scholarly journals Seasonal effects of central leptin infusion on secretion of melatonin and prolactin and on SOCS-3 gene expression in ewes

2008 ◽  
Vol 198 (1) ◽  
pp. 147-155 ◽  
Author(s):  
D A Zieba ◽  
M Szczesna ◽  
B Klocek-Gorka ◽  
E Molik ◽  
T Misztal ◽  
...  
Keyword(s):  
Third Ventricle ◽  
Plasma Concentrations ◽  
Seasonal Effects ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Suppressor Of Cytokine Signaling ◽  
Medial Basal Hypothalamus ◽  
Leptin Sensitivity ◽  
Dose Dependent ◽  
Short Days

Recent studies have demonstrated photoperiodic changes in leptin sensitivity of seasonal mammals. Herein, we examined the interaction of season (long days (LD) versus short days (SD)) and recombinant ovine leptin (roleptin) on secretion of melatonin and prolactin (PRL) and on mRNA expression of suppressor of cytokine signaling-3 (SOCS-3) in the medial basal hypothalamus (MBH) in sheep. Twenty-four Polish Longwool ewes, surgically fitted with third ventricle (IIIV) cannulas, were utilized in a replicated switchback design involving 12 ewes per season. Within-season and replicate ewes were assigned randomly to one of three treatments (four ewes/treatment) and infused centrally three times at 0, 1 and 2 h beginning at sunset. Treatments were 1) control, Ringer–Locke buffer; 2) L1, roleptin, 0.5 μg/kg BW; and 3) L2, roleptin, 1.0 μg/kg BW. Jugular blood samples were collected at 15-min intervals beginning immediately before the start of infusions and continued for 6 h. At the end of blood sampling, a washout period of at least 3 days elapsed before ewes were re-randomized and treated with one of the treatments described above (four ewes/treatment). Ewes were then killed and brains were collected for MBH processing. Leptin treatments increased (P<0.001) circulating leptin concentrations compared with controls during both seasons in a dose-dependent manner. Overall, mean plasma concentrations of melatonin were greater (P<0.001) during LD than SD. However, leptin treatments increased melatonin concentrations during SD in a dose-dependent manner and decreased it during LD. Similarly, plasma concentrations of PRL were greater (P<0.001) during LD than SD. However, unlike changes in melatonin, circulating PRL decreased (P<0.001) in response to leptin during LD. Semi-quantitative PCR revealed that leptin increased (P<0.001) SOCS-3 expression in the MBH region during LD in a dose-dependent manner. Data provide evidence that secretion of photoperiodic hormones such as melatonin and PRL are inversely regulated by leptin during SD and LD. However, the increase in expression of SOCS-3 in the MBH during LD compared with SD fails to fully explain these effects.

scholarly journals Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells

2006 ◽  
Vol 4 (2) ◽  
pp. 123-132 ◽  
Author(s):  
Paul Kievit ◽  
Jane K. Howard ◽  
Michael K. Badman ◽  
Nina Balthasar ◽  
Roberto Coppari ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Leptin Sensitivity

Voluntary running of defined distances reduces body adiposity and its associated inflammation in C57BL/6 mice fed a high-fat diet

2017 ◽  
Vol 42 (11) ◽  
pp. 1179-1184 ◽  
Author(s):  
Lin Yan ◽  
Sneha Sundaram ◽  
Forrest H. Nielsen
Keyword(s):  
High Fat Diet ◽  
Plasma Concentrations ◽  
Standard Diet ◽  
Dependent Manner ◽  
High Fat ◽  
Body Adiposity ◽  
Chemotactic Protein ◽  
Voluntary Running ◽  
Significant Difference ◽  
Dose Dependent

This study investigated the effect of voluntary running of defined distances on body adiposity in male C57BL/6 mice fed a high-fat diet. Mice were assigned to 6 groups and fed a standard AIN93G diet (sedentary) or a modified high-fat AIN93G diet (sedentary; unrestricted running; or 75%, 50%, or 25% of unrestricted running) for 12 weeks. The average running distance was 8.3, 6.3, 4.2, and 2.1 km/day for the unrestricted, 75%, 50%, and 25% of unrestricted runners, respectively. Body adiposity was 46% higher in sedentary mice when fed the high-fat diet instead of the standard diet. Running decreased adiposity in mice fed the high-fat diet in a dose-dependent manner but with no significant difference between sedentary mice and those running 2.1 km/day. In sedentary mice, the high-fat instead of the standard diet increased insulin resistance, hepatic triacylglycerides, and adipose and plasma concentrations of leptin and monocyte chemotactic protein-1 (MCP-1). Running reduced these variables in a dose-dependent manner. Adipose adiponectin was lowest in sedentary mice fed the high-fat diet; running raised adiponectin in both adipose tissue and plasma. Running 8.3 and 6.3 km/day had the greatest, but similar, effects on the aforementioned variables. Running 2.1 km/day did not affect these variables except, when compared with sedentariness, it significantly decreased MCP-1. The findings showed that running 6.3 kg/day was optimal for reducing adiposity and associated inflammation that was increased in mice by feeding a high-fat diet. The findings suggest that voluntary running of defined distances may counteract the obesogenic effects of a high-fat diet.

Reversal of Dabigatran's Anticoagulant Activity in the Monkey by a Specific Antidote and Pharmacokinetic and Pharmacodynamic Modeling

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 22-22 ◽  
Author(s):  
Joshuaine Toth ◽  
Guanfa Gan ◽  
Joanne van Ryn ◽  
Holly Dursema ◽  
Jennifer Isler ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Anticoagulant Activity ◽  
Plasma Concentrations ◽  
Mass Action ◽  
Pharmacodynamic Modeling ◽  
Dependent Manner ◽  
Thrombin Time ◽  
Binding Interaction ◽  
Mass Action Kinetics ◽  
Dose Dependent

Abstract Abstract 22 Background: The objective of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran (a small molecule thrombin inhibitor) and its antidote (a humanized Fab against dabigatran) in the monkey and to develop a combined mechanistic mathematical model to describe the data. Methods: There were three groups: control, antidote alone and dabigatran etexilate (DE) + antidote. Rhesus monkeys (n = 2/group) received either 12 mg/kg/day of DE or vehicle orally on Days 1–4, 15–18 and 29–32 with a single IV dose of the antidote administered 90 minutes after DE on Days 4, 18 and 32. Doses of the antidote were 30, 90 or 175 mg/kg, respectively. PK parameters of the antidote and sum dabigatran (dabigatran plus its glucuronides) were determined after measurements of plasma concentrations. Coagulation activity was measured using a diluted thrombin time assay to determine the activity of the unbound sum dabigatran. Results: The PK of the antidote were not affected by dabigatran. Clearance of the antidote was low (0.87 mL/min/kg) and steady-state volume of distribution was small (0.06 L/kg), indicating that the antidote was mostly restricted to plasma. The plasma profile of the antidote was bi-phasic with a short initial phase t1/2 of 0.4 hour (h) and a terminal phase t1/2 of 4.3 h. Immediately after antidote dosing, plasma concentrations of sum dabigatran increased, a consequence of the rapid redistribution of dabigatran and its glucuronides from tissue to plasma due to binding to the antidote. Complete reversal of dabigatran's anticoagulant activity was observed immediately after antidote dosing at all three dose levels, as measured by the diluted thrombin time assay, which indicates that all dabigatran was bound to the antidote. The degree to which this reversal effect was maintained over an extended period (24 h) was dose-dependent. A mechanistic ordinary differential equation model, based on the mass action kinetics for describing the distribution, binding and elimination of dabigatran and its antidote, was developed by combining the PK models for dabigatran and the antidote and adding the binding interaction (1:1 stoichiometry) between the two compounds. The distribution and elimination parameters of the dabigatran-antidote complex were assumed to be the same as those of the antidote, based on similar measured PK parameters of the antidote with and without dabigatran in the monkey. The combined PK/PD model of dabigatran and antidote was able to describe the in vivo PK/PD data observed in monkeys. Conclusion: The dabigatran-specific antidote successfully reversed the anticoagulant activity of dabigatran in the monkey in a dose-dependent manner, and our combined mathematical model accurately describes monkey PK/PD data of sum dabigatran and its antidote. Insights gained from this model will be used to guide model development for clinical trials. Disclosures: Toth: Boehringer Ingelheim: Employment. Gan:Boehringer Ingelheim: Employment. van Ryn:Boehringer Ingelheim: Employment. Dursema:Boehringer Ingelheim: Employment. Isler:Boehringer Ingelheim: Employment. Coble:Boehringer Ingelheim: Employment. Burke:Boehringer Ingelheim: Employment. Lalovic:Boehringer Ingelheim: Employment. Olson:Boehringer Ingelheim: Employment.

scholarly journals Platelet-activating Factor Mediates Endotoxin Tolerance by Regulating Indoleamine 2,3-Dioxygenase-dependent Expression of the Suppressor of Cytokine Signaling 3

2017 ◽  
Vol 292 (8) ◽  
pp. 3290-3298 ◽  
Author(s):  
Kyung Tae Noh ◽  
In Duk Jung ◽  
Gil Sun Cha ◽  
Myung-Kwan Han ◽  
Yeong-Min Park
Keyword(s):  
Endothelial Cells ◽  
Endotoxic Shock ◽  
Platelet Activating Factor ◽  
Neutrophil Infiltration ◽  
Endotoxin Tolerance ◽  
Organ Injury ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Suppressor Of Cytokine Signaling ◽  
Indoleamine 2,3 Dioxygenase

Indoleamine 2,3-dioxygenase (IDO) mediates immune tolerance, and suppressor of cytokine signaling 3 (SOCS3) negatively regulates the JAK/STAT signal transduction pathway. We determined previously that platelet-activating factor (PAF) protects mice against LPS-induced endotoxic shock, but its detailed mechanism of action was unknown. We performed survival experiments in IDO+/+ and IDO−/− mice using an LPS-induced endotoxemia model and rated organ injury (neutrophil infiltration and liver function). Using ELISA and Western blotting, we also investigated the mechanism of PAF-mediated endotoxin tolerance during endotoxemia. PAF-mediated endotoxin tolerance was dependent on IDO in vivo and in vitro and was not observed in IDO−/− mice. JAK/STAT signaling, crucial for SOCS3 expression, was also impaired in the absence of IDO. In an IDO- and STAT-dependent manner, PAF mediated a decrease in IL-12 and a dramatic increase in IL-10 and reduced mouse mortality. In addition, PAF attenuated LPS-mediated neutrophil infiltration into the lungs and interactions between neutrophil-like (THP-1) and endothelial cells (human umbilical vein endothelial cells). These results indicate that PAF-mediated endotoxin tolerance is initiated via IDO- and JAK/STAT-dependent expression of SOCS3. Our study has revealed a novel tolerogenic mechanism of IDO action and an important association between IDO and SOCS3 with respect to endotoxin tolerance.

scholarly journals Suppressor of Cytokine Signaling 3 Suppresses Hepatitis C Virus Replication in an mTOR-Dependent Manner

2010 ◽  
Vol 84 (12) ◽  
pp. 6060-6069 ◽  
Author(s):  
Run-Xuan Shao ◽  
Leiliang Zhang ◽  
Lee F. Peng ◽  
Eileen Sun ◽  
Woo Jin Chung ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Full Length ◽  
Cytokine Signaling ◽  
Type I ◽  
Dependent Manner ◽  
Suppressor Of Cytokine Signaling ◽  
Protein Levels ◽  
Infected Cells ◽  
Ifn Treatment

ABSTRACT We and others have observed that hepatic levels of suppressor of cytokine signaling 3 (SOCS3) are significantly higher in persons with chronic hepatitis C, particularly those who are nonresponders to interferon (IFN) treatment, than in healthy individuals. However, the relationship between SOCS3 and hepatitis C virus (HCV) replication remains unclear. Given its putative role, we hypothesized that SOCS3 is permissive for viral replication. We therefore used the OR6 cell line, which harbors a genotype 1b full-length HCV replicon, and the genotype 2a full-length HCV strain JFH1 infection system to analyze the effects of SOCS3 overexpression and short hairpin RNA (shRNA)-mediated knockdown on HCV replication. We further analyzed the role of mTOR in the effects of SOCS3 by treating selected cells with rapamycin. OR6 cells and JFH1-infected Huh7.5.1 cells expressed significantly less SOCS3 than control cells. Furthermore, inhibition of HCV replication with the HCV protease inhibitor BILN 2061 restored SOCS3 protein levels. SOCS3 overexpression in OR6 cells and JFH1-infected Huh7.5.1 cells resulted in significantly lower HCV replication than that in the control cells, despite SOCS3-related inhibition of STAT1 phosphorylation and type I IFN signaling. In contrast, JFH1-infected cells with stable SOCS3 knockdown expressed higher levels of HCV proteins and RNA than did control cells. SOCS3-targeting shRNA also knocked down mTOR and phospho-mTOR. The mTOR inhibitor rapamycin reversed the inhibitory effects of SOCS3. In independent investigations, SOCS3 unexpectedly suppressed HCV replication in an mTOR-dependent manner. These findings suggest that increased SOCS3 levels consistently observed in chronic IFN nonresponders may reflect a compensatory host antiviral response to persistent infection and that manipulation of SOCS3/mTOR may offer benefit against HCV infection.

Probucol Slows the Progression of Cataracts in Streptozotocin-Induced Hyperglycemic Rats

Pharmacology ◽  
2019 ◽  
Vol 103 (3-4) ◽  
pp. 212-219 ◽  
Author(s):  
Kentaro Higashi ◽  
Asami Mori ◽  
Kenji Sakamoto ◽  
Kunio Ishii ◽  
Tsutomu Nakahara
Keyword(s):  
Horizontal Plane ◽  
Plasma Concentrations ◽  
Antioxidant Properties ◽  
Digital Camera ◽  
Lipid Lowering ◽  
Protein Carbonyls ◽  
Dependent Manner ◽  
Cataract Formation ◽  
Camera System ◽  
Dose Dependent

We examined the effect of probucol, an antihyperlipidemic drug with potent antioxidant properties, on cataract formation in streptozotocin (STZ)-induced hyperglycemic rats that were given 5% D-glucose as drinking water. Probucol treatment was initiated immediately after the induction of hyperglycemia was confirmed. Using full horizontal-plane lens images captured with an original digital camera system, the opacity of central region of lens was assessed by measuring the opaque area in the region. Central opacities were detected after 3 weeks of hyperglycemia, and progressed in a time-dependent manner. The majority of STZ-induced hyperglycemic rats developed severe cataracts after 9 weeks of hyperglycemia. Probucol slowed the progression of cataracts in a dose-dependent manner. Levels of sorbitol and protein carbonyls in lenses of STZ-induced hyperglycemic rats were higher than those of control rats. Probucol suppressed the increase in protein carbonyls, but not of sorbitol, in lenses of STZ-induced hyperglycemic rats. Probucol had no significant effect on increases in plasma concentrations of glucose, total cholesterol, and triglyceride observed in STZ-induced hyperglycemic rats. These results suggest that probucol slows the progression of sugar cataracts, independent of its lipid-lowering effects. The beneficial effect of probucol on cataracts is partially attributable to the attenuation of oxidative damage to lens proteins.

Epinephrine sensitivity with respect to metabolic rate and other variables in women

1983 ◽  
Vol 245 (5) ◽  
pp. E431-E442 ◽  
Author(s):  
L. Sjostrom ◽  
Y. Schutz ◽  
F. Gudinchet ◽  
L. Hegnell ◽  
P. G. Pittet ◽  
...  
Keyword(s):  
Metabolic Rate ◽  
Metabolic Response ◽  
Plasma Concentrations ◽  
Fat Free Mass ◽  
Metabolic Clearance ◽  
Dependent Manner ◽  
Epinephrine Infusion ◽  
Glucose Plasma ◽  
Dose Dependent

A test for determination of epinephrine sensitivity has been worked out using six healthy young women. Variables considered were metabolic rate, heart rate, respiratory frequency, blood pressure, blood glucose, plasma insulin, glycerol, free fatty acids, and lactate. After established basal conditions, epinephrine was infused at rates of 0.01, 0.03, and 0.1 microgram X kg fat-free mass-1 X min-1. Most variables responded to epinephrine in a dose-dependent manner. Physiological threshold plasma concentrations of epinephrine ranged from 95 to 250 pg/ml for different variables. Calculated maximal responses ranged from approximately -15% to +900% of basal values and infusion rates giving half-maximal responses from approximately 15 to 190 ng X kg fat-free mass-1 X min-1. On an average, metabolic rate increased by 8, 16, and 29%, respectively, at the three infusion rates, and the maximal metabolic response was calculated to be approximately 35%. The error in determining epinephrine-induced increments in metabolic rate was 7% of the response. As calculated from nonprotein RQ, carbohydrate oxidation increased and lipid oxidation decreased rapidly during the first 10 min of epinephrine infusion. Later, fat oxidation became more important. Results on epinephrine plasma metabolic clearance rate agreed with earlier results in the literature.

scholarly journals Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling

2011 ◽  
Vol 300 (5) ◽  
pp. R1185-R1193 ◽  
Author(s):  
Anantha S. Metlakunta ◽  
Maitrayee Sahu ◽  
Hideo Yasukawa ◽  
Sandeep S. Dhillon ◽  
Denise D. Belsham ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Pi3k Pathway ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Suppressor Of Cytokine Signaling ◽  
Leptin Sensitivity ◽  
Pi3k Activity ◽  
Central Leptin Resistance ◽  
Phosphatidylinositol 3

Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30–120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity.

scholarly journals Cannabinoid-induced autophagy regulates suppressor of cytokine signaling-3 in intestinal epithelium

2014 ◽  
Vol 307 (2) ◽  
pp. G140-G148 ◽  
Author(s):  
Luan C. Koay ◽  
Rachael J. Rigby ◽  
Karen L. Wright
Keyword(s):  
Protein Expression ◽  
Intestinal Epithelium ◽  
Intestinal Inflammation ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Suppressor Of Cytokine Signaling ◽  
Cannabinoid Type 1 Receptor ◽  
The Impact ◽  
Socs3 Protein

Autophagy is a catabolic process involved in homeostatic and regulated cellular protein recycling and degradation via the lysosomal degradation pathway. Emerging data associate impaired autophagy, increased activity in the endocannabinoid system, and upregulation of suppressor of cytokine signaling-3 (SOCS3) protein expression during intestinal inflammation. We have investigated whether these three processes are linked. By assessing the impact of the phytocannabinoid cannabidiol (CBD), the synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA), and the endocannabinoid N-arachidonoylethanolamine (AEA) on autophagosome formation, we explored whether these actions were responsible for cyclic SOCS3 protein levels. Our findings show that all three cannabinoids induce autophagy in a dose-dependent manner in fully differentiated Caco-2 cells, a model of mature intestinal epithelium. ACEA and AEA induced canonical autophagy, which was cannabinoid type 1 receptor-mediated. In contrast, CBD was able to bypass the cannabinoid type 1 receptor and the canonical pathway to induce autophagy, albeit to a lesser extent. Functionally, all three cannabinoids reduced SOCS3 protein expression, which was reversed by blocking early and late autophagy. In conclusion, the regulatory protein SOCS3 is regulated by autophagy, and cannabinoids play a role in this process, which could be important when therapeutic applications for the cannabinoids in inflammatory conditions are considered.

Edrophonium Increases Mivacurium Concentrations during Constant Mivacurium Infusion, and Large Doses Minimally Antagonize Paralysis

1995 ◽  
Vol 82 (4) ◽  
pp. 912-918. ◽  
Author(s):  
Paul S. Hart ◽  
Peter M. C. Wright ◽  
Ronald Brown ◽  
Marie Lau ◽  
Manohar L. Sharma ◽  
...  
Keyword(s):  
Cholinesterase Activity ◽  
Plasma Concentrations ◽  
Plasma Cholinesterase ◽  
Constant Infusion ◽  
Dependent Manner ◽  
Plasma Cholinesterase Activity ◽  
Limited Efficacy ◽  
Before And After ◽  
Dose Dependent ◽  
Nondepolarizing Muscle Relaxant

Background Mivacurium, a nondepolarizing muscle relaxant, is metabolized by plasma cholinesterase. Although edrophonium does not alter plasma cholinesterase activity, we have observed that doses of edrophonium that antagonize paralysis from other nondepolarizing muscle relaxants are less effective with mivacurium. We speculated that edrophonium might after metabolism of mivacurium, thereby hindering antagonism of paralysis. Accordingly, we determined the effect of edrophonium on neuromuscular function and plasma mivacurium concentrations during constant mivacurium infusion. Methods We infused mivacurium to maintain 90% depression of adductor pollicis twitch tension and then gave edrophonium in doses ranging from 125-2,000 micrograms/kg without altering the mivacurium infusion. Peak twitch tension after edrophonium was determined to estimate the dose of edrophonium antagonizing 50% of twitch depression for antagonism of mivacurium; plasma cholinesterase activity and mivacurium concentrations before and after edrophonium were measured. Additional subjects were given 500 micrograms/kg edrophonium to antagonize continuous infusions of d-tubocurarine and vecuronium. Results With mivacurium, edrophonium increased twitch tension in a dose-dependent manner: the dose of edrophonium antagonizing 50% of twitch depression was 2,810 micrograms/kg. The largest dose of edrophonium (2,000 micrograms/kg) produced only 45 +/- 7% antagonism. Edrophonium, 500 micrograms/kg, antagonized mivacurium markedly less than it antagonized d-tubocurarine and vecuronium. Edrophonium increased plasma concentrations of the two potent stereoisomers of mivacurium 48% and 79%, these peaking at 1-2 min; plasma cholinesterase activity was unchanged. Conclusions Edrophonium doses that antagonize d-tubocurarine and vecuronium are less effective in antagonizing the neuromuscular effects of mivacurium during constant infusion. Edrophonium increases plasma mivacurium concentrations, partly or completely explaining its limited efficacy; the mechanism by which edrophonium increases mivacurium concentrations remains unexplained. Our results demonstrate that antagonism of mivacurium by edrophonium is impaired, and therefore we question whether edrophonium should be used to antagonize mivacurium.

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