BackgroundIntrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated liver disease with potentially deleterious consequences for the fetus, particularly when maternal serum bile-acid concentration >40 μM. However, the etiology and pathogenesis of ICP remain elusive. To reveal the underlying molecular mechanisms for the association of maternal serum bile-acid level and fetal outcome in ICP patients, DNA microarray was applied to characterize the whole-genome expression profiles of placentas from healthy women and women diagnosed with ICP.MethodsThirty pregnant women recruited in this study were categorized evenly into three groups: healthy group; mild ICP, with serum bile-acid concentration ranging from 10–40 μM; and severe ICP, with bile-acid concentration >40 μM. Gene Ontology analysis in combination with construction of gene-interaction and gene co-expression networks were applied to identify the core regulatory genes associated with ICP pathogenesis, which were further validated by quantitative real-time PCR and histological staining.ResultsThe core regulatory genes were mainly involved in immune response, VEGF signaling pathway and G-protein-coupled receptor signaling, implying essential roles of immune response, vasculogenesis and angiogenesis in ICP pathogenesis. This implication was supported by the observed aggregated immune-cell infiltration and deficient blood vessel formation in ICP placentas.ConclusionsOur study provides a system-level insight into the placental gene-expression profiles of women with mild or severe ICP, and reveals multiple molecular pathways in immune response and blood vessel formation that might contribute to ICP pathogenesis.
Abstract. The present study investigated the expression of miR-150 and miR-3940-5p in non-small cell lung carcinoma (NSCLC) and its relationship with clinicopathologic features. Samples included tumor, tumor-adjacent and normal lung parenchyma tissues from 90 NSCLC patients and 17 cases of embryonic lung cDNA. The expression levels of miR-150, miR-18b-5p, miR-643 and miR-3940-5p were detected by real-time PCR; p53, EGFR, Kras and Ki-67 expression in tumor tissues was determined by immunohistochemistry. p53 mRNA expression levels in NSCLC were examined by SYBR-Green real-time PCR. The relationship between the four miRNAs and clinicopathologic features of 90 cases was analyzed. The expression of miR-150 and miR-3940-5p was significantly downregulated in tumor tissues and embryonic lung tissues compared to normal lung tissues. The expression of miR-150 and miR-3940-5p in tumor tissues was also lower than that in the matched tumor-adjacent tissues. miR-150 was downregulated preferentially in subgroups of patients with a tumor diameter more than or equal to 3 cm, in smokers and in stage III and IV tumors. Specifically, miR-150 and miR-3940-5p expression was decreased in nuclear cell proliferation antigen Ki-67-positive NSCLC cases. miR-150 and miR-3940-5p were found to be significantly downregulated in p53 IHC-positive NSCLC cases and were negatively correlated with p53 mRNA. Reduced miR-150 and miR-3940-5p expression in tumor tissues and embryonic lung tissues suggests that these miRs may be involved in the tumorigenesis or de-differentiation of NSCLC. Due to this associaton with the Ki-67 proliferation index in NSCLC, downregulation of miR-150 and miR-3940-5p may contribute to tumor growth and proliferation. miR-150 and miR-3940-5p may affect p53 expression through a direct or indirect pathway.
miR-3127-5p is a primate-specific miRNA which is down-regulated in recurrent NSCLC tissue vs. matched primary tumor tissue (N = 15) and in tumor tissue vs. normal lung tissue (N = 177). Reduced miR-3127-5p expression is associated with a higher Ki-67 proliferation index and unfavorable prognosis in NSCLC. Overexpression of miR-3127-5p significantly reduced NSCLC cells proliferation, migration, and motility in vitro and in vivo. The oncogene ABL1 was a direct miR-3127-5p target, and miR-3127-5p regulated the activation of the Abl/Ras/ERK pathway and transactivated downstream proliferation/metastasis-associated molecules. Overexpression of miR-3127-5p in A549 or H292 cells resulted in enhanced resistance to dasatinib, an Abl/src tyrosine kinase inhibitor. miR-3127-5p expression levels were correlated with dasatinib sensitivity in NSCLC cell lines without K-Ras G12 mutation. In conclusion, miR-3127-5p acts as a tumor suppressor gene and is a potential biomarker for dasatinib sensitivity in the non-mutated Ras subset of NSCLC.
Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder with potentially deleterious consequences for fetuses. Although a clear correlation between the elevated levels of maternal serum bile acids and deficient fetal outcome has been established in clinical practice, the underlying mechanisms remain elusive. Herein, we report that bile acids induce NF-κB pathway activation via G protein-coupled bile acid receptor 1 (Gpbar1), with consequent upregulation of inflammatory genes in trophoblasts, leading to aberrant leukocyte infiltration and inflammation in placenta. Ursodeoxycholic acid (UDCA), a drug used clinically to treat ICP, competes with other bile acids for binding with Gpbar1 and thus inhibits bile acid-induced inflammatory response in trophoblasts and improves fetal survival in pregnant rats with obstructive cholestasis. Notably, inhibition of NF-κB by andrographolide is more effective than UDCA in benefiting placentas and fetuses. Thus, anti-inflammation therapy targeting Gpbar1/NF-κB pathway could be effective in suppressing bile acid-induced inflammation and alleviating ICP-associated fetal disorders.
BACKGROUND Intrahepatic cholestasis in pregnancy (ICP) is the most common liver disease during pregnancy, and its exact etiology and course of progression are still poorly understood. AIM To investigate the link between the gut microbiota and serum metabolome in ICP patients. METHODS In this study, a total of 30 patients were recruited, including 15 patients with ICP (disease group) and 15 healthy pregnant patients (healthy group). The serum nontarget metabolomes from both groups were determined. Amplification of the 16S rRNA V3-V4 region was performed using fecal samples from the disease and healthy groups. By comparing the differences in the microbiota and metabolite compositions between the two groups, the relationship between the gut microbiota and serum metabolites was also investigated. RESULTS The Kyoto Encyclopedia of Genes and Genomes analysis results showed that the primary bile acid biosynthesis, bile secretion and taurine and hypotaurine metabolism pathways were enriched in the ICP patients compared with the healthy controls. In addition, some pathways related to protein metabolism were also enriched in the ICP patients. The principal coordination analysis results showed that there was a distinct difference in the gut microbiota composition (beta diversity) between the ICP patients and healthy controls. At the phylum level, we observed that the relative abundance of Firmicutes was higher in the healthy group, while Bacteroidetes were enriched in the disease group. At the genus level, most of the bacteria depleted in ICP are able to produce short-chain fatty acids ( e.g. , Faecalibacterium, Blautia and Eubacterium hallii ), while the bacteria enriched in ICP are associated with bile acid metabolism ( e.g. , Parabacteroides and Bilophila ). Our results also showed that specific genera were associated with the serum metabolome. CONCLUSION Our study showed that the serum metabolome was altered in ICP patients compared to healthy controls, with significant differences in the bile, taurine and hypotaurine metabolite pathways. Alterations in the metabolization of these pathways may lead to disturbances in the gut microbiota, which may further affect the course of progression of ICP.
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