scholarly journals Human sperm anatomy and endocrinology in varicocele: role of androgen receptor

Reproduction ◽  
2014 ◽  
Vol 147 (5) ◽  
pp. 589-598 ◽  
Author(s):  
Carmela Guido ◽  
Marta Santoro ◽  
Francesca De Amicis ◽  
Ida Perrotta ◽  
Salvatore Panza ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Human Sperm ◽  
Pi3k Pathway ◽  
Male Reproduction ◽  
Male Gametes ◽  
Human Male ◽  
Normal Sperm ◽  
Triglyceride Content ◽  
Glucose 6 Phosphate Dehydrogenase

The study of androgens involved in male reproduction has been object of intense efforts, while their reported action on human male gametes is limited. We previously described the presence of androgen receptor (AR) in sperm with a role related to the modulation of the PI3K pathway. In the present study, we investigated the expression of AR and its ultrastructural location in normal sperm as well as in spermatozoa obtained from varicocele patients. We observed a reduced AR content in varicocele sperm with respect to healthy sperm by western blot analysis and transmission electron microscopy (TEM). The ultrastructural location of AR was detected mainly on the head membrane as well as in the nucleus, neck, and mitochondria. Influence of dihydrotestosterone (DHT) treatment on cholesterol efflux was increased in normal sperm, while it was reduced or absent in varicocele sperm. To better understand DHT/AR significance in human male gametes, we evaluated triglyceride content and lipase, acyl-CoA dehydrogenase, and glucose-6-phosphate dehydrogenase activities upon DHT treatment. The metabolic outcome glimpsed in normal sperm was an increased metabolic rate, while ‘varicocele’ sperm economized energy. Taken together, our results reveal DHT and AR as new players in sperm endocrinology, indicating that varicocele sperm may have difficulty in switching to the capacitated status. A decreased AR expression and a consequent reduced responsiveness to DHT in sperm may represent molecular mechanisms involved in the pathophysiology of varicocele leading to male infertility. This study revealed new detrimental effects of varicocele on sperm at the molecular level.

scholarly journals PI3K-AKT-mTOR Pathway is Dominant over Androgen Receptor Signaling in Prostate Cancer Cells

2010 ◽  
Vol 32 (1-2) ◽  
pp. 11-27
Author(s):  
Mari Kaarbø ◽  
Øyvind Løveseter Mikkelsen ◽  
Lene Malerød ◽  
Su Qu ◽  
Viola H. Lobert ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Pi3k Pathway ◽  
Prostate Cancer Cells ◽  
Pathway Inhibition

Background: Androgen receptor (AR) and the phosphatidylinositol-3 kinase (PI3K) signaling are two of the most important pathways implicated in prostate cancer. Previous work has shown that there is crosstalk between these two pathways; however, there are conflicting findings and the molecular mechanisms are not clear. Here we studied the AR–PI3K pathway crosstalk in prostate cancer cells in vitro as well as in vivo.Methods: Quantitative PCR, Western analysis, reporter assays, and proliferation analyses in vitro and in vivo were used to evaluate the effect of PI3K pathway inhibition on AR signaling and cell growth.Results: Transcriptional activity of AR was increased when the PI3K pathway was inhibited at different levels. In the androgen responsive prostate cancer cell line LNCaP, androgen and the mTOR inhibitor rapamycin synergistically activated androgen target genes. Despite increased androgen signaling, rapamycin treatment reduced LNCaP cell growth; the AR antagonist bicalutamide potentiated this effect. Furthermore, the rapamycin derivative CCI-779 reduced the growth of CWR22 prostate cancer xenografts while increasing AR target gene expression.Conclusions: These findings suggest that inhibition of the PI3K pathway activates AR signaling. Despite the increase in AR signaling which has proliferative effects, the result of PI3K pathway inhibition is antiproliferative. These findings suggest that the PI3K pathway is dominant over AR signaling in prostate cancer cells which should be considered in developing novel therapeutic strategies for prostate cancer.

scholarly journals Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells

2019 ◽  
Author(s):  
Fatemeh Mazloumi Gavgani ◽  
Thomas Karlsson ◽  
Ingvild L Tangen ◽  
Andrea Papdiné Morovicz ◽  
Victoria Smith Arnesen ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Pi3k Pathway ◽  
Clinical Samples ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Cytoplasmic Staining ◽  
Ec Cells

AbstractGenes encoding for components of the phosphoinositide 3-kinase (PI3K) pathway are frequently mutated in cancer, including inactivating mutations of PTEN and activating mutations of PIK3CA, encoding the PI3K catalytic subunit p110α. PIK3CB, encoding p110β, is rarely mutated, but can contribute to tumourigenesis in some PTEN-deficient tumours. The underlying molecular mechanisms are however poorly understood. By analysing cell lines and annotated clinical samples, we have previously found that p110β is highly expressed in endometrial cancer (EC) cell lines and that PIK3CB mRNA levels increase early in primary tumours correlating with lower survival. Selective inhibition of p110α and p110β led to different effects on cell signalling and cell function, p110α activity being correlated to cell survival in PIK3CA mutant cells and p110β with cell proliferation in PTEN-deficient cells. To understand the mechanisms governing the differential roles of these isoforms, we assessed their sub-cellular localisation. p110α was cytoplasmic whereas p110β was both cytoplasmic and nuclear with increased levels in both compartments in cancer cells. Immunohistochemistry of p110β in clinically annotated patient tumour sections revealed high nuclear/cytoplasmic staining ratio, which correlated significantly with higher grades. Consistently, the presence of high levels of p110β in the nuclei of EC cells, correlated with high levels of its product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) in the nucleus. Using immunofluorescence labelling, we observed both p110β and PtdIns(3,4,5)P3 in the nucleoli of EC cell lines. The production of nucleolar PtdIns(3,4,5)P3 was dependent upon p110β activity. EC cells with high levels of nuclear PtdIns(3,4,5)P3 and p110β showed elevated nucleolar activity as assessed by the increase in 47S pre-rRNA transcriptional levels in a p110β-dependent manner. Altogether, these results present a nucleolar role for the PI3K pathway that may contribute to tumour progression in endometrial cancer.

scholarly journals PRMT7: A Pivotal Arginine Methyltransferase in Stem Cells and Development

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Bingyuan Wang ◽  
Mingrui Zhang ◽  
Zhiguo Liu ◽  
Yulian Mu ◽  
Kui Li
Keyword(s):  
Stem Cells ◽  
Developmental Delay ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Embryonic Stem ◽  
Arginine Methylation ◽  
Male Reproduction ◽  
Protein Arginine Methyltransferases ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

Protein arginine methylation is a posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs), which play critical roles in many biological processes. To date, nine PRMT family members, namely, PRMT1, 2, 3, 4, 5, 6, 7, 8, and 9, have been identified in mammals. Among them, PRMT7 is a type III PRMT that can only catalyze the formation of monomethylarginine and plays pivotal roles in several kinds of stem cells. It has been reported that PRMT7 is closely associated with embryonic stem cells, induced pluripotent stem cells, muscle stem cells, and human cancer stem cells. PRMT7 deficiency or mutation led to severe developmental delay in mice and humans, which is possibly due to its crucial functions in stem cells. Here, we surveyed and summarized the studies on PRMT7 in stem cells and development in mice and humans and herein provide a discussion of the underlying molecular mechanisms. Furthermore, we also discuss the roles of PRMT7 in cancer, adipogenesis, male reproduction, cellular stress, and cellular senescence, as well as the future perspectives of PRMT7-related studies. Overall, PRMT7 mediates the proliferation and differentiation of stem cells. Deficiency or mutation of PRMT7 causes developmental delay, including defects in skeletal muscle, bone, adipose tissues, neuron, and male reproduction. A better understanding of the roles of PRMT7 in stem cells and development as well as the underlying mechanisms will provide information for the development of strategies for in-depth research of PRMT7 and stem cells as well as their applications in life sciences and medicine.

scholarly journals Steroidal Androgens and Nonsteroidal, Tissue-Selective Androgen Receptor Modulator, S-22, Regulate Androgen Receptor Function through Distinct Genomic and Nongenomic Signaling Pathways

2008 ◽  
Vol 22 (11) ◽  
pp. 2448-2465 ◽  
Author(s):  
Ramesh Narayanan ◽  
Christopher C. Coss ◽  
Muralimohan Yepuru ◽  
Jeffrey D. Kearbey ◽  
Duane D. Miller ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Levator Ani ◽  
Reproductive Organs ◽  
Cross Reactivity ◽  
Levator Ani Muscle ◽  
Xenopus Laevis Oocyte ◽  
Muscle Weight

Abstract Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

The biology of human male reproduction: An overview

1983 ◽  
Vol 4 (1) ◽  
pp. 5-15 ◽  
Author(s):  
James W. Overstreet ◽  
William F. Blazak
Keyword(s):  
Male Reproduction ◽  
Human Male

scholarly journals Effect of Dietary n‐3 Source on Rabbit Male Reproduction

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Cesare Castellini ◽  
Simona Mattioli ◽  
Cinzia Signorini ◽  
Elisa Cotozzolo ◽  
Daria Noto ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Sperm Count ◽  
Reproductive Traits ◽  
Human Sperm ◽  
Oxidative Status ◽  
Male Reproduction ◽  
Analytical Determination ◽  
Control Group ◽  
Chain Pufa

In the last two decades, the human sperm count linearly decreased in Western countries. Health problems, lifestyle, pollutants, and dietary behaviours are considered as the main risk factors, and the unbalance of dietary n‐6/n‐3 fatty acids is one of the most relevant. The aim of the present research is to study the effect of different dietary sources of n‐3 polyunsaturated fatty acids (PUFA) on reproductive traits using rabbit buck as the animal model. Fifteen rabbit bucks were assigned to three experimental groups: the control group, the FLAX group fed 10% extruded flaxseed, and the FISH group fed 3.5% fish oil for 110 days (50-day adaptation and 60-day experimental periods). Semen samples were collected weekly, whereas blood was collected every two weeks for the analytical determination of semen traits, oxidative status, fatty acid profiles, isoprostanes, neuroprostanes, and the immunocytochemistry of docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) acid. At the end of the trial, the rabbits were killed and the testes were removed and stored for the analysis of fatty acid profile and immunocytochemistry. Results showed that dietary administration of n‐3 PUFA improved the track speed of the sperm and increased the n‐3 long-chain PUFA mainly confined in the sperm tail. Seminal plasma increased the thiobarbituric reactive substances (TBARs) by three times in the groups fed supplemental n‐3, whereas the F2-isoprotanes (F2-IsoPs) and F4-neuroprostanes (F4-NeuroPs) were lower and higher, respectively, in both supplemented groups than in the control. The testes and sperm showed a higher DHA and EPA distribution in rabbits from the n‐3 supplemented groups compared with the control. In conclusion, supplemental dietary n‐3 PUFA improved sperm motion traits and resulted in an enrichment of membrane fatty acid in the sperm and testes of the rabbits. However, such an increased amount of PUFA negatively affected the sperm oxidative status, which was mainly correlated with the generation of F4-NeuroPs with respect to F2-IsoPs. Accordingly, the latter cannot be considered a good marker of oxidation when diets rich in n‐3 PUFA are provided.

scholarly journals Low amounts of mitochondrial reactive oxygen species define human sperm quality

Reproduction ◽  
2014 ◽  
Vol 147 (6) ◽  
pp. 817-824 ◽  
Author(s):  
Mónica Marques ◽  
Ana Paula Sousa ◽  
Artur Paiva ◽  
Teresa Almeida-Santos ◽  
João Ramalho-Santos
Keyword(s):  
Reactive Oxygen Species ◽  
Assisted Reproduction ◽  
Density Gradient Centrifugation ◽  
Sperm Quality ◽  
Gradient Centrifugation ◽  
Reactive Oxygen ◽  
Human Sperm ◽  
Semen Parameters ◽  
Oxygen Species ◽  
Male Gametes

We have applied the mitochondria-specific superoxide fluorescent probe MitoSOX Red (MitoSOX) to detect mitochondria-specific reactive oxygen species (mROS) production in human sperm samples using flow cytometry. We show that human ejaculates are heterogeneous in terms of mROS production, with three subpopulations clearly detectable, comprising sperm that produce increasing amounts of mROS (MitoSOX−, MitoSOX+, and MitoSOX++). The sperm subpopulation producing the lowest amount of mROS represented the most functional subset of male gametes within the ejaculate, as it was correlated with the highest amount of live and non-apoptotic sperm and increased both in samples with better semen parameters and in samples processed by both density-gradient centrifugation and swim-up, both known to select for higher quality sperm. Importantly, the MitoSOX− subpopulation was clearly more prevalent in samples that gave rise to pregnancies following assisted reproduction. Our work, therefore, not only describe discreet human sperm heterogeneity at the mROS level but also suggests that mROS may represent a strategy to both evaluate sperm samples and isolate the most functional gametes for assisted reproduction.Free Portuguese abstractA Portuguese translation of this abstract is freely available athttp://www.reproduction-online.org/content/147/6/817/suppl/DC1

scholarly journals The Potential Role of Seminal Plasma in the Fertilization Outcomes

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Justyna Szczykutowicz ◽  
Anna Kałuża ◽  
Maria Kaźmierowska-Niemczuk ◽  
Mirosława Ferens-Sieczkowska
Keyword(s):  
Seminal Plasma ◽  
Potential Role ◽  
Human Sperm ◽  
Structure And Function ◽  
Regulatory Mechanisms ◽  
Male And Female ◽  
Healthy Pregnancy ◽  
Male Gametes ◽  
And Function

For human infertility both male and female factors may be equally important. Searching for molecular biomarkers of male infertility, neglected for decades, and the attempts to explain regulatory mechanisms of fertilization become thus extremely important. Apart from examination of the structure and function of male gametes, also the possible importance of seminal plasma components should be considered. In this article we discuss data that indicate for the substantial significance of active seminal plasma components for conception and achievement of healthy pregnancy. Seminal plasma impact on the storage and cryopreservation of human and animal sperm and regulatory role of glycodelin on human sperm capacitation as well as hypothesized course of female immune response to allogenic sperm and conceptus has been discussed. The possible involvement of carbohydrates in molecular mechanism of fetoembryonic defense has been also mentioned.

scholarly journals Aromatase, oestrogens and human male reproduction

2010 ◽  
Vol 365 (1546) ◽  
pp. 1571-1579 ◽  
Author(s):  
Serge Carreau ◽  
Slaweck Wolczynski ◽  
Isabelle Galeraud-Denis
Keyword(s):  
Leydig Cells ◽  
Single Gene ◽  
Mammalian Species ◽  
Male Reproduction ◽  
Biologically Active ◽  
Human Male ◽  
Final Maturation ◽  
Polymerase Chain ◽  
High Degree

In most mammalian species aromatase is encoded by a single gene ( Cyp19 ), which contains 18 exons, nine of them being translated. In man, the presence of a biologically active aromatase and oestrogen receptors (ERα and ERβ) has been reported in Leydig cells, and also in immature germ cells and ejaculated spermatozoa. Concerning aromatase, the amount of transcript and enzymatic activity are decreased in immotile compared with motile sperm. We have amplified aromatase mRNA by real-time polymerase chain reaction in spermatozoa from asthenospermic, teratospermic and asthenoteratospermic men and recorded, respectively, 44, 52 and 67 per cent decreases of the amount of transcripts compared with fertile donors. A high degree of correlation ( r = −0.64) between the abnormal spermatozoa (especially microcephaly and acrosome malformations) and aromatase/GAPDH transcript ratio has been observed. Idiopathic infertility is a wide health problem and no treatment is currently available. In humans, even if the role of oestrogens in spermatogenesis is still a matter of debate, the observations of decreased sperm number and motility in men genetically deficient in aromatase, together with our data and those reported in the literature, may suggest a role for aromatase/oestrogens not only during the development and maintenance of spermatogenesis but also in the final maturation of spermatozoa.

Sign in / Sign up

Export Citation Format

Share Document