Journal articles on the topic 'Cytokines; pre-implantation embryo; inflammation'
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1
Chin, P. Y., J. G. Thompson, and S. A. Robertson. "172. A MODEST INFLAMMATORY INSULT IN THE PRE-IMPLANTATION PERIOD ALTERS OVIDUCT CYTOKINE EXPRESSION AND PROGRAMS FETAL DEVELOPMENT." Reproduction, Fertility and Development 22, no. 9 (2010): 90. http://dx.doi.org/10.1071/srb10abs172.
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The cytokine milieu surrounding the pre-implantation embryo contributes to programming optimal embryo development. Perturbations to the maternal environment such as infection and inflammation during the pre-implantation period can influence cytokine synthesis and may cause changes in embryo development that compromise pregnancy outcome. We aimed to investigate the effect of an inflammatory insult with LPS during the pre-implantation period on later fetal development and the role of oviduct cytokine expression in mediating this response. LPS (at various doses of 0.5–62.5 μg) was administered i.p. to C57Bl/6 mice on both day 3 and day 4 post coitum (pc). The effects of treatment on day 4 blastocysts and day 18 fetal development were analysed. Blastocysts from LPS-treated mothers showed reduced viability and smaller total cell number, but were only significant when doses of >12.5 μg LPS were administered. This was not a direct effect of LPS, as no effect of LPS on embryo development in vitro was seen, even at very high LPS concentrations (25 μg/mL). At day 18 pc, pregnancy rates and the number of viable fetuses, as well as fetal and placenta weights were all reduced after low dose LPS treatment (0.5 μg) compared to control PBS-treated females. qPCR analysis of day 4 oviduct tissue revealed that administration of 12.5ug of LPS resulted in increased mRNA expression of cytokines including IL6, TNFA, IL1B, IFNG, IL10 and LIF. Our findings show that a modest pro-inflammatory insult with LPS in the pre-implantation period programs the embryo for later adverse effects on fetal and placental development. The effects of LPS appear to be mediated indirectly via the maternal tract, and altered oviduct cytokine expression which impairs pre-implantation embryo development is implicated as the underlying mechanism. This model will now be utilised to investigate the potential role of specific inflammatory cytokines TNFA and IFNG in mediating this response.
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Granot, I., Y. Gnainsky, and N. Dekel. "Endometrial inflammation and effect on implantation improvement and pregnancy outcome." REPRODUCTION 144, no. 6 (December 2012): 661–68. http://dx.doi.org/10.1530/rep-12-0217.
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Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal–fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome.
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Snider, Alexandria P., and Jennifer R. Wood. "Obesity induces ovarian inflammation and reduces oocyte quality." Reproduction 158, no. 3 (September 2019): R79—R90. http://dx.doi.org/10.1530/rep-18-0583.
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In the United States, 36.5% of women between the ages of 20 and 39 years are obese. This obesity results in not only metabolic disorders including type II diabetes and cardiovascular disease, but also impaired female fertility. Systemic and tissue-specific chronic inflammation and oxidative stress are common characteristics of obesity. This is also true in the ovary. Several studies have demonstrated that pro-inflammatory cytokines and reactive oxygen species alter estrous cyclicity, steroidogenesis and ovulation. Inflammation and oxidative stress also impair meiotic and cytoplasmic maturation of the oocyte which reduces its developmental competence for fertilization and pre-implantation embryo development. Interestingly, there is recent evidence that obesity- and/or polycystic ovary syndrome (PCOS)-dependent changes to the gut microbiome contributes to ovarian inflammation, steroidogenesis and the expression of mRNAs in the oocyte. However, several gaps remain necessitating future studies to identify inflammation, oxidative stress and gut microbiome mechanisms that reduce ovarian function and oocyte quality.
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Albonici, Loredana, Monica Benvenuto, Chiara Focaccetti, Loredana Cifaldi, Martino Tony Miele, Federica Limana, Vittorio Manzari, and Roberto Bei. "PlGF Immunological Impact during Pregnancy." International Journal of Molecular Sciences 21, no. 22 (November 18, 2020): 8714. http://dx.doi.org/10.3390/ijms21228714.
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During pregnancy, the mother’s immune system has to tolerate the persistence of paternal alloantigens without affecting the anti-infectious immune response. Consequently, several mechanisms aimed at preventing allograft rejection, occur during a pregnancy. In fact, the early stages of pregnancy are characterized by the correct balance between inflammation and immune tolerance, in which proinflammatory cytokines contribute to both the remodeling of tissues and to neo-angiogenesis, thus, favoring the correct embryo implantation. In addition to the creation of a microenvironment able to support both immunological privilege and angiogenesis, the trophoblast invades normal tissues by sharing the same behavior of invasive tumors. Next, the activation of an immunosuppressive phase, characterized by an increase in the number of regulatory T (Treg) cells prevents excessive inflammation and avoids fetal immuno-mediated rejection. When these changes do not occur or occur incompletely, early pregnancy failure follows. All these events are characterized by an increase in different growth factors and cytokines, among which one of the most important is the angiogenic growth factor, namely placental growth factor (PlGF). PlGF is initially isolated from the human placenta. It is upregulated during both pregnancy and inflammation. In this review, we summarize current knowledge on the immunomodulatory effects of PlGF during pregnancy, warranting that both innate and adaptive immune cells properly support the early events of implantation and placental development. Furthermore, we highlight how an alteration of the immune response, associated with PlGF imbalance, can induce a hypertensive state and lead to the pre-eclampsia (PE).
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Fülöp, Vilmos, Gábor Vermes, and János Demeter. "A gyulladásos és immunológiai folyamatok kapcsolata a várandósság alatt. Gyakorlati vonatkozások." Orvosi Hetilap 160, no. 32 (August 2019): 1247–59. http://dx.doi.org/10.1556/650.2019.31448.
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Abstract: The aim of this review is to explore, in addition to revealing the biological background, new conceptual and therapeutic approaches for reproductive clinicians to provide better and more effective care for sterile and infertile couples. In humans, 75% of unsuccessful pregnancies are the result of failures of implantation, and implantation failure is the limiting factor for in vitro fertilization treatment. A modified “good” inflammation is necessary for implantation and parturition, but for most of pregnancy, inflammation threatens the continuation of pregnancy. During this period, maintaining the non-inflammatory condition is extremely important, enabling the maternal epigenetic effects to occur in the fetus, making it possible for the offspring to adapt as much as possible to the extrauterine life. In the maintenance of the non-inflammatory condition of pregnancy, a large amount of progesterone hormone produced by the placenta (after the luteo-placental shift) plays a crucial role. It has been reported that the role of inflammation during implantation is an ancestral response to the embryo as a foreign body. During normal pregnancy, this inflammation is initiated by the trophoblast and involves the suppression of neutrophil infiltration, the recruitment of natural killer cells to the site of implantation as well as the production of a range of proinflammatory cytokines. During the “implantation window”, the uterus is primed to produce several inflammatory signals such as prostaglandin E2 and a range of proinflammatory cytokines, including TNF, IL6 and IFNγ. The feto-placental unit is a semi-foreign graft called a “semi allograft”, and the recognition of pregnancy by the mother (host) and the resulting maternal immune tolerance is an essential part of successful pregnancy and the birth of a healthy fetus. Because of the functional or absolute reduction of circulating progesterone (due to the decreasing hormone production of the physiologically “aging” placenta after around the 36th week of pregnancy) progesterone effects become insufficient. Therefore it is unable to suppress the production of IL8 and other inflammatory cytokines and the term inflammation, leading to cervical ripening, uterus contractions and parturition (“good” inflammation). Orv Hetil. 2019; 160(32): 1247–1259.
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Silva, Jamile R., Lício F. A. A. Ferreira, Percíllia V. S. Oliveira, Ivanéia V. Nunes, Ítalo S. Pereira, Jorge Timenetsky, Lucas M. Marques, Tiana B. Figueiredo, and Robson A. A. Silva. "Intra-uterine experimental infection by Ureaplasma diversum induces TNF-α mediated womb inflammation in mice." Anais da Academia Brasileira de Ciências 88, suppl 1 (February 5, 2016): 643–52. http://dx.doi.org/10.1590/0001-3765201620150244.
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Ureaplasma diversum is an opportunistic pathogen associated with uterine inflammation, impaired embryo implantation, infertility, abortions, premature birth of calves and neonatal pneumonia in cattle. It has been suggested that the intra-uterine infection by Ureaplasma diversum can cause vascular changes that hinder the success of pregnancy. Thus, the aim of this study was to evaluate the changes of intrauterine site of A/J mice in estrus or proestrus phase inoculated with Ureaplasma diversum. The infection was monitored at 24, 48 and 72 hours by the PCR methodology to detect the Ureaplasma in the inoculation site and the profile of circulating blood cells. Morphological changes, intensity of inflammation and the production of cytokines were compared. The infected mice showed local inflammation through the production of IFN-γ and TNF-α. Ureaplasma diversum infections in the reproductive tract of studied mice seemed to be associated with the production of pro-inflammatory cytokines in uterine parenchyma. The levels of TNF-α of infected mice were dependent on the bacterial load of inoculated Ureaplasma. Uterine experimental infections by Ureaplasma diversum have not been mentioned yet and herein we presented the first report of an intrauterine infection model in mice.
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Li, Xilong, Michael J. Large, Chad J. Creighton, Rainer B. Lanz, Jae-Wook Jeong, Steven L. Young, Bruce A. Lessey, Wilder A. Palomino, Sophia Y. Tsai, and Francesco J. DeMayo. "COUP-TFII Regulates Human Endometrial Stromal Genes Involved in Inflammation." Molecular Endocrinology 27, no. 12 (December 1, 2013): 2041–54. http://dx.doi.org/10.1210/me.2013-1191.
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Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2) is an orphan nuclear receptor involved in cell-fate specification, organogenesis, angiogenesis, and metabolism. Ablation of COUP-TFII in the mouse uterus causes infertility due to defects in embryo attachment and impaired uterine stromal cell decidualization. Although the function of COUP-TFII in uterine decidualization has been described in mice, its role in the human uterus remains unknown. We observed that, as in mice, COUP-TFII is robustly expressed in the endometrial stroma of healthy women, and its expression is reduced in the ectopic lesions of women with endometriosis. To interrogate the role of COUP-TFII in human endometrial function, we used a small interfering RNA-mediated loss of function approach in primary human endometrial stromal cells. Attenuation of COUP-TFII expression did not completely block decidualization; rather it had a selective effect on gene expression. To better elucidate the role of COUP-TFII in endometrial stroma cell biology, the COUP-TFII transcriptome was defined by pairing microarray comparison with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrates that COUP-TFII regulates a subset of genes in endometrial stroma cell decidualization such as those involved in cell adhesion, angiogenesis, and inflammation. Importantly this analysis shows that COUP-TFII plays a role in controlling the expression of inflammatory cytokines. The determination that COUP-TFII plays a role in inflammation may add insight into the role of COUP-TFII in embryo implantation and in endometrial diseases such as endometriosis.
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Dimitriadis, E. "004. A NEW ERA IN CONTRACEPTIVE DEVELOPMENT: NON-HORMONAL OPTIONS THAT ALSO TARGET SEXUALLY TRANSMITTED INFECTIONS." Reproduction, Fertility and Development 22, no. 9 (2010): 4. http://dx.doi.org/10.1071/srb10abs004.
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Despite huge increases in access to contraceptives globally more than 700 000 maternal deaths related to unintended pregnancies occurred between 1995 and 2000 mostly in developing countries. Over 80 million women have unintended or unwanted pregnancies annually. Remarkably, there have been no new methods of contraceptives developed in the last 50 years. The extremely high incidence of sexually transmitted infections (STIs) indicates that it is desirable to develop contraceptives that also target STIs. Two interleukin (IL) 6-type cytokines, leukemia inhibitory factor (LIF) and IL11, are obligatory for implantation in mice and are dysregulated in endometrium of some women with infertility. Both LIF and IL11 are also thought to have roles in Chlamydia-induced inflammation which can lead to a multitude of pathologies. LIF and IL11 antagonists were produced and their contraceptive efficacy tested in mice. Polyethylene glycol (PEG) was conjugated to LIF antagonist (LA) or IL11 antagonist (IL11A) to increase their serum half-life. PEGLA injected during the peri-implantation period blocked LIF action in the endometrium and totally prevented embryo implantation while having no embryo toxic effects.1 Similarly, injection of PEGIL11A blocked decidua formation resulting in pregnancy failure.2 In women, vaginally administered drugs preferentially localise to the uterus suggesting that vaginal administration of PEGLA is an appropriate delivery method for contraceptive purposes. Further, vaginally administered PEGLA may be useful as a ‘dual-role’ contraceptive to also block STIs. PEGLA administered via vaginal gel was shown to prevent implantation having minimal effects on non-uterine LIF targets. This is the first study to show the contraceptive efficacy of a PEGylated compound delivered vaginally. It further indicates that PEGLA may be useful as a dual-role contraceptive. Contraceptive trials in non-human primates are currently underway to determine the effect of PEGLA on implantation. If effective, this will offer new opportunities as pharmacological, non-hormonal dual-role contraceptives for women. (1) White CA, Zhang JG, Salamonsen LA, Baca M, Fairlie WD, Metcalf D, Nicola NA, Robb L, Dimitriadis E (2007) Proc Natl Acad Sci USA 104: 19 357–62.(2) Menkhorst E, Salamonsen LA, Robb L, Dimitriadis E (2009) Biol of Reprod 80: 920–927.
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Gopchuk, О. М., and Р. V. Samaniv. "Problems of the thin endometrium. New possibilities of FDE-5 inhibitors." Reproductive health of woman, no. 2 (April 29, 2022): 47–52. http://dx.doi.org/10.30841/2708-8731.2.2022.261807.
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The article is devoted to a review of the literature about the thin endometrium and its correction today. The problem of thin endometrium is very significant in cases of unsuccessful embryo implantation. There is no generally accepted approach to the definition of “thin endometrium” and ways of its correction in the literature. Phosphodiesterase type 5 (PDE5) inhibitors are considered to play a role in increasing endometrial thickness and improving pregnancy outcomes. Their action consists of various mechanisms, in particular, such as the induction of vasodilating effect through the effect on signaling to vascular smooth muscle, through the regulation of cell proliferation and induction of angiogenesis by increasing the expression of tumor suppressor factor (p53) and vascular endothelial growth factor A, the inhibition of inflammation by reducing the regulation of proinflammatory cytokines. Although PDE5 inhibitors increase the endometrial thickness through the various mechanisms, especially in women with thin endometrium, it does not necessarily mean that they have a positive effect in all clinical situations. Meanwhile, the successful outcome may be affected by the time of use of the drug, the type of infertility treatment, the main diseases such as pelvic disorders and inflammation. Therefore, there are ambiguous issues that need further research in this problem. Oral PDE5 inhibitors are also used as first-line therapy for the treatment of erectile dysfunction (ED), they have proven effectiveness, tolerability, action and couple satisfaction. Avanafil is the only selective inhibitor of the PDE5 isoenzyme with a low frequency of side effects compared to other drugs in this group. The high tolerability of these drugs has made them an attractive tool for the study of further physiological functions outside the ED with benefits for many non-sexual consequences.
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Bardi, Massimo, G. Pezzetti, A. Chiesa, G. Gangarossa, A. Iliakis, C. Di Cesare Cristina, and P. Rosaschino. "Which is the best fertility-sparing treatment for uterine fibroids? Review of literature." MOJ Women's Health 9, no. 3 (2020): 84–90. http://dx.doi.org/10.15406/mojwh.2020.09.00276.
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Uterine fibroids are benign tumors of the smooth muscle cells of the uterus that are the most common benign tumors in women during their reproductive years. The etiopathogenesis is multifactorial but we know that mainly estrogen and progesterone induce UF formation and growth. UF vary greatly in size, location, and symptoms: most tumors are largely asymptomatic, but they may also cause a wide range of severe and chronic symptoms that impact negatively with familiar and social relationships. UF might cause infertility. Their adverse effects on pregnancy because distort the endometrial cavity and thin the endometrium. In fact the negative action of fibroids on fertility is mainly due to produce numerous cytokines and growth factors that produce an endometrial inflammation that, with an altered local hormonal environment, may impede embryo-implantation. The type of treatment may depend on the location, size and number of UF and it should be related to understanding if the therapy improves the reproductive capacity of the woman. In this review of the literature we evaluate the various therapeutic possibilities that we have available if we decide to treat UF to improve the fertile capacity of the woman who wishes to have children. We will exclude medical therapy, which is predominantly birth control, although in recent years new substances are being studied, such as vitamin D and epigallocatechin gallate, which promise interesting therapeutic developments. A proper mention will be made of laparotomy, laparoscopic and hysteroscopic myomectomy, but particular importance will be given to the evaluation of new therapeutic trends such as high-intensity focused ultrasound, also guided by nuclear magnetic resonance, and thermal ablation with radio frequency and microwaves. The embolization of UF will also be addressed, but we know it is contraindicated for women who wish to become pregnant.
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Hashimoto, Yoshiko, Tomoko Tsuzuki-Nakao, Naoko Kida, Yoshiyuki Matsuo, Tetsuo Maruyama, Hidetaka Okada, and Kiichi Hirota. "Inflammatory Cytokine-Induced HIF-1 Activation Promotes Epithelial–Mesenchymal Transition in Endometrial Epithelial Cells." Biomedicines 11, no. 1 (January 14, 2023): 210. http://dx.doi.org/10.3390/biomedicines11010210.
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The endometrium undergoes repeated proliferation and shedding during the menstrual cycle. Significant changes to this environment include fluctuations in the partial pressure of oxygen, exposure to a high-cytokine environment associated with intrauterine infection, and inflammation. Chronic endometritis is a condition wherein mild inflammation persists in the endometrium and is one of the causes of implantation failure and miscarriage in early pregnancy. It is thought that the invasion of embryos into the endometrium requires epithelial–mesenchymal transition (EMT)-associated changes in the endometrial epithelium. However, the effects of inflammation on the endometrium remain poorly understood. In this study, we investigated the effects of the intrauterine oxygen environment, hypoxia-inducible factor (HIF), and inflammation on the differentiation and function of endometrial epithelial cells. We elucidated the ways in which inflammatory cytokines affect HIF activity and EMT in an immortalized cell line (EM-E6/E7/TERT) derived from endometrial epithelium. Pro-inflammatory cytokines caused significant accumulation of HIF-1α protein, increased HIF-1α mRNA levels, and enhanced hypoxia-induced accumulation of HIF-1α protein. The combined effect of inflammatory cytokines and hypoxia increased the expression of EMT-inducing factors and upregulated cell migration. Our findings indicate that pro-inflammatory factors, including cytokines and LPS, work synergistically with hypoxia to activate HIF-1 and promote EMT in endometrial epithelial cells.
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Fujiwara, Hiroshi, Masanori Ono, Yukiyasu Sato, Kazuhiko Imakawa, Takashi Iizuka, Kyosuke Kagami, Tomoko Fujiwara, et al. "Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems." International Journal of Molecular Sciences 21, no. 5 (March 10, 2020): 1885. http://dx.doi.org/10.3390/ijms21051885.
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Embryo implantation in the uterus is an essential process for successful pregnancy in mammals. In general, the endocrine system induces sufficient embryo receptivity in the endometrium, where adhesion-promoting molecules increase and adhesion-inhibitory molecules decrease. Although the precise mechanisms remain unknown, it is widely accepted that maternal–embryo communications, including embryonic signals, improve the receptive ability of the sex steroid hormone-primed endometrium. The embryo may utilize repulsive forces produced by an Eph–ephrin system for its timely attachment to and subsequent invasion through the endometrial epithelial layer. Importantly, the embryonic signals are considered to act on maternal immune cells to induce immune tolerance. They also elicit local inflammation that promotes endometrial differentiation and maternal tissue remodeling during embryo implantation and placentation. Additional clarification of the immune control mechanisms by embryonic signals, such as human chorionic gonadotropin, pre-implantation factor, zona pellucida degradation products, and laeverin, will aid in the further development of immunotherapy to minimize implantation failure in the future.
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Zhang, Xuzhe, Mihaela Pavlicev, Helen N. Jones, and Louis J. Muglia. "Eutherian-Specific Gene TRIML2 Attenuates Inflammation in the Evolution of Placentation." Molecular Biology and Evolution 37, no. 2 (October 9, 2019): 507–23. http://dx.doi.org/10.1093/molbev/msz238.
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Abstract Evolution of highly invasive placentation in the stem lineage of eutherians and subsequent extension of pregnancy set eutherians apart from other mammals, that is, marsupials with short-lived placentas, and oviparous monotremes. Recent studies suggest that eutherian implantation evolved from marsupial attachment reaction, an inflammatory process induced by the direct contact of fetal placenta with maternal endometrium after the breakdown of the shell coat, and shortly before the onset of parturition. Unique to eutherians, a dramatic downregulation of inflammation after implantation prevents the onset of premature parturition, and is critical for the maintenance of gestation. This downregulation likely involved evolutionary changes on maternal as well as fetal/placental side. Tripartite-motif family-like2 (TRIML2) only exists in eutherian genomes and shows preferential expression in preimplantation embryos, and trophoblast-derived structures, such as chorion and placental disc. Comparative genomic evidence supports that TRIML2 originated from a gene duplication event in the stem lineage of Eutheria that also gave rise to eutherian TRIML1. Compared with TRIML1, TRIML2 lost the catalytic RING domain of E3 ligase. However, only TRIML2 is induced in human choriocarcinoma cell line JEG3 with poly(I:C) treatment to simulate inflammation during viral infection. Its knockdown increases the production of proinflammatory cytokines and reduces trophoblast survival during poly(I:C) stimulation, while its overexpression reduces proinflammatory cytokine production, supporting TRIML2’s role as a regulatory inhibitor of the inflammatory pathways in trophoblasts. TRIML2’s potential virus-interacting PRY/SPRY domain shows significant signature of selection, suggesting its contribution to the evolution of eutherian-specific inflammation regulation during placentation.
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Fontana, Vanina, Virginia Choren, Liliana Vauthay, Juan Carlos Calvo, Lucrecia Calvo, and Monica Cameo. "Exogenous interferon-γ alters murine inner cell mass and trophoblast development. Effect on the expression of ErbB1, ErbB4 and heparan sulfate proteoglycan (perlecan)." Reproduction 128, no. 6 (December 2004): 717–25. http://dx.doi.org/10.1530/rep.1.00335.
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Implantation is a crucial event in human pregnancy. The participation of cytokines in the implantation process has been widely documented, although the role of many of these molecules is still a matter of controversy. In a previous report from our laboratory, we demonstrated that addition of interferon-γ to the culture medium produces deleterious effects on mouse embryo development. In this study we investigated the effect of this cytokine on outgrowing embryo morphology and on the expression of epidermal growth factor receptors (ErbBs) and heparan sulfate proteoglycan (perlecan) in mouse embryos culturedin vitro. Morphological assessment of inner cell mass and trophoblast development was carried onin-situfixed and stained outgrowths. Localization of ErbB1, ErbB4 and perlecan on pre- and peri-implantation embryos was investigated by immunocytochemistry. Addition of interferon-γ produced a deleterious effect on both inner cell mass and trophoblast morphology. Immunostaining demonstrated that ErbB1, ErbB4 and perlecan are present on pre-implantation embryos and blasto-cysts; interferon-γ altered the expression of ErbB4 and Perlecan at the blastocyst stage. We propose that the effects produced by this cytokine could be related to the altered acquisition of adhesion competence and low implantation rates observed in certain reproductive immunological disorders.
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Cela, Vito, Simona Daniele, Maria Elena Rosa Obino, Maria Ruggiero, Elisa Zappelli, Lorenzo Ceccarelli, Francesca Papini, et al. "Endometrial Dysbiosis Is Related to Inflammatory Factors in Women with Repeated Implantation Failure: A Pilot Study." Journal of Clinical Medicine 11, no. 9 (April 28, 2022): 2481. http://dx.doi.org/10.3390/jcm11092481.
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An abnormal endometrial microbiota has been suggested to impair the process of embryo implantation, thus leading to repeated implantation failure (RIF) in women undergoing in vitro fertilization (IVF). However, the molecular mechanisms linking uterine microbiota and IVF out-comes are still an open question. The aim of this cohort study was to outline the relationship between endometrial microbiota, inflammation and IVF outcomes. To this purpose, endometrial microbiota and selected components of the “cytokine network” were analyzed in women presenting RIF and divided between eubiosis and dysbiosis groups, according to the percentage of endometrial lactobacilli (≥90% or <90%, respectively). The Dysbiosis group presented significantly higher tissue concentrations of the inflammatory markers (IL-6, IL-1β, HIF-1α and COX-2) and significantly lower levels of the anti-inflammatory/well-being factors, IL-10 and IGF-1, with respect to women with eubiosis. Moreover, the Lactobacillus percentage was negatively related to the concentrations of the inflammatory molecules and positively related to IL-10/IGF-1. Interestingly, the number of IVF attempts was directly related to the levels of the inflammatory factors COX-2, IL-1β and HIF-1α in the eubiosis group. Overall, endometrial dysbiosis was demonstrated to be associated with inflammation-related endometrial changes affecting the process of embryo implantation, underlining the importance of assessing uterine microbiota in patients undergoing IVF.
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Caselli, C., A. D'Amico, R. Ragusa, R. Caruso, T. Prescimone, M. Cabiati, S. Nonini, et al. "IL-33/ST2 Pathway and Classical Cytokines in End-Stage Heart Failure Patients Submitted to Left Ventricular Assist Device Support: A Paradoxic Role for Inflammatory Mediators?" Mediators of Inflammation 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/498703.
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Background. Inflammation is a critical process contributing to heart failure (HF). We hypothesized that IL-33/ST2 pathway, a new mechanism regulated during cardiac stress, may be involved in the functional worsening of end-stage HF patients, candidates for left ventricular assist device (LVAD) implantation, and potentially responsible for their outcome.Methods. IL-33, ST2, and conventional cytokines (IL-6, IL-8, and TNF-α) were determined in cardiac biopsies and plasma of 22 patients submitted to LVAD implantation (pre-LVAD) and compared with (1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior circulatory support (HT); (2) patients supported by LVAD at the moment of LVAD weaning (post-LVAD).Results. Cardiac expression of ST2/IL-33 and cytokines was lower in the pre-LVAD than in the HT group. LVAD determined an increase of inflammatory mediators comparable to levels of the HT group. Only ST2 correlated with outcome indices after LVAD implantation.Conclusions. IL-33/ST2 and traditional cytokines were involved in decline of cardiac function of ESHF patients as well as in hemodynamic recovery induced by LVAD. IL-33/ST2 pathway was also associated to severity of clinical course. Thus, a better understanding of inflammation is the key to achieving more favorable outcome by new specific therapies.
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Chin, P. Y., A. M. Macpherson, J. G. Thompson, M. Lane, and S. A. Robertson. "125. REGULATION OF STRESS PROTEIN GENES DURING PRE-IMPLANTATION EMBRYO DEVELOPMENT IN MICE BY GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF)." Reproduction, Fertility and Development 21, no. 9 (2009): 44. http://dx.doi.org/10.1071/srb09abs125.
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In vitro culture has been shown to be detrimental for pre-implantation embryo development and this has been associated with culture stress and elevated expression of apoptotic genes. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to promote development and survival of both human and mouse pre-implantation embryos. To investigate the mechanism of action of GM-CSF in mouse embryos, gene expression was examined in in vitro cultured blastocysts with and without recombinant mouse GM-CSF (rmGM-CSF) and in vivo blastocysts flushed from Csf2 null mutant and wild-type mice. Microarray analysis of the effect of GM-CSF on transcription profile implicated apoptosis and stress response gene pathways in blastocyst responses to rmGM-CSF in vitro. Groups of 30 blastocysts were collected from in vitro cultured and in vivo developed blastocyst were analysed using quantitative real-time polymerase chain reaction (qRT-PCR). qRT-PCR analysis of in vitro blastocysts revealed that addition of rmGM-CSF causes differential expression of several genes associated with apoptosis and cellular stress pathway, including Cbl, Hspa5, Hsp90aa1, Hsp90ab1 and Gas5. Immunocytochemical analysis of common proteins of the apoptosis and cellular stress response pathways BAX, BCL2, TRP53 (p53) and HSPA1A/1B (Hsp70) in in vitro blastocysts revealed that HSPA1A/1B and BCL2 proteins were less abundant in embryos cultured in rmGM-CSF, but BAX and TRP53 were unchanged. In in vivo developed blastocysts, Csf2 null mutation resulted in elevated levels of only the heat shock protein Hsph1, suggesting that in vivo, other cytokines can compensate for GM-CSF deficiency as the absence of GM-CSF has a lesser effect on the stress response pathway. We conclude that GM-CSF is a regulator of the apoptosis and cellular stress response pathways influencing mouse pre-implantation embryo development to facilitate embryo growth and survival, and the effects of GM-CSF are particularly evident in in vitro culture media in the absence of other cytokines.
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Shabunin, Sergey, Vitaliy Mikhalev, Anatoly Nezhdanov, Vladimir Safonov, Pavel Parshin, and Polina Anipchenko. "PSVIII-16 Interferon-TAU in the pathogenesis and prevention of intrauterine growth restriction and embryonic death in dairy cows." Journal of Animal Science 98, Supplement_4 (November 3, 2020): 254–55. http://dx.doi.org/10.1093/jas/skaa278.459.
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Abstract The aim of the research was to assess the state of the hormonal and cytokine blood profiles of Holstein dairy cows during the early period of gestation with physiological formation of the embryo, its intrauterine growth restriction and death, clarify the pathogenetic mechanisms of these embryopathologies development and identify the efficacy of their prevention using recombinant bovine INFT. The dynamics of serum concentration of P4, cortisol (F) and cytokines: INFT, interleukin IL-2, tumor necrosis factor (TNFα), interferon-γ (INF-γ) at the physiological formation of the embryo (n = 9), its growth restriction (n = 9) and death (n = 8) were studied. The blood samples were obtained on the day of artificial insemination, during early blastogenesis (days 8–9), implantation of the embryo (days 15–16), the formation of primary genital organs (days 32–33), and at the end of the embryonic period of development (days 60–65). In cows with intrauterine growth restriction and embryonic death, serum concentration of P4, compared with the cows demonstrating their physiological formation, was lower by 14.0–30.1%, F - by 11.2–35.5%, INFT - by 21.0–37.7% when the content of IL-2 was exceeded by 46.5–310.5%, TNFα - by 11.7–36.2%, INF-γ - by 58.0–296.0%. A statistically significant positive correlative relationship between the content of INFT, P4, F and a negative one with the indices of the concentration of proinflammatory cytokines was found. Violation of the hormonal-cytokine balance in the organisms of fertilized animals is a universal pathogenetic mechanism for the development of early embryopathies. Injections of recombinant bovine INFT to inseminated cows during the pre- and implantation periods increased the level of progesterone production and reduced the synthesis of proinflammatory cytokines. The efficacy of insemination of cows increased by 1.96 times, the manifestation of fetal/embryonic intrauterine growth restriction syndrome decreased by 2.35 times in comparison with the control animals.
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Martal, J., Nicole ChÊne, Sylvaine Camous, L. Huynh, F. Lantier, Paloma Hermier, R. L'Haridon, G. Charpigny, Madia Charlier, and G. Chaouat. "Recent developments and potentialities for reducing embryo mortality in ruminants: the role of IFN-t and other cytokines in early pregnancy." Reproduction, Fertility and Development 9, no. 3 (1997): 355. http://dx.doi.org/10.1071/r96083.
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This review considers the potential reduction of embryo mortality in vitro and in vivo in ruminants. Data on cytokines provided by different fields of reproductive immunology and biology were collated. Because of the crucial importance of the local interactions between the embryo and its dam, the expression of growth-factor and cytokine genes was analysed in the embryo proper, trophoblast, oviduct and endometrium by reverse transcriptase polymerase chain reaction in sheep and in cattle during the pre- and periimplantation periods. Many deleterious cytokines, such as tumour necrosis factor-α, intereron-γ (IFN-γ ), interleukin-2 (IL-2), and beneficial cytokines, such as transforming growth factor-β, leukaemia inhibiting factor, colony-stimulating factor-1 (CSF-1), ganulocyte–macrophage CSF, IL-1, IL-3, IL-4, IL-6, IL-10 and IFN-γ appeared to be involved in embryo survival in ruminants and other species. Their administration is efficient in a murine experimental model (CBA/J DBA/2) of embryonic and fetal mortality. For instance, recombinant ovine IFN-τ (roIFN-τ ) injected at the moment of implantation drastically reduces embryonic mortality in this model. In ruminants, roIFN-τ and recombinant bovine IFN-τ are very efficient in maintaining progesterone luteal secretion in cyclic animals. The involvement of IFN-τ in the mechanisms of maternal pregnancy recognition are particularly detailed in relation to inbition of 13,14 dihydro-15-keto-prostaglandin F2α (PGFM) pulses and oxytocin uterine receptivity. A synthetic model of the anti-luteolytic effects of IFN-τ on the endometrial cell is proposed. Finally, the particular potential of serum pregnancy-specific proteins (PSPs: PSPB, PSP60, pregnancy-associated glycoprotein) for monitoring embryo survival, with examples given for cattle and sheep is underlined.
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O'Leary, S., M. J. Jasper, G. M. Warnes, D. T. Armstrong, and S. A. Robertson. "Seminal plasma regulates endometrial cytokine expression, leukocyte recruitment and embryo development in the pig." Reproduction 128, no. 2 (August 2004): 237–47. http://dx.doi.org/10.1530/rep.1.00160.
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In pigs, uterine exposure to the constituents of semen is known to increase litter size but the underlying physiological mechanisms remain undefined. Studies in rodents and humans implicate immune modulating moieties in seminal plasma as likely candidates, acting through enhancing the receptivity of the female tract. In this study, the acute and longer term effects of seminal plasma on cytokine expression and leukocyte abundance in the pig endometrium during early pregnancy have been characterised. The reproductive tracts of gonadotrophin-primed pre-pubertal gilts treated with intrauterine infusions of either pooled seminal plasma or phosphate-buffered saline (PBS) were retrieved at 34 h, or on day 5 and day 9 after treatment. Seminal plasma elicited an endometrial inflammatory infiltrate comprised of predominantly macrophages and major histocompatibility complex class II+-activated macrophages and dendritic cells. The abundance of these cells was greatest at the pre-ovulatory (34 h) time-point and their increase relative to PBS-treated tissues was maintained until day 9 after seminal plasma treatment. Seminal plasma induced the expression of the cytokines, granulocyte macrophage colony-stimulating factor, interleukin-6 and monocyte chemoattractant protein-1, and the eicosanoid-synthesising enzyme cyclo-oxygenase-2. Expression was maximal 34 h after treatment but altered expression patterns as a consequence of seminal plasma induction persisted through early pregnancy. These changes were accompanied by altered dynamics in pre-implantation embryo development with an increase in the number of embryos and in their viability after seminal plasma treatment. Together, these findings implicate factors in seminal plasma in programming the trajectory of uterine cytokine expression and leukocyte trafficking during early pregnancy and in regulating pre-implantation embryo development in the pig.
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Harvey, M. B., K. J. Leco, M. Y. Arcellana-Panlilio, X. Zhang, D. R. Edwards, and G. A. Schultz. "Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor." Development 121, no. 4 (April 1, 1995): 1005–14. http://dx.doi.org/10.1242/dev.121.4.1005.
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Several proteinases from different multigene families have been implicated in the uterine invasion required for establishment of pregnancy in some mammals. In this study, the expression of matrix metalloproteinase gelatinase B (MMP-9), urokinase-type plasminogen activator (uPA) and their inhibitors was investigated during early mouse embryo development. Transcripts for tissue inhibitors of metalloproteinases (TIMP-1,-2,-3) and uPA receptor were detected throughout pre- and peri-implantation development whilst MMP-9 and uPA mRNAs were first detected in peri-implantation blastocysts associated with the invasive phase of implantation. Through use of in situ hybridization, it was shown that MMP-9 transcripts were strongly expressed in the network of trophoblast giant cells at the periphery of implanting 7.5 day embryos and TIMP-3 transcripts were strongly expressed in the decidua immediately adjacent to the implanting embryo. uPA transcripts were preferentially expressed in the ectoplacental cone and its derivatives. Because these proteinases are regulated by growth factors and cytokines in other tissues, the effect of leukaemia inhibitory factor (LIF) and epidermal growth factor (EGF) on their activity was investigated. Both LIF and EGF, like the proteinases, have been implicated in peri-implantation development. Blastocysts collected on day 4 of pregnancy were cultured 2 days in TCM 199 + 10% fetal bovine serum to allow outgrowth followed by 24 hour culture in defined media containing either LIF or EGF. Conditioned media were assayed for uPA activity by a chromogenic assay and MMP activity by gelatin zymography. Both LIF and EGF stimulated uPA and MMP-9 activity in blastocyst outgrowths after 3 days of culture (day 7). Proteinase activity was assayed again at the 5th to 6th day of culture (day 9 to 10). EGF was found to have no effect whereas LIF decreased production of both proteinases. These results demonstrate that proteinase activity in early embryos can be regulated by growth factors and cytokines during the implantation process and, in particular, they demonstrate the possible involvement of LIF in establishment of the correct temporal programme of proteinase expression.
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Jeske, Walter, Daneyal Syed, Vicki Escalante, Erin Coglianese, Jeffrey Schwartz, and Jeanine M. Walenga. "Inflammatory Cytokines Are Upregulated in Patients with Implanted Ventricular Assist Devices." Blood 124, no. 21 (December 6, 2014): 5049. http://dx.doi.org/10.1182/blood.v124.21.5049.5049.
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Abstract Introduction: Since the implantation of left ventricular assist devices (LVAD) has become more frequent in patients with heart failure, the need to prevent, predict, and treat the associated pathologies has become paramount. The most common complications, which include thrombosis, gastrointestinal bleeds, anemia, and hemolysis, are also the adverse events that carry a less than favorable prognosis. The rate of thrombosis has been steadily increasing to as much as 6%. Pump thrombosis is a complex adverse event in terms of pathophysiology, patient presentation and management. Patients with chronic heart failure exhibit signs of systemic inflammation and the use of LVADs may increase levels of inflammatory cytokines as a result of blood contact with foreign surfaces or prolonged exposure to non-pulsatile flow. Inflammation can promote thrombosis by increasing levels of procoagulant factors, inhibiting natural anticoagulant pathways or damaging endothelium. Our study sought to determine whether alterations in levels of markers of inflammation are observed in patients with implanted LVADs to determine their potential clinical usefulness as biomarkers predictive of thrombosis. Methods: Blood samples were collected peri-operatively and long-term post-operatively (until transplant or expiration) during normal clinic visits from 16 consented patients who were implanted with a HeartMate II LVAD (Thoratec Inc, Pleasanton, CA). Fresh whole blood specimens collected in 3.2% sodium citrate were centrifuged for platelet poor plasma and stored frozen until analysis. Using the Evidence Investigator High Sensitivity Biochip Array from Randox (Crumlin, County Antrim, UK) levels of 12 inflammatory cytokines and growth factors (interleukins 1α,1β, 2, 4, 6, 8, 10, VEGF, INFγ, EGF, MCP-1, TNFα) were quantitated. Blood samples collected from 48 healthy individuals were processed and analyzed in the same manner to establish normal levels. A database of clinical events in the consented patients was created from medical chart reviews by the Heart Failure Clinic. Results: In pre-surgical samples, most patients exhibited IL-6 and IL-8 levels that were above the range observed in healthy individuals. Following implantation of the LVAD, the levels of IL-6 and IL-8, as well as additional acute-phase cytokines such as TNFα and IL-1β, further increased. The systemic inflammatory response was present for approximately two months post-surgery. Up to six months following implantation of the LVAD, in some patients levels of inflammatory cytokines (IL-6 and IL-8 in particular) were at times several hundred-fold higher than in healthy normals. The peak expression of the cytokine gradually reduced, sometimes to normal, over a period of weeks. Levels of cytokines whose function is more closely tied to antigen-mediated immunity were not significantly impacted by LVAD implantation. Conclusions: An elevated inflammatory response is not surprising pre-operatively and immediately post-operatively in these heart failure patients implanted with an LVAD. The variability among patients in absolute levels of cytokines and the exceedingly high peak levels of IL-6 and IL-8 that occur at various time points in the months following implant suggest isolated pathologic activation, unique to each patient. These data will be analyzed in conjunction with ROTEM (thromboelastography), platelet activation, and cellular microparticle data already collected on these patients, at the same time points, to identify relationships between parameters that associate with clinical events. These data combined will support evidence for mechanism(s) of thrombosis and identify clinically useful biomarkers. As new patients emerge they will be enrolled in this study, and we continue to follow all patients long-term. Disclosures No relevant conflicts of interest to declare.
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Hansen, Victoria L., Lauren S. Faber, Ali A. Salehpoor, and Robert D. Miller. "A pronounced uterine pro-inflammatory response at parturition is an ancient feature in mammals." Proceedings of the Royal Society B: Biological Sciences 284, no. 1865 (October 25, 2017): 20171694. http://dx.doi.org/10.1098/rspb.2017.1694.
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Regulating maternal immunity is necessary for successful human pregnancy. Whether this is needed in mammals with less invasive placentation is subject to debate. Indeed, the short gestation times in marsupials have been hypothesized to be due to a lack of immune regulation during pregnancy. Alternatively, the maternal marsupial immune system may be unstimulated in the absence of a highly invasive placenta. Transcripts encoding pro-inflammatory cytokines were found to be overrepresented in the whole uterine transcriptome at terminal pregnancy in the opossum, Monodelphis domestica . To investigate this further, immune gene transcripts were quantified throughout opossum gestation. Transcripts encoding pro-inflammatory cytokines remained relatively low during pre- and peri-attachment pregnancy stages. Levels dramatically increased late in gestation, peaking within 12 h prior to parturition. These results mirror the spike of inflammation seen at eutherian parturition but not at attachment or implantation. Our results are consistent with the role of pro-inflammatory cytokines at parturition being an ancient and conserved birth mechanism in therian mammals.
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Gilbert, Robert O. "The effects of endometritis on the establishment of pregnancy in cattle." Reproduction, Fertility and Development 24, no. 1 (2012): 252. http://dx.doi.org/10.1071/rd11915.
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Endometritis is common in post partum dairy cows and is associated with impaired reproductive performance reflected in reduced first service conception, reduced hazard of pregnancy over the breeding period and increased risk of reproductive culling. The observed effects may be mediated directly by bacterial products, such as lipopolysaccharide (LPS, endotoxin), or indirectly by inflammatory mediators, such as cytokines, eicosanoids, nitric oxide and oxidative stress affecting sperm, ovarian, uterine and embryonic function. An inflammatory milieu in the uterus has been associated with changes in sperm motility and function as well as increased sperm phagocytosis. Zygotes resulting from fertilisation of oocytes with sperm subjected to oxidative stress are less likely to develop to the blastocyst stage. In addition, LPS and tumour necrosis factor-α (TNFα) impair follicular steroidogenesis, growth and ovulation. Oocytes exposed to LPS or prostaglandin (PG) F2α during maturation are less likely to develop to blastocyst stage after fertilisation. Embryos exposed to inflammatory mediators during development have fewer trophoectoderm cells. Nitric oxide impairs development of preimplantation embryos and TNFα increases blastomere apoptosis. Endometritis in women has been associated with higher rates of implantation failure. Extragenital inflammation (e.g. mastitis) is also associated with an increased rate of embryonic loss in cattle. These observations make it clear that direct and indirect effects of endometritis, and inflammation in general, can interrupt successful reproduction at several crucial stages.
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Artus, Jérôme, Isabelle Hue, and Hervé Acloque. "Preimplantation development in ungulates: a ‘ménage à quatre’ scenario." Reproduction 159, no. 3 (March 2020): R151—R172. http://dx.doi.org/10.1530/rep-19-0348.
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In ungulates, early embryonic development differs dramatically from that of mice and humans and is characterized by an extended period of pre- and peri-implantation development in utero. After hatching from the zona pellucida, the ungulate blastocyst will stay free in the uterus for many days before implanting within the uterine wall. During this protracted peri-implantation period, an intimate dialog between the embryo and the uterus is established through a complex series of paracrine signals. The blastocyst elongates, leading to extreme growth of extra-embryonic tissues, and at the same time, the inner cell mass moves up into the trophoblast and evolves into the embryonic disc, which is directly exposed to molecules present in the uterine fluids. In the peri-implantation period, uterine glands secrete a wide range of molecules, including enzymes, growth factors, adhesion proteins, cytokines, hormones, and nutrients like amino and fatty acids, which are collectively referred to as histotroph. The identification, role, and effects of these secretions on the biology of the conceptus are still being described; however, the studies that have been conducted to date have demonstrated that histotroph is essential for embryonic development and serves a critical function during the pre- and peri implantation periods. Here, we present an overview of current knowledge on the molecular dialogue among embryonic, extraembryonic, and maternal tissues prior to implantation. Taken together, the body of work described here demonstrates the extent to which this dialog enables the coordination of the development of the conceptus with respect to the establishment of embryonic and extra-embryonic tissues as well as in preparation for implantation.
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Morton, H., AC Cavanagh, S. Athanasas-Platsis, KA Quinn, and BE Rolfe. "Early pregnancy factor has immunosuppressive and growth factor properties." Reproduction, Fertility and Development 4, no. 4 (1992): 411. http://dx.doi.org/10.1071/rd9920411.
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Early pregnancy factor (EPF) was first described as a pregnancy-associated substance, although recent studies suggest a more general link with cell development. It is a product of actively dividing cells and its apparent functional importance to them suggests its potential as a regulator of cell proliferation. The recent discovery of EPF in platelets has provided a comparatively rich and readily available source of EPF. The purification procedures employed to isolate EPF from this source have also been applied to pregnancy serum and urine, medium conditioned by oestrous mouse ovaries (stimulated with prolactin and embryo-conditioned medium), medium conditioned by tumour cells, and serum from rats 24 h after partial hepatectomy (PH). In all instances, biological activity followed the same pattern throughout. Furthermore, the final active reversed-phase high-performance liquid chromatography fraction from all sources was bound specifically by immobilized anti-EPF monoclonal antibodies (MAbs), indicating that the active fractions produced from these diverse sources are very closely related, if not identical. Some differences have been observed in the behaviour of EPF in various conditions. EPF is produced by proliferating tumour cells and by liver cells post-PH, and passive immunization studies with anti-EPF MAbs have shown that these cells need EPF for survival. In contrast, EPF has not been detected as a product of the pre-embryo, and addition of anti-EPF MAbs to embryo cultures does not adversely affect development from the 2-cell to the blastocyst stage. Although the pre-embryo is not dependent on EPF for its development in vitro, neutralization of EPF in vivo by anti-EPF MAbs retards its development. Thus, EPF appears to play an indirect role in maintaining the pre-embryo. By virtue of its ability to suppress the delayed-type hypersensitivity reaction, it has been suggested that EPF might act as an immunological response modifier of the maternal immune system. Alternatively, the effect of EPF on lymphocytes may be to reduce the expression of all or some cytokines and this could inhibit development. Whether or not EPF acts more directly as an autocrine growth factor from around the time of implantation, when the embryo first begins synthesis of EPF, is not known and remains to be investigated.
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Cartwright, Joanna, W. Colin Duncan, Hilary O. D. Critchley, and Andrew W. Horne. "Serum biomarkers of tubal ectopic pregnancy: current candidates and future possibilities." REPRODUCTION 138, no. 1 (July 2009): 9–22. http://dx.doi.org/10.1530/rep-09-0060.
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Ectopic pregnancy remains a considerable cause of maternal morbidity and mortality worldwide. Currently, it is diagnosed using a combination of transvaginal ultrasound and serial serum β-human chorionic gonadotrophin levels. Diagnosis is often delayed and these tests are time-consuming and costly, both psychologically to the patient and financially to health services. The development of a biomarker that can differentiate a tubal ectopic from an intrauterine implantation is therefore important. In the pre-genomic era, a one-by-one scientific approach has revealed over 20 candidate biomarkers that could be used as a test to diagnose ectopic pregnancy although at present their clinical utility is very limited. These biomarkers cluster into themes: markers of abnormal embryo/trophoblast growth, markers of abnormal corpus luteum function, markers of a growing pregnancy in the Fallopian tube, markers of inflammation and peritoneal irritation, and uterine markers of normal implantation. It is likely that this thematic approach will facilitate the identification of newer biomarkers using microarray technology and inform the development of investigative paradigms using multiple markers at the time of presentation.
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Cela, Vito, Elisa Malacarne, Maria Elena Rosa Obino, Ilaria Marzi, Francesca Papini, Francesca Vergine, Elena Pisacreta, et al. "Exploring Epithelial–Mesenchymal Transition Signals in Endometriosis Diagnosis and In Vitro Fertilization Outcomes." Biomedicines 9, no. 11 (November 12, 2021): 1681. http://dx.doi.org/10.3390/biomedicines9111681.
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Endometriosis (EMS) pathogenesis has been related to the release of inflammatory mediators in peritoneal fluid, creating an altered microenvironment that leads to low-grade oocyte/embryos and to the reduction of implantation rates. The Epithelial–Mesenchymal Transition (EMT), an inflammation-related process, can be a further contributing factor to EMS. This study aimed to investigate, among various cytokines and EMT markers (Cadherins, TGF-β, HIF-1α), diagnostic markers of EMS and prognostic factors of in vitro fertilization (IVF) outcomes. Herein, EMS patients manifested higher serum levels of the inflammatory molecules IL-6, IL-8, and IL-12 and a decrease in the concentrations of the anti-inflammatory IL-10. Moreover, biochemical markers associated with the EMT process were more elevated in serum and follicular fluid (FF) of EMS patients than in controls. At the end, the number of good-quality embryos was inversely related to serum IL-6 and EMT markers. Interestingly, serum IL-6 and FF IL-10 concentrations differentiated EMS patients from controls. Finally, serum IL-8 and E-Cadherin levels, as well as FF IL-10, predicted positive IVF outcome with great accuracy. Our data confirm the pivotal role of inflammatory mediators (i.e., IL-6 and IL-10) in EMS pathogenesis and suggest that EMT-related markers are elevated in EMS patients and can be predictive of IVF outcome.
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Brouillet, Sophie, Guilaine Boursier, Margaux Anav, Bertille Du Boulet De La Boissière, Anna Gala, Alice Ferrieres-Hoa, Isabelle Touitou, and Samir Hamamah. "C-reactive protein and ART outcomes: a systematic review." Human Reproduction Update 26, no. 5 (May 29, 2020): 753–73. http://dx.doi.org/10.1093/humupd/dmaa012.
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Abstract BACKGROUND A dynamic balance between pro- and anti-inflammatory factors contributes to regulating human female reproduction. Chronic low-grade inflammation has been detected in several female reproductive conditions, from anovulation to embryo implantation failure. C-reactive protein (CRP) is a reliable marker of inflammation that is extensively used in clinical practice. Recent studies quantified CRP in the serum of infertile women undergoing ART and suggested its potential for the prediction of ART reproductive outcomes. OBJECTIVE AND RATIONALE The first objective of this systematic review of the available literature was to evaluate the association between pre-implantation circulating CRP concentration and pregnancy rates in women undergoing ART. The second objective was to describe serum CRP concentration changes after early embryo implantation. The changes in circulating CRP throughout the ART cycle, clinical implications of CRP quantification for the management of women undergoing ART, and future therapeutic options will also be discussed. SEARCH METHODS The MEDLINE database was systematically searched from inception to March 2019 using the following key words: (C-reactive protein) AND (assisted reproductive techniques OR ovulation induction OR insemination OR in vitro fertilization). Only articles in English were considered. Studies were selected based on title and abstract. The full text of potentially relevant articles was retrieved and assessed for inclusion by two reviewers (S.B. and S.H.). The protocol was registered in the International prospective register of systematic reviews (PROSPERO; registration number: CRD148687). OUTCOMES In total, 10 studies were included in this systematic review. Most of these studies reported lower circulating CRP values before the window of implantation and higher circulating CRP values during the peri-implantation period in women with successful ART outcome (biochemical or clinical pregnancy) compared to women without a successful outcome. Several lifestyle factors and/or drugs that reduce the concentration of circulating CRP significantly improve ART outcomes. Subgroup analyses according to female BMI and baseline circulating CRP concentration are highly recommended in future analyses. WIDER IMPLICATIONS These findings highlight a possible detrimental impact of preconception high circulating CRP concentration on ART outcomes. However, the biochemical or clinical pregnancy rate endpoints used in the studies examined here are insufficient (there were no data on live birth outcome), and the impact of major variables that can influence CRP and/or ART, for example maternal age, BMI, number of transferred embryos, and use of anti-inflammatory drugs, were not considered in the analyses. CRP quantification may be a potential marker of ART outcome, but its predictive value still needs to be investigated in large prospective studies. In future, the quantification of circulating CRP before starting ART could help to identify patients with a poor ART prognosis, leading to ART cycle cancellation or to preconception treatment to minimize the medical risks and costs.
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Sauerschnig, Martin, Markus Berninger, Theresa Kaltenhauser, Michael Plecko, Gabriele Wexel, Martin Schönfelder, Valerie Wienerroither, et al. "Chondrocyte Culture Parameters for Matrix-Assisted Autologous Chondrocyte Implantation Affect Catabolism and Inflammation in a Rabbit Model." International Journal of Molecular Sciences 20, no. 7 (March 27, 2019): 1545. http://dx.doi.org/10.3390/ijms20071545.
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Cartilage defects represent an increasing pathology among active individuals that affects the ability to contribute to sports and daily life. Cell therapy, such as autologous chondrocyte implantation (ACI), is a widespread option to treat larger cartilage defects still lacking standardization of in vitro cell culture parameters. We hypothesize that mRNA expression of cytokines and proteases before and after ACI is influenced by in vitro parameters: cell-passage, cell-density and membrane-holding time. Knee joint articular chondrocytes, harvested from rabbits (n = 60), were cultured/processed under varying conditions: after three different cell-passages (P1, P3, and P5), cells were seeded on 3D collagen matrices (approximately 25 mm3) at three different densities (2 × 105/matrix, 1 × 106/matrix, and 3 × 106/matrix) combined with two different membrane-holding times (5 h and two weeks) prior autologous transplantation. Those combinations resulted in 18 different in vivo experimental groups. Two defects/knee/animal were created in the trochlear groove (defect dimension: ∅ 4 mm × 2 mm). Four identical cell-seeded matrices (CSM) were assembled and grouped in two pairs: One pair giving pre-operative in vitro data (CSM-i), the other pair was implanted in vivo and harvested 12 weeks post-implantation (CSM-e). CSMs were analyzed for TNF-α, IL-1β, MMP-1, and MMP-3 via qPCR. CSM-i showed higher expression of IL-1β, MMP-1, and MMP-3 compared to CSM-e. TNF-α expression was higher in CSM-e. Linearity between CSM-i and CSM-e values was found, except for TNF-α. IL-1β expression was higher in CSM-i at higher passage and longer membrane-holding time. IL-1β expression decreased with prolonged membrane-holding time in CSM-e. For TNF-α, the reverse was true. Lower cell-passages and lower membrane-holding time resulted in stronger TNF-α expression. Prolonged membrane-holding time resulted in increased MMP levels among CSM-i and CSM-e. Cellular density was of no significant effect. We demonstrated cytokine and MMP expression levels to be directly influenced by in vitro culture settings in ACI. Linearity of expression-patterns between CSM-i and CSM-e may predict ACI regeneration outcome in vivo. Cytokine/protease interaction within the regenerate tissue could be guided via adjusting in vitro culture parameters, of which membrane-holding time resulted the most relevant one.
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Tesfaye, D., A. El-Sayed, M. Hoelker, F. Rings, D. Jennen, E. Tholen, M. A. Sirard, and K. Schellander. "283 TRANSCRIPTIONAL ANALYSIS OF BIOPSIES DERIVED FROM IN VITRO-PRODUCED BOVINE BLASTOCYSTS IN RELATION TO PREGNANCY SUCCESS AFTER TRANSFER TO RECIPIENTS." Reproduction, Fertility and Development 19, no. 1 (2007): 257. http://dx.doi.org/10.1071/rdv19n1ab283.
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Early embryonic mortality is a recognized cause of reproductive failure in cattle leading to the loss of a large number of potential calves, retarded genetic progress, and significant loss of money and time in rebreeding cows. The purpose of this work was to address the relationship between the transcriptional profile of embryos, using the microarray technique, and pregnancy success based on blastocyst biopsies taken prior to transfer to recipients. Biopsies (3 to 40% of the intact embryo) were taken from IVP Day 7 blastocysts (n = 98) and 60 to 70% was transferred to recipients (2-year-old Simmental heifers) after re-expansion. Based on the success of pregnancy, biopsies were pooled in 3 groups: those resulting in no pregnancy (G1), resorption (G2), and calf delivery (G3). Gene expression analysis of these groups of biopsies was performed using a home-made bovine pre-implantation-specific array (with 219 clones) and bovine cDNA array (BlueChip) (with 2000 clones) (Sirard et al. 2005 Reprod. Fertil. Dev. 17, 47–57). Approximately 3 �g of amplified RNA from pooled biopsies (10 biopsies each) was used as a template in reverse transcription reactions incorporating amino-modified dUTPs into labeled cDNA using the CyScribeTM post-labelling kit (Amersham Bioscience, Freiburg, Germany). The synthesized cDNAs from all 3 groups were differentially labeled using Cy3 and Cy5 dyes. Slides were scanned using a GenePix 4000B scanner and images were analyzed using GenePix Pro Version 4.0 software (Axon Instruments, Union City, CA, USA). Data were analyzed using Significant Analysis for Microarray (SAM) software (http//www.stst.stanford.edu/tips/SAM). Quantitative real-time PCR was used to confirm the differentially expressed genes revealed by microarray experiments. Results revealed that 52 genes were differentially regulated between G1 and G3, and 58 genes were differentially regulated between G2 and G3. Biopsies resulting in calf delivery were enriched with genes necessary for implantation (COX-2 and CDX2), signal transduction (PLAU), polyamine biosynthesis (ODC1), response to oxidative stress (TXN), growth factor (BMP15), and placenta-specific 8 (PLAC8). Biopsies that ended up with resorption were enriched with transcripts involving protein phosphorylation (KRT8) plasma membrane (OCLN), and glucose metabolism (PGK1, AKR1B1). Biopsies resulting in no pregnancy were enriched with transcripts involving inflammatory cytokines (TNF), protein amino acid binding (EEF1A1), transcription factors (MSX1, PTTG1), glucose metabolism (PGK1, AKR1B1), and CD9, which is an inhibitor of implantation. In conclusion, we generated direct candidates of blastocyst-specific genes that determine the fate of the embryo after transfer.
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Guo, Y., N. Jahmat, T. Van Shaik, M. Chanrot, J. F. Valarcher, G. Charpigny, E. Bongcam-Rudloff, G. Andersson, and P. Humblot. "124 CHANGES IN GENE EXPRESSION FOLLOWING EXPOSURE OF BOVINE ENDOMETRIAL EPITHELIAL CELLS (bEEC) TO ESCHERICHIA COLI LPS; THEIR POSSIBLE EFFECT ON IMPLANTATION." Reproduction, Fertility and Development 29, no. 1 (2017): 170. http://dx.doi.org/10.1071/rdv29n1ab124.
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Lipopolysaccharide (LPS) is a component of the outer membrane of gram-negative bacteria and is involved in postpartum uterine infection in cattle. Lipopolysaccharide causes inflammation of the endometrium and the activation of immune and pro-inflammatory pathways in uterine cells has been well documented. This study was performed to investigate the effects of LPS on epithelial cells from whole-genome information, and this abstract focuses on genes and pathways involved in the regulation of implantation. Following in vitro culture of bovine endometrial epithelial cells (bEEC), passage 4 epithelial cell samples from 3 cows were exposed to 0, 2, and 8 µg mL−1 LPS (Sigma L2630, Escherichia coli O111:B4, Sigma Chemical Co., St. Louis, MO, USA) for 24 h. At time 0 and at 24 h for each LPS dosage, RNA was extracted by using the All prep DNA/RNA Universal kit (Qiagen, Valencia, CA, USA). Samples were analysed by RNA sequencing performed in the SciLife Laboratory in Uppsala. Differentially expressed genes (DEG) were identified by using Ensemble genes as a reference. No DEG were found between 2 and 8 µg mL−1 LPS-treated samples and at 24 h 2035 DEG were identified (Benjamini-Hochberg adjusted P-value < 0.05) between controls and samples treated with 2 µg mL−1 LPS. Gene ontology analysis did show that DEG were associated to immune response (up), response to stress and external stimuli (up), catalytic activity (up), cell cycle, anatomical structures especially cell membrane, and adhesion (down) pathways. In the latest, numerous specific genes in relation with implantation were highly deregulated. This includes down-regulation of 8 members of the cadherin superfamily. On the contrary, 4 members of the mucin family were strongly up-regulated by LPS (MUC1, MUC13, MUC16, F1MUC1). Molecules such as plakophilins and desmogleins involved in desmosomes, in tight junctions, and in the control of cell adhesion were also deregulated. Specific changes occurred in immune response related with implantation [strong up-regulation of the immunoglobulin superfamily members such ICAM1 (or CD54) and down-regulation of ALCAM]. A set of 10 molecules belonging to the family of integrins and their binding partners were also deregulated [for instance, down-regulation of osteopontin (SPP1)]. In addition, LPS deregulated a large set of genes binding the above molecules (such as galectins LGALS1, S3, S9) and more than 20 transcripts coding for cytokines and their receptors. A large series of interferon-induced genes (IFITS) and genes coding for interferon-induced trans membrane proteins (IFITM) were highly up-regulated by LPS. This may be of functional importance due to the fact that all those genes are normally up-regulated by interferon tau from embryonic origin. The above results show that the function of endometrial epithelial cells is profoundly affected by LPS and that most of the key signals involved in implantation are deregulated. It is likely that these LPS-induced changes strongly perturb lately endometrial responsiveness to embryos at the time of implantation. Research was done with the financial support of FP7 project “Prolific” and RMUTSV (Thailand).
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Equils, Ozlem, Caitlyn Kellogg, James McGregor, Michael Gravett, Genevieve Neal-Perry, and Cem Gabay. "The role of the IL-1 system in pregnancy and the use of IL-1 system markers to identify women at risk for pregnancy complications†." Biology of Reproduction 103, no. 4 (June 16, 2020): 684–94. http://dx.doi.org/10.1093/biolre/ioaa102.
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Abstract The interleukin (IL)-1 system plays a major role in immune responses and inflammation. The IL-1 system components include IL-1α, IL-1β, IL-1 receptor type 1 and IL-1 receptor type 2 (decoy receptor), IL-1 receptor accessory protein, and IL-1 receptor antagonist (IL-1Ra). These components have been shown to play a role in pregnancy, specifically in embryo-maternal communication for implantation, placenta development, and protection against infections. As gestation advances, maternal tissues experience increasing fetal demand and physical stress and IL-1β is induced. Dependent on the levels of IL-1Ra, which regulates IL-1β activity, a pro-inflammatory response may or may not occur. If there is an inflammatory response, prostaglandins are synthesized that may lead to myometrial contractions and the initiation of labor. Many studies have examined the role of the IL-1 system in pregnancy by independently measuring plasma, cervical, and amniotic fluid IL-1β or IL-1Ra levels. Other studies have tested for polymorphisms in IL-1β and IL-1Ra genes in women experiencing pregnancy complications such as early pregnancy loss, in vitro fertilization failure, pre-eclampsia and preterm delivery. Data from those studies suggest a definite role for the IL-1 system in successful pregnancy outcomes. However, as anticipated, the results varied among different experimental models, ethnicities, and disease states. Here, we review the current literature and propose that measurement of IL-1Ra in relation to IL-1 may be useful in predicting the risk of poor pregnancy outcomes.
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Song, B. S., J. S. Kim, D. B. Koo, J. S. Park, K. K. Lee, and Y. M. Han. "178 IMPROVED DEVELOPMENTAL COMPETENCE OF BOVINE EMBRYOS BY PGI2 ANALOG TREATMENT." Reproduction, Fertility and Development 18, no. 2 (2006): 197. http://dx.doi.org/10.1071/rdv18n2ab178.
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The microenvironment of the follopian tube, in which the oviductal fluid contains a variety of cytokines and growth factors, affects pre-implantation development of fertilized embryos in mammals. Prostaglandin I2 (PGI2, prostacyclin) exists in oviductal fluid and is synthesized from arachidonic acid by prostacyclin synthetase. PGI2 also enhances the implantation rate of mouse embryos. In this study, the effect of PGI2 analog on the development of bovine embryos was examined. Bovine cumulus oocytes complexes (COCs) were matured in TCM-199 medium supplemented with 10 IU/mL pregnant mare serum gonadotropin (PMSG), 10 IU/mL hCG, and 10 ng/mL epidermal growth factor (EGF) at 39�C, 5% CO2 in air for 20-22 h. Following in vitro maturation, COCs were fertilized in Fert-TALP medium containing 0.6% BSA using frozen semen. Also, oocytes matured in vitro were enucleated, individually reconstructed with bESF cells, fused, and then activated by treatment with 5 �M ionomycin for 5 min and 2 mM 6-DMAP for 4 h. In vitro-fertilized (IVF) and nuclear-transferred (NT) eggs were cultured in 50 ��L drops of CR1-aa medium supplemented with 0.3% BSA in the absence or presence of 1 �M PGI2 analog at 39�C, 5% CO2 in air, respectively. At 3 days of culture, cleaved embryos were further cultured in the same culture media supplemented with 10% FBS for 4 days. Allocations of blastocysts to inner cell mass (ICM) and trophoblast (TE) cells were investigated to assess embryo quality. All experiments were repeated more than three times. All data were analyzed by using the Duncan test of ANOVA by the Statistical Analysis System (SAS Institute, Inc., Cary, NC, USA) and numbers of nuclei in blastocysts were expressed as mean � SE. No difference was detected in the cleaved rate of the eggs between the treated- and nontreated groups. IVF zygotes treated with PGI2 analog represented a higher developmental rate (33%, 122/418) to the blastocyst stage than nontreated controls (24%, 107/456) (P < 0.05). Among IVF-derived blastocysts, interestingly, the proportion (46%, 84/181) of expanded blastocysts was significantly higher in the PGI2 analog-treated group compared with that in the nontreated group (28%, 46/164). The number of nuclei in (165 � 6.1, n = 15) in blastocysts in the PGI2 analog-treated group was higher than that (146.12 � 5.7, n = 18) in the nontreated group (P < 0.05). No difference was detected in the ratio of ICM to total cells between PGI2 analog-treated (42.0 � 3.0%) and nontreated groups (41.9 � 2.9%). Like the IVF embryos, NT embryos in the PGI2 analog-treated group showed a higher in vitro developmental rate (33.6%, 43/128) than the nontreated embryos (24.2%, 32/132) (P < 0.05). Our results indicate that PGI2 analog improves the kinetics of embryo development in cattle.
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Neighbours, Lauren, Zachary P. McKay, Matthias Gromeier, Garrett Nichols, Andrea True Kelly, Daniel Corum, and Michael Brown. "Safety and efficacy of murine PVSRIPO plus anti-PD-1 immune checkpoint inhibitor (ICI) in a melanoma tumor model." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 2560. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.2560.
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2560 Background: Most patients with advanced melanoma (mel) fail/acquire resistance to ICI, including anti-(α) PD-1. PVSRIPO is a novel intratumoral immunotherapy derived from the Sabin type 1 attenuated poliovirus (PV) that targets CD155, widely expressed on solid tumors and antigen-presenting cells (APCs) of the tumor microenvironment. Therapy leads to direct tumor cell death and type I/III interferon-dominant innate inflammation, mediating priming and recruitment of tumor antigen-specific T cells. Inflammation-mediated upregulation of the PD-1/L1 IC suggests greater anti-tumor response could be achieved with PVSRIPO + αPD-1. The aim of this preclinical study was to evaluate the efficacy and safety of murine PVSRIPO (mRIPO) + αPD-1 in an aggressive mel tumor model (B16-F10.9-OVA in human-CD155 transgenic mice [C56BI/6]). Methods: Mice were randomized to 4 groups (G) of 12: (G1 [control]: vehicle [v] + IgG; G2: v + αPD-1; G3: mRIPO + IgG; G4: mRIPO + αPD-1). Tumor cells (5 x 105) were implanted into the right (R) and left (L) flanks. When tumor volume (vol) was ̃25 mm3, 15 µL v or 1 x 107 TCID50 mRIPO was injected into R (Day 1) and L (Day 4) tumors; αPD-1 or IgG (250 µg, 100 µL ip) was given on Days 1 and 4 and q 3 days until termination (Day 13). Weight, hematology, chemistry, and inflammatory cytokines were assessed pre/post-tumor implantation. Tumor vol was assessed every other day, with gross/histologic exam at termination. Results: 47 mice without health issues were euthanized as planned; 1 G1 animal required early euthanasia for tumor ulceration. Microscopic findings: increased mononuclear cell tumor infiltrates (G2 and G4); less severe L tumor growth necrosis in G2, G3, and G4 vs G1. There were no specific treatment-related changes in serum cytokines in G4. See the table below for summary of total tumor vol changes vs control; the most significant reduction was observed in G4. No tumor cells were observed via histopathology at Day 13 in R flanks of 1 mouse in G2; 3 in G3; and 8 in G4; and only G3 (n=1) and G4 (n=5) mice had no evidence of L flank tumor cells, with regression evident before L tumor mRIPO injection (ie, abscopal response). Conclusions: mRIPO + αPD-1 had the greatest overall anti-tumor response, and the combination was well tolerated. These results suggest combination therapy is not associated with untoward immune-mediated toxicity and highlight the potential for enhanced efficacy in injected and uninjected tumors. A phase 2 clinical trial of PVSRIPO ± αPD-1 in unresectable αPD-1 refractory mel is enrolling (LUMINOS-102, NCT04577807).[Table: see text]
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Tribulo, P., L. G. Siqueira, and P. J. Hansen. "145 OVIDUCTAL EXPRESSION OF GENES INVOLVED IN GROWTH FACTOR, CYTOKINE, HORMONE, AND WNT SIGNALING DURING THE EARLY ESTROUS CYCLE OF THE COW." Reproduction, Fertility and Development 28, no. 2 (2016): 202. http://dx.doi.org/10.1071/rdv28n2ab145.
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Knowledge of the molecules used by the maternal reproductive tract to regulate development of the pre-implantation embryo, called embryokines, is largely incomplete. To identify possible candidates for this function, an experiment was conducted to assess expression patterns during the first 7 days after ovulation for 92 genes that could be involved in control of development. Included were genes for 27 growth factors, 11 cytokines, 22 interleukins, 3 hormones, 19 WNT ligands, and 9 WNT regulatory molecules. Cows were slaughtered at Days 0, 3, 5, and 7 relative to predicted ovulation. Reproductive tracts were obtained and transversal sections from the isthmus of oviducts ipsi- and contralateral to the corpus luteum were harvested for gene expression analysis. Abundance of specific mRNA molecules was determined using the NanoString nCounter analysis system (NanoString Technologies, Seattle, WA, USA). Data were normalized against 6 housekeeping genes (ACTB, ERK1, GAPDH, RPL19, SLC30A6, SUZ12) and internal positive controls. Genes were considered expressed if the number of reads was greater than 2 standard deviations above the mean of negative controls. Data were analysed by ANOVA using the GLM procedure of SAS (SAS Institute Inc., Cary, NC, USA) with day, side, and day × side as fixed effects, and cow as random effect. Side did not have any significant effect so data were analysed without side and day × side in the model. In contrast to what was observed earlier for endometrium (P. Tribulo and P. J. Hansen, unpublished data), we found no difference in gene expression between oviducts ipsi- and contralateral to the corpus luteum. Overall, there was wide variation in the magnitude of gene expression. Among the 20 most expressed genes, average reads varied from 164 to over 10 726. All genes were detected at Days 0, 3, and 7 but only 67 of the 92 genes were expressed at Day 5. The 10 highest-expressed genes were CTGF, CXCL3, CXCL10, CXCL12, GRO1, IGF2, IK, SFRP1, WNT5A, and WNT6. Of these, CTGF, CXCL12, IGF2, IK, HDGF, WNT5A, and CXCL3 were within the 10 highest expressed at all days (P. Tribulo and P. J. Hansen, unpublished data). There were only 6 genes whose expression was significantly affected by day. Expression was highest at oestrus (VEGFA), Day 5 (GRO1, SFRP1) or Day 7 (BMP4, IK, WNT16). This experiment identifies some potential maternal regulators of embryonic development. Expression of most of these putative embryokine genes did not vary with stage of the oestrous cycle, suggesting that expression is either not under endocrine control or varies between cell types within the oviduct. Further studies are needed to determine the effect of these maternally secreted molecules on embryonic development. Study was supported by the National Institutes of Health (HD080855).
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Zhao, Y., T. Zhang, X. Guo, C. C. Wang, and T. C. Li. "P–417 A comparison of baseline and sequential changes of extended cytokine profile during implantation window between women who did and did not conceive after embryo transfer." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.416.
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Abstract Study question To compare the changing peripheral levels of inflammation-related cytokine profile during a 9-day period after blastocyst transfer between women who did and did not conceive. Summary answer:Successful implantation is associated with transient increase in serum pro-inflammatory cytokine profile followed by a switch to anti-inflammatory cytokine profile prior to confirmation of pregnancy.What is known already: Immunomodulation is thought to be important for the prevention of rejection of the implanting semi-allograft embryo and successful establishment of pregnancy. A successful pregnancy is characterized by a dominance of anti-inflammatory cytokine profile in the peripheral blood in the first and second trimesters of pregnancy. It is achieved by a complex interplay between various immune cells and cytokines at the fetal-maternal interface, among which the key-players are interleukine–10 (IL–10) and transforming growth factor-β1 (TGF-β1). The circulating inflammatory response in the first few days after embryo transfer to the pathophysiology of implantation failure remains unclear. Study design, size, duration: This prospective observational and longitudinal study on 47 women with infertility was performed in an in vitro fertilization unit from December 2018 to August 2019. The amounts of a range of cytokines was measured on serial blood samples obtained during a 9-day period after blastocyst transfer. Participants/materials, setting, methods Serial blood samples were obtained on the day of embryo transfer, and 3, 6, and 9 days afterward for measurement of serum interferon gamma (IFN-γ), tumor necrosis factor alpha, interleukin (IL)–2, IL–4, IL–10, IL–12, IL–13, IL–17, IL–18, and IL–22 using cytometric bead arrays; transforming growth factor beta 1 (TGF-β1) was measured using commercial enzyme-linked immunosorbent assay kits. Main results and the role of chance The cytokine profile was similar between the women who conceived and those who did not on the day of blastocyst transfer. In women who conceived, IFN-γ and IL–17 (pro-inflammatory cytokines) exhibited a transient and significant increase on day 3 after blastocyst transfer, which decreased to the baseline levels by day 6. Meanwhile, IL–10 (anti-inflammatory cytokine) was increased significantly on days 6 and 9, and TGF-β1 (anti-inflammatory cytokine) was increased significantly on day 9 after blastocyst transfer. In women who did not conceive, there was a more pronounced increase in IFN-γ and IL–17 (pro-inflammatory cytokines) on day 3, which was sustained on days 6 and 9 without a switch to an anti-inflammatory cytokine profile. Among women who conceived after blastocyst embryo transfer, there was a transient and modest increase in serum pro-inflammatory cytokine profile (IFN-γ and IL–17) 3 days after blastocyst transfer, which was followed by a switch to anti-inflammatory cytokine profile (increase IL–10 and TGF-β1) by 6 days after blastocyst transfer and the latter increase was sustained 9 days after blastocyst transfer, when pregnancy was confirmed. Limitations, reasons for caution This is an observational study on peripheral blood cytokine levels, so it is not possible to draw conclusions if the implantation failure is due primarily to failure of the embryo to elicit a trigger for the switch or failure of maternal response to a normal trigger released by the embryo. Wider implications of the findings: The characteristic change in peripheral cytokine profile during successful implantation, well before confirmation of pregnancy, may provide an opportunity to develop serum biomarkers to monitor implantation and to understand the mechanism of its failure, especially in women who experience recurrent implantation failure after IVF. Trial registration number Not applicable
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Liang, Yu, Xiaokui Yang, Yonglian Lan, Lingling Lei, Ying Li, and Shuyu Wang. "Effect of Endometrioma cystectomy on cytokines of follicular fluid and IVF outcomes." Journal of Ovarian Research 12, no. 1 (October 21, 2019). http://dx.doi.org/10.1186/s13048-019-0572-7.
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Abstract Background Endometriosis patients undergoing in vitro fertilization-embryo transfer (IVF-ET) treatment suffer from lower success rates. The success of IVF-ET is related to the receptivity of the uterus and the quality of embryos, and it is well known a patient’s endometriosis does not impair the receptivity. Whether endometrioma should be removed surgically before IVF remains controversial. Studies have shown that endometrioma removal decreases peritoneal inflammation, but little information is available regarding the alteration in the cytokines of follicular fluid. The objective of this study was to examine the impact of endometrioma cystectomy on the outcome of IVF and the levels of intrafollicular inflammatory cytokines and to investigate correlations between cytokine concentrations and IVF outcomes. Method A total of 41 women with endometriosis-associated infertility undergoing IVF were recruited; 13 patients (surgery group, S group) had surgery to remove the endometrioma before enrollment, and 28 patients (non-surgery group, NS group) were untreated before IVF. The follicular fluid from a dominant follicle was collected during oocyte retrieval, and the concentrations of sixteen soluble cytokines known to be involved in ovarian function were measured. Results Among the soluble molecules examined in this study, chemokines and growth factors and a few are inflammatory cytokines were found in the follicular fluid of patients with endometriosis. In addition, the expression levels of chemokines, growth factors, and most inflammatory cytokines did not differ between the S and NS groups, but interleukin (IL)-18 levels were significantly lower in the NS group. However, the levels of IL-18 in the FF did not correlate with IVF cycle parameters. The implantation and clinical pregnancy rates were similar between the two groups, but the anti-Müllerian hormone (AMH) level was lower in the S group than in the NS group. Conclusions These findings suggest that endometrioma surgery may potentially reduce the ovarian reserve and has little impact on the success rate of IVF. Ovarian endometriomas are not associated with cytokine profiles in FF from infertile women, and they are not likely to affect the quality of the oocyte and embryo as a result of an inflammatory mechanism.
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Chan, Hon Y., Lachlan M. Moldenhauer, Holly M. Groome, John E. Schjenken, and Sarah A. Robertson. "Toll-like receptor-4 null mutation causes fetal loss and fetal growth restriction associated with impaired maternal immune tolerance in mice." Scientific Reports 11, no. 1 (August 16, 2021). http://dx.doi.org/10.1038/s41598-021-95213-1.
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AbstractMaternal immune adaptation to accommodate pregnancy depends on sufficient availability of regulatory T (Treg) cells to enable embryo implantation. Toll-like receptor 4 is implicated as a key upstream driver of a controlled inflammatory response, elicited by signals in male partner seminal fluid, to initiate expansion of the maternal Treg cell pool after mating. Here, we report that mice with null mutation in Tlr4 (Tlr4−/−) exhibit impaired reproductive outcomes after allogeneic mating, with reduced pregnancy rate, elevated mid-gestation fetal loss, and fetal growth restriction, compared to Tlr4+/+ wild-type controls. To investigate the effects of TLR4 deficiency on early events of maternal immune adaptation, TLR4-regulated cytokines and immune regulatory microRNAs were measured in the uterus at 8 h post-mating by qPCR, and Treg cells in uterus-draining lymph nodes were evaluated by flow cytometry on day 3.5 post-coitum. Ptgs2 encoding prostaglandin-endoperoxide synthase 2, cytokines Csf2, Il6, Lif, and Tnf, chemokines Ccl2, Cxcl1, Cxcl2, and Cxcl10, and microRNAs miR-155, miR-146a, and miR-223 were induced by mating in wild-type mice, but not, or to a lesser extent, in Tlr4−/− mice. CD4+ T cells were expanded after mating in Tlr4+/+ but not Tlr4−/− mice, with failure to expand peripheral CD25+FOXP3+ NRP1− or thymic CD25+FOXP3+ NRP1+ Treg cell populations, and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. We conclude that TLR4 is an essential mediator of the inflammation-like response in the pre-implantation uterus that induces generation of Treg cells to support robust pregnancy tolerance and ensure optimal fetal growth and survival.
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Sanchez Pavon, A., H. Mendoza, P. Valdivieso, M. Zambrano, and J. Garcia-Ferreyra. "P-273 Oocyte competence is affected by Body Mass Index in women undergoing in vitro fertilization procedures." Human Reproduction 37, Supplement_1 (June 29, 2022). http://dx.doi.org/10.1093/humrep/deac107.262.
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Abstract Study question Is body mass index (BMI) an important factor that affects oocyte competence in patients subjected to in vitro fertilization procedures? Summary answer High BMI affects oocyte competence, causing abnormal blastocyst development, and reduced clinical outcomes. Overweight and obesity women needed more oocytes to obtain a gestational sac. What is known already Overweight and obesity are systemic and tissue-specific conditions that lead to chronic inflammation and oxidative stress to produce an unregulated and persistent secretion of chemokines and cytokines, which are released into circulation inducing inflammatory responses in several tissues, including the ovaries. Cytokines, chemokines and adipokines play essential roles in steroidogenesis, follicular growth, cumulus expansion, and ovulation; however, alterations in their patterns of synthesis and secretion impair meiotic and cytoplasmic maturation of the oocyte, reducing its developmental competence for fertilization and pre-implantation development. Overweight or obese women had significantly lower clinical pregnancy and live birth rates and significantly higher miscarriage rates. Study design, size, duration The following work is a retrospective nonrandomized study that included a total of 1839 oocytes obtained from 201 IVF/ICSI non-donor cycles performed between January 2018 and December 2019. Participants/materials, setting, methods The oocytes were allocated according to BMI of patients in three groups: Normal group: 18.5-24.9 ( n = 608 oocytes), overweight group: 25.0-29.9 ( n = 832 oocytes) and obese group: ≥30.0 ( n = 399 oocytes). Extended embryo culture until blastocyst stage was done in all patients. Fertilization, development of blastocyst, transferred embryos, pregnancy and implantation rates were compared between groups. Number of oocytes needed to obtain a gestational sac (oocyte competence) were analyzed and compared by group. Main results and the role of chance Fertilization rates (87.7%, 85.3%, and 84.0%), and transferred embryos (1.84, 1.84, and 1.86) were similar between three evaluated groups. Blastocyst development rate (48.2%, 40.0%, and 40.1%), pregnancy rate (67.2%, 41.9%, and 39.5%), and implantation rate (53.7%, 31.8%, and 28.2%) were significantly reduced in women with overweight and obesity compared to women with normal weight ( P < 0.05). To obtain a gestational sac, 2.1 and 1.8 more oocytes were needed by obese and overweight women, respectively, than the control group, suggesting oocyte competence is negatively affected by higher BMI. Limitations, reasons for caution The retrospective nature of this study and the small sample size may be reasons for caution. Wider implications of the findings The findings in this study suggest that a weight above normal will progressively decrease oocyte competence thus, it is necessary to have a greater number of oocytes in patients with overweigh and obesity to have a gestational sac when compared with patients of normal weight. Trial registration number non applicable
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Xue, Zhu, Juanli Li, Jiaxing Feng, Han Han, Jing Zhao, Jiao Zhang, Yanhua Han, Xiaoke Wu, and Yuehui Zhang. "Research Progress on the Mechanism Between Polycystic Ovary Syndrome and Abnormal Endometrium." Frontiers in Physiology 12 (December 17, 2021). http://dx.doi.org/10.3389/fphys.2021.788772.
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As a highly dynamic tissue, the endometrium is periodically shed in response to the secretion of estrogen and progesterone. After menarche, the endometrium of healthy women proliferates and differentiates under the action of steroid hormones (e.g., 17β-estradiol and progesterone) that are secreted by the ovaries to provide appropriate conditions for embryo implantation. Polycystic ovary syndrome (PCOS), a prevalent endocrine and metabolic disorder in reproductive-aged women, is usually associated with multiple cysts within the ovaries and excess levels of androgen and is characterized by hirsutism, acne, menstrual irregularity, infertility, and increased risk of insulin resistance. Multiple factors, such as anovulation, endocrine-metabolic abnormalities, and inflammation, can disrupt the endometrium in PCOS patients and can lead to endometrial hyperplasia, pregnancy complications, or even cancer. Despite many recent studies, the relationship between PCOS and abnormal endometrial function is still not fully understood. In this review, we investigate the correlation of PCOS patient endometrium with anovulation, hyperandrogenemia, insulin resistance, progesterone resistance, and inflammatory cytokines, aiming to provide a theoretical basis for the treatment of disorders caused by endometrial dysfunction in PCOS patients.
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Liu, Junfeng, Qin Liang, Tianyang Wang, Bei Ma, Xin Wang, Ping Li, Aftab Shaukat, Xuefeng Guo, and Ganzhen Deng. "IFN-τ mediated miR-26a targeting PTEN to activate PI3K/AKT signalling to alleviate the inflammatory damage of bEECs." Scientific Reports 12, no. 1 (June 7, 2022). http://dx.doi.org/10.1038/s41598-022-12681-9.
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AbstractEndometritis is the failure of embryo implantation and an important cause of infertility in dairy cows. IFN-τ is a type I interferon unique to ruminants. In regulating the process of inflammatory response, IFN-τ can be expressed through MicroRNAs (miRNAs) to regulate the process of inflammation. However, IFN-τ regulates lipopolysaccharide (LPS)-induced inflammatory injury of bEECs through the highly conserved miR-26a in mammals, and the mechanism remains unclear. Bovine endometrial epithelial cells (bEECs)were isolated and cultured to establish an inflammatory injury model. RT–qPCR and ELISA were used to detect the secretion of inflammatory factors. Dual-luciferase assays and target gene silencing assays determine the regulatory role of miRNAs. The target protein was detected by immunofluorescence and western blotting. This study showed that the expression of miR-26a was significantly down-regulated in mouse endometrium inflammatory injury tissue and LPS stimulated bEECs; and IFN-τ reversed the expression of miR-26a. The study also showed that the overexpression of miR-26a significantly inhibited the secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. In addition, studies have shown that miR-26a inhibits its translation by targeting PTEN 3′-UTR, which in turn activates the Phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT) pathway, so that nuclear factor kappa-B (NF-κB) signaling is inhibited. In summary, the results of this study further confirm that IFN-τ as an anti-inflammatory agent can up-regulate the expression of miR-26a and target the PTEN gene to inhibit the inflammatory damage of bEECs.
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Raghupathy, Raj. "Cytokines and pregnancy complications: modulation for prevention and treatment." Exploration of Immunology, June 27, 2022, 414–27. http://dx.doi.org/10.37349/ei.2022.00059.
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“There is many a slip twist the cup and the lip” is a proverb that dates back to the 3rd century. This proverb comes to mind while writing a review on pregnancy loss; so many complications can occur between fertilization and development of the embryo through the long period of gestation until successful delivery of the baby. These include failure of implantation of the embryo, spontaneous miscarriage in the first trimester, pre-eclampsia in the second trimester, premature rupture of fetal membranes, pre-term labour, and pre-term delivery. The maternal immune system which does a phenomenal job of protecting the host from a daunting variety of infections, sometimes also mounts adverse reactions that complicate pregnancy and endanger the fetus. Maternal immune reactions that can adversely affect pregnancy have been shown to be mediated by lymphocytes, macrophages and natural killer cells, and by cytokines secreted by these cellular effectors. This review summarizes the deleterious effects of cytokines leading to recurrent spontaneous miscarriage, pre-eclampsia and pre-term delivery, which are the major complications of pregnancy. It then goes on to discuss the potential use of progesterone and dydrogesterone, an orally-administered progestogen, as immunomodulatory molecules that can be considered for the prevention and/or treatment of these complications.
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Guo, Ling, Anliang Guo, Fang Yang, Li Li, Junhao Yan, Xiaohui Deng, Caifeng Dai, and Yan Li. "Alterations of Cytokine Profiles in Patients With Recurrent Implantation Failure." Frontiers in Endocrinology 13 (July 11, 2022). http://dx.doi.org/10.3389/fendo.2022.949123.
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Serum cytokine profile and T helper (Th)1/Th2 cell balance are related to the success of embryo implantation, although not yet firmly linked to recurrent implantation failure (RIF), a repeated failure to achieve clinical pregnancy following multiple high-quality embryo transfer. In this prospective study, comprehensive bioinfomatic analysis and logistic regression analysis were used to compare the serum cytokine profiles of 41 RIF patients with those of 29 subjects with first-cycle successful pregnancy in the mid-luteal phase and to assess the alterations of cytokine profiles in patients with clinical pregnancy at five weeks post-transplantation. We found several elevated pro-inflammatory cytokines, decreased anti-inflammatory cytokines, and increased Th1/Th2 cytokine ratios in RIF patients compared to control subjects. Specifically, the receiver operating characteristic (ROC) curve generated using multiple indicators provides a high predictive value for diagnosing RIF (area under the curve [AUC] = 0.94, 95% confidence interval [CI] 0.87-1.00, P < 0.0001), with a sensitivity of 96.55% and a specificity of 87.50%. Meanwhile, at five weeks post-transplantation, patients in both groups diagnosed with clinical pregnancy exhibited increased levels of several cytokines compared with pre-pregnancy levels, and a gradual shift in Th1/Th2 balance toward Th2. These findings suggest that inflammatory serum cytokines and the predominance of Th1 cells likely contribute to RIF and possibly reflect the immune environment at the maternal-fetal interface, suggesting their value as outcome indicators in assisted reproductive therapy.
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Tasma, Zoe, Weilin Hou, Tanvi Damani, Kathleen Seddon, Matthew Kang, Yi Ge, David Hanlon, Fiona Hollinshead, Colin L. Hisey, and Lawrence W. Chamley. "Production of extracellular vesicles from equine embryo-derived mesenchymal stromal cells." Reproduction, August 2022. http://dx.doi.org/10.1530/rep-22-0215.
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Mesenchymal stromal cells (MSC) have recently been explored for their potential use as therapeutics in human and veterinary medicine applications, such as the treatment of endometrial inflammation and infertility. Allogeneic MSC-derived extracellular vesicles (EVs) may also provide therapeutic benefits with advantage of being an “off-the-shelf” solution, provided they can be produced in large enough quantities, without contamination from bovine EVs contained in fetal bovine serum that is a common component of cell culture media. Towards this aim, we demonstrated the successful isolation and characterisation of equine MSCs from pre-implantation embryos. We also demonstrate that many of these lines can be propagated long-term in culture while retaining their differentiation potential, and conducted a head-to-head comparison of two bioreactor systems for scalable EV production including in serum-free conditions. Based on our findings, the CELLineTM AD 1000 flasks enabled higher cell density cultures and significantly more EV production than the FiberCellTM system or conventional culture flasks. These findings will enable future isolation of equine MSCs and the scalable culture of their EVs for a wide range of applications in this rapidly growing field.
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Hadi, Najah, Khalid Amber, and Noor Almousawi. "Coq10 attenuates the acute inflammatory response after Novolimus drug eluting stent implantation in diabetic patients with stable coronary artery disease." International Journal of Research in Pharmaceutical Sciences 9, SPL1 (April 16, 2018). http://dx.doi.org/10.26452/ijrps.v9ispl1.1409.
Full textAbstract:
Developing of percutaneous coronary intervention opens new fields in the treatment of coronary artery disease since the potential of this less invasive technique outweighs the risk of acute occlusion,but the presence of a foreign body within the coronary artery can cause vascular inflammation. This study evaluated coenzyme Q10 in controlling the acute inflammation after stent implantation.Study groups: Forty eight patients who were undergoing elective stent implantation were randomized into two groups. Group 1patients (24) underwent stent implantation only while Group 2patients (24) underwent stent implantation and received coenzyme q10 24 hr. before and after stent. Blood sampling for the two groups was done before stent and after at 12hr. and 24 hr. to measure specific inflammatory biomarkers.The data show that serum levels of inflammatory cytokine (IL-6,IL-8),C-reactive proteins,cardiac troponin–I, pentraxin 3 and soluble vascular cell adhesion molecule-1 (sVCAM-1)were significantly increased (p˂0.05) after stent implantation when compared with (0 time) pre stent. In contrast,IL-10,complement C5a and matrix metaloprotinase-9 (MMP-9)levels were insignificant (p˃0.05) increasedin group 1 when compared at different study time points.Coenzyme Q10 administration before stent led to a significant reduction (p˂0.05) in levels of inflammatory cytokine (IL-6,IL-8),C-reactive proteins, cardiac troponin –I,pentraxin 3, sVCAM-1,complement C5a, MMP-9 and significant increase (p˂0.05) in level of anti-inflammatory cytokine IL-10 in (group 2) of patients when compared with group1 patients.It is concluded that coenzyme Q10 plays a potential role in decreasing the pro-inflammatory cytokines and inflammatory markers with increasing the anti-inflammatory cytokine IL-10.
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Ermisch, Alison F., Katie L. Bidne, Scott G. Kurz, Kerri A. Bochantin, and Jennifer R. Wood. "Ovarian inflammation mediated by TLR-4 increased transcripts of maternal effect genes and decreased embryo development." Biology of Reproduction, December 3, 2022. http://dx.doi.org/10.1093/biolre/ioac212.
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Abstract Obese women are sub-fertile and have reduced assisted reproduction success, which may be due to reduced oocyte competence. We hypothesize that consumption of a high fat high sugar (HFHS) diet induces ovarian inflammation, which is a primary contributor to decreased oocyte quality and pre-implantation embryo development. To test this hypothesis, C57BL/6 (B6) mice with a normal inflammatory response and C3H/HeJ (C3H) mice with a dampened inflammatory response due to dysfunctional toll-like receptor 4, were fed either normal chow (ND) or HFHS diet. In both B6 and C3H females, HFHS diet induced excessive adiposity and hyperglycemia compared to ND-fed counterparts. Conversely, ovarian CD68 levels and oocyte expression of oxidative stress markers were increased when collected from B6-HFHS but not C3H-HFHS mice. Following in vitro fertilization of in vivo matured oocytes, blastocyst development was decreased in B6-HFHS but not C3H-HFHS mice. Expression of cumulus cell markers of oocyte quality (Has2, Ptx3, Ptgs2, Tnfaip6) were altered in both B6-HFHS and C3H-HFHS. However, there were no diet-dependent differences in spindle abnormalities in either B6 or C3H mice, suggesting potential defects in cytoplasmic maturation. Indeed, there were significant increases in the abundance of maternal effect gene mRNAs in oocytes from only B6-HFHS mice. These differentially expressed genes encode proteins of the subcortical maternal complex and associated with mRNA metabolism and epigenetic modifications. These genes regulate maternal mRNA degradation at oocyte maturation, mRNA clearance at the zygotic genome activation, and methylation of imprinted genes suggesting a mechanism by which inflammation induced oxidative stress impairs embryo development.
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Lee, Y. X., C. R. Tzeng, Y. M. Hu, C. H. Chen, C. W. Chen, C. C. Liao, L. Y. Chen, et al. "P–522 Cervical secretion methylation profile is associated with the success of frozen-thawed embryo transfer - a proof-of-concept study." Human Reproduction 36, Supplement_1 (July 1, 2021). http://dx.doi.org/10.1093/humrep/deab130.521.
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Abstract Study question Is cervical secretion gene methylation profile different between receptive and non-receptive endometrium and associated with implantation outcome in frozen-embryo transfer (FET) cycle? Summary answer The combination of candidate genes methylation profiles obtained from cervical secretion showed significant associations with pregnancy outcomes. What is known already Implantation failure remains a black box in reproductive medicine, and the exact mechanism of how endometrial receptivity is regulated is still unknown. Epigenetic modifications play a role in the gene expression pattern and may alter the endometrial receptivity in the human endometrium. Cervical secretion containing various implantation-related cytokines, and the gene methylation change can be used as a non-invasive molecular source that reflects the endometrium condition. Study design, size, duration In this retrospective case-control study, sixty-two women who entered the FET cycle (30 pregnant and 32 non-pregnant women) were enrolled. Participants/materials, setting, methods Cervical secretion was collected before embryo transfer from women enrolled in multicenter university-affiliated reproductive units. The DNA methylation status of six candidate genes was measured using quantitative methylation-specific PCR (qMSP). The correlation between methylation change and the pregnancy outcome was analyzed. Main results and the role of chance The candidate genes were selected from that associated with implantation with literature review and the original genome-wide DNA methylation data from NCBI GEO DataSets (GSE90060) which processed using bioinformatics analysis. Six candidate genes whose CpG-level methylation analysis with β-value statistically higher in receptive endometrium than in a pre-receptive endometrium were selected. All six candidate genes showed different degrees of correlation with the pregnancy outcomes. Among them, PRKAG2 methylation changes showed the highest correlation with the pregnancy outcome. A logistic regression model was used to evaluate the performance of a single gene or a combination of genes for implantation prediction. The results showed a statistically significant association between the methylation status of a combination of genes (PRKAG2, KRS1, HAND2) and the pregnancy outcome (p = 0.008), resulting in an optimal AUC of 0.7 (95% CI: 0.57 - 0.81) for implantation prediction. Limitations, reasons for caution The results obtained from a relatively small cohort size. A larger study and further comprehensive methylome investigations are warranted. Wider implications of the findings: This study is the first proof-of-concept study that cervical secretion methylation profile is associated with implantation outcome in a FET cycle, and showed potential as a non-invasive method for implantation prediction. Trial registration number non applicable
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Junqueira, Talita Vieta, Nadia Simarro Fagundes, Marcelo José Barbosa Silva, João Paulo Elsen Saut, and Marcelo Emílio Beletti. "Gene expression of FOXP3, indoleamine 2,3-dioxygenase (IDO), IL10 and CSF1 in the uterus of cows that received an intrauterine infusion of maternal and paternal antigens." Bioscience Journal 36, no. 6 (September 1, 2020). http://dx.doi.org/10.14393/bj-v36n6a2020-48218.
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Sensitization with conceptus antigens has been shown to be useful for improving reproductive performance facilitating maternal acceptance of an allogeneic embryo through the induction of cytokines and immunoregulatory cells in the uterine microenvironment. As FOXP3, IDO, IL10 and CSF1 in the uterus are important on the recognition and development of embryos during early pregnancy, this study aimed to determine whether simultaneous or isolated administration of paternal (semen) and maternal (PBMCs) antigens in the uterus of cow, on the day of estrus, influence the gene expression of these cytokines. Forty crossbred cows were divided into four treatments: T0: Control; T1: Semen; T2: PBMCs (peripheral blood mononuclear cells) from another cow and T3: PBMCs+Semen. Antigens were administered into the uterine body on the estrus day (D0). Uterine biopsies designed for molecular analysis of gene expression were collected in vivo seven (D7) and fourteen (D14) days after immunostimulation. Transcripts from FOXP3, IDO, IL-10 and CSF-1 were detected in all RNA samples extracted from uterine biopsies. The semiquantitative analysis showed that none of the treatments caused significant increase in the expression of these genes. Furthermore, on D14 all treatments led to a decline in the number of CSF-1 transcripts; moreover, treatment with PBMCs+Semen also led to a drop in the abundance of IL-10 transcripts. Such results suggest that isolated or simultaneous administration of both antigens would not increase maternal tolerance to embryo alloantigens, nor would it create favorable conditions to its growth and pre-implantation development, at least regarding the effects mediated by these genes on D7 and D14 of the estrous cycle.
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Osakue, N., C. C. Onyenekwe, F. A. Ehiaghe, J. E. Ahaneku, J. I. Ikechebelu, G. O. Igberase, and L. O. Alekwe. "Maternal Serum Levels of Interferon-gamma, Tumor Necrotic Factor-alpha and Progesterone of Infertile Women on In vitro Fertilization before and after Treatment." Annual Research & Review in Biology, May 26, 2020, 38–44. http://dx.doi.org/10.9734/arrb/2020/v35i430210.
Full textAbstract:
Background: In vitro fertilization (IVF) is an assisted reproductive technology (ART) that is widely used globally in the treatment of infertility. Infertility can occur due to male factors, female factors or both.
Aim: This is the first Nigerian study that sets out to observe the levels and relationship between circulating pro-inflammatory cytokines (IFN-γ, TNF-α) and progesterone (PG) in Nigerian women undergoing in vitro fertilization pre and post treatment and their possible effect on pregnancy outcome.
Materials and Methods: This observational study randomly selected sixty-two (62) infertile females below 45 year of age who enrolled in the IVF treatment at Lily Hospitals, Warri and Shepherd Specialist Hospital, Warri, Southern Nigeria. Only data of the thirteen (13) infertile females who became pregnant after the IVF treatment where followed up and presented in this study. Five (5) ml of whole blood were collected into plain tubes on day 3 of the menstrual cycle of all the participants from the ante-cubital vein before and after IVF procedure using standard laboratory collection technique. Ovarian stimulation was done using the long gonadotropin-releasing hormone agonist protocol. Oocyte retrieval transfer was done using ultrasound-guided fine-needle aspiration and embryo transfer was done using ultrasound-guided embryo transfer. IFN-γ, TNF-α and PG were estimated using enzyme-linked immunosorbent assay method.
Results and Conclusion: Significant increase in the levels of TNF-α and PG at the second trimester and third trimester of pregnancy when compared with the first trimester of pregnancy (p = 0.000). While the level of IFN-γ was significantly increased in the second trimester of pregnancy when compared with the first trimester of pregnancy (p = 0.000). It is evident from the study that both pro-inflammatory cytokines (IFN-γ and TNF-α) act in synergy to maintain the level of progesterone which act as an anti-inflammatory agent to regulate the activities of the pro-inflammatory cytokines for successful oocytes implantation and maturation.