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Among prostaglandins, Prostaglandin E2 (PGE2) (PGE2) is considered especially important for decidualization, ovulation, implantation and pregnancy. Four major PGE2 receptor subtypes, EP1, EP2, EP3, EP4, as well as peroxisome proliferator-activated receptors (PPARs), mediate various PGE2 effects via their coupling to distinct signaling pathways. This review summarizes up-to-date literatures on the role of prostaglandin E2 receptors in female reproduction, which could provide a broad perspective to guide further research in this field. PGE2 plays an indispensable role in decidualization, ovulation, implantation and pregnancy. However, the precise mechanism of Prostaglandin E2 (EP) receptors in the female reproductive system is still limited. More investigations should be performed on the mechanism of EP receptors in the pathological states, and the possibility of EP agonists or antagonists clinically used in improving reproductive disorders.

The TF (Thomsen–Friedenreich, CD176, Galβ1-3GalNAc) carbohydrate moiety is known as a specific oncofetal carbohydrate epitope present in fetal and neoplastic tissue as well as in stem cells. TF was demonstrated to mediate tumor-promoting features and to be highly immunogenic. The current study aimed to evaluate whether presence of the TF antigen is associated with clinico-pathological parameters and prognosis of early breast cancer (BC). Primary BC tissue (n = 226) was stained for TF using two monoclonal anti-TF antibodies (Nemod-TF1, Nemod-TF2). Staining results were correlated to clinical data including survival. Nemod-TF1 staining was positively correlated to lymph node metastasis (p = 0.03) and the presence of tumor-associated MUC1 (TA-MUC1; p = 0.003). Further, the presence of the Nemod-TF1 epitope predicted worse prognosis in TA-MUC1 positive (overall survival: p = 0.026) as well as in triple negative (overall survival: p = 0.002; distant metastasis-free survival: p = 0.012) BC. The data presented here further support a role of TF in BC tumor biology. Whether anti-TF directed treatment approaches may gain clinical relevance in those cases determined as triple negative or TA-MUC1 positive remains to be determined.

Summary Black tea is the most widely consumed tea drink in the world and has consistently been reported to possess anti-aging benefits. However, whether theaflavins, one type of the characteristic phytochemicals in black tea extracts, are involved in regulating aging and lifespan in consumers remains largely unknown. In this study, we show that theaflavins play a beneficial role in preventing age-onset intestinal leakage and dysbiosis, thus delaying aging in Drosophila. Mechanistically, theaflavins regulate the condensate assembly of Imd to negatively govern the overactivation of Imd signals in fruit fly intestines. In addition, theaflavins prevent DSS-induced colitis in mice, suggesting theaflavins play a role in modulating intestinal integrity. Overall, our study reveals a molecular mechanism by which theaflavins regulate gut homeostasis likely through controlling Imd coalescence., Graphical abstract, Highlights • Theaflavins extend Drosophila lifespan and increase climbing ability • Theaflavins prevent age-onset microbiota dysbiosis and intestinal leakage • Theaflavins downregulate Imd signals maybe through controlling Imd condensation • Theaflavins alleviate DSS-induced colitis in CD-1 mice, Animal Physiology; Molecular Biology; Immunology

Tea, made from leaves of Camellia sinensis, has long been consumed worldwide for its unique taste and aroma. Terpenoids play important roles not only in tea beverage aroma formation, but also in the productivity and quality of tea plantation due to their significant contribution to light harvesting pigments and phytohormones. To date, however, the regulation of terpenoid synthase genes remains unclear. Herein, the analyses of metabolomics, sRNAs, degradome, and transcriptomics were performed and integrated for identifying key regulatory miRNA-target circuits on terpenoid biosynthesis in leaf tissues over five different months in which the amount of terpenoids in tea leaves varies greatly. Four classes of miRNA-TF pairs that might play a central role in the regulation of terpenoid biosynthesis were also uncovered. Ultimately, a hypothetical model was proposed that mature miRNAs maintained by light regulator at both the transcriptional and posttranscriptional levels negatively regulate the targets to control terpenoid biosynthesis.

Terpenoid volatiles are major contributors to the floral odors and are responsible for the sensory quality of teas. However, little is known about the global regulation of various networks to achieve high terpenoids production in tea leaves. Here, metabolomics and transcriptome profiles were obtained from the tea leaves harvested in five different months. Our results showed that most sesquiterpene contents were lowest when sampled in April, increased markedly in June, and declined in August, September and October. An opposite accumulation pattern was observed in the majority of monoterpenes, and similar accumulation patterns were shared among a subset of sesquiterpenes and monoterpenes. We further found expression patterns of many genes in MVA pathway strongly correlated with the accumulation of some monoterpenes; as well, expression profiles of MEP pathway genes were closely associated with a few sesquiterpenes. A crosstalk regulatory network was constructed using co-expression analysis, and 13 transcription factors genes, with possible crucial roles in the regulation of terpene metabolism, were uncovered in the network. Additionally, CsOCS2, one key gene involved in terpenoid biosynthesis was functionally characterized in vitro. These results suggest that there might be crosstalk and competition for substrates between the down-stream monoterpenes and sesquiterpenes biosynthesis, which endow tea with its unique aroma, during different growth months.

// Junyan Zhu 1, 2 , Fabian Trillsch 1 , Doris Mayr 3 , Christina Kuhn 1 , Martina Rahmeh 1 , Simone Hofmann 1 , Marianne Vogel 1 , Sven Mahner 1 , Udo Jeschke 1 and Viktoria von Schonfeldt 4 1 Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany 2 Department of Gynecology and Obstetrics, Shanghai Jiao Tong University, School of Medicine, Renji Hospital, Shanghai, China 3 Department of Pathology, University Hospital, LMU Munich, Munich, Germany 4 Division of Gynecological Endocrinology and Reproductive Medicine, Department of Gynecology and Obstetrics, University Hospital, LMU Munich, Munich, Germany Correspondence to: Fabian Trillsch, email: Fabian.Trillsch@med.uni-muenchen.de Keywords: prostaglandin receptor EP3; endometrial cancer; prognosis; estrogen receptor β; Ras Received: May 23, 2017 Accepted: November 16, 2017 Published: December 09, 2017 ABSTRACT Background: Prostaglandin E2 (PGE2) receptor 3 (EP3) regulates tumor cell proliferation, migration, and invasion in numerous cancers. The role of EP3 as a prognostic biomarker in endometrial cancer remains unclear. The primary aim of this study was to analyze the prognostic significance of EP3 expression in endometrial cancer. Methods: We analyzed the EP3 expression of 140 endometrial carcinoma patients by immunohistochemistry. RL95-2 endometrial cancer cell line was chosen from four endometrial cancer cell lines (RL95-2, Ishikawa, HEC-1-A, and HEC-1-B) according to EP3 expression level. Treated with PGE2 and EP3 antagonist, RL95-2 cells were investigated by MTT, BrdU, and wound healing assay for functional assessment of EP3. Results: EP3 staining differed significantly according to WHO tumor grading in both whole cohort (p = 0.01) and the subgroup of endometrioid carcinoma (p = 0.01). Patients with high EP3 expression in their respective tumors had impaired progression-free survival as well as overall survival in both cohorts above. EP3 expression in the overall cohort was identified as an independent prognostic marker for progression-free survival (HR 1.014, 95%CI 1.003-1.024, p = 0.01) when adjusted for age, stage, grading, and recurrence. Treatment with EP3 antagonists induced upregulation of estrogen receptor β and decreased activity of Ras and led to attenuated proliferation and migration of RL95-2 cells. Conclusions: EP3 seems to play a crucial role in endometrial cancer progression. In the context of limited systemic treatment options for endometrial cancer, this explorative analysis identifies EP3 as a potential target for diagnostic workup and therapy.

Flavonoids are the major class of characteristic secondary compounds in Camellia sinensis that affect quality of tea. However, the temporal variation and the underlying regulatory mechanism of flavonoid biosynthesis during different growth months require a further investigation. Here, we combined analyses of the metabolomics and transcriptomics to tea leaves freshly collected during five different months for a comprehensive understanding of flavonoid metabolism regulation in tea plants. Through loading plot analysis, significant changes in the contents of metabolites during growing months were discovered, and further co-expression and association analysis indicated that one flavone glycoside (naringenin-7-O-glucoside) and two flavonol glycosides (quercetin-3-O-galactoside and kaemferol-3-O-(6″-O-p-courmaroyl)-glucoside) were evaluated as growth markers, which may explain the high bitterness and astringency of August teas; additionally, the high levels of two flavan-3-ols (gallocatechin and catechin gallate) may contribute to the flavor formation of April tea. Meanwhile, multiple flavonoid-related structural genes, MYB and bHLH transcription factors exhibit specific expression patterns to modulate the biosynthesis of these key flavonoids. A co-expression regulatory sub-network was constructed based on profiles of differentially expressed genes; one CsbHLH and six transcription factors (three CsbHLHs and three CsMYBs) exhibited negative and positive roles in the regulation of flavonoid biosynthetic genes, respectively. Taken together, our results provide new insights into the regulation of principle flavonoids for unique flavor of tea regulated by many flavonoid-related structural genes and transcription factors during different growth months.

Background Alternative splicing (AS) regulates mRNA at the post-transcriptional level to change gene function in organisms. However, little is known about the AS and its roles in tea plant (Camellia sinensis), widely cultivated for making a popular beverage tea. Results In our study, the AS landscape and dynamics were characterized in eight tissues (bud, young leaf, summer mature leaf, winter old leaf, stem, root, flower, fruit) of tea plant by Illumina RNA-Seq and confirmed by Iso-Seq. The most abundant AS (~ 20%) was intron retention and involved in RNA processes. The some alternative splicings were found to be tissue specific in stem and root etc. Thirteen co-expressed modules of AS transcripts were identified, which revealed a similar pattern between the bud and young leaves as well as a distinct pattern between seasons. AS events of structural genes including anthocyanidin reductase and MYB transcription factors were involved in biosynthesis of flavonoid, especially in vegetative tissues. The AS isoforms rather than the full-length ones were the major transcripts involved in flavonoid synthesis pathway, and is positively correlated with the catechins content conferring the tea taste. We propose that the AS is an important functional mechanism in regulating flavonoid metabolites. Conclusion Our study provides the insight into the AS events underlying tea plant’s uniquely different developmental process and highlights the important contribution and efficacy of alternative splicing regulatory function to biosynthesis of flavonoids. Electronic supplementary material The online version of this article (10.1186/s12870-018-1497-9) contains supplementary material, which is available to authorized users.

Oxylipins, including jasmonic acid (JA) and volatiles, are important for signaling in plants, and these are formed by the lipoxygenase (LOX) enzyme family. There is a large gap in understanding of the underlying molecular basis of their roles in tea plants. Here, we identified 11 CsLOX genes from the tea plant (Camellia sinensis), and characterized their phylogeny, gene structure and protein features into three subclasses. We then examined their enzymatic activities, LOX expression and alternative splicing of transcripts during development and in response to abiotic or biotic stresses in tea plants. In vitro expressed protein assays showed that the CsLOX2, 3 and 9 enzymatically function to produce 9/13-HPOT, 13-HPOT and 9-HPOT, respectively. CsLOX2 and CsLOX9 green fluorescent protein (GFP) fusion proteins localized to chloroplasts and the cytoplasm, respectively. RNA sequencing, quantitative reverse transcription-PCR and Northern blot analysis suggested that CsLOX5, 6 and 9 were predominantly expressed in seeds, flowers and roots, respectively. CsLOX2, 3, 4, 6 and 7 were up-regulated after attack by the insect Ectropis oblique, while CsLOX1 was induced after infection with the pathogen Glomerella cingulata. CsLOX3, 7 and 10 were up-regulated by JA but not ABA or salicylic acid. Long-term cold stress down-regulated CsLOX expression while a short duration of cold induced the expression of CsLOX1, 6 and 7. Alternatively spliced transcripts of six CsLOX genes were dynamically regulated through time and varied in relative abundances under the investigated stresses; we propose a mechanism of competing or compensating regulation between isoforms. This study improves our understanding of evolution of LOXs and regulation of their diverse functions in plants.

Prostaglandin E2 (PGE2) is well described to be associated with both endometrial functions and disorders. The primary aim of this study was to explore the underlying mechanisms that affect the growth and function of endometrial epithelium and stroma by assessing the staining intensity of PGE2 receptors (EP) in healthy endometrium across the menstrual cycle and in pathological endometrium, such as ovarian endometriosis and endometrial cancer. We retrospectively analyzed the EPs staining intensity in human nonpregnant endometrium throughout the menstrual cycle by immunohistochemistry and further focused on EP1 (n = 42). The variation of EP1 was compared among healthy endometrium, ovarian endometriosis (n = 14), and endometrial cancer (n = 140) crosswise. EP1 presented cyclical changes with increased intensity in both epithelium and stroma during the proliferative phase. EP1 staining in the epithelium was increased in endometriotic tissue compared to healthy endometrium and tumor tissue, while in the stroma, the staining in the tumor was lower than that in both normal tissue and endometriosis. No significant differences in EP1 intensity were detected for histological, stage, grading, metastatic and recurrent subtypes in endometrial cancer. EP1 was also correlated with neither progression-free survival nor overall survival of patients with cancer. EP1 staining in progesterone receptor B (PRB)-positive tumor was stronger compared to PRB-negative tumor. EP1 may play a role in human endometrial physiology and pathology. Further studies on the effect of EP1 on human endometrium are needed.

Characteristic secondary metabolites, including flavonoids, theanine and caffeine, are important components of Camellia sinensis, and their biosynthesis has attracted widespread interest. Previous studies on the biosynthesis of these major secondary metabolites using next-generation sequencing technologies limited the accurately prediction of full-length splice isoforms. Herein, we applied single-molecule sequencing to pooled tea plant tissues, to provide a more complete transcriptome of Camellia sinensis. Moreover, we identified 94 full-length transcripts and four alternative splicing events for enzyme-coding genes involved in the biosynthesis of flavonoids, theanine and caffeine. According to the comparison between long-read isoforms and assemble transcripts, we improved the quality and accuracy of genes sequenced by short-read next-generation sequencing technology. The resulting full-length transcripts, together with the improved assembled transcripts and identified alternative splicing events, enhance our understanding of genes involved in the biosynthesis of characteristic secondary metabolites in Camellia sinensis.

Normal pregnancy is a state of hypercoagulability with diminishing fibrinolytic activity, which is mainly caused by an increase of plasminogen activator inhibitor type 1 (PAI-1). PAI-1 is the main inhibitor of plasminogen activators, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). In human placentas, PAI-1 is expressed in extravillous interstitial trophoblasts and vascular trophoblasts. During implantation and placentation, PAI-1 is responsible for inhibiting extra cellular matrix (ECM) degradation, thereby causing an inhibition of trophoblasts invasion. In the present study, we have reviewed the literature of various reproductive diseases where PAI-1 plays a role. PAI-1 levels are increased in patients with recurrent pregnancy losses (RPL), preeclampsia, intrauterine growth restriction (IUGR), gestational diabetes mellitus (GDM) in the previous pregnancy, endometriosis and polycystic ovary syndrome (PCOS). In general, an increased expression of PAI-1 in the blood is associated with an increased risk for infertility and a worse pregnancy outcome. GDM and PCOS are related to the genetic role of the 4G/5G polymorphism of PAI-1. This review provides an overview of the current knowledge of the role of PAI-1 in reproductive diseases. PAI-1 represents a promising monitoring biomarker for reproductive diseases and may be a treatment target in the near future.

Chromatin remodeling alters gene expression in carcinoma tissue. Although cervical cancer is the fourth most common cancer in women worldwide, a systematic study about the prognostic value of specific changes in the chromatin structure, such as histone acetylation or histone methylation, is missing. In this study, the expression of histone H3 acetyl K9, which is known to denote active regions at enhancers and promoters, and histone H3 tri methyl K4, which preferentially identifies active gene promoters, were examined as both show high metastatic potential. A panel of patients with cervical cancer was selected and the importance of the histone modifications concerning survival-time (overall survival and relapse-free survival) was analyzed in 250 cases. Histone H3 acetyl K9 staining was correlated with low grading, low FIGO (TNM classification and the International Federation of Gynecology and Obstetrics) status, negative N-status and low T-status in cervical cancer, showing a higher expression in adenocarcinoma than in squamous cell carcinoma. Cytoplasmic expression of histone H3 tri methyl K4 in a cervical cancer specimen was correlated with advanced T-status and poor prognosis. While cytoplasmic H3K4me3 expression seemed to be a marker of relapse-free survival, nuclear expression showed a correlation to poor prognosis in overall survival. Within this study, we analyzed the chemical modification of two histone proteins that are connected to active gene expression. Histone H3 acetyl K9 was found to be an independent marker of overall survival. Histone H3 tri methyl K4 was correlated with poor prognosis and it was found to be an independent marker of relapse-free survival. Therefore, we could show that chromatin remodeling plays an important role in cervical cancer biology.