Currently available studies have suggested that a number of exosome-encapsulated microRNAs (miRNAs) are recognized as stable biomarkers for cancers. However, little is known about the effect of exosomal miRNAs on colorectal cancer (CRC). The aim of study is to identify specific miRNAs in serum exosomes, which may serve as potential diagnostic and prognostic biomarkers and therapeutic targets for CRC. Microarray analyses of miRNAs in serum exosomes from 3 primary CRC patients and 3 healthy controls were performed. Those differentially expressed exosome-encapsulated miRNAs were verified in exosome-enriched serum samples from 77 CRC patients and 20 healthy controls by quantitative real-time PCR (qRT-PCR). A total of 39 aberrantly expressed miRNAs in serum exosomes were identified by microarray analysis. After confirmation by qRT-PCR, we found that 5 exosome-encapsulated miRNAs (miR-638, miR-5787, miR-8075, miR-6869-5p and miR-548c-5p) were significantly down-regulated, while 2 exosome-encapsulated miRNAs (miR-486-5p and miR-3180-5p) were significantly up-regulated in serum. Decreased levels of miR-638 in serum exosomes were associated with increased risk of liver metastasis and later TNM stage of CRC. Networks analyses revealed that 5 aberrantly expressed miRNAs (miR-638, miR-5787, miR-8075, miR-6869-5p, and miR-548c-5p) might be involved in the process of glucose metabolism in CRC. The present study shows the specific serum profile of exosome-encapsulated miRNAs in CRC. Those specific miRNAs in serum exosomes may serve as disease biomarkers and novel therapeutic targets for CRC.
Background: Observational studies suggest possible associations between thyroid antibodies and risk of preterm delivery. However, whether thyroid antibodies are risk factors of preterm labor remains controversial. Our goal was to evaluate the associations between thyroid antibodies and risk of preterm delivery by conducting a meta-analysis of prospective cohort studies. Methods: PubMed, Embase, and Wangfang databases were searched through January 2012 to identify studies that met pre-stated inclusion criteria. Data were extracted using standardized forms. Either a fixed-or a random-effects model was used to calculate the overall combined relative ratio (RR) with its corresponding 95% confidence interval (95% CI) to evaluate the relationship between thyroid antibodies and preterm delivery risk. Subgroup analyses were mainly performed by type of thyroid antibodies including thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab). Results: Eleven prospective cohort studies involving 35 467 participants were included. The combined RR of preterm delivery for pregnant women with thyroid antibodies compared with the reference group was 1.41 (95% CI 1.08-1.84, PZ0.011). Subgroup analysis yielded the combined RR of preterm delivery for pregnant women with TPO-Ab compared with the reference group was 1.69 (95% CI 1.19-2.41, PZ0.003), whereas pregnant women with positive TG-Ab had no obvious risk of preterm delivery compared with the reference group (RRZ0.88, 95% CI 0.60-1.29, PZ0.513). Sensitivity analysis restricted to studies excluding women with thyroid dysfunction yielded similar results. Meta-regression analysis suggested that the status of exclusion or inclusion of women with thyroid dysfunction was the major source of heterogeneity in this meta-analysis. No evidence of publication bias was observed. Conclusions: Current evidence suggests that the presence of TPO-Ab in pregnant women significantly increases the risk of preterm delivery.
Many studies have implicated that microRNAs (miRNAs), as non-coding RNAs, play important roles in the development and progression of colorectal cancer (CRC). However, little is known about the role of a newly identified miRNA, miR-6869-5p, in CRC. We aim to investigate the modifying effects and underlying mechanisms of miR-6869-5 in colorectal carcinogenesis and progression. Significantly reduced levels of miR-6869-5p were observed in both serum exosomes tumor tissue samples from patients with CRC. The prediction of targets of miR-6869-5p in databases of targetscan, microRNA. ORG and miRDBA revealed that toll-like receptor 4 (TLR4) is a potential target for this miRNA. MiR-6869-5p could inhibit cell proliferation and the production of inflammatory cytokines (TNF-α and IL-6) in CRC cells via directly targeting TLR4. The protective effect of miR-6869-5p from colorectal carcinogenesis was dependent on TLR4/NF-κB signaling pathway. In addition, the 3-year survival was poor among CRC patients with decreased levels of miR-6869-5p in serum exosomes. Thus, miR-6869-5p may serve as a tumor suppressor in CRC, and serum exosomal miR-6869-5p is a promising circulating biomarker for the prediction of CRC prognosis.
Amino acid substitution and insertions/deletions (indels) are two common events in protein evolution; however, current knowledge on indels is limited. In this study, we investigated the effects of indels on the flanking regions in protein structure superfamilies. Comprehensive analysis of structural classification of proteins superfamilies revealed that indels lead to a series of changes in the flanking regions, including the following: 1) structural shift in the tertiary structure, with a first-order exponential decay relation between structural shift and the distance to indels, 2) instability of the secondary structure elements in which parts of the α helix and β sheet are destroyed, and 3) an increase in the amino acid substitution rate of the primary structure and the nonsimilar amino acid substitution rate. In general, these quality changes are due to the combined effects of the "regional-inherent effect," "indel-accompanied effect," and "indel-following effect." Furthermore, these quality changes reflect changes in selective pressure. Indels are more likely to be preserved in regions with low selective pressure, and indels can further reduce the selective pressure on the flanking regions. These findings improve our understanding of the role of indels in protein evolution.
Preeclampsia is a serious complication of pregnancy and leads to maternal hypertension and proteinuria. It remains a major health problem for mothers and babies across the world due to high maternal and fetal morbidity and mortality. Accumulated data have implicated the critical role of microRNA in preeclampsia. However, to date, the role of miR‐548c‐5p in preeclampsia remains vaguely understood. In this study, we first elucidate the role of miR‐548c‐5p and its underlying molecular mechanism in preeclampsia. Compared with healthy controls, miR‐548c‐5p was obviously downregulated in serum exosomes and placental mononuclear cells in patients with preeclampsia. Nonetheless, PTPRO was significantly upregulated and negatively associated with miR‐548c‐5p in placental mononuclear cells in patients with preeclampsia. PTPRO was a target of miR‐548c‐5p. PTPRO was downregulated in the miR‐548c‐5p‐overexpressed macrophages. In addition, miR‐548c‐5p could inhibit the proliferation and activation of LPS‐stimulated macrophages, as evidenced by decreased levels of inflammatory cytokines (IL‐12 and TNF‐α) and less nuclear translocation of pNF‐κB in pTHP1 cells. MiR‐548c‐5p acts as an anti‐inflammatory factor in preeclampsia. The axis of miR‐548c‐5p/PTPRO/NF‐κB may provide novel targets for the diagnosis and treatment of preeclampsia.
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