The E3 ubiquitin ligase NEDD4-1 protects against acetaminophen-induced liver injury by targeting VDAC1 for degradation

Acetaminophen (APAP) overdose is a major cause of liver injury. Neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ubiquitin ligase that has been implicated in the pathogenesis of numerous liver diseases; however, its role in APAP-induced liver injury (AILI) is unclear. Thus, this study aimed to investigate the role of NEDD4-1 in the pathogenesis of AILI. We found that NEDD4-1 was dramatically downregulated in response to APAP treatment in mouse livers and isolated mouse hepatocytes. Hepatocyte-specific NEDD4-1 knockout exacerbated APAP-induced mitochondrial damage and the resultant hepatocyte necrosis and liver injury, while hepatocyte-specific NEDD4-1 overexpression mitigated these pathological events both in vivo and in vitro. Additionally, hepatocyte NEDD4-1 deficiency led to marked accumulation of voltage-dependent anion channel 1 (VDAC1) and increased VDAC1 oligomerization. Furthermore, VDAC1 knockdown alleviated AILI and weakened the exacerbation of AILI caused by hepatocyte NEDD4-1 deficiency. Mechanistically, NEDD4-1 was found to interact with the PPTY motif of VDAC1 through its WW domain and regulate K48-linked ubiquitination and degradation of VDAC1. Our present study indicates that NEDD4-1 is a suppressor of AILI and functions by regulating the degradation of VDAC1.

Nuciferine protects against high-fat diet-induced hepatic steatosis and insulin resistance via activating TFEB-mediated autophagy-lysosomal pathway

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy-lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.

Establishment and evaluation of anesthesia nurses training system for postoperative delirium assessment / 中华麻醉学杂志

Objective:To establish training system for postoperative delirium (POD) assessment and evaluate the efficacy of training for anesthesia nurses.Methods:Sixteen nurse anesthetists of both sexes in our hospital were selected and received the systemic training for POD assessment.The training system included questionnaire survey, theoretical teaching, simulated visit, clinical observation, independent evaluation, centralized question-answering, evaluation of efficacy and random inspection.The level of POD knowledge tests were performed before the training and at the end of the fourth week of independent evaluation, respectively.At week 1 and 4 of independent evaluation, the diagnostic rate of POD and sensitivity and specificity of the assessment were calculated, and Kappa consistency analysis was used to assess the consistency between anesthesia nurses and training group in diagnosis of POD.In the first week of the third month after the end of training, the evaluation results were randomly inspected, the POD diagnosis rate was calculated between the anesthesia nurses and the training group, and the consistency analysis was conducted.Results:Compared with the scores of POD knowledge questionnaire and sensitivity of the assessment of the anesthesia nurses in the first week of training, the scores were significantly increased ( P<0.05), and no significant change was found in the POD diagnosis rate in the fourth week of training ( P>0.05). Compared with the training group, the diagnosis rate of POD of anesthesia nurses was significantly decreased in the first week of training ( P<0.05), and no significant change was found at the fourth week of training ( P>0.05). In the first and fourth weeks of training, the Kappa value of anesthesia nurses and the training group was 0.676 and 0.954 ( P<0.001), respectively.In the first week of the third month after the end of training, the Kappa value between anesthesia nurses and the training group in diagnosis of POD was 0.862 ( P<0.05). Conclusion:The training system of POD assessment has been successfully established, and the standardized anesthesia nurses training of POD has been achieved with good results.

Comparison of perioperative outcome after endovascular repair between symptomatic and asymptomatic abdominal aortic aneurysm / 中华外科杂志

<p><b>OBJECTIVE</b>To compare the perioperative outcome after endovascular repair (EVAR) of symptomatic abdominal aneurysms (S-AAAs) and elective non-symptomatic AAAs (E-AAAs).</p><p><b>METHODS</b>From January 2008 to February 2013, a total of 230 non-ruptured AAA patients treated by EVAR met the inclusion criteria. S-AAAs were present in 43 (18.7%) patients, 40 patients were male, 3 patients were female, aged (69 ± 10) years and E-AAAs in 187 (81.3%) patients, 162 of which were male, the other 25 patients were female, aged (71 ± 9) years. Patients were followed up at 1 month after EVAR. The primary outcome of the study was perioperative mortality, secondary outcome included procedural data and major perioperative adverse events.</p><p><b>RESULTS</b>At baseline, there were no differences in age, gender, American Society of Anesthesiologists classification score, and basic diseases. S-AAA patients had larger aneurysms on average (6.00 (1.97) cm vs. 5.10 (1.7) cm, Z = 2.51, P = 0.01). S-AAA patients had shorter preoperative hospitalization (5.00 (5.0) days vs. 7.00 (4.0) days, Z = 1.86, P = 0.02). No differences in the perioperative mortality, respectively, 0 and 1.1% (P = 0.66). Technical success and clinical success were all 100% and the other procedure data was similar (P > 0.05). The occurrence of major adverse events, including mortality, within the 30-day after EVAR were similar between S-AAA and E-AAA patients (0 vs. 2.1%, P = 0.43).</p><p><b>CONCLUSIONS</b>There is no difference in perioperative outcome between S-AAA and elective E-AAA patients treated by EVAR. More study is needed to compare the middle and long-outcome between S-AAAs and E-AAAs after EVAR.</p>