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A new cyclic peptide alternarin A (1), along with seven known compounds, alternariol (2), sulfated derivative of alternariol (3), alternariol methyl ether (4), altenuene (5), 2,5-dimethyl-7-hydroxychromone (6), diaporthein A (7), isopterocarpolone (8), were isolated from the betel nut endophytic fungus Alternaria sp. RW-AL. The structure of 1 was elucidated by 1D and 2D NMR spectra as well as HR-ESI-MS analysis. Compounds 1, 4, and 5 showed definite antibacterial activities against Staphylococcus aureus ATCC 6538 and Bacillus subtilis ATCC 6633. [ABSTRACT FROM AUTHOR]

Neuronal apoptosis is one of the main pathophysiological events in the early brain injury (EBI) post subarachnoid hemorrhage (SAH). Wnt-3a, one of the endogenous wnt ligands crucial in neurogenesis, has been proven to be efficacious in neuroprotection in traumatic brain injury and ischemic stroke. The glycolytic enzyme aldolase C and ribosome biogenesis protein PPAN were revealed to be linked to wnt signaling pathway. The aim of the study was to explore the antiapoptotic effects of intranasal wnt-3a through Frizzled-1 (Frz-1)/aldolase C/PPAN pathway in SAH. Approaches for assessment included SAH grade, Garcia test, brain water content evaluation, rotarod test, Morris water maze test, Western blot, immunofluorescence and transmission electron microscopy. The results showed that wnt-3a improved the neurological scores, brain water content and long-term neurobehavioral functions after SAH. Wnt-3a increased the level of Frz-1, aldolase C, β-catenin, PPAN and the Bcl-2/Bax ratio; and decreased the level of axin and cleaved caspase-3 (CC-3). The anti-apoptotic effect of wnt-3a was further evidenced by TUNEL staining and subcellular structure imaging. Frz-1 siRNA and aldolase C siRNA offset the effects of wnt-3a; and restoration of aldolase C by aldolase C CRISPR in Frz-1 siRNA preconditioned SAH rats salvaged the level of Frz-1, aldolase C, PPAN and reduced axin and CC-3. In summary, intranasal administration of wnt-3a alleviates neuronal apoptosis through Frz-1/aldolase C/PPAN pathway in the EBI of SAH rats. The feasible intranasal route and the long-lasting neuroprotective property of wnt-3a is of great clinical relevance. • Intranasal wnt-3a alleviates neuronal apoptosis through Frz-1/aldolase C/PPAN pathway in subarachnoid hemorrhage. • The moonlighting function ofthe glycolytic enzyme aldolase C in mediating wnt signaling through regulating axin. • The anti-apoptotic property of the ribosome biogenesis protein PPANas a wnt target protein. [ABSTRACT FROM AUTHOR]

Highlights • MCC950, a specific NLRP3 inhibitor, plays neuroprotective effects in experimental SAH. • MCC950 efficiently reduced NLRP3 inflammasome and subsequent pro-inflammatory cytokines. • The protective effect of MCC950 in SAH was reversed by lipopolysaccharide. Abstract Nucleotide oligomerization domain(NOD)-like receptor protein-3(NLRP3) inflammasome is a multiprotein complex, which results in the inflammatory response in early brain injury(EBI) after subarachnoid hemorrhage(SAH). MCC950, a specific NLRP3 inhibitor, plays neuroprotective effects in several central nervous system diseases. However, the role of MCC950 in SAH remains elusive. This study aims to investigate whether MCC950 exerts neuroprotection after experimental SAH and further explore the potential mechanisms. The SAH model was induced by endovascular perforation process using adult male Sprague-Dawley rats. MCC950 was injected intraperitoneally 1 h after SAH with a dose of 10 mg/kg. The results showed that MCC950 significantly ameliorated severe brain edema and neurological dysfunction. Furthermore, MCC950 efficiently reduced NLRP3 inflammasome expression as well as the pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. In addition, the protective effect of MCC950 was blunted by lipopolysaccharide. In conclusion, our findings suggest that MCC950 alleviated SAH-induced EBI by suppressing inflammation. [ABSTRACT FROM AUTHOR]

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

Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with few effective pharmacotherapies available. Salvia miltiorrhiza, a traditional Chinese medicinal herb, has been widely used to treat cardiovascular diseases for centuries. Recent studies have demonstrated that magnesium lithospermate B (MLB), a bioactive ingredient extracted from Salvia miltiorrhiza, exerts neuroprotective effects in several central nervous system insults. However, little is known about the role of MLB in SAH-induced brain injury and the exact molecular mechanism. In the current study, we studied the neuroprotective effects of MLB in SAH and explored the potential mechanism. Adult male Sprague–Dawley rats were subjected to an endovascular perforation process to produce an SAH model. MLB was administrated intraperitoneally at 30 min after SAH with a dose of 25 mg/kg or 50 mg/kg. We found that administration of MLB significantly attenuated brain edema and neurological deficits after SAH. In addition, immunofluorescence staining demonstrated that MLB dose-dependently inhibited the activation of microglia and reduced neuronal apoptosis. Western blot analysis showed that MLB decreased the expression of inflammatory cytokine TNF- α and pro-apoptotic protein cleaved caspase-3. More importantly, MLB increased the expression of SIRT1, while inhibited the acetylation of NF- κ B. Furthermore, pretreatment with sirtinol (a selective inhibitor of SIRT1) reversed all the aforementioned effects of MLB after SAH. In conclusion, our results indicated that MLB exerted robust neuroprotective effects against SAH via suppressing neuroinflammation and apoptosis. These neuroprotective effects of MLB against SAH might be exerted via regulating the SIRT1/NF- κ B pathway. MLB or the SIRT1/NF- κ B pathway could be a novel and promising therapeutic strategy for SAH management. [ABSTRACT FROM AUTHOR]

Early brain injury (EBI) is the primary cause of poor outcome in subarachnoid hemorrhage (SAH) patients. Rolipram, a specific phosphodiesterase-4 inhibitor which is traditionally used as an anti-depressant drug, has been recently proven to exert neuroprotective effects in several central nervous system insults. However, the role of rolipram in SAH remains uncertain. The current study was aimed to investigate the role of rolipram in EBI after SAH and explore the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. Rolipram was injected intraperitoneally at 2 h after SAH with a dose of 10 mg/kg. We found that rolipram significantly ameliorated brain edema and alleviated neurological dysfunction after SAH. Rolipram treatment remarkably promoted the expression of Sirtuin 1 (SIRT1) while inhibited NF-κB activation. Moreover, rolipram significantly inhibited the activation of microglia as well as down-regulated the expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6. In addition, rolipram increased the expression of protective cytokine IL-10. Furthermore, rolipram significantly alleviated neuronal death after SAH. In conclusion, these data suggested that rolipram exerts neuroprotective effects against EBI after SAH via suppressing neuroinflammation and reducing neuronal loss. The neuroprotective effects of rolipram were associated with regulating the SIRT1/NF-κB pathway. Rolipram could be a novel and promising therapeutic agent for SAH treatment. [ABSTRACT FROM AUTHOR]

• The first study to show circRNA expression alteration in rat brain after ICH. • 93 circRNAs are up-regulated and 20 are down-regulated at all time points after ICH. • GO and KEGG analyses for parent genes reveal a biological transition over time. • Targeted mRNAs participate in transcriptional regulations and signaling cascades. Circular RNAs (circRNAs) are a class of covalently closed non-coding RNAs, and aberrant alteration of their expression patterns is studied in numerous diseases. This study aimed to investigate whether intracerebral hemorrhage (ICH) affected circRNA expression profiles in the rat brain. Adult male Sprague-Dawley rats were subjected to intrastriatal injection of autologous artery blood to establish the ICH model. The cerebral cortex around hematoma was collected to perform circRNA microarray at 6 h, 12 h and 24 h. Quantitative reverse transcription-PCR (qRT-PCR) was used to validate the results. Bioinformatic methods were applied to predict ceRNA network and perform enrichment analyses for parent genes at three time points and target mRNAs. 111, 1145, 1751 up-regulated and 47, 732, 1329 down-regulated circRNAs were detected in the cerebral cortex of rats at 6 h, 12 h and 24 h after ICH compared with sham group. Most were from exonic regions. 93 were up-regulated and 20 were down-regulated at all three time points. Microarray results of 3 circRNAs were confirmed via qRT-PCR. GO and KEGG analyses for parent genes showed transition from protein complex assembly, cell-cell adhesion and cAMP signaling pathway at 6 h to intracellular signal transduction, protein phosphorylation and glutamatergic synapse at 12 h and 24 h. A circRNA-miRNA-mRNA network was successfully predicted. Enrichment analyses of targeted mRNAs indicated transcriptional regulations and pathways including Rap1, Ras, MAPK, PI3K-Akt, TNF and Wnt signaling and pathways in cancer. This was the first study to demonstrate that ICH significantly altered the expression of circRNAs with promising targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is closely associated with functional outcome in subarachnoid hemorrhage (SAH) patients. Our recent study demonstrated that fluoxetine inhibited NLRP3 inflammasome activation and attenuated necrotic cell death in early brain injury after SAH, while the effects and potential mechanisms of fluoxetine on neuroinflammation after SAH have not been well-studied yet.Methods: One hundred and fifty-three male SD rats were subjected to the endovascular perforation model of SAH. Fluoxetine (10 mg/kg) was administered intravenously at 6 h after SAH induction. TAK-242 (1.5 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h after SAH. SAH grade, neurological scores, brain water content, Evans blue extravasation, immunofluorescence/TUNEL staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot were performed.Results: Fluoxetine administration attenuated BBB disruption, brain edema, and improved neurological function after SAH. In addition, fluoxetine alleviated the number of Iba-1-positive microglia/macrophages, neutrophil infiltration, and cell death. Moreover, fluoxetine reduced the levels of pro-inflammatory cytokines, downregulated the expression of TLR4 and MyD88, and promoted the nuclear translocation of NF-κB p65, which were also found in rats with TAK-242 administration. Combined administration of fluoxetine and TAK-242 did not enhance the neuroprotective effects of fluoxetine.Conclusion: Fluoxetine attenuated neuroinflammation and improved neurological function in SAH rats. The potential mechanisms involved, at least in part, TLR4/MyD88/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]