Increasing expression of dual-specificity phosphatase 12 mitigates oxygen-glucose deprivation/reoxygenation-induced neuronal apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway.

Dual-specificity phosphatase 12 (DUSP12) is abnormally expressed under various pathological conditions and plays a crucial role in the pathological progression of disorders. However, the role of DUSP12 in cerebral ischaemia/reperfusion injury has not yet been investigated. This study explored the possible link between DUSP12 and cerebral ischaemia/reperfusion injury using an oxygen-glucose deprivation/reoxygenation (OGD/R) model. Marked decreases in DUSP12 levels have been observed in cultured neurons exposed to OGD/R. DUSP12-overexpressed neurons were resistant to OGD/R-induced apoptosis and inflammation, whereas DUSP12-deficient neurons were vulnerable to OGD/R-evoked injuries. Further investigation revealed that DUSP12 overexpression or deficiency affects the phosphorylation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) in neurons under OGD/R conditions. Moreover, blockade of ASK1 diminished the regulatory effect of DUSP12 deficiency on JNK and p38 MAPK activation. In addition, DUSP12-deficiency-elicited effects exacerbating neuronal OGD/R injury were reversed by ASK1 blockade. In summary, DUSP12 protects against neuronal OGD/R injury by reducing apoptosis and inflammation through inactivation of the ASK1-JNK/p38 MAPK pathway. These findings imply a neuroprotective function for DUSP12 in cerebral ischaemia/reperfusion injury.

Syringaresinol attenuates Tau phosphorylation and ameliorates cognitive dysfunction induced by sevoflurane in aged rats.

Cognitive dysfunction following anesthesia with agents such as sevoflurane is a significant clinical problem, particularly in elderly patients. This study aimed to explore the protective effects of the phytochemical syringaresinol (SYR) against sevoflurane-induced cognitive deficits in aged Sprague-Dawley rats and to determine the underlying mechanisms involved. We assessed the impact of SYR on sevoflurane-induced cognitive impairment, glial activation, and neuronal apoptosis through behavioral tests (Morris water maze), immunofluorescence, Western blotting for key proteins involved in apoptosis and inflammation, and enzyme-linked immunosorbent assays for interleukin-1ß, tumor necrosis factor-α, and interleukin-6. SYR treatment mitigated sevoflurane-induced cognitive decline, reduced microglial and astrocyte activation (decreased Iba-1 and GFAP expression), and countered neuronal apoptosis (reduced Bax, cleaved-caspase3, and cleaved-PARP expression). SYR also enhanced Sirtuin-1 (SIRT1) expression and reduced p-Tau phosphorylation; these effects were reversed by the SIRT1 inhibitor EX527. SYR exerts neuroprotective effects on sevoflurane-induced cognitive dysfunction by modulating glial activity, apoptotic signaling, and Tau phosphorylation through the SIRT1 pathway. These findings could inform clinical strategies to safeguard cognitive function in patients undergoing anesthesia.

Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma.

Glioblastoma (GBM) is a highly malignant type of brain tumor with limited treatment options. Recent research has focused on epigenetic regulatory factors, such as Enhancer of Zeste Homolog 2 (EZH2), which plays a role in gene expression through epigenetic modifications. EZH2 inhibitors have been developed as potential therapeutic agents for GBM, but resistance to these inhibitors remains a considerable challenge. This study aimed to investigate the role of ribosomal S6 protein kinase 4 (RSK4) in GBM and its association with resistance to EZH2 inhibitors. We first induced drug resistance in primary GBM cell lines by treatment with an EZH2 inhibitor and observed increases in the expression of stemness markers associated with glioblastoma stem cells (GSCs) in the drug-resistant cells. We also found high expression of RSK4 in GBM patient samples and identified the correlation of high RSK4 expression with poor prognosis and GSC marker expression. Further experiments showed that knocking down RSK4 in drug-resistant GBM cells restored their sensitivity to EZH2 inhibitors and decreased the expression of GSC markers, thus reducing their self-renewal capacity. From a mechanistic perspective, we discovered that RSK4 directly phosphorylates EZH2, activating the EZH2/STAT3 pathway and promoting resistance to EZH2 inhibitors in GBM. We also found that combining EZH2 inhibitors with an RSK4 inhibitor called BI-D1870 had better inhibitory effects on GBM occurrence and progression in both in vitro and in vivo experiments. In conclusion, this study demonstrates that RSK4 enhances cancer stemness and mediates resistance to EZH2 inhibitors in GBM. Combination treatment with EZH2 inhibitors and RSK4 inhibitors is a promising potential therapeutic strategy for GBM. Collectively, our results strongly demonstrate that RSK4 regulates the EZH2/STAT3 pathway to promote GSC maintenance and EZH2i resistance in a PRC2-independent manner, indicating that RSK4 is a promising therapeutic target for GBM.

Overexpression of PRKCH promotes tumorigenesis in patients with glioma and influences glioma stem cell properties.

BACKGROUND: PRKCH is a member of the PKC family with the potential to regulate cell proliferation and differentiation. Glioma is the most common primary tumor of the central nervous system, with a high recurrence rate and poor prognosis. Recent studies have demonstrated that PRKCH can promote the proliferation of glioma cells. The purpose of this study was to investigate the promoting effect and possible mechanism of PRKCH on glioma development. METHODS: Tumor tissue and paracancerous tissue were collected from 160 glioma patients treated at the General Hospital of Northern Theater Command. The expression level of PRKCH was detected by immunohistochemistry and immunoblotting. Univariate/multivariate analysis and log-rank analysis, as well as prognosis and survival analysis, were performed using SPSS26 software. The PRKCH overexpression model was constructed in vitro to study the effect of PRKCH expression on the characteristics of glioma stem cells. RESULTS: The expression of PRKCH in glioma tissues was higher than that in adjacent tissues. PRKCH expression level is an independent prognostic factor in glioma patients, promoting poor prognosis and shorter survival in glioma patients. Furthermore, overexpression of PRKCH in glioma stem cells significantly increased stem cell properties and enhanced cell viability. Downregulation of PRKCH significantly inhibited the progression of glioma stem cells. CONCLUSION: PRKCH promotes the development of gliomas and may be a therapeutic target for gliomas.

Carnosol alleviates sevoflurane-induced cognitive dysfunction by mediating NF-κB pathway in aged rats.

Postoperative Cognitive Dysfunction (POCD) is a neurological disorder of unconsciousness due to cognitive regression after surgical anesthesia. However, the specific mechanism has not yet been clarified. Sevoflurane (SEV) is one of the most commonly used anesthetics in clinical practice, and how SEV mediates the generation of POCD is unclear. Carnosol, a natural ingredient, has been reported to have various beneficial effects such as anti-inflammatory, immune enhancement, and so forth, but how it ameliorates SEV-mediated neurotoxicity remains unclear. This study aimed to induce a POCD model in aged rats by SEV and to elucidate how Carnosol ameliorated SEV-mediated neurotoxicity. The effects of Carnosol on the expression of inflammatory factors in rat hippocampus mediated by SEV were determined by enzyme-linked immunoassay and polymerase chain reaction experiments; the effects of Carnosol on the expressions of Iba-1 and glial fibrillary acidic protein after SEV-mediated activation of rat microglia were clarified by immunofluorescence and Western blotting (WB); The effects of Carnosol on SEV-mediated neuronal apoptosis were studied by terminal deoxynucleotidyl transferase dUTP nick end labeling and WB; the specific signaling pathways regulated by Carnosol were elucidated by WB. The results showed that Carnosol can improve the cognitive dysfunction and reduce neuroinflammation in aged rats induced by SEV; Carnosol can reduce the activation of microglia and inhibit neuronal apoptosis in aged rats induced by SEV; Carnosol can phosphorylate p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha regulates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Carnosol can attenuate SEV-induced neuroinflammation, prevent microglial activation and inhibit neuronal apoptosis by modulating the NF-κB pathway.

Identification of the potential molecular targets for human intervertebral disc degeneration based on bioinformatic methods.

The present study aimed to explore potential molecular targets and gain further insights into the mechanism of intervertebral disc degeneration (IDD) progression. Microarray datasets of GSE19943, GSE15227 and GSE34095 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) in 3 IDD specimens compared with 3 controls in GSE34095, DEGs in 7 grade III and 3 grade IV samples compared with 5 grade II samples in GSE19943, and differentially expressed miRNAs in 3 degenerated samples compared with 3 controls in GSE15227 were screened. Grade III­ and IV­specific networks were constructed and grade­specific genes were extracted. The network features were analyzed, followed by Gene Ontology (GO) enrichment analysis and pathway enrichment analysis of grade­specific genes and DEGs identified in GSE34095. Furthermore, miRNA­pathway interactions were analyzed using Fisher's exact test. Tumor protein p53 (TP53) was a hub gene in the grade III­specific network and ubiquitin C (UBC) was identified to be a hub gene in the grade IV­specific network. Six significant features were identified by grade­specific network topology analysis. Grade­specific genes and DEGs were involved in different GO terms and pathways. Differentially expressed miRNAs were identified to participate in 35 pathways, among which 6 pathways were significantly enriched by DEGs, including apoptosis. The present study identified that key genes (TP53 and UBC) and miR­129­5p may participate in the mechanism of IDD progression. Thus, they may be potential therapeutic targets for IDD.