Kolaviron Biflavanoids of Garcinia Kola Seeds Protect Atrazine-Induced Cytotoxicity in Primary Cultures of Rat Leydig Cells

2012 ◽  
Vol 31 (4) ◽  
pp. 407-415 ◽  
Author(s):  
Sunny O. Abarikwu ◽  
Ebenezer O. Farombi ◽  
Aditya B. Pant
Keyword(s):  
Superoxide Dismutase ◽  
Messenger Rna ◽  
Leydig Cells ◽  
Primary Cultures ◽  
Regulatory Protein ◽  
Mrna Levels ◽  
Garcinia Kola ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Steroidogenic Acute Regulatory

We sought to explore the mechanism by which kolaviron (Kol) protects against atrazine (ATZ)-induced toxicity of cultured interstitial Leydig cells (ILCs). In our experiments, treatment with Kol improved Leydig cell viability and significantly reduced malondialdehyde (MDA) and reactive oxygen species (ROS) levels. Further investigations revealed a reduction in glutathione peroxidase (GSH-Px), glutathione reductase (GR), glutathione-S-transferase (GST) and elevation of superoxide dismutase 1 (SOD-1) and superoxide dismutase 2 (SOD-2) as measured by messenger RNA (mRNA) expression. Additionally, the ATZ-induced alterations in the mRNA transcript copy numbers of steroidogenesis genes: steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage enzyme (CYP11A1), and 3β-hydroxysteroid dehydrogenase (3β-HSD) were shifted toward the control values by Kol. Taken together, these findings indicate that Kol protects ILCs from ATZ-induced toxicity via the reduction in ROS and MDA levels and induce normalization of mRNA levels of all the tested genes.

scholarly journals Short term regulation of aldosterone secretion after stimulation and suppression experiments in mice

2009 ◽  
Vol 42 (5) ◽  
pp. 407-413 ◽  
Author(s):  
Ariadni Spyroglou ◽  
Jenny Manolopoulou ◽  
Sibylle Wagner ◽  
Martin Bidlingmaier ◽  
Martin Reincke ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Regulatory Protein ◽  
Zona Glomerulosa ◽  
Mrna Levels ◽  
Aldosterone Secretion ◽  
Sham Injection ◽  
Chain Cleavage ◽  
Sustained Reduction ◽  
Cleavage Enzyme ◽  
Steroidogenic Acute Regulatory

Aldosterone is synthesized acutely from the zona glomerulosa cells upon stimulation by the renin–angiotensin–aldosterone system. Several enzymes are involved in this steroidogenic process including the steroidogenic acute regulatory protein (StAR), P450 side chain cleavage enzyme (Cyp11a1), and aldosterone synthase (Cyp11b2) which has been demonstrated to be transcriptionally regulated by the nuclear transcription factors NGF1-B and Nurr1. We investigated the short time transcriptional regulation of these genes in wild-type mice at 10 min intervals for 1 h following application of 0.2 nmol angiotensin II (ANGII) or sodium chloride in comparison sham injections. Using real-time PCR a fast upregulation of adrenal Cyp11b2 expression (53±5% increase over baseline) could be observed 10 min after sham injection which was accompanied by a transient increase in aldosterone secretion while StAR and Cyp11a1 upregulation was delayed and more sustained. ANGII caused an increase of StAR and Cyp11a1 expression similar to that observed after sham injection while Cyp11b2 upregulation was more pronounced (10 min, 236±39%) and reflected ANGII induced stimulation of aldosterone output. Sodium challenge was followed by a sustained reduction of all three genes examined (Cyp11b2, 20 min, −63±6%) which was accompanied by a significant suppression of aldosterone secretion detectable after 60 min. While increases in NGF1-B mRNA levels were similar between the treatment groups, Nurr1 expression levels were induced only upon ANGII administration. These data suggest that acute regulation of aldosterone synthesis is accompanied by fast transcriptional modulation of steroidogenic enzymes and transcription factors that are likely to be involved in aldosterone secretion.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Rare defects in adrenal steroidogenesis

2018 ◽  
Vol 179 (3) ◽  
pp. R125-R141 ◽  
Author(s):  
Walter L Miller
Keyword(s):  
Genetic Disorders ◽  
Regulatory Protein ◽  
Hydroxylase Deficiency ◽  
Rare Mutations ◽  
Chain Cleavage ◽  
Adrenal Steroidogenesis ◽  
Cleavage Enzyme ◽  
Different Populations ◽  
Steroidogenic Acute Regulatory ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders of adrenal steroidogenesis that impair cortisol synthesis, with compensatory increases in ACTH leading to hyperplastic adrenals. The term ‘CAH’ is generally used to mean ‘steroid 21-hydroxylase deficiency’ (21OHD) as 21OHD accounts for about 95% of CAH in most populations; the incidences of the rare forms of CAH vary with ethnicity and geography. These forms of CAH are easily understood on the basis of the biochemistry of steroidogenesis. Defects in the steroidogenic acute regulatory protein, StAR, disrupt all steroidogenesis and are the second-most common form of CAH in Japan and Korea; very rare defects in the cholesterol side-chain cleavage enzyme, P450scc, are clinically indistinguishable from StAR defects. Defects in 3β-hydroxysteroid dehydrogenase, which also causes disordered sexual development, were once thought to be fairly common, but genetic analyses show that steroid measurements are generally unreliable for this disorder. Defects in 17-hydroxylase/17,20-lyase ablate synthesis of sex steroids and also cause mineralocorticoid hypertension; these are common in Brazil and in China. Isolated 17,20-lyase deficiency can be caused by rare mutations in at least three different proteins. P450 oxidoreductase (POR) is a co-factor used by 21-hydroxylase, 17-hydroxylase/17,20-lyase and aromatase; various POR defects, found in different populations, affect these enzymes differently. 11-Hydroxylase deficiency is the second-most common form of CAH in European populations but the retention of aldosterone synthesis distinguishes it from 21OHD. Aldosterone synthase deficiency is a rare salt-losing disorder. Mild, ‘non-classic’ defects in all of these factors have been described. Both the severe and non-classic disorders can be treated if recognized.

scholarly journals Evaluation of relative roles of LH and FSH in regulation of differentiation of Leydig cells using an ethane 1,2-dimethylsulfonate-treated adult rat model

2003 ◽  
Vol 176 (1) ◽  
pp. 151-161 ◽  
Author(s):  
V Sriraman ◽  
MR Sairam ◽  
AJ Rao
Keyword(s):  
Leydig Cells ◽  
Serum Testosterone ◽  
Side Chain ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Lh Receptor ◽  
Side Chain Cleavage ◽  
Chain Cleavage ◽  
Cleavage Enzyme

The relative role of LH and FSH in regulation of differentiation of Leydig cells was assessed using an ethane 1,2-dimethylsulfonate (EDS)-treated rat model in which endogenous LH or FSH was neutralized from day 3 to day 22 following EDS treatment. Serum testosterone and the in vitro response of the purified Leydig cells to human chorionic gonadotropin (hCG) was monitored. In addition RNA was isolated from the Leydig cells to monitor the steady-state mRNA levels by RT-PCR for 17alpha-hydroxylase, side chain cleavage enzyme, steroidogenic acute regulatory protein (StAR), LH receptor, estrogen receptor (ER-alpha) and cyclophilin (internal control). Serum testosterone was undetected and the isolated Leydig cells secreted negligible amount of testosterone on stimulation with hCG in the group of rats that were treated with LH antiserum following EDS treatment. RT-PCR analysis revealed the absence of message for cholesterol side chain cleavage enzyme and 17alpha-hydroxylase although ER-alpha and LH receptor mRNA could be detected, indicating the presence of undifferentiated precursor Leydig cells. In contrast, the effects following deprival of endogenous FSH were not as drastic as seen following LH neutralization. Deprival of endogenous FSH in EDS-treated rats led to a significant decrease in serum testosterone and in vitro response to hCG by the Leydig cells. Also, there was a significant decrease in the steady-state mRNA levels of 17alpha-hydroxylase, cholesterol side chain cleavage enzyme, LH receptor and StAR as assessed by a semiquantitative RT-PCR. These results establish that while LH is obligatory for the functional differentiation of Leydig cells, repopulation of precursor Leydig cells is independent of LH, and also unequivocally establish an important role for FSH in regulation of Leydig cell function.

scholarly journals Spontaneous Feminization in a 46,XX Female Patient with Congenital Lipoid Adrenal Hyperplasia Due to a Homozygous Frameshift Mutation in the Steroidogenic Acute Regulatory Protein*

1997 ◽  
Vol 82 (5) ◽  
pp. 1511-1515 ◽  
Author(s):  
Himangshu S. Bose ◽  
Ora Hirsch Pescovitz ◽  
Walter L. Miller
Keyword(s):  
Frameshift Mutation ◽  
Regulatory Protein ◽  
Severe Form ◽  
Adrenal Hyperplasia ◽  
Hormone Production ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Low Levels ◽  
Steroidogenic Cells ◽  
Steroidogenic Acute Regulatory

Abstract The most severe form of congenital adrenal hyperplasia (CAH) is lipoid CAH. It was once thought that this disease was due to mutations in the cholesterol side-chain cleavage enzyme system, thus eliminating the ability to convert cholesterol to pregnenolone, causing a complete absence of steroid hormone production. We recently showed that lipoid CAH is due to mutations in the steroidogenic acute regulatory (StAR) protein, thus preventing acutely stimulated adrenal and gonadal responses to tropic stimulation. However, this lesion may permit low levels of StAR-independent steroidogenesis to persist until the accumulation of intracellular lipid deposits destroys steroidogenic capacity. This model would predict that the steroidogenic cells of the ovaries of affected 46,XX females should remain undamaged until puberty, at which time low levels of StAR-independent estrogen biosynthesis should be detectable. We describe a 15.5-yr-old 46,XX female with a classic history of lipoid CAH who underwent spontaneous feminization and cyclical vaginal bleeding beginning at age 13. Genetic analysis of the patient and her parents showed that she was homozygous for the novel StAR frameshift mutation 261delT. This is the first adolescent female with lipoid CAH who has undergone spontaneous feminization and who has been analyzed genetically. Finding an inactive StAR gene in this patient confirms our two-hit model of the pathogenesis of lipoid CAH, in which loss of StAR activity initially preserves StAR-independent steroidogenesis, which is lost only after cells undergo chronic tropic stimulation and subsequent damage from accumulation of cholesterol esters.

scholarly journals Activation of a Neural Brain-Testicular Pathway Rapidly Lowers Leydig Cell Levels of the Steroidogenic Acute Regulatory Protein and the Peripheral-Type Benzodiazepine Receptor while Increasing Levels of Neuronal Nitric Oxide Synthase

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 624-633 ◽  
Author(s):  
Melissa Herman ◽  
Catherine Rivier
Keyword(s):  
Nitric Oxide ◽  
Leydig Cells ◽  
Neuronal Nitric Oxide Synthase ◽  
Benzodiazepine Receptor ◽  
Side Chain ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Peripheral Type ◽  
Steroidogenic Acute Regulatory ◽  
Oxide Synthase

Activation of a neural brain-testicular pathway by the intracerebroventricular injection of the β-adrenergic agonist isoproterenol (ISO), the hypothalamic peptide corticotropin-releasing factor (CRF), or alcohol (EtOH) rapidly decreases the testosterone (T) response to human chorionic gonadotropin. To elucidate the intratesticular mechanisms responsible for this phenomenon, we investigated the influence of intracerebroventricular-injected ISO, CRF, or EtOH on levels of the steroidogenic acute regulatory (StAR) protein, the peripheral-type benzodiazepine receptor (PBR), and the cytochrome P450 side-chain cleavage enzyme in semipurified Leydig cells. ISO (10 μg), CRF (5 μg), or EtOH (5 μl of 200 proof, a dose that does not induce neuronal damage nor leaks to the periphery) rapidly decreased StAR and PBR but not cytochrome P450 side-chain cleavage enzyme protein levels. Levels of the variant of the neuronal nitric oxide synthase (nNOS) that is restricted to Leydig cells, TnNOS, significantly increased in response to ISO, CRF, and EtOH over the time course of altered StAR/PBR concentrations. However, pretreatment of the rats with Nwnitro-arginine methylester, which blocked ISO-induced increases in TnNOS, neither restored the T response to human chorionic gonadotropin nor prevented the decreases in StAR and PBR. These results provide evidence of concomitant changes in Leydig cell StAR and PBR levels in live rats. They also indicate that activation of a neural brain-testicular pathway rapidly decreases concentrations of these steroidogenic proteins while up-regulating testicular NO production. However, additional studies are necessary to elucidate the functional role played by this gas in our model.

scholarly journals Diametric Effects of Bacterial Endotoxin Lipopolysaccharide on Adrenal and Leydig Cell Steroidogenic Acute Regulatory Protein

Endocrinology ◽  
2000 ◽  
Vol 141 (11) ◽  
pp. 4000-4012 ◽  
Author(s):  
Karen Held Hales ◽  
Thorsten Diemer ◽  
Salil Ginde ◽  
Birinder K. Shankar ◽  
Maretha Roberts ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Leydig Cells ◽  
Regulatory Protein ◽  
Serum Testosterone ◽  
Northern Analysis ◽  
Dependent Manner ◽  
Star Protein ◽  
Adrenal Steroidogenesis ◽  
Serum Lh ◽  
Steroidogenic Acute Regulatory

Abstract Immune activation results in the activation of adrenal steroidogenesis and inhibition of gonadal steroidogenesis. Previous studies indicated that these effects were caused primarily by activation and suppression of the secretion of ACTH and LH, respectively. However, other evidence indicated a direct effect of the immune system on the gonads. In this study, serum testosterone, quantitated by RIA after lipopolysaccharide injection, showed a significant decrease within 2 h. Parallel measurement of serum LH showed no change. There were no differences in LH receptor or cAMP produced in Leydig cells between vehicle- and lipopolysaccharide-injected mice. The 30-kDa form of the steroidogenic acute regulatory (StAR) protein was quantitated, by Western blot, in Leydig cells and was found to decrease in a time-dependent manner. No change in StAR protein messenger RNA (mRNA) was detected by Northern analysis during this time, nor were any changes found in the levels of mRNA for the steroidogenic enzymes P450scc, 3β-hydroxysteroid dehydrogenaseΔ 4-Δ5-isomerase, or P450c17. In the adrenal, StAR protein was increased, as was StAR protein mRNA. No changes were observed in the levels of mRNA for P450scc, 3β-hydroxysteroid dehydrogenaseΔ 4-Δ5-isomerase, or P450c21. Thus, although the mechanisms of regulation differ, changes in the levels of StAR protein are a sensitive indicator of the steroidogenic capacity of these two tissues.

Transcriptional Regulation of Steroidogenic Genes: STARD1, CYP11A1 and HSD3B

2009 ◽  
Vol 234 (8) ◽  
pp. 880-907 ◽  
Author(s):  
Holly A. LaVoie ◽  
Steven R. King
Keyword(s):  
Transcriptional Regulation ◽  
Current Knowledge ◽  
Regulatory Protein ◽  
Side Chain ◽  
Combinatorial Regulation ◽  
Cytochrome P450scc ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Steroidogenic Acute Regulatory ◽  
Species Specific

Expression of the genes that mediate the first steps in steroidogenesis, the steroidogenic acute regulatory protein (STARD1), the cholesterol side-chain cleavage enzyme, cytochrome P450scc (CYP11A1) and 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (HSD3B), is tightly controlled by a battery of transcription factors in the adrenal cortex, the gonads and the placenta. These genes generally respond to the same hormones that stimulate steroid production through common pathways such as cAMP signaling and common actions on their promoters by proteins such as NR5A and GATA family members. However, there are distinct temporal, tissue and species-specific differences in expression between the genes that are defined by combinatorial regulation and unique promoter elements. This review will provide an overview of the hormonal and transcriptional regulation of the STARD1, CYP11A1 and specific steroidogenic HSD3B genes in the adrenal, testis, ovary and placenta and discuss the current knowledge regarding the key transcriptional factors involved.

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