scholarly journals Inhibition of testosterone biosynthesis by ethanol. Relation to hepatic and testicular acetaldehyde, ketone bodies and cytosolic redox state in rats

1983 ◽  
Vol 210 (1) ◽  
pp. 29-36 ◽  
Author(s):  
C J P Eriksson ◽  
T V Widenius ◽  
R H Ylikahri ◽  
M Härkönen ◽  
P Leinonen
Keyword(s):  
Ketone Bodies ◽  
Plasma Testosterone ◽  
Testosterone Concentration ◽  
Anaesthetized Rats ◽  
Testosterone Biosynthesis ◽  
Cervical Dislocation ◽  
Acetaldehyde Level ◽  
Pyruvate Ratio

In experiments in which liver and testis freeze-stops were performed on pentobarbital-anaesthetized rats, ethanol (1.5 g/kg body wt.) reduced plasma testosterone concentration from 13.1 to 3.2 nmol/litre. 4-Methylpyrazole abolished the ethanol-induced hepatic and testicular increase in the lactate/pyruvate ratio, and the testicular acetaldehyde level, but did not diminish the reduction in plasma testosterone concentration. In testes, but not in liver, ethanol decreased the 3-hydroxybutyrate/acetoacetate ratio, and 4-methylpyrazole did not prevent this effect. In experiments in which freeze-stop was performed after cervical dislocation, ethanol decreased the testis testosterone concentration from 590 to 220 pmol per g wet wt. The effects of ethanol and 4-methylpyrazole on testis acetaldehyde, lactate/pyruvate and 3-hydroxybutyrate/acetoacetate ratios were the same as found during anaesthesia. The NAD+-dependent ethanol oxidation capacity in testis ranged from 0.1 to 0.2 mumol/min per g wet wt. and seemed to be inhibited by 4-methylpyrazole both in vivo and in vitro. In additional experiments, ethanol doses between 0.3 and 0.9 g/kg body wt. did not alter the plasma testosterone concentration in rats treated, or not treated, with cyanamide, which induced elevated acetaldehyde levels in blood and testes. The results suggest that ethanol-induced inhibition of testosterone biosynthesis was not caused by extratesticular redox increases, or by extra- or intra-testicular acetaldehyde per se. The inhibition is accompanied by changes in testicular ketone-body metabolism.

scholarly journals STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

2012 ◽  
Vol 20 (1) ◽  
pp. 53-64 ◽  
Author(s):  
Joanna M Day ◽  
Paul A Foster ◽  
Helena J Tutill ◽  
Fabien Schmidlin ◽  
Christopher M Sharland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumour Growth ◽  
Plasma Testosterone ◽  
Prostate Hyperplasia ◽  
Testosterone Levels ◽  
Concept Model ◽  
Body Weights ◽  
Type 3

17β-Hydroxysteroid dehydrogenases (17β-HSDs) catalyse the 17-position reduction/oxidation of steroids. 17β-HSD type 3 (17β-HSD3) catalyses the reduction of the weakly androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17β-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17β-HSD3 inhibitor with an IC50 of ∼200 nM in a whole-cell assay. It inhibits adione-stimulated proliferation of 17β-HSD3-expressing androgen receptor-positive LNCaP(HSD3) prostate cancer cells in vitro. An androgen-stimulated LNCaP(HSD3) xenograft proof-of-concept model was developed to study the efficacies of STX2171 and a more established 17β-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1×107 cells 24 h after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks, tumours had not developed in vehicle-dosed mice, but were present in 50% of those mice given TP. One week after switching the stimulus to adione, mice were dosed additionally with the vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumour growth and increased plasma testosterone levels; however, in the presence of either 17β-HSD3 inhibitor, adione-dependent tumour growth was significantly inhibited and plasma testosterone levels reduced. Mouse body weights were unaffected. Both inhibitors also significantly lowered plasma testosterone levels in intact mice. In conclusion, STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumour growth in vivo, indicating that 17β-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.

scholarly journals Identification of Echinacea Purpurea (L.) Moench Root LysM Lectin with Nephrotoxic Properties

Toxins ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 88 ◽  
Author(s):  
Gabriele Balciunaite ◽  
Perttu-Juhani Haimi ◽  
Zoja Mikniene ◽  
Girius Savickas ◽  
Ona Ragazinskiene ◽  
...  
Keyword(s):  
Biological Activity ◽  
Morphological Changes ◽  
Echinacea Purpurea ◽  
Tubular Necrosis ◽  
Lactuca Sativa L ◽  
Kidney Morphology ◽  
Cervical Dislocation ◽  
Hematoxylin And Eosin

Echinacea purpurea (L.) Moench (EP) is a well-studied plant used for health benefits. Even though there are a lot of data on EP secondary metabolites, its active proteins are not studied well enough. The aim of our experiment was to purify lectin fraction from EP roots and evaluate its biological activity in vitro as well as its effect on kidney morphology in vivo. An EP root glycoprotein fraction was purified by affinity chromatography, identified by LC-MS/MS, and used for biological activity tests in vitro and in vivo. Identified glycoproteins were homologous with the LysM domain containing lectins from the Asteraceae plants Helianthus annuus L., Lactuca sativa L., Cynara cardunculus L. A purified fraction was tested by hemagglutination and hemagglutination inhibition (by carbohydrate reactions) in vitro. We purified the hemagglutinating active ~40 kDa size lactose, D-mannose, and D-galactose specific glycoproteins with two peptidoglycan binding LysM (lysine motif) domains. Purified LysM lectin was tested in vivo. Eight-week old Balb/C male mice (n = 15) were treated with 5 μg of the purified lectin. Injections were repeated four times per week. At the fifth experimental week, animals were sedated with carbon dioxide, then euthanized by cervical dislocation and their kidney samples were collected. Morphological changes were evaluated in hematoxylin and eosin stained kidney samples. The purified LysM lectin induced a statistically significant (p < 0.05) kidney glomerular vacuolization and kidney tubular necrosis (p < 0.001).

Release of Dipeptide Hydrolase Activities from Rat Small Intestine Perfused in Vitro and in Vivo

1979 ◽  
Vol 57 (6) ◽  
pp. 529-534 ◽  
Author(s):  
M. L. G. Gardner ◽  
Jane A. Plumb
Keyword(s):  
Small Intestine ◽  
Physiological Significance ◽  
Peptide Transport ◽  
Rat Small Intestine ◽  
Experimental Procedure ◽  
Specific Process ◽  
Whole Cells ◽  
Anaesthetized Rats

1. Hydrolase activities against three dipeptides were measured in mucosal cytoplasm in unperfused intestines and in mucosal cytoplasm, luminal effluents and serosal secretions after perfusion in vitro and in vivo for 1 h. Intestines in vitro were prepared both from anaesthetized rats and from freshly killed rats. 2. Only 0·6–1·9% of the initial cytoplasmic activity was recovered in the luminal effluent when intestines in vitro were prepared from anaesthetized rats. Recoveries in luminal effluents were similar (1·3–3·3%) during perfusion in vivo. 3. Losses of dipeptidases into the luminal effluent were four to eight times greater when intestines in vitro were prepared from freshly killed animals. 4. Similar losses of dipeptidases into the secretion on to the serosal surface were observed; they too were much greater when intestines were prepared from freshly killed animals. 5. Small losses of mucosal DNA during perfusion were also observed; however, losses of cytoplasmic peptidases were consistently slightly greater. 6. Enzyme loss therefore probably occurs both by sloughing of whole cells and by a more specific process which is greatly influenced by experimental procedure. Caution is necessary in the interpretation of peptide transport experiments in vitro, although the possibility that intraluminal hydrolysis is of physiological significance must not be excluded.

scholarly journals Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

2015 ◽  
Vol 35 (5) ◽  
pp. 851-860 ◽  
Author(s):  
Alberto Julio-Amilpas ◽  
Teresa Montiel ◽  
Eva Soto-Tinoco ◽  
Cristian Gerónimo-Olvera ◽  
Lourdes Massieu
Keyword(s):  
Reactive Oxygen Species ◽  
Protective Effect ◽  
Neuronal Death ◽  
Ketone Bodies ◽  
Reactive Oxygen ◽  
Glucose Deprivation ◽  
Oxygen Species ◽  
Atp Production

Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury.

CGS 34226, a thiol-based dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11

2002 ◽  
Vol 103 (s2002) ◽  
pp. 98S-101S ◽  
Author(s):  
Y. Arco JENG ◽  
Paula SAVAGE ◽  
Michael E. BEIL ◽  
Charles W. BRUSEO ◽  
Denton HOYER ◽  
...  
Keyword(s):  
Pressor Response ◽  
Neutral Endopeptidase ◽  
Intravenous Dose ◽  
Renal Diseases ◽  
Dual Inhibitor ◽  
Endopeptidase 24.11 ◽  
Anaesthetized Rats ◽  
Ic50 Values

Endothelins (ETs) are potent vasoconstrictors and have been implicated in the pathogenesis of various cardiovascular and renal diseases. In contrast, atrial natriuretic peptide (ANP) is a potent vasorelaxant and diuretic agent, which is mainly degraded by neutral endopeptidase 24.11 (NEP) in vivo. Thus, compounds that can suppress the biosynthesis of ETs by inhibiting endothelin converting enzymes (ECEs), which catalyse the final step of post-translational processing of the vasoconstrictors, while simultaneously potentiating the levels of ANP by inhibiting NEP may have novel therapeutic utility. Through targeted screening of our compound library and subsequent optimization, CGS 34226 was identified as a potent, dual inhibitor of ECE-1 and NEP, inhibiting the enzymes with respective IC50 values of 11 and 4.6nM. In vivo, CGS 34226 suppressed the big endothelin-1 (big ET-1)-induced pressor response dose-dependently. At 15 and 90min after an intravenous dose of 30mg/kg in anaesthetized rats, this compound inhibited the big ET-1-induced effect by 79% and 65% respectively. In addition, CGS 34226 increased plasma ANP immunoreactivity by 120% up to 4h after an intravenous dose of 10mg/kg in conscious rats infused with ANP at a rate of 450ng/kg per min, intravenously. These results show that CGS 34226 is a potent dual inhibitor of ECE-1 and NEP in vitro and in vivo and that the compound may represent a novel agent for the treatment of cardiovascular and renal dysfunction.

Lactate and pyruvate gradients between red blood cells and plasma during acute asphyxia

1964 ◽  
Vol 19 (6) ◽  
pp. 1100-1104 ◽  
Author(s):  
Salha S. Daniel ◽  
Hisayo O. Morishima ◽  
L. Stanley James ◽  
Karlis Adamsons
Keyword(s):  
Sodium Lactate ◽  
Red Cells ◽  
Red Cell ◽  
Cell Ratio ◽  
Lactate And Pyruvate ◽  
The Mean ◽  
Endogenous Release ◽  
Pyruvate Ratio

The rate of equilibration of lactate and pyruvate between plasma and red cells has been studied during asphyxia and following addition of sodium lactate in vivo and in vitro. In the resting, well-oxygenated guinea pig, the mean plasma/red cell ratio of lactate was 1.55 and that of pyruvate 2.47. During asphyxia, the plasma/red cell ratio of lactate rose and that of pyruvate fell, indicating a delay in equilibration. Incomplete equilibration affected particularly the lactate/pyruvate ratio in the two compartments. Infused neutral sodium lactate penetrated the red cells at a rate comparable to that observed following endogenous release of lactic acid during acute asphyxia. In vitro at pH 6.8@#X2013;7.4 at 38 C, the time to 50% equilibration of lactate between plasma and cells of human blood was less than 2 min. It is concluded that during acute asphyxia and resuscitation whole blood values of lactate and pyruvate do not bear a constant relationship to those of plasma. lactate/pyruvate ratio Submitted on March 16, 1964

In vivo administration of a GnRH antagonist to male mice: effects on pituitary gonadotropin secretion in vitro

1989 ◽  
Vol 120 (3) ◽  
pp. 308-314
Author(s):  
A. M. Ultee-van Gessel ◽  
G.J. van Steenbrugge ◽  
F. G. Leemborg ◽  
F. H. Schroeder ◽  
F. H. de Jong
Keyword(s):  
Gnrh Antagonist ◽  
Term Treatment ◽  
Plasma Testosterone ◽  
High Dose ◽  
Male Mice ◽  
Short Term Treatment ◽  
Gonadotropin Secretion ◽  
Long Term Treatment

Abstract. The potent luteinizing hormone-releasing hormone antagonist [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]GnRH (4 mg/kg) was administered sc once or daily for 21 days to immune-deficient (nude) and normal immune-competent (NIC) male mice derived from the same genetic background. Effects of in vivo pretreatment with the antagonist on gonadotropin secretion from hemipituitary glands from both types of mice were studied in vitro in the presence or absence of synthetic GnRH. Treatment with the GnRH antagonist caused differential effects on release of FSH and LH from and amounts of FSH and LH in hemipituitary glands. Pituitary FSH secretion was effectively inhibited, whereas effects on pituitary LH were less evident or nonsignificant under these experimental conditions. Long-term treatment with the antagonist caused larger effects on pituitary secretion and content of FSH, when compared with short-term treatment. No significant effects of duration of treatment on secretion or pituitary content of LH were detected. Addition of synthetic GnRH to the incubation medium caused stimulation of gonadotropin release. Therefore, it was concluded that the high doses of this GnRH antagonist were not able to block GnRH receptors effectively in the pituitary glands of nude and NIC male mice. The incomplete suppression of LH secretion by this high dose of the GnRH antagonist may partly explain the inability of the antagonist to suppress plasma testosterone levels and the growth of androgen-dependent tumours in male mice.

scholarly journals Effect of hyperphenylalaninaemia on lipid synthesis from ketone bodies by rat brain

1976 ◽  
Vol 154 (2) ◽  
pp. 319-325 ◽  
Author(s):  
M S. Patel ◽  
O E. Owen
Keyword(s):  
Rat Brain ◽  
Ketone Bodies ◽  
Brain Slices ◽  
Lipid Synthesis ◽  
Coa Transferase ◽  
Old Rats ◽  
And Function ◽  
Developing Rat

The effect of hyperphenylalaninaemia on the metabolism of ketone bodies in vivo and in vitro by developing rat brain was investigated. The incorporation in vivo of [14C]acetoacetate into cerebral lipids was decreased by both chronic (for 3 days) and acute (for 6h) hyperphenylalaninaemia induced by injecting phenylalanine into 1-week-old rats. In studies in vitro it was observed that the incorporation of the radioactivity from [14C]acetoacetate and 3-hydroxy[14C]butyrate into cerebral lipids was inhibited by phenyl-pyruvate, but not by phenylalanine. Phenylpyruvate also inhibited the incorporation of 3H from 3H2O into lipids by brain slices metabolizing either 3-hydroxybutyrate or acetoacetate in the presence of glucose. These findings suggest that the decrease in the incorporation in vivo of [14C]acetoacetate into cerebral lipids in hyperphenylalaninaemic rats is most likely caused by phenylpyruvate and not by phenylalanine. Phenylpyruvate as well as phenylalanine had no inhibitory effects on ketone-body-catabolizing enzymes, namely 3-hydroxybutyrate dehydrogenase, 3-oxo acid CoA-transferase and acetoacetyl-CoA thiolase, in rat brain. Phenylpyruvate but not phenylalanine inhibited the activity of the 2-oxoglutarate dehydrogenase complex from rat and human brain. These findings suggest that the metabolism of ketone bodies is impaired in brains of untreated phenylketonuric patients, and in turn may contribute to the diminution of mental development and function associated with phenylketonuria.

Effects of hypoxia on testosterone release in rat Leydig cells

2009 ◽  
Vol 297 (5) ◽  
pp. E1039-E1045 ◽  
Author(s):  
Guey-Shyang Hwang ◽  
Szu-Tah Chen ◽  
Te-Jung Chen ◽  
Shyi-Wu Wang
Keyword(s):  
Calcium Channel ◽  
Adenylyl Cyclase ◽  
Intermittent Hypoxia ◽  
Leydig Cells ◽  
Channel Blocker ◽  
Male Rats ◽  
Plasma Testosterone ◽  
Testosterone Production

The aim of this study was to explore the effect and action mechanisms of intermittent hypoxia on the production of testosterone both in vivo and in vitro. Male rats were housed in a hypoxic chamber (12% O2 + 88% N2, 1.5 l/ml) 8 h/day for 4 days. Normoxic rats were used as control. In an in vivo experiment, hypoxic and normoxic rats were euthanized and the blood samples collected. In the in vitro experiment, the enzymatically dispersed rat Leydig cells were prepared and challenged with forskolin (an adenylyl cyclase activator, 10−4 M), 8-Br-cAMP (a membrane-permeable analog of cAMP, 10−4 M), hCG (0.05 IU), the precursors of the biosynthesis testosterone, including 25-OH-C (10−5 M), pregnenolone (10−7 M), progesterone (10−7 M), 17-OH-progesterone (10−7 M), and androstendione (10−7-10−5 M), nifedipine (L-type Ca2+ channel blocker, 10−6-10−4 M), nimodipine (L-type Ca2+ channel blocker, 10−5 M), tetrandrine (L-type Ca2+ channel blocker, 10−5 M), and NAADP (calcium-signaling messenger causing release of calcium from intracellular stores, 10−6-10−4 M). The concentrations of testosterone in plasma and medium were measured by radioimmunoassay. The level of plasma testosterone in hypoxic rats was higher than that in normoxic rats. Enhanced testosterone production was observed in rat Leydig cells treated with hCG, 8-Br-cAMP, or forskolin in both normoxic and hypoxic conditions. Intermittent hypoxia resulted in a further increase of testosterone production in response to the testosterone precursors. The activity of 17β-hydroxysteroid dehydrogenase was stimulated by the treatment of intermittent hypoxia in vitro. The intermittent hypoxia-induced higher production of testosterone was accompanied with the influx of calcium via L-type calcium channel and the increase of intracellular calcium via the mechanism of calcium mobilization. These results suggested that the intermittent hypoxia stimulated the secretion of testosterone at least in part via stimulatory actions on the activities of adenylyl cyclase, cAMP, L-type calcium channel, and steroidogenic enzymes.

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