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Article ; Online: Cocaine hydrochloride, cocaine methiodide and methylenedioxypyrovalerone (MDPV) cause distinct alterations in the structure and composition of the gut microbiota.

Angoa-Pérez, Mariana / Zagorac, Branislava / Francescutti, Dina M / Shaffer, Zachary D / Theis, Kevin R / Kuhn, Donald M

Scientific reports

2023 Volume 13, Issue 1, Page(s) 13754

Abstract: Cocaine is a highly addictive psychostimulant drug of abuse that constitutes an ongoing public health threat. Emerging research is revealing that numerous peripheral effects of this drug may serve as conditioned stimuli for its central reinforcing ... ...

Abstract	Cocaine is a highly addictive psychostimulant drug of abuse that constitutes an ongoing public health threat. Emerging research is revealing that numerous peripheral effects of this drug may serve as conditioned stimuli for its central reinforcing properties. The gut microbiota is emerging as one of these peripheral sources of input to cocaine reward. The primary objective of the present study was to determine how cocaine HCl and methylenedioxypyrovalerone, both of which powerfully activate central reward pathways, alter the gut microbiota. Cocaine methiodide, a quaternary derivative of cocaine that does not enter the brain, was included to assess peripheral influences on the gut microbiota. Both cocaine congeners caused significant and similar alterations of the gut microbiota after a 10-day course of treatment. Contrary to expectations, the effects of cocaine HCl and MDPV on the gut microbiota were most dissimilar. Functional predictions of metabolic alterations caused by the treatment drugs reaffirmed that the cocaine congeners were similar whereas MDPV was most dissimilar from the other two drugs and controls. It appears that the monoamine transporters in the gut mediate the effects of the treatment drugs. The effects of the cocaine congeners and MDPV on the gut microbiome may form the basis of interoceptive cues that can influence their abuse properties.
MeSH term(s)	Synthetic Cathinone ; Gastrointestinal Microbiome ; Cocaine/pharmacology ; Central Nervous System Stimulants
Chemical Substances	cocaine methiodide (83FKO5XD6J) ; Synthetic Cathinone ; Cocaine (I5Y540LHVR) ; Central Nervous System Stimulants
Language	English
Publishing date	2023-08-23
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-40892-1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Effects of gut microbiota remodeling on the dysbiosis induced by high fat diet in a mouse model of Gulf war illness.

Angoa-Pérez, Mariana / Zagorac, Branislava / Francescutti, Dina M / Theis, Kevin R / Kuhn, Donald M

Life sciences

2021 Volume 279, Page(s) 119675

Abstract: Gulf war illness (GWI) is a chronic disorder of unknown etiology characterized by multiple symptoms such as pain, fatigue, gastrointestinal disturbances and neurocognitive problems. Increasing evidence suggests that gut microbiome perturbations play a ... ...

Abstract	Gulf war illness (GWI) is a chronic disorder of unknown etiology characterized by multiple symptoms such as pain, fatigue, gastrointestinal disturbances and neurocognitive problems. Increasing evidence suggests that gut microbiome perturbations play a key role in the pathology of this disorder. GWI courses with gut microbiota alterations and their metabolites (e.g. short chain fatty acids -SCFA-), which can be aggravated by lifestyle risk factors such as a high fat diet (HF). To investigate the causative role of the gut microbiome, non-absorbable antibiotics (Abx) were administered to mice treated with GWI agents and concomitantly fed with a HF. In light of the wide use of Abx as pseudo-germ-free models, we evaluated the effects of Abx exposure on GWI and HF on body weight, food intake, gut microbiota changes and levels of the SCFA acetate. Results show that HF decreased food intake while increasing body weight in both controls and GWI. Exposure to Abx prevented these HF effects by offsetting the body weight gain in GWI. GWI and HF led to decreases in α-diversity, disruptions in the composition and structure of the gut bacterial community and decreases in acetate levels. This Abx-induced remodeling of the gut microbiome was characterized by an expansion of Proteobacteria, decreases in Bacteroidetes and Firmicutes, and overall increases in acetate levels, as well as by the proliferation of potential pathobionts. Therefore, the use of Abx may not represent a dependable approach to deplete the gut microbiome and its advantages as a pseudo germ-free model warrant further investigation.
MeSH term(s)	Animals ; Bacteria/pathogenicity ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Dysbiosis/etiology ; Dysbiosis/pathology ; Gastrointestinal Microbiome ; Inflammation/etiology ; Inflammation/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Persian Gulf Syndrome/complications
Language	English
Publishing date	2021-05-31
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2021.119675
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Article: Long access heroin self-administration significantly alters gut microbiome composition and structure.

Greenberg, Jonathan M / Winters, Andrew D / Zagorac, Branislava / Kracht, David J / Francescutti, Dina M / Cannella, Nazzareno / Ciccocioppo, Roberto / Woods, Leah C Solberg / Mackle, James / Hardiman, Gary T / Kuhn, Brittany N / Kalivas, Peter W / Kuhn, Donald M / Angoa-Perez, Mariana

Frontiers in psychiatry

2024 Volume 15, Page(s) 1369783

Abstract: Introduction: It is well known that chronic opioid use disorder is associated with alterations in gastrointestinal (GI) function that include constipation, reduced motility, and increased bacterial translocation due to compromised gut barrier function. ... ...

Abstract	Introduction: It is well known that chronic opioid use disorder is associated with alterations in gastrointestinal (GI) function that include constipation, reduced motility, and increased bacterial translocation due to compromised gut barrier function. These signs of disrupted GI function can be associated with alterations in the gut microbiome. However, it is not known if long-access opioid self-administration has effects on the gut microbiome. Methods: We used 16S rRNA gene sequencing to investigate the gut microbiome in three independent cohorts (N=40 for each) of NIH heterogeneous stock rats before onset of long-access heroin self-administration (i.e., naïve status), at the end of a 15-day period of self-administration, and after post-extinction reinstatement. Measures of microbial α- and β-diversity were evaluated for all phases. High-dimensional class comparisons were carried out with MaAsLin2. PICRUSt2 was used for predicting functional pathways impacted by heroin based on marker gene sequences. Results: Community α-diversity was not altered by heroin at any of the three phases by comparison to saline-yoked controls. Analyses of β-diversity showed that the heroin and saline-yoked groups clustered significantly apart from each other using the Bray-Curtis (community structure) index. Heroin caused significant alterations at the ASV level at the self-administration and extinction phases. At the phylum level, the relative abundance of Firmicutes was increased at the self-administration phase. Deferribacteres was decreased in heroin whereas Patescibacteria was increased in heroin at the extinction phase. Potential biomarkers for heroin emerged from the MaAsLin2 analysis. Bacterial metabolomic pathways relating to degradation of carboxylic acids, nucleotides, nucleosides, carbohydrates, and glycogen were increased by heroin while pathways relating to biosynthesis of vitamins, propionic acid, fatty acids, and lipids were decreased. Discussion: These findings support the view that long access heroin self-administration significantly alters the structure of the gut microbiome by comparison to saline-yoked controls. Inferred metabolic pathway alterations suggest the development of a microbial imbalance favoring gut inflammation and energy expenditure. Potential microbial biomarkers and related functional pathways likely invoked by heroin self-administration could be targets for therapeutic intervention.
Language	English
Publishing date	2024-02-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2024.1369783
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Article: Effects of gut microbiota remodeling on the dysbiosis induced by high fat diet in a mouse model of Gulf war illness

Angoa-Pérez, Mariana / Zagorac, Branislava / Francescutti, Dina M / Theis, Kevin R / Kuhn, Donald M

Elsevier Inc. Life sciences. 2021 Aug. 15, v. 279

2021

Abstract	Gulf war illness (GWI) is a chronic disorder of unknown etiology characterized by multiple symptoms such as pain, fatigue, gastrointestinal disturbances and neurocognitive problems. Increasing evidence suggests that gut microbiome perturbations play a key role in the pathology of this disorder. GWI courses with gut microbiota alterations and their metabolites (e.g. short chain fatty acids -SCFA-), which can be aggravated by lifestyle risk factors such as a high fat diet (HF). To investigate the causative role of the gut microbiome, non-absorbable antibiotics (Abx) were administered to mice treated with GWI agents and concomitantly fed with a HF. In light of the wide use of Abx as pseudo-germ-free models, we evaluated the effects of Abx exposure on GWI and HF on body weight, food intake, gut microbiota changes and levels of the SCFA acetate. Results show that HF decreased food intake while increasing body weight in both controls and GWI. Exposure to Abx prevented these HF effects by offsetting the body weight gain in GWI. GWI and HF led to decreases in α-diversity, disruptions in the composition and structure of the gut bacterial community and decreases in acetate levels. This Abx-induced remodeling of the gut microbiome was characterized by an expansion of Proteobacteria, decreases in Bacteroidetes and Firmicutes, and overall increases in acetate levels, as well as by the proliferation of potential pathobionts. Therefore, the use of Abx may not represent a dependable approach to deplete the gut microbiome and its advantages as a pseudo germ-free model warrant further investigation.
Keywords	Bacteroidetes ; Firmicutes ; Proteobacteria ; acetates ; bacterial communities ; body weight changes ; dysbiosis ; etiology ; food intake ; gastrointestinal system ; high fat diet ; intestinal microorganisms ; lifestyle ; metabolites ; mice ; pain
Language	English
Dates of publication	2021-0815
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2021.119675
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Article ; Online: Responses to chronic corticosterone on brain glucocorticoid receptors, adrenal gland, and gut microbiota in mice lacking neuronal serotonin.

Angoa-Pérez, Mariana / Zagorac, Branislava / Francescutti, Dina M / Theis, Kevin R / Kuhn, Donald M

Brain research

2020 Volume 1751, Page(s) 147190

Abstract: Dysregulation of the stress-induced activation of the hypothalamic-pituitary-adrenocortical axis can result in disease. Bidirectional communication exists between the brain and the gut, and alterations in these interactions appear to be involved in ... ...

Abstract	Dysregulation of the stress-induced activation of the hypothalamic-pituitary-adrenocortical axis can result in disease. Bidirectional communication exists between the brain and the gut, and alterations in these interactions appear to be involved in stress regulation and in the pathogenesis of neuropsychiatric diseases, such as depression. Serotonin (5HT) plays a crucial role in the functions of these two major organs but its direct influence under stress conditions remains unclear. To investigate the role of neuronal 5HT on chronic stress responses and its influence on the gut microbiome, mice lacking the gene for tryptophan hydroxylase-2 were treated with the stress hormone corticosterone (CORT) for 21 days. The intake of fluid and food, as well as body weights were recorded daily. CORT levels, expression of glucocorticoid receptors (GR) in the brain and the size of the adrenal gland were evaluated. Caecum was used for 16S rRNA gene characterization of the gut microbiota. Results show that 5HT depletion produced an increase in food intake and a paradoxical reduction in body weight that were enhanced by CORT. Neuronal 5HT depletion impaired the feedback regulation of CORT levels but had no putative effect on the CORT-induced decrease in hippocampal GR expression and the reduction of the adrenal cortex size. Finally, the composition and structure of the gut microbiota were significantly impacted by the absence of neuronal 5HT, and these alterations were enhanced by chronic CORT treatment. Therefore, we conclude that neuronal 5HT influences the stress-related responses at different levels involving CORT levels regulation and the gut microbiome.
MeSH term(s)	Adrenal Glands/drug effects ; Adrenal Glands/metabolism ; Animals ; Brain/metabolism ; Corticosterone/metabolism ; Corticosterone/pharmacology ; Gastrointestinal Microbiome/drug effects ; Gastrointestinal Microbiome/physiology ; Hypothalamo-Hypophyseal System/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/metabolism ; Pituitary-Adrenal System/metabolism ; RNA, Ribosomal, 16S/metabolism ; Receptors, Glucocorticoid/drug effects ; Receptors, Glucocorticoid/metabolism ; Serotonin/genetics ; Serotonin/metabolism ; Stress, Psychological/metabolism ; Tryptophan Hydroxylase/genetics
Chemical Substances	RNA, Ribosomal, 16S ; Receptors, Glucocorticoid ; Serotonin (333DO1RDJY) ; Tph2 protein, mouse (EC 1.14.16.4) ; Tryptophan Hydroxylase (EC 1.14.16.4) ; Corticosterone (W980KJ009P)
Language	English
Publishing date	2020-11-02
Publishing country	Netherlands
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2020.147190
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Article ; Online: Differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice.

Angoa-Pérez, Mariana / Zagorac, Branislava / Winters, Andrew D / Greenberg, Jonathan M / Ahmad, Madison / Theis, Kevin R / Kuhn, Donald M

PloS one

2020 Volume 15, Issue 1, Page(s) e0227774

Abstract: The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat ...

Abstract	The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka "Bath Salts") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a β-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.
MeSH term(s)	Animals ; DNA, Bacterial/isolation & purification ; Designer Drugs/administration & dosage ; Designer Drugs/adverse effects ; Female ; Gastrointestinal Microbiome/drug effects ; Gastrointestinal Microbiome/genetics ; Methamphetamine/administration & dosage ; Methamphetamine/adverse effects ; Methamphetamine/analogs & derivatives ; Mice ; Models, Animal ; Propiophenones/administration & dosage ; Propiophenones/adverse effects ; Psychotropic Drugs/administration & dosage ; Psychotropic Drugs/adverse effects ; RNA, Ribosomal, 16S/genetics
Chemical Substances	DNA, Bacterial ; Designer Drugs ; Propiophenones ; Psychotropic Drugs ; RNA, Ribosomal, 16S ; monomethylpropion (386QA522QG) ; Methamphetamine (44RAL3456C) ; mephedrone (8BA8T27317)
Language	English
Publishing date	2020-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0227774
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Repetitive, mild traumatic brain injury results in a progressive white matter pathology, cognitive deterioration, and a transient gut microbiota dysbiosis.

Angoa-Pérez, Mariana / Zagorac, Branislava / Anneken, John H / Briggs, Denise I / Winters, Andrew D / Greenberg, Jonathan M / Ahmad, Madison / Theis, Kevin R / Kuhn, Donald M

Scientific reports

2020 Volume 10, Issue 1, Page(s) 8949

Abstract: Traumatic brain injury (TBI) is often accompanied by gastrointestinal and metabolic disruptions. These systemic manifestations suggest possible involvement of the gut microbiota in head injury outcomes. Although gut dysbiosis after single, severe TBI has ...

Abstract	Traumatic brain injury (TBI) is often accompanied by gastrointestinal and metabolic disruptions. These systemic manifestations suggest possible involvement of the gut microbiota in head injury outcomes. Although gut dysbiosis after single, severe TBI has been documented, the majority of head injuries are mild, such as those that occur in athletes and military personnel exposed to repetitive head impacts. Therefore, it is important to determine if repetitive, mild TBI (rmTBI) will also disrupt the gut microbiota. Male mice were exposed to mild head impacts daily for 20 days and assessed for cognitive behavior, neuropathology and disruptions in the gut microbiota at 0, 45 or 90 days after injury. Deficits in recognition memory were evident at the late post-injury points. Brains show an early increase in microglial activation at the 0-day time point that persisted until 90 days post-injury. This was compounded by substantial increases in astrocyte reactivity and phosphorylated tau at the 90-day time point. In contrast, changes in the microbial community were minor and transient, and very few differences were observed in mice exposed to rmTBI compared to controls. While the progressive emergence of white matter damage and cognitive alterations after rmTBI resembles the alterations observed in athletes and military personnel exposed to rmTBI, these changes could not be linked to systematic modifications in the gut microbiota.
MeSH term(s)	Animals ; Bacteria/genetics ; Brain/metabolism ; Brain Concussion/metabolism ; Brain Concussion/microbiology ; Brain Concussion/physiopathology ; Brain Injuries/pathology ; Cognition/physiology ; Cognition Disorders/pathology ; Disease Models, Animal ; Dysbiosis/microbiology ; Dysbiosis/physiopathology ; Gastrointestinal Microbiome/physiology ; Male ; Mice ; Mice, Inbred C57BL ; RNA, Ribosomal, 16S/genetics ; White Matter/metabolism ; White Matter/physiopathology
Chemical Substances	RNA, Ribosomal, 16S
Language	English
Publishing date	2020-06-02
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-65972-4
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Article ; Online: Effects of a high fat diet on gut microbiome dysbiosis in a mouse model of Gulf War Illness.

Angoa-Pérez, Mariana / Zagorac, Branislava / Francescutti, Dina M / Winters, Andrew D / Greenberg, Jonathan M / Ahmad, Madison M / Manning, Shannon D / Gulbransen, Brian D / Theis, Kevin R / Kuhn, Donald M

Scientific reports

2020 Volume 10, Issue 1, Page(s) 9529

Abstract: Gulf War Illness (GWI) is a chronic health condition that appeared in Veterans after returning home from the Gulf War. The primary symptoms linked to deployment are posttraumatic stress disorder, mood disorders, GI problems and chronic fatigue. At first ... ...

Abstract	Gulf War Illness (GWI) is a chronic health condition that appeared in Veterans after returning home from the Gulf War. The primary symptoms linked to deployment are posttraumatic stress disorder, mood disorders, GI problems and chronic fatigue. At first glance, these symptoms are difficult to ascribe to a single pathological mechanism. However, it is now clear that each symptom can be linked individually to alterations in the gut microbiome. The primary objective of the present study was to determine if gut microbiome dysbiosis was evident in a mouse model of GWl. Because the majority of Gulf War Veterans are overweight, a second objective was to determine if a high fat diet (HF) would alter GWI outcomes. We found that the taxonomic structure of the gut microbiome was significantly altered in the GWI model and after HF exposure. Their combined effects were significantly different from either treatment alone. Most treatment-induced changes occurred at the level of phylum in Firmicutes and Bacteroidetes. If mice fed HF were returned to a normal diet, the gut microbiome recovered toward normal levels in both controls and GWI agent-treated mice. These results add support to the hypotheses that dysbiosis in the gut microbiome plays a role in GWI and that life-style risk factors such as an unhealthy diet can accentuate the effects of GWI by impacting the gut microbiome. The reversibility of the effect of HF on the gut microbiome suggests new avenues for treating GWI through dietary intervention.
MeSH term(s)	Animals ; Body Weight/drug effects ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Dysbiosis/microbiology ; Eating/drug effects ; Gastrointestinal Microbiome/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Persian Gulf Syndrome/microbiology
Language	English
Publishing date	2020-06-12
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-66833-w
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Article ; Online: Regulation of the gene encoding human thrombin-activatable fibrinolysis inhibitor by estrogen and progesterone.

Garand, Mathieu / Lin, Joellen H H / Zagorac, Branislava / Koschinsky, Marlys L / Boffa, Michael B

Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis

2013 Volume 24, Issue 4, Page(s) 393–404

Abstract: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-carboxypeptidase B-like pro-enzyme that upon activation attenuates fibrinolysis and inflammatory processes. There is a large inter-individual variability in plasma TAFI levels within the ... ...

Abstract	Thrombin-activatable fibrinolysis inhibitor (TAFI) is a pro-carboxypeptidase B-like pro-enzyme that upon activation attenuates fibrinolysis and inflammatory processes. There is a large inter-individual variability in plasma TAFI levels within the population which is primarily due to epigenetic factors. Novel associations between plasma TAFI levels and sex steroids have triggered interest in determining the role of TAFI as a mediator of the cardioprotective effects of estrogens and progestins, or as a mediator of the increased thrombotic risk that accompanies use of oral contraceptives or hormone replacement therapy (HRT). In this study, we measured the effect of sex steroids on hepatic expression of CPB2, the human gene encoding TAFI. Using human hepatocellular carcinoma cells cultured in the presence of progesterone and 17β-estradiol, we demonstrated that the level of TAFI protein is decreased by those sex steroids. These changes in protein expression were paralleled by decreases in CPB2 mRNA abundance and promoter activity. We did not find evidence of estrogen or progesterone receptor binding sites in the CPB2 promoter region, suggesting that the genomic effects of progesterone and 17β-estradiol are mediated indirectly, without receptor binding to the CPB2 promoter. Indeed, we found that the effect of estrogen was independent of the estrogen receptor and was mediated through a novel signaling pathway dependent on phosphatidylinositol 3-kinase and Akt that did not involve GPR30. Our findings provide the molecular explanation for the ability of female sex steroids to decrease plasma TAFI concentrations.
MeSH term(s)	Carboxypeptidase B2/antagonists & inhibitors ; Carboxypeptidase B2/genetics ; Carboxypeptidase B2/metabolism ; Cell Line, Tumor ; Estradiol/pharmacology ; Female ; Gene Expression Regulation ; Genetic Variation ; Hepatocytes/cytology ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Phosphatidylinositol 3-Kinase/genetics ; Phosphatidylinositol 3-Kinase/metabolism ; Progesterone/pharmacology ; Promoter Regions, Genetic ; Proto-Oncogene Proteins c-akt/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Receptors, Estrogen/genetics ; Receptors, Estrogen/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction
Chemical Substances	GPER1 protein, human ; RNA, Messenger ; Receptors, Estrogen ; Receptors, G-Protein-Coupled ; Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E) ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Carboxypeptidase B2 (EC 3.4.17.20)
Language	English
Publishing date	2013-02-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1033551-1
ISSN	1473-5733 ; 0957-5235
ISSN (online)	1473-5733
ISSN	0957-5235
DOI	10.1097/MBC.0b013e32835d543a
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Article: Regulation of the mouse gene encoding TAFI by TNFα: Role of NFκB binding site

Garand, Mathieu / Lin, Joellen H.H / Hill, Ceredwyn E / Zagorac, Branislava / Koschinsky, Marlys L / Boffa, Michael B

Cytokine. 2012 Mar., v. 57, no. 3

2012

Abstract: Thrombin-activable fibrinolysis inhibitor (TAFI) is a plasma pro-carboxypeptidase, encoded by the gene CPB2, with roles in both inhibition of fibrinolysis and inflammation. In mice, plasma TAFI levels and hepatic CPB2 mRNA expression were found to ... ...

Abstract	Thrombin-activable fibrinolysis inhibitor (TAFI) is a plasma pro-carboxypeptidase, encoded by the gene CPB2, with roles in both inhibition of fibrinolysis and inflammation. In mice, plasma TAFI levels and hepatic CPB2 mRNA expression were found to increase within 24h after intra-peritoneal lipopolysaccharide (LPS) injection. On the other hand, plasma TAFI in humans decrease in experimental endotoxemia and sepsis and we have previously demonstrated that CPB2 mRNA abundance in human hepatoma cells is decreased by inflammatory cytokines. Here, we have evaluated the effects of TNFα on mouse CPB2 expression. Treatment of primary mouse hepatocytes or the mouse hepatic cell line FL83B with TNFα for 12–48h resulted in increases in CPB2 mRNA abundance of up to 2-fold; mouse TAFI protein levels secreted from FL83B cells increased 2.7-fold after 48h treatment with TNFα. When FL83B cells were transfected with reporter plasmids containing the mouse CPB2 5′-flanking region, treatment with TNFα for 24 and 48h resulted in a 1.5-fold increased mouse CPB2 promoter activity. Mutation of a putative NFκB site not conserved in the human gene ablated the increased promoter activity observed following TNFα treatment. This site binds NFκB as assessed by gel mobility shift assays, and TNFα treatment increases the translocation of NFκB from the cytoplasm to the nucleus of mouse hepatocytes. These results demonstrate that the unique NFκB site in the mouse CPB2 promoter is functional and mediates the upregulation of mouse CPB2 expression by TNFα via increase in NFκB translocation to the nucleus.
Keywords	binding sites ; cytokines ; cytoplasm ; endotoxemia ; fibrinolysis ; gels ; gene expression ; genes ; hepatocytes ; hepatoma ; humans ; inflammation ; lipopolysaccharides ; mice ; mutation ; plasmids
Language	English
Dates of publication	2012-03
Size	p. 389-397.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2011.11.023
Database	NAL-Catalogue (AGRICOLA)

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In stock of ZB MED Cologne/Königswinter

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