BACKGROUND Crohn’s disease(CD)is an incurable intestinal disorder with unclear etiology and pathogenesis.Currently,there is a lack of specific biomarkers and drug targets for CD in clinical practice.It is essential t...BACKGROUND Crohn’s disease(CD)is an incurable intestinal disorder with unclear etiology and pathogenesis.Currently,there is a lack of specific biomarkers and drug targets for CD in clinical practice.It is essential to identify the precise pathophysiological mechanism of CD and investigate new therapeutic targets.AIM To explore a new biomarker and therapeutic target for CD and verify its role in the CD pathological mechanism.METHODS Proteomics was performed to quantify the protein profile in the plasma of 20 CD patients and 20 matched healthy controls.Hub genes among the selected differentially expressed proteins(DEPs)were detected via the MCODE plugin in Cytoscape software.The expression level of one hub gene with an immunoregulatory role that interested us was verified in the inflamed intestinal tissues of 20 CD patients by immunohistochemical analysis.After that,the effects of the selected hub gene on the intestinal inflammation of CD were identified in a CD cell model by examining the levels of proinflammatory cytokines by enzymelinked immunosorbent assays and the expression of the NF-κB signalling pathway by quantitative real-time PCR analysis and Western blot assays.RESULTS Thirty-five DEPs were selected from 393 credible proteins identified by proteomic analysis.Among the DEPs,fibrinogen-like protein 1(FGL1),which attracted our attention due to its function in the regulation of the immune response,had 1.722-fold higher expression in the plasma of CD patients and was identified as a hub gene by MCODE.Furthermore,the expression of FGL1 in the intestinal mucosal and epithelial tissues of CD patients was also upregulated(P<0.05).In vitro,the mRNA levels of FGL1 and NF-κB;the protein expression levels of FGL1,IKKα,IKKβ,p-IKKα/β,p-IκBα,and p-p65;and the concentrations of the proinflammatory cytokines IL-1β,IL-6,IL-17,and TNF-αwere increased(P<0.05)after stimulation with lipopolysaccharide,which were reversed by knockdown of FGL1 with siRNA transfection(P<0.05).Conversely,FGL1 overexpression enhanced the abovementioned results(P<0.05).CONCLUSION FGL1 can induce intestinal inflammation by activating the canonical NF-κB signalling pathway,and it may be considered a potential biomarker and therapeutic target for CD.展开更多
Partial hepatectomy is a first-line treatment for hepatocellular carcinoma.Within 2 weeks following partial hepatectomy,specific molecular pathways are activated to promote liver regeneration.Nevertheless,residual mic...Partial hepatectomy is a first-line treatment for hepatocellular carcinoma.Within 2 weeks following partial hepatectomy,specific molecular pathways are activated to promote liver regeneration.Nevertheless,residual microtumors may also exploit these pathways to reappear and metastasize.Therapeutically targeting molecules that are differentially regulated between normal cells and malignancies,such as fibrinogen-like protein 1(FGL1),appears to be an effective approach.The potential functions of FGL1 in both regenerative and malignant cells are discussed within the ambit of this review.While FGL1 is normally elevated in regenerative hepatocytes,it is normally downregulated in malignant cells.Hepatectomy does indeed upregulate FGL1 by increasing the release of transcription factors that promote FGL1,including HNF-1α and STAT3,and inflammatory effectors,such as TGF-β and IL6.This,in turn,stimulates certain proliferative pathways,including EGFR/Src/ERK.Hepatectomy alters the phase transition of highly differentiated hepatocytes from G0 to G1,thereby transforming susceptible cells into cancerous ones.Activation of the PI3K/Akt/mTOR pathway by FGL1 allele loss on chromosome 8,a tumor suppressor area,may also cause hepatocellular carcinoma.Interestingly,FGL1 is specifically expressed in the liver via HNF-1α histone acetylase activity,which triggers lipid metabolic reprogramming in malignancies.FGL1 might also be involved in other carcinogenesis processes such as hypoxia,epithelial-mesenchymal transition,immunosuppression,and sorafenib-mediated drug resistance.This study highlights a research gap in these disciplines and the necessity for additional research on FGL1 function in the described processes.展开更多
基金Supported by National Natural Science Foundation of China,No.82074431The Open Projects of the Discipline of Chinese Medicine of Nanjing University of Chinese Medicine Supported by the Subject of Academic Priority Discipline of Jiangsu Higher Education Institutions,No.ZYX03KF034Suzhou Municipal Science and Technology Bureau,No.SYSD2020253 and No.SS202085.
文摘BACKGROUND Crohn’s disease(CD)is an incurable intestinal disorder with unclear etiology and pathogenesis.Currently,there is a lack of specific biomarkers and drug targets for CD in clinical practice.It is essential to identify the precise pathophysiological mechanism of CD and investigate new therapeutic targets.AIM To explore a new biomarker and therapeutic target for CD and verify its role in the CD pathological mechanism.METHODS Proteomics was performed to quantify the protein profile in the plasma of 20 CD patients and 20 matched healthy controls.Hub genes among the selected differentially expressed proteins(DEPs)were detected via the MCODE plugin in Cytoscape software.The expression level of one hub gene with an immunoregulatory role that interested us was verified in the inflamed intestinal tissues of 20 CD patients by immunohistochemical analysis.After that,the effects of the selected hub gene on the intestinal inflammation of CD were identified in a CD cell model by examining the levels of proinflammatory cytokines by enzymelinked immunosorbent assays and the expression of the NF-κB signalling pathway by quantitative real-time PCR analysis and Western blot assays.RESULTS Thirty-five DEPs were selected from 393 credible proteins identified by proteomic analysis.Among the DEPs,fibrinogen-like protein 1(FGL1),which attracted our attention due to its function in the regulation of the immune response,had 1.722-fold higher expression in the plasma of CD patients and was identified as a hub gene by MCODE.Furthermore,the expression of FGL1 in the intestinal mucosal and epithelial tissues of CD patients was also upregulated(P<0.05).In vitro,the mRNA levels of FGL1 and NF-κB;the protein expression levels of FGL1,IKKα,IKKβ,p-IKKα/β,p-IκBα,and p-p65;and the concentrations of the proinflammatory cytokines IL-1β,IL-6,IL-17,and TNF-αwere increased(P<0.05)after stimulation with lipopolysaccharide,which were reversed by knockdown of FGL1 with siRNA transfection(P<0.05).Conversely,FGL1 overexpression enhanced the abovementioned results(P<0.05).CONCLUSION FGL1 can induce intestinal inflammation by activating the canonical NF-κB signalling pathway,and it may be considered a potential biomarker and therapeutic target for CD.
基金supported by the Doctoral Research Fund of Hubei University of Science and Technology,with project number Q201810.
文摘Partial hepatectomy is a first-line treatment for hepatocellular carcinoma.Within 2 weeks following partial hepatectomy,specific molecular pathways are activated to promote liver regeneration.Nevertheless,residual microtumors may also exploit these pathways to reappear and metastasize.Therapeutically targeting molecules that are differentially regulated between normal cells and malignancies,such as fibrinogen-like protein 1(FGL1),appears to be an effective approach.The potential functions of FGL1 in both regenerative and malignant cells are discussed within the ambit of this review.While FGL1 is normally elevated in regenerative hepatocytes,it is normally downregulated in malignant cells.Hepatectomy does indeed upregulate FGL1 by increasing the release of transcription factors that promote FGL1,including HNF-1α and STAT3,and inflammatory effectors,such as TGF-β and IL6.This,in turn,stimulates certain proliferative pathways,including EGFR/Src/ERK.Hepatectomy alters the phase transition of highly differentiated hepatocytes from G0 to G1,thereby transforming susceptible cells into cancerous ones.Activation of the PI3K/Akt/mTOR pathway by FGL1 allele loss on chromosome 8,a tumor suppressor area,may also cause hepatocellular carcinoma.Interestingly,FGL1 is specifically expressed in the liver via HNF-1α histone acetylase activity,which triggers lipid metabolic reprogramming in malignancies.FGL1 might also be involved in other carcinogenesis processes such as hypoxia,epithelial-mesenchymal transition,immunosuppression,and sorafenib-mediated drug resistance.This study highlights a research gap in these disciplines and the necessity for additional research on FGL1 function in the described processes.
