear whether Nur77 can play an important role during EBI after SAH as a proapoptotic protein in cerebral cells. Cytosporone B (Csn-B) was used to demonstrate that Nur77 could be enriched and used to aggravate EBI after SAH. Rats treated with Csn-B were given an intraperitoneal injection (13 mg/kg) 30 min after experimentally induced SAH. We found that Nur77 promotes cerebral cell apoptosis by mediating EBI and triggering a conformational change in BCL-2, resulting in cytoC release. Nur77 activity, along with cerebral cell apoptosis, peaked at 24 hr after SAH onset. After induction of SAH, an injection of Csn-B, an agonist for Nur77, enhanced the expression and function of Nur77. In summary, we have demonstrated the proapoptotic effect of Nur77 within cerebral cells, an effect that can be further exacerbated with Csn-B stimulation.

Amelioration of oxidative stress and protection against early brain injury by astaxanthin after experimental subarachnoid hemorrhage.

UNLABELLED: OBJECT.: Aneurysmal subarachnoid hemorrhage (SAH) causes devastating rates of mortality and morbidity. Accumulating studies indicate that early brain injury (EBI) greatly contributes to poor outcomes after SAH and that oxidative stress plays an important role in the development of EBI following SAH. Astaxanthin (ATX), one of the most common carotenoids, has a powerful antioxidative property. However, the potential role of ATX in protecting against EBI after SAH remains obscure. The goal of this study was to assess whether ATX can attenuate SAH-induced brain edema, blood-brain barrier permeability, neural cell death, and neurological deficits, and to elucidate whether the mechanisms of ATX against EBI are related to its powerful antioxidant property. METHODS: Two experimental SAH models were established, including a prechiasmatic cistern SAH model in rats and a one-hemorrhage SAH model in rabbits. Both intracerebroventricular injection and oral administration of ATX were evaluated in this experiment. Posttreatment assessments included neurological scores, body weight loss, brain edema, Evans blue extravasation, Western blot analysis, histopathological study, and biochemical estimation. RESULTS: It was observed that an ATX intracerebroventricular injection 30 minutes post-SAH could significantly attenuate EBI (including brain edema, blood-brain barrier disruption, neural cell apoptosis, and neurological dysfunction) after SAH in rats. Meanwhile, delayed treatment with ATX 3 hours post-SAH by oral administration was also neuroprotective in both rats and rabbits. In addition, the authors found that ATX treatment could prevent oxidative damage and upregulate the endogenous antioxidant levels in the rat cerebral cortex following SAH. CONCLUSIONS: These results suggest that ATX administration could alleviate EBI after SAH, potentially through its powerful antioxidant property. The authors conclude that ATX might be a promising therapeutic agent for EBI following SAH.

Resveratrol prevents neuronal apoptosis in an early brain injury model.

BACKGROUND: Resveratrol has been shown to attenuate cerebral vasospasm after subarachnoid hemorrhage (SAH); however, no study has explored its neuroprotective effect in early brain injury (EBI) after experimental SAH. The aim of this study was to evaluate the antiapoptotic function of resveratrol in EBI and its relationship with the PI3K/Akt survival pathway. METHODS: Experimental SAH was induced in adult male rats by prechiasmatic cistern injection. Control and SAH rats were divided into six groups and treated with low (20 mg/kg) or high (60 mg/kg) concentrations of resveratrol with or without LY294002 cotreatment. Brain samples of the rats were analyzed by immunohistochemistry, immunofluorescence staining, Western blotting, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assays. RESULTS: High-concentration but not low-concentration resveratrol treatment in SAH rats led to a significant increase in phosphorylated Akt (p-Akt) protein levels compared with SAH rats without treatment. In addition, p-Akt-positive cells mainly colocalized with NeuN-positive cells. Neuronal apoptosis in SAH rat brain was attenuated by high-concentration resveratrol treatment. The antiapoptotic effect of resveratrol in SAH rats could be partially abrogated by the PI3K/Akt signaling inhibitor LY294002. CONCLUSIONS: Our results show that resveratrol has an antiapoptotic effect in EBI and that resveratrol might act through the PI3K/Akt signaling pathway.