Increased circulating circular RNA103516 is a novel biomarker for inflammatory bowel disease in adult patients

BACKGROUND Increasing evidence demonstrates that by acting as microRNA sponges modulating gene expression at the transcriptional or post-transcriptional level,circular RNAs(circRNAs)participate in the pathogenesis of a variety of diseases and are considered ideal biomarkers of human disease.AIM To examine the expression of circRNA_103516 in inflammatory bowel disease(IBD)and its associations with clinical phenotypes and inflammatory cytokines.METHODS Peripheral blood mononuclear cells(PBMCs)were obtained from patients with IBD,healthy controls(HCs),and patient controls(PCs).Expression of circRNA_103516 and hsa-miR-19b-1-5p was assessed by quantitative reverse transcription-polymerase chain reaction.Crohn's disease activity index(CDAI),Mayo score,C-reactive protein(CRP)level,and erythrocyte sedimentation rate(ESR)were measured.To assess the inflammatory cytokines tumour necrosis factorα(TNF-α),interferon-γ(IFN-γ),and interleukin-10(IL-10),blood samples were analysed by flow cytometry.RESULTS Ninety Crohn’s disease(CD)and 90 ulcerative colitis(UC)patients,80 HCs,and 35 PCs were included in the study.CircRNA_103516 was upregulated in CD and UC patients compared with HCs and PCs(P<0.05).The area under the curve of circRNA_103516 for diagnosing CD and UC was 0.790 and 0.687,respectively.In addition,circRNA_103516 levels were increased in active CD and UC compared with remittent groups(P=0.027,P=0.045).Furthermore,in CD,circRNA_103516 correlated positively with CDAI(P<0.001),CRP(P<0.001),ESR(P<0.001),TNFα(P<0.001),and IFN-γ(P<0.001)and negatively correlated with IL-10(P=0.006).In UC patients,circRNA_103516 correlated with Mayo score(P<0.001),CRP(P<0.001),ESR(P<0.001),TNFα(P<0.001),IFN-γ(P=0.011),and IL-10(P=0.002).Additionally,circRNA_103516 correlated positively with stricturing(P=0.018)and penetrating(P=0.031)behaviour.Moreover,hsamiR-19b-1-5p correlated negatively with circRNA_103516 in CD.CONCLUSION CircRNA_103516 levels in PBMCs can be considered an ideal candidate biomarker for diagnosing IBD.Dysregulation of circRNA_103516 may participate in the molecular mechanism of IBD through hsa-miR-19b-1-5p sponging.

Hsa_circRNA_102610 upregulation in Crohn’s disease promotes transforming growth factor-β1-induced epithelial-mesenchymal transition via sponging of hsa-miR-130a-3p

BACKGROUND The incidence of inflammatory bowel disease,a chronic intestinal inflammatory disorder that includes Crohn’s disease(CD)and ulcerative colitis,is rising.Circular RNAs are considered valuable diagnostic biomarkers for CD.Current evidence supports the views that epithelial-mesenchymal transition(EMT)plays an important role in CD pathogenesis,and that hsa-miR-130a-3p can inhibit transforming growth factor-β1(TGF-β1)-induced EMT.Our previous study revealed that hsa_circRNA_102610 was upregulated in CD patients.Moreover,we predicted an interaction between hsa_circRNA_102610 and hsa-miR-130a-3p.Thus,we hypothesized that hsa_circRNA_102610 may play roles in the proliferation and EMT of intestinal epithelial cells by sponging hsa-miR-130a-3p to participate in the pathogenesis of CD.AIM To explore the mechanism of hsa_circRNA_102610 in the pathogenesis of CD.METHODS The relative expression levels of hsa_circRNA_102610 and hsa-miR-130a-3p in patients were detected by quantitative reverse transcription-polymerase chain reaction.The proliferation of human intestinal epithelial cells(HIECs)and normal-derived colon mucosa cell line 460(NCM460)cells was detected by cell counting kit-8,5-ethynyl-2’-deoxyuridine staining and cell cycle assays following overexpression or downregulation of hsa_circRNA_102610.Cell proliferation assays were performed as described above in a rescue experiment with hsa-miR-130a-3p mimics.The interaction of hsa_circRNA_102610 and hsa-miR-130a-3p was verified by fluorescence in situ hybridization and dual luciferase reporter assays.The relative expression levels of CyclinD1,mothers against decapentaplegic homolog 4(SMAD4),E-cadherin,N-cadherin and Vimentin were detected by western blotting following hsa_circRNA_102610 overexpression,TGF-β1-induced EMT or hsa-miR-130a-3p mimic transfection(in rescue experiments).RESULTS Upregulation of hsa_circRNA_102610 was determined to be positively correlated with elevated fecal calprotectin levels in CD(r=0.359,P=0.007)by Pearson correlation analysis.Hsa_circRNA_102610 promoted the proliferation of HIECs and NCM460 cells,while hsa-miR-130a-3p reversed the cell proliferationpromoting effects of hsa_circRNA_102610.Fluorescence in situ hybridization and dual luciferase reporter assays showed that hsa_circRNA_102610 directly bound hsa-miR-130a-3p in NCM460 and 293T cells.An inverse correlation between downregulation of hsa-miR-130a-3p and upregulation of hsa_circRNA_102610 in CD patients was observed(r=-0.290,P=0.024)by Pearson correlation analysis.Moreover,overexpression of hsa_circRNA_102610 promoted SMAD4 and CyclinD1 protein expression validated by western-blotting.Furthermore,overexpression of hsa_circRNA_102610 promoted TGF-β1 induced EMT in HIECs and NCM460 cells via targeting of hsa-miR-130a-3p,with increased expression of Vimentin and N-cadherin and decreased expression of E-cadherin.CONCLUSION Hsa_circRNA_102610 upregulation in CD patients could promote the proliferation and EMT of intestinal epithelial cells via sponging of hsa-miR-130a-3p.

Acceptor-planarized typeⅠphotosensitizer for lipid droplet-targeted two-photon photodynamic therapy by ferroptosis

Two-photon photodynamic therapy(TP-PDT)has garnered significant attention because of its excellent depth of tissue penetration and high spatiotemporal selectivity.However,the limited targeting ability and oxygen dependency of photosensitizers(PSs)significantly hinder the effectiveness of photodynamic therapy in hypoxic tumor treatment.Herein,we designed and synthesized two lipid droplet(LD)-targeted two-photon PSs(TBPCP and TBCP)by reducing benzene rings to achieve“acceptor planarization”.Notably,acceptor planarization not only enhanced the intramolecular charge transfer but also transferred the photochemical reaction from typeⅡ(TBPCP)to typeⅠ(TBCP).Under the irradiation of 940 nm femtosecond pulsed laser,TBPCP and TBCP showed bright two-photon-excited fluorescence and excellent LD targeting in living cells.Comparing TBPCP(typeⅡPS),the outstanding TP-PDT efficacy of TBCP(typeⅠPS)under hypoxic conditions could be obtained in both cellular experiments and multicellular tumor spheroids(MCTS)model.Additionally,both TBPCP and TBCP could induce the lipid peroxidation in the typeⅠor typeⅡPDT due to the location of LD,depleting GSH and inactivating GPX4 to induce nonprogrammed ferroptosis in cells.

Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosa:A multicenter retrospective cohort in China

Background:Histological healing is closely associated with improved long-term clinical outcomes and lowered relapses in patients with ulcerative colitis(UC).Here,we developed a novel diagnostic criterion for assessing histological healing in UC patients.Methods:We conducted a retrospective cohort study in UC patients,whose treatment was iteratively optimized to achieve mucosal healing at Shanghai Tenth People’s Hospital of Tongji University from January 2017 to May 2022.We identified an inflammatory cell enumeration index(ICEI)for assessing histological healing based on the proportions of eosinophils,CD177^(+)neutrophils,and CD40L^(+)T cells in the colonic lamina propria under high power field(HPF),and the outcomes(risks of symptomatic relapses)of achieving histological remission vs.persistent histological inflammation using Kaplan-Meier curves.Intrareader reliability and inter-reader reliability were evaluated by each reader.The relationships to the changes in the Nancy index and the Geboes score were also assessed for responsiveness.The ICEI was further validated in a new cohort of UC patients from other nine university hospitals.Results:We developed an ICEI for clinical diagnosis of histological healing,i.e.,Y=1.701X_(1)+0.758X_(2)+1.347X_(3)-7.745(X_(1),X_(2),and X_(3)represent the proportions of CD177^(+)neutrophils,eosinophils,and CD40L^(+)T cells,respectively,in the colonic lamina propria under HPF).The receiver operating characteristics curve(ROC)analysis revealed that Y<-0.391 was the cutoff value for the diagnosis of histological healing and that an area under the curve(AUC)was 0.942(95%confidence interval[CI]:0.905-0.979)with a sensitivity of 92.5%and a specificity of 83.6%(P<0.001).The intraclass correlation coefficient(ICC)for the intrareader reliability was 0.855(95%CI:0.781-0.909),and ICEI had good inter-reader reliability of 0.832(95%CI:0.748-0.894).During an 18-month follow-up,patients with histological healing had a substantially better outcome compared with those with unachieved histological healing(P<0.001)using ICEI.During a 12-month follow-up from other nine hospitals,patients with histological healing also had a lower risk of relapse than patients with unachieved histological healing.Conclusions:ICEI can be used to predict histological healing and identify patients with a risk of relapse 12 months and 18 months after clinical therapy.Therefore,ICEI provides a promising,simplified approach to monitor histological healing and to predict the prognosis of UC.Registration:Chinese Clinical Trial Registry,No.ChiCTR2300077792.

Synthesis and properties of binaphthyl chiral thermally activated delayed fluorescence molecules using thioxanthone as acceptor

The currently reported axial chiral molecules based on the 3,3'-substitution of the binaphthyl skeleton are limited by intrinsic fluorescence properties,resulting in generally low device efficiencies(EQE<5%)of related organic light emitting diodes(OLEDs).Herein,we designed and synthesized four pair of chiral binaphthyl enantiomers(R/S-1-R/S-4)adopting acceptor-donor-donor-acceptor(ADDA)structure by introducing different thioxanthone modification groups on the 3,3'-position of 2,2'-dimethoxy-1,1'-binaphthalene.Among them,emitter R/S-2 and R/S-4 obtained by enhancing intramolecular charge transfer exhibited TADF characteristics due to relatively small Est of 0.12eV and 0.17eV,and relatively moderate SOC matrix elements of 0.28 cm^(-1)and 0.10 cm^(-1)between the 1CT and 3LE states.The CD spectra of these enantiomers in diluted solutions showed perfect mirror images and reasonable gabs for small organic molecules(10^(-4)-10^(-3)).And the external quantum eficiencies(EQE)of 10.9%and 8.32%for device A and B based on emitter S-2 and S-4 were highest compared with currently reported axial chiral molecules based on the 3,3'-position substitution of binaphthyl skeleton,providing simple molecular design strategies to construct efficient CP-OLED device.

WWP1 targeting MUC1 for ubiquitin-mediated lysosomal degradation to suppress carcinogenesis

Dear Editor,Mucin 1(MUC1)contains N-and C-subunit that forms a heterodimer on the apical surface of luminal epithelial cells.Nevertheless,MUC1 is aberrantly overexpressed in various cancers,such as breast cancer,lung cancer,and prostatic cancer,which critically contributes to tumorigenesis and poor clinical outcomes.1 Several strategies have been developed for targeted-inhibition of MUC1 including vaccines,monoclonal antibodies(MAb),and polypeptide.