Protective Effects Of Ginsenoside Rg(2) Against Glutamate-induced Neurotoxicity In Pc12 Cells
Alzheimer's disease; apoptosis; beta peptide; calpain; damage; excitotoxicity; expression; Integrative & Complementary; ischemic neuronal death; Medicine; neuroprotection; nitric-oxide; Panax ginseng; Panax ginseng; Pharmacology & Pharmacy; Plant Sciences; receptors; system
We investigated the effect of ginsenoside Rg(2) on neurotoxic activities induced by glutamate in PC12 cells. The cells were incubated with glutamate (1 mmol/L), glutamate and ginsenoside Rg(2) (0.05, 0.1, 0.2 mmol/L) or nimodipine (5 mu mol/L for 24 h. The cellular viability was assessed by MTT assay. The lipid peroxidation products malondialdehyde (MDA) and nitrogen oxide (NO) were measured by a spectrophotometric method. Fura2/AM, as a cell permeable fluorescent probe for Ca2+, was used to detect intracellular Ca2+ concentration ([Ca2+](i)) using a monespectrofluorometer. Immunocytochemical techniques were employed to check the protein expression levels of calpain II, caspase-3 and beta-amyloid (A beta)1-40 in PC12 cells. The results showed that glutamate decreased the cell viability, increased [Ca2+](i), lipid peroxidation (the excessive production of MDA, NO) and the protein expression levels of calpain II, caspase-3 and A beta 1-40 in PC12 cells. Ginsenoside Rg(2) significantly attenuated glutamate-induced neurotoxic effects upon these parameters at all doses tested. Our study suggests that ginsenoside Rg(2) has a neuroprotective effect against glutamate-induced neurotoxicity through mechanisms related to anti-oxidation and anti-apoptosis. In addition, the inhibitory effect of ginsenoside Rg(2) against the formation of A beta 1-40 suggests that ginsenoside Rg(2) may also represent a potential treatment strategy for Alzheimer's disease. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
Li N; Liu B; Dluzen D E; Jin Y
Journal of Ethnopharmacology
2007
2007-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.jep.2006.12.015" target="_blank" rel="noreferrer noopener">10.1016/j.jep.2006.12.015</a>
Morphological-changes Of Rat Hippocampal-neurons After Noradrenergic Depletion
6-hydroxydopamine; adult; brain; cortex; deprivation; dsp4; locus coeruleus; postnatal-development; receptors; Zoology
Hwang H M; Lee Y P; Ho P L; Weng S C; Kao H I
Zoological Studies
1995
1995-04
Journal Article or Conference Abstract Publication
n/a
The Fibre Dimensions Of Uterine Smooth Muscle Of The Rabbit Following Treatment By Female Sex Steroids
Anatomy & Morphology; Cell Biology; estradiol; estrogen; gap-junctions; human myometrium; medroxyprogesterone; myometrium; parturition; Pregnancy; progesterone; rabbit; rat myometrium; receptors; smooth-muscle; uterus
Gilloteaux J; Szczepanski M
Tissue & Cell
2000
2000-06
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1054/tice.2000.0112" target="_blank" rel="noreferrer noopener">10.1054/tice.2000.0112</a>
Thermoreversible Gel for Delivery of Activin Receptor-Like Kinase 5 Inhibitor in Glaucoma Filtration Surgery
receptors; Ophthalmology; wound healing; conjunctiva
Miladore N; Nakamura H; Geldenhuys W; Bhatia D; Sutariya V
Investigative Ophthalmology & Visual Science
2010
2010-04
Journal Article or Conference Abstract Publication
n/a
Interactive effects of tamoxifen and oestrogen upon the nigrostriatal dopaminergic system: Long-term treatments
receptors; Neurosciences & Neurology; Endocrinology & Metabolism; estrogen; binding; catecholamines; brain; striatum; time; amphetamine; estradiol; antiestrogens; ovarian steroids; sexual-behavior; anti-oestrogens
In the present report adult female rats were ovariectomized (OVX) and assigned to one of four treatment conditions. Treatments consisted of administering pellets containing 17 beta-oestradiol (E), tamoxifen (TMX), a combination of TMX and E or no further treatment (OVX), Animals received these treatments immediately following OVX and were maintained in these conditions for a 40-day period. Subsequently, the corpus striatum (CS) was dissected from each animal and prepared for determinations of basal and amphetamine stimulated DA output using in-vitro superfusion. No statistically significant differences among the four treatment groups were obtained for basal dopamine output. The highest levels of amphetamine-stimulated dopamine responses were obtained from E treated rats. These values were significantly greater than that obtained from OVX rats and rats treated with a combination of TMX + E. The significance of these findings is that they indicate both a non-traditional central nervous system site and mechanism of action through which tamoxifen-oestrogen interactions can function. Such data may have important implications for administration of tamoxifen to premenopausal women as this anti-oestrogen may compromise nigrostriatal dopaminergic function under conditions where oestrogenic modulation is present.
McDermott J L; Anderson L I; Dluzen D E
Journal of Neuroendocrinology
1999
1999-10
Journal Article or Conference Abstract Publication
n/a
Interactive effects of tamoxifen and estrogen upon the nigrostriatal dopaminergic system
breast-cancer; rat; receptors; Neurosciences & Neurology; Endocrinology & Metabolism; catecholamines; breast-cancer; striatum; uptake sites; amphetamine; Progesterone; female cd-1 mice; release; antiestrogens; brain metastases; chronic estradiol; ovarian steroids; sexual-behavior
Adult female rats were ovariectomized and received a 21-day release pellet containing either (17)beta-estradiol (0.1 mg), tamoxifen (5.0 mg), a combination of estradiol and tamoxifen or no further treatment. At 14 days following ovariectomy +/- hormone treatments rats were sacrificed, the corpus striatum removed and prepared for assessment of dopamine release using in vitro superfusion. Maximal potassium-stimulated dopamine release rates were obtained with the estradiol + tamoxifen-treated rats and these levels were significantly greater than those from animals receiving only tamoxifen. Similarly, maximally amphetamine-stimulated responses were obtained from estradiol + tamoxifen-treated rats, however, in contrast to potassium, these values were significantly greater than both animals receiving either estradiol or tamoxifen alone. These data demonstrate that the nigrostriatal dopaminergic system appears particularly sensitive to the modulatory effects of a combined treatment with estradiol + tamoxifen. Moreover, some of the potential mechanisms of these responses are indicated by the differential dopamine outputs as evoked by potassium or amphetamine. The significance of these synergistic actions is their potential to mimic changes that may occur under conditions of tamoxifen treatment of premenopausal women as has been suggested for women at risk for breast cancer.
McDermott J L; Anderson L I; Dluzen D E
Neuroendocrinology
1997
1997-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1159/000127236" target="_blank" rel="noreferrer noopener">10.1159/000127236</a>
Vascular Endothelial Growth Factor and the Collateral Circulation The Story Continues
angiogenesis; arteriogenesis; receptors; cells; Cardiovascular System & Cardiology; expression; Hematology; skeletal-muscle; permeability factor; vasculogenesis; vasculotropin; vegf family-members
Chilian W M; Pung Y F
Circulation Research
2008
2008-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1161/01.RES.0000338258.90706.2c" target="_blank" rel="noreferrer noopener">10.1161/01.RES.0000338258.90706.2c</a>
Low-density lipoprotein receptor-related protein mediates in PC12 cell cultures the inhibition of nerve growth factor-promoted neurite outgrowth by pregnancy zone protein and alpha(2)-macroglobulin
phosphorylation; Signal transduction; receptors; Neurosciences & Neurology; binding; gene-expression; Signal transduction; alpha-2-macroglobulin; alpha-macroglobulin; alpha-macroglobulins; amyloid precursor protein; cytosolic adapter; low-density lipoprotein receptor-related protein; lrp; neurological diseases; rat alpha-1-macroglobulin; trk; Trk regulation
Human pregnancy zone protein (PZP) is a major pregnancy-associated plasma protein closely related to human alpha(2)-macroglobulin (alpha(2)M). It has been demonstrated that monoamine-activated forms of human and rat alpha(2)M and rat alpha(2)M can bind to TrkA and, respectively, inhibit and stimulate NGF-promoted neurite outgrowth, Trk phosphorylation, and intracellular signal transduction in PC12 cells. However, the effect of PZP on neurons is unknown, and the molecular mechanism of neuroinhibition by monoamine-activated alpha(2)M is still unclear. In this report, we show that methylamine-activated PZP (MA-PZP), like MA-alpha(2)M, inhibits in a dose-dependent way the NGF-promoted neurite extension and TrkA phosphorylation in PC12 cells. On the other hand, normal PZP (N-PZP) had little or no effect. In addition, the inhibitory effect of activated alpha-macroglobulins (alphaMs) was reversible upon its removal from the cell culture. In addition, PZP, as well as alpha(2)M, is neuroinhibitory without being directly cytotoxic. It is known that the activated alphaMs bind to the multiligand receptor termed low-density lipoprotein receptor-related protein (LRP) and that the receptor-associated protein (RAP) specifically blocks uptake of all known LRP ligands. To investigate the potential role of LRP in neuromodulation by activated PZP/alpha(2)M, the effect of RAP on the neuroinhibitory activities of these alphaMs was also studied. Data presented here show that RAP blocked the neurite- and Trk- inhibitory activities of both MA-PZP and MA-alpha(2)M whereas RAP itself had no neuromodulatory effect. Hence, we conclude that these data suggest that the LRP receptor and its alphaM ligands may play a role in regulating Trk receptors. (C) 2002 Wiley-Liss, Inc.
Chiabrando G A; Sanchez M C; Skornicka E L; Koo P H
Journal of Neuroscience Research
2002
2002-10
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/jnr.10369" target="_blank" rel="noreferrer noopener">10.1002/jnr.10369</a>
DEVELOPMENTAL ALTERATIONS IN N-METHYL-D-ASPARTATE STIMULATED H-3 NOREPINEPHRINE RELEASE IN RAT-BRAIN CORTEX AND HIPPOCAMPUS
hippocampus; cortex; development; receptors; Neurosciences & Neurology; system; ethanol; postnatal-development; cerebral-cortex; visual cortex; excitatory amino-acids; [h-3]norepinephrine release; n-methyl-d-aspartate; nmda-binding-sites; norepinephrine release; slice
Developmental alterations in N-methyl-D-aspartate (NMDA)-stimulated [H-3]norepinephrine release from rat brain cortical and hippocampal slices were studied. NMDA (10-1000 muM) resulted in a concentration-dependent increase in [H-3]norepinephrine efflux; maximal responses (% released) in the cortex were: (1.53 +/- 0. 12, 3.68 +/- 0.20, 2.94 +/- 0.20, 4.60 +/- 0.28 and 5.28 +/- 0.33) and the hippocampal responses were: (1.90 +/- 0.18, 3.84 +/- 0.23, 3.60 +/- 0.28, 5.16 +/- 0.38 and 5.81 +/- 0.45) at varying postnatal ages (1, 7, 14, 21 and 90 days) respectively. Cortical tissue from 7-day-old pups exhibited a transient increase in maximal efflux and a decrease in EC50. These results indicated that developmental alterations in the NMDA receptor appear to be translated into differences in NMDA stimulated [H-3]norepinephrine release.
Brown L M
Neuroscience Letters
1993
1993-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/0304-3940(93)90167-j" target="_blank" rel="noreferrer noopener">10.1016/0304-3940(93)90167-j</a>
REDUCTION OF LEARNED HELPLESSNESS BY CENTRAL ADMINISTRATION OF QUATERNARY NALTREXONE
analgesia; Psychology; receptors; Behavioral Sciences; deficits; antagonists; intracerebroventricular; central mediation; escape performance; inescapable shock; learned helplessness; quaternary naltrexone
Prior research has established that escape impairment resulting from prior inescapable shock (IS) could be reversed by the peripheral administration of the opiate antagonist naltrexone (NTX), but not the quaternary form of naltrexone (QNTX), which when systemically administered, does not readily pass the blood-brain barrier. As it was unclear whether the failure of systemically administered QNTX to reduce shuttle escape deficits following exposure to IS could be attributed to reasons other than the restricted access of QNTX to receptor sites in the brain, rats were affixed with chronic indwelling ventricular cannulae to allow direct brain administration of QNTX. The present experiment found a significant attenuation of the escape deficit produced by prior inescapable shock following the intracerebroventricular (ICV) administration of QNTX (10-mu-g/rat). These data provide further evidence of a mediational role for central opiate receptors in the expression of escape interference following inescapable shock.
Blustein J E; Whitehouse W G; Calcagnetti D J; Troisi J R; Margules D L; Bersh P J
Physiology & Behavior
1992
1992-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/0031-9384(92)90095-j" target="_blank" rel="noreferrer noopener">10.1016/0031-9384(92)90095-j</a>
HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7 alpha-hydroxylase gene (CYP7A1)
bile-acid synthesis; bile acids; Biochemistry & Molecular Biology; chicken ovalbumin; cholesterol metabolism; dna-binding; hepatocyte nuclear factor 4; hepatocyte nuclear factor 4; hormone-receptor superfamily; messenger-rna; orphan receptors; promoter; receptors; response elements; retinoic acid; thyroid-hormone; transcriptional regulation; upstream promoter transcription factor II
The gene for cholesterol 7 alpha-hydroxylase (CYP7A1) contains a sequence at nt -149 to -118 that was found to play a large role in determining the overall transcriptional activity and regulation of the promoter. Hepatocyte nuclear factor 4 (HNF4) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) synergistically activate transcription of the CYP7A1 promoter, Transactivation of CYP7A1 by HNF4 in the human hepatoma cell line, HepG2, was enhanced by cotransfection with COUP-TFII or the basal transcription element binding protein (BTEB), HNF4 prepared from rat liver nuclear extracts bound to oligomers homologous to the nt -146 to -134 sequences in electrophoretic mobility shift assays (EMSA), which corresponded to a conserved region containing a direct repeat of hormone response elements spaced by one nucleotide (DR1), The sequences surrounding this DR1 were found to be essential for the HNF4 transactivation. In vitro-translated COUP-TFII was found to bind the adjacent sequences from nt -139 to -128 (DRO), but COUP-TFII interacted with this region at a much lower affinity than to the COUP-TFII-site at nt -72 to -57 (DR4), Mutations at nt -139 to -128 or nt -72 to -57 reduced the COUP-TFII and HNF4 synergy; however, these COUP-TFII-binding sequences were not absolutely required for the cooperative effect of HNF4 and COUP-TFII on transactivation. These results indicated that the observed transactivation was the result of protein/protein interactions facilitated by the juxtaposition of the binding elements.
Stroup D; Chiang J Y L
Journal of Lipid Research
2000
2000-01
Journal Article
n/a
Forms of associative synaptic plasticity
2 forms; apical dendrites; area ca1; glutamate; hippocampal ca1; in-vivo; long-term potentiation; ltp; nmda receptors; protein-phosphorylation; receptors
Teyler T J
2001
2001
Book/Monograph
n/a
Suppression of Ocular Scarring After Glaucoma Filtration Surgery in Rabbits by Activin Receptor-Like Kinase 5 Inhibitor
growth factors/growth factor; inhibitory receptors; Ophthalmology; receptors; Wound healing
Sapitro J; Dunmire J J; Sutariya V; Geldenhuys W J; Hewit M; Yue Byjt; Nakamura H
Investigative Ophthalmology & Visual Science
2010
2010-04
Journal Article
n/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>
Phentermine plus fenfluramine produce cocaine-like discriminative cues
analogs; cocaine; combinations; drug discrimination; fenfluramine; Pharmacology & Pharmacy; phentermine; receptors; Research & Experimental Medicine; serotonin; stimulus properties
Drug discrimination studies were conducted in six male Sprague-Dawley rats trained to discriminate the interoceptive cues produced by 10 mg/kg cocaine in an effort to investigate if there is stimulus generalization to phentermine or phentermine + fenfluramine. Once having reached criterion performance, these rats were tested with lower doses of cocaine and generated a typical dose-response curve allowing for calculation of an ED(50) value: 2.798 mg/kg. Testing of phentermine in doses of 1.25-5.0 mg/kg indicated generalization with the highest dose producing 80% cocaine-appropriate responding and allowing for an ED(50) value of 2.356 mg/kg. When the phentermine doses were tested in combination 2.0 mg/kg fenfluramine, however, there was an increase in the discriminability of the highest phentermine dose and a slight decrease in the ED(50) value of the combination. Thus, administration of phentermine + fenfluramine, having both dopamine-releasing and serotonin-releasing properties, respectively, may mimic the neurochemical activity by which cocaine acts in the central nervous system and may possibly allow for cocaine-like effects as these two drugs see increased use in obesity control.
Schechter M D; McBurney D
Life Sciences
1996
1996-10
Journal Article
<a href="http://doi.org/10.1016/s0024-3205(96)00513-9" target="_blank" rel="noreferrer noopener">10.1016/s0024-3205(96)00513-9</a>
CONTINUOUS-INFUSION OF PYRIDOSTIGMINE IN THE MANAGEMENT OF MYASTHENIC CRISIS
cholinergic; cholinesterase inhibitors; compounds; edrophonium; General & Internal Medicine; gravis; injections; intravenous; kinetics; myasthenia gravis; neostigmine; neuromuscular diseases; ocular motility disorders; pyridinium; pyridostigmine bromide; receptors; ventilatory weaning
Saltis L M; Martin B R; Traeger S M; Bonfiglio M F
Critical Care Medicine
1993
1993-06
Journal Article
<a href="http://doi.org/10.1097/00003246-199306000-00025" target="_blank" rel="noreferrer noopener">10.1097/00003246-199306000-00025</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>
Understanding Bile Acid Signaling in Diabetes: From Pathophysiology to Therapeutic Targets
Bile acids and salts; cytoplasmic and nuclear; G-protein-coupled; Gastrointestinal microbiome; Non-alcoholic fatty liver disease; Receptors
Diabetes and obesity have reached an epidemic status worldwide. Diabetes increases the risk for cardiovascular disease and non-alcoholic 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.
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>
Cysteinyl leukotriene 2 receptor promotes endothelial permeability, tumor angiogenesis, and metastasis.
*angiogenesis; *cysteinyl leukotriene receptors; *endothelial cells; *metastasis; *tumor growth; Male; Animals; Mice; Gene Knockout Techniques; Lung Neoplasms/drug therapy; Neoplasm Transplantation; Neoplasms; Receptors; Inbred C57BL; Neovascularization; Experimental; Capillary Permeability/drug effects; Cyclohexanecarboxylic Acids/pharmacology; Endothelial Cells/*drug effects; Leukotriene Antagonists/pharmacology; Neoplasm Metastasis/drug therapy; Phthalic Acids/pharmacology; Leukotriene/drug effects/*metabolism; Pathologic/*chemically induced/drug therapy
Cysteinyl leukotrienes (cys-LTs) are proinflammatory mediators that enhance vascular permeability through distinct receptors (CysLTRs). We found that CysLT2R regulates angiogenesis in isolated mouse endothelial cells (ECs) and in Matrigel implants in WT mice and enhances EC contraction and permeability via the Rho-dependent myosin light chain 2 and vascular endothelial (VE)-cadherin axis. Since solid tumors utilize aberrant angiogenesis for their growth and metastasis and their vessels exhibit vascular hyperpermeability, we hypothesized that CysLT2R, via its actions on the endothelium, might regulate tumor growth. Both tumor growth and metastases of adoptively transferred syngeneic Lewis lung carcinoma (LLC) cells are significantly reduced in CysLT2R-null mice (Cysltr2 (-/-)) compared with WT and CysLT1R-null mice (Cysltr1 (-/-)). In WT recipients of LLC cells, CysLT2R expression is significantly increased in the tumor vasculature, compared with CysLT1R. Further, the tumor vasculature in Cysltr2 (-/-) recipients exhibited significantly improved integrity, as revealed by increased pericyte coverage and decreased leakage of i.v.-administered Texas Red-conjugated dextran. Administration of a selective CysLT2R antagonist significantly reduced LLC tumor volume, vessel density, dextran leakage, and metastases in WT mice, highlighting CysLT2R as a VEGF-independent regulator of the vasculature promoting risk of metastasis. Thus, both genetic and pharmacological findings establish CysLT2R as a gateway for angiogenesis and EC dysregulation in vitro and ex vivo and in an in vivo model with a mouse tumor. Our data suggest CysLT2R as a possible target for intervention.
Duah Ernest; Teegala Lakshminarayan Reddy; Kondeti Vinay; Adapala Ravi K; Keshamouni Venkateshwar G; Kanaoka Yoshihide; Austen K Frank; Thodeti Charles K; Paruchuri Sailaja
Proceedings of the National Academy of Sciences of the United States of America
2019
2019-01
<a href="http://doi.org/10.1073/pnas.1817325115" target="_blank" rel="noreferrer noopener">10.1073/pnas.1817325115</a>
Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.
Humans; Male; Animals; Mice; *Atherosclerosis; *Farnesoid X receptor; *NAFLD; *Obesity; *TGR5; Diet; Hep G2 Cells; Receptors; Inbred C57BL; High-Fat/adverse effects; Cytoplasmic and Nuclear/*agonists; Bile Acids and Salts/pharmacology/*therapeutic use; Hypercholesterolemia/*drug therapy/etiology/metabolism; Non-alcoholic Fatty Liver Disease/*drug therapy/etiology/metabolism; Obesity/*drug therapy/etiology/metabolism; G-Protein-Coupled/*agonists
OBJECTIVES: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. METHODS: Wild-type (WT), Tgr5(-/-), Fxr(-/-), Apoe(-/-) and Shp(-/-) mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. RESULTS: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (CEBPalpha) as novel
Jadhav Kavita; Xu Yang; Xu Yanyong; Li Yuanyuan; Xu Jiesi; Zhu Yingdong; Adorini Luciano; Lee Yoon Kwang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Molecular metabolism
2018
2018-03
<a href="http://doi.org/10.1016/j.molmet.2018.01.005" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2018.01.005</a>
Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism.
Male; Animals; Mice; Random Allocation; Sensitivity and Specificity; *Signal Transduction; Lipid Metabolism; Bile Acids and Salts/*metabolism; GTP-Binding Proteins/*metabolism; Receptors; Inbred C57BL; Animal; Disease Models; G-Protein-Coupled/*metabolism; Gastrointestinal Microbiome/*drug effects; Glucagon-Like Peptide 1/metabolism; Cytoplasmic and Nuclear/*antagonists & inhibitors/pharmacology
Bile acids activate farnesoid X receptor (FXR) and G protein-coupled bile acid receptor-1 (aka Takeda G protein-coupled receptor-5 [TGR5]) to regulate bile acid metabolism and glucose and insulin sensitivity. FXR and TGR5 are coexpressed in the enteroendocrine L cells, but their roles in integrated regulation of metabolism are not completely understood. We reported recently that activation of FXR induces TGR5 to stimulate glucagon-like peptide-1 (GLP-1) secretion to improve insulin sensitivity and hepatic metabolism. In this study, we used the intestine-restricted FXR agonist fexaramine (FEX) to study the effect of activation of intestinal FXR on the gut microbiome, bile acid metabolism, and FXR and TGR5 signaling. The current study revealed that FEX markedly increased taurolithocholic acid, increased secretion of fibroblast growth factors 15 and 21 and GLP-1, improved insulin and glucose tolerance, and promoted white adipose tissue browning in mice. Analysis of 16S ribosomal RNA sequences of the gut microbiome identified the FEX-induced and lithocholic acid-producing bacteria Acetatifactor and Bacteroides. Antibiotic treatment completely reversed the
Pathak Preeti; Xie Cen; Nichols Robert G; Ferrell Jessica M; Boehme Shannon; Krausz Kristopher W; Patterson Andrew D; Gonzalez Frank J; Chiang John Y L
Hepatology (Baltimore, Md.)
2018
2018-10
<a href="http://doi.org/10.1002/hep.29857" target="_blank" rel="noreferrer noopener">10.1002/hep.29857</a>
Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction.
Mice; Myocardium; Cells; Receptors; Proteins; Animal Studies; Cell Physiology; Cardiovascular System Physiology; Myocardial Infarction; Myocardial Infarction – Therapy; Stem Cells – Metabolism; Cytokines – Metabolism; Cell Surface – Metabolism; Myocardial Infarction – Pathology; Apoptosis – Physiology; Cell Movement – Physiology; Cell Surface; Coronary Circulation – Physiology; Gene Expression – Physiology; Stem Cells – Transplantation
BACKGROUND: Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction. METHODS AND RESULTS: Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100 000 MSC or saline via tail vein. We show [alpha]-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P\textless0.01), increased cardiac progenitor cell recruitment (100.9%, P\textless0.01), and increased cardiac myosin-positive area (39%, P\textless0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P\textless0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and CM-CXCR4 null mice. CONCLUSIONS: These data demonstrate that the local trophic effects of MSC require cardiac progenitor cell and CM-CXCR4 expression and are mediated by MSC stromal cell-derived factor-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. In the absence of CM-CXCR4 expression, there is a significant loss of functional benefit in MSC-mediated repair despite equal increases in vascular density.
Dong F; Harvey J; Finan A; Weber K; Agarwal U; Penn M S
Circulation
2012
2012-07-17
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/circulationaha.111.082453" target="_blank" rel="noreferrer noopener">10.1161/circulationaha.111.082453</a>
Modern outcomes of inflammatory breast cancer.
Adult; Female; Aged; Survival; Radiation Dosage; Antibodies; Human; Middle Age; Retrospective Design; Receptors; Hydrocarbons; Treatment Outcomes; Breast Neoplasms; 80 and Over; Antineoplastic Agents – Therapeutic Use; Breast Neoplasms – Mortality; Breast Neoplasms – Pathology; Monoclonal – Therapeutic Use; Breast Neoplasms – Therapy; Cell Surface – Analysis; Combined Modality Therapy – Methods; Cyclic – Therapeutic Use; Hydrocarbons – Therapeutic Use; Lumpectomy – Statistics and Numerical Data; Proteins – Analysis
Purpose: To report contemporary outcomes for inflammatory breast cancer (IBC) patients treated in the modern era of trastuzumab and taxane-based chemotherapy. Methods and Materials: We retrospectively reviewed the charts of 104 patients with nonmetastatic IBC treated between January 2000 and December 2009. Patients who received chemotherapy, surgery, and radiation therapy were considered to have completed the intended therapy. Kaplan-Meier curves estimated locoregional control (LRC), distant metastases-free survival (DMFS), and overall survival. Results: The median follow-up time was 34 months; 57 (55%) patients were estrogen receptor progesterone receptor (ER/PR) negative, 34 (33%) patients were human epidermal growth factor receptor 2 (her2)/neu amplified, and 78 (75%) received definitive postoperative radiation. Seventy-five (72%) patients completed all of the intended therapy, of whom 67 (89%) received a taxane and 18/28 (64%) of her2/neu-amplified patients received trastuzumab. For the entire cohort, the 5-year rates of overall survival, LRC, and DMFS were 46%, 83%, and 44%, respectively. The ER/PR-negative patients had a 5-year DMFS of 39% vs. 52% for ER/PR-positive patients (p = 0.03). The 5-year DMFS for patients who achieved a pathologic complete response compared with those who did not was 83% vs. 44% (p \textless 0.01). Those patients who received \textgreater60.4 Gy (n = 15) to the chest wall had a 5-year LRC rate of 100% vs. 83% for those who received 45 to 60.4 Gy (n = 49; p = 0.048). On univariate analysis, significant predictors of DMFS included achieving a complete response to neoadjuvant chemotherapy (hazard ratio [HR] = 5.8; 95% confidence interval [CI] = 1.4-24.4; p = 0.02) and pathologically negative lymph nodes (HR = 4.1; 95% CI = 1.4-11.9; p \textless 0.01), but no factor was significant on multivariate analysis. Conclusions: For IBC patients, the rate of distant metastases is still high despite excellent local control, particularly for patients who received \textgreater60.4 Gy to the chest wall. Despite the use of taxanes and trastuzumab, outcomes remain modest, particularly for those with ER/PR-negative disease and those without a pathologic complete response.
Rehman S; Reddy CA; Tendulkar RD; Rehman Sana; Reddy Chandana A; Tendulkar Rahul D
International Journal of Radiation Oncology, Biology, Physics
2012
2012-11
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<a href="http://doi.org/10.1016/j.ijrobp.2012.01.030" target="_blank" rel="noreferrer noopener">10.1016/j.ijrobp.2012.01.030</a>
A neurochemical heterogeneity of the rat striatum as measured by in vivo electrochemistry and microdialysis.
Male; Animals; Rats; Dopamine/*metabolism; Corpus Striatum/*metabolism; Amphetamines/*pharmacology; Electrochemistry; Sulpiride/*pharmacology; Inbred Strains; Receptors; 3; 4-Dihydroxyphenylacetic Acid/metabolism; Dopamine/drug effects; Dopamine D2
The neurochemical heterogeneity of the rat striatum was assessed in vivo by measuring subregional changes in extracellular dopamine and DOPAC by in vivo electrochemistry and microdialysis in response to amphetamine and the D2 antagonist, (-)-sulpiride. Both in vivo electrochemical and microdialysis experiments indicated a significant rostrocaudal gradient in dopamine release following amphetamine. The increase in dopamine release was highest in the rostral areas (over 800% of baseline values) and lowest in the most caudal subregion (425% of baseline). No lateromedial differences in dopamine release were observed. DOPAC levels decreased in dialysates but were similar for all 6 subregions examined. In contrast, D2 blockade with (-)-sulpiride revealed a lateromedial gradient in the increases seen for dopamine and DOPAC such that greater increases were observed in the lateral subregions. (-)-Sulpiride did not produce any differential effects along the rostrocaudal axis. The regional gradients detected in extracellular fluid changes of dopamine and DOPAC indicate that dopamine release is locally regulated by an interaction between the density of dopaminergic innervation to a particular subregion and the D2 receptor density.
Yamamoto B K; Pehek E A
Brain research
1990
1990-01
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<a href="http://doi.org/10.1016/0006-8993(90)91256-g" target="_blank" rel="noreferrer noopener">10.1016/0006-8993(90)91256-g</a>
Transcriptional regulation of the human cholesterol 7 alpha-hydroxylase gene (CYP7A) in HepG2 cells.
Humans; Binding Sites; Gene Expression Regulation; Cell Line; Transfection; Base Sequence; Molecular Sequence Data; Phorbol Esters/pharmacology; DNA-Binding Proteins/genetics/metabolism; *Transcription Factors; Enzyme Repression; Cholesterol 7-alpha-Hydroxylase/biosynthesis/*genetics; Consensus Sequence; Glucocorticoids/pharmacology; Hepatocyte Nuclear Factor 3-alpha; Insulin/pharmacology; Nuclear Proteins/genetics/metabolism; Recombinant Fusion Proteins/biosynthesis; Thyroid Hormones/pharmacology; Genes; Receptors; Enzymologic/*drug effects; Genetic; *Promoter Regions; Reporter; *Transcription; Glucocorticoid/genetics/metabolism
A stable HepG2 cell line harboring a human cholesterol 7 alpha-hydroxylase (CYP7A) minigene/luciferase reporter gene construct was selected for studying transcriptional regulation of CYP7A gene promoter. Insulin and phorbol
Wang D P; Stroup D; Marrapodi M; Crestani M; Galli G; Chiang J Y
Journal of lipid research
1996
1996-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Ontogenesis of the depressant activity of carbachol on synaptic activity in rat visual cortex.
Animals; Rats; Synapses/drug effects/*physiology; Carbachol/*pharmacology; Visual Cortex/drug effects/metabolism/*physiology; Receptors; Muscarinic/drug effects/metabolism
We studied the ontogeny of muscarinic depression in the developing rat visual cortex using carbachol (a nonhydrolyzable cholinergic agonist) application to neocortical slices obtained from four postnatal age groups: 9-10 days, 15 days,
Vaknin G; Teyler T J
Brain research bulletin
1991
1991-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0361-9230(91)90228-c" target="_blank" rel="noreferrer noopener">10.1016/0361-9230(91)90228-c</a>
Comparative aspects of hippocampal and neocortical long-term potentiation.
Animals; Electric Stimulation; Action Potentials; Hippocampus/*physiology; Visual Cortex/*physiology; Evoked Potentials; Memory/physiology; Receptors; N-Methyl-D-Aspartate; Neurotransmitter/*physiology
Long-term potentiation (LTP) is a candidate for the synaptic alternations underlying memory storage in the mammalian CNS. In this chapter LTP in hippocampus and in visual neocortex are compared. Comparisons of the optimal tetanus parameters revealed that 2-3 trains of high-frequency stimulation (100-400 Hz) delivered within a brief period of time (minutes) results in maximal potentiation in hippocampal synapses. In contrast, the parameters most effective in neocortex were either low-frequency (2 Hz for 60 min) or high-frequency bursts (100 Hz, 100 ms train at 1/5 s for 10 min), both of which deliver at least an order of magnitude more afferent activation than that required for hippocampus. Hippocampal population spike potentiation averages 250% and the population excitatory postsynaptic potential (EPSP) potentiation averages 50%. Neocortical LTP also averages about 50%. The expression of LTP requires about 5 min in CA1 hippocampus, whereas about 30 min are required for expression of neocortical potentiation. Both hippocampus and visual neocortex display an enhanced potentiation early in development, with a later stabilization at lower adult levels. Centering at postnatal day 15, hippocampal CA1 displays an LTP magnitude that is over twice that seen at day 60. Neocortical responses display a similar peak at postnatal day 15 and a subsequent adult stabilization at approximately half of the day 15 maximum. Both tissues first display LTP during the early stages of synapse formation between postnatal days 6-10. The role of the NMDA receptor is implicated in aspects of both hippocampal and neocortical LTP.
Teyler T J
Journal of neuroscience methods
1989
1989-05
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/10.1016/0165-0270(89)90015-0" target="_blank" rel="noreferrer noopener">10.1016/0165-0270(89)90015-0</a>
Orphan receptors chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and retinoid X receptor (RXR) activate and bind the rat cholesterol 7alpha-hydroxylase gene (CYP7A).
Animals; Rats; *Gene Expression Regulation; Cholesterol 7-alpha-Hydroxylase/*genetics/metabolism; Nuclear Proteins/*metabolism; Chickens; Transcription Factors/*metabolism; DNA-Binding Proteins/*metabolism; Retinoid X Receptors; COUP Transcription Factor II; COUP Transcription Factors; Circadian Rhythm; COUP Transcription Factor I; Recombinant Proteins/genetics/metabolism; Receptors; Models; Genetic; Enzymologic; Molecular; Electrophoresis; Polyacrylamide Gel; Promoter Regions; *Receptors; Steroid; Glucocorticoid/*genetics; Retinoic Acid/*metabolism
The cholesterol 7alpha-hydroxylase gene (CYP7A) is transcriptionally regulated by a number of factors, including hormones, bile acids, and diurnal rhythm. Previous studies have identified a region from nucleotides (nt) -74 to -55 of the rat CYP7A promoter that enhanced bile acid repression of the SV40 early promoter, as assayed with a luciferase reporter gene in transiently transfected HepG2 cells. The rat CYP7A promoter/reporter activity was strongly stimulated by cotransfection with an expression plasmid encoding the nuclear hormone receptor chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) in a dose-dependent manner. Site-directed mutagenesis in the region of nt -74 to -55 altered this stimulation. Recombinant COUP-TFII expressed in HepG2 or COS-1 cells were found to bind to nt -74 -55 and nt -149 -128 probes by electrophoretic mobility shift assay (EMSA) and by supershifting the corresponding band with
Stroup D; Crestani M; Chiang J Y
The Journal of biological chemistry
1997
1997-04
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 comparative analysis of monoaminergic involvement in the spinal antinociceptive action of DAMPGO and DPDPE.
Male; Animals; Rats; Injections; Enkephalins/*pharmacology; Naloxone/pharmacology; Anesthetics/*pharmacology; Biogenic Monoamines/*physiology; Pain/*metabolism; Spinal Cord/drug effects/metabolism/*physiopathology; Dose-Response Relationship; Drug; Inbred Strains; Receptors; Enkephalin; Ala(2)-MePhe(4)-Gly(5)-; Spinal; 5)-; D-Penicillamine (2; Opioid/drug effects/*physiology; Enkephalins; Intraspinal; Amines – Physiology; Anesthetics – Pharmacodynamics; Cell Surface – Drug Effects; Cell Surface – Physiology; Enkephalins – Pharmacodynamics; Naloxone – Pharmacodynamics; Pain – Metabolism; Spinal Cord – Drug Effects; Spinal Cord – Metabolism; Spinal Cord – Physiopathology
The antinociceptive properties of intrathecally (i.t.) administered [D-Ala2,
Spanos L J; Stafinsky J L; Crisp T
Pain
1989
1989-12
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/10.1016/0304-3959(89)90046-8" target="_blank" rel="noreferrer noopener">10.1016/0304-3959(89)90046-8</a>
Acute and subchronic effects of methylenedioxymethamphetamine [(+/-)MDMA] on locomotion and serotonin syndrome behavior in the rat.
Male; Time Factors; Animals; Rats; Behavior; Motor Activity/*drug effects; Amphetamines/*pharmacology; Designer Drugs/*pharmacology; Dose-Response Relationship; Drug; Inbred Strains; Receptors; 3; Animal/*drug effects; N-Methyl-3; 4-methylenedioxyamphetamine; 4-Methylenedioxyamphetamine/analogs & derivatives/*pharmacology; Serotonin/*drug effects
Specific behaviors comprising the serotonin syndrome (low body posture, forepaw treading, headweaving) and the autonomic signs of piloerection and salivation were determined and analyzed with locomotor activity in response to MDMA at three doses (2.5, 5.0, and 7.5 mg/kg). All behaviors were dose-responsive. Serotonin syndrome behaviors increased in both intensity and duration of response with increasing doses. In contrast, locomotion varied only in intensity. Subchronic injections, in the same group of animals, permitted an analysis of acute vs. subchronic effects on these same behaviors. Both the serotonin syndrome and locomotor behaviors were augmented on subsequent testing, indicating that, (+/-)MDMA, like amphetamine, is capable of producing behavioral sensitization.
Spanos L J; Yamamoto B K
Pharmacology, biochemistry, and behavior
1989
1989-04
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/10.1016/0091-3057(89)90044-0" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(89)90044-0</a>
The role of dopamine and serotonin receptors in the mediation of the ethanol interoceptive cue.
Male; Animals; Rats; Ethanol/*pharmacology; Cues; Discrimination (Psychology)/*physiology; Dose-Response Relationship; Drug; Inbred Strains; Receptors; Conditioning; Serotonin/drug effects/*physiology; Dopamine/drug effects/*physiology; Operant/physiology
The drug discrimination paradigm was used to evaluate the contribution of dopamine or serotonin receptors in the mediation of the stimulus properties of ethanol. Briefly, rats were trained to discriminate between ethanol (600 mg/kg, IP) and water vehicle. Dose-response relationships were observed for ethanol and rats were tested with various dopamine and serotonin receptor agonists and antagonists. The specific dopamine receptor agonists SKF 38393 (DA1) and LY 171555 (DA2) failed to produce appreciable ethanol-like stimulus effects. Furthermore, the dopamine receptor antagonists SCH 23390 (DA1) and haloperidol (DA2) did not affect ethanol-appropriate responding when administered in combination with the training dose of ethanol. A number of specific serotonergic receptor ligands were also tested. Quipazine, 5-MeODMT, buspirone, 8-OH-DPAT elicited intermediate ethanol-like stimulus properties in rats. The serotonin receptor blockers pizotifen, pirenperone and (-)propranolol were ineffective in blocking the interoceptive cue produced by 600 mg/kg ethanol. However, TFMPP produced strong ethanol-like discriminative properties and completely substituted for the training dose of ethanol. These results indicate that the stimulus properties of TFMPP are similar to those of a low dose of ethanol.
Signs S A; Schechter M D
Pharmacology, biochemistry, and behavior
1988
1988-05
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/10.1016/0091-3057(88)90424-8" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(88)90424-8</a>
Use of TFMPP stimulus properties as a model of 5-HT1B receptor activation.
Male; Animals; Rats; Serotonin/pharmacology; Pharmaceutical Vehicles; Discrimination Learning/*drug effects; Norfenfluramine/pharmacology; Piperazines/*pharmacology; Dose-Response Relationship; Drug; Receptors; Biological; Models; Serotonin/*drug effects/physiology
Recent evidence indicates that when 1-(3-trifluoromethylphenyl)piperazine (TFMPP) is used as a training drug in the drug discrimination paradigm it produces a stimulus effect that is site-selective at the 5-HT1B receptor. The present study sought to employ this procedure in order to assess the similarity of novel agents to TFMPP. First, rats were trained to reliably discriminate between the stimulus properties of intraperitoneally administered 1.0 mg/kg TFMPP and its vehicle. Following the acquisition of this discrimination, administration of various doses of TFMPP produced a typical dose-response relationship with an ED50 of 0.27 mg/kg. Rats were subsequently tested with another 5-HT1B specific agonist
Schechter M D
Pharmacology, biochemistry, and behavior
1988
1988-09
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/10.1016/0091-3057(88)90310-3" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(88)90310-3</a>
Tetrahydro-beta-carboline may produce its stimulus effects via 5HT1B receptors.
Male; Animals; Rats; Serotonin/*metabolism; Piperazines/pharmacology; Discrimination Learning/drug effects; Serotonin Antagonists/pharmacology; Carbolines/*pharmacology; Metergoline/pharmacology; Inbred Strains; Receptors
To further clarify the role of 5-hydroxytryptamine (5HT) in the behavioral effects of tetrahydro-beta-carboline, male rats were trained to discriminate either 20 mg/kg THBC from its vehicle (n = 10) or 2.0 mg/kg fenfluramine from saline (n = 5). THBC was observed to produce fenfluramine-like effects in the fenfluramine-trained rats while fenfluramine produced THBC-like effects in the
Schechter M D
Pharmacology, biochemistry, and behavior
1987
1987-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Effect of learned behavior upon conditioned place preference to cathinone.
Male; Animals; Rats; Dopamine/physiology; Cues; Discrimination (Psychology)/drug effects; Discrimination Learning/drug effects; Thiazepines/pharmacology; Antipsychotic Agents/pharmacology; Alkaloids/*pharmacology; Learning/*physiology; Inbred Strains; Receptors; Conditioning; Operant/*drug effects; Dopamine/drug effects
The purpose of this study was to examine whether first training rats to discriminate the stimulus cues produced by an indirect dopamine agonist, cathinone, would influence a subsequent test of preference. The conditioned place preference (CPP) paradigm was used to evaluate the reinforcing effects of l-cathinone in four differently treated groups of rats. Half of the animals were trained to discriminate the interoceptive cues produced by 0.8 mg/kg cathinone in a two-lever, food-motivated operant task. The other animals were equally divided between two groups, one receiving saline and noncontingent reinforcements on the same schedule as those trained to discriminate cathinone; the other group, the "yoked-control" rats, received the same cathinone and saline regimen of administration as the discrimination-trained animals. Results of CPP testing indicate that cathinone produced a statistically significant conditioned place preference only in the group trained to discriminate cathinone and not in the saline or yoked control groups. Furthermore, when half of the cathinone discrimination-trained rats were pretreated with the dopamine release inhibitor CGS 10746B, the conditioned place preference to cathinone was attenuated. The results would indicate that pairing cathinone with a nonpreferred environment tended to make the rat spend more time in that environment and the amount of time spent in the cathinone-associated environment can be increased by prior discrimination training and decreased by diminished dopamine function in the brain.
Schechter M D
Pharmacology, biochemistry, and behavior
1991
1991-01
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/10.1016/0091-3057(91)90582-m" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(91)90582-m</a>
Discriminative stimulus effect of phenylephrine.
Male; Animals; Rats; Cues; Adrenergic alpha-Antagonists/pharmacology; Discrimination (Psychology)/*drug effects; Reinforcement Schedule; Phenylephrine/*pharmacology; Adrenergic alpha-Agonists/pharmacology; Dose-Response Relationship; Drug; Inbred Strains; Receptors; Generalization; Stimulus/drug effects; Adrenergic; alpha/drug effects
Rats were trained to discriminate phenylephrine in a two-lever, food-motivated operant task by increasing the i.p. administered training dose from 0.8 to 2 mg/kg. Stable discrimination to 2 mg/kg phenylephrine was established and testing of 0.5-2.5 mg/kg was shown to be dose-responsive and allowed for a calculated ED50 value of 0.87 mg/kg. Administration of methoxamine (0.5-6 mg/kg), another alpha 1-adrenoceptor agonist, produced a dose-responsive generalization, whereas only the lowest (0.04 mg/kg) and highest (0.12 mg/kg) doses of the alpha
Schechter M D
Archives internationales de pharmacodynamie et de therapie
1991
1991-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Estrogen receptor-alpha and -beta coexist in a subpopulation of sensory neurons of female rat dorsal root ganglia.
Female; Animals; Rats; Cell Count; *Sex Characteristics; Fluorescent Antibody Technique; Estrous Cycle/*physiology; Estrogen Receptor alpha; Cell Nucleus/metabolism/ultrastructure; Estrogen Receptor beta; Estrogens/*metabolism; Ganglia; Neurons; Sprague-Dawley; Receptors; Spinal/cytology/*metabolism; Genitalia; Estrogen/*metabolism; Afferent/cytology/*metabolism; Female/innervation
Immunoreactivities for estrogen receptor-alpha (ER-alpha) and ER-beta are expressed in sensory neurons of the dorsal root ganglia (DRG). It has not been established, however, if the two receptor subtypes coexist in the same neuron. Double-staining immunohistochemical techniques were used to determine if subpopulations of neurons in the lumbosacral DRG exist based on their content of ERs. Results indicate that some neurons (approximately 17%) of the L6-S1 DRG contain ER-alpha -, some (approximately 23%) contain ER-beta - immunoreactivity and some (approximately 5%) express immunoreactivity for both subtypes of the ER. These results suggest that many sensory neurons can respond to estrogens, but estrogens may produce different morphofunctional effects in different neurons based on their expression of ER subtypes.
Papka Raymond E; Storey-Workley Megan
Neuroscience letters
2002
2002-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Estrogen receptor-alpha and beta- immunoreactivity and mRNA in neurons of sensory and autonomic ganglia and spinal cord.
Female; Animals; Immunohistochemistry; Rats; Tissue Distribution; Ovariectomy; Spinal Cord/cytology/*metabolism; In Situ Hybridization; Estrogen Receptor alpha; Uterus/innervation; Estrogen Receptor beta; Calcitonin Gene-Related Peptide/metabolism; Neurons/cytology/*metabolism; Nodose Ganglion/cytology/metabolism; Ganglia; Sprague-Dawley; Receptors; RNA; Messenger/*metabolism; Autonomic/cytology/*metabolism; Drug/metabolism; Estrogen/*analysis/immunology; Sensory/cytology/*metabolism; Spinal/cytology/metabolism
Estrogen receptor-alpha immunoreactivity and mRNAs are present in neurons in locales that innervate genital organs, e.g., parasympathetic pelvic autonomic ganglia, sensory dorsal root and nodose ganglia, and autonomic areas of the lumbosacral spinal cord. With the availability of probes for the beta-isoform of the estrogen receptor, we studied this receptor in autonomic, sensory, and spinal cord neurons and compared it with the distribution of the alpha-receptor. Estrogen receptor-alpha and -beta immunoreactivity were located in the nuclei of neurons, were in subpopulations of parasympathetic neurons in pelvic ganglia, and sensory neurons of dorsal root and nodose ganglia. Both receptor subtypes were present in the lumbosacral spinal cord: in neurons of the outer laminae of the dorsal horn, lateral collateral and medial collateral pathways, sacral parasympathetic nucleus, dorsal intermediate gray, and lamina X. Similar numbers of spinal cord neurons were immunoreactive for estrogen receptor-beta and estrogen receptor-alpha. However, estrogen receptor-beta-immunoreactive neurons appeared less numerous in the outer dorsal horn, but more numerous in the deeper layers of the spinal cord than estrogen receptor-alpha neurons. Retrograde tracing from the uterus revealed "uterine-related" neurons in dorsal root and pelvic ganglia that contained estrogen receptor-alpha and -beta. In situ hybridization revealed both estrogen receptor-alpha and -beta mRNA transcripts in sensory neurons of the dorsal root and nodose ganglia, parasympathetic neurons of pelvic ganglia, and spinal cord neurons in the dorsal horn, sacral parasympathetic nucleus, and dorsal intermediate gray of L6-S1 segments. These studies show that both estrogen receptor-alpha and -beta are synthesized by autonomic and sensory neurons in parts of the nervous system that have connections with the female reproductive system. Such neurons contain neurotransmitters that have important functions in the female reproductive organs; thus, it is likely that estrogen can influence the activity of such neurons and consequently, through them, the activities of the reproductive organs.
Papka R E; Storey-Workley M; Shughrue P J; Merchenthaler I; Collins J J; Usip S; Saunders P T; Shupnik M
Cell and tissue research
2001
2001-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene.
Humans; Cell Line; Gene Expression Regulation/drug effects; Pregnane X Receptor; Cholesterol 7-alpha-Hydroxylase/*genetics; ATP-Binding Cassette Transporters/*genetics; Chenodeoxycholic Acid/antagonists & inhibitors; DNA-Binding Proteins/*antagonists & inhibitors/metabolism; Pregnenediones/*pharmacology; Transcription Factors/*antagonists & inhibitors/metabolism; Transcriptional Activation/drug effects; Dose-Response Relationship; Drug; Receptors; ATP Binding Cassette Transporter; Subfamily B; Cytoplasmic and Nuclear/*metabolism; Steroid/*metabolism; Member 11
Bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces bile salt export pump (BSEP) but inhibits cholesterol 7alpha-hydroxylase (CYP7A1) gene transcription in the liver. Guggulsterone, a plant sterol that lowers serum cholesterol, has been shown to antagonize FXR activated genes. Transient transfection assay of a human BSEP/luciferase reporter in HepG2 cells transfected with FXR reveals that guggulsterone strongly antagonizes bile acid induction of the BSEP gene. On the other hand, guggulsterone has no effect on FXR inhibition of the CYP7A1 gene, but strongly inhibits the human CYP7A1 gene by activation of pregnane X receptor (PXR). These results suggest that guggulsterone inhibits bile acid secretion from hepatocytes into bile and activates PXR to inhibit bile acid synthesis in the liver. Reduced conversion of cholesterol and bile acid excretion may lead to an increase of hepatic cholesterol and decrease of intestinal cholesterol absorption, and results in lowering serum cholesterol.
Owsley Erika; Chiang John Y L
Biochemical and biophysical research communications
2003
2003-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription.
Humans; Animals; Binding Sites; Protein Binding; Rats; Gene Expression Regulation; Species Specificity; Liver/metabolism; Transcriptional Activation; Hepatocyte Nuclear Factor 4; Response Elements; *DNA-Binding Proteins; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Retinoid X Receptors; Anticholesteremic Agents/pharmacology; Cholesterol 7-alpha-Hydroxylase/biosynthesis/*genetics; Clofibric Acid/pharmacology; Peroxisome Proliferators/pharmacology; Phosphoproteins/metabolism; Pyrimidines/pharmacology; Transcription Factors/*agonists/metabolism; Genes; Receptors; Models; Transcription; Genetic; Enzymologic; Reporter; Retinoic Acid/metabolism; Promoter Regions; Nucleic Acid; Cytoplasmic and Nuclear/*agonists; *Regulatory Sequences
Fibrates are widely used hypolipidemic drugs that regulate the expression of many genes involved in lipid metabolism by activating the peroxisome proliferator-activated receptor alpha (PPARalpha). The objective of this study was to investigate the mechanism of action of peroxisome proliferators and PPARalpha on the transcription of cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol to bile acids in the liver. When cotransfected with the expression vectors for PPARalpha and RXRalpha, Wy14,643 reduced human and rat cholesterol 7alpha-hydroxylase gene (CYP7A1)/luciferase reporter activities by 88% and 43%, respectively, in HepG2 cells, but not in CV-1 or CHO cells. We have mapped the peroxisome proliferator response element (PPRE) to a conserved sequence containing the canonical AGGTCA direct repeats separated by one nucleotide (DR1). This DR1 sequence was mapped previously as a binding site for the hepatocyte nuclear factor 4 (HNF-4) which stimulates CYP7A1 transcription. Electrophoretic mobility shift assay (EMSA) showed no direct binding of in vitro synthesized PPARalpha/RXRalpha heterodimer to the DR1 sequence. PPARalpha and Wy14,643 did not affect HNF-4 binding to the DR1. However, Wy14,643 and PPARalpha/RXRalpha significantly reduced HNF-4 expression in HepG2 cells. These results suggest that PPARalpha and agonist repress cholesterol 7alpha-hydroxylase activity by reducing the availability of
Marrapodi M; Chiang J Y
Journal of lipid research
2000
2000-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Incorporating the Oncotype DX breast cancer assay into community practice: an expert Q&A and case study sampling.
Adult; Female; Humans; Middle Aged; Genotype; Clinical Trials as Topic; *Gene Expression Profiling; *Breast Neoplasms/diagnosis/genetics/therapy; Breast Neoplasms/classification/*drug therapy/*genetics/surgery; Gene Expression Profiling/*methods; Polymerase Chain Reaction/methods; Tamoxifen/therapeutic use; Receptors; Antineoplastic Agents; Adjuvant; Chemotherapy; Adjuvant/methods; Estrogen/analysis; Hormonal/therapeutic use
Advances in breast cancer research have confirmed that this malignancy is not a single disease, but rather a collection of genetically distinct diseases with different treatment requirements. In recent years, several studies have confirmed the clinical validity of the Oncotype DX breast cancer assay, not only as a way to predict recurrence but also as a tool for determining therapeutic benefit from adjuvant chemotherapy. Recently, Drs. Terry Mamounas, G. Thomas Budd, and Kathy Miller answered questions about the Oncotype DX assay that are particularly relevant to routine clinical practice. This expert dialog provides a useful update and essential clinical insights about how, why, and when community oncologists may want to incorporate this multi-gene assay into their care of breast cancer patients. In addition, sample case studies offer tangible examples of the practical application of Oncotype DX.
Mamounas Eleftherios P; Budd G Thomas; Miller Kathy D
Clinical advances in hematology & oncology : H&O
2008
2008-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).