Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofib...Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibromatosis 1-associated malignant peripheral nerve sheath tumor(MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values.Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining.Their prognostic values were evaluated with Kaplan-Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors.Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19(32.8%), 32(55.2%), and 16(27.6%)samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression(r = 0.334, P = 0.010) and Cyclin D1 expression(r = 0.309, P = 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression(χ~2 = 4.642, P = 0.031).Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.展开更多
Epstein-Barr virus (EBV) infects over 90% of the global population, establishing latent infections in most individuals. Under specific conditions like inflammation and immune suppression, EBV can be reactivated, leadi...Epstein-Barr virus (EBV) infects over 90% of the global population, establishing latent infections in most individuals. Under specific conditions like inflammation and immune suppression, EBV can be reactivated, leading to the initiation and progression of related diseases. While inflammation is known to induce EBV reactivation, the precise mechanisms underlying this phenomenon remain unclear. Chemokine (C-X-C motif) ligand (CXCL10), a key inflammatory factor, plays a significant role in various infectious diseases. In this study, we investigated how CXCL10 levels regulate the transition between the latent and lytic replication phases of the EBV lifecycle using cell culture, Western blot, fluorescent quantitative PCR, immunofluorescence, and flow cytometric apoptosis assays. Our findings indicate that CXCL10 induces EBV transition from latency to lytic replication through its receptor CXCR3 by regulating the downstream effector, exostosis-like glycosyltransferase 1. Additionally, CXCL10 activates the JAK2/STAT3 pathway. This study confirms the role of CXCL10 in promoting EBV lytic replication, providing crucial insights into the pathogenic mechanisms of inflammation-triggered EBV reactivation.展开更多
We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation r...We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.展开更多
目的:观察趋化因子配体5(chemokine C-C motif ligand 5,CCL5)、趋化因子CXC配体[chemokine(C-X-C motif)ligand,CXCL]10、CXCL13在创伤性脑损伤(traumatic brain injury,TBI)患者外周血液中的表达变化,分析这些趋化因子对损伤程度和预...目的:观察趋化因子配体5(chemokine C-C motif ligand 5,CCL5)、趋化因子CXC配体[chemokine(C-X-C motif)ligand,CXCL]10、CXCL13在创伤性脑损伤(traumatic brain injury,TBI)患者外周血液中的表达变化,分析这些趋化因子对损伤程度和预后的影响。方法:选取39例重度TBI患者[格拉斯哥昏迷评分(Glasgow coma scale,GCS)3~8分]与13例健康对照者。酶联免疫吸附测定法检测TBI患者术后1、3、7 d和对照组外周血中CCL5、CXCL10、CXCL13蛋白含量;Spearman相关分析对不同时间点外周血中CCL5、CXCL10、CXCL13和入院GCS、术后30 d GCS和格拉斯哥结局量表评分(Glasgow outcome scale,GOS)进行相关性分析。结果:与对照组相比,重度TBI患者外周血液中CCL5、CXCL10、CXCL13的表达量均明显升高(均P<0.05)。重度TBI患者术后1 d血液中CCL5、CXCL13的蛋白浓度与入院GCS评分呈负相关(P<0.05),术后3 d CXCL10的浓度与术后30 d GCS评分呈负相关(P<0.05)。重度TBI患者术后1 d CCL5的蛋白含量、术后1 d和3 d CXCL10蛋白含量及术后7 d CXCL13的蛋白含量与术后30 d GOS评分呈负相关(P<0.05)。结论:趋化因子CCL5、CXCL10、CXCL13在TBI早期表达量迅速增加,且表达量越高,损伤程度越重,预后可能越差。展开更多
Objective:Vitiligo is a relatively common skin disfiguring disorder that exhibits a fluctuating course between activity and stability,making monitoring and management challenging.Autoimmunity plays a crucial role in t...Objective:Vitiligo is a relatively common skin disfiguring disorder that exhibits a fluctuating course between activity and stability,making monitoring and management challenging.Autoimmunity plays a crucial role in the pathogenesis of vitiligo.Numerous autoimmune disorders have been associated with both CD27 and chemokine(C-X-C motif)ligand 10(CXCL10).However,trials evaluating their role in vitiligo are lacking in the Egyptian setting.We evaluated the circulating levels of these 2 biomarkers in patients with vitiligo and the possible correlation between their levels and disease activity.Methods:This cross-sectional study included 70 patients with vitiligo and 20 healthy controls.The patients were clinically assessed and then divided into active and stable groups according to clinical signs of activity and Vitiligo Disease Activity scores.The levels of CD27 and CXCL10 in the serum were assessed using an enzyme-linked immunosorbent assay in both the patients and the controls,then the Mann-Whitney U and Kruskal-Wallis tests were used to analyze the difference between the groups.Results:Active and stable vitiligo patients have significantly higher median serum CXCL10(385.9 and 245.2 pg/mL)and CD27(61.6 and 66.5 ng/mL)levels compared to the controls(193 pg/mL and 52.5 ng/mL,respectively,all P<0.05).In vitiligo cases,although CXCL10 levels significantly increased with disease activity(P<0.001),CD27 levels were comparable between the 2 subgroups(P=0.953).CXCL10 positively correlated with disease activity(r=0.887,P<0.001).CXCL10 had a higher sensitivity and a lower specificity(95.7%and 60.0%,respectively)compared to CD27(71.4%and 75%,respectively)for differentiating cases from controls.Conclusion:There is a possibility that CXCL10 and CD27 are involved in the development and course of vitiligo.展开更多
Esophageal cancer is the eighth most common malignant tumor and the sixth leading cause of cancer-related death worldwide.Esophageal squamous cell carcinoma(ESCC)is the main histological type of esophageal cancer,and ...Esophageal cancer is the eighth most common malignant tumor and the sixth leading cause of cancer-related death worldwide.Esophageal squamous cell carcinoma(ESCC)is the main histological type of esophageal cancer,and accounts for 90%of all cancer cases.Despite the progress made in surgery,chemotherapy,and radiotherapy,the mortality rate from esophageal cancer remains high,and the overall 5-year survival rate is less than 20%,even in developed countries.The C-X-C motif chemokine ligand 12(CXCL12)is a member of the CXC chemokine subgroup,which is widely expressed in a variety of tissues and cells.CXCL12 participates in the regulation of many physiological and pathological processes by binding to its specific receptor,C-X-C motif chemokine receptor type 4(CXCR4),where it causes embryonic development,immune response,and angiogenesis.In addition,increasing evidence indicates that the CXCL12/CXCR4 axis plays an important role in the biological processes of tumor cells.Studies have shown that CXCL12 and its receptor,CXCR4,are highly expressed in ESCC.This abnormal expression contributes to tumor proliferation,lymph node and distant metastases,and worsening prognosis.At present,antagonists and imaging agents against CXCL12 or CXCR4 have been developed to interfere with the malignant process and monitor metastasis of tumors.This article summarizes the structure,function,and regulatory mechanism of CXCL12/CXCR4 and its role in the malignancy of ESCC.Current results from preclinical research targeting CXCL12/CXCR4 are also summarized to provide a reference for the clinical diagnosis and treatment of ESCC.展开更多
BACKGROUND Ulcerative colitis(UC)is an inflammatory bowel disease that is difficult to diagnose and treat.To date,the degree of inflammation in patients with UC has mainly been determined by measuring the levels of no...BACKGROUND Ulcerative colitis(UC)is an inflammatory bowel disease that is difficult to diagnose and treat.To date,the degree of inflammation in patients with UC has mainly been determined by measuring the levels of nonspecific indicators,such as C-reactive protein and the erythrocyte sedimentation rate,but these indicators have an unsatisfactory specificity.In this study,we performed bioinformatics analysis using data from the National Center for Biotechnology Information-Gene Expression Omnibus(NCBI-GEO)databases and verified the selected core genes in a mouse model of dextran sulfate sodium(DSS)-induced colitis.AIM To identify UC-related differentially expressed genes(DEGs)using a bioinformatics analysis and verify them in vivo and to identify novel biomarkers and the underlying mechanisms of UC.METHODS Two microarray datasets from the NCBI-GEO database were used,and DEGs between patients with UC and healthy controls were analyzed using GEO2R and Venn diagrams.We annotated these genes based on their functions and signaling pathways,and then protein-protein interactions(PPIs)were identified using the Search Tool for the Retrieval of Interacting Genes.The data were further analyzed with Cytoscape software and the Molecular Complex Detection(MCODE)app.The core genes were selected and a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed.Finally,colitis model mice were established by administering DSS,and the top three core genes were verified in colitis mice using real-time polymerase chain reaction(PCR).RESULTS One hundred and seventy-seven DEGs,118 upregulated and 59 downregulated,were initially identified from the GEO2R analysis and predominantly participated in inflammation-related pathways.Seven clusters with close interactions in UC formed:Seventeen core genes were upregulated[C-X-C motif chemokine ligand 13(CXCL13),C-X-C motif chemokine receptor 2(CXCR2),CXCL9,CXCL5,C-C motif chemokine ligand 18,interleukin 1 beta,matrix metallopeptidase 9,CXCL3,formyl peptide receptor 1,complement component 3,CXCL8,CXCL1,CXCL10,CXCL2,CXCL6,CXCL11 and hydroxycarboxylic acid receptor 3]and one was downregulated[neuropeptide Y receptor Y1(NYP1R)]in the top cluster according to the PPI and MCODE analyses.These genes were substantially enriched in the cytokinecytokine receptor interaction and chemokine signaling pathways.The top three core genes(CXCL13,NYP1R,and CXCR2)were selected and verified in a mouse model of colitis using real-time PCR Increased expression was observed compared with the control mice,but only CXCR2 expression was significantly different.CONCLUSION Core DEGs identified in UC are related to inflammation and immunity inflammation,indicating that these reactions are core features of the pathogenesis of UC.CXCR2 may reflect the degree of inflammation in patients with UC.展开更多
AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was...AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.展开更多
基金supported by the National Nature Science Foundation of China(81372872 to Jilong Yang,81672650 to Ze Zhu,and 81402215 to Xiaoling Du)funds from the University Cancer Foundation via the Sister Institution Network Fund(to Jilong Yang)
文摘Background: Recent studies indicate that C-X-C motif chemokine receptor 4(CXCR4) and its ligand, C-X-C motif chemokine ligand 12(CXCL12), stimulate expression of the cell cycle regulatory protein Cyclin D1 in neurofibromatosis 1-associated malignant peripheral nerve sheath tumor(MPNST) cells and promote their proliferation. In this study, we measured the expression of CXCR4, CXCL12, and Cyclin D1 proteins in sporadic MPNST tissues from Chinese patients and investigated their prognostic values.Methods: CXCR4, CXCL12, and Cyclin D1 protein expression in samples from 58 Chinese patients with sporadic MPNST was assessed with immunohistochemical staining.Their prognostic values were evaluated with Kaplan-Meier analysis and a log-rank test. Multivariate Cox regression analysis was used to identify independent prognostic factors.Results: High expression of CXCR4, CXCL12, and Cyclin D1 was observed in 19(32.8%), 32(55.2%), and 16(27.6%)samples, respectively. CXCR4 expression was positively correlated with CXCL12 expression(r = 0.334, P = 0.010) and Cyclin D1 expression(r = 0.309, P = 0.018). Patients with high CXCR4 expression showed longer overall survival than those with low CXCR4 expression(χ~2 = 4.642, P = 0.031).Conclusion: High CXCR4 expression may define a specific subtype of sporadic MPNST with favorable prognosis.
文摘Epstein-Barr virus (EBV) infects over 90% of the global population, establishing latent infections in most individuals. Under specific conditions like inflammation and immune suppression, EBV can be reactivated, leading to the initiation and progression of related diseases. While inflammation is known to induce EBV reactivation, the precise mechanisms underlying this phenomenon remain unclear. Chemokine (C-X-C motif) ligand (CXCL10), a key inflammatory factor, plays a significant role in various infectious diseases. In this study, we investigated how CXCL10 levels regulate the transition between the latent and lytic replication phases of the EBV lifecycle using cell culture, Western blot, fluorescent quantitative PCR, immunofluorescence, and flow cytometric apoptosis assays. Our findings indicate that CXCL10 induces EBV transition from latency to lytic replication through its receptor CXCR3 by regulating the downstream effector, exostosis-like glycosyltransferase 1. Additionally, CXCL10 activates the JAK2/STAT3 pathway. This study confirms the role of CXCL10 in promoting EBV lytic replication, providing crucial insights into the pathogenic mechanisms of inflammation-triggered EBV reactivation.
基金supported by the National Natural Science Foundation of China,Nos.82271327(to ZW),82072535(to ZW),81873768(to ZW),and 82001253(to TL).
文摘We previously showed that hydrogen sulfide(H2S)has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice.However,the precise mechanism underlying the role of H2S in this situation remains unclear.In this study,we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine,a H2S precursor,attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionineβsynthase(a major H2S synthetase in the brain)in the prefrontal cortex.We also found that an miR-9-5p inhibitor blocked the expression of cystathionineβsynthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia.Furthermore,miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury.L-cysteine decreased the expression of CXCL11,an miR-9-5p target gene,in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3,FSTL1,SOCS2 and SOCS5,while treatment with an miR-9-5p inhibitor reversed these changes.These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoringβ-synthase expression,thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.
文摘目的:观察趋化因子配体5(chemokine C-C motif ligand 5,CCL5)、趋化因子CXC配体[chemokine(C-X-C motif)ligand,CXCL]10、CXCL13在创伤性脑损伤(traumatic brain injury,TBI)患者外周血液中的表达变化,分析这些趋化因子对损伤程度和预后的影响。方法:选取39例重度TBI患者[格拉斯哥昏迷评分(Glasgow coma scale,GCS)3~8分]与13例健康对照者。酶联免疫吸附测定法检测TBI患者术后1、3、7 d和对照组外周血中CCL5、CXCL10、CXCL13蛋白含量;Spearman相关分析对不同时间点外周血中CCL5、CXCL10、CXCL13和入院GCS、术后30 d GCS和格拉斯哥结局量表评分(Glasgow outcome scale,GOS)进行相关性分析。结果:与对照组相比,重度TBI患者外周血液中CCL5、CXCL10、CXCL13的表达量均明显升高(均P<0.05)。重度TBI患者术后1 d血液中CCL5、CXCL13的蛋白浓度与入院GCS评分呈负相关(P<0.05),术后3 d CXCL10的浓度与术后30 d GCS评分呈负相关(P<0.05)。重度TBI患者术后1 d CCL5的蛋白含量、术后1 d和3 d CXCL10蛋白含量及术后7 d CXCL13的蛋白含量与术后30 d GOS评分呈负相关(P<0.05)。结论:趋化因子CCL5、CXCL10、CXCL13在TBI早期表达量迅速增加,且表达量越高,损伤程度越重,预后可能越差。
文摘Objective:Vitiligo is a relatively common skin disfiguring disorder that exhibits a fluctuating course between activity and stability,making monitoring and management challenging.Autoimmunity plays a crucial role in the pathogenesis of vitiligo.Numerous autoimmune disorders have been associated with both CD27 and chemokine(C-X-C motif)ligand 10(CXCL10).However,trials evaluating their role in vitiligo are lacking in the Egyptian setting.We evaluated the circulating levels of these 2 biomarkers in patients with vitiligo and the possible correlation between their levels and disease activity.Methods:This cross-sectional study included 70 patients with vitiligo and 20 healthy controls.The patients were clinically assessed and then divided into active and stable groups according to clinical signs of activity and Vitiligo Disease Activity scores.The levels of CD27 and CXCL10 in the serum were assessed using an enzyme-linked immunosorbent assay in both the patients and the controls,then the Mann-Whitney U and Kruskal-Wallis tests were used to analyze the difference between the groups.Results:Active and stable vitiligo patients have significantly higher median serum CXCL10(385.9 and 245.2 pg/mL)and CD27(61.6 and 66.5 ng/mL)levels compared to the controls(193 pg/mL and 52.5 ng/mL,respectively,all P<0.05).In vitiligo cases,although CXCL10 levels significantly increased with disease activity(P<0.001),CD27 levels were comparable between the 2 subgroups(P=0.953).CXCL10 positively correlated with disease activity(r=0.887,P<0.001).CXCL10 had a higher sensitivity and a lower specificity(95.7%and 60.0%,respectively)compared to CD27(71.4%and 75%,respectively)for differentiating cases from controls.Conclusion:There is a possibility that CXCL10 and CD27 are involved in the development and course of vitiligo.
基金supported by the National Natural Science Foundation of China(Grant Nos.81772619 and 81702405)Wu Jieping Medical Foundation(Grant No.320.6750.17519)+1 种基金Bethune Charitable Foundation(Grant No.HZB-20190528-18)Tianjin Natural Science Foundation for Youth(Grant No.19JCQNJC10800)。
文摘Esophageal cancer is the eighth most common malignant tumor and the sixth leading cause of cancer-related death worldwide.Esophageal squamous cell carcinoma(ESCC)is the main histological type of esophageal cancer,and accounts for 90%of all cancer cases.Despite the progress made in surgery,chemotherapy,and radiotherapy,the mortality rate from esophageal cancer remains high,and the overall 5-year survival rate is less than 20%,even in developed countries.The C-X-C motif chemokine ligand 12(CXCL12)is a member of the CXC chemokine subgroup,which is widely expressed in a variety of tissues and cells.CXCL12 participates in the regulation of many physiological and pathological processes by binding to its specific receptor,C-X-C motif chemokine receptor type 4(CXCR4),where it causes embryonic development,immune response,and angiogenesis.In addition,increasing evidence indicates that the CXCL12/CXCR4 axis plays an important role in the biological processes of tumor cells.Studies have shown that CXCL12 and its receptor,CXCR4,are highly expressed in ESCC.This abnormal expression contributes to tumor proliferation,lymph node and distant metastases,and worsening prognosis.At present,antagonists and imaging agents against CXCL12 or CXCR4 have been developed to interfere with the malignant process and monitor metastasis of tumors.This article summarizes the structure,function,and regulatory mechanism of CXCL12/CXCR4 and its role in the malignancy of ESCC.Current results from preclinical research targeting CXCL12/CXCR4 are also summarized to provide a reference for the clinical diagnosis and treatment of ESCC.
基金Chinese Medicine Inheritance and Innovation“One Hundred Million”Talent Project Qihuang Scholar(to Li JX)The National Key R&D Program of China during the 13th Five-Year Plan Period,No.2018YFC1705405and The 66th China Postdoctoral Science Foundation,No.2019M660575.
文摘BACKGROUND Ulcerative colitis(UC)is an inflammatory bowel disease that is difficult to diagnose and treat.To date,the degree of inflammation in patients with UC has mainly been determined by measuring the levels of nonspecific indicators,such as C-reactive protein and the erythrocyte sedimentation rate,but these indicators have an unsatisfactory specificity.In this study,we performed bioinformatics analysis using data from the National Center for Biotechnology Information-Gene Expression Omnibus(NCBI-GEO)databases and verified the selected core genes in a mouse model of dextran sulfate sodium(DSS)-induced colitis.AIM To identify UC-related differentially expressed genes(DEGs)using a bioinformatics analysis and verify them in vivo and to identify novel biomarkers and the underlying mechanisms of UC.METHODS Two microarray datasets from the NCBI-GEO database were used,and DEGs between patients with UC and healthy controls were analyzed using GEO2R and Venn diagrams.We annotated these genes based on their functions and signaling pathways,and then protein-protein interactions(PPIs)were identified using the Search Tool for the Retrieval of Interacting Genes.The data were further analyzed with Cytoscape software and the Molecular Complex Detection(MCODE)app.The core genes were selected and a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed.Finally,colitis model mice were established by administering DSS,and the top three core genes were verified in colitis mice using real-time polymerase chain reaction(PCR).RESULTS One hundred and seventy-seven DEGs,118 upregulated and 59 downregulated,were initially identified from the GEO2R analysis and predominantly participated in inflammation-related pathways.Seven clusters with close interactions in UC formed:Seventeen core genes were upregulated[C-X-C motif chemokine ligand 13(CXCL13),C-X-C motif chemokine receptor 2(CXCR2),CXCL9,CXCL5,C-C motif chemokine ligand 18,interleukin 1 beta,matrix metallopeptidase 9,CXCL3,formyl peptide receptor 1,complement component 3,CXCL8,CXCL1,CXCL10,CXCL2,CXCL6,CXCL11 and hydroxycarboxylic acid receptor 3]and one was downregulated[neuropeptide Y receptor Y1(NYP1R)]in the top cluster according to the PPI and MCODE analyses.These genes were substantially enriched in the cytokinecytokine receptor interaction and chemokine signaling pathways.The top three core genes(CXCL13,NYP1R,and CXCR2)were selected and verified in a mouse model of colitis using real-time PCR Increased expression was observed compared with the control mice,but only CXCR2 expression was significantly different.CONCLUSION Core DEGs identified in UC are related to inflammation and immunity inflammation,indicating that these reactions are core features of the pathogenesis of UC.CXCR2 may reflect the degree of inflammation in patients with UC.
基金Supported by NHMRC Medical Postgraduate Scholarship and the Royal Brisbane and Women’s Hospital Research Foundation to Wood MJthe National Health and Medical Research Council(NHMRC)to Ramm GA and Powell LW+1 种基金the recipient of an NHMRC Senior Research Fellowship,1024672 to Subramaniam VNan NHMRC Senior Research Fellowship,No.552409 to Ramm GA
文摘AIM:To investigate the role of genetic polymorphisms in the progression of hepatic fibrosis in hereditary haemochromatosis.METHODS:A cohort of 245 well-characterised C282Y homozygous patients with haemochromatosis was studied,with all subjects having liver biopsy data and DNA available for testing.This study assessed the association of eight single nucleotide polymorphisms(SNPs)in a total of six genes including toll-like receptor 4(TLR4),transforming growth factor-beta(TGF-β),oxoguanine DNA glycosylase,monocyte chemoattractant protein 1,chemokine C-C motif receptor 2 and interleukin-10 with liver disease severity.Genotyping was performed using high resolution melt analysis and sequencing.The results were analysed in relation to the stage of hepatic fibrosis in multivariate analysis incorporating other cofactors including alcohol consumption and hepatic iron concentration.RESULTS:There were significant associations between the cofactors of male gender(P=0.0001),increasing age(P=0.006),alcohol consumption(P=0.0001),steatosis(P=0.03),hepatic iron concentration(P<0.0001)and the presence of hepatic fibrosis.Of the candidate gene polymorphisms studied,none showed a significant association with hepatic fibrosis in univariate or multivariate analysis incorporating cofactors.We also specifically studied patients with hepatic iron loading above threshold levels for cirrhosis and compared the genetic polymorphisms between those with no fibrosis vs cirrhosis however there was no significant effect from any of the candidate genes studied.Importantly,in this large,well characterised cohort of patients there was no association between SNPs for TGF-βor TLR4and the presence of fibrosis,cirrhosis or increasing fibrosis stage in multivariate analysis.CONCLUSION:In our large,well characterised group of haemochromatosis subjects we did not demonstrate any relationship between candidate gene polymorphisms and hepatic fibrosis or cirrhosis.
