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.

Alkaline sphingomyelinase(NPP7) in hepatobiliary diseases: A field that needs to be closely studied

Alkaline sphingomyelinase cleaves phosphocholine from sphingomyelin, platelet-activating factor, lysophosphatidylcholine, and less effectively phosphatidyl-choline. The enzyme shares no structure similarities with acid or neutral sphingomyelinase but belongs to ectonucleotide pyrophosphatase/phosphodiesterase(NPP) family and therefore is also called NPP7 nowadays. The enzyme is expressed in the intestinal mucosa in many species and additionally in human liver. The enzyme in the intestinal tract has been extensively studied but not that in human liver. Studies on intestinal alkaline sphingomyelinase show that it inhibits colonic tumorigenesis and inflammation, hydrolyses dietary sphingomyelin, and stimulates cholesterol absorption. The review aims to summarize the current knowledge on liver alkaline sphingomyelinase in human and strengthen the necessity for close study on this unique human enzyme in hepatobiliary diseases.

Inhibition of extracellular vesicle pathway using neutral sphingomyelinase inhibitors as a neuroprotective treatment for brain injury

Traumatic brain injury is a sudden trauma or blow on the head,and severe traumatic brain injury is a major cause of death and disability worldwide.The acute and chronic consequences following traumatic brain injury can lead to progressive secondary neurodegenerative changes and cognitive dysfunction.To date,there is no effective pharmaceutical products for the treatment to reduce secondary damage after brain injury.The discovery of extracellular vesicles has attracted considerable scientific attention due to their role in cell-to-cell communication.Extracellular vesicles have shown their potential to carry not only biological molecules but also as a drug delivery vehicle.As a carrier of molecular information,extracellular vesicles have been involved in physiological functions as well as in the modulation of immune responses.Here,we aim to provide new insights into the contrasting role of extracellular vesicles in the propagation of inflammatory responses after brain injury.As a carrier of pro-inflammatory molecules,their role as functional mediators in the pathophysiology of brain injury is discussed,addressing the inhibition of the extracellular vesicle pathway as an anti-inflammatory or neuroprotective approach to improve the outcome of both acute and chronic inflammation following brain injury.Here,we summarize therapeutic strategies to diminish the risk the neurodegeneration post brain injury and propose that neutral sphingomyelinase inhibitors could be used as potentially useful therapeutic agents for the treatment of brain injury associated neuroinflammation.

The relationship among amyloid-βdeposition,sphingomyelin level,and the expression and function of P-glycoprotein in Alzheimer’s disease pathological process

In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.

The yins and yangs of ceramide

Since their discovery over 100 years ago, sphingolipids have caught the eyes and the imagination of scientists.Modern science has made many new insights on the cell biology and day-to-day functions of many integral sphingolipids, especially those of ceramide. Ceramide is recognized as a vital second messenger in the signal transduction process mediated by receptors of many cytokines and growth factors.A great part of our current understanding of ceramide has been achieved from apoptosis-related studies, however recent data in the fields of immunology, endocrinology and neurobiology, also suggest a fundamental involvement of ceramide in the onset of diseases. Therefore, understanding the biology of ceramide could be a key to unraveling many biological mechanisms and provide information for the treatment of some common diseases.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model

Background Cognitive decline in Alzheimer’s disease(AD)is associated with hyperphosphorylated tau(pTau)propagation between neurons along synaptically connected networks,in part via extracellular vesicles(EVs).EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin.We report,for the first time,that human tau expression elevates brain ceramides and nSMase2 activity.Methods To determine the therapeutic benefit of inhibiting this elevation,we evaluated PDDC,the first potent,selective,orally bioavailable,and brain-penetrable nSMase2 inhibitor in the transgenic PS19 AD mouse model.Additionally,we directly evaluated the effect of PDDC on tau propagation in a mouse model where an adeno-associated virus(AAV)encoding P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus.The contralateral transfer of the double mutant human tau to the dentate gyrus was monitored.We examined ceramide levels,histopathological changes,and pTau content within EVs isolated from the mouse plasma.Results Similar to human AD,the PS19 mice exhibited increased brain ceramide levels and nSMase2 activity;both were completely normalized by PDDC treatment.The PS19 mice also exhibited elevated tau immunostaining,thinning of hippocampal neuronal cell layers,increased mossy fiber synaptophysin immunostaining,and glial activation,all of which were pathologic features of human AD.PDDC treatment reduced these changes.The plasma of PDDC-treated PS19 mice had reduced levels of neuronal-and microglial-derived EVs,the former carrying lower pTau levels,compared to untreated mice.In the tau propagation model,PDDC normalized the tau-induced increase in brain ceramides and significantly reduced the amount of tau propagation to the contralateral side.Conclusions PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity,leading to the slowing of tau spread in AD mice.

A novel SMPD1 mutation in two Chinese sibling patients with type B Niemann-Pick disease

Type B Niemann-Pick disease is an autosomal recessive sphingolipidosis due to mutations in the sphingomyelin phosphodiesterase 1 gene （SMPD1）, Here we present molecular findings for two sibling patients. One mutation V36A due to c.107T〉C in exon 1 is a single nucleotide polymorphism and the other N522S due to c.1565 A〉G in exon 6 is a novel missense mutation. This non-fatal missense mutation leads to -20% residual lysosomal acid sphingomyelinase activity in vitro and only results in hepatosplenomegaly without neurologic involvement,