AIM:To determine the expression characteristics of connective tissue growth factor(CTGF/CCN2) in human hepatocellular carcinoma(HCC) in histology and to elucidate the roles of CCN2 on hepatoma cell cycle progression a...AIM:To determine the expression characteristics of connective tissue growth factor(CTGF/CCN2) in human hepatocellular carcinoma(HCC) in histology and to elucidate the roles of CCN2 on hepatoma cell cycle progression and metastasis in vitro.METHODS:Liver samples from 36 patients(who underwent hepatic resection for the first HCC between 2006 and 2011) and 6 normal individuals were examined for transforming growth factor β1(TGF-β1) or CCN2 mRNA by in situ hybridization.Computer image analysis was performed to measure integrated optimal density of CCN2 mRNA-positive cells in carcinoma foci and the surrounding stroma.Fibroblast-specific protein-1(FSP-1) and E-cadherin were examined to evaluate the process of epithelial to mesenchymal transition,α-smooth muscle actin and FSP-1 were detected to identify hepatic stellate cells,and CD34 was measured to evaluate the extent of vascularization in liver tissues by immunohistochemical staining.CCN2 was assessed for its stimulation of HepG2 cell migration and invasion using commercial kits while flow cytometry was used to determine CCN2 effects on HepG2 cell-cycle.RESULTS:In situ hybridization analysis showed that TGF-β1 mRNA was mainly detected in connective tissues and vasculature around carcinoma foci.In comparison to normal controls,CCN2 mRNA was enhanced 1.9-fold in carcinoma foci(12.36 ± 6.08 vs 6.42 ± 2.35) or 9.4-fold in the surrounding stroma(60.27 ± 28.71 vs 6.42 ± 2.35),with concomitant expression of CCN2 and TGF-β1 mRNA in those areas.Epithelial-mesenchymal transition phenotype related with CCN2 was detected in 12/36(33.3%) of HCC liver samples at the edges between carcinoma foci and vasculature.Incubation of HepG2 cells with CCN2(100 ng/mL) resulted in more of the cells transitioning into S phase(23.85 ± 2.35 vs 10.94 ± 0.23),and induced a significant migratory(4.0-fold) and invasive(5.7-fold) effect.TGF-β1-induced cell invasion was abrogated by a neutralizing CCN2 antibody showing that CCN2 is a downstream mediator of TGF-β1-induced hepatoma cell invasion.CONCLUSION:These data support a role for CCN2 in the growth and metastasis of HCC and highlight CCN2 as a potential novel therapeutic target.展开更多
BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutati...BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD.CASE SUMMARY Here,we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen,thrombocytopenia,and bone pain,diagnosed by enzymatic and genetic testing.Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C(p.L483P)and exon 7 c.928A>G(p.S310G)of GBA1.The latter was first reported in patients with GD.Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site.The p.S310G mutation in domain 1 may decrease stability between theα2 andα3 helices of GBA1.The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminalβ-sheet.The patient was treated with imiglucerase replacement therapy,and her condition was stable.CONCLUSION The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function.This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.展开更多
The use of an antibiotic with immunomodulatory properties could be fascinating in treating multifactorial inflammatory conditions such as ulcerative colitis(UC).We report our investigations into the immunomodulatory p...The use of an antibiotic with immunomodulatory properties could be fascinating in treating multifactorial inflammatory conditions such as ulcerative colitis(UC).We report our investigations into the immunomodulatory properties of levornidazole,the S-enantiomer of ornidazole,which displayed a tremendous therapeutic potential in UC induced by dextran sodium sulfate(DSS).Levornidazole administration to DSS-colitic mice attenuated the intestinal inflammatory process,with an efficacy better than that shown by 5-amino salicylic acid.This was evidenced by decreased disease activity index,ameliorated macroscopic and microscopic colon damages,and reduced expression of inflammatory cytokines.Additionally,levornidazole displayed anti-inflammatory activity through Caveolin-1-dependent reducing IL-1βand IL-18 secretion by macrophages contributing to its improvement of the intestinal inflammation,as confirmed in vitro and in vivo.In conclusion,these results pointed out that the immunomodulatory effects of levornidazole played a vital role in ameliorating the intestinal inflammatory process,which would be crucial for the translation of its use into clinical settings.展开更多
基金Supported by National Natural Scientific Foundation,No. 30872236,81070370,to Gao RPNIH 5R01AA016003,to Brigstock DR
文摘AIM:To determine the expression characteristics of connective tissue growth factor(CTGF/CCN2) in human hepatocellular carcinoma(HCC) in histology and to elucidate the roles of CCN2 on hepatoma cell cycle progression and metastasis in vitro.METHODS:Liver samples from 36 patients(who underwent hepatic resection for the first HCC between 2006 and 2011) and 6 normal individuals were examined for transforming growth factor β1(TGF-β1) or CCN2 mRNA by in situ hybridization.Computer image analysis was performed to measure integrated optimal density of CCN2 mRNA-positive cells in carcinoma foci and the surrounding stroma.Fibroblast-specific protein-1(FSP-1) and E-cadherin were examined to evaluate the process of epithelial to mesenchymal transition,α-smooth muscle actin and FSP-1 were detected to identify hepatic stellate cells,and CD34 was measured to evaluate the extent of vascularization in liver tissues by immunohistochemical staining.CCN2 was assessed for its stimulation of HepG2 cell migration and invasion using commercial kits while flow cytometry was used to determine CCN2 effects on HepG2 cell-cycle.RESULTS:In situ hybridization analysis showed that TGF-β1 mRNA was mainly detected in connective tissues and vasculature around carcinoma foci.In comparison to normal controls,CCN2 mRNA was enhanced 1.9-fold in carcinoma foci(12.36 ± 6.08 vs 6.42 ± 2.35) or 9.4-fold in the surrounding stroma(60.27 ± 28.71 vs 6.42 ± 2.35),with concomitant expression of CCN2 and TGF-β1 mRNA in those areas.Epithelial-mesenchymal transition phenotype related with CCN2 was detected in 12/36(33.3%) of HCC liver samples at the edges between carcinoma foci and vasculature.Incubation of HepG2 cells with CCN2(100 ng/mL) resulted in more of the cells transitioning into S phase(23.85 ± 2.35 vs 10.94 ± 0.23),and induced a significant migratory(4.0-fold) and invasive(5.7-fold) effect.TGF-β1-induced cell invasion was abrogated by a neutralizing CCN2 antibody showing that CCN2 is a downstream mediator of TGF-β1-induced hepatoma cell invasion.CONCLUSION:These data support a role for CCN2 in the growth and metastasis of HCC and highlight CCN2 as a potential novel therapeutic target.
基金Supported by Shanxi Key Research and Development Project,No.201903D321133Shanxi Bethune Hospital’s Talent Introduction Scientific Research Start-up Fund Project,No.2021RC038 and 2021RC017。
文摘BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD.CASE SUMMARY Here,we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen,thrombocytopenia,and bone pain,diagnosed by enzymatic and genetic testing.Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C(p.L483P)and exon 7 c.928A>G(p.S310G)of GBA1.The latter was first reported in patients with GD.Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site.The p.S310G mutation in domain 1 may decrease stability between theα2 andα3 helices of GBA1.The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminalβ-sheet.The patient was treated with imiglucerase replacement therapy,and her condition was stable.CONCLUSION The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function.This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.
基金supported by National Natural Science Foundation of China(81703523,81701821,81771337)Natural Science Foundation of Jiangsu Province(BK20170244)+3 种基金Natural Science Foundation of Xuzhou City(KH17024)Science&Technology Foundation of Xuzhou(KC18027)Natural Science Foundation of Jiangsu Normal University(16XLR045)Foundation for Distinguished Medical Talents of Xuzhou.
文摘The use of an antibiotic with immunomodulatory properties could be fascinating in treating multifactorial inflammatory conditions such as ulcerative colitis(UC).We report our investigations into the immunomodulatory properties of levornidazole,the S-enantiomer of ornidazole,which displayed a tremendous therapeutic potential in UC induced by dextran sodium sulfate(DSS).Levornidazole administration to DSS-colitic mice attenuated the intestinal inflammatory process,with an efficacy better than that shown by 5-amino salicylic acid.This was evidenced by decreased disease activity index,ameliorated macroscopic and microscopic colon damages,and reduced expression of inflammatory cytokines.Additionally,levornidazole displayed anti-inflammatory activity through Caveolin-1-dependent reducing IL-1βand IL-18 secretion by macrophages contributing to its improvement of the intestinal inflammation,as confirmed in vitro and in vivo.In conclusion,these results pointed out that the immunomodulatory effects of levornidazole played a vital role in ameliorating the intestinal inflammatory process,which would be crucial for the translation of its use into clinical settings.
