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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]

Endocrine therapy is considered as an effective strategy for estrogen and progestogen receptor (ER and PR)-positive breast cancer (BRCA) patients, whereas resistance to these agents is the major cause of BRCA mortality in women. Immune checkpoint receptor (ICR) blockade is another approach to treat BRCA, but the response rate of this approach for non-triple-negative breast cancer (non-TNBC) is relatively low. Recently, the androgen receptor (AR) has been identified as a tumor suppressor in ER-positive BRCA; however, the relationship between the levels of androgens and ICRs on T cells in BRCA is unclear. We observed that testosterone and dihydrotestosterone (DHT) in patients with HER2 and Luminal B were significantly lower than those in healthy controls, and the expression of AR has significant correlation with overall survival (OS) advantage for Luminal B patients. Moreover, testosterone and DHT were positively correlated with the PD-1 expression on Vd1+ T cells in HER2 and Luminal B patients. These results suggest a potential approach of combining androgens with PD-1 blockade for treating HER2 and Luminal B breast cancer. [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]

Studies have suggested that blood-brain barrier (BBB) disruption contributes to the pathogenesis of early brain injury after subarachnoid haemorrhage (SAH). Activation of the receptor tyrosine kinase ErbB4 can cause intramembrane proteolysis and release a soluble intracellular domain (ICD) that modulates transcription in the nucleus. This study was carried out to investigate the potential roles of ErbB4 in preserving BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective effects. Endovascular perforation was used to prepare a rat SAH model. The SAH grade, neurological score, brain edema and BBB permeability were evaluated after surgery. Immunohistochemistry was used to determine the localization of ErbB4 and yes-associated protein (YAP). ErbB4 activator Nrg1 isoform β1 (Nrg1β1), Specific ErbB4 siRNA, YAP siRNA and PIK3CB specific inhibitor TGX 221 were used to manipulate the proposed pathway. The expression levels of ErbB4 ICD and YAP were markly increased after SAH. Double immunohistochemistry labeling showed that ErbB4 and YAP were expressed in endothelial cells and neurons. Activation of ErbB4 by Nrg1β1 (dosage 150 ng/kg) treatment promoted the neurobehavioral deficit, alleviated the brain water content and reduced albumin leakage 24 and 72 h after SAH. ErbB4 activation significantly promoted YAP and PIK3CB activity and increased the expression of tight junction proteins Occludin and Claudin-5. Depletion of ErbB4 aggravated neurological impairment and BBB disruption after SAH. The beneficial effects of ErbB4 activation were abolished by YAP small-interfering RNA and specific PIK3CB inhibitor. Activation of ErbB4 improved neurological performance after SAH through the YAP/PIK3CB signaling pathway, this neuroprotective effects may associated with BBB maintenance. [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]

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]