USP11 modulates mitotic progression and senescence by regulating the p53-p21 axis through MDM2 deubiquitination.

USP11 is overexpressed in colorectal cancer (CRC) and breast cancer tissues compared to normal tissues, suggesting a role in promoting cell proliferation and inhibiting cell death. In this study, we observed that depleting USP11 inhibits cell proliferation and delays cell cycle progression. This depletion leads to increased p53 protein levels due to an extended half-life, resulting in elevated p21 mRNA levels in a p53-dependent manner. The rise in p53 protein upon USP11 depletion is linked to a reduced half-life of MDM2, a known E3 ligase for p53, via enhanced polyubiquitination of MDM2. These findings indicate that USP11 might act as a deubiquitinase for MDM2, regulating the MDM2-p53-p21 axis. Additionally, USP11 depletion promotes the induction of senescent cells in a manner dependent on its deubiquitinase activity. Our findings provide insights into the physiological significance of high USP11 expression in primary tumors and its reduction in senescent cells, highlighting its potential as a therapeutic target.

Risk Factors and Temporal Patterns of Poststroke Epilepsy across Stroke Subtypes: Insights from a Nationwide Cohort Study in Korea.

INTRODUCTION: We aimed to investigate the risk factors associated with poststroke epilepsy (PSE) among patients with different subtypes of stroke, focusing on age-related risk and time-varying effects of stroke subtypes on PSE development. METHODS: A retrospective, nationwide, population-based cohort study was conducted using Korean National Health Insurance Service-National Sample Cohort data. Patients hospitalized with newly diagnosed stroke from 2005 to 2015 were included and followed up for up to 10 years. The primary outcome was the development of PSE, defined as having a diagnostic code and a prescription for anti-seizure medication. Multivariable Cox proportional hazard models were used to estimate PSE hazard ratios (HRs), and time-varying effects were also assessed. RESULTS: A total of 8,305 patients with ischemic stroke, 1,563 with intracerebral hemorrhage (ICH), and 931 with subarachnoid hemorrhage (SAH) were included. During 10 years of follow-up, 4.6% of patients developed PSE. Among patients with ischemic stroke, significant risk factors for PSE were younger age (HR = 1.47), living in rural areas (HR = 1.35), admission through the emergency room (HR = 1.33), and longer duration of hospital stay (HR = 1.45). Time-varying analysis revealed elevated HRs for ICH and SAH, particularly in the first 2 years following the stroke. The age-specific HRs also showed an increased risk for those under the age of 65, with a noticeable decrease in risk beyond that age. CONCLUSION: The risk of developing PSE varies according to stroke subtype, age, and other demographic factors. These findings underscore the importance of tailored poststroke monitoring and management strategies to mitigate the risk of PSE.

Changes in heart rate variability over time from symptom onset of transient global amnesia.

Transient global amnesia (TGA) often involves precipitating events associated with changes in autonomic nervous system (ANS), and heart rate variability (HRV) reflects the ANS state. This study aimed to investigate HRV changes after TGA. A retrospective analysis of HRV included patients diagnosed with TGA between January 2015 and May 2020. The time and frequency domains of HRV were compared among three groups: early (< 1 week after TGA, n = 19), late (1-4 weeks after TGA, n = 38), and healthy control (HC, n = 19). The Pearson's correlation between time and time-domain HRV was also examined. The standard deviation of NN intervals (SDNN) (early, 47.2; late, 35.5; HC, 41.5; p = 0.033) and root mean square of successive RR interval differences (RMSSD) (early, 38.5; late, 21.3; HC, 31.0; p = 0.006) differed significantly among the three groups. Post-hoc analysis showed statistically significant differences only in the early and late groups in both SDNN (p = 0.032) and RMSSD (p = 0.006) values. However, the frequency domain with total power, low-frequency and high-frequency powers, and low-frequency/high-frequency ratio did not differ. SDNN (Pearson correlation coefficient =- 0.396, p = 0.002) and RMSSD (Pearson correlation coefficient =- 0.406, p = 0.002) were negatively correlated with time after TGA. Changes in HRV occurred over time after the onset of TGA, with the pattern showing an increase in the first week and then a decrease within 4 weeks.

Sirtuin 3 regulates astrocyte activation by reducing Notch1 signaling after status epilepticus.

Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3 exerts anti-inflammatory effects in several neuropathophysiological disorders. As epilepsy is a common neurological disease, in the present study, we investigated the role of Sirt3 in astrocyte activation and inflammatory processes after epileptic seizures. We found the elevated expression of Sirt3 within reactive astrocytes as well as in the surrounding cells in the hippocampus of patients with temporal lobe epilepsy and a mouse model of pilocarpine-induced status epilepticus (SE). The upregulation of Sirt3 by treatment with adjudin, a potential Sirt3 activator, alleviated SE-induced astrocyte activation; whereas, Sirt3 deficiency exacerbated astrocyte activation in the hippocampus after SE. In addition, our results showed that Sirt3 upregulation attenuated the activation of Notch1 signaling, nuclear factor kappa B (NF-κB) activity, and the production of interleukin-1ß (IL1ß) in the hippocampus after SE. By contrast, Sirt3 deficiency enhanced the activity of Notch1/NF-κB signaling and the production of IL1ß. These findings suggest that Sirt3 regulates astrocyte activation by affecting the Notch1/NF-κB signaling pathway, which contributes to the inflammatory response after SE. Therefore, therapies targeting Sirt3 may be a worthy direction for limiting inflammatory responses following epileptic brain injury.