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      Testosterone regulates the expression and functional activity of sphingosine‐1‐phosphate receptors in the rat corpus cavernosum

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          Abstract

          The bioactive lipid sphingosine‐1‐phosphate (S1P) regulates smooth muscle ( SM) contractility predominantly via three G protein‐coupled receptors. The S1P1 receptor is associated with nitric oxide ( NO)‐mediated SM relaxation, while S1P2 & S1P3 receptors are linked to SM contraction via activation of the Rho‐kinase pathway. This study is to determine testosterone (T) modulating the expression and functional activity of S1P receptors in corpus cavernosum ( CC). Adult male Sprague‐Dawley rats were randomly divided into three groups: sham‐operated controls, surgical castration and T supplemented group. Serum S1P levels were detected by high‐performance liquid chromatography. The expression of S1P1‐3 receptors and sphingosine kinases was detected by real‐time RTPCR. In vitro organ bath contractility and in vivo intracavernous pressure ( ICP) measurement were also performed. T deprivation significantly decreased ICP rise. Meanwhile, surgical castration induced a significant increase in serum S1P level and the expression of S1P2‐3 receptors by twofold ( <  0.05) but a decrease in the expression of S1P1 receptor. Castration also augmented exogenous phenylephrine ( PE), S1P, S1P1,3 receptor agonist FTY720‐P contractility and S1P2‐specific antagonist JTE013 relaxation effect. T supplemented could restore the aforementioned changes. We provide novel data that castration increased serum S1P concentration and up‐regulated the expression of S1P2‐3 receptors in CC. Consistently, agonizing S1P receptors induced CCSM contraction and antagonizing mediated relaxation were augmented. This provides the first clear evidence that S1P system dysregulation may contribute to hypogonadism‐related erectile dysfunction ( ED), and S1P receptors may be expected as a potential target for treating ED.

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          Most cited references 53

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

           K Livak,  T Schmittgen (2001)
          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720.

            Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1. Sphk1 null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in most Sphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from the Sphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs of Sphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.
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              Erythrocytes store and release sphingosine 1-phosphate in blood.

              The blood constituent sphingosine 1-phosphate (S1P) is a specific ligand for five G-protein-coupled receptors designated S1P(1-5). Expression of the S1P1 receptor on lymphocytes is required for their exit from secondary lymphoid organs, suggesting that S1P serves as a stimulus for maintaining lymphocyte circulation in blood. Despite its potential role in immune surveillance, the regulatory system that controls blood S1P levels is not well understood. This report reveals that erythrocytes constitute a buffer system for S1P in blood. They efficiently incorporated and stored S1P, and protected it from cellular degradation. They also released S1P into plasma, but not into other serum-free media, indicating that S1P release was controlled by a plasma factor. Erythrocytes did not generate S1P since an increase in plasma S1P levels was always accompanied by a decrease in cellular S1P levels. Thrombocytes that were reported to generate and release S1P after activation did not contribute to the observed S1P release in blood. The amount of erythrocytes as well as the proportion of plasma in the medium determined the magnitude of S1P release. Adoptively transferred S1P-loaded and unloaded mouse erythrocytes displayed a normal life span and similar S1P levels 24 h after recovery, indicating that S1P incorporation and release are dynamically regulated in vivo.
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                Author and article information

                Affiliations
                [ 1 ] Department of Rehabilitation Zhongnan Hospital of Wuhan University Wuhan China
                [ 2 ] Department of Urology Zhongnan Hospital of Wuhan University Wuhan China
                [ 3 ] Surgery and Biomedical Sciences Cooper Medical School of Rowan University Camden NJ USA
                Author notes
                [* ] Correspondence to: Dr. Xin‐hua ZHANG MD, Ph.D.

                E‐mail: zhangxinhuad@ 123456163.com

                [†]

                These authors contributed equally to this work.

                Contributors
                ORCID: http://orcid.org/0000-0003-0267-428X, zhangxinhuad@163.com
                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                20 December 2017
                March 2018
                : 22
                : 3 ( doiID: 10.1111/jcmm.2018.22.issue-3 )
                : 1507-1516
                29266713 5824404 10.1111/jcmm.13416 JCMM13416
                © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Counts
                Figures: 9, Tables: 0, Pages: 10, Words: 6064
                Product
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: N.81270843
                Award ID: N.81160086
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm13416
                March 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:23.02.2018

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