Histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones, regulating gene transcription. Decidualization is the progestin-induced differentiation of estrogen-primed endometrial stromal cells (ESCs), which is crucial for implantation and maintenance of pregnancy. We here show that trichostatin A (TSA), a specific HDAC inhibitor, enhances the up-regulation of decidualization markers such as insulin-like growth factor binding protein-1 (IGFBP-1) and prolactin in a dose-dependent manner that is directed by 17-estradiol (E 2 ) plus progesterone (P 4 ) in cultured ESCs, but not glandular cells, both isolated from human endometrium. Morphological changes resembling decidual transformation were also augmented by co-addition of TSA. Acid urea triton gel analysis and immunoblot using acetylated histone typespecific antibodies demonstrated that treatment with E 2 plus P 4 significantly increased the levels of acetylated H3 and H4 whose increment was augmented by cotreatment with TSA. Chromatin immunoprecipitation assay revealed that treatment with E 2 plus P 4 increased the amount of proximal progesterone-responsive region of IGFBP-1 promoter associated with acetylated H4, which was dramatically enhanced by co-addition of TSA. Taken together, our results suggest that histone acetylation is deeply involved in differentiation of human ESCs and that TSA has a potential as an enhancer of decidualization through promotion of progesterone action.
FSH-secreting pituitary adenoma (FSHoma) is often associated with increased levels of serum FSH and ovarian hyperstimulation syndrome (OHSS). The OHSS has historically been attributed to elevated FSH production by the FSHoma; however, some FSHoma patients with OHSS have normal serum FSH levels. OHSS may result not from increased FSH levels, but also from increased bioactivity of the FSH derived from the adenoma. To address this, we measured the FSH bioactivity in the serum of a 40-year-old woman with an FSHoma and OHSS, whose FSH levels were normal. Chinese hamster ovary cells stably expressing FSH receptors were prepared and transfected with a cAMP-responsive element-driven luciferase reporter plasmid. Cells were then treated with recombinant human FSH (rhFSH), the patient's sera, or sera from controls, collected at different time points, and subjected to a luciferase assay. Luciferase activity was increased in response to rhFSH in a dose-dependent manner. The responsiveness was further augmented by co-addition of a 3-methyl isobutylxanthine, which improved the sensitivity of our assay. Unexpectedly, the serum FSH bioactivity/immunoactivity ratio of the patient was mostly equal to that of normal subjects. This was confirmed with a granulosa cell aromatase assay. This case report suggests that alternate explanations may exist for the OHSS phenotype seen in some FSHoma patients.
Reversible protein tyrosine phosphorylation, coordinately controlled by protein tyrosine kinases and phosphatases, is a critical element in signal transduction pathways regulating a wide variety of biological processes, including cell growth, differentiation, and tumorigenesis. We have previously reported that c-Src belonging to the Src family tyrosine kinase (SFK) becomes dephosphorylated at tyrosine 530 (Y530) and thereby activated during progestin-induced differentiation of human endometrial stromal cells (i.e., decidualization). In this study, to elucidate the role of decidual c-Src activation, we examined whether 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), both potent and selective SFK inhibitors, affected the ovarian steroid-induced decidualization in vitro. Unexpectedly, PP1 paradoxically increased the kinase activity of decidual c-Src together with dephosphorylation of Y530 in the presence of ovarian steroids. Concomitantly, PP1 enhanced morphological and functional decidualization, as determined by induction of decidualization markers, such as insulin-like growth factor binding protein-1 and prolactin. PP2 also advanced decidualization along with up-regulation of the active form of c-Src whose Y-530 was dephosphorylated. In contrast to PP1 and PP2, herbimycin A, a tyrosine kinase inhibitor with less specificity for SFKs, showed little enhancing effect on the expression of both IGFBP-1 and active c-Src. These results suggest that SFKs, including c-Src, may play a significant role in stromal cell differentiation, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting signaling pathway(s) involving SFKs.
A 53-year-old woman with severe coronavirus disease 2019 (COVID-19) pneumonia was admitted and treated with intravenous unfractionated heparin for thromboprophylaxis under general anesthesia with mechanical ventilation. She developed right hemiparesis after hospitalization due to a large hemorrhagic infarction. Her platelet count decreased from 243,000/μL at administration to 121,000/μL. Anti-platelet factor 4heparin antibody testing was positive according to a latex immunoturbidimetric assay. She was therefore diagnosed with heparin-induced thrombocytopenia. We immediately stopped the heparin and started argatroban; the platelet count recovered, and thrombosis did not relapse. Physicians should consider heparin-induced thrombocytopenia as a cause of ischemic stroke in patients with COVID-19 infection.
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