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1.
Trauma Case Rep ; 32: 100434, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33665324

ABSTRACT

A 77-year-old woman with no medical history fell, and her face was strongly impacted on the ground. On arrival at our hospital, her initial vital signs were stable. She underwent an endoscopy to stop the bleeding. However, identification of the origin of the bleeding failed, and her injury resulted in hemorrhagic shock during the procedure. Head to face contrast computed tomography showed extravasation of contrast media into the maxillary sinus. Transcatheter arterial embolization was performed for the ruptured infraorbital artery branching from the maxillary artery. She recovered from the "shock" state after transcatheter arterial embolization and was admitted to the intensive care unit. There were no complications associated with transcatheter arterial embolization during hospitalization. For this case, early recognition of an active hemorrhage was challenging because the hemorrhage was pooled in the sinuses. Although epistaxis is sometimes fatal, transcatheter arterial embolization can be the first choice for the treatment of life-threatening epistaxis, owing to its safety and effectiveness.

2.
Intern Med ; 59(22): 2903-2906, 2020 Nov 15.
Article in English | MEDLINE | ID: mdl-32963170

ABSTRACT

Severe coronavirus disease (COVID-19) can induce serious complications, including acute respiratory distress syndrome, septic shock, and acute kidney injury. However, few reports have associated COVID-19 with pancreatitis. We herein report the case of a 55-year-old patient who developed acute pancreatitis associated with severe COVID-19 pneumonia and was successfully treated with veno-venous extracorporeal membrane oxygenation (ECMO). Elevated pancreatic enzymes levels and computed tomography findings led to the diagnosis of acute pancreatitis due to COVID-19. Although we found that severe COVID-19 pneumonia can lead to pancreatitis, the underlying pathophysiology remains unknown.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Extracorporeal Membrane Oxygenation/methods , Pancreatitis/etiology , Pneumonia, Viral/complications , Acute Disease , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Humans , Male , Middle Aged , Pancreatitis/diagnosis , Pancreatitis/therapy , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , SARS-CoV-2 , Tomography, X-Ray Computed/methods
3.
Endocrinology ; 147(6): 2773-80, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16543366

ABSTRACT

Bisphenol A [2,2-bis-(4-hydroxyphenyl) propane; BPA] is a versatile industrial material for plastic products, but is increasingly being recognized as a pervasive industrial pollutant as well. Accumulating evidence indicates that the environmental contaminant BPA is one of the endocrine-disrupting chemicals that potentially can adversely affect humans as well as wildlife. To define the molecular aspects of BPA action, we first investigated the molecules with which it physically interacts. High BPA-binding activity was detected in the P2 membrane fraction prepared from rat brains. As determined by SDS-PAGE analysis, the molecular mass of a BPA-binding protein purified from the rat brain P2 fraction was 53 kDa. The N-terminal amino acid sequence of the purified BPA-binding protein was identical with that of the rat protein disulfide isomerase (PDI), which is a multifunctional protein that is critically involved in the folding, assembly, and shedding of many cellular proteins via its isomerase activity in addition to being considered to function as an intracellular hormone reservoir. The Kd value of BPA binding to recombinant rat PDI was 22.6 +/- 6.6 microm. Importantly, the binding activity of L-T3 and 17beta-estradiol hormones to PDI was competitively inhibited by BPA in addition to abolishing its isomerase activities. In this paper we report that the ubiquitous and multifunctional protein PDI is a target of BPA and propose that binding to PDI and subsequent inhibition of PDI activity might be mechanistically responsible for various actions of BPA.


Subject(s)
Estradiol/metabolism , Phenols/pharmacology , Protein Disulfide-Isomerases/antagonists & inhibitors , Triiodothyronine/metabolism , Animals , Benzhydryl Compounds , Carrier Proteins/isolation & purification , Carrier Proteins/metabolism , Male , Phenols/metabolism , Protein Binding , Protein Disulfide-Isomerases/metabolism , Rats , Rats, Sprague-Dawley , Recombinant Proteins/metabolism
4.
FEBS Lett ; 575(1-3): 59-63, 2004 Sep 24.
Article in English | MEDLINE | ID: mdl-15388333

ABSTRACT

Apigenin, a plant-derived flavone, is a potent inhibitor of cell proliferation and angiogenesis, but the mechanisms leading to the pathological anti-angiogenic effects of apigenin are still unclear. In this study, we found that apigenin inhibited the hypoxia-induced expression of vascular endothelial growth factor (VEGF) mRNA in human umbilical artery endothelial cells. Apigenin also suppressed the expression of erythropoietin mRNA, which is a typical hypoxia-inducible gene, via the degradation of hypoxia-inducible factor 1 (HIF-1) alpha. We investigated the effect of apigenin on the interaction of HIF-1alpha with heat shock protein 90 (Hsp90), which is reported to be important for the stabilization of HIF-1alpha, and found that VEGF expression was inhibited via degradation of HIF-1alpha through interference with the function of Hsp90.


Subject(s)
Angiogenesis Inhibitors/metabolism , Apigenin/metabolism , Endothelial Cells/metabolism , Transcription Factors/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Antineoplastic Agents/metabolism , Cell Line , Cobalt/metabolism , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Erythropoietin/genetics , Erythropoietin/metabolism , Gene Expression Regulation , HSP90 Heat-Shock Proteins/metabolism , Humans , Hypoxia , Hypoxia-Inducible Factor 1, alpha Subunit , Vascular Endothelial Growth Factor A/genetics
5.
Biochem Biophys Res Commun ; 318(4): 1006-11, 2004 Jun 11.
Article in English | MEDLINE | ID: mdl-15147973

ABSTRACT

Bisphenol A (BpA), an endocrine-disrupting chemical, is known to be a xenoestrogen and to affect the reproductive functions of animals. Recent reports have documented BpA-induced developmental abnormalities in the neuronal systems of humans and animals, and these effects appear to be non-estrogenic. In this study, we found that BpA inhibited the hypoxic response of human hepatoma cells. The expression of hypoxic response genes such as the erythropoietin (EPO) gene is done via a hypoxia inducible factor 1 (HIF-1)-dependent signaling pathway. To investigate possible structural requirements for this inhibitory effect, several BpA analogs were synthesized and added to this system. The blocking of two phenol groups in BpA did not change the effect, but the inhibition completely disappeared by the removal of two central methyl groups in BpA (the resulting compound is designated BpF). BpA, but not BpF, promoted degradation of the HIF-1alpha protein, which is a component of HIF-1, followed by inhibition of EPO induction. An immunoprecipitation assay indicated that BpA dissociated heat shock protein 90 (Hsp90) from HIF-1alpha and destabilized HIF-1alpha protein. HIF-1alpha is usually degraded first by ubiquitination and then by the proteasome pathway. Cobalt ion inhibits ubiquitination of HIF-1alpha and stabilizes it. In the present study, BpA promoted HIF-1alpha degradation in the presence of cobalt and in the presence of proteasome inhibitor. These results suggest that BpA degraded HIF-1alpha via a currently unknown pathway, and that this phenomenon required two methyl groups in BpA.


Subject(s)
Cell Hypoxia/physiology , Erythropoietin/antagonists & inhibitors , Phenols/chemistry , Phenols/pharmacology , Transcription Factors/metabolism , Air Pollutants, Occupational/chemistry , Air Pollutants, Occupational/pharmacology , Benzhydryl Compounds , Cell Hypoxia/drug effects , Cell Line, Tumor , Cobalt/chemistry , Cobalt/pharmacology , Erythropoietin/biosynthesis , Erythropoietin/genetics , Estrogens, Non-Steroidal/chemistry , Estrogens, Non-Steroidal/pharmacology , Gene Expression Regulation/drug effects , HSP90 Heat-Shock Proteins/metabolism , Humans , Hypoxia-Inducible Factor 1, alpha Subunit , Precipitin Tests , Structure-Activity Relationship
6.
Cancer Lett ; 203(2): 117-25, 2004 Jan 20.
Article in English | MEDLINE | ID: mdl-14732219

ABSTRACT

We investigated the biological effects of the active oxygen produced by P450s. First, we identified which isoforms of P450 efficiently produced active oxygen using electron spin resonance. Eight forms of P450 purified from rat liver were used. Of these, CYP1A2, 2B1, 2C11 and 3A2 produced hydroxyl radicals efficiently. Phenobarbital (PB) which is a typical inducer of CYP2B1 and 3A2 induced production of hydroxyl radicals by rat liver and ketoconazole, an inhibitor of P450, inhibited production of hydroxyl radicals in vitro. PB is a tumor promoter as well as the P450-inducer. We investigated oxidation of the genomic DNA by the hydroxyl radicals produced by PB-inducible P450 in vitro and in vivo. 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidation in vivo was assayed by HPLC. PB strongly induced the production of 8-OHdG in the rat liver. While ketoconazole inhibited the production of 8-OHdG in vivo. These results suggest that active oxygen produced by P450 oxidized genomic DNA and induction of P450 increased oxidative stress that may contribute to tumor initiation and promotion.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , DNA/metabolism , Liver/enzymology , Oxygen/metabolism , Phenobarbital/pharmacology , Animals , Aryl Hydrocarbon Hydroxylases/metabolism , Chromatography, High Pressure Liquid , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP2B1/metabolism , Cytochrome P-450 CYP3A , Cytochrome P450 Family 2 , Electron Spin Resonance Spectroscopy , Excitatory Amino Acid Antagonists/pharmacology , Hydroxyl Radical , Immunochemistry , Immunohistochemistry , Ketoconazole/pharmacology , Lipid Peroxidation , Liver/metabolism , Membrane Proteins/metabolism , Microsomes, Liver/metabolism , Protein Isoforms , Proto-Oncogene Proteins c-jun/biosynthesis , Proto-Oncogene Proteins c-myc/biosynthesis , Rats , Rats, Sprague-Dawley , Steroid 16-alpha-Hydroxylase/metabolism , Superoxides/metabolism
7.
Endocrinology ; 145(2): 699-705, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14563706

ABSTRACT

mRNA of cytochrome P450 21-hydroxylase (P450c21) is expressed in the brain, but little is known about the enzymatic properties of P450c21 in the brain. In the present study, we showed, by using various recombinant cytochrome P450 (CYP)2D enzymes and anti-CYP2D4- or P450c21-specific antibodies, that rat brain microsomal steroid 21-hydroxylation is catalyzed not by P450c21, but by CYP2D isoforms. Rat CYP2D4 and human CYP2D6, which are the predominant CYP2D isoforms in the brain, possess 21-hydroxylation activity for both progesterone and 17alpha-hydroxyprogesterone. In rat brain microsomes, these activities were not inhibited by anti-P450c21 antibodies, but they were effectively inhibited by the CYP2D-specific chemical inhibitor quinidine and by anti-CYP2D4 antibodies. mRNA and protein of CYP2D4 were expressed throughout the brain, especially in cerebellum, striatum, pons, and medulla oblongata, whereas the mRNA and protein levels of P450c21 were extremely low or undetectable. These results support the idea that CYP2D4, not P450c21, works as steroid 21-hydroxylase in the brain. Allopregnanolone, a representative gamma-aminobutyric acid receptor modulator, was also hydroxylated at the C-21 position by recombinant CYP2D4 and CYP2D6. Rat brain microsomal allopregnanolone 21-hydroxylation was inhibited by fluoxetine with an IC(50) value of 2 microm, suggesting the possibility that the brain CYP2D isoforms regulate levels of neurosteroids such as allopregnanolone, and that this regulation is modified by central nervous system-active drugs such as fluoxetine.


Subject(s)
Aryl Hydrocarbon Hydroxylases/metabolism , Brain/enzymology , Cytochrome P-450 CYP2D6/metabolism , Mixed Function Oxygenases/metabolism , 17-alpha-Hydroxyprogesterone/metabolism , Animals , Aryl Hydrocarbon Hydroxylases/analysis , Aryl Hydrocarbon Hydroxylases/genetics , Blotting, Western , Brain Chemistry , Cytochrome P-450 CYP2D6/analysis , Cytochrome P-450 CYP2D6/genetics , Fluoxetine/pharmacology , Humans , Hydroxylation , Male , Microsomes/enzymology , Mixed Function Oxygenases/analysis , Mixed Function Oxygenases/genetics , Pregnanolone/metabolism , Progesterone/metabolism , RNA, Messenger/analysis , Rats , Recombinant Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Selective Serotonin Reuptake Inhibitors/pharmacology , Steroid 21-Hydroxylase/analysis , Steroid 21-Hydroxylase/genetics , Steroid 21-Hydroxylase/metabolism , Substrate Specificity , Tissue Distribution
8.
Drug Metab Pharmacokinet ; 18(3): 163-72, 2003.
Article in English | MEDLINE | ID: mdl-15618732

ABSTRACT

Nine different antibodies against P450 isoforms were prepared using purified cytochrome P450s (P450) expressed in E. coli. Purified isozymes were injected into rabbits to raise specific antibody. The resulting antibodies were characterized for their specificity and sensitivity through each particular P450 enzyme-mediated probe reaction.Anti-CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 antibodies proved to be strong immunoinhibitors with inhibitory effects specific to their corresponding antigen. Antiserum derived from the CYP2C19-immunized rabbits was reacted with CYP2C9 as well as CYP2C19 and immunoabsorbed with membrane-bound CYP2C9 expressed in E. coli. Antibody specific for CYP2C19 was obtained. Anti-CYP2C19 together with the anti-CYP2C8 and anti-CYP2C9 can be very useful for determining the contribution of a particular P450 in the metabolism of a drug. The developed inhibitory antibodies will serve as in vitro-specific tools for evaluating the quantitative contribution of individual P450 enzymes to drug metabolism.

9.
J Neurochem ; 87(6): 1499-508, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14713305

ABSTRACT

An endocrine disruptor chemical, bisphenol-A (BPA), is reported to have several short-term actions in various tissues and/or cells; however, the mechanisms of these actions have not been fully elucidated. We investigated short-term actions evoked by BPA in pheochromocytoma PC12 cells. BPA elicited dopamine release in PC12 cells in a dose-dependent manner. A selective N-type calcium channel antagonist (omega-conotoxin GVIA) and a ryanodine receptor blocker (ryanodine) inhibited the BPA-induced dopamine release. The expression of ryanodine receptor mRNA was detected by RT-PCR in PC12 cells. Subsequently, in order to prove whether membrane receptors participate in BPA-evoked dopamine release, a guanine nucleotide-binding protein inhibitor [guanosine 5'-(beta-thio) diphosphate], cyclic AMP antagonist (Rp-cAMPS) or protein kinase A inhibitor (H7 or H89) was added to PC12 cells prior to BPA-treatment. All of these agents suppressed BPA-evoked dopamine release, indicating that multiple signaling pathways may be involved in BPA-evoked dopamine release in PC12 cells. In conclusion, we demonstrated that BPA induced dopamine release in a non-genomic manner through guanine nucleotide-binding protein and N-type calcium channels. These findings illustrate a novel function of BPA and suggest that exposure to BPA influences the function of dopaminergic neurons.


Subject(s)
Cyclic AMP/analogs & derivatives , Dopamine/metabolism , Free Radical Scavengers/pharmacology , Guanosine Diphosphate/analogs & derivatives , PC12 Cells/drug effects , Phenols/pharmacology , Animals , Benzhydryl Compounds , Blotting, Northern , Calcium Channel Blockers/pharmacology , Cyclic AMP/antagonists & inhibitors , Cyclic AMP/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/pharmacology , Gene Expression Regulation/drug effects , Guanosine Diphosphate/pharmacology , Models, Biological , Monoamine Oxidase Inhibitors/pharmacology , PC12 Cells/metabolism , RNA, Messenger/biosynthesis , Rats , Reverse Transcriptase Polymerase Chain Reaction/methods , Ruthenium/pharmacology , Ryanodine Receptor Calcium Release Channel/genetics , Ryanodine Receptor Calcium Release Channel/metabolism , Thionucleotides/pharmacology
10.
J Biol Chem ; 277(26): 23367-73, 2002 Jun 28.
Article in English | MEDLINE | ID: mdl-11971899

ABSTRACT

Hypoxia induces a group of physiologically important genes that include erythropoietin (EPO) and vascular endothelial growth factor (VEGF). Hypoxia-inducible factor 1 (HIF-1) was identified as a hypoxia-activated transcription factor; however, the molecular mechanisms that underlie hypoxia signal transduction in mammalian cells remain undefined. In this study, we found that a flavoprotein, NADPH-P450 reductase (NPR), could regulate the induction of EPO mRNA under hypoxic conditions. Hypoxic EPO mRNA induction in Hep3B cells was inhibited by diphenyleneiodonium chloride, which is an inhibitor of NADPH-dependent enzymes. NPR antisense cDNA was transfected into Hep3B cells, and NPR-deficient hepatocyte cells (NPR(-) cells) were established. NPR(-) cells lacked EPO induction under hypoxia, and HIF-1alpha in NPR(-) cells did not respond to either transcriptional activation or translocation to the nucleus based on electrophoretic mobility shift assays and reporter gene assay including hypoxia response element. In contrast, NPR overexpression in Hep3B cells enhanced the DNA binding activity of HIF-1alpha by luciferase reporter gene assay. A study with HeLa S3 cells produced the same results. Furthermore, anti-NPR IgG inhibited EPO induction. EPO induction inhibited by diphenyleneiodonium chloride was recovered by bovine serum albumin-NADPH (a covalent binding complex of bovine serum albumin and NADPH) as well as NADPH. These results suggested that NPR located at the plasma membrane regulates EPO expression in hypoxia, including HIF-1 activation and translocation. We further studied the expression of NPR and VEGF mRNAs in human tumor tissues and found that the NPR mRNA levels were correlated with the VEGF mRNA levels, suggesting that NPR might be an important factor in the hypoxic induction of genes such as VEGF in vivo.


Subject(s)
Cell Membrane/enzymology , DNA-Binding Proteins/metabolism , NADPH-Ferrihemoprotein Reductase/physiology , Nuclear Proteins/metabolism , Transcription Factors , DNA/metabolism , Endothelial Growth Factors/pharmacology , Erythropoietin/genetics , Gene Expression Regulation , Humans , Hypoxia-Inducible Factor 1 , Hypoxia-Inducible Factor 1, alpha Subunit , Lymphokines/pharmacology , NADPH Oxidases/physiology , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
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