RESUMO
Primary sclerosing cholangitis (PSC) is characterised by the co-occurrence of inflammatory bowel diseases, particularly ulcerative colitis (UC). We investigated how the interaction of miR-125b with the sphingosine-1-phosphate (S1P)/ceramide axis may predispose patients with PSC, PSC/UC, and UC to carcinogenesis in the ascending and sigmoid colons. The overexpression of miR-125b was accompanied by the upregulation of S1P, ceramide synthases, ceramide kinases, and the downregulation of AT-rich interaction domain 2 in the ascending colon of PSC/UC, which contributed to the progression of high microsatellite instability (MSI-H) colorectal carcinoma. We also showed that the overexpression of sphingosine kinase 2 (SPHK2) and the genes involved in the glycolytic pathway in the sigmoid colon of UC led to the upregulation of Interleukin 17 (IL-17). In vitro stimulation of human intestinal epithelial cells (Caco-2, HT-29, and NCM460D) with lipopolysaccharide suppressed miR-125b and increased proinflammatory cytokines, whereas the induction of miR-125b activity by either a miR-125b mimetic or lithocholic acid resulted in the inhibition of miR-125b targets. In summary, miR-125b overexpression was associated with an imbalance in the S1P/ceramide axis that can lead to MSI-H cancer progression in PSC/UC. Furthermore, SPHK2 overexpression and a change in the cellular metabolic flux are important players in inflammation-associated colon cancer in UC.
Assuntos
Colangite Esclerosante , Colite Ulcerativa , Neoplasias do Colo , MicroRNAs , Humanos , Células CACO-2 , Colangite Esclerosante/complicações , Colangite Esclerosante/genética , Colangite Esclerosante/metabolismo , Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Inflamação/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
OBJECTIVES: The aim of this study was to evaluate characteristics of patients with unilateral transmigration of a mandibular canine in the largest study group presented until now. MATERIALS AND METHODS: The study group consisted of 93 patients with unilateral transmigration of mandibular canine; the control group included 85 non-affected patients. Type of transmigration, status of deciduous and permanent canines, prevalence of missing teeth, class of occlusion, and space conditions were assessed to draw comparisons between groups. RESULTS: In this study, 64.5 per cent patients presented type 1 of transmigration; types 2, 3, 4, and 5 were present in, respectively, 23.7, 5.4, 4.3, and 2.1 per cent patients. There was a clear, statistically significant difference (P < 0.0001) between the mean crown and apex migration and angulation for the three groups of canines (transmigrated, contralateral, and control), whereas no differences were observed for the total number of permanent teeth present. In the study group, 73.1 per cent patients retained their primary canine on the affected side and 18.3 per cent on the contralateral side; in the control group, 22.3 per cent subjects had at least one primary canine. There was a statistically significant difference in the distribution of types of malocclusion between the study and the control groups. CONCLUSIONS: Transmigration of mandibular canine was associated with the presence of retained primary canine on the affected side, higher mesial tilting of contralateral mandibular canine when compared to the canines in the control group. Additionally, higher prevalence of Angle's Class I occlusion in patients with canine transmigration was recorded.
Assuntos
Dente Impactado , Grupos Controle , Dente Canino , Humanos , Mandíbula , Radiografia Panorâmica , Estudos RetrospectivosRESUMO
5-aminosalicylic acid (5-ASA) is a first-line treatment for maintaining colitis remission. It is a highly effective, safe, and well-tolerated drug with anti-inflammatory and chemo-preventive properties. While patients with primary sclerosing cholangitis (PSC) with concomitant ulcerative colitis are treated with 5-ASA, the molecular mechanisms underlying the drug's chemo-preventive effects are not entirely understood. We previously reported that bile acids and lipopolysaccharide-induced miR-155 expression was associated with downregulating mismatch repair (MMR) proteins in CACO-2 cell lines. Therefore, in this investigation, a set of in vitro functional studies was performed to show the possible mechanisms behind the epigenetic relationship between miR-155 and 5-ASA's prevention of high microsatellite instability (MSI-H). In transient transfection with miR-155Mimic, which behaves like endogenous miRNA, we confirmed the relationships between miR-155 and its target MMR in three human intestinal epithelial cell lines: CACO-2, NCM460D and HT-29. We have shown, for the first time, that 5-ASA modulates MLH1, MSH2, MSH6 in miR-155 transfected cells. These findings underline that chemoprotective 5-ASA therapy can effectively attenuate the expression of miR-155 and potentially prevent a development of MSI-H in a subset of colorectal cancers associated with PSC.
RESUMO
Sex-dependent patterns in chronic immune-mediated cholangiopathies, like primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), remain poorly understood. Peroxisome proliferator-activated receptor alpha (PPAR-α), expressed in immune cells, plays a key role in innate defence. In this study, the relationship between PPAR-α expression in peripheral blood mononuclear cells (PBMCs), serum androgen levels, IFNγ production, and sex-dependent tendencies during the development of PBC and PSC was investigated. We confirmed that normal cholangiocytes respond to PPAR-α and inhibit the lipopolysaccharide-induced expression of IL-6, IL-1b, and TNFα. Compared with PSC patients, PPAR-α was downregulated, while IFNγ was upregulated, in the PBMCs of PBC patients. When the analysis was conducted on females only, there was no difference in PPAR-α, but IFNγ was elevated in females with PBC compared with those with PSC. Serum testosterone concentrations in females with PBC were below the normal range (regardless of age) and correlated positively with PPAR-α and negatively with IFNγ. While PPAR-α has been reported to be a target of miR-155 and miR-21, no correlations with these microRNAs were observed in the PBMCs. However, a positive correlation between miR-21 and IFNγ was observed. Our results showed suppressed PPAR-α expression accompanied by reduced testosterone levels in women with PBC, which should elicit interest in the role of testosterone in PBC development.
Assuntos
Cirrose Hepática Biliar , MicroRNAs , Humanos , Feminino , Leucócitos Mononucleares , Células Epiteliais , PPAR alfaRESUMO
BACKGROUND: PPARα is a ligand-activated transcription factor that shows protective effects against metabolic disorders, inflammation and apoptosis. Primary biliary cholangitis and primary sclerosing cholangitis result in the intrahepatic accumulation of bile acids that leads to liver dysfunction and damage. Small, non-coding RNAs such as miR-155 and miR-21 are associated with silencing PPARα. METHODS: The expression of miR-155, miR-21 and PPARα were evaluated using real-time PCR on liver tissue, as well as on human hepatocytes (HepG2) or cholangiocytes (NHCs) following exposure to lipopolysaccharide (LPS), glycodeoxycholic acid (GCDCA), lithocholic acid (LCA) and/or ursodeoxycholic acid (UDCA). RESULTS: A reduction of PPARα in primary biliary cholangitis (PBC) livers was associated with miR-21 and miR-155 upregulation. Experimental overexpression of either miR-155 or miR-21 inhibited PPARα in hepatocytes, whereas, in cholangiocytes, only miR-21 suppressed PPARα. Both GCDCA and LCA induced the cell type-specific upregulation of miR-155 or miR-21. In HepG2, LPS-induced miR-155 expression was blocked by a cotreatment with UDCA and was associated with PPARα upregulation. In NHC cells, the expression of miR-21 was induced by LPS but did not affect PPARα expression. CONCLUSIONS: Hepatic PPARα expression is reduced in PBC livers as a likely result of miR-155 overexpression. UDCA effectively reduced both baseline and LPS-induced miR-155 expression, thus preventing the suppression of PPARα.