The Gut Microbiota Affects Corticosterone Production in the Murine Small Intestine

Glucocorticoids (GCs) are hormones that are released in response to stressors and exhibit many activities, including immunomodulatory and anti-inflammatory activities. They are primarily synthesized in the adrenal gland but are also produced in peripheral tissues via regeneration of adrenal 11-oxo metabolites or by de novo synthesis from cholesterol. The present study investigated the influence of the microbiota on de novo steroidogenesis and regeneration of corticosterone in the intestine of germ-free (GF) and specific pathogen-free mice challenged with a physical stressor (anti-CD3 antibody i.p. injection). In the small intestine, acute immune stress resulted in increased mRNA levels of the proinflammatory cytokines IL1β, IL6 and Tnfα and genes involved in de novo steroidogenesis (Stard3 and Cyp11a1), as well as in regeneration of active GCs from their 11-oxo metabolites (Hsd11b1). GF mice showed a generally reduced transcriptional response to immune stress, which was accompanied by decreased intestinal corticosterone production and reduced expression of the GC-sensitive marker Fkbp5. In contrast, the interaction between stress and the microbiota was not detected at the level of plasma corticosterone or the transcriptional response of adrenal steroidogenic enzymes. The results indicate a differential immune stress-induced intestinal response to proinflammatory stimuli and local corticosterone production driven by the gut microbiota.

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Thyroid hormone and retinoic acid induce the synthesis of insulin-like growth factor-binding protein-4 in prepubertal pig sertoli cells

Acta Endocrinologica ◽

10.1530/eje.0.1410637 ◽

1999 ◽

pp. 637-643 ◽

Cited By ~ 10

Author(s):

G Bardi ◽

C Bottazzi ◽

I Demori ◽

S Palmero

Keyword(s):

Retinoic Acid ◽

Sertoli Cells ◽

Transcriptional Activation ◽

De Novo ◽

Large Body ◽

Transcriptional Response ◽

Mrna Levels ◽

Direct Role ◽

Igf System ◽

Dose Dependent Increase

A large body of evidence suggests the existence of an intratesticular IGF system complete with ligands, receptors and binding proteins (IGFBPs); the aim of the present study was to evaluate tri-iodothyronine (T(3)) and retinoic acid (RA) effects on IGFBP production by Sertoli cells. A significant dose-dependent increase in IGFBP-4 mRNA levels was observed in Sertoli cells cultured in the presence of physiological concentrations of T(3) or RA. This response was inhibited by cycloheximide, indicating that de novo protein synthesis is required, as well as by actinomycin D, suggesting that the increase in mRNA levels requires transcriptional activation. As shown by ligand blot assays the stimulatory effects of both agents on IGFBP-4 mRNA expression appears to be consistent with an enhanced synthesis and secretion of IGFBP-4, thus suggesting that the transcriptional response is transduced to the protein level. Our data establish an important direct role for T(3) and RA in regulating IGFBP-4 expression and consequently IGF activity at the testis level.

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Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00629.2007 ◽

2008 ◽

Vol 295 (2) ◽

pp. E436-E445 ◽

Cited By ~ 18

Author(s):

Xing Xian Yu ◽

Susan F. Murray ◽

Lynnetta Watts ◽

Sheri L. Booten ◽

Justin Tokorcheck ◽

...

Keyword(s):

Fatty Acid ◽

Antisense Oligonucleotide ◽

De Novo ◽

Plasma Cholesterol ◽

Liver Steatosis ◽

Whole Body ◽

Acid Oxidation ◽

Mrna Levels ◽

Obese Mice ◽

Peripheral Tissues

To investigate the role of JNK1 in metabolism, male ob/ ob and diet-induced obese mice were treated with a JNK1-specific antisense oligonucleotide (ASO) or control ASO at 25 mg/kg or saline twice/wk for 6 and 7 wk, respectively. JNK1 ASO reduced JNK1 mRNA and activity by 65–95% in liver and fat tissues in both models. Compared with controls, treatment with JNK1 ASO did not change food intake but lowered body weight, fat pad weight, and whole body fat content. The treatment increased metabolic rate. In addition, the treatment markedly reduced plasma cholesterol levels and improved liver steatosis and insulin sensitivity. These positive observations were accompanied by the following changes: 1) increased mRNA levels of AR-β3 and UCP1 by >60% in BAT, 2) reduced mRNA levels of ACC1, ACC2, FAS, SCD1, DGAT1, DGAT2, and RBP4 by 30–60% in WAT, and 3) reduced mRNA levels of ACC1, FAS, G-6-Pase, and PKCε by 40–70% and increased levels of UCP2 and PPARα by more than twofold in liver. JNK1 ASO-treated mice demonstrated reduced levels of pIRS-1 Ser302 and pIRS-1 Ser307 and increased levels of pAkt Ser473 in liver and fat in response to insulin. JNK1 ASO-transfected mouse hepatocytes showed decreased rates of de novo sterol and fatty acid synthesis and an increased rate of fatty acid oxidation. These results indicate that inhibition of JNK1 expression in major peripheral tissues can improve adiposity via increasing fuel combustion and decreasing lipogenesis and could therefore provide clinical benefit for the treatment of obesity and related metabolic abnormalities.

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Faculty Opinions recommendation of Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1092481.546926 ◽

2007 ◽

Author(s):

Arthur Hurwitz

Keyword(s):

Dendritic Cells ◽

Small Intestine ◽

Retinoic Acid ◽

Lamina Propria ◽

De Novo

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Adaptive response to a future life challenge: consequences of early-life environmental complexity in dual-purpose chicks

Journal of Animal Science ◽

10.1093/jas/skaa348 ◽

2020 ◽

Vol 98 (11) ◽

Author(s):

Chao Yan ◽

Kate Hartcher ◽

Wen Liu ◽

Jinlong Xiao ◽

Hai Xiang ◽

...

Keyword(s):

Gene Expression ◽

Gut Microbiota ◽

Early Life ◽

Plasma Corticosterone ◽

Adaptive Plasticity ◽

Environmental Complexity ◽

Dual Purpose ◽

Stress Related Genes ◽

Life Challenge ◽

Environmental Challenge

Abstract Conditions in early life play profound and long-lasting effects on the welfare and adaptability to stress of chickens. This study aimed to explore the hypothesis that the provision of environmental complexity in early life improves birds’ adaptive plasticity and ability to cope with a challenge later in life. It also tried to investigate the effect of the gut-brain axis by measuring behavior, stress hormone, gene expression, and gut microbiota. One-day-old chicks were split into 3 groups: (1) a barren environment (without enrichment items) group (BG, n = 40), (2) a litter materials group (LG, n = 40), and (3) a perches with litter materials group (PLG, n = 40). Then, enrichment items were removed and simulated as an environmental challenge at 31 to 53 d of age. Birds were subjected to a predator test at 42 d of age. In the environmental challenge, when compared with LG, PLG birds were characterized by decreased fearfulness, lower plasma corticosterone, improved gut microbial functions, lower relative mRNA expression of GR, and elevated mRNA expressions of stress-related genes CRH, BDNF, and NR2A in the hypothalamus (all P < 0.05). Unexpectedly, the opposite was true for the LG birds when compared with the BG (P < 0.05). Decreased plasma corticosterone and fearfulness were accompanied by altered hypothalamic gene mRNA expressions of BDNF, NR2A, GR, and CRH through the HPA axis in response to altered gut microbial compositions and functions. The findings suggest that gut microbiota may integrate fearfulness, plasma corticosterone, and gene expression in the hypothalamus to provide an insight into the gut-brain axis in chicks. In conclusion, having access to both perches and litter materials in early life allowed birds to cope better with a future challenge. Birds in perches and litter materials environment may have optimal development and adaptive plasticity through the gut-brain axis.

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Examination of the Transcriptional Response to LaMIR166a Overexpression in Larix kaempferi (Lamb.) Carr

Biology ◽

10.3390/biology10070576 ◽

2021 ◽

Vol 10 (7) ◽

pp. 576

Author(s):

Yanru Fan ◽

Wanfeng Li ◽

Zhexin Li ◽

Shaofei Dang ◽

Suying Han ◽

...

Keyword(s):

Cell Lines ◽

Molecular Mechanisms ◽

Target Genes ◽

De Novo ◽

Pearson Correlation ◽

Transcriptional Response ◽

Correlation Coefficients ◽

Embryonic Cell ◽

Larix Kaempferi ◽

Transgenic Cell

The study of somatic embryogenesis can provide insight into early plant development. We previously obtained LaMIR166a-overexpressing embryonic cell lines of Larix kaempferi (Lamb.) Carr. To further elucidate the molecular mechanisms associated with miR166 in this species, the transcriptional profiles of wild-type (WT) and three LaMIR166a-overexpressing transgenic cell lines were subjected to RNA sequencing using the Illumina NovaSeq 6000 system. In total, 203,256 unigenes were generated using Trinity de novo assembly, and 2467 differentially expressed genes were obtained by comparing transgenic and WT lines. In addition, we analyzed the cleaved degree of LaMIR166a target genes LaHDZ31–34 in different transgenic cell lines by detecting the expression pattern of LaHdZ31–34, and their cleaved degree in transgenic cell lines was higher than that in WT. The downstream genes of LaHDZ31–34 were identified using Pearson correlation coefficients. Yeast one-hybrid and dual-luciferase report assays revealed that the transcription factors LaHDZ31–34 could bind to the promoters of LaPAP, LaPP1, LaZFP5, and LaPHO1. This is the first report of gene expression changes caused by LaMIR166a overexpression in Japanese larch. These findings lay a foundation for future studies on the regulatory mechanism of miR166.

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Blood functional assay for rapid clinical interpretation of germline TP53 variants

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107059 ◽

2020 ◽

pp. jmedgenet-2020-107059 ◽

Cited By ~ 1

Author(s):

Sabine Raad ◽

Marion Rolain ◽

Sophie Coutant ◽

Céline Derambure ◽

Raphael Lanos ◽

...

Keyword(s):

Mononuclear Cells ◽

Transcriptional Response ◽

Functional Assay ◽

Mrna Levels ◽

Peripheral Blood Mononuclear ◽

Patients With Cancer ◽

Pathogenic Variants ◽

Functional Variants ◽

Multiplex Ligation Probe Amplification ◽

P53 Mrna

BackgroundThe interpretation of germline TP53 variants is critical to ensure appropriate medical management of patients with cancer and follow-up of variant carriers. This interpretation remains complex and is becoming a growing challenge considering the exponential increase in TP53 tests. We developed a functional assay directly performed on patients’ blood.MethodsPeripheral blood mononuclear cells were cultured, activated, exposed to doxorubicin and the p53-mediated transcriptional response was quantified using reverse transcription–multiplex ligation probe amplification and RT-QMPSF assays, including 10 p53 targets selected from transcriptome analysis, and two amplicons to measure p53 mRNA levels. We applied this blood functional assay to 77 patients addressed for TP53 analysis.ResultsIn 51 wild-type TP53 individuals, the mean p53 functionality score was 12.7 (range 7.5–22.8). Among eight individuals harbouring likely pathogenic or pathogenic variants, the scores were reduced (mean 4.8, range 3.1–7.1), and p53 mRNA levels were reduced in patients harbouring truncating variants. We tested 14 rare unclassified variants (p.(Pro72His), p.(Gly105Asp), p.(Arg110His), p.(Phe134Leu), p.(Arg158Cys), p.(Pro191Arg), p.(Pro278Arg), p.(Arg283Cys), p.(Leu348Ser), p.(Asp352Tyr), p.(Gly108_Phe109delinsVal), p.(Asn131del), p.(Leu265del), c.-117G>T) and 12 yielded functionally abnormal scores. Remarkably, the assay revealed that the c.*1175A>C polymorphic variant within TP53 poly-adenylation site can impact p53 function with the same magnitude as a null variant, when present on both alleles, and may act as a modifying factor in pathogenic variant carriers.ConclusionThis blood p53 assay should therefore be a useful tool for the rapid clinical classification of germline TP53 variants and detection of non-coding functional variants.

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CHOP and c-JUN up-regulate the mutant Z α1-antitrypsin, exacerbating its aggregation and liver proteotoxicity

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014307 ◽

2020 ◽

Vol 295 (38) ◽

pp. 13213-13223

Author(s):

Sergio Attanasio ◽

Rosa Ferriero ◽

Gwladys Gernoux ◽

Rossella De Cegli ◽

Annamaria Carissimo ◽

...

Keyword(s):

Liver Disease ◽

Er Stress ◽

Proteinase Inhibitors ◽

Pediatric Population ◽

Transcriptional Response ◽

Luciferase Reporter ◽

Mrna Levels ◽

Primary Role ◽

Loss Of Function ◽

Human Livers

α1-Antitrypsin (AAT) encoded by the SERPINA1 gene is an acute-phase protein synthesized in the liver and secreted into the circulation. Its primary role is to protect lung tissue by inhibiting neutrophil elastase. The Z allele of SERPINA1 encodes a mutant AAT, named ATZ, that changes the protein structure and leads to its misfolding and polymerization, which cause endoplasmic reticulum (ER) stress and liver disease through a gain-of-function toxic mechanism. Hepatic retention of ATZ results in deficiency of one of the most important circulating proteinase inhibitors and predisposes to early-onset emphysema through a loss-of-function mechanism. The pathogenetic mechanisms underlying the liver disease are not completely understood. C/EBP-homologous protein (CHOP), a transcription factor induced by ER stress, was found among the most up-regulated genes in livers of PiZ mice that express ATZ and in human livers of patients homozygous for the Z allele. Compared with controls, juvenile PiZ/Chop−/− mice showed reduced hepatic ATZ and a transcriptional response indicative of decreased ER stress by RNA-Seq analysis. Livers of PiZ/Chop−/− mice also showed reduced SERPINA1 mRNA levels. By chromatin immunoprecipitations and luciferase reporter–based transfection assays, CHOP was found to up-regulate SERPINA1 cooperating with c-JUN, which was previously shown to up-regulate SERPINA1, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. In summary, CHOP and c-JUN up-regulate SERPINA1 transcription and play an important role in hepatic disease by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.

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The Early Transcriptional Response of Human Granulocytes to Infection with Candida albicans Is Not Essential for Killing but Reflects Cellular Communications

Infection and Immunity ◽

10.1128/iai.01651-06 ◽

2006 ◽

Vol 75 (3) ◽

pp. 1493-1501 ◽

Cited By ~ 28

Author(s):

Chantal Fradin ◽

Abigail L. Mavor ◽

Günther Weindl ◽

Martin Schaller ◽

Karin Hanke ◽

...

Keyword(s):

Candida Albicans ◽

Mononuclear Cells ◽

De Novo ◽

Transcriptional Response ◽

Mononuclear Leukocytes ◽

General Notion ◽

Genes Encoding ◽

Global Transcriptional Profile ◽

Life Threatening ◽

Systemic Infections

ABSTRACT Candida albicans is a polymorphic opportunistic fungus that can cause life-threatening systemic infections following hematogenous dissemination in patients susceptible to nosocomial infection. Neutrophils form part of the innate immune response, which is the first line of defense against microbes and is particularly important in C. albicans infections. To compare the transcriptional response of leukocytes exposed to C. albicans, we investigated the expression of key cytokine genes in polymorphonuclear and mononuclear leukocytes after incubation with C. albicans for 1 h. Isolated mononuclear cells expressed high levels of genes encoding proinflammatory signaling molecules, whereas neutrophils exhibited much lower levels, similar to those observed in whole blood. The global transcriptional profile of neutrophils was examined by using an immunology-biased human microarray to determine whether different morphological forms or the viability of C. albicans altered the transcriptome. Hyphal cells appeared to have the broadest effect, although the most strongly induced genes were regulated independently of morphology or viability. These genes were involved in proinflammatory cell-cell signaling, cell signal transduction, and cell growth. Generally, genes encoding known components of neutrophil granules showed no upregulation at this time point; however, lactoferrin, a well-known candidacidal peptide, was secreted by neutrophils. Addition to inhibitors of RNA or protein de novo synthesis did not influence the killing activity within 30 min. These results support the general notion that neutrophils do not require gene transcription to mount an immediate and direct attack against microbes. However, neutrophils exposed to C. albicans express genes involved in communication with other immune cells.

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Metabolic and endocrine changes induced by chronic heatexposure in broiler chickens : biological and endocrinological variables

British Journal Of Nutrition ◽

10.1017/bjn19960125 ◽

1996 ◽

Vol 75 (2) ◽

pp. 205-216 ◽

Cited By ~ 2

Author(s):

P. A. Geraert ◽

J. C. F. Padilha ◽

S. Guillaumin

Keyword(s):

Amino Acids ◽

Ambient Temperature ◽

Broiler Chickens ◽

De Novo ◽

Heat Exposure ◽

Plasma Corticosterone ◽

Plasma Metabolites ◽

Exogenous Insulin ◽

Plasma Insulin Concentration ◽

Esterified Fatty Acids

Abstract:The present study was designed to investigate the effect of chronic heat exposure (32° constant) on plasma metabolites and hormone concentrations in broiler chickens. At 2 and 4 weeks of age, fifty-four male Shaver broiler chickens were allocated to one of three treatments: 22°ad lib. feeding (22AL), 32°ad lib. feeding (32AL) and 22°,pair-feeding with the 32AL group (22PF). Ambient temperature was kept constant at either 22 or 32° for 2 weeks. Plasma glucose, triacylglycerols, phospholipids, non-esterified fatty acids (NEFA), individual amino acids, uric acid, insulin, triiodothyronine (T3), thyroxine, corticosterone were determined. Sensitivity to exogenous insulin was also measured at 7 weeks of age. At 4 and 6 weeks of age, i.e. after 2 weeks at high ambient temperature, fasted 32AL chickens displayed similar concentrations of glucose and triacylglycerols to those of 22AL birds. When fed, 32AL chickens exhibited higher plasma levels of glucose and decreased concentrations of NEFAand amino acids. Feed restriction resulted in intermediate values. Concentrations of all plasmafree amino acids were decreased under heat exposure except for aspartic acid, glutamic acid andphenylalanine. At 6 weeks of age, plasma T3 was reduced irrespective of the nutritional state, while plasma corticosterone concentrations were increased in 32AL birds compared with 22AL birds. Heat exposure did not change plasma insulin concentration in either fasted or fed chickens. The 32AL chickens displayed significantly reduced sensitivity to exogenous insulin when fasted,but an enhanced response to insulin when fed, compared with both 22° groups. Such endocrinological changes could stimulate lipid accumulation through increasedde novolipogenesis, reduced lipolysis and enhanced amino acid catabolism under chronic heat exposure.

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