Inhibition of Histone H3K27 Acetylation Orchestrates Interleukin-9-Mediated and Plays an Anti-Inflammatory Role in Cisplatin-Induced Acute Kidney Injury.
acid; acute kidney injury; apoptosis; bmp-7; cisplatin; expression; H3K27Ac; il-9; inflammation; interleukin-9; macrophage; receptor; renal inflammation; tubular epithelial-cells
Nephrotoxicity is a major side effect of cisplatin (CP)- and platinum-related chemotherapy, and inflammation contributes to disease pathogenesis. Interleukin-9 (IL-9) is a pleiotropic cytokine associated with inflammation. Here, we investigated the key role of IL-9 as a regulator of protective mechanisms in
Jiang Wenjuan; Yuan Xinrong; Zhu Hong; He Changsheng; Ge Caiqiong; Tang Qing; Xu Chuanting; Hu Bingfeng; Huang Cheng; Ma Taotao
Frontiers in immunology
2020
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.3389/fimmu.2020.00231" target="_blank" rel="noreferrer noopener">10.3389/fimmu.2020.00231</a>
Knockdown Of Leptin A Expression Dramatically Alters Zebrafish Development
atlantic salmon; Auditory; bhlh genes; bone; carp cyprinus-carpio; cell fate specification; central-nervous-system; cloning; danio-rerio; differentiation; Endocrinology & Metabolism; gene; metabolism; n-cadherin; receptor; sensory ganglia; Visual; visual-system
Using morpholino antisense oligonucleotide (MO) technology, we blocked leptin A or leptin receptor expression in embryonic zebrafish, and analyzed consequences of leptin A knock-down on fish development. Embryos injected with leptin A or leptin receptor MOs (leptin A or leptin receptor morphants) had smaller bodies and eyes, undeveloped inner ear, enlarged pericardial cavity, curved body and/or tail and larger yolk compared to control embryos of the same stages. The defects persisted in 6-9 days old larvae. We found that blocking leptin A function had little effect on the development of early brain (1 day old), but differentiation of both the morphant dorsal brain and retinal cells was severely disrupted in older (2 days old) embryos. Despite the enlarged pericardial cavity, differentiation of cardiac cells appeared to be similar to control embryos. Formation of the morphants' inner ear is also severely disrupted, which corroborates existing reports of leptin receptor expression in inner ear of both zebrafish and mammals. Co-injection of leptin A MO and recombinant leptin results in partial rescue of the wild-type phenotype. Our results suggest that leptin A plays distinct roles in zebrafish development. (c) 2012 Elsevier Inc. All rights reserved.
Liu Q; Dalman M; Chen Y; Akhter M; Brahmandam S; Patel Y; Lowe J; Thakkar M; Gregory A V; Phelps D; Riley C; Londraville R L
General and Comparative Endocrinology
2012
2012-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.ygcen.2012.07.011" target="_blank" rel="noreferrer noopener">10.1016/j.ygcen.2012.07.011</a>
Testosterone Decreases 3 Beta-hydroxysteroid Dehydrogenase-isomerase Messenger Ribonucleic Acid In Cultured Mouse Leydig Cells By A Strain-specific Mechanism
17-alpha-hydroxylase/c17-20 lyase; adult-rats; androgen; denovo synthesis; Endocrinology & Metabolism; expression; human chorionic-gonadotropin; inbred mice; luteinizing-hormone; receptor; rna; side-chain cleavage; steroidogenesis; testicular cells; testis
We previously reported a strain-related difference in basal 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta HSD) activity in response to testosterone in cultured Leydig cells. The data suggested that the response to testosterone was androgen receptor mediated and that testosterone was acting via a irans-acting factor distal to the androgen receptor to regulate Leydig cell basal 3 beta HSD activity. This study was designed to determine whether the previous reported strain-related difference in basal 3 beta HSD activity in response to testosterone was due to a difference at the 3 beta HSD protein and/or at the mRNA level, In C57BL/6J Leydig cells, 2.0 mu M testosterone significantly decreased basal 3 beta HSD immunoreactive mass by day 6 in culture. Treatment with 2.0 mu M testosterone and 2.0 mu M hydroxyflutamide, an androgen receptor antagonist, negated the inhibitory effect of testosterone on C57BL/6J 3 beta HSD immunoreactive mass, Treatment with 2.0 mu M testosterone also significantly decreased 3 beta HSD mRNA content in C57BL/6J Leydig cells, which was detectable on day 3 in culture, In contrast to Leydig cells from C57BL/6J mice, Leydig cells from C3H/HeJ mice were not susceptible to the inhibitory effect of testosterone on 3 beta HSD. Treatment with 2.0 mu M testosterone had no detectable effect on C3H/HeJ 3 beta HSD immunoreactive mass or mRNA content at any time point in culture. These data indicate that the testosterone-induced loss of basal 3 beta HSD activity in C57BL/6J Leydig cells can he accounted for by the lass of 3 beta HSD immunoreactive mass, which is preceded by the loss of 3 beta HSD mRNA, and that the strain-related difference in the regulation of 3 beta HSD is present at all three levels. Thus, the putative trans-acting factor involved in the mechanism whereby testosterone decreases basal 3 beta HSD is likely to regulate the amount of 3 beta HSD mRNA.
Heggland S J; Signs S A; Stalvey J R D
Journal of Andrology
1997
1997-11
Journal Article or Conference Abstract Publication
n/a
Age And Lymph Node Status In Breast Cancer: Not A Straightforward Relationship
axillary dissection; biopsy; metastases; morbidity; Oncology; predictors; receptor
Mamounas E P
Journal of Clinical Oncology
2009
2009-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1200/jco.2009.22.0509" target="_blank" rel="noreferrer noopener">10.1200/jco.2009.22.0509</a>
Role Of Urokinase Pais In The Control Of Cancer Invasion And Metastasis
adenocarcinomas; angiogenesis; cells; degradation; inhibition; in-vitro; migration; Pharmacology & Pharmacy; plasminogen-activator; receptor; tumor-metastasis
Evans D M; Sloan-Stakleff K
Drug News & Perspectives
1997
1997-03
Journal Article or Conference Abstract Publication
n/a
Suppression Of The Invasive Capacity Of Human Breast Cancer Cells By Inhibition Of Urokinase Plasminogen Activator Via Amiloride And B428
angiogenesis; carcinoma; integrins; migration; prevention; prognostic marker; proliferation; pulmonary metastases; receptor; Surgery; tumor-cells
Evans D M; Sloan-Stakleff K
American Surgeon
2000
2000-05
Journal Article or Conference Abstract Publication
n/a
The Local Monoaminergic Dependency Of Spinal Ketamine
(intrathecal); 5-ht (5-hydroxytryptamine; analgesia; antinociception; cord; inhibition; ketamine; neurons; norepinephrine; opiate; opioid receptors; optical isomers; pharmacology; Pharmacology & Pharmacy; rat-brain; receptor; serotonin; tail-flick test
Crisp T; Perrotti J M; Smith D L; Stafinsky J L; Smith D J
European Journal of Pharmacology
1991
1991-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/0014-2999(91)90101-u" target="_blank" rel="noreferrer noopener">10.1016/0014-2999(91)90101-u</a>
EVALUATION OF THE INTERACTIONS OF SEROTONERGIC AND ADRENERGIC-DRUGS WITH MU, DELTA, AND KAPPA OPIOID BINDING-SITES
receptor; Neurosciences & Neurology; involvement; rat-brain; morphine; dorsal horn; adrenergic; cord; mu opioid; nociceptive; periaqueductal gray; phentolamine; raphe magnus stimulation; reflexes; serotonergic; spinal antinociceptive action; spiroxatrine; delta opioid; kappa opioid
Several serotonergic and adrenergic agents were tested for an ability to interact with mu, delta, and kappa opioid binding sites. Spiroxatrine interacted nearly equipotently with all three opioid subtypes, yielding K(i) values near 110 nM. A number of other serotonergic and adrenergic agents interacted with affinities in the 1-50-mu-M range. Most of the other compounds tested in this study were found to compete for opioid binding to some degree, though not achieving a 50% inhibition of binding at concentrations up to 100-mu-M. If this interaction between monoaminergic agents and opioid receptors is found to have functional significance, it must be considered in the interpretation of results from studies using these agents to evaluate the contribution of monoaminergic systems to opioid-mediated events.
Monroe P J; Perschke S E; Crisp T; Smith D J
Neuroscience Letters
1991
1991-12
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/0304-3940(91)90576-f" target="_blank" rel="noreferrer noopener">10.1016/0304-3940(91)90576-f</a>
Tamoxifen alters dopamine output through direct actions upon superfused corpus striatal tissue fragments
breast-cancer; receptor; Biochemistry & Molecular Biology; Neurosciences & Neurology; estrogen; breast-cancer; antagonist; estradiol; nigrostriatal; release; anti-estrogen; antiestrogens; metabolites; brain metastases; sexual-behavior; non-genomic
Tamoxifen (10 pg/ml) was infused directly into superfused striatal tissue fragments of ovariectomized rats for a 50 min period. Immediately following the termination of tamoxifen there was a significant increase in dopamine output compared with non-infused controls. No such significant increase was observed with use of a 100 pg/ml tamoxifen dose. Although dopamine output was again increased upon termination of a 2 h infusion of tamoxifen, these levels failed to differ significantly from that of non-infused controls. Similarly, a shorter 10 min duration infusion of tamoxifen failed to alter dopamine output. Finally, we examined whether the tamoxifen-induced, post-infusion increase in dopamine output, as observed following a 50 min infusion of 10 pg/ml, involved a calcium dependent process. To achieve this goal, superfusions were performed with Calcium/Tamoxifen, No Calcium/Tamoxifen, No Calcium/No Tamoxifen and Calcium/No Tamoxifen. A significant increase in dopamine output post-tamoxifen infusion was obtained for the Calcium/Tamoxifen condition compared with the remaining three groups which failed to differ from one another. Taken together these results show that tamoxifen can alter dopamine output through direct, non-genomic effects upon striatal neurons. Responses to this anti-estrogen are intriguing since they are apparent following removal, but not during tamoxifen infusion and represent a calcium-dependent process. These data suggest that tamoxifen may represent an important modulator of nigrostriatal dopaminergic function. (C) 1998 Elsevier Science Ltd. All rights reserved.
McDermott J L; Anderson L I; Dluzen D E
Neurochemistry International
1998
1998-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/s0197-0186(97)00086-7" target="_blank" rel="noreferrer noopener">10.1016/s0197-0186(97)00086-7</a>
Stimulation of Coronary Collateral Growth by Granulocyte Stimulating Factor Role of Reactive Oxygen Species
ischemia; ROS; cardiomyocytes; receptor; Cardiovascular System & Cardiology; endothelial progenitor cells; expression; Hematology; activation; angiotensin-ii; neutrophils; neovascularization; bone-marrow; coronary collateral circulation; G-CSF; G-CSF
Objective-The purpose of this study was to determine whether G-CSF promotes coronary collateral growth (CCG) and decipher the mechanism for this stimulation. Methods and Results-In a rat model of repetitive episodic myocardial ischemia (RI, 40 seconds LAD occlusion every 20 minutes for 2 hours and 20 minutes, 3 times/d for 5 days) CCG was deduced from collateral-dependent flow (flow to LAD region during occlusion). After RI, G-CSF (100 mu g/kg/d) increased CCG (P < 0.01) (0.47 +/- 0.15) versus vehicle (0.14 +/- 0.06). Surprisingly, G-CSF treatment without RI increased CCG (0.57 +/- 0.18) equal to G-CSF + RI. We evaluated ROS by dihydroethidine (DHE) fluorescence (LV injection, 60 mu g/kg, during two episodes of ischemia). DHE fluorescence was double in G-CSF + RI versus vehicle + RI (P < 0.01), and even higher in G-CSF without RI (P < 0.01). Interestingly, the DHE signal did not colocalize with myeloperoxidase (immunostaining, neutrophil marker) but appeared in cardiac myocytes. The study of isolated cardiac myocytes revealed the cytokine stimulates ROS which elicit production of angiogenic factors. Apocynin inhibited G-CSF effects both in vivo and in vitro. Conclusions-G-CSF stimulates ROS production directly in cardiomyocytes, which plays a pivotal role in triggering adaptations of the heart to ischemia including growth of the coronary collaterals. (Arterioscler Thromb Vasc Biol. 2009; 29: 1817-1822.)
Carrao A C R; Chilian W M; Yun J; Kolz C; Rocic P; Lehmann K; van den Wijngaard Jphm; van Horssen P; Spaan J A E; Ohanyan V; Pung Y F; Buschmann I
Arteriosclerosis Thrombosis and Vascular Biology
2009
2009-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1161/atvbaha.109.186445" target="_blank" rel="noreferrer noopener">10.1161/atvbaha.109.186445</a>
Signaling pathways mediating the neuroprotective effects of sex steroids and SERMs in Parkinson's disease
Signaling; Neuroprotection; MPTP; mice; Akt; 3; 2; 1-methyl-4-phenyl-1; 6-tetrahydropyridine; receptor; Neurosciences & Neurology; Endocrinology & Metabolism; nervous-system; plasma-membrane; estrogen-receptor-alpha; er-alpha; gender-differences; rat-brain; striatum; estrogen; ERK; estradiol; growth-factor-i; protein-coupled receptor-30; selective estrogen; SERMs; Substantia nigra
Studies with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of Parkinson's disease have shown the ability of 17 beta-estradiol to protect the nigrostriatal dopaminergic system. This paper reviews the signaling pathways mediating the neuroprotective effect of 17 beta-estradiol against MPTP-induced toxicity. The mechanisms of 17 beta-estradiol action implicate activation of signaling pathways such as the phosphatidylinositol-3 kinase/Akt and the mitogen-activated protein kinase pathways. 17 beta-estradiol signaling is complex and integrates multiple interactions with signaling molecules that act to potentiate a protective effect. 17 beta-estradiol signaling is mediated via estrogen receptors, including GPER1, but others receptors, such as the IGF-1 receptor, are implicated in the neuroprotective effect. Glial and neuronal crosstalk is a critical factor in the maintenance of dopamine neuronal survival and in the neuroprotective action of 17 beta-estradiol. Compounds that stimulate GPER1 such as selective estrogen receptor modulators and phytoestrogens show neuroprotective activity and are alternatives to 17 beta-estradiol. (C) 2012 Published by Elsevier Inc.
Bourque M; Dluzen D E; Di Paolo T
Frontiers in Neuroendocrinology
2012
2012-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.yfrne.2012.02.003" target="_blank" rel="noreferrer noopener">10.1016/j.yfrne.2012.02.003</a>
Modulation of Mast Cell Proliferative and Inflammatory Responses by Leukotriene D-4 and Stem Cell Factor Signaling Interactions
activation; Cell Biology; cysteinyl leukotrienes; fc-epsilon-ri; immune; induced airway hyperreactivity; innate; kit ligand; Physiology; protein-kinase-c; receptor; survival
Mast cells (MCs) are important effector cells in asthma and pulmonary inflammation, and their proliferation and maturation is maintained by stem cell factor (SCF) via its receptor, c-Kit. Cysteinyl leukotrienes (cys-LTs) are potent inflammatory mediators that signal through CysLT(1)R and CysLT(2)R located on the MC surface, and they enhance MC inflammatory responses. However, it is not known if SCF and cys-LTs cross-talk and influence MC hyperplasia and activation in inflammation. Here, we report the concerted effort of the growth factor SCF and the inflammatory mediator LTD4 in MC activation. Stimulation of MCs by LTD4 in the presence of SCF enhances c-Kit-mediated proliferative responses. Similarly, SCF synergistically enhances LTD4-induced calcium, c-fos expression and phosphorylation, as well as MIP1 generation in MCs. These findings suggest that integration of SCF and LTD4 signals may contribute to MC hyperplasia and hyper-reactivity during airway hyper-response and inflammation. J. Cell. Physiol. 230: 595-602, 2015. (c) 2014 Wiley Periodicals, Inc., A Wiley Company
Al-Azzam N; Kondeti V; Duah E; Gombedza F; Thodeti C K; Paruchuri S
Journal of Cellular Physiology
2015
2015-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/jcp.24777" target="_blank" rel="noreferrer noopener">10.1002/jcp.24777</a>
On the mechanism of bile acid inhibition of rat sterol 12 alpha-hydroxylase gene (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and hepatocyte nuclear factor 4 alpha
activation; bile acid synthesise; Biochemistry & Molecular Biology; Biophysics; biosynthesis; Cell Biology; cholesterol 7-alpha-hydroxylase gene; Cyp7a1; cytochrome P450; expression; feedback-regulation; gene regulation; liver microsomal metabolism; nuclear receptor; promoter; receptor; repression
The sterol 12alpha-hydroxylase (CYP8B1) is a key enzyme of the bile acid biosynthetic pathway. It regulates the composition of bile acids in bile, i.e. ratio between cholic acid (CA) and chenodeoxycholic acid (CDCA). In similarity with cholesterol 7alpha-hydroxylase (CYP7A1), this enzyme is subjected to a negative feedback regulation by bile acids, It has been recently reported that bile acid-activated famesoid X receptor (FXR) induces the small heterodimer partner (SHP) that interacts with alpha-fetoprotein transcription factor (FTF) and down-regulates CYP7A1 transcription. We studied whether the same mechanism also regulated rat CYP8B1 gene transcription. Feeding rats with CDCA caused a 40-50% decrease of CYP8B1 and hepatocyte nuclear factor 4alpha (HNF4alpha) mRNA expression levels. This was associated with an increase in FTF mRNA expression, but SHP mRNA expression was not altered. Electrophoretic mobility shift assay (EMSA) and transient transfection assay of promoter/reporter genes coupled to mutagenesis analysis identified a putative bile acid response element (BARE) that has an HNF4alpha binding site embedded in two overlapping FTF binding sites. Mutation of the HNF4alpha binding site markedly reduced basal promoter activity and its repression by bile acids. Cotransfection with FTF strongly repressed CYP8B1 transcription. Interestingly, HNF4alpha could overcome the inhibitory effects of FTF and bile acids. We conclude that FTF and HNF4alpha not only play critical roles on CYP8B1 gene transcription, but also mediate bile acid feedback inhibition. This study reveals a novel mechanism by which bile acids inhibit rat CYP8B1 gene transcription by inducing FTF and inhibiting HNF4alpha expression. (C) 2002 Elsevier Science B.V. All rights reserved.
Yang Y Z; Zhang M; Eggertsen G; Chiang J Y L
Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids
2002
2002-06
Journal Article
<a href="http://doi.org/10.1016/s1388-1981(02)00186-5" target="_blank" rel="noreferrer noopener">10.1016/s1388-1981(02)00186-5</a>
Comparison of inotropic and chronotropic effects of vasoactive intestinal peptide in isolated dog atria
adenylate-cyclase; anesthetized dogs; atrium; autonomic nervous system; cardiac; conscious dogs; contractile force; heart rate; heart rate; isoproterenol; neuropeptide; neuropeptides; Neurosciences & Neurology; parasympathetic; performance; polypeptide; receptor; receptors; Substance P; vip
The positive chronotropic and inotropic effects of vasoactive intestinal peptide, VIP, were studied in an isolated canine right atrial preparation, Atria were removed, maintained in a bath, and perfused with Tyrode's solution. Contractile force and atrial depolarization were measured, VIP (18.8-600 pmol) was injected into a cannulated sinoatrial nodal artery and dose response curves were obtained. The mean EC(50) was similar for the inotropic and the chronotropic responses (136 and 144 pmol, respectively). Time courses of the onset and of recovery from the responses were measured. Times for onset of VIP effects were similar but, once the effect was initiated, rate of development of the response and recovery time from the responses were dose dependent, The increases in atrial rate lasted two to four times longer than did the increases in contractile force. Recovery from the chronotropic and inotropic responses to VIP differ, suggesting that the intracellular responses are coupled differently to the receptors. The responses to VIP were compared to those of 100 pmol isoproterenol, another positive chronotropic and inotropic agent. Isoproterenol was a slightly more potent chronotropic and inotropic agent than VIP. Desensitization of the responses was determined. Repeated exposures to VIP decreased the chronotropic response but not the inotropic response to VIP. There was no significant decrease in responsiveness to isoproterenol.
Wallick D W; Stuesse S L
Journal of the Autonomic Nervous System
1996
1996-12
Journal Article
<a href="http://doi.org/10.1016/s0165-1838(96)00091-4" target="_blank" rel="noreferrer noopener">10.1016/s0165-1838(96)00091-4</a>
Correlation of menstrual cycle at time of breast cancer surgery to disease-free and overall survival
carcinoma; General & Internal Medicine; killer cell-activity; mastectomy; operation; phase; premenopausal women; prognosis; receptor; stage; status; surgical cure
The timing of surgery during the menstrual cycle of premenopausal breast cancer patients was correlated with their disease-free survival (DFS) and overall survival (OS). The study included 150 premenopausal patients treated for breast cancer between 1977 and 1992. The data were analyzed using three different menstrual cycle phase categorization schemes: (1) days 0 to 6 and 21 to 32 vs 7 to 20; (2) days 0 to 2 and 19 to 32 vs 3 to 12; and (3) days 0 to 14 vs 14 to 32, Two different surgery dates used for analysis were biopsy date and definitive surgery date. There was no association of the timing of surgery with OS. Only one categorization scheme correlated with DFS (scheme No, 2), and this correlation was significant using either surgery or biopsy dates, Thus, premenopausal breast cancer patients who have biopsy and/or definitive surgery during their perimenstrual phase (days 0 to 2 or after day 13) of the menstrual cycle may have a longer DFS than patients operated on during their midcycle phase (days 3 to 13); however, this may not affect overall survival.
Vanek V W; Kadivar T F; Bourguet C C
Southern Medical Journal
1997
1997-08
Journal Article
<a href="http://doi.org/10.1097/00007611-199708000-00003" target="_blank" rel="noreferrer noopener">10.1097/00007611-199708000-00003</a>
Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling
angiotensin-ii; Cardiovascular System & Cardiology; differentiation; fibrosis; gene-expression; Heart failure; identification; induction; Kirsten Ras; mineralocorticoid; mitogen-activated protein kinase; myofibroblast; na+ reabsorption; Physiology; receptor; spironolactone; transcription
Aldosterone plays a pathological role in cardiac fibrosis by directly affecting cardiac fibroblasts. Understanding of the cellular mechanisms of aldosterone action in cardiac fibroblasts, however, is rudimentary. One possibility is that aldosterone promotes proliferation of cardiac fibroblasts by activating specific cellular signaling cascades. The current study tests whether aldosterone stimulates proliferation of isolated adult rat cardiac myofibroblasts (RCF) by activating Kirsten Ras (Ki-RasA) and its effector, the MAPK1/2 cascade. Aldosterone (10 nM) significantly increased RCF proliferation. This action was sensitive to the mineralocorticoid receptor (MR) antagonist spironolactone. Expression of MR in RCF and the whole rat heart was confirmed by immunoblotting. Aldosterone significantly increased absolute and active (GTP bound) Ki-RasA levels in RCF. Aldosterone, in addition, significantly increased phospho-c-Raf and phospho-MAPK1/2. The effects of aldosterone on Ki-RasA and phospho-c-Raf proteins were inhibited by spironolactone but not RU-486, suggesting that aldosterone acts via MR. Inhibitors of MEK1/2 and c-Raf prevented aldosterone-induced activation of MAPK1/2 and proliferation. These results show that aldosterone directly increases RCF proliferation through MR-dependent activation of Ki-RasA and its effector, the MAPK1/2 cascade. Activation of cardiac fibroblasts through such a cascade may play a role in the pathological actions exerted by aldosterone on the heart.
Stockand J D; Meszaros J G
American Journal of Physiology-Heart and Circulatory Physiology
2003
2003-01
Journal Article
<a href="http://doi.org/10.1152/ajpheart.00421.2002" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00421.2002</a>
Changes of the responses of single sympathetic ganglionic neurones to substance P following desensitization
adenylate-cyclase; binding; cells; desensitization; G protein; inhibition; k+ current; kinase-c; M current; muscarine; Neurosciences & Neurology; Pharmacology & Pharmacy; phosphorylation; protein alpha-subunits; receptor; rgs proteins; Substance P
1 The neuropeptide substance P (SP) exerts an excitatory effect on sympathetic neurones by inhibiting a time- and voltage-dependent potassium current. During prolonged application of SP, the response desensitizes. The changes in kinetics of the SP response in single neurones after desensitization have been studied in an attempt to gain some insight as to the molecular mechanism of desensitization in live, functioning neurones. 2 Desensitization to SP resulted in subsequent SP responses being smaller, but the time course was unchanged in desensitized cells compared with non-desensitized cells. 3 Experimental manipulations were performed to decrease receptor and G protein function for comparison to desensitization. Intracellular application of GDP betaS, to decrease G protein function, led to successive responses to agonist becoming smaller and slower. When functional muscarinic receptors were decreased by extracellular application of propylbenzilylcholine mustard (PrBCM), the response to muscarine became smaller, but the time course was unchanged compared with the change in time course produced by PrBCM vehicle alone. 4 The results have also been compared with simulations from a mathematical model of drug-receptor-G protein interactions. Under a constrained set of conditions, the model predicts that decreasing the size of the G protein pool will decrease both the magnitude and the time course of the response to agonist. Decreasing receptor levels results in a more efficient decrease in the magnitude of the response but no change in the time course of the response. 5 These data provide evidence that desensitization of the response to SP in single neurones results from a decrease in functional receptors.
Simmons M A
Journal of Autonomic Pharmacology
2001
2001-04
Journal Article
<a href="http://doi.org/10.1046/j.1365-2680.2001.00214.x" target="_blank" rel="noreferrer noopener">10.1046/j.1365-2680.2001.00214.x</a>
An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXR alpha
7-alpha-hydroxylase gene; activity; bile-acid biosynthesis; cholesterol; cholesterol 7 alpha-hydroxylase; dietary-cholesterol; down-regulation; farnesoid X; fetoprotein transcription factor; Gastroenterology & Hepatology; heterodimer partner; liver X receptor; LXR binding site; messenger-rna; metabolism; orphan nuclear receptor; Physiology; rat; receptor; regulation; short; transcriptional; x-receptor
An overlapping binding site in the CYP7A1 promoter allows activation of FXR to override the stimulation by LXR alpha. Am J Physiol Gastrointest Liver Physiol 293: G817-G823, 2007. First published August 9, 2007; doi:10.1152/ajpgi.00209.2007.-The aim of this study was to explore why in rabbits activation of farnesoid X receptor (FXR) is dominant over activated liver X receptor-alpha (LXR alpha) in the regulation of CYP7A1. We cloned the rabbit CYP7A1 promoter and found a fetoprotein transcription factor (FTF) binding element embedded within the LXR alpha binding site (LXRE). Gel shift assays demonstrated that FTF competes with LXR alpha for binding to LXRE. Short heterodimer partner (SHP) enhances the competitive ability of FTF. Studies in HepG2 cells showed that SHP combined with FTF had more powerful effect to offset the stimulation of CYP7A1 by LXR alpha. Gel shift and chromatin immunoprecipitation assays demonstrated that SHP with FTF diminished LXR alpha\binding to the CYP7A1 promoter. In vivo studies in rabbits fed cholesterol for 10 days showed that hepatic expression of SHP but not FTF rose and LXR alpha-bound LXRE decreased. We propose that the SHP/FTF heterodimer occupies LXRE via the embedded FTF binding element and blocks LXR alpha from recruiting to LXRE. Therefore, activation of FXR, which upregulates SHP expression, will eliminate the stimulatory effect of LXR alpha on the CYP7A1 promoter because increased levels of SHP combined with FTF diminish the recruitment of LXR alpha to CYP7A1 promoter.
Shang Q; Pan L X; Saumoy M; Chiang J Y L; Tint G S; Salen G; Xu G R
American Journal of Physiology-Gastrointestinal and Liver Physiology
2007
2007-10
Journal Article
<a href="http://doi.org/10.1152/ajpgi.00209.2007" target="_blank" rel="noreferrer noopener">10.1152/ajpgi.00209.2007</a>
Characterization of a conformationally sensitive TOAC spin-labeled substance P
activation; adrenergic-receptor; agonist; amino-acid; binding-site; Biochemistry & Molecular Biology; Endocrinology & Metabolism; EPR; ESR; GPCR; neurokinin-1; nk-1; peptide-synthesis; Pharmacology & Pharmacy; protein-coupled-receptors; receptor; Substance P; tachykinin nk1 receptor; TOAC spin label
To probe the binding of a peptide agonist to a G-protein coupled receptor in native membranes, the spin-labeled amino acid analogue 4-amino-4-carboxy-2,2,6,6-tetramethyl-piperidino-1-oxyl (TOAC) was substituted at either position 4 or 9 within the substance P peptide (RPKPQQFFGLM-NH2), a potent agonist of the neurokinin-1 receptor. The affinity of the 4-TOAC analog is comparable to the native peptide while the affinity of the 9-TOAC derivative is similar to 250-fold lower. Both peptides activate receptor signaling, though the potency of the 9-TOAC peptide is substantially lower. The utility of these modified ligands for reporting conformational dynamics during the neurokinin-1 receptor activation was explored using EPR spectroscopy, which can determine the real-time dynamics of the TOAC nitroxides in solution. While the binding of both the 4-TOAC substance P and 9-TOAC substance P peptides to isolated cell membranes containing the neurokinin-1 receptor is detected, a bound signal for the 9-TOAC peptide is only obtained under conditions that maintain the receptor in its high-affinity binding state. In contrast, 4-TOAC substance P binding is observed by solution EPR under both low- and high-affinity receptor states, with evidence of a more strongly immobilized peptide in the presence of GDP. In addition, to better understand the conformational consequences of TOAC substitution into substance P as it relates to receptor binding and activation, atomistic models for both the 4- and 9-TOAC versions of the peptide were constructed, and the molecular dynamics calculated via simulated annealing to explore the influence of the TOAC substitutions on backbone structure. (C) 2008 Elsevier Inc. All rights reserved.
Shafer A M; Nakaie C R; Deupi X; Bennett V J; Voss J C
Peptides
2008
2008-11
Journal Article
<a href="http://doi.org/10.1016/j.peptides.2008.08.002" target="_blank" rel="noreferrer noopener">10.1016/j.peptides.2008.08.002</a>
alpha(2)-Macroglobulin modulates the immunoregulatory function of the lipocalin placental protein 14
alpha-2-macroglobulin; alpha-macroglobulin; binding; Biochemistry & Molecular Biology; factor-beta; glycodelin; human; immunosuppressive; inhibition; nerve growth-factor; phosphorylation; phytohemagglutinin; pregnancy proteins; proteins; receptor; serum carrier; serum transport; signal-transduction
Human placental protein 14 (PP14; also known as glycodelin and progesterone-associatcd endometrial protein) is an immuno-suppressive protein of the lipocalin structural superfamily. Mechanisms regulating serum PP14's inmunosuppressive activity remain to be elucidated. In the present study, an interaction between PP14 and a major serum protein carrier, alpha (2)-macroglobulin (alpha M-2), was documented for the first time. Using native gel electrophoresis, we showed that PP14, as well as its alternative splice variant PP14.2, binds to both alpha M-2 and methylamine-activated (MA)-alpha M-2. Cross-competition studies demonstrated that the variants compete for binding to alpha M-2. PP14 bound to alpha M-2 and MA-alpha M-2 with K-d values of 167+/-70 and 221+/-56 nM (means+/-S.D.) respectively, as determined by surface plasmon resonance. Significantly, the addition of alpha M-2 or MA-alpha M-2 to a T-cell proliferation assay strongly potentiated the inhibitory capacity of PP14. On the basis of these findings, alpha M-2 emerges as the first serum protein that can physically associate with, and thereby regulate, PP14. Moreover, this represents the first documented interaction between the protein carrier alpha M-2 and a lipocalin protein.
Riely G J; Rachmilewitz J; Koo P H; Tykocinski M L
Biochemical Journal
2000
2000-10
Journal Article
<a href="http://doi.org/10.1042/0264-6021:3510503" target="_blank" rel="noreferrer noopener">10.1042/0264-6021:3510503</a>
NEUROTROPHIN EXPRESSION IN RAT HIPPOCAMPAL SLICES - A STIMULUS PARADIGM INDUCING LTP IN CA1 EVOKES INCREASES IN BDNF AND NT-3 MESSENGER-RNAS
alzheimers-disease; choline-acetyltransferase activity; dopamine-beta-hydroxylase; factor family; nerve growth-factor; neuronal death; Neurosciences & Neurology; ngf; protein-kinase; receptor; selective induction; tyrosine-hydroxylase
We report that stimulation inducing long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus evokes significant increases in both BDNF and NT-3 mRNAs in CA1 neurons. No changes in BDNF or NT-3 mRNA levels were seen in the nonstimulated regions of the pyramidal cell layer or the dentate. No change was seen in the levels of NGF mRNA at the time point examined. These results suggest that relatively normal levels of activity may regulate region-specific neurotrophin levels in the hippocampus. Given that known effects of NGF (and presumably of BDNF and NT-3) include elevation of neurotransmitter levels, elevation of sodium channels, and promotion of axonal terminal sprouting, activity-associated changes in neurotrophin levels may play a role in regulating neural connections in the adult as well as the developing nervous system.
Patterson S L; Grover L M; Schwartzkroin P A; Bothwell M
Neuron
1992
1992-12
Journal Article
<a href="http://doi.org/10.1016/0896-6273(92)90067-n" target="_blank" rel="noreferrer noopener">10.1016/0896-6273(92)90067-n</a>
Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets.
BILE acids; Bile acids and salts; cholesterol 7-alpha-hydroxylase; Cytoplasmic and Nuclear; Endocrinology & Metabolism; FARNESOID X receptor; farnesoid-x-receptor; FATTY liver; fatty liver-disease; G protein coupled receptors; G-protein-coupled; Gastrointestinal microbiome; growth-factor 19; gut microbiota; hepatic steatosis; improves insulin sensitivity; liver disease; metabolic; Non-alcoholic fatty; Non-alcoholic Fatty Liver Disease; nuclear; receptor; Receptors; serum fgf21 levels; syndrome
Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and nonalcoholic fatty liver disease. Primary bile acids are synthesized in hepatocytes and are transformed to secondary bile acids in the intestine by gut bacteria. Bile acids are nutrient sensors and metabolic integrators that regulate lipid, glucose, and energy homeostasis by activating nuclear farnesoid X receptor and membrane Takeda G protein-coupled receptor 5. Bile acids control gut bacteria overgrowth, species population, and protect the integrity of the intestinal barrier. Gut bacteria, in turn, control circulating bile acid composition and pool size. Dysregulation of bile acid homeostasis and dysbiosis causes diabetes and obesity. Targeting bile acid signaling and the gut microbiome have therapeutic potential for treating diabetes, obesity, and non-alcoholic fatty liver disease. [ABSTRACT FROM AUTHOR]
Ferrell Jessica M; Chiang John Y L
Diabetes & Metabolism Journal
2019
2019-06
<a href="http://doi.org/10.4093/dmj.2019.0043" target="_blank" rel="noreferrer noopener">10.4093/dmj.2019.0043</a>
Endothelin-1 as a therapeutic target in autosomal dominant polycystic kidney disease
proliferation; hypertension; receptor; expression; Urology & Nephrology; growth-factor; renal damage; endothelin-1; excretion; polycystic kidney disease; chronic kidney disease; ADPKD; endothelin-1 antagonists; autosomal dominant; tolvaptan; urinary endothelin-1; water permeability
Aims: Endothelin-1 (ET-1) is associated with the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) via cyst progression. Elevated concentrations of ET-1 in ADPKD correlate with many phenotypic changes in the kidney such as renal cyst development, interstitial fibrosis, and glomerulosclerosis. In addition, an imbalance between renal ETA and ETB receptors possibly leads to more severe disease progression. The objective of this review is to determine whether evaluating the efficacy of these drugs in treatment of cystic kidney disease may be a worthwhile aim, as determined by results from animal and human models. Materials and methods: PubMed/Medline, Embase, and Google Scholar databases were searched using the key words "endothelin, endothelin-1 antagonists, and autosomal dominant polycystic kidney disease". All animal and human studies describing the effects of endothelin and endothelin-1 antagonists in ADPKD subjects were included in the review. Results: Urinary ET-1 concentrations could serve as a noninvasive surrogate biomarker for kidney ET-1 levels, as it is inversely associated with eGFR, independent of age, sex, and blood pressure. Elevated urinary excretion of ET-1 may be a biomarker for early renal injury. Antagonization of ET-1 may hopefully be a novel therapy for slowing progression of kidney damage in ADPKD. Conclusion: Based on the literature reviewed in this manuscript, it is proposed that further research evaluating the efficacy of endothelin antagonists in treatment of cystic kidney disease is warranted. More human studies need to be performed with larger sample sizes. Therefore, the recommendation for treatment is inconclusive at this time.
Raina R; Chauvin A; Vajapey R; Khare A; Krishnappa V
Clinical Nephrology
2019
2019-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.5414/cn109598" target="_blank" rel="noreferrer noopener">10.5414/cn109598</a>
Rat alpha1-macroglobulin enhances nerve growth factor-promoted neurite outgrowth, TrkA phosphorylation, and gene expression of pheochromocytoma PC12 cells.
Animals; Phosphorylation/drug effects; Rats; Transcription Factors/genetics; Gene Expression/*drug effects; Nerve Growth Factor/*pharmacology; *Immediate-Early Proteins; alpha-Macroglobulins/drug effects/metabolism/*pharmacology; Carrier Proteins; DNA-Binding Proteins/genetics; Early Growth Response Protein 1; Matrix Metalloproteinase 3/metabolism; Membrane Proteins; Nerve Growth Factors/genetics; Neurites/drug effects/*physiology; PC12 Cells/drug effects/metabolism/*physiology; Proto-Oncogene Proteins c-jun/genetics; Serotonin/pharmacology; Sprague-Dawley; Receptor; trkA/*metabolism
Monoamine-activated human alpha2-macroglobulin (alpha2M) has been previously demonstrated to inhibit TrkA-, TrkB-, and TrkC-mediated signal transduction. Rat alpha1-macroglobulin (alpha1M) and alpha2M are structural homologues of human alpha2M, but rat alpha1M is distinctly different from rat alpha2M in many ways and its role in the mammalian nervous system is unknown. In this report, monoamine-activated rat alpha1M was demonstrated to enhance in a dose-dependent manner nerve growth factor (NGF)-promoted neurite outgrowth in pheochromocytoma PC12 cells. Monoamine-activated alpha1M by itself, however, was neither neurotrophic nor mitogenic to PC12 cells. To investigate further its possible mode of action, the ability of monoamine-activated alpha1M and normal alpha1M to bind and to activate the NGF receptor (TrkA) was investigated. Monoamine-activated alpha1M formed a more stable complex with TrkA than normal alpha1 M, but the binding of monoamine-activated alpha1M to TrkA was adversely affected by prior stimulation of TrkA with NGF. In addition, monoamine-activated alpha1M enhanced the NGF-promoted TrkA phosphorylation and up-regulated the expression of NGF-inducible immediate-early genes (c-jun and NGFI-A) and delayed-response genes (SCG10 and transin) in PC12 cells; normal alpha1M, in contrast, produced little or no effect. This study demonstrates that alpha1M, the constitutive form of alpha-macroglobulin in the rat, possesses the ability to promote NGF-mediated differentiation in PC12 cells, possibly via its direct action on TrkA receptors and TrkA-mediated signal transduction and gene expression.
Lee P G; Koo P H
Journal of neurochemistry
2000
2000-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Rat alpha(2)-macroglobulin inhibits NGF-promoted neurite outgrowth, TrK phosphorylation, and gene expression of pheochromocytoma PC12 cells.
Animals; Rats; Gene Expression Regulation; Phosphorylation; PC12 Cells; Proto-Oncogene Proteins c-jun/genetics; Adrenal Gland Neoplasms/metabolism; alpha-Macroglobulins/*pharmacology; Nerve Growth Factors/*antagonists & inhibitors; Neurites/*drug effects; Pheochromocytoma/metabolism; Sprague-Dawley; Receptor; Neoplastic/*drug effects; trkA/*metabolism
Rat alpha-1-macroglobulin (alpha(1)M) and alpha-2-macroglobulin (alpha(2)M) are murine homologs of human alpha(2)M, and rat alpha(2)M is generally known as an acute-phase protein. Monoamine-activated forms of human alpha(2)M have been shown to inhibit various neuronal functions, but the effect of rat alpha(1)M and acute-phase alpha(2)M on neurons is largely unknown. In this report, rat serotonin-activated alpha(2)M (5HT-alpha(2)M) has been demonstrated to inhibit nerve growth factor (NGF)-promoted neurite extension in pheochromocytoma PC12 cells, and we investigated its possible mechanism of action including its effect on NGF-promoted signal transduction and gene expression in these cells. Especially in the absence of NGF, 5HT-alpha(2)M was found to bind to TrkA (the high-affinity receptor for NGF) much better than normal alpha(2)M (N-alpha(2)M).
Lee P G; Koo P H
Journal of neuroscience research
1999
1999-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Monoamine-activated alpha 2-macroglobulin binds trk receptor and inhibits nerve growth factor-stimulated trk phosphorylation and signal transduction.
Humans; Male; Animals; Mice; Signal Transduction/drug effects/*physiology; Phosphorylation; PC12 Cells; Protein-Serine-Threonine Kinases/metabolism; Neurites/drug effects/*physiology; Nerve Growth Factors/*pharmacology; Adrenal Gland Neoplasms; alpha-Macroglobulins/isolation & purification/*metabolism/pharmacology; ErbB Receptors/isolation & purification/metabolism; Fibrinolysin/metabolism; Mitogen-Activated Protein Kinase 1; Pheochromocytoma; Protein-Tyrosine Kinases/metabolism; Proto-Oncogene Proteins/drug effects/isolation & purification/*metabolism; Receptor Protein-Tyrosine Kinases/drug effects/isolation & purification/*metabolism; Serotonin/*metabolism/pharmacology; Receptors; Receptor; Nerve Growth Factor/drug effects/isolation & purification/*metabolism; Platelet-Derived Growth Factor/isolation & purification/metabolism; trkA
Monoamine-activated alpha 2-macroglobulin (alpha 2M) has been shown to inhibit beta-nerve growth factor (NGF)-promoted neurite outgrowth and the survival of embryonic sensory and forebrain neurons, whereas normal alpha 2M has little or no such activity. The objective of this study is to elucidate the mechanism of inhibition by monoamine-activated alpha 2M. Methylamine-activated alpha 2M (MA-alpha 2M) and serotonin-activated alpha 2M (5HT-alpha 2M) dose dependently inhibit NGF-promoted neurite outgrowth of the pheochromocytoma PC12 cell and its subline PC12(6-24) which overexpresses human trk protooncogene product, but have no effect on their viability, and this inhibition can be blocked by high concentrations of NGF. The binding of MA-alpha 2M to trk, which is a part of high-affinity NGF receptor, was studied with PC12(6-24) cells and NIH-3T3 fibroblasts expressing trk (trk-3T3). In each case MA-alpha 2M readily forms stable complexes with trk in vivo, whereas normal alpha 2M does not. Both
Koo P H; Qiu W S
The Journal of biological chemistry
1994
1994-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Inhibition of phosphorylation of TrkB and TrkC and their signal transduction by alpha2-macroglobulin.
Humans; Animals; Mice; Signal Transduction/drug effects/*physiology; Phosphorylation; Mitogen-Activated Protein Kinase 1/metabolism; Antineoplastic Agents/pharmacology; Type C Phospholipases/metabolism; Cell Differentiation/drug effects; Neuroprotective Agents/*metabolism; Neuroblastoma; alpha-Macroglobulins/*pharmacology; *Mitogen-Activated Protein Kinases; 3T3 Cells/chemistry/cytology/enzymology; Brain-Derived Neurotrophic Factor/pharmacology; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Isoenzymes/metabolism; Mitogen-Activated Protein Kinase 3; Nerve Growth Factors/pharmacology; Neurotrophin 3; Phospholipase C gamma; Receptor Protein-Tyrosine Kinases/*metabolism; Serotonin/metabolism; Tretinoin/pharmacology; Ciliary Neurotrophic Factor; Receptors; Receptor; Tumor Cells; Cultured/chemistry/cytology/enzymology; Nerve Growth Factor/*metabolism; trkC
Monoamine-activated alpha2-macroglobulin (alpha2M) was shown to reduce the dopamine concentration in corpus striatum of adult rat brains and inhibit other neuronal functions in vivo and in vitro. As brain-derived neurotrophic factor, neurotrophin-4, and neurotrophin-3 are important neurotrophic factors for dopaminergic neurons, the effect of monoamine-activated alpha2M on signal transduction by trkB and trkC was investigated. The results show that monoamine-activated alpha2M binds to trkB and inhibits brain-derived neurotrophic factor/neurotrophin-4-promoted autophosphorylation of trkB in a dose-dependent manner in both trkB-expressing NIH3T3 (NIH3T3-trkB) and human neuroblastoma
Hu Y Q; Koo P H
Journal of neurochemistry
1998
1998-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Thermoreversible gel for delivery of activin receptor-like kinase 5 inhibitor
Time Factors; Animals; Body Temperature; *Drug Delivery Systems; Temperature; Rabbits; Benzodioxoles/*administration & dosage/pharmacokinetics/toxicity; Delayed-Action Preparations; Drug Carriers/chemistry/toxicity; Fibroblasts/drug effects/metabolism; Filtering Surgery/*methods; Gels; Glaucoma/*surgery; Imidazoles/*administration & dosage/pharmacokinetics/toxicity; Poloxamer/chemistry/toxicity; Protein-Serine-Threonine Kinases/antagonists & inhibitors; Pyridines/*administration & dosage/pharmacokinetics/toxicity; Viscosity; Receptors; Receptor; Animal; Disease Models; Transforming Growth Factor-beta Type I; Transforming Growth Factor beta/antagonists & inhibitors
The purpose of this study is to investigate a thermoreversible gel using Pluronic
Sutariya Vijaykumar; Miladore Nicholas; Geldenhuys Werner; Bhatia Deepak; Wehrung Daniel; Nakamura Hiroshi
Pharmaceutical development and technology
2013
2013-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/10837450.2011.647035" target="_blank" rel="noreferrer noopener">10.3109/10837450.2011.647035</a>
A class of genes in the HER2 regulon that is poised for transcription in breast cancer cell lines and expressed in human breast tumors.
Humans; Cell Line; *Gene Expression Regulation; Reverse Transcriptase Polymerase Chain Reaction; *Gene Expression Profiling; Breast Neoplasms/genetics/pathology; Gene Regulatory Networks; Homeodomain Proteins/genetics/metabolism; MCF-7 Cells; Nanog Homeobox Protein; Neoplastic Stem Cells/metabolism; Octamer Transcription Factor-3/genetics/metabolism; Regulon/*genetics; RNA Polymerase II/metabolism; SOXB1 Transcription Factors/genetics/metabolism; Tumor Microenvironment/genetics; Receptor; Blotting; Western; Tumor; Neoplastic; ErbB-2/*genetics/metabolism
HER2-positive breast cancer accounts for 25% of all cases and has a poor prognosis. Although progress has been made in understanding signal transduction, little is known of how HER2 achieves gene regulation. We performed whole genome expression analysis on a HER2(+) and HER2(-) breast cancer cell lines and compared these results to expression in 812 primary tumors stratified by their HER2 expression level. Chip-on-chip with anti-RNA polymerase II was compared among breast cancer cell lines to identify genes that are potentially activated by HER2. The expression levels of these HER2-dependent POL II binding genes were determined for the 812 HER2+/- breast cancer tissues. Genes differentially expressed between HER2+/- cell lines were generally regulated in the same direction as in breast cancer tissues. We identified genes that had POLII binding in HER2(+) cell lines, but without significant gene expression. Of 737 such genes "poised" for expression in cell lines, 113 genes were significantly differentially expressed in breast tumors in a HER2-dependent manner. Pathway analysis of these 113 genes revealed that a large group of genes were associated with stem cell and progenitor cell control as indicated by networks centered on NANOG, SOX2, OCT3/4. HER2 directs POL II binding to a large number of genes in breast cancer cells. A "poised" class of genes in HER2(+) cell lines with POLII binding and low RNA expression but is differentially expressed in primary tumors, strongly suggests a role of the microenvironment and further suggests a role for stem cells proliferation in HER2-regulated breast cancer tissue.
Rahmatpanah Farah B; Jia Zhenyu; Chen Xin; Char Jessica E; Men Bozhao; Franke Anna-Clara; Jones Frank E; McClelland Michael; Mercola Dan
Oncotarget
2015
2015-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.18632/oncotarget.2676" target="_blank" rel="noreferrer noopener">10.18632/oncotarget.2676</a>
The mechanistic basis for the disparate effects of angiotensin II on coronary collateral growth.
Angiotensin; Angiotensin II/*physiology; Animal; Animals; Coronary Occlusion/drug therapy/*physiopathology; Disease Models; Hemorheology; Ischemia/drug therapy/*physiopathology; Male; Neovascularization; Oxidative Stress/*physiology; Physiologic/*physiology; Rats; Reactive Oxygen Species/adverse effects/metabolism; Receptor; Type 1/*drug effects/physiology; Vasoconstrictor Agents/pharmacology
OBJECTIVE: We hypothesize that controversial effects of angiotensin II (Ang II) are attributable to its regulation of reactive oxygen species (ROS) and
Reed Ryan; Kolz Christopher; Potter Barry; Rocic Petra
Arteriosclerosis, thrombosis, and vascular biology
2008
2008-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.107.154294" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.107.154294</a>
The adenosine 2A receptor agonist GW328267C improves lung function after acute lung injury in rats.
Acute Lung Injury/*drug therapy/metabolism/pathology; Adenosine A2A/*chemistry; Adenosine/*analogs & derivatives/therapeutic use; Amiloride/pharmacology; Animals; Biological Transport; Bronchoalveolar Lavage; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism; Endotoxemia/*drug therapy/metabolism/microbiology; Epithelial Sodium Channel Blockers; Epithelial Sodium Channels/metabolism; Escherichia coli; Escherichia coli Infections/drug therapy/metabolism/microbiology; Immunoblotting; Male; Pneumonia/*drug therapy/metabolism/microbiology; Pulmonary Alveoli/cytology/*drug effects/metabolism; Pulmonary Edema/*drug therapy/metabolism/pathology; Rats; Receptor; Respiratory Physiological Phenomena; Sodium Channel Blockers/pharmacology; Sprague-Dawley; Triazoles/*therapeutic use
There is a significant unmet need for treatments of patients with acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS). The primary mechanism that leads to resolution of alveolar and pulmonary edema is active vectorial Na(+) and Cl(-) transport across the alveolar epithelium. Several studies have suggested a role for adenosine receptors in regulating this fluid transport in the lung. Furthermore, these studies point to the A(2A) subtype of adenosine receptor (A(2A)R) as playing a role to enhance fluid transport, suggesting that activation of the A(2A)R may enhance alveolar fluid clearance (AFC). The current studies test the potential therapeutic value of the A(2A)R agonist GW328267C to accelerate resolution of alveolar edema and ALI/ARDS in rats. GW328267C, at concentrations of 10(-5) M to 10(-3) M, instilled into the airspaces, increased AFC in control animals. GW328267C did not increase AFC beyond that produced by maximal beta-adrenergic stimulation. The effect of GW328267C was inhibited by amiloride but was not affected by cystic fibrosis transmembrane conductance regulator inhibition. The drug was tested in three models of ALI, HCl instillation 1 h, LPS instillation 16 h, and live Escherichia coli instillation 2 h before GW328267C instillation. After either type of injury, GW328267C (10(-4) M) decreased pulmonary edema formation and restored AFC, measured 1 h after GW328267C instillation. These findings show that GW328267C has beneficial effects in experimental models of ALI and may be a useful agent for treating patients with ALI or prophylactically to prevent ALI.
Folkesson Hans G; Kuzenko Stephanie R; Lipson David A; Matthay Michael A; Simmons Mark A
American journal of physiology. Lung cellular and molecular physiology
2012
2012-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajplung.00395.2011" target="_blank" rel="noreferrer noopener">10.1152/ajplung.00395.2011</a>
Endothelin-mediated in vivo pressor responses following TRPV1 activation.
*Blood Pressure/drug effects; *Vasoconstriction/drug effects; Adrenergic alpha-Agonists/administration & dosage; Analysis of Variance; Animal; Animals; Azepines/administration & dosage; Biphenyl Compounds/administration & dosage; Capsaicin/administration & dosage; Cells; Cultured; Diabetes Mellitus; Diabetic Angiopathies/genetics/*metabolism/physiopathology; Dipeptides/administration & dosage; Disease Models; Dose-Response Relationship; Drug; Endothelial Cells/metabolism; Endothelin A Receptor Antagonists; Endothelin A/metabolism; Endothelin B Receptor Antagonists; Endothelin B/metabolism; Endothelin-1/*metabolism; Enzyme-Linked Immunosorbent Assay; Femoral Artery/drug effects/*metabolism/physiopathology; Inbred C57BL; Indoles/administration & dosage; Infusions; Intravenous; Knockout; Male; Mice; Phenylephrine/administration & dosage; Receptor; TRPV Cation Channels/agonists/deficiency/genetics/*metabolism; Type 2/genetics/*metabolism/physiopathology; Vasoconstrictor Agents/administration & dosage
Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1((-/-))], db/db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the alpha-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 mug/kg) dose dependently increased MAP in control mice (5.7 +/- 1.6, 11.7 +/- 2.1, 25.4 +/- 3.4, and 51.6 +/- 3.9%), which was attenuated in db/db mice (3.4 +/- 2.1, 3.9 +/- 2.1, 7.0 +/- 3.3, and 17.9 +/- 6.2%). TRPV1((-/-)) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ET(A) /ET(B)). Inhibition of ET(A) receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ET(A) and ET(B) receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ET(A) receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.
Ohanyan Vahagn A; Guarini Giacinta; Thodeti Charles K; Talasila Phani K; Raman Priya; Haney Rebecca M; Meszaros J Gary; Damron Derek S; Bratz Ian N
American journal of physiology. Heart and circulatory physiology
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00082.2011" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00082.2011</a>
Estrogen-related receptor gamma controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol.
Alcohol-Induced Injury; Alcoholic Liver Disease; Alcoholic/genetics/*metabolism/prevention & control; Animals; Cannabinoid; CB1/*physiology; Cytochrome P-450 CYP2E1 Inhibitors; Cytochrome P-450 CYP2E1/genetics/*metabolism; Enzyme Inhibitors/pharmacology/therapeutic use; Enzymologic/drug effects/physiology; Estrogen/deficiency/genetics/*physiology; Ethanol/pharmacology; Gene Expression Profiling/methods; Gene Expression Regulation; Gene Regulation; Genetic/physiology; Inbred C57BL; Knockout; Liver; Liver Diseases; Liver Metabolism; Liver/metabolism; Male; Mice; Oxidation-Reduction; Oxidative Stress/physiology; Receptor; Receptors; Signal Transduction/drug effects/physiology; Tamoxifen/analogs & derivatives/pharmacology/therapeutic use; Transcription
BACKGROUND: The hepatic endocannabinoid system and cytochrome P450 2E1 (CYP2E1), a key enzyme causing alcohol-induced reactive oxygen species (ROS) generation, are major contributors to the pathogenesis of alcoholic liver disease. The nuclear hormone receptor oestrogen-related receptor gamma (ERRgamma) is a constitutively active transcriptional activator regulating gene expression. OBJECTIVE: To investigate the role of ERRgamma in the alcohol-mediated regulation of CYP2E1 and to examine the possibility to control alcohol-mediated oxidative stress and liver injury through an ERRgamma inverse agonist. DESIGN: For chronic alcoholic hepatosteatosis study, C57BL/6J wild-type and CB1(-/-) mice were administered alcohol for 4 weeks. GSK5182 and chlormethiazole (CMZ) were given by oral gavage for the last 2 weeks of alcohol feeding. Gene expression profiles and biochemical assays were performed using the liver or blood of mice. RESULTS: Hepatic ERRgamma gene expression induced by alcohol-mediated activation of CB1 receptor results in induction of CYP2E1, while liver-specific ablation of ERRgamma gene expression blocks alcohol-induced expression of CYP2E1 in mouse liver. An ERRgamma inverse agonist significantly ameliorates chronic alcohol-induced liver injury in mice through inhibition of CYP2E1-mediated generation of ROS, while inhibition of CYP2E1 by CMZ abrogates the beneficial effects of the inverse agonist. Finally, chronic alcohol-mediated ERRgamma and CYP2E1 gene expression, ROS generation and liver injury in normal mice were nearly abolished in CB1(-/-) mice. CONCLUSIONS: ERRgamma, as a previously unrecognised transcriptional regulator of hepatic CB1 receptor, controls alcohol-induced oxidative stress and liver injury through CYP2E1 induction, and its inverse agonist could ameliorate oxidative liver injury due to chronic alcohol exposure.
Kim Don-Kyu; Kim Yong-Hoon; Jang Hyun-Hee; Park Jinyoung; Kim Jung Ran; Koh Minseob; Jeong Won-Il; Koo Seung-Hoi; Park Tae-Sik; Yun Chul-Ho; Park Seung Bum; Chiang John Y L; Lee Chul-Ho; Choi Hueng-Sik
Gut
2013
2013-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1136/gutjnl-2012-303347" target="_blank" rel="noreferrer noopener">10.1136/gutjnl-2012-303347</a>
Orphan nuclear receptor oestrogen-related receptor gamma (ERRgamma) plays a key role in hepatic cannabinoid receptor type 1-mediated induction of CYP7A1 gene expression.
Animals; bile acid; Bile Acids and Salts/metabolism; Cannabinoid; cannabinoid receptors; CB1/agonists/genetics/*metabolism; Cells; Cholesterol 7-alpha-Hydroxylase/*biosynthesis/genetics; cholesterol 7alpha-hydroxylase (CYP7A1); Cultured; Cytoplasmic and Nuclear/metabolism; Drug Inverse Agonism; Estrogen/genetics/*metabolism; Ethanol/pharmacology; Gene Expression; Genetic; Glycerides/pharmacology; GSK5182; HEK293 Cells; Hepatocytes/metabolism; Humans; Inbred C57BL; Knockout; Liver/*metabolism; Mice; oestrogen-related receptor gamma (ERRgamma); orphan nuclear receptor; Promoter Regions; Rats; Receptor; Receptors; small heterodimer partner (SHP); Sprague-Dawley; Transcription
Bile acids are primarily synthesized from cholesterol in the liver and have important roles in dietary lipid absorption and cholesterol homoeostasis. Detailed roles of the orphan nuclear receptors regulating cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, have not yet been fully elucidated. In the present study, we report that oestrogen-related receptor gamma (ERRgamma) is a novel transcriptional regulator of CYP7A1 expression. Activation of cannabinoid receptor type 1 (CB1 receptor) signalling induced ERRgamma-mediated transcription of the CYP7A1 gene. Overexpression of ERRgamma increased CYP7A1 expression in vitro and in vivo, whereas knockdown of ERRgamma attenuated CYP7A1 expression. Deletion analysis of the CYP7A1 gene promoter and a ChIP assay revealed an ERRgamma-binding site on the CYP7A1 gene promoter. Small heterodimer partner (SHP) inhibited the transcriptional activity of ERRgamma and thus regulated CYP7A1 expression. Overexpression of ERRgamma led to increased bile acid levels, whereas an inverse agonist of ERRgamma, GSK5182, reduced CYP7A1 expression and bile acid synthesis. Finally, GSK5182 significantly reduced hepatic CB1 receptor-mediated induction of CYP7A1 expression and bile acid synthesis in alcohol-treated mice. These results provide the molecular mechanism linking ERRgamma and bile acid metabolism.
Zhang Yaochen; Kim Don-Kyu; Lee Ji-Min; Park Seung Bum; Jeong Won-Il; Kim Seong Heon; Lee In-Kyu; Lee Chul-Ho; Chiang John Y L; Choi Hueng-Sik
The Biochemical journal
2015
2015-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1042/BJ20141494" target="_blank" rel="noreferrer noopener">10.1042/BJ20141494</a>
Glutamate and metabotropic glutamate receptors associated with innervation of the uterine cervix during pregnancy: receptor antagonism inhibits c-Fos expression in rat lumbosacral spinal cord at parturition.
Animals; Cervix Uteri/*innervation; Excitatory Amino Acid Antagonists/pharmacology; Female; Ganglia; Gene Expression Regulation/drug effects/*physiology; Glutamates/*metabolism; Lumbosacral Region; Messenger/biosynthesis; Metabotropic Glutamate 5; Metabotropic Glutamate/*metabolism; Neurons/drug effects; Oncogene Proteins v-fos/metabolism; Parturition/*metabolism; Pregnancy/*metabolism; Pyridines/pharmacology; Rats; Receptor; Receptors; Reverse Transcriptase Polymerase Chain Reaction/methods; RNA; Spinal Cord/drug effects/*physiology; Spinal/cytology; Sprague-Dawley; Vesicular Glutamate Transport Protein 1/metabolism
Dorsal root ganglia (DRG) neurons connect the spinal cord and uterine cervix, and are activated at parturition with subsequent stimulation of secondary neurons in the spinal dorsal horn and autonomic areas. Neuropeptide neurotransmitters and receptors have been studied in these areas, but amino acid transmitters, e.g., glutamate, an excitatory neurotransmitter involved in sensory and nociceptive processing, have not been characterized. To determine if glutamate is involved in innervation of the cervix, rats were examined for markers of glutamatergic neurons in the L6-S1 spinal cord, DRG and cervix. Metabotropic glutamate receptors mGluR5 in the spinal dorsal horn and their expression over pregnancy were examined in pregnant rats and pregnant rats treated continuously with an antagonist of mGluR5, 2-methyl-6-(phenylethynyl) pyridine (MPEP). Rats were allowed to deliver pups to determine if the antagonist altered the expression of an early response gene protein, Fos, in the L6-S1 cord. Immunohistochemistry showed glutamate- and vesicular glutamate transporter1 (VGluT1)-positive fibers in the cervix, glutamate- and VGluT1-expressing neurons in the DRG, some of which also exhibited retrograde tracer from cervical injections, and VGluT1 and mGluR5 immunoreactivities in the L6-S1 spinal dorsal horns. Expression of mGluR5 receptors increased over pregnancy. Fos-positive neurons were present among mGluR5-immunoreactivity in the spinal dorsal horn. Parturition-induced Fos-positive neurons in the spinal cords were abundant in control rats, but were reduced by 70% in MPEP-treated animals. These results suggest that glutamate is likely involved in the transmission of sensory signals, possibly pain, from the cervix to the spinal cord at parturition.
Ghosh Chaitali; Storey-Workley Megan; Usip Sharon; Hafemeister Jen; Miller Kenneth E; Papka Raymond E
Journal of neuroscience research
2007
2007-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jnr.21225" target="_blank" rel="noreferrer noopener">10.1002/jnr.21225</a>
Transgenic Expression of Osteoactivin/gpnmb Enhances Bone Formation In Vivo and Osteoprogenitor Differentiation Ex Vivo.
Animals; Bone and Bones/*metabolism; Bone Density/physiology; Bone Remodeling/genetics/*physiology; Bone Resorption/metabolism; Cell Differentiation/genetics/*physiology; Eye Proteins/genetics/*metabolism; Membrane Glycoproteins/genetics/*metabolism; Mice; Osteoblasts/*cytology; Osteoclasts/*cytology; Osteogenesis/genetics; Protein-Serine-Threonine Kinases/metabolism; Receptor; Receptors; Transforming Growth Factor beta/metabolism; Transforming Growth Factor-beta Type I; Transgenic
Initial identification of osteoactivin (OA)/glycoprotein non-melanoma clone B (gpnmb) was demonstrated in an osteopetrotic rat model, where OA expression was increased threefold in mutant bones, compared to normal. OA mRNA and protein expression increase during active bone regeneration post-fracture, and primary rat osteoblasts show increased OA expression during differentiation in vitro. To further examine OA/gpnmb as an osteoinductive agent, we characterized the skeletal phenotype of transgenic mouse overexpressing OA/gpnmb under the
Frara Nagat; Abdelmagid Samir M; Sondag Gregory R; Moussa Fouad M; Yingling Vanessa R; Owen Thomas A; Popoff Steven N; Barbe Mary F; Safadi Fayez F
Journal of cellular physiology
2016
2016-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jcp.25020" target="_blank" rel="noreferrer noopener">10.1002/jcp.25020</a>
Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.
Butadienes/pharmacology; Carcinoma; Cell Line; Chenodeoxycholic Acid/*pharmacology; Cholesterol 7-alpha-Hydroxylase/*biosynthesis; Cytoplasmic and Nuclear/metabolism/physiology; DNA-Binding Proteins/metabolism; Fibroblast Growth Factor; Fibroblast Growth Factors/drug effects/*physiology; Gene Expression/drug effects; Hepatocellular/metabolism; Hepatocytes/metabolism; Humans; Isoxazoles/pharmacology; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Nitriles/pharmacology; Receptor; Receptors; Signal Transduction/drug effects; Transcription Factors/metabolism; Tumor; Type 4/antagonists & inhibitors
UNLABELLED: Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7alpha-hydroxylase gene (C YP7A1) transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and the farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 messenger RNA (mRNA) levels in primary human hepatocytes. FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. Kinase inhibition and phosphorylation assays revealed that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway played a major role in mediating FGF19 inhibition of CYP7A1. However, small interfering RNA (siRNA) knockdown of SHP did not affect FGF19 inhibition of CYP7A1. Interestingly, CDCA stimulated tyrosine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes. FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism. CONCLUSION: The hepatic FGF19/FGFR4/Erk1/2 pathway may inhibit CYP7A1 independent of SHP. In addition to inducing FGF19 in the intestine, bile acids in hepatocytes may activate the liver FGF19/FGFR4 signaling pathway to inhibit bile acid synthesis and prevent accumulation of toxic bile acid in human livers.
Song Kwang-Hoon; Li Tiangang; Owsley Erika; Strom Stephen; Chiang John Y L
Hepatology (Baltimore, Md.)
2009
2009-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.22627" target="_blank" rel="noreferrer noopener">10.1002/hep.22627</a>
Age- and site-specific decline in insulin-like growth factor-I receptor expression is correlated with differential growth plate activity in the mouse hindlimb.
Age Factors; Animals; Biological Evolution; Growth Plate/*metabolism/physiology; Hindlimb/*growth & development/metabolism; IGF Type 1/*metabolism; Inbred C57BL; Mice; Proliferating Cell Nuclear Antigen/metabolism; Receptor
The proximal and distal growth plates of the principal long bones do not contribute equally to longitudinal growth. Most forelimb elongation occurs at the shoulder and wrist, while most hindlimb growth occurs at the knee. This study examined whether insulin-like growth factor-I (IGF-I), a potent growth regulator, could underlie this variation via differential receptor expression. The spatiotemporal distribution of the IGF-I receptor (IGF-IR) was mapped in hindlimb growth plates (overall and within regional zones) from immature mice using immunohistochemistry. Growth activity was assessed by size/morphology of the growth plate and proliferating cell nuclear antigen (PCNA) expression. Both
Serrat Maria A; Lovejoy C Owen; King Donna
Anatomical record (Hoboken, N.J. : 2007)
2007
2007-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/ar.20480" target="_blank" rel="noreferrer noopener">10.1002/ar.20480</a>