Regulation of de Novo Synthesis of Cytochrome P-450 17Α in Mouse LeydigCell Cultures a

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73047/1/j.1749-6632.1987.tb25049.x.pd

Time-Dependent Regulation of Apoptosis by Aen and Bax in Response to 2-Aminoanthracene Dietary Consumption

Background/Objective: The modulation of the toxic effects of 2-aminoanthracene (2AA) on the liver by apoptosis was investigated. Fisher-344 (F344) rats were exposed to various concentrations of 2AA for 14 and 28 days. The arylamine 2AA is an aromatic hydrocarbon employed in manufacturing chemicals, dyes, inks, and it is also a curing agent in epoxy resins and polyurethanes. 2AA has been detected in tobacco smoke and cooked foods. Methods: Analysis of total messenger ribonucleic acid (mRNA) extracts from liver for apoptosis-related gene expression changes in apoptosis enhancing nuclease (AEN), Bcl2-associated X protein (BAX), CASP3, Jun proto-oncogene (JUN), murine double minute-2 p53 binding protein homolog (MDM2), tumor protein p53 (p53), and GAPDH genes by quantitative real-time polymerase chain reaction (qRT-PCR) was coupled with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3 (Casp3) activity assays. Results: Specific apoptosis staining result does not seem to show significant difference between control and treated animals. This may be due to freeze-thaw artifacts observed in the liver samples. However, there appears to be a greater level of apoptosis in medium- and high-dose (MD and HD) 2AA treated animals. Analyses of apoptosis-related genes seem to show AEN and BAX as the main targets in the induction of apoptosis in response to 2AA exposure, though p53, MDM2, and JUN may play supporting roles. Conclusion: Dose-dependent increases in mRNA expression were observed in all genes except Casp3. BAX was very highly expressed in the HD rats belonging to the 2-week exposure group. This trend was not observed in the animals treated for 4 weeks. Instead, AEN was rather very highly expressed in the liver of the MD animals that were treated with 2AA for 28 days

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Flaxseed Reduces Cancer Risk by Altering Bioenergetic Pathways in Liver: Connecting SAM Biosynthesis to Cellular Energy

This article illustrates how dietary flaxseed can be used to reduce cancer risk, specifically by attenuating obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). We utilize a targeted metabolomics dataset in combination with a reanalysis of past work to investigate the “metabo-bioenergetic” adaptations that occur in White Leghorn laying hens while consuming dietary flaxseed. Recently, we revealed how the anti-vitamin B6 effects of flaxseed augment one-carbon metabolism in a manner that accelerates S-adenosylmethionine (SAM) biosynthesis. Researchers recently showed that accelerated SAM biosynthesis activates the cell’s master energy sensor, AMP-activated protein kinase (AMPK). Our paper provides evidence that flaxseed upregulates mitochondrial fatty acid oxidation and glycolysis in liver, concomitant with the attenuation of lipogenesis and polyamine biosynthesis. Defatted flaxseed likely functions as a metformin homologue by upregulating hepatic glucose uptake and pyruvate flux through the pyruvate dehydrogenase complex (PDC) in laying hens. In contrast, whole flaxseed appears to attenuate liver steatosis and body mass by modifying mitochondrial fatty acid oxidation and lipogenesis. Several acylcarnitine moieties indicate Randle cycle adaptations that protect mitochondria from metabolic overload when hens consume flaxseed. We also discuss a paradoxical finding whereby flaxseed induces the highest glycated hemoglobin percentage (HbA1c%) ever recorded in birds, and we suspect that hyperglycemia is not the cause. In conclusion, flaxseed modifies bioenergetic pathways to attenuate the risk of obesity, type 2 diabetes, and NAFLD, possibly downstream of SAM biosynthesis. These findings, if reproducible in humans, can be used to lower cancer risk within the general population

Time-Dependent Regulation of Apoptosis by Aen and Bax in Response to 2-Aminoanthracene Dietary Consumption

The modulation of the toxic effects of 2AA on the liver by apoptosis was investigated. The arylamine 2-aminoanthracene (2AA) is an aromatic hydrocarbon employed in manufacturing chemicals, dyes, inks, and as curing agents in epoxy resins and polyurethanes. 2AA has been detected in tobacco smoke and cooked foods. Analysis of total mRNA extracts from liver for apoptosis-related gene expression changes was coupled with liver tissue histology (H&E staining), TUNEL and Caspase-3 activity assays. Specific apoptosis staining showed greater level of apoptosis in medium- and high-dose 2AA treated animals. Apoptosis does not seem to occur directly via caspase-3 activation mechanism. Analyses of apoptosis-related genes seem to show AEN and BAX as the main targets in the induction of apoptosis in response to 2AA exposure. Dose-dependent increases in mRNA expression were observed in all genes except caspase 3. Bax was highly expressed in the high-dose rats belonging to the 2-week exposure group

Apoptosis Modulates Hepatotoxic Effects of 2-Aminoanthracene in Fisher 344 Rat

The arylamine 2-amino-anthracene (2-AA) is an aromatic hydrocarbon employed in manufacturing of chemicals, dyes, inks, and as curing agents in epoxy resins and polyurethanes. 2-AA has been detected tobacco smoke and cooked foods. The modulation of the toxic effects of 2-AA on the liver by apoptosis was investigated on twenty four post-weaning 3-4 week old F-344 male rats exposed to 0 mg/kg-diet (control), 50 mg/kg-diet (LD), 75 mg/kg-diet (MD) and 100 mg/kg-diet (HD) 2-AA for 14 [2WK] and 28 days [4WK]. Analysis of total mRNA extracts from liver for apoptosis-related gene expression changes in AEN, BAX, CASP3, JUN, MDM2, P53, and GAPDH genes by qRT-PCR was coupled with liver tissue histology (H&E staining), TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end-labeling) assay and Caspase (Caspase Glo assay) activity. Dose-related histological changes in liver cell architecture were observed at the highest doses in both 2WK and 4WK exposures. Dose-related increases in TUNEL-positive staining were also observed. Caspase3 assays showed dose-dependent increases (2WK) but suppression in LD and MD [4WK] rat livers and an increase in HD rats. Dose-related increases in expression were observed in all genes measured