scholarly journals Zearalenone Inhibits Rat and Human 11β-Hydroxysteroid Dehydrogenase Type 2

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Linxi Li ◽  
Xiaolong Wu ◽  
Hongguo Guan ◽  
Baiping Mao ◽  
Huang Wang ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Local Level ◽  
Hydroxysteroid Dehydrogenase ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Hydroxysteroid Dehydrogenases ◽  
Steroid Substrate ◽  
Potent Inhibition ◽  
Glucocorticoid Action

Zearalenone is a mycotoxin produced byFusariumspp. 11β-Hydroxysteroid dehydrogenases, isoforms 1 (HSD11B1) and 2 (HSD11B2), have been demonstrated to be the regulators of the local level of active glucocorticoid, which has a broad range of physiological actions. In the present study, the potency of zearalenone was tested for the inhibition of HSD11B1 and HSD11B2 in rat and human tissues. Zearalenone showed potent inhibition of HSD11B2 with the half-maximal inhibitory concentration (IC50) calculated at 49.63 and 32.22 μM for the rat and human, respectively. Results showed that zearalenone competitively inhibited HSD11B2 when a steroid substrate was used. However, it served as an uncompetitive inhibitory factor when the cofactor NAD+was used. In contrast, the potency of zearalenone to inhibit both rat and human HSD11B1 was diminished, with the concentration of 100 μM causing almost no inhibitory effect on the isoform. In conclusion, we observed that zearalenone is a selective inhibitor of HSD11B2, implying that this agent may cause excessive glucocorticoid action in local tissues such as kidney and placentas.

scholarly journals The Herbal Combination CPA4-1 Inhibits Changes in Retinal Capillaries and Reduction of Retinal Occludin in db/db Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 627 ◽  
Author(s):  
Young Sook Kim ◽  
Junghyun Kim ◽  
Chan-Sik Kim ◽  
Ik Soo Lee ◽  
Kyuhyung Jo ◽  
...  
Keyword(s):  
Inhibitory Concentration ◽  
Inhibitory Effect ◽  
Advanced Glycation ◽  
Blood Retinal Barrier ◽  
Breaking Effect ◽  
Fenofibrate Treatment ◽  
Glycation End Products ◽  
Paeoniae Radix ◽  
Retinal Capillaries

Increased formation of advanced glycation end products (AGEs) plays an important role in the development of diabetic retinopathy (DR) via blood-retinal barrier (BRB) dysfunction, and reduction of AGEs has been suggested as a therapeutic target for DR. In this study, we examined whether CPA4-1, a herbal combination of Cinnamomi Ramulus and Paeoniae Radix, inhibits AGE formation. CPA4-1 and fenofibrate were tested to ameliorate changes in retinal capillaries and retinal occludin expression in db/db mice, a mouse model of obesity-induced type 2 diabetes. CPA4-1 (100 mg/kg) or fenofibrate (100 mg/kg) were orally administered once a day for 12 weeks. CPA4-1 (the half maximal inhibitory concentration, IC50 = 6.84 ± 0.08 μg/mL) showed approximately 11.44-fold higher inhibitory effect on AGE formation than that of aminoguanidine (AG, the inhibitor of AGEs, IC50 = 78.28 ± 4.24 μg/mL), as well as breaking effect on AGE-bovine serum albumin crosslinking with collagen (IC50 = 1.30 ± 0.37 μg/mL). CPA4-1 treatment ameliorated BRB leakage and tended to increase retinal occludin expression in db/db mice. CPA4-1 or fenofibrate treatment significantly reduced retinal acellular capillary formation in db/db mice. These findings suggested the potential of CPA4-1 as a therapeutic supplement for protection against retinal vascular permeability diseases.

Lack of Renal 11β-Hydroxysteroid Dehydrogenase Type 2 at Birth in Humans and Mice: A Targeted Temporal Window for Glucocorticoid Action?

2011 ◽  
pp. P2-577-P2-577
Author(s):  
Laetitia Martinerie ◽  
Pascal Boileau ◽  
Geri Meduri ◽  
Anne-Lise Delezoide ◽  
Eric Pussard ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Temporal Window ◽  
Glucocorticoid Action

11β-Hydroxysteroid dehydrogenase type 1 and bone

2016 ◽  
Vol 25 (04) ◽  
pp. 256-261
Author(s):  
M. S. Cooper
Keyword(s):  
Bone Cells ◽  
Enzyme System ◽  
Hydroxysteroid Dehydrogenase ◽  
Hydroxysteroid Dehydrogenases ◽  
Clinical Consequences ◽  
Functional Consequences ◽  
Expression Activity ◽  
New Treatments ◽  
Glucocorticoid Action

SummaryIntracellular enzymatic metabolism of glucocorticoids is an important contributor to glucocorticoid action. The most extensively studied glucocorticoid metabolising enzymes are the 11β-hydroxysteroid dehydrogenases (11β-HSDs). These enzymes interconvert hormonally inactive glucocorticoids such as cortisone and dehydrocorticosterone with their active counterparts cortisol and corticosterone. 11β-HSDs have been reported to be expressed in bone and bone cells. This article reviews the literature relating to the expression, activity and functional consequences of 11β-HSD expression in bone. This activity appears to have clinical consequences in terms of predisposition towards osteoporosis and fracture and in the variation between individuals in the sensitivity of bone to therapeutic glucocorticoids. The existence of this enzyme system within bone opens up opportunities for new treatments to protect bone from the adverse effects of glucocorticoids.

scholarly journals Lack of Renal 11 Beta-Hydroxysteroid Dehydrogenase Type 2 at Birth, a Targeted Temporal Window for Neonatal Glucocorticoid Action in Human and Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (2) ◽  
pp. e31949 ◽  
Author(s):  
Laetitia Martinerie ◽  
Eric Pussard ◽  
Geri Meduri ◽  
Anne-Lise Delezoide ◽  
Pascal Boileau ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Temporal Window ◽  
Glucocorticoid Action

scholarly journals Transgenic Expression of 11β-Hydroxysteroid Dehydrogenase Type 2 in Osteoblasts Reveals an Anabolic Role for Endogenous Glucocorticoids in Bone

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 922-929 ◽  
Author(s):  
Lorin B. Sher ◽  
Henning W. Woitge ◽  
Douglas J. Adams ◽  
Gloria A. Gronowicz ◽  
Zygmunt Krozowski ◽  
...  
Keyword(s):  
Trabecular Bone ◽  
Collagen Synthesis ◽  
Hydroxysteroid Dehydrogenase ◽  
Inhibitory Effect ◽  
In Vitro Models ◽  
Transgenic Expression ◽  
Glucocorticoid Signaling ◽  
Osteoid Surface

Abstract Glucocorticoid excess leads to bone loss, primarily by decreasing bone formation. However, a variety of in vitro models show that glucocorticoids can promote osteogenesis. To elucidate the role of endogenous glucocorticoids in bone metabolism, we developed transgenic (TG) mice in which a 2.3-kb Col1a1 promoter fragment drives 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression in mature osteoblasts. 11β-HSD2 should metabolically inactivate endogenous glucocorticoids in the targeted cells, thereby reducing glucocorticoid signaling. The inhibitory effect of 300 nm hydrocortisone on percent collagen synthesis was blunted in TG calvariae, demonstrating that the transgene was active. Collagen synthesis rates were lower in TG calvarial organ cultures compared with wild-type. Trabecular bone parameters measured by microcomputed tomography were reduced in L3 vertebrae, but not femurs, of 7- and 24-wk-old TG females. These changes were also not seen in males. In addition, histomorphometry showed that osteoid surface was increased in TG female vertebrae, suggesting that mineralization may be impaired. Our data demonstrate that endogenous glucocorticoid signaling is required for normal vertebral trabecular bone volume and architecture in female mice.

Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1–AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones

2000 ◽  
Vol 351 (1) ◽  
pp. 67-77 ◽  
Author(s):  
Trevor M. PENNING ◽  
Michael E. BURCZYNSKI ◽  
Joseph M. JEZ ◽  
Chien-Fu HUNG ◽  
Hseuh-Kung LIN ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Hydroxysteroid Dehydrogenase ◽  
Reaction Products ◽  
Functional Plasticity ◽  
Dominant Form ◽  
Female Sex Hormones ◽  
Steroid Substrate ◽  
Type 3

The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3α-hydroxysteroid dehydrogenase (3α-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3α-HSD (AKR1C4), type 2 3α(17β)-HSD (AKR1C3), type 3 3α-HSD (AKR1C2) and 20α(3α)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3α-, 17β- and 20α-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with kcat/Km values for substrates that exceeded those obtained with other isoforms by 10–30-fold. In the reduction direction, all isoforms inactivated 5α-dihydrotestosterone (17β-hydroxy-5α-androstan-3-one; 5α-DHT) to yield 5α-androstane-3α,17β-diol (3α-androstanediol). However, only AKR1C3 reduced ∆4-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17β-oestradiol, and progesterone to 20α-hydroxy-pregn-4-ene-3,20-dione (20α-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3α-androstanediol to the active hormone 5α-DHT. AKR1C3 and AKR1C4 oxidized testosterone to ∆4-androstene-3,17-dione. All isoforms oxidized 17β-oestradiol to oestrone, and 20α-hydroxyprogesterone to progesterone. Discrete tissue distribution of these AKR1C enzymes was observed using isoform-specific reverse transcriptase-PCR. AKR1C4 was virtually liver-specific and its high kcat/Km allows this enzyme to form 5α/5β-tetrahydrosteroids robustly. AKR1C3 was most prominent in the prostate and mammary glands. The ability of AKR1C3 to interconvert testosterone with ∆4-androstene-3,17-dione, but to inactivate 5α-DHT, is consistent with this enzyme eliminating active androgens from the prostate. In the mammary gland, AKR1C3 will convert ∆4-androstene-3,17-dione to testosterone (a substrate aromatizable to 17β-oestradiol), oestrone to 17β-oestradiol, and progesterone to 20α-hydroxyprogesterone, and this concerted reductive activity may yield a pro-oesterogenic state. AKR1C3 is also the dominant form in the uterus and is responsible for the synthesis of 3α-androstanediol which has been implicated as a parturition hormone. The major isoforms in the brain, capable of synthesizing anxiolytic steroids, are AKR1C1 and AKR1C2. These studies are in stark contrast with those in rat where only a single AKR with positional- and stereo-specificity for 3α-hydroxysteroids exists.

Selective Inhibition of Thromboxane Synthetase with Dazoxiben - Basis of Its Inhibitory Effect on Platelet Adhesion

1983 ◽  
Vol 49 (02) ◽  
pp. 096-101 ◽  
Author(s):  
V C Menys ◽  
J A Davies
Keyword(s):  
Arachidonic Acid ◽  
Platelet Adhesion ◽  
Fold Increase ◽  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Coated Glass ◽  
Thromboxane Synthetase ◽  
Pre Treatment

SummaryPlatelet adhesion to rabbit aortic subendothelium or collagen-coated glass was quantitated in a rotating probe device by uptake of radio-labelled platelets. Under conditions in which aspirin had no effect, dazoxiben, a selective inhibitor of thromboxane synthetase, reduced platelet adhesion to aortic subendothelium by about 40% but did not affect adhesion to collagen-coated glass. Pre-treatment of aortic segments with 15-HPETE, a selective inhibitor of PGI2-synthetase, abolished the inhibitory effect of dazoxiben on adhesion. Concentrations of 6-oxo-PGFlα in the perfusate were raised in the presence of dazoxiben alone, and following addition of thrombin (10 units/ml) there was a 2-3 fold increase in concentration. Perfusion of damaged aorta with platelets labelled with (14C)-arachidonic acid in the presence of thrombin and dazoxiben resulted in the appearance of (14C)-labelled-6-oxo-PGFiα. Inhibition of thromboxane synthetase limits platelet adhesion probably by promoting vascular synthesis of PGI2 from endoperoxides liberated from adherent platelets, which subsequently promotes detachment of cells from the surface.

scholarly journals In Vitro Effects of Doxycycline on Replication of Feline Coronavirus

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 312
Author(s):  
Magdalena Dunowska ◽  
Sayani Ghosh
Keyword(s):  
Inhibitory Concentration ◽  
Infectious Virus ◽  
Treatment Options ◽  
Inhibitory Effect ◽  
Virus Titration ◽  
Reverse Transcription Quantitative Pcr ◽  
In Vitro Effects ◽  
Dose Dependent ◽  
Feline Coronavirus

Feline infectious peritonitis (FIP) is a sporadic fatal disease of cats caused by a virulent variant of feline coronavirus (FCoV), referred to as FIP virus (FIPV). Treatment options are limited, and most of the affected cats die or are euthanized. Anecdotally, doxycycline has been used to treat FIP-affected cats, but there are currently no data to support or discourage such treatment. The aim of this study was to establish whether doxycycline inhibits replication of FIPV in vitro. The virus was cultured in Crandell-Rees feline kidney cells with various concentrations of doxycycline (0 to 50 µg/mL). The level of FIPV in cultures was determined by virus titration and FCoV-specific reverse-transcription quantitative PCR. Cell viability was also monitored. There was no difference in the level of infectious virus or viral RNA between doxycycline-treated and untreated cultures at 3, 12- and 18-hours post-infection. However, at 24 h, the growth of FIPV was inhibited by approximately two logs in cultures with >10 µg/mL doxycycline. This inhibition was dose-dependent, with inhibitory concentration 50% (IC50) 4.1 µg/mL and IC90 5.4 µg/mL. Our data suggest that doxycycline has some inhibitory effect on FIPV replication in vitro, which supports future clinical trials of its use for the treatment of FIP-affected cats.

Sign in / Sign up

Export Citation Format

Share Document