scholarly journals Glucocorticoids Affect Male Testicular Steroidogenesis

2020 ◽  
pp. S205-S210
Author(s):  
R. HAMPL ◽  
L. STÁRKA
Keyword(s):  
Leydig Cells ◽  
Glucocorticoid Receptors ◽  
Molecular Mechanisms ◽  
Target Cells ◽  
Clinical Effects ◽  
Steroid Production ◽  
Glucocorticoid Treatment ◽  
Testicular Steroidogenesis ◽  
And Function

Through their receptors at each level of hypothalamo-pituitary-gonadal axis glucocorticoid excess, either endogenous or administered or stress-induced, could affect steroid production in the testis and thus male fertility. The main ways by which glucocorticoids act are as follows: 1) Affecting gonadoliberin and LH synthesis and release through glucocorticoid receptors in hypothalamic neurons and pituitary gonadotropes. 2) By so far not clearly evidenced reduction of the number of LH receptors on the membrane of Leydig cells. 3) By affecting expression and function of steroidogenic enzymes in the testis. 4) By regulation of in situ access of glucocorticoid to its target cells in the testis. 5) By promotion Leydig cell apoptosis. The review provides a survey of physiological and molecular mechanisms staying behind these effects. It does not deal with the clinical effects of glucocorticoid treatment which would substantially exceed the scope of the pater.

scholarly journals Ribavirin and Alpha Interferon Enhance Death Receptor-Mediated Apoptosis and Caspase Activation in Human Hepatoma Cells

2003 ◽  
Vol 47 (6) ◽  
pp. 1912-1921 ◽  
Author(s):  
Stephan F. Schlosser ◽  
Markus Schuler ◽  
Christoph P. Berg ◽  
Kirsten Lauber ◽  
Klaus Schulze-Osthoff ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Death Receptor ◽  
Alpha Interferon ◽  
Target Cells ◽  
Clinical Effects ◽  
Caspase Activation ◽  
Human Hepatoma Cells ◽  
Promoting Effect

ABSTRACT The molecular mechanisms underlying the clinical effects of alpha interferon (IFN) and ribavirin are not understood. Elimination of infected cells occurs in part by cytotoxic T lymphocytes (CTLs) expressing CD95 ligand and thereby attacking target cells which are positive for the death receptor CD95. Since many viruses have evolved mechanisms to inhibit apoptosis, the opposite, namely, promotion of apoptosis, could be a strategy to strengthen the host antiviral response. In the present study, we have asked whether the antiviral substances IFN and ribavirin could support CD95-mediated apoptosis by interfering with the activation of caspases, a family of proteases known for their essential role in apoptosis. HepG2 cells, stimulated with the agonistic anti-CD95 antibody, served as a minimal model to mimic the CD95 stimulation ocurring during a CTL attack of target cells in vivo. Apoptosis was quantitated by flow cytometric detection of hypodiploid nuclei. Caspase activity was measured by cytofluorometry, immunocytochemistry, and immunoblot analysis. IFN and ribavirin sensitized HepG2 cells for CD95-mediated apoptosis. This effect was correlated with an increase in CD95-mediated caspase activation and enhanced cleavage of the caspase substrate poly(ADP-ribose) polymerase. Furthermore, the positive effect on CD95-mediated caspase activation by IFN and ribavirin was confirmed by immunocytochemistry for activated caspase-3 and by immunoblot detection of activated caspase-3, caspase-7, and caspase-8. Our data demonstrate that the antiviral substances IFN and ribavirin are able to sensitize for CD95-mediated apoptosis. IFN and ribavirin also enhance CD95-mediated caspase activation, which might in part be responsible for the apoptosis-promoting effect of these antiviral compounds.

scholarly journals Free and sulfated steroids secretion in postpubertal boars (Sus scrofa domestica)

Reproduction ◽  
2014 ◽  
Vol 148 (3) ◽  
pp. 303-314 ◽  
Author(s):  
G Schuler ◽  
Y Dezhkam ◽  
L Bingsohn ◽  
B Hoffmann ◽  
K Failing ◽  
...  
Keyword(s):  
Venous Blood ◽  
Low Frequency ◽  
Peripheral Circulation ◽  
Target Cells ◽  
Sulfated Steroids ◽  
Liquid Chromatography Tandem Mass ◽  
Testicular Steroidogenesis ◽  
High Production ◽  
And Function

Sulfated steroids have been traditionally regarded as inactive metabolites. However, they may also serve as precursors for the production of active free steroids in target cells. In this study, we used the boar as a model to study the metabolism, transport, and function of steroid sulfates due to their high production in the porcine testicular–epididymal compartment, of which the role is unknown. To characterize the secretion of free and sulfated steroids, plasma samples were collected from six postpubertal boars over 6 h every 20 min from the jugular vein. Long-term secretion profiles were also established in seven boars stimulated with human chorionic gonadotropin. To directly characterize the testicular output, samples were collected from superficial testicular arterial and venous blood vessels. Testosterone, androstenedione and sulfated pregnenolone, DHEA, estrone (E1), and estradiol-17β (E2) were determined by liquid chromatography–tandem mass spectrometry. Free E1 and E2 were measured by RIA. Irrespective of a high variability between individuals, the results suggest that i) all steroids assessed are primarily produced in the testis, ii) they exhibit similar profiles pointing to a pulsatile secretion with low frequency (three to five pulses per day), and iii) after synthesis at least a major proportion is immediately released into peripheral circulation. The fact that all steroid sulfates assessed are original testicular products and their high correlations with one another suggest their role as being intermediates of testicular steroidogenesis rather than as being inactivated end products. Moreover, a substantial use of sulfated steroids in porcine testicular steroidogenesis would assign a crucial regulatory role to steroid sulfatase, which is highly expressed in Leydig cells.

scholarly journals The effect of neurogenin3 deficiency on pancreatic gene expression in embryonic mice

2006 ◽  
Vol 37 (2) ◽  
pp. 301-316 ◽  
Author(s):  
Andreas Petri ◽  
Jonas Ahnfelt-Rønne ◽  
Klaus Stensgaard Frederiksen ◽  
David George Edwards ◽  
Dennis Madsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Microarray Analysis ◽  
Molecular Mechanisms ◽  
Homeobox Gene ◽  
Specific Gene ◽  
Wild Type ◽  
Specific Gene Expression ◽  
And Function ◽  
Deficient Mice

To understand the molecular mechanisms regulating pancreatic endocrine development and function, pancreatic gene expression was compared between Ngn3-deficient mice and littermate controls on embryonic days 13 and 15. Microarray analysis identified 504 genes with significant differences in expression. Fifty-two of these showed at least twofold reduction in Ngn3 knockouts compared to controls. Many of them were previously described to be involved in endocrine development and function. Among the genes not previously characterized were Rhomboid veinlet-like 4, genes involved in tetrahydrobiopterin biosynthesis and the Iroquois-type homeobox gene Irx1, the latter was selected for further investigation. In situ hybridisation demonstrated that two Iroquois genes, Irx1 and Irx2, were expressed in pancreatic endoderm of wild-type, but not Ngn3 mutant embryos. Furthermore, ectopic Ngn3 induced prominent Irx2 expression in chicken endoderm. Co-labelling established that Irx1 and Irx2 mRNA is located to glucagon-, but not insulin- or somatostatin-producing cells in mice and chicken. These data suggest that Irx1 and Irx2 serve an evolutionary conserved role in the regulation of α-cell-specific gene expression.

Testicular steroidogenesis in the testicular feminized (Tfm) mouse: loss of 17α-hydroxylase activity

1991 ◽  
Vol 131 (3) ◽  
pp. 443-449 ◽  
Author(s):  
L. Murphy ◽  
P. J. O'Shaughnessy
Keyword(s):  
Leydig Cells ◽  
Smooth Endoplasmic Reticulum ◽  
Reductase Activity ◽  
Serum Testosterone ◽  
Normal Activity ◽  
Testicular Descent ◽  
Hydroxylase Activity ◽  
Steroid Production ◽  
And Function

ABSTRACT Testicular feminized (Tfm) mice are totally insensitive to androgen and may be used to study the role of the androgen receptor in normal development and function. We have examined testicular and Leydig cell steroidogenesis in Tfm mice. Serum bioactive LH was high in Tfm mice but serum testosterone was low and this was associated with a severe reduction in testicular testosterone production in vitro. Examination of [3H]pregnenolone metabolism by testes of Tfm mice indicated that progesterone, rather than testosterone, was the major steroid produced. Leydig cells were isolated from normal and Tfm mice and from normal mice in which testicular descent was surgically prevented before puberty. As in whole testes, androgen production in response to human chorionic gonadotrophin was severely reduced in Leydig cells from testes of Tfm mice compared with normal or cryptorchid groups. In contrast, progesterone production by Leydig cells from testes of Tfm mice was markedly increased in comparison with other groups. Total steroid production (progesterone plus androstenedione plus testosterone), however, was only 24% of normal in Leydig cells from Tfm mice. The pattern of steroid production by Leydig cells from cryptorchid testes was similar to control, although total steroid production was reduced to about 50% (this was significantly higher than the Tfm group, P<0·05). The high progesterone/androgen ratio in testes from Tfm mice suggested that 17α-hydroxylase was depleted in these animals. To confirm this, activity of the four major steroidogenic enzymes associated with the smooth endoplasmic reticulum was measured. Activities (per testis) of 3β-hydroxysteroid dehydrogenase and 5α-reductase were normal in Tfm and cryptorchid mice but, as expected, 17α-hydroxylase activity was only 2·4% of control and 4·5% of cryptorchid testes. 17-Ketosteroid reductase activity was markedly reduced in cryptorchid testes (14·4% of control) but there was a further reduction in testes from Tfm mice to 0·1% of control. Results show that the Tfm mutation is associated with marked loss of 17α-hydroxylase and 17-ketosteroid reductase activities. This suggests that these enzymes may require receptor-mediated androgen stimulation during development to express normal activity. Journal of Endocrinology (1991) 131, 443–449

scholarly journals The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes

2022 ◽  
Author(s):  
Haohao Zhang ◽  
Yiming Hu ◽  
Dandan Liu ◽  
Zhi Liu ◽  
Ningxia Xie ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Intraepithelial Lymphocytes ◽  
Target Cells ◽  
Histone 3 ◽  
Intestinal Intraepithelial Lymphocytes ◽  
H3k27me3 Level ◽  
Small Intestinal ◽  
And Function ◽  
Cytotoxic Function

AbstractIntestinal intraepithelial lymphocytes (IELs) are distributed along the length of the intestine and are considered the frontline of immune surveillance. The precise molecular mechanisms, especially epigenetic regulation, of their development and function are poorly understood. The trimethylation of histone 3 at lysine 27 (H3K27Me3) is a kind of histone modifications and associated with gene repression. Kdm6b is an epigenetic enzyme responsible for the demethylation of H3K27Me3 and thus promotes gene expression. Here we identified Kdm6b as an important intracellular regulator of small intestinal IELs. Mice genetically deficient for Kdm6b showed greatly reduced numbers of TCRαβ+CD8αα+ IELs. In the absence of Kdm6b, TCRαβ+CD8αα+ IELs exhibited increased apoptosis, disturbed maturation and a compromised capability to lyse target cells. Both IL-15 and Kdm6b-mediated demethylation of histone 3 at lysine 27 are responsible for the maturation of TCRαβ+CD8αα+ IELs through upregulating the expression of Gzmb and Fasl. In addition, Kdm6b also regulates the expression of the gut-homing molecule CCR9 by controlling H3K27Me3 level at its promoter. However, Kdm6b is dispensable for the reactivity of thymic precursors of TCRαβ+CD8αα+ IELs (IELPs) to IL-15 and TGF-β. In conclusion, we showed that Kdm6b plays critical roles in the maturation and cytotoxic function of small intestinal TCRαβ+CD8αα+ IELs.

scholarly journals Exosomes as Naturally Occurring Vehicles for Delivery of Biopharmaceuticals: Insights from Drug Delivery to Clinical Perspectives

Nanomaterials ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1481
Author(s):  
Arun Butreddy ◽  
Nagavendra Kommineni ◽  
Narendar Dudhipala
Keyword(s):  
Drug Delivery ◽  
Molecular Mechanisms ◽  
Extracellular Fluid ◽  
Bilayer Membrane ◽  
Target Cells ◽  
Clinical Use ◽  
Routes Of Administration ◽  
Isolation And Characterization ◽  
And Function

Exosomes as nanosized vesicles are emerging as drug delivery systems for therapeutics owing to their natural origin, their ability to mediate intercellular communication, and their potential to encapsulate various biological molecules such as proteins and nucleic acids within the lipid bilayer membrane or in the lumen. Exosomes contain endogenous components (proteins, lipids, RNA) that could be used to deliver cargoes to target cells, offering an opportunity to diagnose and treat various diseases. Owing to their ability to travel safely in extracellular fluid and to transport cargoes to target cells with high efficacy, exosomes offer enhanced delivery of cargoes in vivo. However, several challenges related to the stabilization of the exosomes, the production of sufficient amounts of exosomes with safety and efficacy, the efficient loading of drugs into exosomes, the clearance of exosomes from circulation, and the transition from the bench scale to clinical production may limit their development and clinical use. For the clinical use of exosomes, it is important to understand the molecular mechanisms behind the transport and function of exosome vesicles. This review exploits techniques related to the isolation and characterization of exosomes and their drug delivery potential to enhance the therapeutic outcome and stabilization methods. Further, routes of administration, clinical trials, and regulatory aspects of exosomes will be discussed in this review.

scholarly journals Mechanisms of Melanocortin-2 Receptor (MC2R) Internalization and Recycling in Human Embryonic Kidney (HEK) Cells: Identification of Key Ser/Thr (S/T) Amino Acids

2011 ◽  
Vol 25 (11) ◽  
pp. 1961-1977 ◽  
Author(s):  
Simon Roy ◽  
Sébastien Jean Roy ◽  
Sandra Pinard ◽  
Louis-Daniel Taillefer ◽  
Mohamed Rached ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Molecular Mechanisms ◽  
Surface Expression ◽  
Receptor Internalization ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Camp Accumulation ◽  
Human Embryonic Kidney ◽  
And Function

Abstract ACTH is the most important stimulus of the adrenal cortex. The precise molecular mechanisms underlying the ACTH response are not yet clarified. The functional ACTH receptor includes melanocortin-2 receptor (MC2R) and MC2R accessory proteins (MRAP). In human embryonic kidney 293/Flp recombinase target cells expressing MC2R, MRAP1 isoforms, and MRAP2, we found that ACTH induced a concentration-dependent and arrestin-, clathrin-, and dynamin-dependent MC2R/MRAP1 internalization, followed by intracellular colocalization with Rab (Ras-like small guanosine triphosphate enzyme)4-, Rab5-, and Rab11-positive recycling endosomes. Preincubation of cells with monensin and brefeldin A revealed that 28% of the internalized receptors were recycled back to the plasma membrane and participated in total accumulation of cAMP. Moreover, certain intracellular Ser and Thr (S/T) residues of MC2R were found to play important roles not only in plasma membrane targeting and function but also in promoting receptor internalization. The S/T residues T131, S140, T204, and S280 were involved in MRAP1-independent cell-surface MC2R expression. Other mutants (S140A, S208A, and S202D) had lower cell-surface expressions in absence of MRAPβ. In addition, T143A and T147D drastically impaired cell-surface expression and function, whereas T131A, T131D, and S280D abrogated MC2R internalization. Thus, the modification of MC2R intracellular S/T residues may positively or negatively regulate its plasma membrane expression and the capacity of ACTH to induce cAMP accumulation. Mutations of T131, T143, T147, and S280 into either A or D had major repercussions on cell-surface expression, cAMP accumulation, and/or internalization parameters, pointing mostly to the second intracellular loop as being crucial for MC2R expression and functional regulation.

scholarly journals Differential Regulation Of Steroidogenic Enzyme Genes by TRα Signaling in Testicular Leydig Cells

2014 ◽  
Vol 28 (6) ◽  
pp. 822-833 ◽  
Author(s):  
Eunsook Park ◽  
Yeawon Kim ◽  
Hyun Joo Lee ◽  
Keesook Lee
Keyword(s):  
Thyroid Hormone ◽  
Leydig Cells ◽  
Promoter Activity ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Regulatory Protein ◽  
Differential Regulation ◽  
Gene Promoters ◽  
Steroidogenic Enzyme ◽  
Testicular Steroidogenesis

Abstract Thyroid hormone signaling has long been implicated in mammalian testicular function, affecting steroidogenesis in testicular Leydig cells. However, its molecular mechanism is not well understood. Here, we investigated the molecular action of thyroid hormone receptor-α (TRα) on mouse testicular steroidogenesis. TRα/thyroid hormone (T3) signaling differentially affected the expression of steroidogenic enzyme genes, mainly regulating their promoter activity. TRα directly regulated the promoter activity of the cytochrome P450 17α-hydroxylase/C17–20 lyase gene, elevating its expression in the presence of T3. TRα also indirectly regulated the expression of steroidogenic enzyme genes, such as steroidogenic acute regulatory protein and 3β-hydroxysteroid dehydrogenase, by modulating the transactivation of Nur77 on steroidogenic enzyme gene promoters through protein-protein interaction. TRα enhanced Nur77 transactivation by excluding histone deacetylases from Nur77 in the absence of T3, whereas liganded TRα inhibited Nur77 transactivation, likely due to interfering with the recruitment of coactivator such as the steroid receptor coactivator-1 to Nur77. Together, these findings suggest a role of TRα/T3 in testicular steroidogenesis and may provide molecular mechanisms for the differential regulation of steroidogenic enzyme genes by thyroid hormone.

A Mucin-Specific Protease Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins

2018 ◽  
Author(s):  
Stacy A. Malaker ◽  
Kayvon Pedram ◽  
Michael J. Ferracane ◽  
Elliot C. Woods ◽  
Jessica Kramer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
High Resolution Mass Spectrometry ◽  
Human Cancer ◽  
Glycosylation Sites ◽  
Bacterial Protease ◽  
Specific Protease ◽  
To Come ◽  
And Function

<div> <div> <div> <p>Mucins are a class of highly O-glycosylated proteins that are ubiquitously expressed on cellular surfaces and are important for human health, especially in the context of carcinomas. However, the molecular mechanisms by which aberrant mucin structures lead to tumor progression and immune evasion have been slow to come to light, in part because methods for selective mucin degradation are lacking. Here we employ high resolution mass spectrometry, polymer synthesis, and computational peptide docking to demonstrate that a bacterial protease, called StcE, cleaves mucin domains by recognizing a discrete peptide-, glycan-, and secondary structure- based motif. We exploited StcE’s unique properties to map glycosylation sites and structures of purified and recombinant human mucins by mass spectrometry. As well, we found that StcE will digest cancer-associated mucins from cultured cells and from ovarian cancer patient-derived ascites fluid. Finally, using StcE we discovered that Siglec-7, a glyco-immune checkpoint receptor, specifically binds sialomucins as biological ligands, whereas the related Siglec-9 receptor does not. Mucin-specific proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of glycoprotein structure and function and for deorphanizing mucin-binding receptors. </p> </div> </div> </div>

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