BackgroundMany previous clinical studies have demonstrated that the nigrostriatal pathway, which plays a vital role in movement adjustment, is significantly impaired after stroke, according to medical imaging and autopsies. However, the basic pathomorphological changes have been poorly investigated to date. This study was designed to explore the pathomorphological changes, mechanism, and therapeutic method of nigrostriatal impairment after intracerebral hemorrhage (ICH).Methods and ResultsIntrastriatal injection of autologous blood or microtubule depolymerization reagent nocodazole was performed to mimic the pathology of ICH in C57/BL6 mice. Immunofluorescence, Western blotting, electron microscopy, functional behavioral tests, and anterograde and retrograde neural circuit tracking techniques were used in these mice. The data showed that the number of dopamine neurons and the dopamine concentration were severely decreased and that fine motor function was impaired after ICH. Microtubule depolymerization was the main contributor to the loss of dopamine neurons and to motor function deficits after ICH, as was also proven by intrastriatal injection of nocodazole. Moreover, administration of the microtubule stabilizer epothilone B (1.5 mg/kg) improved the integrity of the nigrostriatal pathway neural circuit, increased the number of dopamine neurons (4598±896 versus 3125±355; P=0.034) and the dopamine concentration (4.28±0.99 versus 3.08±0.75 ng/mg; P=0.041), and enhanced fine motor functional recovery associated with increased acetylated α‐tubulin expression to maintain microtubule stabilization after ICH.ConclusionsOur results clarified the pathomorphological changes of the nigrostriatal pathway after ICH and found that epothilone B helped alleviate nigrostriatal pathway injury after ICH, associated with promoting α‐tubulin acetylation to maintain microtubule stabilization, thus facilitating motor recovery.
Background. RNF12 has been linked to a variety of biological activities, including the control of the MDM2/P53 pathway, although its additional functions remain unclear. RNF12 was discovered to be a new ubiquitin ligase (E3) for RB1, amongst the most frequently repressed proteins in cancer of human. Method. Cell Counting Kit-8 was used to detect the cell proliferation; coimmunoprecipitation was used to determine that RNF12 interacts with RB1. Xenograft studies were used to verify the results. Result. In vivo and in vitro RNF12 interacts with RB1 regardless of E3 ligase activity. The ubiquitination of RB1 by RNF12 had an effect on its stability. RNF12 inhibits the RB1 protein and stimulates the MAPK pathway, promoting the growth of GBMs. Conclusion. Our findings show that RNF12 may operate as a tumour promoter by modulating the cancerous proliferation of glioblastoma by controlling the activity of a new RNF12/RB1/MAPK pathway regulatory axis and that this regulatory axis might be a valuable diagnostic focus in glioblastoma.
Mitophagy, the selective removal of damaged mitochondria through autophagy, is crucial for mitochondrial turnover and quality control. Docosahexaenoic acid (DHA), an essential omega-3 fatty acid, protects mitochondria in various diseases. This study aimed to investigate the neuroprotective role of DHA in ischaemic stroke models in vitro and in vivo and its involvement in mitophagy and mitochondrial dysfunction. A mouse model of ischaemic stroke was established through middle cerebral artery occlusion (MCAO). To simulate ischaemic stroke in vitro, PC12 cells were subjected to oxygen–glucose deprivation (OGD). Immunofluorescence analysis, western blotting (WB), electron microscopy (EM), functional behavioural tests, and Seahorse assay were used for analysis. DHA treatment significantly alleviated the brain infarction volume, neuronal apoptosis, and behavioural dysfunction in mice with ischaemic stroke. In addition, DHA enhanced mitophagy by significantly increasing the number of autophagosomes and LC3-positive mitochondria in neurons. The Seahorse assay revealed that DHA increased glutamate and succinate metabolism in neurons after ischaemic stroke. JC-1 and MitoSox staining, and evaluation of ATP levels indicated that DHA-induced mitophagy alleviated reactive oxygen species (ROS) accumulation and mitochondrial injury. Mechanistically, DHA improved mitochondrial dynamics by increasing the expression of dynamin-related protein 1 (Drp1), LC3, and the mitophagy clearance protein Pink1/Parkin. Mdivi-1, a specific mitophagy inhibitor, abrogated the neuroprotective effects of DHA, indicating that DHA protected neurons by enhancing mitophagy. Therefore, DHA can protect against neuronal apoptosis after stroke by clearing the damaged mitochondria through Pink1/Parkin-mediated mitophagy and by alleviating mitochondrial dysfunction.
Objective: We were aimed to develop a clinical-radiomics nomogram that could predict the cervical lymph node metastasis (CLNM) of patients with papillary thyroid carcinoma (PTC) using clinical characteristics as well as radiomics features of dualenergy computed tomography (DECT).Method: Patients from our hospital with suspected PTC who underwent DECT for preoperative assessment between January 2021 and February 2022 were retrospectively recruited. Clinical characteristics, were obtained from the medical record system. Clinical characteristics and rad-scores were examined by univariate and multivariate logistic regression. All features were incorporated into the LASSO regression model, with penalty parameter tuning performed using 10-fold cross-validation, to screen risk factors for CLNM. An easily accessible radiomics nomogram was constructed. Receiver Operating Characteristic (ROC) curve together with Area Under the Curve (AUC) analysis was conducted to evaluate the discrimination performance of the model. Calibration curves were employed to assess the calibration performance of the clinical-radiomics nomogram, followed by goodness-of-t testing.Decision curve analysis (DCA) was performed to determine the clinical utility of the established models by estimating net bene ts at varying threshold probabilities for training and testing groups.Results: A total of 461 patients were retrospectively recruited. The rates of CLNM were 49.3% (70 /142) in the training cohort and 53.3% (32 / 60) in the testing cohort. Out of the 960 extracted radiomics features, 192 were signi cantly different in positive and negative groups (p < 0.05). On the basis of the training cohort, 12 stable features with nonzero coe cients were selected using LASSO regression. LASSO regression identi ed 7 risk factors for CLNM, including male gender, maximum tumor size > 10 mm, multifocality, CT-reported central CLN status, US-reported central CLN status, rad-score, and TGAb. A nomogram was developed using these factors to predict the risk of CLNM. The AUC values in each cohort were 0.85 and 0.797, respectively. The calibration curve together with Hosmer-Lemeshow test for the nomogram indicated good agreement between predicted and pathological CLN statuses in the training and testing cohorts. Results of DCA proved that the nomogram offers a superior net bene t for predicting CLNM compared to the "treat all or none" strategy across the majority of risk thresholds. Conclusion: A nomogram comprising the clinical characteristics as well as radiomics features of DECTand US was constructed for the prediction of CLNM for patients with PTC.
Background. The HOX gene family of transcription factors, characterized by conserved homeodomains, is positively correlated with the resistance to chemotherapy drugs and poor prognosis, as well as the initiating potential of gliomas. However, there are few studies regarding the HOXC6 gene in glioma cells. Therefore, in the present study, we explored the regulatory roles and detailed mechanisms underlying the relationship between HOXC6 and the progression of GBM. Methods. The expression levels and prognostic value of HOXC6 in GBM were evaluated using the data obtained from the GCCA, GEPIA, and ONCOMINE databases. The relationship between GBM prognosis and levels of HOXC6 was identified using Kaplan-Meier curves. The protein levels of HOXC6 in GBM and adjacent normal tissues were identified via Western blot and immunohistochemistry (IHC) staining methods. Lentiviruses containing full-length HOXC6 and HOXC6 specific siRNA sequences were used to overexpress and knock down, respectively, the expression of HOXC6 in U87 and U251 cells. The role of HOXC6 in the regulation of migration and proliferation of GBM cells was accessed using Transwell, wound healing, CCK-8, and colony formation assays. The activation of the TGF-β/Smad signaling pathway was detected via Western blotting. Results. Compared to normal tissues and control cells, GBM tissues and cell lines showed higher expressions of HOXC6. The expression of HOXC6 was associated with disease-free and the overall survival of GBM patients. Additionally, positive correlations between the expression of HOXC6 and the migration and proliferation of GBM cells were observed in vitro. The mechanistic analyses indicated that HOXC6 exerts its promotive effect on the progression and invasion of glioma cells by promoting the activation of the EMT and TGF-β/Smad signaling pathways. Conclusions. HOXC6 enhances the migration and proliferation of GBM by activating the EMT signaling pathway.
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