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.

Spatiotemporal Dynamics of the Molecular Expression Pattern and Intercellular Interactions in the Glial Scar Response to Spinal Cord Injury / 神经科学通报·英文版

Nerve regeneration in adult mammalian spinal cord is poor because of the lack of intrinsic regeneration of neurons and extrinsic factors - the glial scar is triggered by injury and inhibits or promotes regeneration. Recent technological advances in spatial transcriptomics (ST) provide a unique opportunity to decipher most genes systematically throughout scar formation, which remains poorly understood. Here, we first constructed the tissue-wide gene expression patterns of mouse spinal cords over the course of scar formation using ST after spinal cord injury from 32 samples. Locally, we profiled gene expression gradients from the leading edge to the core of the scar areas to further understand the scar microenvironment, such as neurotransmitter disorders, activation of the pro-inflammatory response, neurotoxic saturated lipids, angiogenesis, obstructed axon extension, and extracellular structure re-organization. In addition, we described 21 cell transcriptional states during scar formation and delineated the origins, functional diversity, and possible trajectories of subpopulations of fibroblasts, glia, and immune cells. Specifically, we found some regulators in special cell types, such as Thbs1 and Col1a2 in macrophages, CD36 and Postn in fibroblasts, Plxnb2 and Nxpe3 in microglia, Clu in astrocytes, and CD74 in oligodendrocytes. Furthermore, salvianolic acid B, a blood-brain barrier permeation and CD36 inhibitor, was administered after surgery and found to remedy fibrosis. Subsequently, we described the extent of the scar boundary and profiled the bidirectional ligand-receptor interactions at the neighboring cluster boundary, contributing to maintain scar architecture during gliosis and fibrosis, and found that GPR37L1_PSAP, and GPR37_PSAP were the most significant gene-pairs among microglia, fibroblasts, and astrocytes. Last, we quantified the fraction of scar-resident cells and proposed four possible phases of scar formation: macrophage infiltration, proliferation and differentiation of scar-resident cells, scar emergence, and scar stationary. Together, these profiles delineated the spatial heterogeneity of the scar, confirmed the previous concepts about scar architecture, provided some new clues for scar formation, and served as a valuable resource for the treatment of central nervous system injury.

Effects of a compound Chinese medicine Xinji' erkang on isoproterenol-induced ventricular remodeling in mice / 中西医结合学报

To investigate the effects of Xinji' erkang (XJEK), a compound Chinese herbal medicine, on isoproterenol-induced ventricular remodeling in mice.

The Expression of Twist, E-cadherin and β-catenin in Hepatocellular Carcinoma and Its Correlation with Recurrence, Metastasis and Prognosis / 中国肿瘤临床

Objective: To investigate the effect of Twist, β-catenin and E-cadherin on the recurrence and metastasis of hepatocellular carcinoma (HCC) and its correlation with clinical prognosis.Methods; Immunohistochemical staining (SP) was conducted to detect the expression of Twist, β-catenin and E-cadherin in 97 hepatocellular carcinoma patients (49 with recurrence and metastasis and 48 without recurrence and metastasis).Results: The recurrence and metastasis of HCC were correlated with clinical stage (P=0.000), but were not correlated with sex or age (P=0.424, P=0.738).The abnormal expression of Twist and β-catenin in the recurrence and metastasis group was higher than that in the group without recur-rence or metastasis (,0=-0.000, P=0.000).The positive ratio of E-cadherin in the recurrence and metastasis group was lower than that in the group without recurrence or metastasis (P=0.027).The mean survival was 28.880±3.285 months in patients with positive expression of Twist and 31.477±3.359 months in patients with positive expression of β-catenin.The median survival time of them was 26 and 28 months, respctively.The mean survival was 44.603±3.521 months in patients without Twist expression and 42.009±3.720 months in patients without β-catenin expression.The median survival time of them was 49 and 45 months, respectively.The survival of patients with positive expression of Twist and β-catenin was shorter than that in patients without expression of Twist and β-catenin (P=0.002, P=0.029).The mean survival time and median survival time of patients with Twist and β-catenin expression were 44.514±3.447 months and 49 months, respectively, significantly higher than those in patients without Twist and β-catenin expression (P=0.002), which were 29.110±3.581 months and 25 months, respectively.Conclusion: The overexpression of Twist and β-catenin as well as decreased expression of E-cad-herin may play critical roles in the recurrence and metastasis of HCC and indicate poor prognosis.

Effects of light on body weight,learning and memory of growing mice / 西安交通大学学报(医学版)

Objective To study the effects of light on body weight,learning and memory of mice.Methods Fifty mice aged 20 days were randomly assigned to one of the five groups: 200 W light group,100 W light group,60 W light group,40 W light group and normal control group,with 10 in each.They were exposed to different intensities of light 8 hours per day for 1 week.Then we monitored their body weight,examined the mean latency and inaccuracy number in step-down test,and examined the mean latency using a Morris' water maze to observe the effect of light pollution on the mice's learning and memory.Results Compared with the other four groups,there were significant decelerations of body weight increase in 200 W light group.No significant difference in body weight gain was found among the other four groups.The four light-treatment groups had no significant differences from control group in the mean latency,inaccuracy number in step-down test or the mean latency,or the mean crosses to the target in the Morris' water maze.Conclusion Short time high-intensity light can inhibit body weight increase in mice,but short-time light has no effect on the learning and memory of mice.