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Raghvendra K Dubey - One of the best experts on this subject based on the ideXlab platform.
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the estrogen metabolites 2 methoxyestradiol and 2 Hydroxyestradiol inhibit endometriotic cell proliferation in estrogen receptor independent manner
Gynecological Endocrinology, 2016Co-Authors: Eleftherios P Samartzis, Raghvendra K Dubey, Patrick Imesch, Anja Twiehaus, Brigitte LeenersAbstract:AbstractEndometriosis, a painful disorder associated with infertility, is estimated to occur in approximately 7–10% of reproductive age women. Although endometriosis is considered as an estrogen-dependent disease, the role of estrogen metabolites via receptor-independent mechanisms has not yet been comprehensively clarified. In the present study, growth studies were performed comparing the effect of estradiol (E2), estrogen metabolites, that is, 2-Hydroxyestradiol (2-OHE2) and 2-methoxyestradiol (2-ME), as well as estrogen-receptor-independent mechanisms using the estrogen receptor antagonist fulvestrant, on cell proliferation of endometriotic cells. The estrogen metabolites 2-OHE2 and 2-ME inhibited cell growth in a dose-dependent manner in pharmacological doses. Lower concentrations of 2-OHE2 had a stimulating effect on cell proliferation while pharmacologic doses exerted an antimitogenic effect. The effects on cell growth were at least partially receptor-independent, as demonstrated by simultaneous rec...
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2 Hydroxyestradiol is a prodrug of 2 methoxyestradiol
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Lefteris C Zacharia, Raghvendra K Dubey, Claude A Piche, Robert M Fielding, Kathleen M Holland, Dean S Allison, Edwin K JacksonAbstract:Previous in vivo studies indicate that 2-Hydroxyestradiol (2OHE) attenuates cardiovascular and renal diseases. In vitro studies suggest that the biological effects of 2OHE are mediated by 2-methoxyestradiol (2MEOE) after methylation of 2OHE by catechol-O-methyltransferase (COMT). This study tested the hypothesis that in vivo 2OHE is a prodrug of 2MEOE. We administered to male rats i.v. boluses of either 2OHE or 2MEOE and measured plasma levels of 2OHE and 2MEOE by gas chromatography-mass spectrometry at various time points after drug administration. After administration of 2OHE, plasma levels of 2OHE declined extremely rapidly [t(1/2(1)) = 0.94 min and t(1/2(2)) = 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t(1/2(1)) = 7.9 min and t(1/2(2)) = 24.9 min]. The peak concentration and total exposure (area under the curve) for 2OHE were much lower than for 2MEOE. 2OHE had a much higher plasma clearance (CL) and volume of distribution (V(d)) compared with 2MEOE (2OHE: CL = 1215 ml min(-1) kg(-1) and V(d) = 17,875 ml/kg; 2MEOE: CL = 50 ml min(-1) kg(-1) and V(d) = 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t(1/2(1)) = 2.5 min and t(1/2(2)) = 20.2 min] with a plasma CL of 50 ml min(-1) kg(-1) and a V(d) of 1500 ml/kg. We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.
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methylation of 2 Hydroxyestradiol in isolated organs
Hypertension, 2003Co-Authors: Lefteris C Zacharia, Raghvendra K Dubey, Edwin K JacksonAbstract:Vascular smooth muscle and glomerular mesangial cells in culture express a biochemical pathway that methylates 2-Hydroxyestradiol (17β-estradiol metabolite) to produce 2-methoxyestradiol, a cell growth inhibitor that may mediate the cardiorenal protective effects of 17β-estradiol. Whether this pathway exists in intact organ systems is currently unclear. Accordingly, the purpose of the present investigation was to characterize the methylation of 2-hydroxestradiol in intact organs from both male and female rats. No significant differences were detected in the ability of male and female tissues to methylate 2-Hydroxyestradiol. In isolated hearts, kidneys, and mesenteries perfused with Tyrode’s solution, K m values for 2-Hydroxyestradiol methylation were 0.175±0.021, 0.387±0.054, and 0.495±0.089 μmol/L, respectively, and V max values were 21.0±1.58, 24.9±1.49, and 1.01±0.148 pmol 2-methoxyestradiol · min −1 · ml −1 per gram, respectively. The catalytic efficiency (V max /K m ) was greatest in the heart compared with the kidney and mesentery (132±14.3, 78.4±15.1, and 2.30±0.263 pmol 2-methoxyestradiol · min −1 · mL −1 · μmol/L −1 per gram, respectively). In the kidney, the catechol-O-methyltransferase inhibitor quercetin and norepinephrine (10 μmol/L) reduced methylation of 2-Hydroxyestradiol by approximately 90% and 41%, respectively. Importantly, methylation in the kidney was inhibited by an average of 16.6±1.80% by endogenous norepinephrine released by renal artery nerve stimulation. Our results indicate that a robust 2-Hydroxyestradiol methylation pathway exists in the kidney and heart, but not in the mesentery, and that this pathway is mediated by catechol-O-methyltransferase. Our findings also suggest that catecholamines may interfere with 2-Hydroxyestradiol methylation and thereby attenuate the cardiorenal protective effects of 17β-estradiol.
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2 Hydroxyestradiol attenuates renal disease in chronic puromycin aminonucleoside nephropathy
Journal of The American Society of Nephrology, 2002Co-Authors: Stevan P Tofovic, Raghvendra K Dubey, Eman M. Salah, Edwin K JacksonAbstract:It has been previously shown that 2-Hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syn- drome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)-induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 mol/L; P 0.001) inhibited serum (2.5%)-induced cell growth ( 3 H-thymi- dine incorporation), collagen synthesis ( 3 H-proline incorpora- tion), and cell proliferation (cell number). Importantly, the inhibitory effects of 2-OHE (0.1 mol/L) were not blocked by ICI182780 (50 mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg 5 20 mg/kg) over 12 wk induced severe chronic renal disease. Chronic treatment with 2-OHE significantly (P 0.05) atten- uated PAN-induced decrease in glomerular filtration, reduced proteinuria, and the elevated BP, and it had no effect on PAN-induced increase in plasma cholesterol and triglycerides levels. 2-OHE had no effects on plasma testosterone levels in male nephropathic animals. Immunohistochemical staining for collagen IV and proliferating cell nuclear antigen (PCNA) in glomeruli and transforming growth factor- (TGF-) in renal tubular cells were significantly higher in PAN nephropatic rats versus control animals with intact kidneys. PAN also markedly increased glomerular and interstitial macrophage infiltration (ED1 cells). 2-OHE had no effects on renal tubular cell TGF-, but it significantly reduced glomerular PCNA and collagen IV and glomerular and interstitial macrophage infil- tration. In summary, this study provides the first evidence that 2-OHE exerts direct renoprotective effects in vivo. These ef- fects are mediated by estrogen receptor-independent mecha- nisms and are due, at least in part, to the inhibition of some of the key proliferative mechanisms involved in glomerular re- modeling and sclerosis.
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catecholamines block 2 Hydroxyestradiol induced antimitogenesis in mesangial cells
Hypertension, 2002Co-Authors: Lefteris C Zacharia, Edwin K Jackson, Delbert G Gillespie, Raghvendra K DubeyAbstract:Methylation of 2-Hydroxyestradiol to 2-methoxyestradiol by catechol-O-methyl transferase (COMT) mediates the antimitogenic effects of 2-Hydroxyestradiol on vascular smooth muscle cells. Moreover, 2-Hydroxyestradiol inhibits growth of glomerular mesangial cells (GMCs). Because catecholamines are substrates for COMT, which is expressed in GMCs, we hypothesize that catecholamines may abrogate the antimitogenic effects of 2-Hydroxyestradiol on GMCs by competing for COMT and inhibiting 2-methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic effects of 2-Hydroxyestradiol on rat GMCs in the presence and absence of catecholamines. The capability of GMCs to methylate 2-Hydroxyestradiol in the presence and absence of catecholamines was also evaluated. GMCs metabolized 2-hydoxyestradiol in a concentration-dependent manner with a V max of 12.03±0.32 pmol/10 6 cells/min and an apparent K m of 0.23±0.04 μmol/L. Norepinephrine (10 μmol/L) and epinephrine (10 μmol/L) significantly inhibited methylation of 0.25 μmol/L 2-Hydroxyestradiol. Norepinephrine concentration-dependently abrogated the ability of 2-Hydroxyestradiol to inhibit 3 H-thymidine incorporation (index of DNA synthesis). In the presence of 5, 10, and 40 μmol/L norepinephrine, the inhibitory effect of 0.1 μmol/L 2-Hydroxyestradiol on 3 H-thymidine incorporation was reduced from 51±0.7% to 46±0.4%, 39±0.3%, and 25±0.7%, respectively. Similar to DNA synthesis, the inhibitory effects of 2-Hydroxyestradiol on cell number and 3 H-proline incorporation (index of collagen synthesis) on GMCs were abrogated by catecholamines. Our findings provide evidence that methylation of 2-Hydroxyestradiol inhibits GMC proliferation and extracellular matrix synthesis and may in part protect against renal proliferative diseases. Moreover, catecholamines may abrogate the renoprotective effects of 2-Hydroxyestradiol in the glomeruli by inhibiting COMT and 2-methoxyestradiol formation.
Edwin K Jackson - One of the best experts on this subject based on the ideXlab platform.
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J Am Soc Nephrol 13: 2737–2747, 2002 2-Hydroxyestradiol Attenuates Renal Disease in Chronic
2013Co-Authors: Puromycin Aminonucleoside Nephropathy, Stevan P Tofovic, Raghvendra Dubey, Eman M. Salah, Edwin K JacksonAbstract:Abstract. It has been previously shown that 2-Hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syndrome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 �g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)–induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 �mol/L; P � 0.001) inhibited serum (2.5%)–induced cell growth ( 3 H-thymidine incorporation), collagen synthesis ( 3 H-proline incorporation)
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2 methoxyestradiol and 2 ethoxyestradiol retard the progression of renal disease in aged obese diabetic zsf1 rats
Journal of Cardiovascular Pharmacology, 2007Co-Authors: Xinchen Zhang, Edwin K Jackson, Youhong Jia, Stevan P TofovicAbstract:Abstract:The metabolic syndrome is a main cause for cardiovascular disease and for the accelerating epidemic of chronic renal failure. Previous studies show that 2-Hydroxyestradiol (2-HE), an estradiol metabolite with little estrogenic activity, decreases obesity and arterial blood pressure and atte
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2 Hydroxyestradiol is a prodrug of 2 methoxyestradiol
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Lefteris C Zacharia, Raghvendra K Dubey, Claude A Piche, Robert M Fielding, Kathleen M Holland, Dean S Allison, Edwin K JacksonAbstract:Previous in vivo studies indicate that 2-Hydroxyestradiol (2OHE) attenuates cardiovascular and renal diseases. In vitro studies suggest that the biological effects of 2OHE are mediated by 2-methoxyestradiol (2MEOE) after methylation of 2OHE by catechol-O-methyltransferase (COMT). This study tested the hypothesis that in vivo 2OHE is a prodrug of 2MEOE. We administered to male rats i.v. boluses of either 2OHE or 2MEOE and measured plasma levels of 2OHE and 2MEOE by gas chromatography-mass spectrometry at various time points after drug administration. After administration of 2OHE, plasma levels of 2OHE declined extremely rapidly [t(1/2(1)) = 0.94 min and t(1/2(2)) = 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t(1/2(1)) = 7.9 min and t(1/2(2)) = 24.9 min]. The peak concentration and total exposure (area under the curve) for 2OHE were much lower than for 2MEOE. 2OHE had a much higher plasma clearance (CL) and volume of distribution (V(d)) compared with 2MEOE (2OHE: CL = 1215 ml min(-1) kg(-1) and V(d) = 17,875 ml/kg; 2MEOE: CL = 50 ml min(-1) kg(-1) and V(d) = 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t(1/2(1)) = 2.5 min and t(1/2(2)) = 20.2 min] with a plasma CL of 50 ml min(-1) kg(-1) and a V(d) of 1500 ml/kg. We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.
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methylation of 2 Hydroxyestradiol in isolated organs
Hypertension, 2003Co-Authors: Lefteris C Zacharia, Raghvendra K Dubey, Edwin K JacksonAbstract:Vascular smooth muscle and glomerular mesangial cells in culture express a biochemical pathway that methylates 2-Hydroxyestradiol (17β-estradiol metabolite) to produce 2-methoxyestradiol, a cell growth inhibitor that may mediate the cardiorenal protective effects of 17β-estradiol. Whether this pathway exists in intact organ systems is currently unclear. Accordingly, the purpose of the present investigation was to characterize the methylation of 2-hydroxestradiol in intact organs from both male and female rats. No significant differences were detected in the ability of male and female tissues to methylate 2-Hydroxyestradiol. In isolated hearts, kidneys, and mesenteries perfused with Tyrode’s solution, K m values for 2-Hydroxyestradiol methylation were 0.175±0.021, 0.387±0.054, and 0.495±0.089 μmol/L, respectively, and V max values were 21.0±1.58, 24.9±1.49, and 1.01±0.148 pmol 2-methoxyestradiol · min −1 · ml −1 per gram, respectively. The catalytic efficiency (V max /K m ) was greatest in the heart compared with the kidney and mesentery (132±14.3, 78.4±15.1, and 2.30±0.263 pmol 2-methoxyestradiol · min −1 · mL −1 · μmol/L −1 per gram, respectively). In the kidney, the catechol-O-methyltransferase inhibitor quercetin and norepinephrine (10 μmol/L) reduced methylation of 2-Hydroxyestradiol by approximately 90% and 41%, respectively. Importantly, methylation in the kidney was inhibited by an average of 16.6±1.80% by endogenous norepinephrine released by renal artery nerve stimulation. Our results indicate that a robust 2-Hydroxyestradiol methylation pathway exists in the kidney and heart, but not in the mesentery, and that this pathway is mediated by catechol-O-methyltransferase. Our findings also suggest that catecholamines may interfere with 2-Hydroxyestradiol methylation and thereby attenuate the cardiorenal protective effects of 17β-estradiol.
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2 Hydroxyestradiol attenuates renal disease in chronic puromycin aminonucleoside nephropathy
Journal of The American Society of Nephrology, 2002Co-Authors: Stevan P Tofovic, Raghvendra K Dubey, Eman M. Salah, Edwin K JacksonAbstract:It has been previously shown that 2-Hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syn- drome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)-induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 mol/L; P 0.001) inhibited serum (2.5%)-induced cell growth ( 3 H-thymi- dine incorporation), collagen synthesis ( 3 H-proline incorpora- tion), and cell proliferation (cell number). Importantly, the inhibitory effects of 2-OHE (0.1 mol/L) were not blocked by ICI182780 (50 mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg 5 20 mg/kg) over 12 wk induced severe chronic renal disease. Chronic treatment with 2-OHE significantly (P 0.05) atten- uated PAN-induced decrease in glomerular filtration, reduced proteinuria, and the elevated BP, and it had no effect on PAN-induced increase in plasma cholesterol and triglycerides levels. 2-OHE had no effects on plasma testosterone levels in male nephropathic animals. Immunohistochemical staining for collagen IV and proliferating cell nuclear antigen (PCNA) in glomeruli and transforming growth factor- (TGF-) in renal tubular cells were significantly higher in PAN nephropatic rats versus control animals with intact kidneys. PAN also markedly increased glomerular and interstitial macrophage infiltration (ED1 cells). 2-OHE had no effects on renal tubular cell TGF-, but it significantly reduced glomerular PCNA and collagen IV and glomerular and interstitial macrophage infil- tration. In summary, this study provides the first evidence that 2-OHE exerts direct renoprotective effects in vivo. These ef- fects are mediated by estrogen receptor-independent mecha- nisms and are due, at least in part, to the inhibition of some of the key proliferative mechanisms involved in glomerular re- modeling and sclerosis.
K P Joy - One of the best experts on this subject based on the ideXlab platform.
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in vitro effects of 2 Hydroxyestradiol 17β on ovarian follicular steroid secretion in the catfish heteropneustes fossilis and identification of the receptor and signaling mechanisms
General and Comparative Endocrinology, 2012Co-Authors: T K Chourasia, K P JoyAbstract:Abstract Ovarian pieces containing postvitellogenic follicles were incubated in vitro with different concentrations of the catecholestrogen 2-Hydroxyestradiol-17β (2-OHE 2 ) to evaluate its effects on steroid production and germinal vesicle breakdown (GVBD) in the catfish Heteropneustes fossilis . The incubation with 2-OHE 2 induced a shift in steroidogenic pattern: the C 19 and C 18 steroids testosterone (T) and estradiol-17β (E 2 ), respectively were significantly decreased with a concomitant significant increase in the C 21 steroids progesterone (P 4 ), 17-hydroxyprogesterone (17-OHP), 17,20β-dihydroxy-4-pregnen-3-one (17,20β-DP), 17,20α-dihydroxy-4-pregnen-3-one (17,20α-DP) and cortisol (F). Concomitantly, the catecholestrogen induced dose-dependently GVBD response, the first sign of meiosis resumption. The co- and pre-incubations of the ovarian pieces with 2-OHE 2 , and adrenergic (phentolamine, α-blocker and propranolol, β-blocker) or estrogen (tamoxifen) receptor blockers resulted in inhibition of the stimulatory effect of the catecholestrogen on C 21 steroids and reversed the inhibition of testosterone and E 2 . The α-blocker was more effective than the β-blocker. Our results suggest that 2-OHE 2 appears to employ both adrenergic (α-type) and estrogen receptor mechanisms in mediating the effects. The co- or pre-incubation of ovarian pieces with IBMX (a cAMP elevating drug), H89 (a protein kinase A inhibitor), and PD098059 (a MAP kinase kinase inhibitor) significantly inhibited the stimulatory effect of 2-OHE 2 on the C 21 steroids. The effect of chelerythrine (a protein kinase C inhibitor), on the other hand, varied with the incubation condition. In the co-incubation, the steroids showed varied effects: 17,20β-DP, testosterone and E 2 were elevated, and P 4 and 17-OHP were decreased. In the pre-incubation set up, all the steroids were inhibited except E 2 . The inhibition by the blockers was higher in the pre-incubation groups. Taken together, the data suggest the involvement cAMP–protein kinase A, protein kinase C and MAP kinase pathways in the modulation of the steroidogenic activity.
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2 Hydroxyestradiol 17β induced oocyte maturation in catfish heteropneustes fossilis involves protein kinase c and its interaction with protein phosphatases
Comparative Biochemistry and Physiology A-molecular & Integrative Physiology, 2006Co-Authors: Abha Mishra, K P JoyAbstract:Abstract In vitro effects of phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, calphostin C (PKC inhibitor) and okadaic acid [OA, a protein phosphatase (PP; PP1 and PP2A) inhibitor] on 2-Hydroxyestradiol-17β (2-OHE 2 )-induced oocyte maturation were investigated in the catfish Heteropneustes fossilis . Incubations of postvitellogenic follicles with PMA or OA alone did not induce oocyte maturation. However, co-incubations with 2-OHE 2 and PMA (0.05, 0.5 and 5 μM) or 2-OHE 2 and OA (0.5, 1.0 or 2.0 μM) increased germinal vesicle breakdown (GVBD) significantly over that of 2-OHE 2 . Incubation of follicles with calphostin C elicited varied effects on GVBD, low (0.005 and 0.01 μM) and high (5.0 and 10.0 μM) concentrations did not affect GVBD, but medium concentrations (0.05, 0.1, 0.5, 1.0 and 2.5 μM) stimulated it. The medium concentrations elicited a biphasic stimulatory response with peak GVBD at 0.1 μM (54%). Calphostin C (≥ 2.5 μM) inhibited the 2-OHE 2 -induced GVBD in a concentration-dependent manner during the 24 h incubation. Pre- or post-treatment with calphostin C inhibited the steroid-induced GVBD only at 6 h. In co-incubation studies, both PMA and OA reversed the inhibitory effect of calphostin C: the former partially and the latter fully. The results of the present study show that PKC appears to modulate the 2-OHE 2 -induced oocyte maturation. The OA-sensitive PP may be involved in the PKC modulation of steroid-induced oocyte maturation.
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2 Hydroxyestradiol 17β induced oocyte maturation involvement of camp protein kinase a and okadaic acid sensitive protein phosphatases and their interplay in oocyte maturation in the catfish heteropneustes fossilis
The Journal of Experimental Biology, 2006Co-Authors: Abha Mishra, K P JoyAbstract:SUMMARY In Heteropneustes fossilis , in vitro incubation of postvitellogenic follicles with 2-Hydroxyestradiol-17β (2-OHE 2 , 5 μmol l –1 ) decreased significantly the total cAMP level, concomitant with germinal vesicle breakdown (GVBD). The incubation of the follicles with cAMP or cAMP-elevating drugs [phosphodiesterase (PDE) inhibitors], such as IBMX (3-isobutyl-1-methyl-xanthine), theophylline and caffeine, inhibited the 2-OHE 2 -induced GVBD in a concentration-dependent manner. The magnitude of the response varied: both cAMP and IBMX were effective at all concentrations (0.1–2.0 mmol l –1 ), followed by theophylline (0.5–2.0 mmol l –1 ) and caffeine (1–2.0 mmol l –1 ). The protein kinase A (PKA) inhibitor H89 stimulated oocyte maturation in a concentration-dependent manner. However, when co-incubated with 2-OHE 2 for 24 h it produced a biphasic effect: low concentrations (0.1 and 1.0 μmol l –1 ) did not alter the 2-OHE 2 -induced GVBD, but high concentrations (5 and 10μ mol l –1 ) inhibited it. The incubation of the follicles with H89 lowered the inhibitory effect of IBMX on the 2-OHE 2 -induced GVBD. The incubation of the follicles with okadaic acid (OA), a protein phosphatase 1 and 2A inhibitor did not affect GVBD but when co-incubated with 2-OHE 2 , it enhanced the GVBD response. OA reversed the inhibitory effect of IBMX. The results suggest that OA may overcome the inhibition of 2-OHE 2 -induced GVBD by IBMX at a step distal to the cAMP–PKA pathway.
Stevan P Tofovic - One of the best experts on this subject based on the ideXlab platform.
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J Am Soc Nephrol 13: 2737–2747, 2002 2-Hydroxyestradiol Attenuates Renal Disease in Chronic
2013Co-Authors: Puromycin Aminonucleoside Nephropathy, Stevan P Tofovic, Raghvendra Dubey, Eman M. Salah, Edwin K JacksonAbstract:Abstract. It has been previously shown that 2-Hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syndrome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 �g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)–induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 �mol/L; P � 0.001) inhibited serum (2.5%)–induced cell growth ( 3 H-thymidine incorporation), collagen synthesis ( 3 H-proline incorporation)
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2 methoxyestradiol and 2 ethoxyestradiol retard the progression of renal disease in aged obese diabetic zsf1 rats
Journal of Cardiovascular Pharmacology, 2007Co-Authors: Xinchen Zhang, Edwin K Jackson, Youhong Jia, Stevan P TofovicAbstract:Abstract:The metabolic syndrome is a main cause for cardiovascular disease and for the accelerating epidemic of chronic renal failure. Previous studies show that 2-Hydroxyestradiol (2-HE), an estradiol metabolite with little estrogenic activity, decreases obesity and arterial blood pressure and atte
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2 Hydroxyestradiol attenuates renal disease in chronic puromycin aminonucleoside nephropathy
Journal of The American Society of Nephrology, 2002Co-Authors: Stevan P Tofovic, Raghvendra K Dubey, Eman M. Salah, Edwin K JacksonAbstract:It has been previously shown that 2-Hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syn- drome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)-induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 mol/L; P 0.001) inhibited serum (2.5%)-induced cell growth ( 3 H-thymi- dine incorporation), collagen synthesis ( 3 H-proline incorpora- tion), and cell proliferation (cell number). Importantly, the inhibitory effects of 2-OHE (0.1 mol/L) were not blocked by ICI182780 (50 mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg 5 20 mg/kg) over 12 wk induced severe chronic renal disease. Chronic treatment with 2-OHE significantly (P 0.05) atten- uated PAN-induced decrease in glomerular filtration, reduced proteinuria, and the elevated BP, and it had no effect on PAN-induced increase in plasma cholesterol and triglycerides levels. 2-OHE had no effects on plasma testosterone levels in male nephropathic animals. Immunohistochemical staining for collagen IV and proliferating cell nuclear antigen (PCNA) in glomeruli and transforming growth factor- (TGF-) in renal tubular cells were significantly higher in PAN nephropatic rats versus control animals with intact kidneys. PAN also markedly increased glomerular and interstitial macrophage infiltration (ED1 cells). 2-OHE had no effects on renal tubular cell TGF-, but it significantly reduced glomerular PCNA and collagen IV and glomerular and interstitial macrophage infil- tration. In summary, this study provides the first evidence that 2-OHE exerts direct renoprotective effects in vivo. These ef- fects are mediated by estrogen receptor-independent mecha- nisms and are due, at least in part, to the inhibition of some of the key proliferative mechanisms involved in glomerular re- modeling and sclerosis.
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2 Hydroxyestradiol attenuates the development of obesity the metabolic syndrome and vascular and renal dysfunction in obese zsf1 rats
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Stevan P Tofovic, Raghvendra K Dubey, Edwin K JacksonAbstract:A pandemic of obesity is contributing importantly to the prevalence of the metabolic syndrome characterized by hypertension, insulin resistance, and hyperlipidemia. In turn, the metabolic syndrome is contributing to vascular disease and the accelerating epidemic of chronic renal failure. Currently, pharmacological approaches to attenuate obesity and its cardiovascular/renal sequelae are limited. The purpose of this study was to determine the effects of 2-Hydroxyestradiol, a metabolite of 17β-estradiol with minimal estrogenic activity, on the development of obesity, the metabolic syndrome, and heart, vascular, and renal dysfunction in obese ZSF1 rats, a well-characterized genetic model of obesity and the metabolic syndrome with concomitant heart, vascular, and kidney disease. ZSF1 rats were treated, beginning at 12 weeks of age, for 26 weeks with vehicle or 2-Hydroxyestradiol (10 μg/kg/h). At baseline and after 24 weeks of treatment, animals were placed in metabolic cages, and food intake, water intake, urine output, and urinary excretion of proteins and glucose were determined. Next, in fasting animals, plasma cholesterol was measured, an oral glucose tolerance test was conducted, and total glycated hemoglobin levels were determined. At the end of the study, animals were anesthetized and instrumented for assessment of heart performance, renal hemodynamics, and mesenteric vascular reactivity. 2-Hydroxyestradiol attenuated the development of obesity and improved endothelial function, decreased nephropathy, decreased the severity of diabetes, lowered arterial blood pressure, and reduced plasma cholesterol. 2-Hydroxyestradiol may be an important lead for the development of safe and effect drugs to attenuate obesity and its metabolic, vascular, and renal sequelae.
Maurizio Zuccotti - One of the best experts on this subject based on the ideXlab platform.
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In Vitro Maturation of Fully Grown Mouse Antral Follicles in the Presence of 1 nM 2-Hydroxyestradiol Improves Oocytes’ Developmental Competence
Reproductive Sciences, 2020Co-Authors: Valeria Merico, Mario Zanoni, Alexis Parada-bustamante, Silvia Garagna, Maurizio ZuccottiAbstract:Cathecolestrogens are estradiol metabolites produced during folliculogenesis in the mammalian ovary. 2-Hydroxyestradiol (2-OHE_2) is one of the most abundant although its role remains unknown. The aim of this study is to investigate whether the presence of 2-OHE_2 during the germinal vesicle-to-metaphase II transition affects oocyte meiotic and preimplantation developmental competence. Mouse cumulus-oocyte complexes (COCs), isolated from fully grown antral follicles, were in vitro–matured (IVM) in the presence of 2-OHE_2 (0.1, 1, 10 or 100 nM) for 6 or 15 h; then, their meiotic and developmental competence was evaluated using a number of cytological quality markers. With the exception of the highest dose (100 nM), the addition of 2-OHE_2 to the IVM medium, did not alter, compared with untreated control, the frequency of oocytes that reached the MII stage. Instead, IVM in the presence of 1 nM 2-OHE_2 highly increased the rate of preimplantation development and blastocyst quality. To understand whether this positive effect could be attributed to the events occurring during meiosis resumption, we analysed a number of specific cytological quality markers of the asymmetric division, such as PB-I volume and position, presence and extension of the cortical F-actin cap, meiotic spindle shape and area, and microtubule organisation centre localisation. The results highlighted how the presence of 1 nM 2-OHE_2 significantly improved the overall cytological organisation required for a correct asymmetric division. Our results contribute a first step to acknowledge a potential role of this estradiol metabolite during the GV-to-MII transition, contributing to the acquisition of oocytes developmental competence.
