Alkaline sphingomyelinase deficiency impairs intestinal mucosal barrier integrity and reduces antioxidant capacity in dextran sulfate sodium-induced colitis

BACKGROUND Ulcerative colitis is a chronic inflammatory disease of the colon with an unknown etiology.Alkaline sphingomyelinase(alk-SMase)is specifically expressed by intestinal epithelial cells,and has been reported to play an anti-inflammatory role.However,the underlying mechanism is still unclear.AIM To explore the mechanism of alk-SMase anti-inflammatory effects on intestinal barrier function and oxidative stress in dextran sulfate sodium(DSS)-induced colitis.METHODS Mice were administered 3%DSS drinking water,and disease activity index was determined to evaluate the status of colitis.Intestinal permeability was evaluated by gavage administration of fluorescein isothiocyanate dextran,and bacterial translocation was evaluated by measuring serum lipopolysaccharide.Intestinal epithelial cell ultrastructure was observed by electron microscopy.Western blotting and quantitative real-time reverse transcription-polymerase chain reaction were used to detect the expression of intestinal barrier proteins and mRNA,respectively.Serum oxidant and antioxidant marker levels were analyzed using commercial kits to assess oxidative stress levels.RESULTS Compared to wild-type(WT)mice,inflammation and intestinal permeability in alk-SMase knockout(KO)mice were more severe beginning 4 d after DSS induction.The mRNA and protein levels of intestinal barrier proteins,including zonula occludens-1,occludin,claudin-3,claudin-5,claudin-8,mucin 2,and secretory immunoglobulin A,were significantly reduced on 4 d after DSS treatment.Ultrastructural observations revealed progressive damage to the tight junctions of intestinal epithelial cells.Furthermore,by day 4,mitochondria appeared swollen and degenerated.Additionally,compared to WT mice,serum malondialdehyde levels in KO mice were higher,and the antioxidant capacity was significantly lower.The expression of the transcription factor nuclear factor erythroid 2-related factor 2(Nrf2)in the colonic mucosal tissue of KO mice was significantly decreased after DSS treatment.mRNA levels of Nrf2-regulated downstream antioxidant enzymes were also decreased.Finally,colitis in KO mice could be effectively relieved by the injection of tertiary butylhydroquinone,which is an Nrf2 activator.CONCLUSION Alk-SMase regulates the stability of the intestinal mucosal barrier and enhances antioxidant activity through the Nrf2 signaling pathway.

CircLphn3 protects the blood-brain barrier in traumatic brain injury

Circular RNAs(circRNAs)are a new and large group of non-coding RNA molecules that are abundantly expressed in the central nervous system.However,very little is known about their roles in traumatic brain injury.In this study,we firstly screened differentially expressed circ RNAs in normal and injured brain tissues of mice after traumatic brain injury.We found that the expression of circ Lphn3 was substantially decreased in mouse models of traumatic brain injury and in hemin-treated b End.3(mouse brain cell line)cells.After overexpressing circ Lphn3 in b End.3 cells,the expression of the tight junction proteins,ZO-1,ZO-2,and occludin,was upregulated,and the expression of mi R-185-5 p was decreased.In b End.3 cells transfected with mi R-185-5 p mimics,the expression of ZO-1 was decreased.Dual-luciferase reporter assays showed that circ Lphn3 bound to mi R-185-5 p,and that mi R-185-5 p bound to ZO-1.Additionally,circ Lphn3 overexpression attenuated the hemin-induced high permeability of the in vitro b End.3 cell model of the blood-brain barrier,while mi R-185-5 p transfection increased the permeability.These findings suggest that circ Lphn3,as a molecular sponge of mi R-185-5 p,regulates tight junction proteins'expression after traumatic brain injury,and it thereby improves the permeability of the blood-brain barrier.This study was approved by the Animal Care and Use Committee of Chongqing Medical University of China(approval No.2021-177)on March 22,2021.

The DIRECT consortium and the REST-meta-MDD project:towards neuroimaging biomarkers of major depressive disorder

Despite a growing neuroimaging literature on the pathophysiology of major depressive disorder(MDD),repro-ducible findings are lacking,probably reflecting mostly small sample sizes and heterogeneity in analytic approaches.To address these issues,the Depression Imaging REsearch ConsorTium(DIRECT)was launched.The REST-meta-MDD project,pooling 2428 functional brain images processed with a standardized pipeline across all participating sites,has been the first effort from DIRECT.In this review,we present an overview of the moti-vations,rationale,and principal findings of the studies so far from the REST-meta-MDD project.Findings from the first round of analyses of the pooled repository have included alterations in functional connectivity within the default mode network,in whole-brain topological properties,in dynamic features,and in functional lat-eralization.These well-powered exploratory observations have also provided the basis for future longitudinal hypothesis-driven research.Following these fruitful explorations,DIRECT has proceeded to its second stage of data sharing that seeks to examine ethnicity in brain alterations in MDD by extending the exclusive Chinese original sample to other ethnic groups through international collaborations.A state-of-the-art,surface-based preprocessing pipeline has also been introduced to improve sensitivity.Functional images from patients with bipolar disorder and schizophrenia will be included to identify shared and unique abnormalities across diag-nosis boundaries.In addition,large-scale longitudinal studies targeting brain network alterations following antidepressant treatment,aggregation of diffusion tensor images,and the development of functional magnetic resonance imaging-guided neuromodulation approaches are underway.Through these endeavours,we hope to accelerate the translation of functional neuroimaging findings to clinical use,such as evaluating longitudinal effects of antidepressant medications and developing individualized neuromodulation targets,while building an open repository for the scientific community.

Advances in neuroimaging studies of alcohol use disorder(AUD)

Alcohol use disorder(AUD)is a worldwide problem and themost common substance use disorder.Chronic alcohol consumptionmay have negative effects on the body,the mind,the family,and even society.With the progress of current neuroimaging methods,an increasing number of imaging techniques are being used to objectively detect brain impairment induced by alcoholism and serve a vital role in the diagnosis,prognosis,and treatment assessment of AUD.This article organizes and analyzes the research on alcohol dependence concerning the main noninvasive neuroimaging methods,structural magnetic resonance imaging,functional magnetic resonance imaging,and electroencephalography,as well as the most common noninvasive brain stimulation-transcranial magnetic stimulation,and intersperses the article with joint intra-and intergroup studies,providing an outlook on future research directions.