ENTPD1-AS1-miR-144-3p-mediated high expression of COL5A2 correlates with poor prognosis and macrophage infiltration in gastric cancer

BACKGROUND Gastric cancer(GC)is a malignant tumor with high morbidity and mortality.Expression of COL5A2 is significantly elevated in GC.Abnormal expression of noncoding RNAs(ncRNAs)have been found in GC,including microRNA(miRNA)and long noncoding RNA(lncRNA).Competing endogenous RNA network plays an important regulatory role in GC.However,its specific regulatory mechanism has not been elucidated.AIM To gain insight into the ncRNA regulatory mechanism and immune microenvironment related to COL5A2 in GC.METHODS RNA sequencing data and clinical information from The Cancer Genome Atlas data portal were used to analyze the expressions of COL5A2,miRNA and lncRNA related to the prognosis of GC.Cox regression analysis and Kyoto Encyclopedia of Genes and Genomes analysis were performed to assess the risk factors and relevant function of COL5A2.StarBase was used to predict the interaction of miRNA–lncRNA or miRNA–mRNA in GC.The relationship between COL5A2,miR-144-3p and ENTPD1-AS1 were verified by dual luciferase reporter assay.The association of COL5A2 with immune cell infiltration were analyzed using the Tumor Immune Estimation Resource database and single sample gene set enrichment analysis.The expression of COL5A2 and macrophages in paired GC tissues were detected by immunohistochemical staining.RESULTS We verified that the upregulation of COL5A2 expression was associated with the prognosis of GC and was an independent risk factor for GC.miR-144-3p was downregulated and correlated with the prognosis of GC.miR-144-3p regulated the expression of COL5A2 through direct interaction with COL5A2.ENTPD1-AS1 was elevated in GC and competitively bound to miR-144-3p,thus inhibiting the expression of miR-144-3p.ENTPD1-AS1 enhanced the expression of COL5A2 through sponging miR-144-3p.Compared to paired normal tissue,COL5A2 expression was upregulated at the protein level,especially in the middle and late stages of GC.The high expression of COL5A2 was positively linked to macrophage infiltration in GC.CONCLUSION COL5A2 regulated by ENTPD1-AS1–miR-144-3p was associated with poor prognosis and macrophage infiltration in GC.This could be a new biomarker and therapeutic target in GC.

Fibrinogen-like protein 2 deficiency inhibits virus-induced fulminant hepatitis through abrogating inflammatory macrophage activation

BACKGROUND Heterogeneous macrophages play an important role in multiple liver diseases,including viral fulminant hepatitis(VFH).Fibrinogen-like protein 2(FGL2)is expressed on macrophages and regulates VFH pathogenesis;however,the underlying mechanism remains unclear.AIM To explore how FGL2 regulates macrophage function and subsequent liver injury during VFH.METHODS Murine hepatitis virus strain 3(MHV-3)was used to induce VFH in FGL2-deficient(Fgl2-/-)and wild-type(WT)mice.The dynamic constitution of hepatic macrophages was examined.Adoptive transfer of Fgl2-/-or WT bone marrowderived macrophages(BMDMs)into WT recipients with macrophages depleted prior to infection was carried out and the consequent degree of liver damage was compared.The signaling cascades that may be regulated by FGL2 were detected in macrophages.RESULTS Following MHV-3 infection,hepatic macrophages were largely replenished by proinflammatory monocyte-derived macrophages(MoMFs),which expressed high levels of FGL2.In Fgl2-/-mice,the number of infiltrating inflammatory MoMFs was reduced compared with that in WT mice after viral infection.Macrophage depletion ameliorated liver damage in WT mice and further alleviated liver damage in Fgl2-/-mice.Adoptive transfer of Fgl2-/-BMDMs into macrophage-removed recipients significantly reduced the degree of liver damage.Inhibition of monocyte infiltration also significantly ameliorated liver damage.Functionally,Fgl2 deletion impaired macrophage phagocytosis and the antigen presentation potential and attenuated the proinflammatory phenotype.At the molecular level,FGL2 deficiency impaired IRF3,IRF7,and p38 phosphorylation,along with NF-κB activation in BMDMs in response to viral infection.CONCLUSION Infiltrated MoMFs represent a major source of hepatic inflammation during VFH progression,and FGL2 expression on MoMFs maintains the proinflammatory phenotype via p38-dependent positive feedback,contributing to VFH pathogenesis.

Inhibiting the kynurenine pathway in spinal cord injury: multiple therapeutic potentials?

Chronic induction of the kynurenine pathway（KP） contributes to neuroinflammation by producing the excitotoxin quinolinic acid（QUIN）. This has led to significant interest in the development of inhibitors of this pathway, particularly in the context of neurodegenerative disease. However, acute spinal cord injury（SCI） also results in deleterious increases in QUIN, as secondary inflammatory processes mediated largely by infiltrating macrophages, become predominant. QUIN mediates significant neurotoxicity primarily by excitotoxic stimulation of the N-methyl-D-aspartate receptor, but other mechanisms of QUIN toxicity are known. More recent focus has assessed the contribution that neuroinflammation and modulations in the KP make in mood and psychiatric disorders with recent studies linking inflammation and modulations in the KP, to impaired cognitive performance and depressed mood in SCI patients. We hypothesize that these findings suggest that in SCI, inhibition of QUIN production and other metabolites, may have multiple therapeutic modalities and further studies investigating this are warranted. However, for central nervous system-based conditions, achieving good blood-brain-barrier permeability continues to be a limitation of current KP inhibitors.

The suppression of cervical cancer ferroptosis by macrophages:The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes

Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types.Tumor-associated macrophages(TAMs)play a key role in promoting tumor malignant progression and therapy resistance.However,the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic.This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo.TAMs have been found to suppress cervical cancer cells ferroptosis.Mechanistically,macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells.In cancer cells,miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis.Moreover,the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway.Importantly,in clinical cervical cancer cases,ALOX15 is negatively associated with macrophages infiltration,which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer.Moreover,both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer.Altogether,this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.

Mizoribine in the treatment of pediatric-onset glomerular disease

Background:Mizoribine(MZR)is a selective inhibitor of inosine monophosphate dehydrogenase,a key enzyme in the pathway responsible for de novo synthesis of guanine nucleotides.As an immunosuppressant,MZR has been used successfully without any serious adverse effects in the treatment of renal diseases in children as well as adults.Besides its immunosuppressive effect,MZR has been reported to ameliorate tubulointerstitial fibrosis in rats via suppression of macrophage infiltration.Data Sources:In this review,we summarize reported possible benefits of MZR in the treatment of pediatric-onset glomerular disease.Results:We recently observed that MZR itself selectively attenuates the expression of monocyte chemoattractant protein-1 at both the mRNA and protein levels in human mesangial cells.Since MZR binds specifically to 14-3-3 proteins and heat shock protein 60,both of which are reportedly expressed in inflamed glomeruli,MZR may bind directly to inflamed glomerular cells,thereby possibly preventing progressive damage from glomerulonephritis through a suppressive effect on activated macrophages and intrinsic renal cells.Moreover,it has recently been reported that MZR directly prevents podocyte injury through correction of the intracellular energy balance and nephrin biogenesis in cultured podocyte and rat models,suggesting a direct anti-proteinuric effect of MZR.Conclusions:These beneficial mechanisms of action of MZR as well as its immunosuppressive effect would warrant its use in the treatment of pediatric-onset glomerular disease.Although further studies remain to be done,we believe that MZR may be an attractive treatment of choice for children with glomerular diseases from a histologic as well as clinical standpoint.