ACTH response in rats during biphasic fever induced by interleukin-1

1991 ◽  
Vol 261 (5) ◽  
pp. R1104-R1108 ◽  
Author(s):  
T. Watanabe ◽  
A. Morimoto ◽  
N. Murakami
Keyword(s):  
Adrenocorticotropic Hormone ◽  
Potent Inhibitor ◽  
Interleukin 1 ◽  
High Dose ◽  
Dependent Manner ◽  
Interleukin 1 Beta ◽  
Beta 2 ◽  
High Concentrations ◽  
Dose Dependent ◽  
The Brain

Injection of a low concentration (0.3 micrograms/kg iv) of interleukin-1 beta (IL-1 beta) produced monophasic fever, but high concentrations (15 micrograms/kg iv) produced biphasic fever in rats. Treatment with IL-1 beta caused dose-dependent rises in the plasma concentration of adrenocorticotropic hormone (ACTH) 30 min after injection. Moreover, significant increases in plasma levels of ACTH were observed 90 and 180 min after injection of the high dose of IL-1 beta. ACTH response induced by IL-1 beta (15 micrograms/kg iv) was suppressed by pretreatment with injection of indomethacin (Indo), a potent inhibitor of prostaglandin (PG) synthesis, in a dose-dependent manner (1 and 10 mg/kg iv). Also, biphasic fever induced by the high dose of IL-1 beta was completely abolished by pretreatment with the intravenous injection of Indo. Intracerebroventricular (icv) injection of Indo (50 micrograms) did not affect febrile and ACTH responses induced by intravenous IL-1 beta, whereas those responses induced by IL-1 beta (2 ng icv) were significantly suppressed by injection of Indo (50 micrograms icv). Although it is possible that intracerebroventricular Indo does not reach the site of intravenous IL-1 beta action within the brain, these results suggest that in rats febrile and ACTH responses induced by intravenous IL-1 beta are caused by IL-1 beta-acting structures outside the blood-brain barrier. It is likely that these structures subsequently synthesize and release PGE2, which in turn induces ACTH and febrile responses in rats.

Involvement of organum vasculosum of lamina terminalis and preoptic area in interleukin 1 beta-induced ACTH release

1990 ◽  
Vol 258 (1) ◽  
pp. E163-E171 ◽  
Author(s):  
G. Katsuura ◽  
A. Arimura ◽  
K. Koves ◽  
P. E. Gottschall
Keyword(s):  
Kainic Acid ◽  
Adrenocorticotropic Hormone ◽  
Preoptic Area ◽  
Interleukin 1 ◽  
Prostaglandin E ◽  
Lamina Terminalis ◽  
Interleukin 1 Beta ◽  
Plasma Acth ◽  
Organum Vasculosum ◽  
The Brain

Intravenous administration of recombinant human interleukin 1 beta (IL-1 beta, 1 micrograms/100 g body wt) resulted in a marked elevation of plasma adrenocorticotropic hormone (ACTH) levels, with peak levels at 10 min, in conscious unrestrained rats. One week after the placement of a lesion by radiofrequency or microinjection of kainic acid in the organum vasculosum of lamina terminalis (OVLT) but not in subfornical organ, ACTH response to intravenous IL-1 beta was enhanced, whereas both radiofrequency-induced lesion and kainic acid in the preoptic area (POA) suppressed the response. Indomethacin or a prostaglandin E (PGE) antagonist microinjected into the OVLT or POA suppressed or abolished the response. On the other hand, PGE, but not PGD2, microinjected into the POA increased plasma ACTH levels. These results suggest an important role for the OVLT, which lacks blood-brain barrier, as a possible site of entry of blood-borne IL-1 beta into the brain and for the POA, which may contain the neurons required for the response. Involvement of PGE in the OVLT and POA in the ACTH response to intravenous IL-1 beta is also suggested.

High-Dose Calcitriol Modulates the Expression and Activity of Tissue Factor and Thrombomodulin in Tumor Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 921-921
Author(s):  
Enriqueta Coll-Sangrona ◽  
Ali Amirkhosravi ◽  
Alshad S. Lalani ◽  
Liza Robles ◽  
Hina Desai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Endothelial Cells ◽  
Tumor Cells ◽  
High Dose ◽  
Dependent Manner ◽  
High Concentrations ◽  
Dose Dependent ◽  
A549 Lung

Abstract Calcitriol, the hormonally-active metabolite of Vitamin D3, plays critical roles in calcium homeostasis, cell growth and differentiation, and immunoregulation. The anti-tumor activities of high-dose calcitriol have been demonstrated in a variety of preclinical models of solid tumors, leukemias and lymphomas. Recently, a new dose-intense formulation of calcitriol, termed DN-101 (Asentar™), was developed specifically for cancer therapy which allows for supraphysiological concentrations of calcitriol to be safely delivered in vivo to patients with cancer. In a recent Phase 2 clinical trial, DN-101 significantly increased overall survival and also reduced the incidence of thromboembolic events in men with androgen-independent prostate cancer receiving docetaxel-based chemotherapy. Based on previous observations we hypothesized that calcitriol’s anti-thrombotic effects in vivo may be due to the downregulation of Tissue Factor (TF) antigen and activity and/or upregulation of Thrombomodulin (TM). To test this hypothesis, we incubated A549 lung carcinoma, A375-C15 metastatic melanoma, THP-1 monocytic leukemia, and Eahy926 endothelial cells with increasing concentrations of calcitriol for 24 hrs. For TF induction, tumor cells were stimulated with TNFα for 5 hrs and activity was measured by a clotting assay and a thrombin generation assay (TGA). TM activity was measured by a chromogenic assay. TF and TM surface antigen were assessed by flow cytometry. Calcitriol prevented the induction of TF in TNFα-stimulated THP-1 cells in a dose-dependent manner (from 33% at 1 nM to 94% at 100 nM) as evidenced by a prolongation of plasma clotting time, a decrease in endogenous thrombin potential (ETP), and a reduction of surface TF antigen. In addition, the activity and surface expression of TM on THP-1 cells was increased significantly (40% and 3-fold respectively, P < 0.01) following 100 nM calcitriol treatment. Similarly, in TNFα-stimulated melanoma cells, calcitriol prevented the induction of TF activity (from 26% at 1 nM to 60% at 1 μM) and expression in a dose-dependent manner. High-dose calcitriol treatment also increased melanoma cell TM activity between 8% and 62%. In contrast, constitutively expressed TF activity and antigen were less affected by calcitriol in A549 lung carcinoma cells (12 to 28% reduction at concentrations between 1–100 nM) whilst TM activity and antigen were unaffected. In comparison to the tumor cells, calcitriol had no significant effect on TM or TF activity or antigen in TNFα-stimulated EAhy926 endothelial cells. In conclusion, we have demonstrated that high concentrations of calcitriol inhibit the induction of surface TF expression and upregulates TM in multiple tumor cell lines in vitro. The degree of the inhibition is proportional to the extent of TF induction by TNF-α. These in vitro results provide further support for the anticoagulant properties associated with high concentrations of calcitriol and may provide a rationale for understanding the lower incidence of thromboembolic complications observed in patients with metastatic prostate cancer treated with DN-101.

Interaction between nitric oxide and prostaglandin E2 pathways in pregnant rat uteri

1996 ◽  
Vol 270 (3) ◽  
pp. E471-E476 ◽  
Author(s):  
Y. L. Dong ◽  
C. Yallampalli
Keyword(s):  
Nitric Oxide ◽  
Prostaglandin E2 ◽  
Interleukin 1 ◽  
Pge2 Production ◽  
Dependent Manner ◽  
Interleukin 1 Beta ◽  
Uterine Contractility ◽  
Pregnant Rat ◽  
Nitrite Production ◽  
Dose Dependent

We examined the possible interrelationship between nitric oxide (NO) and cyclooxygenase (COX) products in the uterus during pregnancy and labor. Results indicate that 1) rat uteri during labor, at term, demonstrated a 69% decrease in nitrite production and a 217% increase in prostaglandin E2 (PGE2) production compared with day 18 of pregnancy; 2) interleukin-1 beta (IL-1 beta) induced a pronounced elevation of both nitrites and PGE2 in rat uteri; 3) diethylenetriamine/NO, a donor of NO, induced a significant increase of PGE2 production by the uterus in a dose-dependent manner; 4) NG-nitro-L-arginine methyl ester, an inhibitor of NO synthesis, markedly inhibited IL-1 beta-induced nitrite and PGE2 in rat uteri; this inhibitory action was reversed by coincubation with L-arginine; 5)exogenous PGE2 significantly inhibited IL-1 beta-induced, but not constitutive, nitrite production; and 6) inhibition of endogenous PGE2 by indomethacin substantially increased IL-1 beta-induced nitrite production. Thus the interaction between NO and COX pathways might be important in the regulation of uterine contractility during pregnancy and labor.

Interleukin-8 induces fever by a prostaglandin-independent mechanism

1994 ◽  
Vol 266 (5) ◽  
pp. R1670-R1674 ◽  
Author(s):  
A. R. Zampronio ◽  
G. E. Souza ◽  
C. A. Silva ◽  
F. Q. Cunha ◽  
S. H. Ferreira
Keyword(s):  
Body Temperature ◽  
Interleukin 1 ◽  
Interleukin 8 ◽  
Cyclooxygenase Inhibitors ◽  
Interleukin 1 Beta ◽  
Independent Mechanism ◽  
Intracerebroventricular Injections ◽  
Beta 2 ◽  
Dose Dependent ◽  
Pyrogenic Activity

We have studied the mechanism by which interleukin-8 (IL-8) induces fever in rats. Intracerebroventricular injections of IL-8 (5.5-50 ng) evoked dose-dependent increases in body temperature, which reached a plateau 5 h after injection, i.e., later than intracerebroventricular interleukin-1 beta (IL-1 beta; 2 h). The pyrogenic activity of IL-8 was not due to contamination with lipopolysaccharide (LPS) because preincubation of IL-8 with a specific antibody or boiling the IL-8 for 30 min abolished its activity but not that of LPS; also, IL-8 but not LPS induced fever in LPS-tolerant rats. Indomethacin significantly reduced the pyrogenic effects of intracerebroventricular injections of LPS and IL-1 beta but not responses to IL-8, suggesting that pyrogenic responses to IL-8 were mediated independently of prostaglandins. In contrast, dexamethasone markedly attenuated pyrogenic responses to IL-8 and IL-1 beta. These data suggest that inhibition of IL-8 by glucocorticoids contributes to the antipyretic effects of these drugs in fevers resistant to cyclooxygenase inhibitors.

Effect of interleukin-1 beta converting enzyme inhibitor on acute myelogenous leukemia progenitor proliferation

Blood ◽  
1995 ◽  
Vol 86 (12) ◽  
pp. 4594-4602 ◽  
Author(s):  
Z Estrov ◽  
RA Black ◽  
PR Sleath ◽  
D Harris ◽  
Q Van ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Interleukin 1 ◽  
Active Form ◽  
Biologically Active ◽  
Myelogenous Leukemia ◽  
Dependent Manner ◽  
Interleukin 1 Beta ◽  
Converting Enzyme ◽  
Acute Myelogenous ◽  
Dose Dependent

Interleukin-1 beta (IL-1 beta) converting enzyme (ICE) is a cysteine protease that specifically cleaves precursor IL-1 beta to its biologically active form. Recent studies have also implicated ICE in the induction of apoptosis in vertebrate cells. Because IL-1 plays a major role in acute myelogenous leukemia (AML) blast proliferation, we sought to investigate the effect of ICE inhibition on AML progenitors. To do this, we used bocaspartyl (benzyl) chloromethylketone (BACMK) an inhibitor designed to penetrate cells and bind covalently to the active site of ICE. Our preliminary experiments showed that incubation of activated peripheral blood cells with 2.5 mumol/L of BAMCK downregulated production of mature IL-1 beta but had no effect on tumor necrosis factor-alpha. To test the effects of the inhibitor on AML cells, we first used the OCI/AML3 cell line. We found that these cells produce IL-1 beta and bind the biotinylated cytokine and that IL-1 inhibitors, such as IL-1 neutralizing antibodies, IL-1 receptor antagonist, and soluble IL-1 receptors, specifically inhibit OCI/AML3 proliferation, indicating that IL-1 beta is an autocrine growth factor for OCI/AML3 cells. The ICE inhibitor suppressed OCI/AML3 growth in a dose-dependent manner (at 0.4 to 4 mumol/L) and downregulated mature IL- 1 beta production, as assessed by Western immunoblotting. Similar results were obtained with marrow aspirates from 16 AML patients. The ICE inhibitor suppressed proliferation of AML precursors (by up to 78%; mean, 44%) in a dose-dependent fashion at concentrations ranging from 0.4 to 5 mumol/L but not proliferation of normal marrow progenitors; the suppressive effect was reversed by IL-1 beta. Furthermore, incubation of AML cells with 4 mumol/L BAMCK downregulated the production of mature IL-1 beta, suggesting that the growth-inhibitory effect is mediated through suppression of the biologically active cytokine. Our data indicate that inhibition of ICE suppresses AML blast proliferation and suggest that ICE inhibitors may have a role in future therapies for AML.

scholarly journals Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats

2010 ◽  
Vol 60 (2) ◽  
pp. 129-140 ◽  
Author(s):  
Farhat Batool ◽  
Ambreen Hasnat ◽  
Muhammad Haleem ◽  
Darakhshan Haleem
Keyword(s):  
Dopamine Metabolism ◽  
High Dose ◽  
Dependent Manner ◽  
Saline Administration ◽  
Hydroxyindoleacetic Acid ◽  
High Doses ◽  
Home Cage Activity ◽  
Dose Dependent ◽  
The Brain

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.

scholarly journals High-dose Glycerol Monolaurate Up-Regulated Beneficial Indigenous Microbiota without Inducing Metabolic Dysfunction and Systemic Inflammation: New Insights into Its Antimicrobial Potential

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1981 ◽  
Author(s):  
Qiufen Mo ◽  
Aikun Fu ◽  
Lingli Deng ◽  
Minjie Zhao ◽  
Yang Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Systemic Inflammation ◽  
Body Weight Gain ◽  
High Dose ◽  
Dependent Manner ◽  
Glucose And Lipid Metabolism ◽  
Glycerol Monolaurate ◽  
Indigenous Microbiota ◽  
Anti Inflammatory ◽  
Dose Dependent

Glycerol monolaurate (GML) has potent antimicrobial and anti-inflammatory activities. The present study aimed to assess the dose-dependent antimicrobial-effects of GML on the gut microbiota, glucose and lipid metabolism and inflammatory response in C57BL/6 mice. Mice were fed on diets supplemented with GML at dose of 400, 800 and 1600 mg kg−1 for 4 months, respectively. Results showed that supplementation of GML, regardless of the dosages, induced modest body weight gain without affecting epididymal/brown fat pad, lipid profiles and glycemic markers. A high dose of GML (1600 mg kg−1) showed positive impacts on the anti-inflammatory TGF-β1 and IL-22. GML modulated the indigenous microbiota in a dose-dependent manner. It was found that 400 and 800 mg kg−1 GML improved the richness of Barnesiella, whereas a high dosage of GML (1600 mg kg−1) significantly increased the relative abundances of Clostridium XIVa, Oscillibacter and Parasutterella. The present work indicated that GML could upregulate the favorable microbial taxa without inducing systemic inflammation and dysfunction of glucose and lipid metabolism.

Serotonin elicits long-lasting enhancement of rhythmic respiratory activity in turtle brain stems in vitro

2001 ◽  
Vol 91 (6) ◽  
pp. 2703-2712 ◽  
Author(s):  
Stephen M. Johnson ◽  
Julia E. R. Wilkerson ◽  
Daniel R. Henderson ◽  
Michael R. Wenninger ◽  
Gordon S. Mitchell
Keyword(s):  
Brain Stem ◽  
Respiratory Activity ◽  
Dependent Manner ◽  
Frequency Increase ◽  
Burst Frequency ◽  
Bath Application ◽  
Burst Amplitude ◽  
Dose Dependent ◽  
The Brain

Brain stem preparations from adult turtles were used to determine how bath-applied serotonin (5-HT) alters respiration-related hypoglossal activity in a mature vertebrate. 5-HT (5–20 μM) reversibly decreased integrated burst amplitude by ∼45% ( P < 0.05); burst frequency decreased in a dose-dependent manner with 20 μM abolishing bursts in 9 of 13 preparations ( P < 0.05). These 5-HT-dependent effects were mimicked by application of a 5-HT1A agonist, but not a 5-HT1B agonist, and were abolished by the broad-spectrum 5-HT antagonist, methiothepin. During 5-HT (20 μM) washout, frequency rebounded to levels above the original baseline for 40 min ( P < 0.05) and remained above baseline for 2 h. A 5-HT3 antagonist (tropesitron) blocked the post-5-HT rebound and persistent frequency increase. A 5-HT3 agonist (phenylbiguanide) increased frequency during and after bath application ( P < 0.05). When phenylbiguanide was applied to the brain stem of brain stem/spinal cord preparations, there was a persistent frequency increase ( P < 0.05), but neither spinal-expiratory nor -inspiratory burst amplitude were altered. The 5-HT3receptor-dependent persistent frequency increase represents a unique model of plasticity in vertebrate rhythm generation.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

scholarly journals Genistein reduced the neural apoptosis in the brain of ovariectomised rats by modulating mitochondrial oxidative stress

2010 ◽  
Vol 104 (9) ◽  
pp. 1297-1303 ◽  
Author(s):  
Yan-Hong Huang ◽  
Qing-Hong Zhang
Keyword(s):  
Oxidative Stress ◽  
Learning And Memory ◽  
Caspase 3 ◽  
Visual Learning ◽  
Morris Water Maze Test ◽  
High Dose ◽  
Dependent Manner ◽  
Ovx Rats ◽  
Neural Apoptosis ◽  
The Brain

The present study was undertaken to investigate the antioxidant effect of chronic ingestion of genistein (Gen) against neural death in the brain of ovariectomised (Ovx) rats. The rats were randomly divided into five groups, i.e. sham-operated (sham), Ovx-only, Ovx with 17β-oestradiol, Ovx with low (15 mg/kg) and high (30 mg/kg) doses of Gen (Gen-L and Gen-H), and were orally administered daily with drugs or vehicle for 6 weeks. The learning and memory abilities were measured by Morris water maze test. Oxidative damages in the brain were evaluated by the level of superoxide dismutase (SOD), malondialdehyde (MDA) and monoamine oxidase (MAO) activities. Neural apoptosis was shown by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining and caspase-3 activity. In the visual learning and memory test, there were no significant differences among the population means of the five groups. While in the probe trial test, the Gen-L group instead of the Gen-H group exhibited reduced escape latency and increased memory frequency than the Ovx group. Although both doses of Gen could reduce acetylcholinesterase activity, only a low dose of Gen could diminish MDA activity significantly in frontal cortex and enhance SOD content in the hippocampus. In contrast, MAO content was decreased in the cortex by either dose of Gen, while in the hippocampus, only a high dose of Gen appeared to be effective. Interestingly, Gen at both the doses could attenuate the increased number of TUNEL-positive neurons and caspase-3 activity in Ovx rats. These results suggest that Gen confers protection against Ovx-induced neurodegeneration by attenuating oxidative stress, lipid peroxidation and the mitochondria-mediated apoptotic pathway in a region- and dose-dependent manner.

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