The Mechanism of Astragaloside IV in NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome-mediated Pyroptosis after Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is one of the most common subtypes of stroke. OBJECTIVES: This study aimed to investigate the mechanism of Astragaloside IV (AS-IV) on inflammatory injury after ICH. METHODS: The ICH model was established by the injection of collagenase and treated with ASIV (20 mg/kg or 40 mg/kg). The neurological function, water content of the bilateral cerebral hemisphere and cerebellum, and pathological changes in brain tissue were assessed. The levels of interleukin-1 beta (IL-1ß), IL-18, tumor necrosis factor-alpha, interferon-gamma, and IL-10 were detected by enzyme-linked immunosorbent assay. The levels of Kruppel-like factor 2 (KLF2), NOD-like receptor family pyrin domain containing 3 (NLRP3), GSDMD-N, and cleaved-caspase-1 were detected by reverse transcription-quantitative polymerase chain reaction and Western blot assay. The binding relationship between KLF2 and NLRP3 was verified by chromatin-immunoprecipitation and dual-luciferase assays. KLF2 inhibition or NLRP3 overexpression was achieved in mice to observe pathological changes. RESULTS: The decreased neurological function, increased water content, severe pathological damage, and inflammatory response were observed in mice after ICH, with increased levels of NLRP3/GSDMD-N/cleaved-caspase-1/IL-1ß/IL-18 and poorly-expressed KLF2 in brain tissue. After AS-IV treatment, the neurological dysfunction, high brain water content, inflammatory response, and pyroptosis were alleviated, while KLF2 expression was increased. KLF2 bonded to the NLRP3 promoter region and inhibited its transcription. Down-regulation of KLF2 or upregulation of NLRP3 reversed the effect of AS-IV on inhibiting pyroptosis and reducing inflammatory injury in mice after ICH. CONCLUSION: AS-IV inhibited NLRP3-mediated pyroptosis by promoting KLF2 expression and alleviated inflammatory injury in mice after ICH.

Comparison of clinical efficacy and safety between interventional embolization and craniotomy clipping for anterior circulation aneurysms.

Objective: To investigate the clinical efficacy and safety of interventional embolization in the treatment of anterior circulation aneurysms. Methods: Eighty patients with anterior circulation aneurysms admitted to People's Hospital of Leshan from June 2019 to December 2021 were retrospectively analyzed. According to the different surgical methods, they were divided into two groups: the observation group and the control group. Patients in the observation group were given interventional embolization, while those in the control group were given craniotomy clipping. The surgical efficacy, postoperative neurological function and quality of life, surgical prognosis and surgical complications of the two groups were compared. Results: The intraoperative blood loss and hospitalization time in the observation group were lower than those in the control group (p<0.05). The scores of the Hunt-Hess and modified Rankin scale in the observation group were significantly lower than those in the control group three months after surgery (p<0.05). The good prognosis rate of the observation group was higher than that of the control group (p<0.05). Moreover, the complication rate of the observation group was 12.50%, which was significantly lower than 32.50% in the control group (p<0.05). Conclusion: Interventional embolization shows the advantages of minimally invasive procedures such as shorter operative times and shorter hospital stays. It has better clinical safety because it can significantly improve the neurological function and quality of life of patients, improve the prognosis of patients, and reduce the incidence of complications.

Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme.

Immunogenic cell death (ICD), a unique form of cancer cell death, has therapeutic potential in anti-tumour immunotherapy. The aim of this study is to explore the predictive potential of ICD in the prognosis and immunotherapy outcomes of glioblastoma multiforme (GBM). RNA sequencing data and clinical information were downloaded from three databases. Unsupervised consistency clustering analysis was used to identify ICD-related clusters and gene clusters. Additionally, the ICD scores were determined using principal component analysis and the Boruta algorithm via dimensionality reduction techniques. Subsequently, three ICD-related clusters and three gene clusters with different prognoses were identified, with differences in specific tumour immune infiltration-related lymphocytes in these clusters. Moreover, the ICD score was well differentiated among patients with GBM, and the ICD score was considered an independent prognostic factor for patients with GBM. Furthermore, two datasets were used for the external validation of ICD scores as predictors of prognosis and immunotherapy outcomes. The validation analysis suggested that patients with high ICD scores had a worse prognosis. Additionally, a higher proportion of patients with high ICD scores were non-responsive to immunotherapy. Thus, the ICD score has the potential as a biomarker to predict the prognosis and immunotherapy outcomes of patients with GBM.

Silencing of ALOX15 reduces ferroptosis and inflammation induced by cerebral ischemia-reperfusion by regulating PHD2/HIF2α signaling pathway.

OBJECTIVE: To investigate the potential mechanism of arachidonic acid deoxyribozyme 15 (ALOX15) in ferroptosis and inflammation induced by cerebral ischemia reperfusion injury. METHODS: The mice and cell models of cerebral ischemia-reperfusion injury were constructed. Western Blot was used to detect the protein expression levels of ALOX15, glutathione peroxidase (GPX4), hypoxia-inducible factor-2α (HIF-2α), prolyl hydroxylase (PHD) and inflammatory factors (NLRP3, IL-1ß, IL-18) in brain tissues and cells. Cell proliferation activity was detected by CCK-8 method. LDH assay was used to detect the release of lactate dehydrogenase. TTC staining was used to observe cerebral infarction. RESULTS: In cerebral ischemia-reperfusion mice and cell models, the expression of ALOX15 protein was increased, the expression of GPX4, a key marker of ferroptosis was decreased, and silencing of ALOX15 down-regulated the GPX4 expression. HIF-2α expression was down-regulated in animal and cell models of cerebral ischemia reperfusion, and silencing of ALOX15 increased the HIF-2α expression by inhibiting PHD2 expression. Inhibition of ALOX15 expression reduced inflammatory factors levels (NLRP3, IL-1ß, and IL-18) in cerebral ischemia. Inhibitor of PHD2 (IXOC-4) alleviating brain injury and cell death induced by cerebral ischemia reperfusion and stabilize HIF-2α expression in vivo. CONCLUSION: The expression of ALOX15 was up-regulated in cerebral ischemia-reperfusion animals and cells model. Inhibition of ALOX15 up-regulated the GPX4 expression, and promoted HIF-2α expression by inhibiting PHD2, thus alleviating ferroptosis and inflammation caused by cerebral ischemia-reperfusion injury.

The protective role of circ_0016760 downregulation against sevoflurane­induced neurological impairment via modulating miR­145 expression in aged rats.

Sevoflurane can produce toxicity to the hippocampal tissues of brain, leading to nerve damage, causing learning and cognitive dysfunction. CircRNAs have been indicated to act as a key mediator in anesthetic neurotoxicity. This study focused on the effect of circ_0016760 on sevoflurane­induced neurological impairment. The GEO database (GSE147277) and RT­qPCR were used to predict and  measure the circ_0016760 expression. The interaction of circ_0016760 and miR­145 was verified by dual­luciferase reporter assay. The CCK­8 assay, flow cytometry, ELISA, ROS kit, MWM test were carried out to measure the cell viability, apoptosis, inflammation indicators, ROS level, and cognitive and memory function of the rats. Sevoflurane exacerbated neurotoxicity by restraining cell viability, inducing cell apoptosis, neuroinflammation, and ROS generation, and causing learning and cognitive dysfunction. Circ_0016760 expression was increased in POCD patients from the GEO database and upregulated after sevoflurane exposure. miR­145 was a target miRNA of circ_0016760. Silencing of circ_0016760 weakened the effect of sevoflurane on cell viability, cell apoptosis, inflammation­related factors, oxidative stress, which could be reversed by miR­145 inhibitor. The animal experiments results showed that circ_0016760 played a protective effect on regulating the cognitive behavior of sevoflurane­treated aged rats, expression of inflammation cytokine, and oxidative stress factors through targeting miR­145 in sevoflurane­treated aged rat's hippocampal neurons. Our results revealed that silencing of circ_0016760 attenuated sevoflurane­induced hippocampal neuron injury by regulating miR­145 expression, which may provide potential insights into the treatment of sevoflurane­induced neurological impairment.

Discovery of fusidic acid derivatives as novel STING inhibitors for treatment of sepsis.

Sepsis is often caused by systemic inflammatory responses. Stimulator of interferon genes (STING) could be a promising treatment target for sepsis. In this study, we report the design and synthesis of a new series of fusidic acid derivatives. Among the synthesized derivatives, the promising compound 30 inhibited lipopolysaccharide (LPS)-induced nitric oxide production in macrophages with an IC50 of 1.15 µM. Compound 30 was then identified as a STING inhibitor that suppressed LPS-induced inflammatory responses and inhibited the abnormal activation of the TBK1, IRF3, and NF-κB signaling pathways by targeting STING. In vivo treatment with compound 30 significantly inhibited the inflammatory response and ameliorated the histopathological changes of the liver, and the mechanism of its anti-inflammatory effect in vivo was the same as that in vitro. Our studies identified compound 30 as a potent STING inhibitor, laying the groundwork for future drug development of anti-inflammatory agents for the treatment of sepsis.

Diagnostic accuracy of arterial spin labeling in differentiating between primary central nervous system lymphoma and high-grade glioma: a systematic review and meta-analysis.

BACKGROUND: Existing studies have confirmed the accuracy of arterial spin labeling (ASL) in differentiating between primary central nervous system lymphoma (PCNSL) and high-grade glioma (HGG). We aimed to consolidate the existing evidence with a meta-analysis. METHODS: Six literature databases were searched for relevant papers. After assessing the quality of studies, bivariate regression was performed, and the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic score, diagnostic odds ratio (DOR), and the area under the curve (AUC) of the summary receiver operating characteristic (SROC) curve were calculated, along with the corresponding 95% confidence intervals (CIs). Deeks' test was used to determine risk of publication bias. RESULTS: Ten high-quality studies, comprising 151 patients with PCNSL and 455 with HGG, were included. The pooled SEN was 0.79 (95% CI: 0.72-0.85), pooled SPE was 0.90 (95% CI: 0.84-0.94), pooled PLR was 8.07 (95% CI: 5.01-13.02), pooled NLR was 0.23 (95% CI: 0.17-0.32), pooled diagnostic score was 3.56 (95% CI: 2.94-4.18), and pooled DOR was 35.10 (95% CI: 18.83-65.45). The AUC of SROC was 0.86 (95% CI: 0.83-0.89). No publication bias was found. CONCLUSIONS: ASL demonstrated high diagnostic accuracy in differentiating between PCNSL and HGG.

Protective effect of phillyrin against cerebral ischemia/reperfusion injury in rats and oxidative stress-induced cell apoptosis and autophagy in neurons.

This study explored the role and potential molecular mechanism of phillyrin in cerebral ischemia/reperfusion (I/R) injury. The rat middle cerebral artery occlusion (MCAO)/R model was constructed, and cerebral infarction volume, brain water content, and neurological score were measured. Neuron morphological structures in brain tissues and primary neuron apoptosis were detected using hematoxylin and eosin (H&E) staining and Hoechst 33258 staining, respectively. In MCAO/R rats, phillyrin markedly reduced cerebral infarction volume, neurological score, and brain water content and inhibited neuron apoptosis. In vitro experiments showed that phillyrin remarkably increased viability and decreased lactate dehydrogenase (LDH) release of H2O2-injured neurons. Moreover, phillyrin remarkably downregulated the proportion of apoptosis-related protein B-associated X (Bax)/B-cell lymphoma protein 2 (Bcl-2) and reduced procaspase-3, phospho-Akt (p-Akt-1), and phosphorylation-mammalian target of rapamycin (p-mTOR) levels in H2O2-injured neurons. Furthermore, phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 weakened the effects of phillyrin on p-mTOR, p-Akt-1, characteristic proteins of autophagy 3-II (LC3-II) and beclin-1 levels, and H2O2-induced neuronal apoptosis and autophagy. Taken together, phillyrin alleviates I/R injury by inhibiting neuronal cell apoptosis and autophagy pathway, which may provide a new treatment strategy for cerebral I/R injury.

Growth hormone-secreting adenoma coexisted with gangliocytoma: a rare case.

A gangliocytoma in the sellar region is extremely rare. We report a rare case of mixed gangliocytoma and growth hormone (GH)-secreting adenoma in a 50-year-old woman, who presented with acromegaly. Laboratory investigations revealed high levels of GH and insulinlike growth factor 1 (IGF-1). Sellar computed tomography scan and contrast enhanced magnetic resonance imaging (CE-MRI) showed a sellar mass. Based on clinical, biochemical, and radiologic evaluations, GH-secreting adenoma was diagnosed and operated by endonasal transsphenoidal approach achieving total removal of the tumor. After surgery, histopathological examination demonstrated mixed gangliocytoma and GH-secreting adenoma in the resected lesion. The clinical, radiological, and operative data are reviewed, as are the histological findings. To our knowledge, few cases of mixed gangliocytoma and GH-secreting adenoma have been reported.