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Gonçalo Pereira, Ricardo Bexiga, João Chagas e Silva, Elisabete Silva, Christelle Ramé, Joëlle Dupont, Yongzhi Guo, Patrice Humblot and Luís Lopes-da-Costa

Adipokines emerged as regulators of metabolism and inflammation in several scenarios. This study evaluated the relationship between adipokines (adiponectin, chemerin and visfatin) and cytological (subclinical) endometritis, by comparing healthy (without), transient (recovered by 45 days postpartum (DPP)) and persistent (until 45 DPP) endometritis cows (n = 49). Cows with persistent endometritis had higher adiponectin concentrations in plasma (at 21 DPP, P < 0.05 and at 45 DPP, P < 0.01) and in uterine fluid (at 45 DPP, P < 0.001), and higher chemerin concentrations in plasma (P < 0.05) and uterine fluid (P < 0.01) at 45 DPP than healthy cows. Cows with persistent endometritis had higher gene transcription in the cellular pellet of uterine fluid and protein expression in the endometrium of these adipokines and their receptors than healthy cows. Adiponectin plasma concentrations allowed to discriminate healthy from persistent endometritis cows, in 87% (21 DPP) and 98% (45 DPP) of cases, and adiponectin and chemerin uterine fluid concentrations at 45 DPP allowed for this discrimination in 100% of cases. Cows with concentrations above the cutoff were a minimum of 3.5 (plasma 21 DPP), 20.4 (plasma 45 DPP), and 33.3 (uterine fluid 45 DPP) times more at risk of evidencing persistent endometritis at 45 DPP than cows with concentrations below the cutoff. Overall, results indicate a relationship between adipokine signalling and the inflammatory status of the postpartum uterus of dairy cows, evidencing that adipokines represent suitable biomarkers of subclinical endometritis, able to predict the risk of persistence of inflammation.

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Jin-Young Lee, Jiyeon Ham, Whasun Lim and Gwonhwa Song

Apomorphine is a derivative of morphine that is used for the treatment of Parkinson’s disease because of its effects on the hypothalamus. Therapeutic effects of apomorphine have also been reported for various neurological diseases and cancers. However, the molecular mechanisms of the antitumor effects of apomorphine are not clear, especially with respect to choriocarcinoma. This is the first study to elucidate the anticancer effects of apomorphine on choriocarcinoma. We found that apomorphine suppressed the viability, proliferation, ATP production, and spheroid formation of JEG3 and JAR choriocarcinoma cells. Moreover, apomorphine activated the intrinsic apoptosis pathway by activating caspases and inhibited the production of anti-apoptotic proteins in choriocarcinoma cells. Further, apomorphine caused depolarization of mitochondria, calcium overload, energy deprivation, and endoplasmic reticulum stress in JEG3 and JAR cells. We confirmed synergistic effects of apomorphine with paclitaxel, a traditional chemotherapeutic agent, and propose that apomorphine could be a potential therapeutic agent in choriocarcinoma and an important candidate for drug repositioning that could help overcome resistance to conventional chemotherapy.

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Maria-Luisa Lazo-de-la-Vega-Monroy, Karen-Alejandra Mata-Tapia, Juan-Antonio Garcia-Santillan, Maria-Angelica Corona-Figueroa, Martha-Isabel Gonzalez-Dominguez, Hector-Manuel Gomez-Zapata, Juan-Manuel Malacara, Leonel Daza-Benitez and Gloria Barbosa-Sabanero

Birth weight (BW) is an important indicator for newborn health. Both high and low BW is associated with increased risks for adult metabolic diseases. AMPK (AMP-activated protein kinase), mTOR (mechanistic target of rapamycin), and insulin/IGF1 (insulin-like growth factor 1) pathways may function as placental sensors of maternal hormonal and nutritional status. However, the physiological role of these pathways in placenta has not been completely elucidated. To evaluate expression and activation of AMPK, mTOR, and insulin/IGF1 pathways and its association with placental weight (PW), BW, and maternal hormonal and metabolic status, we performed a cross-sectional study in placentas from non-obese mothers with SGA (n = 17), AGA (n = 19) and LGA (n = 10) newborns. We analyzed placental expression of total and phosphorylated key proteins from the AMPK, mTOR and insulin/IGF1 pathways. Maternal and cord blood hormones were determined by ELISA. AMPK and LKB1 activation correlated negatively with PW and BW, cord leptin, and pregestational BMI. Placental SIRT1 inversely correlated with BW, cord leptin, neonatal HOMA-IR, and maternal IGF1. PGC1α correlated negatively with PW and BW. Phosphorylated mTOR positively correlated with maternal glucose, PW and BW. IGF1R was lower in SGA. No changes in p-IGF1R, INSRb, total AKT or p-AKT were found, and pPDK1 was lower in SGA and LGA. These results suggest that placental AMPK, insulin/IGF1, and mTOR pathways may influence fetal growth, perhaps regulating placental physiology, even in metabolically healthy pregnancies. Our study highlights these nutrient sensing pathways as potential molecular mechanisms modulating placental adaptations and, thus, long-term metabolic health.

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Tania Reyes-Miguel, Ana L Roa-Espitia, Rafael Baltiérrez-Hoyos and Enrique O Hernández-González

Mammalian sperm cells acquire fertilizing capacity as a result of a process termed capacitation. Actin polymerization is important for capacitation; inhibiting actin polymerization prevents the adhesion and fusion of the sperm with the ovule. The main function of RHO proteins CDC42 and RHOA is to direct actin polymerization. Although these two RHO proteins are present in mammalian sperm, little is known about their role in capacitation, the acrosome reaction, and the way in which they direct actin polymerization. The purpose of this study was to determine the participation of CDC42 and RHOA in capacitation and the acrosome reaction and their relationship with actin polymerization using guinea pig sperm. Our results show that the inhibition of CDC42 and RHOA alters the kinetics of actin polymerization, capacitation, and the acrosome reaction in different ways. Our results also show that the initiation of actin polymerization and RHOA activation depend on the activation of CDC42 and that RHOA starts its activity and effect on actin polymerization when CDC42 reaches its maximum activity. Given that the inhibition of ROCK1 failed to prevent the acrosomal reaction, the participation of RHOA in capacitation and the acrosomal reaction is independent of its kinase 1 (ROCK1). In general, our results indicate that CDC42 and RHOA have different roles in capacitation and acrosomal reaction processes and that CDC42 plays a preeminent role.

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Tao Yu, Shuai Lin, Rui Xu, Tian-Xi Du, Yang Li, Hui Gao, Hong-Lu Diao and Xiu-Hong Zhang

Embryo implantation is a crucial step for the successful establishment of mammalian pregnancy. Cyclophilin A (CYPA) is a ubiquitously expressed intracellular protein and is secreted in response to inflammatory stimuli to regulate diverse cellular functions. However, there are currently no reports about the role of CYPA in embryo implantation. Here, we examine the expression pattern of CYPA during mouse early pregnancy and explore the potential role of CYPA during implantation. CYPA is expressed in the subluminal stroma surrounding the implanting blastocyst on day 5 of pregnancy, but not at inter-implantation sites. In ovariectomized mice, estrogen and progesterone significantly stimulate CYPA expression. When pregnant mice are injected intraperitoneally with CYPA inhibitor, the numbers of implantation sites are significantly reduced. Using an in vitro stromal cell culture system, Ppia siRNA knockdown of CYPA and CYPA-specific inhibitor treatment partially inhibits levels of CD147, MMP3 and MMP9. Decreased CYPA expression also significantly inhibits Stat3 activity and expands estrogen responsiveness. Taken together, CYPA may play an important role during mouse embryo implantation.

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Qiaoge Niu, Maosheng Cao, Chenfeng Yuan, Yuwen Huang, Zijiao Zhao, Boqi Zhang, Xin Wang, Yameng Wei, Wenjing Fan, Xu Zhou and Chunjin Li

Nerve growth factor (NGF) has been proved to play important roles in male reproductive physiology, but the molecular mechanisms of NGF action remain unclear. In this study, the effects of NGF on the growth of newborn bovine testicular Sertoli (NBS) cells and the related signaling pathways were investigated. The NBS cells were treated in vitro with NGF (100 ng/mL) for 18 h. The expression levels of cell proliferation related genes, INHBB, and cytoplasmic specialization related gene were determined using real-time PCR and Western blot. The roles of PI3K/AKT and MAPK/ERK pathways in NGF-induced cell proliferation were investigated. It was found that NGF regulates proliferation and function of NBS cells via its receptor NTRK1 by activating the PI3K/ATK and MAPK/ERK signaling pathways. The study will help to further understand the role of NGF in male reproduction and provide new therapeutic targets for reproductive dysfunctions in male animals.

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Yan Wang, Hualin Huang, Minghua Zeng, Ru-Ping Quan, Jun-Ting Yang, Dan Guo, Ying Sun, Hongwen Deng and Hongmei Xiao

In this study, we investigated a gene-edited (Zp2 MT/MT) rat model of infertility caused by the failure to express the zona pellucida glycoprotein 2 (ZP2) due to the significant reduction of mRNA amount. We examined the defects in the zona pellucida (ZP) caused by ZP2 nullification and the influence of these defects on aspects of oocyte development, including apoptosis and fertilization ability. To investigate the cause of the influence to the oocytes’ development, we evaluated the morphology of follicular transzonal projections (TZPs), known as ‘bridges’, which mediate the bidirectional signaling between the oocyte and surrounding granulosa cells and the level of reactive oxygen species (ROS) in ovulated eggs. Our results showed that two types of ZP defects were generated in the Zp2 MT/MT rat,that is, ZP intact but thinned and ZP cracked (or even absent). The fertilization rate of the ovulated eggs reduced in both types, while increased oocyte apoptosis was observed only in the latter type. Moreover, the increased oocyte apoptosis rate correlated closely with the reduction in follicular TZPs and increased ROS levels in ovulated egg. In conclusion, nullification of rat ZP2 destroyed the integrity of the ZP, impaired the bidirectional signaling between the oocyte and surrounding granulosa cells. Therefore, the resulting infertility likely occurs via elevation of oxidative stress and oocytes apoptosis.

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Jithine Jayakumar Rajeswari and Suraj Unniappan

Nesfatin-1 is a naturally occurring orphan ligand in fish and mammals. Research in our lab resulted in the identification of an inhibitory role for nesfatin-1 on pituitary hormones (goldfish) and oocyte maturation (zebrafish). The present study is an extension of these original findings and aimed to determine whether nesfatin-1 has any additional effects on HPG genes in male and female goldfish. We found that a single i.p. injection of synthetic nesfatin-1 (50 ng/g body weight) downregulated the expression of salmon gonadotropin-releasing hormone (sgnrh), chicken gnrh-II (cgnrh-II), kisspeptin receptor (gpr54a) and brain aromatase (cyp19a1b) mRNAs in the hypothalamus of both male and female goldfish at 15 min post-administration. In the pituitary of both males and females, nesfatin-1 reduced luteinizing hormone beta (lhβ) and follicle stimulating hormone beta (fshβ) mRNA expression at 60 min and gpr54a mRNA at 15 min. Similarly, the gonadotropin receptors lhr and fshr were downregulated in the gonads. Meanwhile, gonadotropin inhibiting hormone (gnih), gnih receptor, kisspeptin 1 (kiss1) and gpr54a mRNA expression in the gonads were increased post-nesfatin-1 treatment. Nesfatin-1 negatively influences the star, cytochrome P450 family 11 subfamily A member 1, anti-mullerian hormone and aromatase mRNAs. In agreement with these results, nesfatin-1 reduced plasma estradiol and testosterone in female and male goldfish circulation at 60 min post-injection. The information generated through this research further solidified nesfatin-1 as an inhibitor of reproductive hormones in fish. Targeting nesfatin-1 and related peptides could yield beneficial effects in fish reproduction and aquaculture.

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Hadrian M Kinnear, Claire E Tomaszewski, Faith L Chang, Molly B Moravek, Min Xu, Vasantha Padmanabhan and Ariella Shikanov

Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding critical keys to understanding complex ovarian dynamics. Ovarian follicles, which are the functional units of the ovary, comprise the ovarian parenchyma, while the ovarian stroma thus refers to the inverse or the components of the ovary that are not ovarian follicles. The ovarian stroma includes more general components such as immune cells, blood vessels, nerves, and lymphatic vessels, as well as ovary-specific components including ovarian surface epithelium, tunica albuginea, intraovarian rete ovarii, hilar cells, stem cells, and a majority of incompletely characterized stromal cells including the fibroblast-like, spindle-shaped, and interstitial cells. The stroma also includes ovarian extracellular matrix components. This review combines foundational and emerging scholarship regarding the structures and roles of the different components of the ovarian stroma in normal physiology. This is followed by a discussion of key areas for further research regarding the ovarian stroma, including elucidating theca cell origins, understanding stromal cell hormone production and responsiveness, investigating pathological conditions such as polycystic ovary syndrome (PCOS), developing artificial ovary technology, and using technological advances to further delineate the multiple stromal cell types.

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Robert John Aitken, Diatsendoula Gregoratos, Leslie Kutzera, Emma Towney, Minjie Lin, Alexandra Wilkins and Zamira Gibb

MTT is widely used in biology as a probe for cell viability by virtue of its ability to generate deposits of insoluble formazan at sites of intense oxidoreductase activity. This response is generally held to reflect mitochondrial redox activity; however, extra-mitochondrial MTT reduction has also been recorded in certain cell types. Given this background, we set out to determine the major sites of formazan deposition in mammalian spermatozoa. In the mouse, most MTT reduction took place within the extensive mitochondrial gyres, with a single minor site of formazan deposition on the sperm head. By contrast, human spermatozoa generally displayed small disorganized midpieces exhibiting moderate MTT reduction activity accompanied by a major extra-mitochondrial formazan deposit on various locations in the sperm head from the neck to the anterior acrosome. Equine spermatozoa presented a combination of these two patterns, with major formazan deposition in the mitochondria accompanied by an extra-mitochondrial formazan deposit in around 20% of cells. The functionality of human spermatozoa was positively associated with the presence of an extra-mitochondrial formazan granule. Subsequent studies indicated that this extra-mitochondrial activity was suppressed by the presence of diphenylene iodonium, zinc, 2-deoxyglucose, co-enzyme Q, an SOD mimetic and NADPH oxidase inhibitors. We conclude that the pattern of MTT reduction to formazan by spermatozoa is species specific and conveys significant information about the relative importance of mitochondrial vs extra-mitochondrial redox activity that, in turn, defines the functional qualities of these cells.