NEW SYNTHETIC STEROIDS WHICH INHIBIT RAT GONADAL STEROIDOGENIC ENZYMES BOTH IN VITRO AND IN VIVO

1973 ◽  
Vol 73 (1) ◽  
pp. 146-170 ◽  
Author(s):  
Allen S. Goldman ◽  
Jan-Åke Gustafsson ◽  
Sven A. Gustafsson
Keyword(s):  
Female Rats ◽  
Gas Liquid Chromatography ◽  
Liquid Chromatography Mass Spectrometry ◽  
Hydroxylase Activity ◽  
Hormone Production ◽  
Oxidoreductase Activity ◽  
Site Of Action ◽  
Synthetic Steroids

ABSTRACT Six different steroidal analogues with previously suggested effects on gonadal Δ5,3β-hydroxysteroid oxidoreductase, 17α-hydroxylase and C17-20 lyase were investigated in vitro and in vivo. Testicular microsomal conversion of dehydroepiandrosterone to androstenedione and testosterone and of pregnenolone to progesterone and 5α-pregnane-3,20-dione was used as an index of Δ5,3β-hydroxysteroid oxidoreductase activity. 17α-hydroxylase activity was estimated from testicular microsomal formation of 17α-hydroxyprogesterone, androstenedione and testosterone from progesterone and the activity of C17-20 lyase was determined from the conversion of 17α-hydroxyprogesterone into androstenedione and testosterone. Analysis by gas-liquid chromatography – mass spectrometry of the steroidal excretion patterns in urine and faeces from female rats treated with two inhibitors of 17α-hydroxylase and C17-20 lyase in vivo, (I) 16β-bromo-3β,17α-dihydroxy-5α-pregnane-11,20-dione and (II) 17β-ureido-1,4-androstadien-3-one, and a third inhibitor (VI) 17α-cyano-5-androstene-3β,17β-diol, which also inhibits Δ5,3β-hydroxysteroid oxidoreductase in vitro, demonstrates the absence of C19 steroids of ovarian origin. C19 steroids are not excreted by rats treated with I and II up to 7 days after the last dose suggesting that the effects of these inhibitors are persistent. Two other steroids (III) 17-cyano-5,16-androstadien-3β-ol 3-acetate and (V) 17-cyano-5,16-androstadien-3β-ol, inhibit Δ5,3β-hydroxysteroid oxidoreductase in vitro in addition to 17α-hydroxylase and C17-20 lyase and cause the abnormal appearance of Δ5,3β-hydroxy-C19 steroids in the urines of normal and adrenalectomized females but not in those of ovariectomized or in ovariectomized and adrenalectomized rats. Each of these inhibitors also eliminates urinary 3α,17α-dihydroxy-5α-pregnan-20-one of ovarian origin. The pattern of C21O4 and C21O5 steroids of adrenal origin was only slightly affected or not affected at all by I–III and V and VI. The steroidal excretion patterns obtained in treated animals indicate a predominantly ovarian site of action of these inhibitors in vivo. Thus, the present results indicate three agents which block sex hormone production in the rat and two which inhibit gonadal Δ5,3β-hydroxysteroid oxidoreductase with moderate or no inhibition of the adrenal excretion.

CYANOKETONE-INDUCED INHIBITION OF ADRENAL 3β-HYDROXY-Δ5-STEROID OXIDOREDUCTASE ACTIVITY IN FEMALE AND MALE RATS IN VITRO

1976 ◽  
Vol 83 (3) ◽  
pp. 576-582 ◽  
Author(s):  
Sven A. Gustafsson
Keyword(s):  
Sex Differences ◽  
Single Injection ◽  
Female Rats ◽  
Male Rats ◽  
Oxidoreductase Activity ◽  
Control Female ◽  
Lower Affinity ◽  
And Control

ABSTRACT The inhibition of adrenal 3β-hydroxy-Δ5-steroid oxidoreductase activity was studied in vitro 24 h after a single injection of 2α-cyano-4,4,17α-trimethyl-5-androsten-17β-ol-3-one (cyanoketone) to adult castrated female and male rats. The inhibition of conversion of dehydroepiandrosterone1) to androstenedione was about 80 % as compared to adult castrated control rats treated with vehicle only. The conversion of pregnenolone to progesterone and 5α-pregnane-3,20-dione was also inhibited by about 80 % in both sexes. The activity of 3β-hydroxy-Δ5-steroid oxidoreductase was greater both in cyanoketone-treated and control female rats as compared to the corresponding male rats. It is concluded that the previously observed sex differences in response to cyanoketone in vivo are not due to a lower affinity of male adrenal 3β-hydroxy-Δ5-steroid oxidoreductase to cyanoketone.

THYROID STIMULATORS AND THYROID STIMULATION

1971 ◽  
Vol 66 (3) ◽  
pp. 558-576 ◽  
Author(s):  
Gerald Burke
Keyword(s):  
Regulatory System ◽  
Control Site ◽  
Thyroid Cell ◽  
Primary Control ◽  
Physico Chemical ◽  
Site Of Action ◽  
Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

Effects of in vivo gonadal hormone environment on in vitro hGRF-40-stimulated GH release

1985 ◽  
Vol 249 (3) ◽  
pp. E276-E280 ◽  
Author(s):  
W. S. Evans ◽  
R. J. Krieg ◽  
E. R. Limber ◽  
D. L. Kaiser ◽  
M. O. Thorner
Keyword(s):  
Female Rats ◽  
Male Rats ◽  
Gonadal Hormone ◽  
Base Line ◽  
Pituitary Cells ◽  
Intact Male ◽  
Castrate Male ◽  
Basal Release

The effects of gender and the gonadal hormone environment on basal and stimulated growth hormone (GH) release by dispersed and continuously perifused rat anterior pituitary cells were examined. Cells from intact male and diestrus day 2 female rats and from castrate male rats either untreated or treated with testosterone (T) or 17 beta-estradiol (E2) were used. Basal GH release (ng/min per 10(7) cells; mean +/- SE) by cells from diestrus day 2 female rats was less than by cells from castrate rats treated with T (4.3 +/- 0.6 vs. 11.4 +/- 2.7, respectively; P less than 0.025). No other differences in basal release were detected. Concentration-response relationships were documented between human GH-releasing factor 40 (hGRF-40; 0.03-100 nM given as 2.5-min pulses every 27.5 min) and GH release. Mean (+/- SE) overall GH release (ng/min per 10(7) cells) above base line was greater by cells from intact male rats (496 +/- 92) than by cells from castrate (203 +/- 37.3; P less than 0.0001), castrate and T-treated (348 +/- 52.8; P = 0.008), or castrate and E2-treated (58.1 +/- 6.8; P less than 0.001) male rats or by diestrus day 2 rats (68.6 +/- 9.5; P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1912
Author(s):  
Kaushik Chakravarty ◽  
Victor G. Antontsev ◽  
Maksim Khotimchenko ◽  
Nilesh Gupta ◽  
Aditya Jagarapu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Renin Angiotensin System ◽  
Mechanistic Modeling ◽  
Channel Blockers ◽  
Angiotensin System ◽  
In Silico Modeling ◽  
Site Of Action ◽  
Line Of Therapy

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.

scholarly journals Suppression of parathyroid hormone production in vitro and in vivo by RNA interference

2009 ◽  
Vol 75 (5) ◽  
pp. 490-498 ◽  
Author(s):  
Genta Kanai ◽  
Takatoshi Kakuta ◽  
Kaichiro Sawada ◽  
Tun A. Yokoyama ◽  
Reika Tanaka ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Rna Interference ◽  
Hormone Production

scholarly journals HOXA5 Expression Is Elevated in Breast Cancer and Is Transcriptionally Regulated by Estradiol

2020 ◽  
Vol 11 ◽  
Author(s):  
Imran Hussain ◽  
Paromita Deb ◽  
Avisankar Chini ◽  
Monira Obaid ◽  
Arunoday Bhan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Female Rats ◽  
Er Positive ◽  
Gene Regulatory ◽  
Cancer Tissues ◽  
Positive Breast Cancer

HOXA5 is a homeobox-containing gene associated with the development of the lung, gastrointestinal tract, and vertebrae. Here, we investigate potential roles and the gene regulatory mechanism in HOXA5 in breast cancer cells. Our studies demonstrate that HOXA5 expression is elevated in breast cancer tissues and in estrogen receptor (ER)-positive breast cancer cells. HOXA5 expression is critical for breast cancer cell viability. Biochemical studies show that estradiol (E2) regulates HOXA5 gene expression in cultured breast cancer cells in vitro. HOXA5 expression is also upregulated in vivo in the mammary tissues of ovariectomized female rats. E2-induced HOXA5 expression is coordinated by ERs. Knockdown of either ERα or ERβ downregulated E2-induced HOXA5 expression. Additionally, ER co-regulators, including CBP/p300 (histone acetylases) and MLL-histone methylases (MLL2, MLL3), histone acetylation-, and H3K4 trimethylation levels are enriched at the HOXA5 promoter in present E2. In summary, our studies demonstrate that HOXA5 is overexpressed in breast cancer and is transcriptionally regulated via estradiol in breast cancer cells.

scholarly journals Mining the Microbiota of the Neonatal Gastrointestinal Tract for Conjugated Linoleic Acid-Producing Bifidobacteria

2004 ◽  
Vol 70 (8) ◽  
pp. 4635-4641 ◽  
Author(s):  
E. Rosberg-Cody ◽  
R. P. Ross ◽  
S. Hussey ◽  
C. A. Ryan ◽  
B. P. Murphy ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Bifidobacterium Bifidum ◽  
Genomic Diversity ◽  
Gas Liquid Chromatography ◽  
Fecal Material ◽  
Single Strain ◽  
Different Strains

ABSTRACT This study was designed to isolate different strains of the genus Bifidobacterium from the fecal material of neonates and to assess their ability to produce the cis-9, trans-11 conjugated linoleic acid (CLA) isomer from free linoleic acid. Fecal material was collected from 24 neonates aged between 3 days and 2 months in a neonatal unit (Erinville Hospital, Cork, Ireland). A total of 46 isolates from six neonates were confirmed to be Bifidobacterium species based on a combination of the fructose-6-phosphate phosphoketolase assay, RAPD [random(ly) amplified polymorphic DNA] PCR, pulsed-field gel electrophoresis (PFGE), and partial 16S ribosomal DNA sequencing. Interestingly, only 1 of the 11 neonates that had received antibiotic treatment produced bifidobacteria. PFGE after genomic digestion with the restriction enzyme XbaI demonstrated that the bifidobacteria population displayed considerable genomic diversity among the neonates, with each containing between one and five dominant strains, whereas 11 different macro restriction patterns were obtained. In only one case did a single strain appear in two neonates. All genetically distinct strains were then screened for CLA production after 72 h of incubation with 0.5 mg of free linoleic acid ml−1 by using gas-liquid chromatography. The most efficient producers belonged to the species Bifidobacterium breve, of which two different strains converted 29 and 27% of the free linoleic acid to the cis-9, trans-11 isomer per microgram of dry cells, respectively. In addition, a strain of Bifidobacterium bifidum showed a conversion rate of 18%/μg dry cells. The ability of some Bifidobacterium strains to produce CLA could be another human health-promoting property linked to members of the genus, given that this metabolite has demonstrated anticarcinogenic activity in vitro and in vivo.

Further studies on the melanophores of periodic albino mutant of Xenopus laevis

Development ◽  
1986 ◽  
Vol 91 (1) ◽  
pp. 65-78
Author(s):  
T. Fukuzawa ◽  
H. Ide
Keyword(s):  
Xenopus Laevis ◽  
Microscopic Level ◽  
Wild Type ◽  
Light Microscopic Level ◽  
In Vitro Proliferation ◽  
Albino Mutant ◽  
Site Of Action ◽  
Periodic Albino

It is still unknown why dermal melanophores disappear during larval development, and why no or very few epidermal melanophores appear during and after metamorphosis, in Xenopus laevis showing periodic albinism (ap). To elucidate these points, we investigated (1) the occurrence of depigmentation in mutant (ap/ap) melanophores during in vitro proliferation and (2) the incidence of melanophore differentiation from mutant melanoblasts in the skin in vitro. During in vitro proliferation of mutant melanophores, ap-type melanosomes decreased in number gradually and instead the number of premelanosomes increased in the cells, which caused depigmentation at the light microscopic level in the culture. Depigmentation was observed only in mutant melanophores, and not in wild-type (+/+) melanophores. These results suggest that autonomous depigmentation of mutant dermal melanophores is the cause of the disappearance of these cells in vivo. Dopa-positive melanoblasts were demonstrated in both wild-type and mutant skins. However, the melanoblasts of metamorphosed mutant froglets did not differentiate in vitro, while those of wild-type froglets did. These results suggest that mutant melanoblasts in the skin of froglets lose the potency to differentiate into melanophores, and that this causes the lack of mutant melanophores in the froglets. The site of action of the ap gene is also discussed.

In vivo effects of flavonoid EMD 21388 on thyroid hormone secretion and metabolism in rats

1991 ◽  
Vol 261 (2) ◽  
pp. E227-E232 ◽  
Author(s):  
J. P. Schroder-van der Elst ◽  
D. van der Heide ◽  
J. Kohrle
Keyword(s):  
Thyroid Hormone ◽  
Hormone Secretion ◽  
Male Rats ◽  
Intact Male ◽  
Hormone Production ◽  
Iodide Uptake ◽  
Brown Adipose ◽  
In Vivo Effects

In vitro, the synthetic flavonoid EMD 21388 appears to be a potent inhibitor of thyroxine (T4) 5'-deiodinase and diminishes binding of T4 to transthyretin. In this study, in vivo effects of long-term administration of EMD 21388 on thyroid hormone production and metabolism were investigated. Intact male rats received EMD 21388 (20 mumol.kg body wt-1.rat-1.day-1) for 14 days. [125I]T4 and 3,5,3'-[131I]triiodotyronine (T3) were infused continuously and intravenously in a double-isotope protocol for the last 10 and 7 days, respectively. EMD 21388 decreased plasma thyroid hormone concentrations, but thyrotropin levels in plasma and pituitary did not change. Plasma clearance rates for T4 and T3 increased. Thyroidal T4 secretion was diminished, but T3 secretion was elevated. Extrathyroidal T3 production by 5'-deiodination was lower. T4 concentrations were markedly lower in all tissues investigated. Total tissue T3 was lower in brown adipose tissue, brain, cerebellum, and pituitary, tissues that express the type II 5'-deiodinase isozyme due to decreased local T3 production. Most tissues showed increased tissue/plasma ratios for T4 and T3. These results indicate that this flavonoid diminished T4 and increased T3 secretion by the thyroid, probably in analogy with other natural flavonoids, by interference with one or several steps between iodide uptake, organification, and hormone synthesis.

Rat renal 25-hydroxyvitamin D3 1- and 24-hydroxylases: their in vivo regulation

1984 ◽  
Vol 246 (2) ◽  
pp. E168-E173 ◽  
Author(s):  
Y. Tanaka ◽  
H. F. DeLuca
Keyword(s):  
Vitamin D ◽  
Inorganic Phosphorus ◽  
Hydroxylase Activity ◽  
Deficient Diet ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Dietary Phosphorus ◽  
Low Calcium

The effects of thyroparathyroidectomy, parathyroid hormone, 1,25-dihydroxyvitamin D3, dietary calcium, dietary phosphorus, age, and sex on the renal 25-hydroxyvitamin D3 1- and 24-hydroxylases measured in vitro in rats have been studied. Thyroparathyroidectomy of vitamin D-deficient rats abolishes 25-hydroxyvitamin D3 1-hydroxylase activity, and administration of bovine parathyroid extract to the thyroparathyroidectomized rat restores diminished 1-hydroxylase activity. Both suppression and restoration of the enzyme activities require many hours (18-24 h) independent of rapid changes in serum calcium and inorganic phosphorus levels in response to these manipulations. Administration of 1,25-dihydroxyvitamin D3 to vitamin D-deficient rats suppresses 25-hydroxyvitamin D3 1-hydroxylase activity and stimulates 25-hydroxyvitamin D3 24-hydroxylase activity within 48 h. Rats maintained on a low-calcium or a low-phosphorus diet with a daily supplement of 20 IU vitamin D3 show high 25-hydroxyvitamin D3 1-hydroxylase activity and low 24-hydroxylase activity as compared with rats similarly treated but fed a diet containing adequate calcium or adequate phosphorus. When vitamin D-sufficient rats having suppressed renal 25-hydroxyvitamin D3 1-hydroxylase activity are placed on a low-calcium vitamin D-deficient diet for 7 days, the 1-hydroxylase activity is greatly stimulated in 6-wk-old rats but much less so in rats with advancing age.

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