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15 pages, 3962 KiB

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Immunohistochemical Study on the Expression of G-CSF, G-CSFR, VEGF, VEGFR-1, Foxp3 in First Trimester Trophoblast of Recurrent Pregnancy Loss in Pregnancies Treated with G-CSF and Controls

by Fabio Scarpellini, Francesca Gioia Klinger, Gabriele Rossi and Marco Sbracia

Int. J. Mol. Sci. 2020, 21(1), 285; https://doi.org/10.3390/ijms21010285 - 31 Dec 2019

Cited by 23 | Viewed by 4340

Abstract

Background: Recurrent Pregnancy Loss (RPL) is a syndrome recognizing several causes, and in some cases the treatment with Granulocyte Colony Stimulating Factor (G-CSF) may be successful, especially when karyotype of the previous miscarriage showed no embryo chromosomal abnormalities. In order to evaluate the [...] Read more.

Background: Recurrent Pregnancy Loss (RPL) is a syndrome recognizing several causes, and in some cases the treatment with Granulocyte Colony Stimulating Factor (G-CSF) may be successful, especially when karyotype of the previous miscarriage showed no embryo chromosomal abnormalities. In order to evaluate the effects of G-CSF treatment on the decidual and trophoblast expression of G-CSF and its receptor, VEGF and its receptor and Foxp3, specific marker of putative Tregs we conducted an immunohistochemical study. Methods: This study was conducted on three groups of patients for a total of 38 women: in 8 cases decidual and trophoblast tissue were obtained from 8 women with unexplained RPL treated with G-CSF that miscarried despite treatment; in 15 cases the tissue were obtained from 15 women with unexplained RPL no treated; 15 cases of women who underwent voluntary pregnancy termination were used as controls. Tissue collected from these patients were used for immunohistochemistry studies testing the expression of G-CSF, G-CSFR, VEGF, VEGFR-1 and Foxp3. Results: G-CSF treatment increased the concentration of cells expressing Foxp3, specific marker for Tregs, in the decidua, whereas in no treated RPL a reduction of these cells was found when compared to controls. Furthermore, G-CSF treatment increased the expression of G-CSF and VEGF in the trophoblast. Conclusions: Our study showed that G-CSF treatment increased the number of decidual Treg cells in RPL patients as well as the expression of G-CSF and VEGF in villus trophoblast. These finding may explain the effectiveness of this treatment in RPL, probably regulating the maternal immune response through Tregs recruitment in the decidua, as well as stimulating trophoblast growth. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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17 pages, 4267 KiB

Open AccessArticle

Fucoxanthin-Rich Brown Algae Extract Improves Male Reproductive Function on Streptozotocin-Nicotinamide-Induced Diabetic Rat Model

by Zwe-Ling Kong, Sabri Sudirman, Yu-Chun Hsu, Chieh-Yu Su and Hsiang-Ping Kuo

Int. J. Mol. Sci. 2019, 20(18), 4485; https://doi.org/10.3390/ijms20184485 - 11 Sep 2019

Cited by 32 | Viewed by 5318

Abstract

Hypogonadism and oxidative stress are occurring commonly in men with diabetes and associated male infertility. This study aimed to investigate the capability of anti-oxidative and anti-inflammatory properties of fucoxanthin as well as to evaluate its protective effects on male reproduction in diabetic rats. [...] Read more.

Hypogonadism and oxidative stress are occurring commonly in men with diabetes and associated male infertility. This study aimed to investigate the capability of anti-oxidative and anti-inflammatory properties of fucoxanthin as well as to evaluate its protective effects on male reproduction in diabetic rats. The RAW 264.7 macrophage cells were used to evaluate the anti-oxidative and anti-inflammatory activity. Thirty male Sprague-Dawley rats were induced by streptozotocin-nicotinamide for a diabetes model and fed either with three different doses of fucoxanthin (13, 26, and 65 mg/kg) or rosiglitazone (0.571 mg/kg) for four weeks. The fucoxanthin significantly inhibited nitric oxide production and reduced reactive oxygen species level in lipopolysaccharide-induced RAW 264.7 cells. In the animal study, fucoxanthin administration improved insulin resistance, restored sperm motility, decreased abnormal sperm number, and inhibited lipid peroxidation. Moreover, it restored GPR54 and SOCS-3 mRNA expression in the hypothalamus and recovered luteinizing hormone level, as well as the testosterone level. In conclusion, fucoxanthin not only possessed antioxidant and anti-inflammatory properties but also decreased the diabetes signs and symptoms as well as improved spermatogenesis and male reproductive function. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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15 pages, 7292 KiB

Open AccessArticle

Transcriptomics and Immunological Analyses Reveal a Pro-Angiogenic and Anti-Inflammatory Phenotype for Decidual Endothelial Cells

by Chiara Agostinis, Elisa Masat, Fleur Bossi, Giuseppe Ricci, Renzo Menegazzi, Letizia Lombardelli, Gabriella Zito, Alessandro Mangogna, Massimo Degan, Valter Gattei, Marie-Pierre Piccinni, Uday Kishore and Roberta Bulla

Int. J. Mol. Sci. 2019, 20(7), 1604; https://doi.org/10.3390/ijms20071604 - 31 Mar 2019

Cited by 12 | Viewed by 4503

Abstract

Background: In pregnancy, excessive inflammation and break down of immunologic tolerance can contribute to miscarriage. Endothelial cells (ECs) are able to orchestrate the inflammatory processes by secreting pro-inflammatory mediators and bactericidal factors by modulating leakiness and leukocyte trafficking, via the expression of adhesion [...] Read more.

Background: In pregnancy, excessive inflammation and break down of immunologic tolerance can contribute to miscarriage. Endothelial cells (ECs) are able to orchestrate the inflammatory processes by secreting pro-inflammatory mediators and bactericidal factors by modulating leakiness and leukocyte trafficking, via the expression of adhesion molecules and chemokines. The aim of this study was to analyse the differences in the phenotype between microvascular ECs isolated from decidua (DECs) and ECs isolated from human skin (ADMECs). Methods: DECs and ADMECs were characterized for their basal expression of angiogenic factors and adhesion molecules. A range of immunological responses was evaluated, such as vessel leakage, reactive oxygen species (ROS) production in response to TNF-α stimulation, adhesion molecules expression and leukocyte migration in response to TNF-α and IFN-γ stimulation. Results: DECs produced higher levels of HGF, VEGF-A and IGFBP3 compared to ADMECs. DECs expressed adhesion molecules, ICAM-2 and ICAM-3, and a mild response to TNF-α was observed. Finally, DECs produced high levels of CXCL9/MIG and CXCL10/IP-10 in response to IFN-γ and selectively recruited Treg lymphocytes. Conclusion: DEC phenotype differs considerably from that of ADMECs, suggesting that DECs may play an active role in the control of immune response and angiogenesis at the foetal-maternal interface. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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13 pages, 2685 KiB

Open AccessArticle

Testis-Specific SEPT12 Expression Affects SUN Protein Localization and is Involved in Mammalian Spermiogenesis

by Chung-Hsin Yeh, Ya-Yun Wang, Shi-Kae Wee, Mei-Feng Chen, Han-Sun Chiang, Pao-Lin Kuo and Ying-Hung Lin

Int. J. Mol. Sci. 2019, 20(5), 1163; https://doi.org/10.3390/ijms20051163 - 7 Mar 2019

Cited by 10 | Viewed by 3806

Abstract

Male infertility is observed in approximately 50% of all couples with infertility. Intracytoplasmic sperm injection (ICSI), a conventional artificial reproductive technique for treating male infertility, may fail because of a severe low sperm count, immotile sperm, immature sperm, and sperm with structural defects [...] Read more.

Male infertility is observed in approximately 50% of all couples with infertility. Intracytoplasmic sperm injection (ICSI), a conventional artificial reproductive technique for treating male infertility, may fail because of a severe low sperm count, immotile sperm, immature sperm, and sperm with structural defects and DNA damage. Our previous studies have revealed that mutations in the septin (SEPT)-coding gene SEPT12 cause teratozoospermia and severe oligozoospermia. These spermatozoa exhibit morphological defects in the head and tail, premature chromosomal condensation, and nuclear damage. Sperm from Sept12 knockout mice also cause the developmental arrest of preimplantation embryos generated through in vitro fertilization and ICSI. Furthermore, we found that SEPT12 interacts with SPAG4, a spermatid nuclear membrane protein that is also named SUN4. Loss of the Spag4 allele in mice also disrupts the integration nuclear envelope and reveals sperm head defects. However, whether SEPT12 affects SPAG4 during mammalian spermiogenesis remains unclear. We thus conducted this study to explore this question. First, we found that SPAG4 and SEPT12 exhibited similar localizations in the postacrosomal region of elongating spermatids and at the neck of mature sperm through isolated murine male germ cells. Second, SEPT12 expression altered the nuclear membrane localization of SPAG4, as observed through confocal microscopy, in a human testicular cancer cell line. Third, SEPT12 expression also altered the localizations of nuclear membrane proteins: LAMINA/C in the cells. This effect was specifically due to the expression of SEPT12 and not that of SEPT1, SEPT6, SEPT7, or SEPT11. Based on these results, we suggest that SEPT12 is among the moderators of SPAG4/LAMIN complexes and is involved in the morphological formation of sperm during mammalian spermiogenesis. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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15 pages, 904 KiB

Open AccessArticle

Reactive Species Interactome Alterations in Oocyte Donation Pregnancies in the Absence and Presence of Pre-Eclampsia

by Manon Bos, Mirthe H. Schoots, Bernadette O. Fernandez, Monika Mikus-Lelinska, Laurie C. Lau, Michael Eikmans, Harry van Goor, Sanne J. Gordijn, Andreas Pasch, Martin Feelisch and Marie-Louise P. van der Hoorn

Int. J. Mol. Sci. 2019, 20(5), 1150; https://doi.org/10.3390/ijms20051150 - 6 Mar 2019

Cited by 10 | Viewed by 3112

Abstract

In pregnancy, maternal physiology is subject to considerable adaptations, including alterations in cardiovascular and metabolic function as well as development of immunological tolerance towards the fetus. In an oocyte donation pregnancy, the fetus is fully allogeneic towards the mother, since it carries both [...] Read more.

In pregnancy, maternal physiology is subject to considerable adaptations, including alterations in cardiovascular and metabolic function as well as development of immunological tolerance towards the fetus. In an oocyte donation pregnancy, the fetus is fully allogeneic towards the mother, since it carries both oocyte donor antigens and paternal antigens. Therefore, oocyte donation pregnancies result in an immunologically challenging pregnancy, which is reflected by a higher-than-normal risk to develop pre-eclampsia. Based on the allogeneic conditions in oocyte donation pregnancies, we hypothesized that this situation may translate into alterations in concentration of stable readouts of constituents of the reactive species interactome (RSI) compared to normal pregnancies, especially serum free thiols, nitric oxide (NO) and hydrogen sulfide (H₂S) related metabolites. Indeed, total free thiol levels and nitrite (NO₂⁻) concentrations were significantly lower whereas protein-bound NO and sulfate (SO₄²⁻) concentrations were significantly higher in both oocyte donation and naturally conceived pregnancies complicated by pre-eclampsia. The increased concentrations of nitrite observed in uncomplicated oocyte donation pregnancies suggest that endothelial NO production is compensatorily enhanced to lower vascular tone. More research is warranted on the role of the RSI and bioenergetic status in uncomplicated oocyte donation pregnancies and oocyte donation pregnancies complicated by pre-eclampsia. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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18 pages, 5418 KiB

Open AccessArticle

Early Pregnancy Human Decidua is Enriched with Activated, Fully Differentiated and Pro-Inflammatory Gamma/Delta T Cells with Diverse TCR Repertoires

by Antonia Terzieva, Violeta Dimitrova, Lyubomir Djerov, Petya Dimitrova, Silvina Zapryanova, Iana Hristova, Ivaylo Vangelov and Tanya Dimova

Int. J. Mol. Sci. 2019, 20(3), 687; https://doi.org/10.3390/ijms20030687 - 5 Feb 2019

Cited by 33 | Viewed by 6851

Abstract

Pregnancy is a state where high and stage-dependent plasticity of the maternal immune system is necessary in order to equilibrate between immunosuppression of harmful responses towards the fetus and ability to fight infections. TCR γδ cells have been implicated in the responses in [...] Read more.

Pregnancy is a state where high and stage-dependent plasticity of the maternal immune system is necessary in order to equilibrate between immunosuppression of harmful responses towards the fetus and ability to fight infections. TCR γδ cells have been implicated in the responses in infectious diseases, in the regulation of immune responses, and in tissue homeostasis and repair. The variety of functions makes γδ T cells a particularly interesting population during pregnancy. In this study, we investigated the proportion, phenotype and TCR γ and δ repertoires of γδ T cells at the maternal–fetal interface and in the blood of pregnant women using FACS, immunohistochemistry and spectratyping. We found an enrichment of activated and terminally differentiated pro-inflammatory γδ T-cell effectors with specific location in the human decidua during early pregnancy, while no significant changes in their counterparts in the blood of pregnant women were observed. Our spectratyping data revealed polyclonal CDR3 repertoires of the δ1, δ2 and δ3 chains and γ2, γ3, γ4 and γ5 chains and oligoclonal and highly restricted CDR3γ9 repertoire of γδ T cells in the decidua and blood of pregnant women. Early pregnancy induces recruitment of differentiated pro-inflammatory γδ T-cell effectors with diverse TCR repertoires at the maternal–fetal interface. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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17 pages, 2391 KiB

Open AccessArticle

Placental CX3CL1 is Deregulated by Angiotensin II and Contributes to a Pro-Inflammatory Trophoblast-Monocyte Interaction

by Olivia Nonn, Jacqueline Güttler, Désirée Forstner, Sabine Maninger, Julianna Zadora, András Balogh, Alina Frolova, Andreas Glasner, Florian Herse and Martin Gauster

Int. J. Mol. Sci. 2019, 20(3), 641; https://doi.org/10.3390/ijms20030641 - 2 Feb 2019

Cited by 22 | Viewed by 4672

Abstract

CX3CL1, which is a chemokine involved in many aspects of human pregnancy, is a membrane-bound chemokine shed into circulation as a soluble isoform. Placental CX3CL1 is induced by inflammatory cytokines and is upregulated in severe early-onset preeclampsia. In this study, the hypothesis was [...] Read more.

CX3CL1, which is a chemokine involved in many aspects of human pregnancy, is a membrane-bound chemokine shed into circulation as a soluble isoform. Placental CX3CL1 is induced by inflammatory cytokines and is upregulated in severe early-onset preeclampsia. In this study, the hypothesis was addressed whether angiotensin II can deregulate placental CX3CL1 expression, and whether CX3CL1 can promote a pro-inflammatory status of monocytes. qPCR analysis of human placenta samples (n = 45) showed stable expression of CX3CL1 and the angiotensin II receptor AGTR1 throughout the first trimester, but did not show a correlation between both or any influence of maternal age, BMI, and gestational age. Angiotensin II incubation of placental explants transiently deregulated CX3CL1 expression, while the angiotensin II receptor antagonist candesartan reversed this effect. Overexpression of recombinant human CX3CL1 in SGHPL-4 trophoblasts increased adhesion of THP-1 monocytes and significantly increased IL8, CCL19, and CCL13 in co-cultures with human primary monocytes. Incubation of primary monocytes with CX3CL1 and subsequent global transcriptome analysis of CD16⁺ subsets revealed 81 upregulated genes, including clusterin, lipocalin-2, and the leptin receptor. Aldosterone synthase, osteopontin, and cortisone reductase were some of the 66 downregulated genes present. These data suggest that maternal angiotensin II levels influence placental CX3CL1 expression, which, in turn, can affect monocyte to trophoblast adhesion. Release of placental CX3CL1 could promote the pro-inflammatory status of the CD16⁺ subset of maternal monocytes. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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12 pages, 1310 KiB

Open AccessArticle

Increased HLA-G Expression in Term Placenta of Women with a History of Recurrent Miscarriage Despite Their Genetic Predisposition to Decreased HLA-G Levels

by Moniek H. C. Craenmehr, Iris Nederlof, Milo Cao, Jos J. M. Drabbels, Marijke J. Spruyt-Gerritse, Jacqueline D. H. Anholts, Hanneke M. Kapsenberg, Janine A. Stegehuis, Carin van der Keur, Esther Fasse, Geert W. Haasnoot, Marie-Louise P. van der Hoorn, Frans H. J. Claas, Sebastiaan Heidt and Michael Eikmans

Int. J. Mol. Sci. 2019, 20(3), 625; https://doi.org/10.3390/ijms20030625 - 1 Feb 2019

Cited by 26 | Viewed by 4765

Abstract

Human leukocyte antigen (HLA)-G is an immune modulating molecule that is present on fetal extravillous trophoblasts at the fetal-maternal interface. Single nucleotide polymorphisms (SNPs) in the 3 prime untranslated region (3′UTR) of the HLA-G gene can affect the level of HLA-G expression, which [...] Read more.

Human leukocyte antigen (HLA)-G is an immune modulating molecule that is present on fetal extravillous trophoblasts at the fetal-maternal interface. Single nucleotide polymorphisms (SNPs) in the 3 prime untranslated region (3′UTR) of the HLA-G gene can affect the level of HLA-G expression, which may be altered in women with recurrent miscarriages (RM). This case-control study included 23 women with a medical history of three or more consecutive miscarriages who delivered a child after uncomplicated pregnancy, and 46 controls with uncomplicated pregnancy. Genomic DNA was isolated to sequence the 3′UTR of HLA-G. Tissue from term placentas was processed to quantify the HLA-G protein and mRNA levels. The women with a history of RM had a lower frequency of the HLA-G 3′UTR 14-bp del/del genotype as compared to controls (Odds ratio (OR) 0.28; p = 0.039), which has previously been related to higher soluble HLA-G levels. Yet, HLA-G protein (OR 6.67; p = 0.006) and mRNA (OR 6.33; p = 0.010) expression was increased in term placentas of women with a history of RM as compared to controls. In conclusion, during a successful pregnancy, HLA-G expression is elevated in term placentas from women with a history of RM as compared to controls, despite a genetic predisposition that is associated with decreased HLA-G levels. These findings suggest that HLA-G upregulation could be a compensatory mechanism in the occurrence of RM to achieve an ongoing pregnancy. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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11 pages, 7311 KiB

Open AccessArticle

Involvement of the PD-1/PD-L1 Co-Inhibitory Pathway in the Pathogenesis of the Inflammatory Stage of Early-Onset Preeclampsia

by Matyas Meggyes, Eva Miko, Adrienn Lajko, Beata Csiszar, Barbara Sandor, Peter Matrai, Peter Tamas and Laszlo Szereday

Int. J. Mol. Sci. 2019, 20(3), 583; https://doi.org/10.3390/ijms20030583 - 29 Jan 2019

Cited by 20 | Viewed by 3396

Abstract

The programmed cell death protein 1 (PD-1) receptor has been reported to downregulate T cell activation effectively via binding to its ligands PD-L1 or PD-L2 in a negative co-stimulatory manner. Little is known about the involvement of PD-1 mediated immunoregulation in pregnancy and [...] Read more.

The programmed cell death protein 1 (PD-1) receptor has been reported to downregulate T cell activation effectively via binding to its ligands PD-L1 or PD-L2 in a negative co-stimulatory manner. Little is known about the involvement of PD-1 mediated immunoregulation in pregnancy and in pregnancy-related disorders. In this work, we investigated the possible role of the PD-1 co-stimulatory pathway in the pathogenesis of the clinical phase of early-onset preeclampsia characterized by a systemic maternal inflammatory response. We performed a cross-sectional study for comparative analysis of phenotypic and functional characteristics of peripheral blood mononuclear cells in women with early-onset preeclampsia and third-trimester healthy pregnant controls. According to our findings, enhanced expression of either PD-1 or its ligand PD-L1, or both, on the cell surface of effector cells (T cells, natural killer (NK) cells, natural killer T (NKT)-like cells) and Tregs could be observed, but PD-1 expression did not correlate with effector cells exhaustion. These results suggest the failure of the axis to downregulate Th1 responses, contributing thereby to the exaggerated immunoactivation observed in early-onset preeclampsia. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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18 pages, 2254 KiB

Open AccessArticle

Decidual Interleukin-22-Producing CD4+ T Cells (Th17/Th0/IL-22+ and Th17/Th2/IL-22+, Th2/IL-22+, Th0/IL-22+), Which Also Produce IL-4, Are Involved in the Success of Pregnancy

by Federica Logiodice, Letizia Lombardelli, Ornela Kullolli, Herman Haller, Enrico Maggi, Daniel Rukavina and Marie-Pierre Piccinni

Int. J. Mol. Sci. 2019, 20(2), 428; https://doi.org/10.3390/ijms20020428 - 19 Jan 2019

Cited by 40 | Viewed by 6071

Abstract

Trophoblast expressing paternal HLA-C resembles a semiallograft, and could be rejected by maternal T cells. IL-22 seems to be involved in allograft rejection and thus could be responsible for miscarriages. We examined the role of decidual IL-22-producing CD4+ T on human pregnancy. In [...] Read more.

Trophoblast expressing paternal HLA-C resembles a semiallograft, and could be rejected by maternal T cells. IL-22 seems to be involved in allograft rejection and thus could be responsible for miscarriages. We examined the role of decidual IL-22-producing CD4+ T on human pregnancy. In those experiencing successful pregnancy and those experiencing unexplained recurrent abortion (URA), the levels of IL-22 produced by decidual CD4+ T cells are higher than those of peripheral blood T cells. We found a correlation of IL-22 and IL-4 produced by decidual CD4+ T cells in those experiencing successful pregnancy, not in those experiencing URA. The correlation of IL-22 and IL-4 was also found in the serum of successful pregnancy. A prevalence of CD4+ T cells producing IL-22 and IL-4 (Th17/Th2/IL-22+, Th17/Th0/IL-22+, Th17/Th2/IL-22+, and Th0/IL-22+ cells) was observed in decidua of those experiencing successful pregnancy, whereas Th17/Th1/IL-22+ cells, which do not produce IL-4, are prevalent in those experiencing URA. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells are exclusively present at the embryo implantation site where IL-4, GATA-3, IL-17A, ROR-C, IL-22, and AHR mRNA are expressed. T-bet and IFN-γ mRNA are found away from the implantation site. There is no pathogenic role of IL-22 when IL-4 is also produced by decidual CD4+ cells. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells seem to be crucial for embryo implantation. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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11 pages, 2243 KiB

Open AccessArticle

A Proteome Approach Reveals Differences between Fertile Women and Patients with Repeated Implantation Failure on Endometrial Level—Does hCG Render the Endometrium of RIF Patients?

by Alexandra P. Bielfeld, Sarah Jean Pour, Gereon Poschmann, Kai Stühler, Jan-Steffen Krüssel and Dunja M. Baston-Büst

Int. J. Mol. Sci. 2019, 20(2), 425; https://doi.org/10.3390/ijms20020425 - 19 Jan 2019

Cited by 31 | Viewed by 5121

Abstract

Background: The molecular signature of endometrial receptivity still remains barely understood, especially when focused on the possible benefit of therapeutical interventions and implantation-related pathologies. Therefore, the protein composition of tissue and isolated primary cells (endometrial stromal cells, ESCs) from endometrial scratchings of ART [...] Read more.

Background: The molecular signature of endometrial receptivity still remains barely understood, especially when focused on the possible benefit of therapeutical interventions and implantation-related pathologies. Therefore, the protein composition of tissue and isolated primary cells (endometrial stromal cells, ESCs) from endometrial scratchings of ART (Assisted Reproductive Techniques) patients with repeated implantation failure (RIF) was compared to volunteers with proven fertility during the time of embryo implantation (LH + 7). Furthermore, an analysis of the endometrial tissue of fertile women infused with human chorionic gonadotropin (hCG) was conducted. Methods: Endometrial samples (n = 6 RIF, n = 10 fertile controls) were split into 3 pieces: 1/3 each was frozen in liquid nitrogen, 1/3 fixed in PFA and 1/3 cultured. Protein lysates prepared from fresh frozen tissue were processed for mass spectrometric analysis. Results: Three proteins (EPPK1, BCLAF1 and PTMA) showed a statistically altered abundance in the endometrial tissue of RIF patients. Furthermore, pathways like metabolism, immune system, ferroptosis and the endoplasmic reticulum were altered in RIF patients. Remarkably, endometrial tissues of RIF patients showed a significantly higher (p-value = 9 × 10⁻⁸) protein intensity correlation (Pearson’s correlation coefficient = 0.95) compared to fertile women (Pearson’s correlation coefficient = 0.88). The in vivo infusion of hCG stimulated proteins of endocytosis, HIF1 signalling and chemokine production. Notably, patients suffering from RIF had a clinical pregnancy rate of 19% after the intrauterine infusion of hCG before embryo transfer (ET) compared to their failed previous cycles. Conclusion: Our study showed for the first time that the endometrial proteome composition of RIF patients differs from fertile controls during the window of implantation. The intrauterine infusion of hCG prior to an embryo transfer might improve the chemokine triggered embryo-endometrial dialogue and intensify the angiogenesis and immune response. From a clinical point of view, the hCG infusion prior to an embryo transfer might increase the pregnancy rate of RIF patients. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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16 pages, 2880 KiB

Open AccessArticle

Melatonin Improves Parthenogenetic Development of Vitrified–Warmed Mouse Oocytes Potentially by Promoting G1/S Cell Cycle Progression

by Bo Pan, Haoxuan Yang, Zhenzheng Wu, Izhar Hyder Qazi, Guoshi Liu, Hongbing Han, Qingyong Meng and Guangbin Zhou

Int. J. Mol. Sci. 2018, 19(12), 4029; https://doi.org/10.3390/ijms19124029 - 13 Dec 2018

Cited by 24 | Viewed by 4716

Abstract

This study aimed to investigate the effect of melatonin on the cell cycle of parthenogenetic embryos derived from vitrified mouse metaphase II (MII) oocytes. Fresh oocytes were randomly allocated into three groups: untreated (control), or vitrified by the open-pulled straw method without (Vitrification [...] Read more.

This study aimed to investigate the effect of melatonin on the cell cycle of parthenogenetic embryos derived from vitrified mouse metaphase II (MII) oocytes. Fresh oocytes were randomly allocated into three groups: untreated (control), or vitrified by the open-pulled straw method without (Vitrification group) or with melatonin (MT) supplementation (Vitrification + MT group). After warming, oocytes were parthenogenetically activated and cultured in vitro, then the percentage of embryos in the G1/S phase, the levels of reactive oxygen species (ROS) and glutathione (GSH), and the mRNA expression of cell cycle-related genes (P53, P21 and E2F1) in zygotes and their subsequent developmental potential in vitro were evaluated. The results showed that the vitrification/warming procedures significantly decreased the frequency of the S phase, markedly increased ROS and GSH levels and the expression of P53 and P21 genes, and decreased E2F1 expression in zygotes at the G1 stage and their subsequent development into 2-cell and blastocyst stage embryos. However, when 10⁻⁹ mol/L MT was administered for the whole duration of the experiment, the frequency of the S phase in zygotes was significantly increased, while the other indicators were also significantly improved and almost recovered to the normal levels shown in the control. Thus, MT might promote G1-to-S progression via regulation of ROS, GSH and cell cycle-related genes, potentially increasing the parthenogenetic development ability of vitrified–warmed mouse oocytes. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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12 pages, 2771 KiB

Open AccessArticle

Gosha-Jinki-Gan Recovers Spermatogenesis in Mice with Busulfan-Induced Aspermatogenesis

by Ning Qu, Miyuki Kuramasu, Yoshie Hirayanagi, Kenta Nagahori, Shogo Hayashi, Yuki Ogawa, Hayato Terayama, Kaori Suyama, Munekazu Naito, Kou Sakabe and Masahiro Itoh

Int. J. Mol. Sci. 2018, 19(9), 2606; https://doi.org/10.3390/ijms19092606 - 3 Sep 2018

Cited by 16 | Viewed by 4739

Abstract

Busulfan is an anti-cancer chemotherapeutic drug and is often used as conditioning regimens prior to bone marrow transplant for treatment of chronic myelogenous leukemia. Male infertility, including spermatogenesis disturbance, is known to be one of the side effects of anticancer drugs. While hormone [...] Read more.

Busulfan is an anti-cancer chemotherapeutic drug and is often used as conditioning regimens prior to bone marrow transplant for treatment of chronic myelogenous leukemia. Male infertility, including spermatogenesis disturbance, is known to be one of the side effects of anticancer drugs. While hormone preparations and vitamin preparations are used for spermatogenesis disturbance, their therapeutic effects are low. Some traditional herbal medicines have been administered to improve spermatogenesis. In the present study, we administered Gosha-jinki-gan (TJ107; Tsumura Co., Ltd., Tokyo, Japan) to mice suffering from severe aspermatogenesis after busulfan treatment to determine whether TJ107 can recover spermatogenesis. Male 4-week-old C57BL/6J mice were administered a single intraperitoneal injection of busulfan, and they were then fed a normal diet for 60 days and then a TJ107 diet or TJ107-free normal diet for another 60 days. After busulfan treatment, the weight of the testes and the epididymal sperm count progressively decreased in the normal diet group. On the other hand, in the TJ107 group, these variables dramatically recovered at 120 days. These results suggest that busulfan-induced aspermatogenesis is irreversible if appropriate treatment is not administered. Supplementation of TJ107 can completely recover the injured seminiferous epithelium via normalization of the macrophage migration and reduction of the expressions of Tool-like receptor (TLR) 2 and TLR4, suggesting that TJ107 has a therapeutic effect on busulfan-induced aspermatogenesis. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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13 pages, 2940 KiB

Open AccessArticle

Aggregation of Human Trophoblast Cells into Three-Dimensional Culture System Enhances Anti-Inflammatory Characteristics through Cytoskeleton Regulation

by Kotomi Seno, Yasuhisa Munakata, Michiya Sano, Ryouka Kawahara-Miki, Hironori Takahashi, Akihide Ohkuchi, Hisataka Iwata, Takehito Kuwayama and Koumei Shirasuna

Int. J. Mol. Sci. 2018, 19(8), 2322; https://doi.org/10.3390/ijms19082322 - 8 Aug 2018

Cited by 7 | Viewed by 4363

Abstract

Background: Three-dimensional (3D) culture changes cell characteristics and function, suggesting that 3D culture provides a more physiologically relevant environment for cells compared with 2D culture. We investigated the differences in cell functions depending on the culture model in human trophoblast cells (Sw.71). Methods: [...] Read more.

Background: Three-dimensional (3D) culture changes cell characteristics and function, suggesting that 3D culture provides a more physiologically relevant environment for cells compared with 2D culture. We investigated the differences in cell functions depending on the culture model in human trophoblast cells (Sw.71). Methods: Sw.71 cells were incubated in 2D monolayers or simple 3D spheroids. After incubation, cells were corrected to assess RNA-seq transcriptome or protein expression, and culture medium were corrected to detect cytokines. To clarify the role of actin cytoskeleton, spheroid Sw.71 cells were treated mycalolide B (inhibitor of actin polymerization) in a 3D culture. Results: RNA-seq transcriptome analysis, results revealed that 3D-cultured cells had a different transcriptional profile compared with 2D-cultured cells, especially regarding inflammation-related molecules. Although interleukin-6 (IL-6) mRNA level was higher in 3D-culured cells, its secretion levels were higher in 2D-cultured cells. In addition, the levels of mRNA and protein expression of regnase-1, regulatory RNase of inflammatory cytokine, significantly increased in 3D culture, suggesting post-translational modification of IL-6 mRNA via regnase-1. Treatment with mycalolide B reduced cell-to-cell contact to build 3D formation and increased expression of actin cytoskeleton, resulting in increased IL-6 secretin. Conclusion: Cell dimensionality plays an essential role in governing the spatiotemporal cellular outcomes, including inflammatory cytokine production and its negative regulation associated with regnase-1. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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29 pages, 1005 KiB

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Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

by Carlo Ticconi, Adalgisa Pietropolli, Nicoletta Di Simone, Emilio Piccione and Asgerally Fazleabas

Int. J. Mol. Sci. 2019, 20(21), 5332; https://doi.org/10.3390/ijms20215332 - 26 Oct 2019

Cited by 146 | Viewed by 8959

Abstract

Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on [...] Read more.

Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal–fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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39 pages, 1503 KiB

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Beneficial and Deleterious Effects of Female Sex Hormones, Oral Contraceptives, and Phytoestrogens by Immunomodulation on the Liver

by Luis E. Soria-Jasso, Raquel Cariño-Cortés, Víctor Manuel Muñoz-Pérez, Elizabeth Pérez-Hernández, Nury Pérez-Hernández and Eduardo Fernández-Martínez

Int. J. Mol. Sci. 2019, 20(19), 4694; https://doi.org/10.3390/ijms20194694 - 22 Sep 2019

Cited by 14 | Viewed by 5939

Abstract

The liver is considered the laboratory of the human body because of its many metabolic processes. It accomplishes diverse activities as a mixed gland and is in continuous cross-talk with the endocrine system. Not only do hormones from the gastrointestinal tract that participate [...] Read more.

The liver is considered the laboratory of the human body because of its many metabolic processes. It accomplishes diverse activities as a mixed gland and is in continuous cross-talk with the endocrine system. Not only do hormones from the gastrointestinal tract that participate in digestion regulate the liver functions, but the sex hormones also exert a strong influence on this sexually dimorphic organ, via their receptors expressed in liver, in both health and disease. Besides, the liver modifies the actions of sex hormones through their metabolism and transport proteins. Given the anatomical position and physiological importance of liver, this organ is evidenced as an immune vigilante that mediates the systemic immune response, and, in turn, the immune system regulates the hepatic functions. Such feedback is performed by cytokines. Pro-inflammatory and anti-inflammatory cytokines are strongly involved in hepatic homeostasis and in pathological states; indeed, female sex hormones, oral contraceptives, and phytoestrogens have immunomodulatory effects in the liver and the whole organism. To analyze the complex and interesting beneficial or deleterious effects of these drugs by their immunomodulatory actions in the liver can provide the basis for either their pharmacological use in therapeutic treatments or to avoid their intake in some diseases. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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31 pages, 2353 KiB

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European Patent in Immunoncology: From Immunological Principles of Implantation to Cancer Treatment

by Franziska M. Würfel, Christoph Winterhalter, Peter Trenkwalder, Ralph M. Wirtz and Wolfgang Würfel

Int. J. Mol. Sci. 2019, 20(8), 1830; https://doi.org/10.3390/ijms20081830 - 12 Apr 2019

Cited by 12 | Viewed by 5999

Abstract

The granted European patent EP 2 561 890 describes a procedure for an immunological treatment of cancer. It is based on the principles of the HLA-supported communication of implantation and pregnancy. These principles ensure that the embryo is not rejected by the mother. [...] Read more.

The granted European patent EP 2 561 890 describes a procedure for an immunological treatment of cancer. It is based on the principles of the HLA-supported communication of implantation and pregnancy. These principles ensure that the embryo is not rejected by the mother. In pregnancy, the placenta, more specifically the trophoblast, creates an “interface” between the embryo/fetus and the maternal immune system. Trophoblasts do not express the “original” HLA identification of the embryo/fetus (HLA-A to -DQ), but instead show the non-classical HLA groups E, F, and G. During interaction with specific receptors of NK cells (e.g., killer-immunoglobulin-like receptors (KIR)) and lymphocytes (lymphocyte-immunoglobulin-like receptors (LIL-R)), the non-classical HLA groups inhibit these immunocompetent cells outside pregnancy. However, tumors are known to be able to express these non-classical HLA groups and thus make use of an immuno-communication as in pregnancies. If this occurs, the prognosis usually worsens. This patent describes, in a first step, the profiling of the non-classical HLA groups in primary tumor tissue as well as metastases and recurrent tumors. The second step comprises tailored antibody therapies, which is the subject of this patent. In this review, we analyze the underlying mechanisms and describe the currently known differences between HLA-supported communication of implantation and that of tumors. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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24 pages, 1756 KiB

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IL-36 Cytokines: Regulators of Inflammatory Responses and Their Emerging Role in Immunology of Reproduction

by José Martin Murrieta-Coxca, Sandra Rodríguez-Martínez, Mario Eugenio Cancino-Diaz, Udo R. Markert, Rodolfo R. Favaro and Diana M. Morales-Prieto

Int. J. Mol. Sci. 2019, 20(7), 1649; https://doi.org/10.3390/ijms20071649 - 3 Apr 2019

Cited by 54 | Viewed by 7101

Abstract

The IL-36 subfamily of cytokines has been recently described as part of the IL-1 superfamily. It comprises three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ), their receptor (IL-36R), and one antagonist (IL-36Ra). Although expressed in a variety of cells, the biological relevance of IL-36 [...] Read more.

The IL-36 subfamily of cytokines has been recently described as part of the IL-1 superfamily. It comprises three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ), their receptor (IL-36R), and one antagonist (IL-36Ra). Although expressed in a variety of cells, the biological relevance of IL-36 cytokines is most evident in the communication between epithelial cells, dendritic cells, and neutrophils, which constitute the common triad responsible for the initiation, maintenance, and expansion of inflammation. The immunological role of IL-36 cytokines was initially described in studies of psoriasis, but novel evidence demonstrates their involvement in further immune and inflammatory processes in physiological and pathological situations. Preliminary studies have reported a dynamic expression of IL-36 cytokines in the female reproductive tract throughout the menstrual cycle, as well as their association with the production of immune mediators and cellular recruitment in the vaginal microenvironment contributing to host defense. In pregnancy, alteration of the placental IL-36 axis has been reported upon infection and pre-eclampsia suggesting its pivotal role in the regulation of maternal immune responses. In this review, we summarize current knowledge regarding the regulatory mechanisms and biological actions of IL-36 cytokines, their participation in different inflammatory conditions, and the emerging data on their potential role in normal and complicated pregnancies. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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12 pages, 890 KiB

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Effects of Chemotherapy and Radiotherapy on Spermatogenesis: The Role of Testicular Immunology

by Ning Qu, Masahiro Itoh and Kou Sakabe

Int. J. Mol. Sci. 2019, 20(4), 957; https://doi.org/10.3390/ijms20040957 - 22 Feb 2019

Cited by 56 | Viewed by 6609

Abstract

Substantial improvements in cancer treatment have resulted in longer survival and increased quality of life in cancer survivors with minimized long-term toxicity. However, infertility and gonadal dysfunction continue to be recognized as adverse effects of anticancer therapy. In particular, alkylating agents and irradiation [...] Read more.

Substantial improvements in cancer treatment have resulted in longer survival and increased quality of life in cancer survivors with minimized long-term toxicity. However, infertility and gonadal dysfunction continue to be recognized as adverse effects of anticancer therapy. In particular, alkylating agents and irradiation induce testicular damage that results in prolonged azoospermia. Although damage to and recovery of spermatogenesis after cancer treatment have been extensively studied, there is little information regarding the role of differences in testicular immunology in cancer treatment-induced male infertility. In this review, we briefly summarize available rodent and human data on immunological differences in chemotherapy or radiotherapy. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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23 pages, 1074 KiB

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The Impact of Autoantibodies on IVF Treatment and Outcome: A Systematic Review

by Mara Simopoulou, Konstantinos Sfakianoudis, Evangelos Maziotis, Sokratis Grigoriadis, Polina Giannelou, Anna Rapani, Petroula Tsioulou, Agni Pantou, Theodoros Kalampokas, Nikolaos Vlahos, Konstantinos Pantos and Michael Koutsilieris

Int. J. Mol. Sci. 2019, 20(4), 892; https://doi.org/10.3390/ijms20040892 - 19 Feb 2019

Cited by 44 | Viewed by 9045

Abstract

The role of autoantibodies in in vitro fertilization (IVF) has been discussed for almost three decades. Nonetheless, studies are still scarce and widely controversial. The aim of this study is to provide a comprehensive systematic review on the possible complications associated to autoantibodies [...] Read more.

The role of autoantibodies in in vitro fertilization (IVF) has been discussed for almost three decades. Nonetheless, studies are still scarce and widely controversial. The aim of this study is to provide a comprehensive systematic review on the possible complications associated to autoantibodies (AA) impeding the chances of a successful IVF cycle. An Embase, PubMed/Medline and Cochrane Central Database search was performed on 1 December 2018, from 2006 until that date. From the 598 articles yielded in the search only 44 relevant articles ultimately fulfilled the inclusion criteria and were qualitatively analyzed. Five subsets of results were identified, namely, thyroid related AA, anti-phospholipid antibodies, anti-nuclear antibodies, AA affecting the reproductive system and AA related to celiac disease. It may be implied that the majority of auto-antibodies exert a statistically significant effect on miscarriage rates, whereas the effects on clinical pregnancy and live birth rates differ according to the type of auto-antibodies. While significant research is performed in the field, the quality of evidence provided is still low. The conduction of well-designed prospective cohort studies is an absolute necessity in order to define the impact of the different types of autoantibodies on IVF outcome. Full article

(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)

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