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S1P receptor antagonists (JTE-013)-induced relaxation of rat corpus cavernosum smooth muscle (CCSM) in vitro. Panel A, B and C are JTE013-induced dose-response relaxation force tracings of rats CCSM pre-contracted with 1 lM phenylephrine (PE) from sham (A), castration (B) and castration + T (C) groups, respectively. For typical tracings, the x-axis represents time (min.), while the y-axis represents force (mg). Panel D is summary graph of JTE-013-induced relaxing effects on rat CCSM in vitro from all experimental groups. The stable response to PE stimulation was taken as 100%, while the relaxant effects of JTE-013 were evaluated as a percentage of this response. *P < 0.05 versus sham or castration + T. (n = CC strips obtained from 4 to 8 different rats for each group).
Source publication
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...
Citations
... In accordance with this, it was shown that estrogens can stimulate S1P synthesis in females [24]. Instead, testosterone can limit S1P synthesis [25,26]. Moreover, while circulating estrogens from the ovary (mainly β-estradiol and estrone) are regulated by menstrual status and are much higher in premenopausal than in postmenopausal females, local sources of estrogen in tissues (which may not enter the circulation) are also important. ...
Sex is a biological variable that can reflect clinical outcomes in terms of quality of life, therapy effectiveness, responsiveness and/or toxicity. Sphingosine-1-phosphate (S1P) is a lipidic mediator whose activity can be influenced by sex. To evaluate whether the S1P axis underlies sex ‘instructions’ in the lung during physiological and oncological lung conditions, sphingosine and S1P were quantified in the blood of healthy (H) volunteers, lung adenocarcinoma (ADK) and squamous cell carcinoma (SCC) patients of both sexes. S1P receptors and their metabolic enzymes were evaluated in the tissues. Circulating levels of S1P were similar among H female and male subjects and female SCC patients. Instead, male and female ADK patients had lower circulating S1P levels. S1P receptor 3 (S1PR3) was physiologically expressed in the lung, but it was overexpressed in male SCC, and female and male ADK, but not in female SCC patients, who showed a significantly reduced ceramide synthase 1 (CERS1) mRNA and an overexpression of the ceramidase (ASAH1) precursor in lung tumor tissues, compared to male SCC and both male and female ADK patients. These findings highlighted sex differences in S1P rheostat in pathological conditions, but not in physiological conditions, identifying S1P as a prognostic mediator depending on lung cancer histotype.
... To our knowledge, the relationship with sphingosine has not been reported previously in humans, although Li et al (58) showed that an array of biosynthetic pathways were altered in PCOS, including those involved in steroid hormone biosynthesis, fatty acid metabolism and oxidation, and sphingolipid metabolism (58). Functionally, sphingosine acts via Sph-kinase to synthesize the bioactive metabolite, sphingosine-1-phosphate (S1P), which modulates several proliferative cellular processes (59). In animal models, testosterone regulates the expression and functional activities of S1P receptors (59) which protect cells against oxidative stress via activating the Akt pathway (60). ...
Background
Dyslipidaemia is a feature of polycystic ovary syndrome (PCOS) and may augment metabolic dysfunction in this population.
Objective
Using comprehensive lipidomic profiling and gold-standard metabolic measures, we examined whether distinct lipid biomarkers were associated with metabolic risk in women with and without PCOS.
Methods
Using pre-existing data and bio-banked samples from 76 women (n=42 with PCOS), we profiled >700 lipid species by mass spectrometry. Lipids were compared between women with and without PCOS and correlated with direct measures of adiposity (dual X-ray absorptiometry and computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), as well as fasting insulin, HbA1c, and hormonal parameters (luteinizing and follicle stimulating hormones; total and free testosterone; sex hormone-binding globulin [SHBG]; and free androgen index [FAI]). Multivariable linear regression was used with correction for multiple testing.
Results
Despite finding no differences by PCOS status, lysophosphatidylinositol (LPI) species esterified with an 18:0 fatty acid were the strongest lipid species associated with all the metabolic risk factors measured in women with and without PCOS. Across the cohort, higher concentrations of LPI(18:0) and lower concentrations of lipids containing docosahexaenoic acid (DHA, 22:6) n-3 polyunsaturated fatty acids (PUFA) were associated with higher adiposity, insulin resistance, fasting insulin, HbA1c and FAI, and lower SHBG.
Conclusions
Our data indicate that a distinct lipidomic signature comprising high LPI(18:0) and low DHA-containing lipids are associated with key metabolic risk factors that cluster in PCOS, independent of PCOS status. Prospective studies are needed to corroborate these findings in larger cohorts of women with varying PCOS phenotypes.
... In vitro and molecular studies demonstrated that estradiol markedly improves S1P synthesis and export by activating SphK1 in normal and breast cancer cells .Compared to men, higher level was reported in childbearing women in one study while irrelevant to sex but higher in menopausal women in another study ( 27,28,39). The positive association of SIP with various testosterone forms in male and female HCC was in one hand with previous experimental nding of T deprivation down-regulated SphK1 expression but up-regulated SphK2 Hence, SphK1 is more contributor to S1P synthesis than SphK2 (40). SIP was correlated to estradiol in entire HCC only but was correlated to testosterone and E/ T in only strati ed male and female HCC. ...
Backgroundcirculating sphingosine 1-phosphate (S1P) showed oncogenic roles in various cancers. It showed conflict data in Hepatitis B virus- hepatocellular carcinoma (HCC). Adiponectin and sex hormones were contributing factors for gender disparity in HCC. Up to date, no clinical study among HCC patients addresses interplay of S1P, adiponectin and sex hormones that was described in experimental studies. The current study aimed to evaluate circulating SIP, adiponectin and sex hormones among sex stratified HCC subgroups and to assess gender disparity of theses parameters regarding HCC development and diagnosis, their interplay and association with clinic -morphological and staging of HCC.Method
We measures serum S1P, adiponectin, testosterone (T), estradiol (E) and sex hormone binding globulin (SHBG), calculated free and bioavailable T and E/T ratio among HCV – HCC group in comparing with comparable HCV- cirrhotic and healthy groups with their sex stratified male and female subgroupsResultsAmong all, male and female HCC patients, S1P was significant higher than corresponding cirrhotic and healthy subjects with cut off value ≥ 113ng/l as screening test (sensitivity 95%, specificity 56%) for HCC diagnosis. Compared to sex respective cirrhotic subgroups, male-HCC had significant higher SHBG and lower adiponectin and estradiol while opposite profile was observed among female-HCC. Female-HCC had significant higher SIP and adiponectin than male-HCC. Although S1P was positively correlated with adiponectin, testosterone and negatively with E/T ratio among male and female HCC, adiponectin was correlated negatively with testosterone and SHBG and positively with estradiol and E/T ratio among entire HCC group but reverse associations were observed in female (not- male) subgroup. Associations of large tumor size and higher T-class TNM staging with higher adiponectin and testosterone and lower E/T ratio and link of multiplicity with higher estradiol in females while association of higher testosterone among higher T-class TNM staging male were observed. Portal vein thrombosis was related to lower SHBG and higher testosterone in male and female respectively.Conclusion
We suggested S1P as screening test for diagnosis of HCC among HCV-cirrhotic and healthy subjects. There was gender disparity as regard association and interaction of S1P, adiponectin and sex hormone with respect of HCC development and its clinic-morphological features and staging.
... S1P regulates cellular activities via S1P receptors (S1PRs). Five types of S1PRs have been identified in mammalian cells, and S1PR2 and S1PR3 are the major types of S1PRs to transduce cellular effects of S1P in most of cell types (19,(31)(32)(33). To address above hypothesis and to clarify which S1PR is involved in this process, we intervened STAT3, miR-135b, β-TrCP, YAP, Notch3, and S1PR2/3 in primary cultured PASMCs stimulated with exogenous S1P, separately. ...
... These results suggest that STAT3/miR-135b/β-TrCP/YAP/Notch3 cascade mediates S1P-induced PASMCs proliferation. S1PR2 mediates S1P-induced changes of the STAT3/miR-135b/ β-TrCP/YAP/Notch3 signal pathway and PASMCs proliferation Studies have demonstrated that S1PR2 and S1PR3 are the major types of S1PRs to transduce cellular effects of S1P in most of mammalian cell types (19,(31)(32)(33). To examine whether S1PR2 and S1PR3 mediate S1P-induced activation of the STAT3/miR-135b/β-TrCP/YAP/Notch3 signal pathway and PASMCs proliferation, cells were previously treated with JTE013 (a selective S1PR2 antagonist, 10-μM) or CAY10444 (a selective S1PR3 antagonist, 10-μM) for 1 h and then stimulated with S1P, the phosphorylation level and total protein level of STAT3 and protein levels of β-TrCP, YAP, Notch3, and NICD3 were examined using Western blotting, the level of miRNA-135b was detected using qRT-PCR, and proliferation of cells was evaluated by the EdU incorporation assay. ...
... Together, these results indicate that β-TrCP mediated YAP ubiquitinated degradation in PASMCs, and it may be inferred that the downregulation of β-TrCP induced by S1P was responsible for elevated YAP and PASMCs hyperproliferation. S1P regulates cellular activities via five types of S1PRs in mammalian cells, and S1PR2 and S1PR3 are the major types to transduce cellular effects of S1P in most of cell types (19,(31)(32)(33). Chen et al. (33) have reported that S1P promotes human PASMCs proliferation via S1PR2, and blocking S1PR2 with JTE013 prevents the development of PAH in hypoxia mice. ...
Sphingosine-1-phosphate (S1P), a natural multifunctional phospholipid, is highly increased in plasma from patients with pulmonary arterial hypertension (PAH) and mediates proliferation of pulmonary artery smooth muscle cell (PASMC) by activating Notch3 signaling pathway. However, the mechanisms underpinning S1P-mediated induction of PASMC proliferation remain unclear. In this study, using biochemical and molecular biology approaches, RNA-interference and gene expression analyses, 5′-Ethynyl-2′-deoxyuridine (EdU) incorporation assay and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, we demonstrated that S1P promoted the activation of STAT3 through sphingosine-1-phosphate receptor 2 (S1PR2), and subsequently upregulated the expression of the microRNA miR-135b, which further reduced the expression of E3 ubiquitin ligase β-transduction repeat-containing protein (β-TrCP) and led to a reduction in YAP ubiquitinated degradation in PASMC. YAP is the core effector of Hippo pathway and mediates the expression of particular genes. The accumulation of YAP further increased the expression and activation of Notch3, and ultimately promoted the proliferation of PASMC. In addition, we showed that pre-blocking S1PR2, prior silencing STAT3, miR-135b or YAP, and prior inhibition of Notch3 all attenuated S1P-induced PASMC proliferation. Taken together, our study indicates that S1P stimulates PASMC proliferation by activation of S1PR2/STAT3/miR-135b/β-TrCP/YAP/Notch3 pathway, and our data suggest that targeting this cascade might have potential value in ameliorating PASMC hyperproliferation and benefit PAH.
... Similarly, RBCs and RBC precursors may scavenge or respond to hormonal stimulation, a factor contributing to RBCspecific sex dimorphisms and testosterone-mediated antioxidant responses in the maturing erythrocyte [64,65]. By controlling the expression sphingosine 1-phosphate receptors [66], testosterone may also control systemic hypoxic responses. ...
Introduction: Recently, the classification of two “novel” organs, the mesentere and interstitium, was saluted as a scientific breakthrough and disseminated into mainstream media. The novelty of these findings did not pertain to the characterization of some previously unexplored phenomena, rather to the appreciation that well-established tissues may play some hitherto unexplored functions critical to system homeostasis.
Areas covered: Here we provocatively comment on the potential classification of red blood cells – by far the most abundant host cell in the human body (~83% of the total cells) – as an organ involved in many functions beyond gas transport. In this perspective article, we describe some of these functions with a special emphasis on the role erythrocytes play with respect to systemic metabolic homeostasis. We thus focus on how these functions modulate the cross-talk of red blood cells among each other and with other cell types including immune cells.
Expert commentary: The appreciation of RBCs as an organ impacting systemic metabolic homeostasis and other cell functions while engaging in complex metabolic activity beyond oxygen transport can foster the development of novel therapeutic interventions in pathologic hypoxemia, inflammation, neurodgenerative diseases, aging and cancer.
Context:
Sphingosine-1-phosphate (S1P) is synthesised by follicle granulosa cells under the influence of follicle-stimulating hormone and seems to be necessary for the biological effects of this gonadotrophin.
Aims:
To determine if luteinising hormone (LH) increases S1P production and if this sphingolipid, either induced by LH or added to culture media, regulates steroidogenesis and cell viability in bovine theca cells.
Methods:
We used bovine theca cell cultures treated with: S1P (0, 0.1, 1 and 10μM; Experiment 1), LH (0, 0.02, 0.2 and 2ngmL-1; Experiment 2) and LH (0.02ngmL-1) plus a sphingosine kinase inhibitor (SKI-178; 0, 5 and 10μM; Experiment 3).
Key results:
Treatment with S1P did not affect (P>0.05) theca cell viability or their ability to produce progesterone and testosterone. LH (0.02ngmL-1) increased (P<0.05) S1P production, and stimulated the expression of phosphorylated sphingosine kinase-1 (pSPHK1). However, the inhibition of SPHK1, by a specific SPHK1 inhibitor (SKI-178), reduced (P<0.05) cell viability and progesterone secretion. Additionally, the use of SKI-178 increased theca cell testosterone production (P<0.05).
Conclusions:
S1P added to culture media did not affect cell viability or steroid synthesis. However, LH stimulated the production of S1P, by increasing phosphorylation of SPHK1 in theca cells. This intracellular S1P was inhibitory on testosterone production but augmented progesterone and viable cell number.
Implications:
These results suggest a novel signalling pathway for LH in theca cells and underline the importance of S1P in the regulation of steroid synthesis.
Testosterone (T) deficiency and erectile dysfunction (ED) are independently functionally and socially impairing, and their concurrence in men can be challenging to treat. Successful management requires an understanding of the mechanisms through which T underlies normal erectile function. While the literature elucidating some of these mechanisms is vast (e.g., androgen regulation of the activity of nitric oxygen synthase and phosphodiesterase type 5) for others it is scarce (e.g., catalysts of castration-induced corporal fibrosis). The randomized controlled trial data for the efficacy of T replacement as mono- or combination therapy to treat ED has been conflicting. Positive results were frequently not clinically meaningful. Meta-analyses have been helpful in illuminating trends that seem to be promising. Consensus is still lacking in several areas, such as the threshold of low T severity for which replacement therapy is most beneficial; the timing for initiating combination therapy; and the duration of treatment.
To explore how alterations in the phosphodiesterase type 5 (PDE5) signalling pathway and oxidative stress correlate with changes in the expression of relaxation and contraction molecules and erectile dysfunction (ED) in the corpus cavernosum smooth muscle (CCSM) of spontaneously hypertensive rats (SHR). In this study, SHR and Wistar-Kyoto (WKY) rats were used. Erectile function was determined by apomorphine test and electrical stimulation (ES) of cavernous nerve. Masson's trichrome staining and confocal microscopy were performed. Nitric oxide synthase (NOS), PDE5, phosphorylated-PDE5 and α1-adrenergic receptor (α1AR) were determined by RT-PCR and Western blotting while oxidative stress in CC was determined by colorimetric analysis. SHR exhibited obvious ED. CC of SHR showed less SM but more collagen fibres. The expression of NOS isoforms in SHR was significantly decreased while all α1AR isoforms were increased. In addition, PDE5 and phosphorylated-PDE5 were down-regulated and its activity attenuated in the hypertensive rats. Meanwhile, the SHR group suffered oxidative stress, which may be modulated by endoplasmic reticulum stress and NADPH oxidase up-regulation. Dysregulation of NOS and α1AR, histological changes and oxidative stress in CC may be associated with the pathophysiology of hypertension-induced ED. In addition, PDE5 down-regulation may lead to the decreased efficacy of PDE5 inhibitors in some hypertensive ED patients and treatment of oxidative stress could be used as a new therapeutic target for this type of ED.
Introduction:
Testosterone deficiency is known to induce endothelial dysfunction, which can lead to erectile dysfunction and/or vascular dysfunction. In some basic and clinical reports, testosterone has been shown to regulate the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway and thereby influence endothelial function and endothelial progenitor cells (EPCs), which are key for the endothelial repair system.
Aim:
To review the association between testosterone and endothelial dysfunction focusing on NO and EPCs.
Methods:
A review of relevant literature up to September 2018 was performed via PubMed.
Main outcome measures:
We reviewed the association between testosterone and endothelial dysfunction focusing on NO derived from endothelial NO synthase, phosphodiesterase type 5 (PDE-5), asymmetric dimethylarginine (ADMA), inflammation, and EPCs.
Results:
Numerous articles describing the association between testosterone deficiency and endothelial dysfunction have been published. Some reports have shown that testosterone deficiency decreases NO production by altering the expression and activity of NO synthase and by regulating ADMA expression. Testosterone also regulates the expression of phosphodiesterase type 5. In addition, some basic and clinical studies have shown that testosterone affects the function and number of EPCs. However, some inconsistencies among these reports have been noted.
Conclusion:
Testosterone deficiency might cause endothelial dysfunction by decreasing NO levels through regulating the expression and activity of NO synthase and increasing ADMA expression. In addition, testosterone might affect the endothelial repair system by regulating the proliferation and migration of EPCs. Testosterone replacement therapy might be useful for treating endothelial dysfunction, considering that some reports have shown that this therapy improved NO bioavailability and EPC function. Hotta Y, Kataoka T, Kimura K. Testosterone Deficiency and Endothelial Dysfunction: Nitric Oxide, Asymmetric Dimethylarginine, and Endothelial Progenitor Cells. Sex Med Rev 2019;7:661-668.
