Vialinin A alleviates oxidative stress and neuronal injuries after ischaemic stroke by accelerating Keap1 degradation through inhibiting USP4-mediated deubiquitination.

BACKGROUND: Oxidative stress is known as a hallmark of cerebral ischaemia‒reperfusion injury and it exacerbates the pathologic progression of ischaemic brain damage. Vialinin A, derived from a Chinese edible mushroom, possesses multiple pharmacological activities in cancer, Kawasaki disease, asthma and pathological scarring. Notably, vialinin A is an inhibitor of ubiquitin-specific peptidase 4 (USP4) that shows anti-inflammatory and antioxidative properties. However, the precise effect of vialinin A in ischaemic stroke, as well as its underlying mechanisms, remains largely unexplored. PURPOSE: The present research focuses on the impacts of vialinin A on oxidative stress and explores the underlying mechanisms involved while also examining its potentiality as a therapeutic candidate for ischaemic stroke. METHODS: Mouse ischaemic stroke was conducted by MCAO surgery. Vialinin A was administered via lateral ventricular injection at a dose of 2 mg/kg after reperfusion. Subsequent experiments were meticulously conducted at the appropriate time points. Stroke outcomes were evaluated by TTC staining, neurological score, Nissl staining and behavioural analysis. Co-IP assays were operated to examine the protein-protein interactions. Immunoblot analysis, qRT-PCR, and luciferase reporter assays were conducted to further investigate its underlying mechanisms. RESULTS: In this study, we initially showed that administration of vialinin A alleviated cerebral ischaemia‒reperfusion injury-induced neurological deficits and neuronal apoptosis. Furthermore, vialinin A, which is an antioxidant, reduced oxidative stress injury, promoted the activation of the Keap1-Nrf2-ARE signaling pathway and increased the protein degradation of Keap1. The substantial neuroprotective effects of vialinin A against ischaemic stroke were compromised by the overexpression of USP4. Mechanistically, vialinin A inhibited the deubiquitinating enzymatic activity of USP4, leading to enhanced ubiquitination of Keap1 and subsequently promoting its degradation. This cascade caused the activation of Nrf2-dependent antioxidant response, culminating in a reduction of neuronal apoptosis and the amelioration of neurological dysfunction following ischaemic stroke. CONCLUSIONS: This study demonstrates that inhibition of USP4 to activate Keap1-Nrf2-ARE signaling pathway may represent a mechanism by which vialinin A conferred protection against cerebral ischaemia‒reperfusion injury and sheds light on its promising prospects as a therapeutic intervention for ischaemic stroke.

A retrospective study of mortality for perioperative cardiac arrests toward a personalized treatment.

Perioperative cardiac arrest (POCA) is associated with a high mortality rate. This work aimed to study its prognostic factors for risk mitigation by means of care management and planning. A database of 380,919 surgeries was reviewed, and 150 POCAs were curated. The main outcome was mortality prior to hospital discharge. Patient demographic, medical history, and clinical characteristics (anesthesia and surgery) were the main features. Six machine learning (ML) algorithms, including LR, SVC, RF, GBM, AdaBoost, and VotingClassifier, were explored. The last algorithm was an ensemble of the first five algorithms. k-fold cross-validation and bootstrapping minimized the prediction bias and variance, respectively. Explainers (SHAP and LIME) were used to interpret the predictions. The ensemble provided the most accurate and robust predictions (AUC = 0.90 [95% CI, 0.78-0.98]) across various age groups. The risk factors were identified by order of importance. Surprisingly, the comorbidity of hypertension was found to have a protective effect on survival, which was reported by a recent study for the first time to our knowledge. The validated ensemble classifier in aid of the explainers improved the predictive differentiation, thereby deepening our understanding of POCA prognostication. It offers a holistic model-based approach for personalized anesthesia and surgical treatment.

Application of parecoxib in post-uvulopalatopharyngoplasty analgesia.

OBJECTIVE: To investigate the postoperative analgesic effects of parecoxib for uvulopalatopharyngoplasty (UPPP). METHODS: Patients with obstructive sleep apnoea syndrome who underwent UPPP were randomly divided into two groups. In group A, the incision-local block was performed with 5 ml of 0.5% ropivacaine injected subcutaneously before the end of surgery, then 20 ml of physiological saline was injected intravenously every 12 h for 2 days. In group B, in addition to the incision-local block, 40 mg parecoxib was injected intravenously 30 min before the end of UPPP and 40 mg parecoxib was injected intravenously every 12 h for 2 days. Postoperative pain was measured using a visual analogue scale (VAS). Adverse reactions were recorded. RESULTS: A total of 40 patients were randomized (n = 20 per group). Under resting conditions, the mean ± SD VAS pain scores were significantly higher in group A compared with group B at 24 h and 48 h after UPPP (24 h 4.0 ± 0.8 versus 2.6 ± 0.6; 48 h 3.8 ± 0.7 versus 2.4 ± 0.5; respectively). Under swallowing conditions, the mean ± SD VAS pain scores were significantly higher in group A compared with group B at 8 h, 24 h and 48 h after UPPP. Postoperative adverse reactions were similar in the two groups. CONCLUSION: Intravenous parecoxib combined with incision-local ropivacaine provided effective postoperative analgesia for patients with obstructive sleep apnoea syndrome, undergoing UPPP.