scholarly journals Dose-dependent acinar induction of cytochromes P450 in rat liver. Evidence for a differential mechanism of induction of P450IA1 by β-naphthoflavone and dioxin

1991 ◽  
Vol 277 (2) ◽  
pp. 577-580 ◽  
Author(s):  
R G Bars ◽  
C R Elcombe
Keyword(s):  
Western Blotting ◽  
Rat Liver ◽  
Low Dose ◽  
Cytochromes P450 ◽  
Aroclor 1254 ◽  
Hepatic Expression ◽  
Differential Mechanism ◽  
Tetrachlorodibenzo P Dioxin ◽  
High Doses ◽  
Dose Dependent

Rats received various doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), Aroclor 1254 (ARO), beta-naphthoflavone (BNF) or phenobarbital (PB), and the hepatic expression of cytochromes P450IA1 and/or P450IIB1/IIB2 was analysed by immunohistochemistry and Western blotting. A clear heterogeneous acinar induction of IA1 was detected when a low dose of TCDD, ARO or BNF was administered. When a low dose of TCDD or ARO was administered, IA1 was found to be induced primarily in hepatocytes located in acinus zone 3, whereas when a low dose of BNF was administered, IA1 was found to be preferentially induced in hepatocytes located in acinus zone 1. A clear zonal induction of IIB1/IIB2 was also observed when a low dose of PB or ARO was administered. Both compounds induced IIB1/IIB2 preferentially in hepatocytes located in acinus zone 3. When rats were administered high doses of TCDD, ARO, BNF or PB there was no zonal pattern of induction of IA1 or IIB1/IIB2; instead, a pan-acinar induction of these enzymes was observed. These results indicate that the overall hepatic concentration of IA1 or IIB1/IIB2 is merely dependent on the proportion of ‘induced hepatocytes’ within the acinus, which in turn depends on the dose of the inducer.

scholarly journals Effects of Low-Dose versus High-Doseγ-Tocotrienol on the Bone Cells Exposed to the Hydrogen Peroxide-Induced Oxidative Stress and Apoptosis

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Nizar Abd Manan ◽  
Norazlina Mohamed ◽  
Ahmad Nazrun Shuid
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Antioxidant Enzymes ◽  
Low Dose ◽  
Bone Cells ◽  
Dependent Manner ◽  
Low Doses ◽  
Antioxidant Enzymes Activities ◽  
High Doses ◽  
Dose Dependent

Oxidative stress and apoptosis can disrupt the bone formation activity of osteoblasts which can lead to osteoporosis. This study was conducted to investigate the effects ofγ-tocotrienol on lipid peroxidation, antioxidant enzymes activities, and apoptosis of osteoblast exposed to hydrogen peroxide (H2O2). Osteoblasts were treated with 1, 10, and 100 μM ofγ-tocotrienol for 24 hours before being exposed to 490 μM (IC50) H2O2for 2 hours. Results showed thatγ-tocotrienol prevented the malondialdehyde (MDA) elevation induced by H2O2in a dose-dependent manner. As for the antioxidant enzymes assays, all doses ofγ-tocotrienol were able to prevent the reduction in SOD and CAT activities, but only the dose of 1 μM of GTT was able to prevent the reduction in GPx. As for the apoptosis assays,γ-tocotrienol was able to reduce apoptosis at the dose of 1 and 10 μM. However, the dose of 100 μM ofγ-tocotrienol induced an even higher apoptosis than H2O2. In conclusion, low doses ofγ-tocotrienol offered protection for osteoblasts against H2O2toxicity, but itself caused toxicity at the high doses.

scholarly journals Dose-Dependent Inhibition of Experimental Arterial Thrombosis by Carbenicillin and Ticarcillin

1977 ◽  
Author(s):  
B.T. Lyman ◽  
G.J. Johnson ◽  
J.G. White
Keyword(s):  
Arterial Thrombosis ◽  
Low Dose ◽  
Thrombosis Prophylaxis ◽  
High Dose ◽  
Antithrombotic Agents ◽  
Total Occlusion ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
High Doses ◽  
Dose Dependent

Drugs that inhibit platelet (PL) function may be useful in the prophylaxis of arterial thrombosis. We have shown that carbenicillin (CARB) and ticarcillin (TIC) cause dose-dependent inhibition of PL aggregation (AGG) in dogs, and that high doses of either of these penicillins significantly decrease the frequency of thrombosis in pronase (PN) injected arteries of dogs. Using this model we have compared the thrombosis prophylaxis effectiveness of these penicillins administered in low dose (250mg/Kg/24 hr, s.c.) (LD-P) versus high dose (750mg/Kg/24 hr, s.c.) (HD-P). Treatment for 3 to 7 days with LD-P resulted in marked inhibition of ADP-induced AGG, but had little or no effect on collagen-induced AGG, while HD-P routinely inhibited collagen as well as ADP-induced AGG. Control dogs were untreated, and their PL function remained normal. Thrombosis with total occlusion occurred in 13 of 15 arteries in control dogs, while only 3 of 29 segments totally occluded in HD-P treated dogs (χ2 = 21.7; p<0.001). However, total occlusion developed in 13 of 20 arteries in dogs receiving LD-P (χ2 = 1.1; p<0.3). The frequency of occlusion was significantly lower (p<0.001) following treatment with HD-P than LD-P. Aspirin (ASA) administration in low dose (650mg/24 hr p.o.) (LD-A) or high dose (2600mg/24 hr p.o.) (HD-A) uniformly inhibited collagen-induced PL AGG, but total occlusion developed in 11 of 16 PN injected arteries in dogs given LD-A, and in 10 of 12 arteries in dogs given HD-A. We conclude that CARB and TIC are effective experimental antithrombotic agents. Their effect is dose-dependent and closely correlated with inhibition of collagen-induced PL AGG. In high doses CARB and TIC are more effective than ASA in preventing PN induced arterial thrombosis. CARB and TIC warrant further study as potentially useful antithrombotic agents in humans.

Effects of ovariectomy and oestradiol replacement on hypothalamic serotonergic and monoamine oxidase activity in the catfish, Heteropneustes fossilis: a study correlating plasma oestradiol and gonadotrophin levels

1994 ◽  
Vol 142 (2) ◽  
pp. 193-203 ◽  
Author(s):  
B Senthilkumaran ◽  
K P Joy
Keyword(s):  
Body Weight ◽  
Monoamine Oxidase ◽  
Plasma Levels ◽  
Low Dose ◽  
Feedback Effect ◽  
Dependent Manner ◽  
Heteropneustes Fossilis ◽  
Mao Activity ◽  
High Doses ◽  
Dose Dependent

Abstract Hypothalamic serotonin (5-HT; content and turnover) and monoamine oxidase (MAO) activity were measured in female catfish, Heteropneustes fossilis, after ovariectomy and supplementation with oestradiol-17β (OE2) in the recrudescent and quiescent phases. These factors were correlated with changes in plasma levels of OE2 and gonadotrophin. In the quiescent phase (December), neither ovariectomy nor OE2 supplementation had any significant effect on 5-HT content and MAO activity. Plasma levels of OE2 and gonadotrophin were undetectable in both control and treated fish, indicating that there was no feedback effect. In the recrudescent phase (prespawning, May), ovariectomy caused biphasic responses of MAO activity and 5-HT content. The enzyme activity decreased significantly after 2, 3, 4 and 5 weeks but increased significantly 6 weeks after ovariectomy. The 5-HT content varied in a biphasic manner with a significant increase at 2, 3 or 4 weeks and a significant decrease in week 6; there being no effect in week 5. 5-HT turnover was inhibited significantly only in week 4 after ovariectomy and did not show a biphasic pattern. In the ovariectomized groups, the OE2 level decreased significantly in a progressive manner with a maximum reduction in week 6. The plasma level of gonadotrophin showed a significant bimodal pattern of increase with the peak in week 4 after ovariectomy, indicating a strong negative feedback effect of OE2. The bimodal pattern of pituitary gonadotrophin release could be correlated with a similar pattern of increase in 5-HT content. OE2 treatment of fish which had been ovariectomized 3 weeks previously had dose-dependent effects on the enzyme; the low dose (0·1 μg/g body weight) was stimulatory and the higher doses (0·5, 1·0 and 5·0 μg/g body weight) were inhibitory. The reverse was true for 5-HT content. Serotonergic turnover increased significantly only in the groups given high doses (1·0 and 5·0 μg/g body weight). The low dose of OE2 (0·1 μg/g body weight) restored the gonadotrophin and OE2 levels to those of the sham-ovariectomized vehicle-treated control group, whereas the high doses (0·5, 1·0 and 5·0 μg/g body weight) decreased the release of gonadotrophin in a dose-dependent manner. Our results suggest that OE2 modulates MAO activity to alter hypothalamic 5-HT in a seasonally dependent manner. The ovariectomy-induced changes in plasma levels of gonadotrophin appear to be mediated, at least partly, by the feedback action of OE2 on 5-HT metabolism. Journal of Endocrinology (1994) 142, 193–203

Mechanism of Action of Trazodone: a Multifunctional Drug

CNS Spectrums ◽  
2009 ◽  
Vol 14 (10) ◽  
pp. 536-546 ◽  
Author(s):  
Stephen M. Stahl
Keyword(s):  
Controlled Release ◽  
Adrenergic Receptors ◽  
Low Dose ◽  
Low Doses ◽  
Release Formulation ◽  
Therapeutic Mechanism ◽  
High Doses ◽  
Pharmacologic Actions ◽  
Dose Dependent ◽  
Higher Doses

Multifunctional drugs are those with more than one therapeutic mechanism. Trazodone is a multifunctional drug with dose-dependent pharmacologic actions. That is, it has hypnotic actions at low doses due to blockade of 5-HT2A receptors, as well as H1 histamine receptors and α1 adrenergic receptors. Higher doses recruit the blockade of the serotonin transporter (SERT) and turn trazodone into an antidepressant. Although trazodone has traditionally been used as a low dose hypnotic, a new controlled release formulation that has the potential to improve the tolerability of high doses may provide an opportunity to revisit this multifunctional drug as an antidepressant as well.

scholarly journals CNS Stimulation and PGE2 Release. III. Pentamethylenetetrazole-Induced Seizures

1989 ◽  
Vol 9 (2) ◽  
pp. 180-186 ◽  
Author(s):  
E. Navarro ◽  
S. D. Romero ◽  
T. L. Yaksh
Keyword(s):  
Low Dose ◽  
Seizure Activity ◽  
Prostaglandin E ◽  
Pge2 Release ◽  
Time Courses ◽  
High Doses ◽  
Cns Stimulation ◽  
Dose Dependent ◽  
Secretion Rates ◽  
Energy Failure

Measurement of prostaglandin E2 (PGE2) in the ventriculocisternal perfusate of the halothane anesthetized, artificially ventilated cat has revealed low but measurable levels of the prostanoid (64 ± 5 pg/min). Administration of pentamethylenetetrazole (PTZ) resulted in a rapid appearance of paroxysmal bursting, the magnitude and duration of which was dose dependent. During the 30-min interval after seizure initiation, PGE2 secretion rates into the ventriculocisternal perfusate rose by five- to sevenfold. Though the initial rate of PGE2 secretion correlated closely with the initial magnitude of bursting, there were significant differences, viz. the time courses. Thus, after a low dose of PTZ (200 mg/kg) the increase and return to normal of PGE2 secretion was time locked with the onset and offset of seizures. In contrast, after high doses of PTZ (250 mg/kg i. v.), seizure activity returned to near baseline by 90 min, while the levels of PGE2 secretion remained elevated for periods in excess of 150 min. Pretreatment with clonazepam (CLP: 3 mg/kg i. v. infusion) blocked seizures otherwise induced by PTZ (250 mg/kg) and the increase in PGE2 secretion. CLP administration 60 min after the initiation of seizures, blocked further seizure activity but did not alter the elevated secretion of PGE2. We thus believe these data jointly support the hypothesis that under intense paroxysmal bursting there is a change in neuronal state such that large stores of free fatty acids are available either because they have accumulated during the seizure because of a continued Ca2+ influx or the presence of large and continuing concentrations of Ca2+ accumulating in the cytosol secondary to energy failure.

Melatonin actions in the heart; more than a hormone

2018 ◽  
Vol 1 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Darío Acuña-Castroviejo ◽  
Maria T Noguiera-Navarro ◽  
Russel J Reiter ◽  
Germaine Escames
Keyword(s):  
Cell Membranes ◽  
Myocardial Cell ◽  
Rat Tissues ◽  
Dependent Manner ◽  
Broad Distribution ◽  
Multiple Organs ◽  
High Doses ◽  
Extrapineal Melatonin ◽  
Dose Dependent ◽  
Different Doses

Due to the broad distribution of extrapineal melatonin in multiple organs and tissues, we analyzed the presence and subcellular distribution of the indoleamine in the heart of rats. Groups of sham-operated and pinealectomized rats were sacrificed at different times along the day, and the melatonin content in myocardial cell membranes, cytosol, nuclei and mitochondria, were measured. Other groups of control animals were treated with different doses of melatonin to monitor its intracellular distribution. The results show that melatonin levels in the cell membrane, cytosol, nucleus, and mitochondria vary along the day, without showing a circadian rhythm. Pinealectomized animals trend to show higher values than sham-operated rats. Exogenous administration of melatonin yields its accumulation in a dose-dependent manner in all subcellular compartments analyzed, with maximal concentrations found in cell membranes at doses of 200 mg/kg bw melatonin. Interestingly, at dose of 40 mg/kg b.w, maximal concentration of melatonin was reached in the nucleus and mitochondrion. The results confirm previous data in other rat tissues including liver and brain, and support that melatonin is not uniformly distributed in the cell, whereas high doses of melatonin may be required for therapeutic purposes.

Hepatic uptake of intact glutathione S-conjugate, inhibition by organic anions, and sinusoidal catabolism

1993 ◽  
Vol 265 (3) ◽  
pp. G547-G554
Author(s):  
C. A. Hinchman ◽  
A. T. Truong ◽  
N. Ballatori
Keyword(s):  
Guinea Pig ◽  
Rat Liver ◽  
Marked Decrease ◽  
Hepatic Uptake ◽  
Half Time ◽  
High Concentrations ◽  
Rat Livers ◽  
Dose Dependent ◽  
Uptake And Metabolism ◽  
Guinea Pig Liver

To identify potential mechanisms for hepatic removal of circulating glutathione (GSH) conjugates, uptake and metabolism of S-2,4-dinitrophenylglutathione (DNP-SG) were examined in isolated perfused livers from rat and guinea pig. Guinea pig livers perfused with 5 mumol of DNP-SG in a recirculating system (50 microM initial concn) rapidly cleared the conjugate from the perfusate (half time 3.7 min), whereas clearance was considerably slower in rat liver (half time 35 min). Disappearance of DNP-SG from the perfusate was accompanied by a simultaneous appearance of DNP-SG and its metabolites in bile. Addition of acivicin, an inhibitor of gamma-glutamyltransferase (gamma-GT), to the perfusate resulted in a marked decrease in DNP-SG clearance by guinea pig liver but had no effect in rat liver, suggesting that in the guinea pig this process is largely dependent on sinusoidal gamma-GT activity. However, even in the presence of acivicin, rat and guinea pig livers removed nearly one-half of the administered DNP-SG from the recirculating perfusate over 30 min. High concentrations of DNP-SG were found in bile (up to 3.7 mM), indicating that the liver is capable of transporting the intact conjugate from the circulation. When rat livers were perfused with higher concentrations of DNP-SG (100 and 250 microM), biliary excretion of DNP-SG increased dose dependently, with concentrations in bile reaching 10 mM at the higher dose. This was accompanied by a dose-dependent choleresis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aroclor 1254 as a 2,3,7,8-tetrachlorodibenzo-p-dioxin antagonist in mice

Chemosphere ◽  
1989 ◽  
Vol 18 (1-6) ◽  
pp. 709-714 ◽  
Author(s):  
S. Safe ◽  
R. Bannister ◽  
D. Davis ◽  
J.M. Haake ◽  
T. Zacharewski ◽  
...  
Keyword(s):  
Aroclor 1254 ◽  
Tetrachlorodibenzo P Dioxin

scholarly journals The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

2021 ◽  
Vol 22 (5) ◽  
pp. 2578
Author(s):  
Trim Lajqi ◽  
Christian Marx ◽  
Hannes Hudalla ◽  
Fabienne Haas ◽  
Silke Große ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Immune Tolerance ◽  
Immune Cells ◽  
Low Dose ◽  
Innate Immune ◽  
Immune Memory ◽  
Innate Immune Cells ◽  
Atp Production ◽  
Dose Dependent

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.

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