Obesity contributes to the development of non-alcoholic fatty liver disease (NAFLD), which is characterized by the upregulated expression of two key inflammatory mediators: tumor necrosis factor (Tnfa) and monocyte chemotactic protein 1 (Mcp1; also known as Ccl2). However, the chromatin make-up at these genes in the liver in obese individuals has not been explored. In this study, to identify obesity-mediated epigenetic changes at Tnfa and Ccl2, we used a murine model of obesity induced by a high-fat diet (HFD) and hyperphagic (ob/ob) mice. Chromatin immunoprecipitation (ChIP) assay was used to determine the abundance of permissive histone marks, namely histone H3 lysine 9 and 18 acetylation (H3K9/K18Ac), H3 lysine 4 trimethylation (H3K4me3) and H3 lysine 36 trimethylation (H3K36me3), in conjunction with polymerase 2 RNA (Pol2) and nuclear factor (Nf)-κB recruitment in the liver. Additionally, to correlate the liver tissue-derived ChIP measurements with a robust in vitro transcriptional response at the Tnfa and Ccl2 genes, we used lipopolysaccharide (LPS) treatment to induce an inflammatory response in Hepa1-6 cells, a cell line derived from murine hepatocytes. ChIP revealed increased H3K9/K18Ac at Tnfa and Ccl2 in the obese mice, although the differences were only statistically significant for Tnfa (p<0.05). Unexpectedly, the levels of H3K4me3 and H3K36me3 marks, as well as Pol2 and Nf-κB recruitment, did not correspond with the increased expression of these two genes in the obese mice. By contrast, the acute treatment of Hepa1-6 cells with LPS significantly increased the H3K9/K18Ac marks, as well as Pol2 and Nf-κB recruitment at both genes, while the levels of H3K4me3 and H3K36me3 marks remained unaltered. These results demonstrate that increased Tnfa and Ccl2 expression in fatty liver at the chromatin level corresponds to changes in the level of histone H3 acetylation.
BackgroundProstate cancer (PCa) and colorectal cancer (CRC) are the most commonly diagnosed cancers and cancer-related causes of death in Poland. To date, numerous single nucleotide polymorphisms (SNPs) associated with susceptibility to both cancer types have been identified, but their effect on disease risk may differ among populations.MethodsTo identify new SNPs associated with PCa and CRC in the Polish population, a genome-wide association study (GWAS) was performed using DNA sample pools on Affymetrix Genome-Wide Human SNP 6.0 arrays. A total of 135 PCa patients and 270 healthy men (PCa sub-study) and 525 patients with adenoma (AD), 630 patients with CRC and 690 controls (AD/CRC sub-study) were included in the analysis. Allele frequency distributions were compared with t-tests and χ2-tests. Only those significantly associated SNPs with a proxy SNP (p<0.001; distance of 100 kb; r2>0.7) were selected. GWAS marker selection was conducted using PLINK. The study was replicated using extended cohorts of patients and controls. The association with previously reported PCa and CRC susceptibility variants was also examined. Individual patients were genotyped using TaqMan SNP Genotyping Assays.ResultsThe GWAS selected six and 24 new candidate SNPs associated with PCa and CRC susceptibility, respectively. In the replication study, 17 of these associations were confirmed as significant in additive model of inheritance. Seven of them remained significant after correction for multiple hypothesis testing. Additionally, 17 previously reported risk variants have been identified, five of which remained significant after correction.ConclusionPooled-DNA GWAS enabled the identification of new susceptibility loci for CRC in the Polish population. Previously reported CRC and PCa predisposition variants were also identified, validating the global nature of their associations. Further independent replication studies are required to confirm significance of the newly uncovered candidate susceptibility loci.
Problematyka zakresu obowiązywania zasad ogólnych sformułowanych w art. 6-16 k.p.a. ma charakter sporny i dyskusyjny. Przedmiotem analizy w niniejszym artykule będzie obowiązywanie zasad ogólnych w postępowaniu jurysdykcyjnym, w innych postępowaniach unormowanych w k.p.a. oraz w postępowaniach unormowanych poza k.p.a. W doktrynie prezentowane są zróżnicowane poglądy co do mocy obowiązywania zasad ogólnych we wskazanych postępowaniach. Nie budzi wątpliwości jedynie fakt, że zasady ogólne k.p.a. są normami prawa, które zostały wyodrębnione w jurysdykcyjnym postępowaniu administracyjnym i obowiązują w nim w pełnym zakresie. Zasięg obowiązywania zasad ogólnych k.p.a. nie ogranicza się tylko do jurysdykcyjnego postępowania administracyjnego. Niektóre zasady ogólne mają pełne zastosowanie w postępowaniach uproszczonych z uwagi na istotę i specyfikę tych postępowań. Ponadto zasady ogólne k.p.a. należy stosować również w postępowaniach pozakodeksowych, unormowanych w innych aktach regulujących procedurę administracyjną. Słowa kluczowe: zasady ogólne postępowania administracyjnego; obowiązywanie zasad ogólnych; postępowanie administracyjne; kodeks postępowania administracyjnego Wśród wielu problemów, jakie powstają na tle unormowań k.p.a. 1 w części odnoszącej się do zasad ogólnych, niewątpliwie do podstawowych należy kwestia zakresu mocy obowiązującej przepisów ustanawiających te zasady, a co za tym idzie zasięgu wyrażonych w tych przepisach reguł postępowania. Problematyka ta tylko z pozoru wydaje się mieć charakter formalny. Zagadnienie to miałoby
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