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Abnormal arachidonic acid metabolic network may reduce sperm motility via P38 MAPK.

ABSTRACT: Asthenozoospermia is a common cause of male infertility, the aetiology of which remains unclear in 50-60% of cases. The current study aimed to characterize metabolic alterations in asthenozoospermic seminal plasma and to explore the signalling pathways involved in sperm motility regulation. At first, high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to detect the targeted metabolic network of arachidonic acid (AA). Metabolomic multivariate data analysis showed significant distinction of AA metabolites between asthenozoospermic and healthy seminal plasma. AA as well as its lipoxygenase (LOX) and cytochrome P450 metabolites were found to be abnormally increased, while cyclooxygenase (COX) metabolites were complicatedly disturbed in asthenozoospermic volunteers compared with those in healthy ones. In vitro experiments and western blot analysis of sperm cells revealed a decrease in sperm motility and upregulation of sperm phosphor-P38 induced by AA. P38 inhibitor could increase AA-reduced sperm motility. Also, all the inhibitors of the three metabolic pathways of AA could block AA-induced P38 mitogen-activated protein kinase (MAPK) activation and further improve sperm motility. We report here for the first time that an abnormal AA metabolic network could reduce sperm motility via P38 MAPK activation through the LOX, cytochrome P450 and COX metabolic pathways, which might be an underlying pathomechanism of asthenozoospermia.

SUBMITTER: Yu L

PROVIDER: S-EPMC6501647 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Abnormal arachidonic acid metabolic network may reduce sperm motility via P38 MAPK.

Yu Lisha L Yang Xiaojing X Ma Bo B Ying Hanjie H Shang Xuejun X He Bingfang B Zhang Qi Q

Open biology 20190401 4

Asthenozoospermia is a common cause of male infertility, the aetiology of which remains unclear in 50-60% of cases. The current study aimed to characterize metabolic alterations in asthenozoospermic seminal plasma and to explore the signalling pathways involved in sperm motility regulation. At first, high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to detect the targeted metabolic network of arachidonic acid (AA). Metabolomic multivariate data anal ...[more]

PMID: 31014201

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Project description:Extensive research has demonstrated a tumor-promoting role of increased WNT5A expression in malignant melanoma. However, very little light has been shed upon how WNT5A expression is up-regulated in melanoma. A potential regulator of WNT5A expression is the pro-inflammatory cytokine Interleukin (IL)-6, which shares the ability of WNT5A to increase melanoma cell invasion. Here, we investigate whether IL-6 can promote melanoma cell motility through an increased expression of WNT5A. We clearly demonstrate that the WNT5A-antagonistic peptide Box5 could inhibit IL-6-induced melanoma cell migration and invasion. Furthermore, IL-6 stimulation of the human melanoma cell lines HTB63 and A375 increased the expression of WNT5A in a dose-dependent manner. To identify the signaling mechanism responsible for this up-regulation, we explored the involvement of the three main signals induced by IL-6; STAT3, Akt and ERK 1/2. Of these, only STAT3 was activated by IL-6 in the melanoma cell lines tested. However, the STAT3 inhibitor S3I-201 failed to inhibit IL-6-induced WNT5A up-regulation in HTB63 and A375 cells. Nor did STAT3 siRNA silencing affect the expression of WNT5A. In search of an alternative signaling mechanism, we detected IL-6-induced activation of p38-MAPK in HTB63 and A375 cells. The p38-MAPK inhibitor SB203580 abolished the IL-6-induced WNT5A up-regulation and blocked IL-6-induced melanoma cell invasion. The latter effect could be rescued by the addition of recombinant WNT5A. Notably, immunoprecipitation analysis revealed that only the p38?-MAPK isoform was activated by IL-6, and subsequent siRNA silencing of p38?-MAPK abolished the IL-6-induced up-regulation of WNT5A. Taken together, we demonstrate a novel link between the two melanoma pro-metastatic agents IL-6 and WNT5A explaining how IL-6 can increase melanoma cell invasion and thus promote the metastatic process. This finding provides a basis for future therapeutic intervention of melanoma progression.

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Abnormal arachidonic acid metabolic network may reduce sperm motility via P38 MAPK.

Publications

Abnormal arachidonic acid metabolic network may reduce sperm motility via P38 MAPK.

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