Intestinal barrier dysfunction, facilitating translocation of bacteria and bacterial products, plays an important role in the pathophysiology of liver cirrhosis and its complications. Intestinal defense system includi...Intestinal barrier dysfunction, facilitating translocation of bacteria and bacterial products, plays an important role in the pathophysiology of liver cirrhosis and its complications. Intestinal defense system including microbial barrier, immunologic barrier, mechanical barrier, chemical barrier, plays an important role in the maintenance of intestinal function. Under normal circumstances, the intestinal barrier can prevent intestinal bacteria through the intestinal wall from spreading to the body. Severe infection, trauma, shock, cirrhosis, malnutrition, immune suppression conditions, intestinal bacteria and endotoxin translocation, can lead to multiple organ dysfunction. The intestinal microflora is not only involved in the digestion of nutrients, but also in local immunity, forming a barrier against pathogenic microorganisms. The derangement of the gut microflora may lead to microbial translocation, defined as the passage of viable microorganisms or bacterial products from the intestinal lumen to the mesenteric lymph nodes and other extraintestinal sites. In patients with cirrhosis, primary and intestinal flora imbalance, intestinal bacterial overgrowth, intestinal mucosal barrier dysfunction, endotoxemia is associated with weakened immunity.展开更多
Background:The transcription factor paired box 8(PAX8)was associated with type 2 congenital non-goitrous hypothyroidism(CHNG2),a clinical phenotype of congenital hypothyroidism(CH).Though studied in a few regions with...Background:The transcription factor paired box 8(PAX8)was associated with type 2 congenital non-goitrous hypothyroidism(CHNG2),a clinical phenotype of congenital hypothyroidism(CH).Though studied in a few regions with different ethnicities,the incidence of PAX8 mutations varied,even among Chinese cohorts in different regions.This study aimed to identify and characterize PAX8 mutations and explore the prevalence of its mutations in another cohort of CH.Methods:The 105 unrelated Chinese patients with CH were collected from four major hospitals.Exomes of the 105 samples were sequenced by Hiseq 2000 platform to identify mutations of PAX8 on genomic DNAs extracted from peripheral blood samples.Luciferase reporter assays were used to assess the effects of mutations on the transcription of thyroid peroxidase(TPO).Results:Three PAX8 mutations in four subjects were identified in 105 samples.One variant,rsl 89229644,was detected in two subjects,and categorized as uncertain significance.The other two missense mutations(275T>C/Ile92Thr and 398G>A/Argl33Gln)were not detected in three large-scale genotyping projects,namely 1000 Genome Project,Exome Aggregation Consortium and GO Exome Sequencing Project.Functional studies for the two mutations revealed that they could impair the transcription ability of PAX8 on one of its target genes,TPO.Therefore,the two mutations were causative for the pathogenesis of CHNG2.After combining the studies of PAX8 mutations,an average frequency of 1.74%(21/1209)could be obtained in Chinese patients with CH.Conclusion:The study specifically demonstrates the role of two mutations in impairing the transcription ability of PAX8,which should be considered as pathogenic variants for CH.展开更多
文摘Intestinal barrier dysfunction, facilitating translocation of bacteria and bacterial products, plays an important role in the pathophysiology of liver cirrhosis and its complications. Intestinal defense system including microbial barrier, immunologic barrier, mechanical barrier, chemical barrier, plays an important role in the maintenance of intestinal function. Under normal circumstances, the intestinal barrier can prevent intestinal bacteria through the intestinal wall from spreading to the body. Severe infection, trauma, shock, cirrhosis, malnutrition, immune suppression conditions, intestinal bacteria and endotoxin translocation, can lead to multiple organ dysfunction. The intestinal microflora is not only involved in the digestion of nutrients, but also in local immunity, forming a barrier against pathogenic microorganisms. The derangement of the gut microflora may lead to microbial translocation, defined as the passage of viable microorganisms or bacterial products from the intestinal lumen to the mesenteric lymph nodes and other extraintestinal sites. In patients with cirrhosis, primary and intestinal flora imbalance, intestinal bacterial overgrowth, intestinal mucosal barrier dysfunction, endotoxemia is associated with weakened immunity.
基金supported by the Major Program of the National Natural Science Foundation of China (grant nos.82192910 and 82192911)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (grant nos.ZYYCXTD-D-202207 and ZYYCXTD-C-202009)。
基金National Natural Science Foundation of China(No.81101490).
文摘Background:The transcription factor paired box 8(PAX8)was associated with type 2 congenital non-goitrous hypothyroidism(CHNG2),a clinical phenotype of congenital hypothyroidism(CH).Though studied in a few regions with different ethnicities,the incidence of PAX8 mutations varied,even among Chinese cohorts in different regions.This study aimed to identify and characterize PAX8 mutations and explore the prevalence of its mutations in another cohort of CH.Methods:The 105 unrelated Chinese patients with CH were collected from four major hospitals.Exomes of the 105 samples were sequenced by Hiseq 2000 platform to identify mutations of PAX8 on genomic DNAs extracted from peripheral blood samples.Luciferase reporter assays were used to assess the effects of mutations on the transcription of thyroid peroxidase(TPO).Results:Three PAX8 mutations in four subjects were identified in 105 samples.One variant,rsl 89229644,was detected in two subjects,and categorized as uncertain significance.The other two missense mutations(275T>C/Ile92Thr and 398G>A/Argl33Gln)were not detected in three large-scale genotyping projects,namely 1000 Genome Project,Exome Aggregation Consortium and GO Exome Sequencing Project.Functional studies for the two mutations revealed that they could impair the transcription ability of PAX8 on one of its target genes,TPO.Therefore,the two mutations were causative for the pathogenesis of CHNG2.After combining the studies of PAX8 mutations,an average frequency of 1.74%(21/1209)could be obtained in Chinese patients with CH.Conclusion:The study specifically demonstrates the role of two mutations in impairing the transcription ability of PAX8,which should be considered as pathogenic variants for CH.
