Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Brain Damage Following Subarachnoid Hemorrhage via the Interaction of miR-140-5p and HDAC7.

Subarachnoid hemorrhage (SAH) triggers severe neuroinflammation and cognitive impairment, where microglial M1 polarization exacerbates the injury and M2 polarization mitigates damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), carrying microRNA (miR)-140-5p, offer therapeutic promise by targeting the cAMP/PKA/CREB pathway and modulating microglial responses, demonstrating a novel approach for addressing SAH-induced brain injury. This research explored the role of miR-140-5p delivered by MSC-EVs in mitigating brain damage following SAH. Serum from SAH patients and healthy individuals was analyzed for miR-140-5p and cAMP levels. The association between miR-140-5p levels, brain injury severity, and patient survival was examined, along with the target relationship between miR-140-5p and histone deacetylases 7 (HDAC7). MSC-EVs were characterized for their ability to cross the blood-brain barrier and modulate the HDAC7/AKAP12/cAMP/PKA/CREB axis, reducing M1 polarization and inflammation. The therapeutic effect of MSC-EV-miR-140-5p was demonstrated in an SAH mouse model, showing reduced neuronal apoptosis and improved neurological function. This study highlights the potential of MSC-EV-miR-140-5p in mitigating SAH-induced neuroinflammation and brain injury, providing a foundation for developing MSC-EV-based treatments for SAH.

Hypothermia protects the integrity of corticospinal tracts and alleviates mitochondria injury after intracerebral hemorrhage in mice.

Disruption of corticospinal tracts (CST) is a leading factor for motor impairments following intracerebral hemorrhage (ICH) in the striatum. Previous studies have shown that therapeutic hypothermia (HT) improves outcomes of ICH patients. However, whether HT has a direct protection effect on the CST integrity and the underlying mechanisms remain largely unknown. In this study, we employed a chemogenetics approach to selectively activate bilateral warm-sensitive neurons in the preoptic areas to induce a hypothermia-like state. We then assessed effects of HT treatment on the integrity of CST and motor functional recovery after ICH. Our results showed that HT treatment significantly alleviated axonal degeneration around the hematoma and the CST axons at remote midbrain region, ultimately promoted skilled motor function recovery. Anterograde and retrograde tracing revealed that HT treatment protected the integrity of the CST over an extended period. Mechanistically, HT treatment prevented mitochondrial swelling in degenerated axons around the hematoma, alleviated mitochondrial impairment by reducing mitochondrial ROS accumulation and improving mitochondrial membrane potential in primarily cultured cortical neurons with oxyhemoglobin treatment. Serving as a proof of principle, our study provided novel insights into the application of HT to improve functional recovery after ICH.

A nomogram for predicting the necessity of tracheostomy after severe acute brain injury in patients within the neurosurgery intensive care unit: A retrospective cohort study.

Objective: This retrospective study was aimed to develop a predictive model for assessing the necessity of tracheostomy (TT) in patients admitted to the neurosurgery intensive care unit (NSICU). Method: We analyzed data from 1626 NSICU patients with severe acute brain injury (SABI) who were admitted to the Department of NSICU at the Affiliated People's Hospital of Jiangsu University between January 2021 and December 2022. Data of the patients were retrospectively obtained from the clinical research data platform. The patients were randomly divided into training (70%) and testing (30%) cohorts. The least absolute shrinkage and selection operator (LASSO) regression identified the optimal predictive features. A multivariate logistic regression model was then constructed and represented by a nomogram. The efficacy of the model was evaluated based on discrimination, calibration, and clinical utility. Results: The model highlighted six predictive variables, including the duration of NSICU stay, neurosurgery, orotracheal intubation time, Glasgow Coma Scale (GCS) score, systolic pressure, and respiration rate. Receiver operating characteristic (ROC) analysis of the nomogram yielded area under the curve (AUC) values of 0.854 (95% confidence interval [CI]: 0.822-0.886) for the training cohort and 0.865 (95% CI: 0.817-0.913) for the testing cohort, suggesting commendable differential performance. The predictions closely aligned with actual observations in both cohorts. Decision curve analysis demonstrated that the numerical model offered a favorable net clinical benefit. Conclusion: We developed a novel predictive model to identify risk factors for TT in SABI patients within the NSICU. This model holds the potential to assist clinicians in making timely surgical decisions concerning TT.

Radiomics features from whole thyroid gland tissue for prediction of cervical lymph node metastasis in the patients with papillary thyroid carcinoma.

OBJECTIVE: We 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 dual energy 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 tenfold 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-fit testing. Decision curve analysis (DCA) was performed to determine the clinical utility of the established models by estimating net benefits 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 significantly different in positive and negative groups (p < 0.05). On the basis of the training cohort, 12 stable features with nonzero coefficients were selected using LASSO regression. LASSO regression identified 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 0.850 and 0.797, respectively. The calibration curve together with the 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 benefit 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 DECT and US was constructed for the prediction of CLNM for patients with PTC, which in determining whether lateral compartment neck dissection is warranted.

Manifestation of the malignant progression of glioma following initial intracerebral hemorrhage: A case report.

BACKGROUND: Intracranial hemorrhage is extremely rare during the initial stages of glioma. Here, we report a case of glioma with unclassified pathology and intracranial bleeding. CASE SUMMARY: After the second surgery for intracerebral hemorrhage, the patient experienced weakness in the left arm and leg, but could walk unassisted. One month after discharge, the weakness in the left limbs had exacerbated and the patient also suffered from headaches and dizziness. A third surgery was ineffective against the rapidly growing tumor. Intracerebral hemorrhage may be the initial symptom of glioma in some rare cases, and atypical perihematomal edema can be used for diagnosis during an emergency. Certain histological and molecular features seen in our case were similar to that of glioblastoma with a primitive neuronal component, which is termed diffuse glioneuronal tumor with features similar to oligodendroglioma and nuclear clusters (DGONC). The patient underwent three surgeries to remove the tumor. The first tumor resection had been performed when the patient was 14-years-old. Resection of the hemorrhage and bone disc decompression were performed when the patient was 39-years-old. One month after the last discharge, the patient underwent neuronavigation-assisted resection of the right frontotemporal parietal lesion plus extended flap decompression. On the 50th d after the third operation, computed tomography imaging showed rapid tumor growth accompanied by brain hernia. The patient was discharged and died 3 d later. CONCLUSION: Glioma can present as bleeding in the initial stage and should be considered in such a setting. We have reported a case of DGONC, which is a rare molecular subtype of glioma with a unique methylation profile.

An endoscopic-assisted contralateral paramedian supracerebellar infratentorial approach in the treatment of thalamic hemorrhage with hematoma extension into the brainstem: a case report.

Objective: Thalamic hemorrhage (TH) with hematoma extension into the brainstem can lead to poor outcomes. In this study, we discuss the feasibility of the endoscopic-assisted contralateral paramedian supracerebellar infratentorial (SCIT) approach as a therapeutic method for treating such patients. Case presentation: A patient suffered from a sudden loss of consciousness and right limb weakness, and a CT scan indicated TH with hematoma extension into the brainstem. She consented to undergo surgery by the endoscopic-assisted contralateral paramedian SCIT approach. Results: Now, the patient can open her eyes on her own and move her left arm in response to commands. Conclusion: The endoscopic-assisted contralateral paramedian SCIT approach may be a viable therapeutic method for treating TH patients with hematoma extension into the brainstem.

Docosahexaenoic Acid Alleviates Brain Damage by Promoting Mitophagy in Mice with Ischaemic Stroke.

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.

RNF12 Promotes Glioblastoma Malignant Proliferation via Destructing RB1 and Regulating MAPK Pathway.

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.

Selective activation of TWIK-related acid-sensitive K+ 3 subunit-containing channels is analgesic in rodent models.

The paucity of selective agonists for TWIK-related acid-sensitive K+ 3 (TASK-3) channel, a member of two-pore domain K+ (K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a druggable transmembrane cavity using a structure-based drug design approach, we discovered a biguanide compound, CHET3, as a highly selective allosteric activator for TASK-3-containing K2P channels, including TASK-3 homomers and TASK-3/TASK-1 heteromers. CHET3 displayed potent analgesic effects in vivo in a variety of acute and chronic pain models in rodents that could be abolished pharmacologically or by genetic ablation of TASK-3. We further found that TASK-3-containing channels anatomically define a unique population of small-sized, transient receptor potential cation channel subfamily M member 8 (TRPM8)-, transient receptor potential cation channel subfamily V member 1 (TRPV1)-, or tyrosine hydroxylase (TH)-positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting CHET3 analgesic effects in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3-containing K2P channels as a druggable target for treating pain.

Epothilone B Benefits Nigrostriatal Pathway Recovery by Promoting Microtubule Stabilization After Intracerebral Hemorrhage.

BACKGROUND: Many 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 RESULTS: Intrastriatal 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. CONCLUSIONS: Our 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.