{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T19:57:55Z","timestamp":1775159875356,"version":"3.50.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,1,28]],"date-time":"2020-01-28T00:00:00Z","timestamp":1580169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UID\/MULTI\/04378\/2019"],"award-info":[{"award-number":["UID\/MULTI\/04378\/2019"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PORTUGAL 2020 Partnership Agreement","award":["NORTE-01-0145-FEDER-000024"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,2,29]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>STUDY QUESTION<\/jats:title><jats:p>What are the effects of endocannabinoid anandamide (AEA) in uterine natural killer (unK) cells from miscarriage decidua, regarding their cytokine profile and endometrial stromal cell (ESC) crosstalk?<\/jats:p><\/jats:sec><jats:sec><jats:title>SUMMARY ANSWER<\/jats:title><jats:p>uNK-conditioned media from miscarriage samples present high TNF-\u03b1 levels which inhibit ESC decidualisation.<\/jats:p><\/jats:sec><jats:sec><jats:title>WHAT IS KNOWN ALREADY<\/jats:title><jats:p>AEA plasma levels are higher in women who have suffered a miscarriage. Moreover, AEA inhibits ESC proliferation and differentiation, although the levels and impact on the uNK cell cytokine profile at the feto-maternal interface remain elusive.<\/jats:p><\/jats:sec><jats:sec><jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title><jats:p>This laboratory-based study used human primary uNK cells which were isolated from first-trimester decidua (gestational age, 5\u201312\u00a0weeks) derived from 8 women with elective pregnancy termination and 18 women who suffered a miscarriage.<\/jats:p><\/jats:sec><jats:sec><jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title><jats:p>The first-trimester placental tissues were assayed for AEA levels by UPLC-MS\/MS and respective enzymatic profile by western blot. The uNK cells were isolated and maintained in culture. The expression of angiogenic markers in uNK cells was examined by quantitative PCR (qPCR). The uNK-conditioned medium was analysed for IFN-\u03b3, TNF-\u03b1 and IL-10 production by enzyme-linked immunosorbent assay, and the impact on ESC differentiation was assessed by measuring decidual markers Prl, Igfbp-1 and Fox01 mRNA expression using qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title><jats:p>AEA levels were higher in miscarriage decidua compared with decidua from elective terminations. The uNK cell-conditioned medium from the miscarriage samples exhibited high TNF-\u03b1 levels and interfered with the decidualisation of ESCs. Exacerbated inflammation and elevated TNF-\u03b1 levels at the feto-maternal interface may trigger AEA signalling pathways that, in turn, may impact decidualisation and the angiogenic ability of uNK cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>LARGE-SCALE DATA<\/jats:title><jats:p>N\/A.<\/jats:p><\/jats:sec><jats:sec><jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title><jats:p>Primary uNK cell responses are based on a simple in vitro model. Thus, in complex microenvironments, such as the feto-maternal interface, the mechanisms may not be exactly the same. Also, the inflammatory events of miscarriage that, in this study, have happened prior to processing of the samples may cause different responses to that observed. In addition, the magnitude of the inflammatory response, required to trigger the AEA pathways that impact decidualisation and the uNK angiogenic ability in vivo, is still unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title><jats:p>The endocannabinoid AEA is a modulator of reproductive competence. AEA not only may contribute to neuroendocrine homeostasis but also can take part in uterine changes occurring during early pregnancy.<\/jats:p><\/jats:sec><jats:sec><jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title><jats:p>The work was supported by UID\/MULTI\/04378\/2019 with funding from Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)\/MCTES through national funds and PORTUGAL 2020 Partnership Agreement, NORTE-01-0145-FEDER-000024. S.C. Cunha acknowledges FCT for the IF\/01616\/2015 contract. There are no conflicts of interest.<\/jats:p><\/jats:sec>","DOI":"10.1093\/humrep\/dez260","type":"journal-article","created":{"date-parts":[[2019,11,18]],"date-time":"2019-11-18T20:10:18Z","timestamp":1574107818000},"page":"265-274","source":"Crossref","is-referenced-by-count":34,"title":["Decidual NK cell-derived conditioned medium from miscarriages affects endometrial stromal cell decidualisation: endocannabinoid anandamide and tumour necrosis factor-\u03b1 crosstalk"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8873-5591","authenticated-orcid":false,"given":"B M","family":"Fonseca","sequence":"first","affiliation":[{"name":"UCIBIO, REQUIMTE, Laborat\u00f3rio de Bioqu\u00edmica, Departamento de Ci\u00eancias Biol\u00f3gicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"}]},{"given":"S C","family":"Cunha","sequence":"first","affiliation":[{"name":"LAQV, REQUIMTE, Laborat\u00f3rio de Bromatologia e Hidrologia, Departamento de Ci\u00eancias Qu\u00edmicas, Faculdade de Farm\u00e1cia, Universidade do Porto, Porto, Portugal"}]},{"given":"D","family":"Gon\u00e7alves","sequence":"first","affiliation":[{"name":"Departamento da Mulher e da Medicina Reprodutiva, Servi\u00e7o de Obstetr\u00edcia, Centro Materno-Infantil do Norte, Centro Hospitalar do Porto, Porto, Portugal"}]},{"given":"A","family":"Mendes","sequence":"first","affiliation":[{"name":"Departamento da Mulher e da Medicina Reprodutiva, Servi\u00e7o de Obstetr\u00edcia, Centro Materno-Infantil do Norte, Centro Hospitalar do Porto, Porto, Portugal"}]},{"given":"J","family":"Braga","sequence":"first","affiliation":[{"name":"Departamento da Mulher e da Medicina Reprodutiva, Servi\u00e7o de Obstetr\u00edcia, Centro Materno-Infantil do Norte, Centro Hospitalar do Porto, Porto, Portugal"}]},{"given":"G","family":"Correia-da-Silva","sequence":"first","affiliation":[{"name":"UCIBIO, REQUIMTE, Laborat\u00f3rio de Bioqu\u00edmica, Departamento de Ci\u00eancias 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