An immunomodulatory effect of combined melatonin and gemcitabine treatment on gut microbiome-host proteome interactions in cholangiocarcinoma animal models
Ontology highlight
ABSTRACT:
ORGANISM(S): Cellular Organisms
SUBMITTER: Somchai Pinlaor
PROVIDER: PXD056449 | JPOST Repository | Thu Oct 02 00:00:00 BST 2025
REPOSITORIES: jPOST
Dataset's files
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| NC1_GB2_01_28290.mzXML | Mzxml | |||
| NC1_GB2_01_28291.mzXML | Mzxml | |||
| NC1_GB2_01_28292.mzXML | Mzxml | |||
| NC2_GB3_01_28293.mzXML | Mzxml | |||
| NC2_GB3_01_28294.mzXML | Mzxml |
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Project description:The mammalian gastrointestinal tract contains a diverse ecosystem of microbial species collectively making up the gut microbiome. Emerging evidence highlights a critical relationship between gut microbiota and neurocognitive development. Consumption of unhealthy yet palatable dietary factors associated with obesity and metabolic dysfunction (e.g., saturated fat, added sugar) produces microbiota dysbiosis and negatively impacts neurocognitive function, particularly when consumed during early life developmental periods. Here we explore whether excessive early life consumption of added sugars negatively impacts neurocognitive development via the gut microbiome. Using a rodent model of habitual sugar-sweetened beverage (SSB) consumption during the adolescent stage of development, we first show that excessive early life sugar intake impairs hippocampal-dependent memory function when tested during adulthood while preserving other neurocognitive domains. Gut microbiome genomic sequencing analyses reveal that early life SSB consumption alters the abundance of various bacterial populations, including elevations in operational taxonomic units within the genus Parabacteroides (P. distasonis and P. johnsonii) whose abundance negatively correlated with memory task performance. Additional results reveal that in vivo Parabacteroides enrichment of cultured P. distasonis and P. johnsonii bacterial species in adolescent rats severely impairs memory function during adulthood. Hippocampus transcriptome analyses identify gene expression alterations in neurotransmitter synaptic signaling, intracellular kinase signaling, metabolic function, neurodegenerative disease, and dopaminergic synaptic signaling-associated pathways as potential mechanisms linking microbiome outcomes with memory impairment. Collectively these results identify microbiota dysbiosis as a mechanism through which early life unhealthy dietary patterns negatively impact neurocognitive outcomes.
2021-02-25 | GSE150091 | GEO
Project description:Cholangiocarcinoma (CCA) is a dismal, heterogeneous malignancy with limited treatment options. One of the key epigenetic dysregulations in CCA is aberrant DNA methylation, suggesting that targeted DNA methylation is a promising therapeutic strategy for this disease. However, the clinical utility of DNA demethylation reagents is not well documented. Here, we established patient-derived CCA cell lines and demonstrated that the demethylating agents decitabine and 5-azacytidine had minimal effects on antitumor proliferation of CCA cells. A combinatorial drug screen using a kinase inhibitor library identified PARP inhibitors as sensitizers that synergistically enhanced the antitumor effects of decitabine. The combination of DNMT inhibitors and PARP inhibitors significantly blocks tumor growth in both CCA patient-derived xenograft models and the somatic CCA model induced by hydrodynamic tail vein injection. Transcriptomic profiling analysis showed that the combination treatment activated the inflammatory signaling pathway and upregulated senescence-associated secretory phenotype gene expression, resulting in genomic instability in CCA. Mechanistically, combination treatment disrupted XRCC1 function and increased PARP1 trapping, leading to persistent DNA damage and senescence. Together, our study provides a preclinical proof-of-concept for the use of DNMT inhibitors in combination with PARP inhibitors as a novel therapeutic strategy and potentially optimizes current clinical practice in the treatment of CCA.
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Project description:Background - Prepregnancy overweight and obesity promote deleterious health impacts on both mothers during pregnancy and the offspring. Significant changes in the maternal peripheral blood mononuclear cells (PBMCs) gene expression due to obesity are well-known. However, during pregnancy the impact of overweight on immune cell gene expression and its association with maternal and infant outcomes is not well explored. Methods – Blood samples were collected from healthy normal weight (NW, BMI 18.5-24.9) or overweight (OW, BMI 25-29.9) 2nd parity pregnant women at 12, 24 and 36 weeks of pregnancy. PBMCs were isolated from the blood and subjected to mRNA sequencing. Maternal and infant microbiota were analyzed by 16S rRNA gene sequencing. Integrative multi-omics data analysis was performed to evaluate the association of gene expression with maternal diet, gut microbiota, milk composition, and infant gut microbiota. Results - Gene expression analysis revealed that 453 genes were differentially expressed in the OW women compared to NW women at 12 weeks of pregnancy, out of which 354 were upregulated and 99 were downregulated. Several up-regulated genes in the OW group were enriched in inflammatory, chemokine-mediated signaling and regulation of interleukin-8 production-related pathways. At 36 weeks of pregnancy healthy eating index score was positively associated with several genes that include, DTD1, ELOC, GALNT8, ITGA6-AS1, KRT17P2, NPW, POT1-AS1 and RPL26. In addition, at 36 weeks of pregnancy, genes involved in adipocyte functions, such as NG2 and SMTNL1, were negatively correlated to human milk 2’FL and total fucosylated oligosaccharides content collected at 1 month postnatally. Furthermore, infant Akkermansia was positively associated with maternal PBMC anti-inflammatory genes that include CPS1 and RAB7B, at 12 and 36 weeks of pregnancy. Conclusions – These findings suggest that prepregnancy overweight impacts the immune cell gene expression profile, particularly at 12 weeks of pregnancy. Further, deciphering the complex association of PBMC’s gene expression levels with maternal gut microbiome and milk composition and infant gut microbiome may aid in developing strategies to mitigate obesity-mediated effects.
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Project description:Genetic abnormalities of cholangiocarcinoma (CCA) have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterized. We have profiled the DNA methylomes of 28 primary CCA and six matched adjacent normal tissues using Infinium’s HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly epigenetically regulated in CCA. Using a linear model for microarray data we identified 1610 differentially methylated autosomal CpG sites with 809 CpG sites (representing 603 genes) being hypermethylated and 801 CpG sites (representing 712 genes) being hypomethylated in CCA versus adjacent normal (false discovery rate ? 0.05). Gene Ontology and Gene Set Enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in CCA including homeobox genes and target genes of PRC2, EED, SUZ12 and Histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of CCA (n = 103). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in CCA. These data have implications for CCA carcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. Methods: Thirty-two primary CCA, 6 matched adjacent normal, 5 CCA cell lines and an immortal biliary cell line were analyzed for DNA methylation profiles using the Infinium HumanMethylation27 BeadChip. Differential methylation was statistically analyzed using LIMMA. Specific functional terms and Gene Set Enrichment Analysis were performed to identify specific function of aberrantly methylated genes. Results: We identified 711 and 590 autosomal CpG sites as being hypermethylated and hypomethylated representing 527 and 521 genes, respectively, in CCA compared to adjacent normal (false discovery rate 0.05). A number of gene sets were significantly associated with hypermethylation at linked CpG sites in CCA including homeobox genes and the target genes of PRC2, EED, SUZ12, and H3K27me3, whereas target genes of NOS and OCT4 were hypomethylated at linked CpG sites in tumors. Frequent aberrant DNA methylation at HOXA9 and HOXD9 was confirmed by bisulfite pyrosequencing in a larger cohort of CCA (n = 107). Conclusions: This is the first report of a DNA methylation profile of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in CCA. These data have implications for CCA carcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. Array-based methylation profiling was performed using the Infinium HumanMethylation27 BeadChip in 28 primary cholangiocarcinomas and six matched adjacent normal tissues. The reproducibility of the Infinium HumanMethylation27 BeadChips was evaluated using five technical replicates of the ovarian cancer cell line PEO1. Differential methylation cutoff was estimated from five technical replicates by bootstrap resampling and set at ?? ? 0.15 corresponding to a FDR ? 0.05.
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