scholarly journals Differences in genetics and microenvironment of lung adenocarcinoma patients with or without TP53 mutation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dejun Zeng ◽  
Zhengyang Hu ◽  
Yanjun Yi ◽  
Besskaya Valeria ◽  
Guangyao Shan ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Immune Genes ◽  
Survival Difference ◽  
New Concepts ◽  
Significant Survival ◽  
In The Wild ◽  
Immune Related Genes ◽  
Multiple Domains

Abstract Background Differences in genetics and microenvironment of LUAD patients with or without TP53 mutation were analyzed to illustrate the role of TP53 mutation within the carcinogenesis of LUAD, which will provide new concepts for the treatment of LUAD. Methods In this study, we used genetics and clinical info from the TCGA database, including somatic mutations data, RNA-seq, miRNA-seq, and clinical data. More than one bioinformatics tools were used to analyze the unique genomic pattern of TP53-related LUAD. Results According to TP53 gene mutation status, we divided the LUAD patients into two groups, including 265 in the mutant group (MU) and 295 in the wild-type group (WT). 787 significant somatic mutations were detected between the groups, including mutations in titin (TTN), type 2 ryanodine receptor (RYR2) and CUB and Sushi multiple domains 3(CSMD3), which were up-regulated in the MU. However, no significant survival difference was observed. At the RNA level, we obtained 923 significantly differentially expressed genes; in the MU, α-defensin 5(DEFA5), pregnancy-specific glycoprotein 5(PSG5) and neuropeptide Y(NPY) were the most up-regulated genes, glucose-6-phosphatase (G6PC), alpha-fetoprotein (AFP) and carry gametocidal (GC) were the most down-regulated genes. GSVA analysis revealed 30 significant pathways. Compared with the WT, the expression of 12 pathways in the mutant group was up-regulated, most of which pointed to cell division. There were significant differences in tumor immune infiltrating cells, such as Macrophages M1, T cells CD4 memory activated, Mast cells resting, and Dendritic cells resting. In terms of immune genes, a total of 35 immune-related genes were screened, of which VGF (VGF nerve growth factor inducible) and PGC (peroxisome proliferator-activated receptor gamma coactivator) were the most significant up-regulated and down-regulated genes, respectively. Research on the expression pattern of immunomodulators found that 9 immune checkpoint molecules and 6 immune costimulatory molecules were considerably wholly different between the two groups. Conclusions Taking the mutant group as a reference, LUAD patients in the mutant group had significant differences in somatic mutations, mRNA-seq, miRNA-seq, immune infiltration, and immunomodulators, indicating that TP53 mutation plays a crucial role in the occurrence and development of LUAD.

scholarly journals Differences in Genetics and Microenvironment of Lung Adenocarcinoma Patients with or without TP53 Mutation

2021 ◽  
Author(s):  
Dejun Zeng ◽  
Zhengyang Hu ◽  
Yanjun Yi ◽  
Besskaya Valeria ◽  
Guangyao Shan ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tp53 Mutation ◽  
Somatic Mutations ◽  
Tp53 Gene ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Immune Genes ◽  
Survival Difference ◽  
In The Wild ◽  
Immune Related Genes

Abstract Background: Differences in genetics and microenvironment of lung adenocarcinoma (LUAD) patients with or without TP53 mutation were analyzed to illustrate the role of TP53 mutation within the carcinogenesis of LUAD, which will provide new concepts for the treatment of LUAD.Methods: In this study, we used genetics and clinical info from the TCGA database, including somatic mutations data, RNA-seq, miRNA-seq, and clinical data. More than one bioinformatics tools were used to analyze the unique genomic pattern of TP53-related LUAD.Results: According to TP53 gene mutation status, we divided the LUAD patients into two groups, including 265 in the mutant group (MU) and 295 in the wild-type group (WT). 787 significant somatic mutations were detected between the groups, includingmutations in titin (TTN), type 2 ryanodine receptor (RYR2) and CUB and Sushi multiple domains 3(CSMD3), which were up-regulated in the MU. However, no significant survival difference was observed. At the RNA level, we obtained 923 significantly differentially expressed genes; in the MU, α-defensin 5(DEFA5),pregnancy-specific glycoprotein 5(PSG5) and neuropeptide Y(NPY) were the most up-regulated genes, glucose-6-phosphatase (G6PC), alpha-fetoprotein (AFP) and carry gametocidal (GC) were the most down-regulated genes. GSVA analysis revealed 30 significant pathways. Compared with the WT, the expression of 12 pathways in the mutant group was up-regulated, most of which pointed to cell division. There were significant differences in tumor immune infiltrating cells, such as Macrophages M1, T cells CD4 memory activated, Mast cells resting, and Dendritic cells resting. In terms of immune genes, a total of 35 immune-related genes were screened, of which VGF (VGF nerve growth factor inducible) and PGC (peroxisome proliferator-activated receptor gamma coactivator) were the most significant up-regulated and down-regulated genes, respectively. Research on the expression pattern of immunomodulators found that 9 immune checkpoint molecules and 6 immune costimulatory molecules were considerably wholly different between the two groups.Conclusion: Taking the mutant group as a reference, LUAD patients in the mutant group had significant differences in somatic mutations, mRNA-seq, miRNA-seq, immune infiltration, and immunomodulators, indicating that TP53 mutation plays a crucial role in the occurrence and development of LUAD.

scholarly journals Effects of Wheat Bran Applied to Maternal Diet on the Intestinal Architecture and Immune Gene Expression in Suckling Piglets

Animals ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 2051
Author(s):  
Julie Leblois ◽  
Yuping Zhang ◽  
José Wavreille ◽  
Julie Uerlings ◽  
Martine Schroyen ◽  
...  
Keyword(s):  
Wheat Bran ◽  
Maternal Diet ◽  
Peroxisome Proliferator ◽  
Immune Gene ◽  
Ileal Mucosa ◽  
Peroxisome Proliferator Activated Receptor ◽  
Absorption Area ◽  
Fiber Diet ◽  
Suckling Piglets ◽  
Immune Related Genes

The strategy of improving the growth and health of piglets through maternal fiber diet intervention has attracted increasing attention. Therefore, 15 sows were conducted to a wheat bran (WB) group, in which the sows’ diets included 25% of WB in gestation and 14% in lactation, and a control (CON) group, in which the sows’ diets at all stages of reproduction did not contain WB. The results show that maternal high WB intervention seems not to have an impact on the growth of the offspring or the villus height of the duodenum, and the ratio of villi/crypts in the duodenum and jejunum were all higher in piglets born from WB sows, which may indicate that WB piglets had a larger absorption area and capacity for nutrients. The peroxisome proliferator-activated receptor gamma (PPARγ) and interleukin 6 (IL6) expression levels were notably upregulated in the ileal mucosa of WB piglets, while no immune-related genes in the colonic mucosa were affected by the maternal WB supplementation. In conclusion, adding a high proportion of wheat bran to the sow’s gestation and lactation diet can affect the intestinal architecture and the expression of some inflammation genes, to some extent, in the ileal mucosa in the progeny.

scholarly journals Targeted disruption of Pparγ1 promotes trophoblast endoreplication in the murine placenta

2020 ◽  
Author(s):  
Takanari Nakano ◽  
Hidekazu Aochi ◽  
Masataka Hirasaki ◽  
Yasuhiro Takenaka ◽  
Koji Fujita ◽  
...  
Keyword(s):  
Cell Lineage ◽  
Giant Cells ◽  
Maternal Blood ◽  
Peroxisome Proliferator ◽  
Nucleosome Assembly ◽  
Gene Expressions ◽  
Peroxisome Proliferator Activated Receptor ◽  
Functional Roles ◽  
Expression Of Genes ◽  
In The Wild

AbstractIn murine placentas, peroxisome proliferator-activated receptor (PPAR) γ1, a nuclear receptor, is abundant at the late stage of pregnancy (E15–E16), but its functional roles are still elusive because PPARγ-full knockout embryos die early (E10). We generated mice disrupted in only Pparγ1, one of the two major mRNA splicing variants of PPARγ1. Pparγ1- knockout embryos developed normally until 15.5 dpc, but their growth was retarded thereafter and they did not survive. At 15.5 dpc, in the wild-type placentas, intense PPARγ-immunostaining was detected in sinusoidal trophoblast giant cells (sTGCs), a cell lineage that coordinates the maternal blood microcirculation in the labyrinth, whereas they were absent in the knockouts. Although Pparγ1-knockout placentas were normal in morphology, we observed severely dilated maternal blood sinuses in the labyrinth. The Pparγ1-knockout sTGCs had abnormally large nuclei, an enhanced endocycling phenotype, indicating insufficient differentiation. RNA-sequencing of the placentas showed increased expression of genes coding for nucleosome assembly factors. Labyrinthine gene expressions for atypical E2Fs and cyclin E, key drivers for endocycling, were increased >3-fold. These findings suggested that PPARγ1 plays a key role in endocycle termination.

Contribution of PPARγ in modulation of acrolein-induced inflammatory signaling in gp91phox knock-out mice

2017 ◽  
Vol 95 (4) ◽  
pp. 482-490 ◽  
Author(s):  
Zivar Yousefipour ◽  
Neha Chug ◽  
Katarzyna Marek ◽  
Alicia Nesbary ◽  
Joseph Mathew ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Mass ◽  
Total Antioxidant Status ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
Total Antioxidant ◽  
In The Wild ◽  
Knock Out Mice

Oxidative stress and inflammation are major contributors to acrolein toxicity. Peroxisome proliferator activated receptor gamma (PPARγ) has antioxidant and anti-inflammatory effects. We investigated the contribution of PPARγ ligand GW1929 to the attenuation of oxidative stress in acrolein-induced insult. Male gp91phox knock-out (KO) mice were treated with acrolein (0.5 mg·(kg body mass)–1 by intraperitoneal injection for 7 days) with or without GW1929 (GW; 0.5 mg·(kg body mass)–1·day–1, orally, for 10 days). The livers were processed for further analyses. Acrolein significantly increased 8-isoprostane and reduced PPARγ activity (P < 0.05) in the wild type (WT) and KO mice. GW1929 reduced 8-isoprostane (by 32% and 40% in WT and KO mice, respectively) and increased PPARγ activity (by 81% and 92% in WT and KO, respectively). Chemokine activity was increased (by 63%) in acrolein-treated WT mice, and was reduced by GW1929 (by 65%). KO mice exhibited higher xanthine oxidase (XO). Acrolein increased XO and COX in WT mice and XO in KO mice. GW1929 significantly reduced COX in WT and KO mice and reduced XO in KO mice. Acrolein significantly reduced the total antioxidant status in WT and KO mice (P < 0.05), which was improved by GW1929 (by 75% and 74%). The levels of NF-κB were higher in acrolein-treated WT mice. GW1929 reduced NF-κB levels (by 51%) in KO mice. Acrolein increased CD36 in KO mice (by 43%), which was blunted with GW1929. Data confirms that the generation of free radicals by acrolein is mainly through NAD(P)H, but other oxygenates play a role too. GW1929 may alleviate the toxicity of acrolein by attenuating NF-κB, COX, and CD36.

scholarly journals Protecting against vascular disease in brain

2011 ◽  
Vol 300 (5) ◽  
pp. H1566-H1582 ◽  
Author(s):  
Frank M. Faraci
Keyword(s):  
Vascular Disease ◽  
Renin Angiotensin System ◽  
Peroxisome Proliferator ◽  
Vascular Protection ◽  
Peroxisome Proliferator Activated Receptor ◽  
Angiotensin System ◽  
New Concepts ◽  
Vascular Component ◽  
Inflammatory Molecules

Endothelial cells exert an enormous influence on blood vessels throughout the circulation, but their impact is particularly pronounced in the brain. New concepts have emerged recently regarding the role of this cell type and mechanisms that contribute to endothelial dysfunction and vascular disease. Activation of the renin-angiotensin system plays a prominent role in producing these abnormalities. Both oxidative stress and local inflammation are key mechanisms that underlie vascular disease of diverse etiology. Endogenous mechanisms of vascular protection are also present, including antioxidants, anti-inflammatory molecules, and peroxisome proliferator-activated receptor-γ. Despite their clear importance, studies of mechanisms that underlie cerebrovascular disease continue to lag behind studies of vascular biology in general. Identification of endogenous molecules and pathways that protect the vasculature may result in targeted approaches to prevent or slow the progression of vascular disease that causes stroke and contributes to the vascular component of dementia and Alzheimer's disease.

scholarly journals Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages

2010 ◽  
Vol 30 (9) ◽  
pp. 2078-2089 ◽  
Author(s):  
Martina I. Lefterova ◽  
David J. Steger ◽  
David Zhuo ◽  
Mohammed Qatanani ◽  
Shannon E. Mullican ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Histone Acetylation ◽  
Histone Modifications ◽  
High Throughput Sequencing ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Open Chromatin ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Immune Genes

ABSTRACT The nuclear receptor peroxisome proliferator activator receptor γ (PPARγ) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side effects that limit widespread use. PPARγ is required for adipocyte differentiation, but it is also expressed in other cell types, notably macrophages, where it influences atherosclerosis, insulin resistance, and inflammation. A central question is whether PPARγ binding in macrophages occurs at genomic locations the same as or different from those in adipocytes. Here, utilizing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we demonstrate that PPARγ cistromes in mouse adipocytes and macrophages are predominantly cell type specific. In thioglycolate-elicited macrophages, PPARγ colocalizes with the hematopoietic transcription factor PU.1 in areas of open chromatin and histone acetylation, near a distinct set of immune genes in addition to a number of metabolic genes shared with adipocytes. In adipocytes, the macrophage-unique binding regions are marked with repressive histone modifications, typically associated with local chromatin compaction and gene silencing. PPARγ, when introduced into preadipocytes, bound only to regions depleted of repressive histone modifications, where it increased DNA accessibility, enhanced histone acetylation, and induced gene expression. Thus, the cell specificity of PPARγ function is regulated by cell-specific transcription factors, chromatin accessibility, and histone marks. Our data support the existence of an epigenomic hierarchy in which PPARγ binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation.

Branched-chain amino acids regulate hyaluronan synthesis and PPARα expression in the skin

2021 ◽  
Author(s):  
Takumi Yamane ◽  
Yasuyuki Kitaura ◽  
Ken Iwatsuki ◽  
Yoshiharu Shimomura ◽  
Yuichi Oishi
Keyword(s):  
Branched Chain Amino Acids ◽  
Peroxisome Proliferator ◽  
Keto Acid ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Branched Chain Amino Acid ◽  
Key Enzyme ◽  
In The Wild ◽  
Branched Chain ◽  
Gene Expression Levels

Abstract We examined the effects of deletion of branched-chain α-keto acid dehydrogenase kinase (BDK), a key enzyme in branched-chain amino acid catabolism, on hyaluronan synthesis in mice. The skin levels of hyaluronan and the gene expression levels of hyaluronan synthase (Has)2, Has3 and peroxisome proliferator-activated receptor-α (PPARα) were significantly lower in the BDK-knockout group than in the wild type group.

scholarly journals Enhanced lipogenesis through Pparγ helps cavefish adapt to food scarcity

2021 ◽  
Author(s):  
Shaolei Xiong ◽  
Wei Wang ◽  
Alexander Kenzior ◽  
Luke Olsen ◽  
Jaya Krishnan ◽  
...  
Keyword(s):  
Nutrient Availability ◽  
Primary Energy ◽  
Peroxisome Proliferator ◽  
Cellular Mechanisms ◽  
Promoter Regions ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Available Energy ◽  
Body Regions ◽  
In The Wild

AbstractNutrient availability varies seasonally and spatially in the wild. The resulting nutrient limitation or restricted access to nutrients pose a major challenge for every organism. While many animals, such as hibernating animals, evolved strategies to overcome periods of nutrient scarcity, the cellular mechanisms of these strategies are poorly understood. Cave environments represent an extreme example of nutrient deprived environments since the lack of sunlight and therefore primary energy production drastically diminishes the nutrient availability. Here, we used Astyanax mexicanus, which includes river-dwelling surface fish and cave adapted cavefish populations to study the genetic adaptation to nutrient limitations. We show that cavefish populations store large amounts of fat in different body regions when fed ad libitum in the lab. We found higher expression of lipogenesis genes in cavefish livers when fed the same amount of food as surface fish, suggesting an improved ability of cavefish to use lipogenesis to convert available energy into triglycerides for storage into adipose tissue. Moreover, the lipid metabolism regulator, Peroxisome proliferator-activated receptor γ (Pparγ), is upregulated at both transcript and protein levels in cavefish livers. Chromatin Immunoprecipitation sequencing (ChIP seq) showed that Pparγ binds cavefish promoter regions of genes to a higher extent than surface fish. Finally, we identified two possible regulatory mechanisms of Pparγ in cavefish: higher amounts of ligands of the nuclear receptor, and nonsense mutations in per2, a known repressor of Pparγ. Taken together, our study reveals that upregulated Pparγ promotes higher levels of lipogenesis in the liver and contributes to higher body fat accumulation in cavefish populations, an important adaptation to nutrient limited environments.

scholarly journals Peroxisome Proliferator-Activated Receptor Gamma Exacerbates Concanavalin A-Induced Liver Injury via Suppressing the Translocation of NF-κB into the Nucleus

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Yuji Ogawa ◽  
Masato Yoneda ◽  
Wataru Tomeno ◽  
Kento Imajo ◽  
Yoshiyasu Shinohara ◽  
...  
Keyword(s):  
Liver Injury ◽  
Concanavalin A ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Peroxisome Proliferator ◽  
Con A ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
In The Wild ◽  
Mobility Shift Assay

Peroxisome proliferator-activated receptor-γ(PPARγ) has been reported to reduce inflammation and attenuate fibrosis in the liver. In this study, we investigated the effects of PPARγon the liver injury induced by 20 mg/kg Concanavalin A (Con A). The mice were administered one of the three types of PPARγligands (pioglitazone, ciglitazone, and troglitazone) for 1 week, and the serum alanine aminotransferase (ALT) levels at 20 h after Con A injection were significantly elevated in the PPARγligand-treated mice. Furthermore, the serum ALT levels after Con A injection in the PPARγhetero-knock-out mice (PPARγ+/−mice) were lower than those in the wild-type mice (WT mice). Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) revealed extensive liver damage induced by Con A in the pioglitazone-treated mice. Electrophoresis mobility shift assay (EMSA) revealed that activation of translocation of nuclear factor- (NF-)κB, which is a suppressor of apoptosis, in the nucleus of the hepatocytes was suppressed in the pioglitazone-treated mice after Con A injection. In this study, we showed that PPARγexacerbated Con A-induced liver injury via suppressing the translocation of NF-κB into the nucleus, thereby inhibiting the suppression of liver cell apoptosis.

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