Microglia-associated neuroinflammation plays essential roles in pathology of acute stroke. Cedrol, a natural compound extracted from ginger, has been shown to confer inhibitory effects on inflammation in various diseases. However, whether Cedrol suppresses neuroinflammation and protects brains from acute ischemic injury still remains unclear. In this study, we found that Cedrol inhibited microglia activation and the production of inflammatory factors in LPS-challenged microglia and the penumbra region of middle cerebral artery occlusion (MCAO) mice. We also found that Cedrol reduced the infarct size and mNSS scores and improved acute cerebral ischemia-induced behavioral outcomes, suggesting remarked neuroprotection of Cedrol. Molecular docking analysis showed that Cedrol bound to estrogen receptor β (ERβ) with moderate-strong affinity. Intriguingly, treatment with fulvestrant, an ER blocker, abolished the anti-inflammatory effects of Cedrol. Cedrol significantly reversed the LPS- and MCAO-induced increases in phosphorylation levels of IκB and NF-κB P65 in primary microglia and MCAO mice, respectively. Additionally, Cedrol was observed to rescue LPS-induced shuttling of NF-κB P65 from cytoplasm to nuclei in primary microglia, indicating inhibitory effects of Cedrol on NF-κB signaling. These results suggest microglia associated neuroinflammation may be mediated by ERβ-NF-κB signaling pathway. Together, our study reveals that Cedrol protected brain function from acute cerebral ischemia through inhibition of microglia-associated neuroinflammation via ERβ-NF-κB signaling pathways, and Cedrol may serve as an alternative option for treatment of acute stroke injury.

Background. Pyroptosis is closely related to the programmed death of cancer cells as well as the tumor immune microenvironment (TIME) via the host-tumor crosstalk. However, the role of pyroptosis-related genes as prognosis and TIME-related biomarkers in skin cutaneous melanoma (SKCM) patients remains unknown. Methods. We evaluated the expression profiles, copy number variations, and somatic mutations (CNVs) of 27 genes obtained from MSigDB database regulating pyroptosis among TCGA-SKCM patients. Thereafter, we conducted single-sample gene set enrichment analysis (ssGSEA) for evaluating pyroptosis-associated expression patterns among cases and for exploring the associations with clinicopathological factors and prognostic outcome. In addition, a prognostic pyroptosis-related signature (PPRS) model was constructed by performing Cox regression, weighted gene coexpression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO) analysis to score SKCM patients. On the other hand, we plotted the ROC and survival curves for model evaluation and verified the robustness of the model through external test sets (GSE22153, GSE54467, and GSE65904). Meanwhile, we examined the relations of clinical characteristics, oncogene mutations, biological processes (BPs), tumor stemness, immune infiltration degrees, immune checkpoints (ICs), and treatment response with PPRS via multiple methods, including immunophenoscore (IPS) analysis, gene set variation analysis (GSVA), ESTIMATE, and CIBERSORT. Finally, we constructed a nomogram incorporating PPRS and clinical characteristics to improve risk evaluation of SKCM. Results. Many pyroptosis-regulated genes showed abnormal expression within SKCM. TP53, TP63, IL1B, IL18, IRF2, CASP5, CHMP4C, CHMP7, CASP1, and GSDME were detected with somatic mutations, among which, a majority displayed CNVs at high frequencies. Pyroptosis-associated profiles established based on pyroptosis-regulated genes showed markedly negative relation to low stage and superior prognostic outcome. Blue module was found to be highly positively correlated with pyroptosis. Later, this study established PPRS based on the expression of 8 PAGs (namely, GBP2, HPDL, FCGR2A, IFITM1, HAPLN3, CCL8, TRIM34, and GRIPAP1), which was highly associated with OS, oncogene mutations, tumor stemness, immune infiltration degrees, IC levels, treatment responses, and multiple biological processes (including cell cycle and immunoinflammatory response) in training and test set samples. Conclusions. Based on our observations, analyzing modification patterns associated with pyroptosis among diverse cancer samples via PPRS is important, which can provide more insights into TIME infiltration features and facilitate immunotherapeutic development as well as prognosis prediction.

Aims: Stroke is a major public health concern leading to high rates of death and disability worldwide, unfortunately with no effective treatment available for stroke recovery during the repair phase.Methods: Photothrombotic stroke was induced in mice. Adeno‐associated viruses (AAV) were microinjected into the peri‐infarct cortex immediately after photothrombotic stroke. Grid‐walking task and cylinder task were used to assess motor function. Western blotting, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms.Results: The ternary complex of neuronal nitric oxide synthase (nNOS), carboxy‐terminal PDZ ligand of nNOS (CAPON) and dexamethasone‐induced ras protein 1 (Dexras1) is structurally beneficial for S‐nitrosylation of Dexras1 (SNO‐Dexras1). In our previous study, uncoupling nNOS‐CAPON interaction by Tat‐CAPON‐12C promoted functional recovery after stroke. Here, we show that ischemia elevated the levels of nNOS‐Dexras1 complex and SNO‐Dexras1 in the peri‐infarct cortex in the days 4–10 after stroke induction, and as excepted, Tat‐CAPON‐12C, a peptide disrupting nNOS‐CAPON interaction, significantly reversed these changes. The above information implies that repressed SNO‐Dexras1 may mediate functional‐promoting effects of Tat‐CAPON‐12C and SNO‐Dexras1 could be the vital molecular substrate for post‐stroke functional recovery in the repair phage. Inhibiting the ischemia‐induced SNO‐Dexras1 by AAV vector‐mediated knockdown of Dexras1 or over‐expression of dominant negative Dexras1 (Dexras1‐C11S) produced sustained recovery of motor function from stroke. In contrast, up‐regulation of SNO‐Dexras1 by over‐expressing Dexras1 worsened stroke outcome. Using electrophysiology recordings, we also observed that silence of Dexras1 in the peri‐infarct cortex increased the spike number and the miniature excitatory postsynaptic currents (mEPSCs) frequency, suggesting enhancement of neuronal excitability. In addition, silence of Dexras1 increased dendritic complexity in cultured neuron and more importantly enhanced dendritic spine density in the peri‐infarct cortex, implying dendritic remodeling.Conclusion: Thus, inhibition of SNO‐Dexras1 positively regulates post‐stroke functional recovery via enhanced neuronal excitability and dendritic remodeling. Our results identify that SNO‐Dexras1 may serve as a novel target for promoting motor functional restoration from stroke in the delayed phase, shedding light on stroke treatment.

Background: The treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has shifted from androgen deprivation therapy (ADT) alone to doublet or triplet regimens building on ADT. However, the cost-effectiveness analysis of first-line treatments for mHSPC in China is uncertain. This study aims to perform a 10-year horizon health economic evaluation to comparatively analyze the cost-effectiveness of eight treatment regimens for mHSPC from the perspective of China’s healthcare system, including (1) ADT alone and ADT plus one of the following: (2) docetaxel, (3) abiraterone, (4) apalutamide, (5) enzalutamide, (6) rezvilutamide, (7) darolutamide and docetaxel, (8) abiraterone and docetaxel. Methods: Partitioned survival model was developed to evaluate the cost-effectiveness of eight first-line treatment regimens for mHSPC. Drug costs were primarily extracted from pharmaceutical databases. The key outcomes were quality adjusted life years (QALYs), costs and the incremental cost-effectiveness ratio (ICER). Willingness-to-pay (WTP) threshold was set as three-time China’s gross domestic product (GDP) per capita (US$38,024) per QALY. Results: For costs, the 10-year cost estimates ranged from US$120,844 for ADT alone to US$216,294 for darolutamide plus ADT with docetaxel. For clinical effectiveness, enzalutamide plus ADT yielded the highest QALYs (4.55), while ADT alone gained lowest QALYs (3.01). For cost-effectiveness, the three treatment regimens of ADT alone, abiraterone plus ADT and enzalutamide plus ADT constituted the cost-effectiveness frontier. Abiraterone plus ADT emerged as the most cost-effective strategy, indicative of an ICER of US$17437.16 per QALY, substantially below WTP threshold. Conclusion: Abiraterone plus ADT was likely to be cost-effective for mHSPC treatment at a WTP threshold of three-time per capita GDP per QALY.