DGAMDA: Predicting miRNA-disease association based on dynamic graph attention network.

MiRNA (microRNA)-disease association prediction has essential applications for early disease screening. The process of traditional biological experimental validation is both time-consuming and expensive. However, as artificial intelligence technology continues to advance, computational methods have become efficient tools for predicting miRNA-disease associations. These methods often rely on the combination of multiple sources of association data and require improved feature mining. This study proposes a dynamic graph attention-based association prediction model, DGAMDA, which combines feature mapping and dynamic graph attention mechanisms through feature mining on a single miRNA-disease association network. DGAMDA effectively solves the problems of feature heterogeneity and inadequate feature mining by previous static graph attention mechanisms and achieves high-precision feature mining and association scoring prediction. We conducted a five-fold cross-validation experiment and obtained the mean values of Accuracy, Precision, Recall, and F1-score, which were .8986, .8869, .9115, and .8984, respectively. Our proposed model outperforms other advanced models in terms of experimental results, demonstrating its effectiveness in feature mining and association prediction based on a single association network. In addition, our model can also be used to predict miRNAs associated with unknown diseases.

Evaluating the effects of S-ketamine on postoperative delirium in elderly patients following total hip or knee arthroplasty under intraspinal anesthesia: a single-center randomized, double-blind, placebo-controlled, pragmatic study protocol.

Introduction: Postoperative delirium (POD) is an acute, transient brain disorder associated with decreased postoperative quality of life, dementia, neurocognitive changes, and mortality. A small number of trials have explored the role of S-ketamine in the treatment of POD due to its neuroprotective effects. Surprisingly, these trials have failed to yield supportive results. However, heterogeneity in delirium assessment methodologies, sample sizes, and outcome settings as well as deficiencies in S-ketamine use methods make the evidence provided by these studies less persuasive. Given the severe impact of POD on the health of elderly patients and the potential for S-ketamine to prevent it, we believe that designing a large sample size, and rigorous randomized controlled trial for further evaluation is necessary. Methods: This is a single-center, randomized, double-blind, placebo-controlled, pragmatic study. Subjects undergoing total hip or knee arthroplasty will be randomized in a 1:1 ratio to intervention (n = 186) and placebo (n = 186) groups. This trial aims to explore the potential role of S-ketamine in the prevention of POD. Its primary outcome is the incidence of POD within 3 postoperative days. Secondary outcomes include the number of POD episodes, the onset and duration of POD, the severity and subtype of POD, pain scores and opioid consumption, sleep quality, clinical outcomes, and safety outcomes. Discussion: To our knowledge, this is the first pragmatic study that proposes to use S-ketamine to prevent POD. We reviewed a large body of literature to identify potential preoperative confounding variables that may bias associations between the intervention and primary outcome. We will use advanced statistical methods to correct potential confounding variables, improving the test's power and external validity of test results. Of note, the patient population included in this trial will undergo intraspinal anesthesia. Although large, multicenter, randomized controlled studies have found no considerable difference in the effects of regional and general anesthesia on POD, patients receiving intraspinal anesthesia have less exposure to at-risk drugs, such as sevoflurane, propofol, and benzodiazepines, than patients receiving general anesthesia. At-risk drugs have been shown to negatively interfere with the neuroprotective effects of S-ketamine, which may be the reason for the failure of a large number of previous studies. There is currently a lack of randomized controlled studies evaluating S-ketamine for POD prevention, and our trial helps to fill a gap in this area.Trial registration: http://www.chictr.org.cn, identifier ChiCTR2300075796.

Depletion of PSMD14 suppresses bladder cancer proliferation by regulating GPX4.

Objective: The aim of this study was to investigate the role of deubiquitinase (DUB) 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) in patients with bladder cancer. Methods: From 2016 to 2018, 181 patients diagnosed with primary bladder cancer at the Affiliated Hospital of Qingdao University were recruited. The expression of PSMD14 in bladder cancer tissues was tested by immunochemistry. The association between PSMD14 expression and clinical and pathological data and outcomes of bladder cancer patients was determined. Overexpression and knockdown cells were constructed to evaluate the effects of PSMD14 on proliferation of bladder cancer cells. Results: Our results showed that PSMD14 was significantly overexpressed in bladder cancer tissues compared to adjacent non-tumor tissues (76.24% vs 23.76%, P = 0.02). The expression of PSMD14 was significantly higher in patients with larger tumor diameters (85.14% vs 70.09%, P = 0.019) and patients with a family history of cancer (92.16% vs 70.00%, P = 0.002). Patients with high expression of PSMD14 had poor disease-free survival (DFS) (HR = 2.89, 95% CI [1.247-6.711], P = 0.013). Gain and loss of function experiments demonstrated that PSMD14 deficiency inhibited bladder cancer cell proliferation. Additionally, depletion of PSMD14 suppressed bladder cancer cell growth via down-regulation of GPX4, and the promotion of PSMD14-induced cell growth was observably reversed by the GPX4 inhibitor RSL3. Conclusion: We determined that PSMD14 is highly expressed in bladder cancer tissues, and that PSMD14 expression correlated with poor disease-free survival. Depletion of PSMD14 could inhibit the proliferation of bladder cancer cells through the downregulation of GPX4. Therefore, PSMD14 may be an effective target for the treatment of bladder cancer.

Establishment and Verification of a Gene Signature for Diagnosing Type 2 Diabetics by WGCNA, LASSO Analysis, and In Vitro Experiments.

Objective: The incidence and prevalence of type 2 diabetes are increasing with age. Nevertheless, there is lack of sensitive diagnostic tools and effective therapeutic regimens. We aimed to establish and verify a practical and valid diagnostic tool for this disease. Methods: WGCNA was presented on the expression profiling of type 2 diabetic and normal islets in combined GSE25724 and GSE38642 datasets. By LASSO Cox regression analyses, a gene signature was constructed based on the genes in diabetes-related modules. ROC curves were plotted for assessing the diagnostic efficacy. Correlations between the genes and immune cell infiltration and pathways were analyzed. BST2 and BTBD1 expression was verified in glucotoxicity-induced and normal islet ß cells. The influence of BST2 on ß cell dysfunction was investigated under si-BST2 transfection. Results: Totally, 14 coexpression modules were constructed, and red and cyan modules displayed the correlations to diabetes. The LASSO gene signature (BST2, BTBD1, IFIT1, IFIT3, and RTP4) was developed. The AUCs in the combined datasets and GSE20966 dataset were separately 0.914 and 0.910, confirming the excellent performance in diagnosing type 2 diabetes. Each gene in the model was distinctly correlated to immune cell infiltration and key signaling pathways (TGF-ß and P53, etc.). The abnormal expression of BST2 and BTBD1 was confirmed in glucotoxicity-induced ß cells. BST2 knockdown ameliorated ß cell dysfunction and altered the activation of TGF-ß and P53 pathways. Conclusion: Our findings propose a gene signature with high efficacy to diagnose type 2 diabetes, which could assist and improve early diagnosis and therapy.

Mechanisms of Dexmedetomidine in Neuropathic Pain.

Dexmedetomidin is a new-generation, highly selective α2 adrenergic receptor agonist with a large number of advantages, including its sedative and analgesic properties, its ability to inhibit sympathetic nerves, its reduced anesthetic dosage, its hemodynamic stability, its mild respiratory depression abilities, and its ability to improve postoperative recognition. Its safety and effectiveness, as well as its ability to provide a certain degree of comfort to patients, make it a useful anesthetic adjuvant for a wide range of clinical applications. For example, dexmedetomidine is commonly used in patients undergoing general anesthesia, and it also exerts sedative effects during tracheal intubation or mechanical ventilation in intensive care unit patients. In recent years, with the deepening of clinical research on dexmedetomidine, the drug is still applied in the treatment of spastic pain, myofascial pain, neuropathic pain, complex pain syndrome, and chronic headache, as well as for multimodal analgesia. However, we must note that the appropriateness of patient and dose selection should be given attention when using this drug; furthermore, patients should be observed for adverse reactions such as hypotension and bradycardia. Therefore, the safety and effectiveness of this drug for long-term use remain to be studied. In addition, basic experimental studies have also found that dexmedetomidine can protect important organs, such as the brain, heart, kidney, liver, and lung, through various mechanisms, such as antisympathetic effects, the inhibition of apoptosis and oxidative stress, and a reduction in the inflammatory response. Moreover, the neuroprotective properties of dexmedetomidine have received the most attention from scholars. Hence, in this review, we mainly focus on the characteristics and clinical applications of dexmedetomidine, especially the role of dexmedetomidine in the nervous system and the use of dexmedetomidine in the relief of neuropathic pain.

The Application and Analytical Pathway of Dexmedetomidine in Ischemia/Reperfusion Injury.

Ischemia/reperfusion cerebral injury can cause serious damage to nerve cells. The injured organelles are cleared by autophagy eventually, which is critical for cell survival. Dexmedetomidine is neuroprotective in various ischemia/reperfusion models. Mitochondrial calcium uniporter (MCU) is the most important channel of mitochondrial Ca2+ influx into mitochondria, where Ca2+ has a potential effect on mitochondrial autophagy. However, the role of MCU in the changes of mitophagy and autophagy caused by dexmedetomidine is unknown. In this study, we constructed an in vitro I/R model by subjecting the oxygen and glucose deprivation/reperfusion model to SH-SY5Y cells to mimic the cerebral I/R injury. We found that postconditioning with dexmedetomidine and 3-methyladenine (3MA, an autophagy inhibitor) increased the cell survival meanwhile reduced the production of autophagic vesicles and the expression of LC3 and Beclin 1. This process also increased the expression of BCL-2, P62, and TOM20. After applied with spermine (MCU-specific agonist), the expression of autophagy proteins by dexmedetomidine was reversed, and the same changes were also observed in immunofluorescence. The results of our study suggested that dexmedetomidine can inhibit MCU and reduce excessive mitophagy and autophagy for conferring protection against I/R injury.

Effects of sevoflurane on rats with ischemic brain injury and the role of the TREK-1 channel.

The purpose of this investigation was to determine the effects of sevoflurane on rats with ischemic brain injury and to determine the potential role of the TREK-1 channel in this process. Normal rats were randomly divided into three groups: Sham operation, sevoflurane anesthesia or chloral hydrate anesthesia group, an additional group of TREK-1 knockout rats were also studied. Semi-quantitative PCR and western blot analysis confirmed the lack of TREK-1 expression in the brain of TREK-1 knockout rats. The thread-tie method was used to establish middle cerebral artery occlusion (MCAO) model to induce cerebral ischemic brain injury. All rates were treated for 4 days prior to ischemia (for 2 h) followed by a 24 h reperfusion period. Physiological indexes of rats in each group both prior to and after surgery showed no statistical difference (P>0.05). Neurological function was scored both before (no statistical difference) and after surgery where it was found to be significantly better (lower score) in the sevoflurane anesthesia group than in chloral hydrate anesthesia and TREK-1 knockout groups (P<0.01). The area of cerebral infarction was measured by triphenyl tetrazolium chloride staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to detect the apoptosis of brain cells. TTC staining showed different degrees of cerebral infarction in the various groups; the area of cerebral infarction in sevoflurane anesthesia group was significantly lower than that in chloral hydrate anesthesia and TREK-1 knockout groups (P<0.01). TUNEL assay showed that the number of TUNEL-positive cells was significantly lower in sevoflurane anesthesia group than in TREK-1 knockout and chloral hydrate anesthesia groups (P<0.01). In conclusion, results from this investigation showed that sevoflurane can protect the nerve function of rats with cerebral ischemic brain injury possibly by affecting the expression of proteins involved in the TREK-1 signaling pathway.

Propofol-induced neurotoxicity in hESCs involved in activation of miR-206/PUMA signal pathway.

BACKGROUND AND OBJECTIVE: Studies in developing animals have demonstrated that when anesthetic agents, such as propofol, are early administered in life, it can lead to neuronal cell death and learning disabilities. However, the mechanisms causing these effects remains unknown. A recent report found that propofol could significantly upregulat miR-206 expression in the human ASCs. miR-206 could also induce apoptosis in human malignant cancers. Therefore, in this study, we hypothesized that propofol induces neurotoxicity in human embryonic stem cells (hESCs). METHODS: hESCs were exposed to propofol (50 µM) for 6 hr and cell death was assessed using TUNEL staining, and cleaved caspase-3 expression. miR-206 was knocked down using antagomir. PUMA was knocked down using a small interfering RNA. microRNA-206 (miR-206) expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). PUMA protein expression was detected using western blot assay. RESULTS: hESCs exposed to propofol showed a significant increase in TUNEL positive cells and cleaved caspase-3 expression, followed by the upregulation of miR-206 and PUMA expression. Targeting PUMA inhibits propofol-induced cell apoptosis; miR-206 knockdown decreased propofol-induced cell apoptosis, cleaved caspase-3 and PUMA expression. CONCLUSIONS: Propofol induce s cell death in hESC-derived neurons via activation of miR-206/PUMA signal pathway.

The Effect of Propofol on Mitochondrial Fission during Oxygen-Glucose Deprivation and Reperfusion Injury in Rat Hippocampal Neurons.

The neuroprotective role of propofol in transient global and focal cerebral ischemia reperfusion (I/R) animal model has recently been highlighted. However, no studies have conducted to explore the relationship between mitochondrial fission/fusion and I/R injury under the intervention of propofol. Moreover, neuroprotective mechanism of propofol is yet unclear. Culturing primary hippocampal cells were subjected to oxygen-glucose deprivation and re-oxygenation (OGD/R) model, as a model of cerebral I/R in vitro. Methods CCK-8 assay was used to test the effect of propofol on cell viability. We examined the effect of propofol on mitochondrial ultrastructure and mitochondrial fission evoked by OGD/R with transmission electron microscopy and immunofluorescence assay. To investigate possible neuroprotective mechanisms, the authors then examined whether propofol could inhibit calcium-overload, calcineurin (CaN) activation and the phosphorylation of dynamin-related protein 1 (Drp1) during the period of OGD/R, as well as the combination of Drp1-ser 637 and fission 1 (Fis1) protein by immunofluorescence assay, ELISA and double-labeling immunofluorescence analysis. Finally, the expression of Drp1-ser 637 and Fis1, apoptosis inducing factor (AIF) and cytochrome C (Cyt C) were detected by western blot. When added in culture media during OGD period, propofol (0.1µM-50µM) could alleviate neurons injury and protect mitochondrial ultrastructure, meanwhile inhibit mitochondrial fission. Furthermore, the concentration of intracellular free Ca2+, CaN activition and the phosphorylation of Drp1-ser637 were suppressed, as well as the translocation and combination of Drp1-ser 637 and Fis1. The authors also found that the expression of Cyt C, AIF, Drp1-ser637 and Fis1 were down-regulated. Notably, high dose of propofol (100µM-200µM) were confirmed to decrease the survival of neurons based on results of cell viability. Propofol could inhibit mitochondrial fission and mitochondrial apoptotic pathway evoked by OGD/R in rat hippocampal neurons, which may be via depressing calcium-overload.