Explore the vast range of titles available.

Micro-RNAs (miRNAs) are short non-coding single-stranded RNAs that modulate the expression of various target genes after transcription. The expression and distribution of kinds of miRNAs have been characterized in human placenta during different gestational stages. The identified miRNAs are recognized as key mediators in the regulation of placental development and in the maintenance of human pregnancy. Aberrant expression of miRNAs is associated with compromised pregnancies in humans, and dysregulation of those miRNAs contributes to the occurrence and development of related diseases during pregnancy, such as pre-eclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), recurrent miscarriage, preterm birth (PTB) and small-for-gestational-age (SGA). Thus, having a better understanding of the expression and functions of miRNAs in human placenta during pregnancy and thereby developing novel drugs targeting the miRNAs could be a potentially promising method in the prevention and treatment of relevant diseases in future. Here, we summarize the current knowledge of the expression pattern and function regulation of miRNAs in human placental development and related diseases.

The Hedgehog (HH) signaling is one of the key agents that govern the precisely regulated developmental processes of multicellular organisms in vertebrates and invertebrates. The HH pathway in the receiving cell includes Patched1, a twelve-pass transmembrane receptor, and Smoothened, a seven-transmembrane G-protein coupled receptor (GPCR), and the downstream GLI family of three transcriptional factors (GLI1-GLI3). Mutations of HH gene and the main components in HH signaling are also associated with numerous types of diseases. Before secretion, the HH protein undergoes post-translational cholesterol modification to gain full activity, and cholesterol is believed to be essential for proper HH signaling transduction. In addition, results from recent studies show the reciprocal effect that HH signaling functions in cholesterol metabolism as well as in cholesterol homeostasis, which provides feedback to HH pathway. Here, we hope to provide new insights into HH signaling function by discussing the role of cholesterol in HH protein maturation, secretion and HH signaling transduction, and the potential role of HH in regulation of cholesterol as well.

Background Insufficient migration and invasion during trophoblast epithelial-mesenchymal transition (EMT) results in the occurrence and development of preeclampsia (PE), and our previous study has screened 52 miRNAs, whose expression levels are altered in the placental samples from PE patients, compared with the normal group. Among those, miR-3935 is one of the miRNAs being most significantly down-regulated, indicating its involvement in PE. However, the exact effect and molecular mechanisms remain unknown. Methods In the present study, we investigate the roles and underlying mechanisms of miR-3935 in trophoblast EMT by use of the human extra-villous trophoblast cell line HTR-8/SVneo as well as human placental tissues and maternal blood samples obtained from 15 women with normal pregnancies and 15 women with PE. Experimental methods include transfection, quantitative reverse transcription-PCR (qRT-PCR), western blot, immunofluorescence staining, dual-luciferase assays, in vitro invasion and migration assays, RNA-Seq analysis, bisulfite sequencing and immunohistochemistry staining. Results MiR-3935 expression is significantly decreased in both placentas and peripheral blood specimens of PE, and functionally, miR-3935 promotes EMT of trophoblast cells. Mechanistically, TRAF6 is identified to be a direct target of miR-3935 and TRAF6 exerts its negative effect on EMT of trophoblast cells by inhibition of RGS2, which down-regulates the methylation status of promoter of CDH1 gene that encodes E-Cadherin protein through induction of ALKBH1, resulting in increase of E-Cadherin and subsequently insufficient trophoblast EMT. Conclusions Together these results uncover a hitherto uncharacterized role of miR-3935/TRAF6/RGS2 axis in the function of human trophoblasts, which may pinpoint the molecular pathogenesis of PE and may be a prognostic biomarker and therapeutic target for such obstetrical diseases as PE.

Background Ovarian cancer (OC) progression is one of the commonest cause of female cancer death. While treatments in clinic includes primary surgery and targeted chemotherapy, curative and survival trends in OC have not significantly improved. Thus, further investigation of the mechanisms regarding OC carcinogenesis and discovery of novel targets is of great importance. Methods Human ovarian tissue specimens, RNA sequencing, GEPIA database and bioinformatics analyses were used to analyze the gene correlation, and to identify and validate potential downstream candidates. The biological effects of GPR137-RAB8A-Hedgehog(HH) were investigated using in vitro and in vivo models and methods including qRT-PCR, RNA stability assay, RNA immunoprecipitation assay, GLI-luciferase reporter assay, nucleo-cytoplasmic separation assay, membrane-cytoplasmic separation assay, western blot, co-immunoprecipitation, immunofluorescence staining, cell counting kit-8 assay, wound healing assay, matrigel invasion assay, colony formation assay, xenografts assay, in situ transplantation tumor model of ovarian cancer in nude mice, and immunohistochemistry staining. Results GPR137 expression was significantly higher in collected clinical OC tissues, compared with the adjacent normal tissues. Consistently, suppression of GPR137 inhibited human SK-OV-3 and A2780 OC cell proliferation, migration, invasion, and colony formation, whereas overexpression of GPR137 in human OC HO8910 cell exerted the opposite effects on cell biological behaviors. Mechanistically, RAB8A was identified as a downstream target of GPR137 , and GPR137 promotes RAB8A expression by promoting RAB8A mRNA stability. By RNA-sequencing and experiments in vitro using multiple ovarian cancer cell models as well as in vivo using subcutaneous xenografts assay and in situ transplantation ovarian cancer model in nude mice, we further demonstrated that RAB8A positively mediated OC progression through activating HH signaling pathway by disassociating the protein–protein complex formation of GLI and SuFu (Suppressor of Fused), which reciprocally enhanced GPR137 activity, forming a regulation loop between HH signaling and GPR137. Conclusions Collectively, this study depicts the role of GPR137-RAB8A-HH cascade in the development of OC, deepening our understanding of tumor biomechanics regarding OC progression and providing novel targets for OC therapy in future.

As the fifth most common cancer in the world, gastric cancer (GC) ranks as the third major cause of cancer-related death globally. Although surgical resection and chemotherapy still remains the mainstay of potentially curative treatment for GC, chemotherapy resistance and adverse side effects limit their clinical applications. Thus, further investigation of the mechanisms of carcinogenesis in GC and discovery of novel biomarkers is of great concern. We herein report that the elevated expression of GPR137 is correlated with GC. Overexpression of GPR137 potentiates human gastric cancer AGS cell malignancy, including proliferation, migration, invasion, colony formation and xenograft growth in nude mice in vivo, whereas knockout of GPR137 by CRISPR/Cas9 gene editing exerts the opposite effects. Mechanistically, GPR137 could bind to MST, the upstream kinases in Hippo pathway, which disrupts the association of MST with LATS, subsequently activating the transcriptional co-activators, YAP and TAZ, and thereby triggering the target transcription and the alterations in GC cell biological actions consequently. Therefore, our findings may provide with the evidence of developing a potentially novel treatment method with specific target for GC.

Production of estradiol (E2) by the placenta during human pregnancy ensures successful maintenance of placental development and fetal growth by stimulating trophoblast proliferation and the differentiation of cytotrophoblasts into syncytiotrophoblasts. Decreased levels of E2 are closely associated with obstetrical diseases such as preeclampsia (PE) in the clinic. However, the mechanisms underlying the inhibition of placental E2 biosynthesis remain poorly understood. Here, we report that regulator of G-protein signaling 2 (RGS2) affects E2 levels by regulating aromatase, a rate-limiting enzyme for E2 biosynthesis, by using human trophoblast-derived JEG-3 cells and human placental villus tissues. RGS2 enhanced the protein degradation of the transcription factor heart and neural crest derivatives expressed 1 (HAND1) by suppressing ubiquitin-specific protease 14 (USP14)-mediated deubiquitination of HAND1, resulting in the restoration of HAND1-induced trans-inactivation of the aromatase gene and subsequent increases in E2 levels. However, aromatase bound to RGS2 and repressed RGS2 GTPase activating protein (GAP) activity. Moreover, we observed a positive correlation between RGS2 and aromatase expression in clinical normal and preeclamptic placental tissues. Our results uncover a hitherto uncharacterized role of the RGS2-aromatase axis in the regulation of E2 production by human placental trophoblasts, which may pinpoint the molecular pathogenesis and highlight potential biomarkers for related obstetrical diseases. Reproduction: a placental pathway to pre-eclampsia Pre-eclampsia can arise from mutations that affect the production of estradiol, a hormone with a critical role in sustaining the placenta during fetal development. Roughly one in 20 pregnancies are affected by this complication, which can put both mother and child at risk and typically manifests as high blood pressure and elevated levels of protein in the urine. The causes of pre-eclampsia are poorly understood, but Chao Tang of Zhejiang University School of Medicine, Hangzhou, China, and colleagues have now linked this condition to defective hormone synthesis. Working with cultured human cells and mouse models, they showed that mutations in a gene called RGS2 disrupt expression of an enzyme that produces estradiol in the placenta. The researchers also determined that RGS2 expression is consistently lower in placentas from mothers with pre-eclampsia than from unaffected mothers.

Preeclampsia (PE), a pregnancy-specific syndrome with the major molecular determinants of placenta-borne oxidative stress and consequently impaired nitric oxide (NO) generation, has been considered to be one of the leading causes of maternal morbidity as well as mortality and preterm delivery worldwide. Several medical conditions have been found to be associated with increased PE risk, however, the treatment of PE remains unclear. Here, we report that Tianma Gouteng Decoction (TGD), which is used clinically for hypertension treatment, regulates oxidative stress and NO production in human extravillous trophoblast-derived TEV-1 cells. In human preeclamptic placental explants, reactive oxygen species (ROS) levels were elevated and NO production was inhibited, while TGD treatment at different periods effectively down-regulated the H 2 O 2 -induced ROS levels and significantly up-regulated the H 2 O 2 -suppressed NO production in human TEV-1 cells. Mechanistically, TGD enhanced the activity of total nitric oxide synthase (TNOS), which catalyze L-arginine oxidation into NO, and simultaneously , TGD promoted the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), two isoforms of nitric oxide synthetases (NOS) in human placenta, resulting in the increased NO generation. More importantly, TGD administration not only increased the weight gain during pregnancy and revealed a hypotensive effect, but also improved the placental weight gain and attenuated fetal growth restriction in an NG-nitro-L-arginine methyl ester (L-NAME)-induced mouse PE-like model. Our results thereby provide new insights into the role of TGD as a potentially novel treatment for PE.

Polarization smoothing can effectively improve the uniformity of focal spots. In this study, we theoretically and experimentally investigated the polarization synthesis of the focal spot under a birefringent wedge (BW) and speckle under the coupling of the BW and continuous phase plate. Polarization distribution was experimentally obtained using rotating quarter-wave plate measurement under a specific wedge angle. The simulated and experimental results are consistent, demonstrating that the focal spot is in a state of coexistence of elliptical and linear polarizations. In addition, the polarization state is determined by the ratio of the amplitudes and the phase difference between the sub-beams. The simulation results showed that the proportion of linear polarization increased with the separation angle of the sub-beam. In contrast, it decreased with the incident light aperture. This research is crucial for accurately describing the polarization distribution and further understanding the laser–plasma interactions.

Background Heterologous expression in Streptomyces provides a platform for mining natural products (NPs) encoded by cryptic biosynthetic gene clusters (BGCs) of bacteria. The BGCs are first engineered in hosts with robust recombineering systems, such as Escherichia coli , followed by expression in optimized heterologous hosts, such as Streptomyces , with defined metabolic backgrounds. Results We developed a highly efficient heterologous expression platform, named Micro-HEP ( micro bial h eterologous e xpression p latform), that uses versatile E. coli strains capable of both modification and conjugation transfer of foreign BGCs and optimized chassis Streptomyces strain for expression. The stability of repeat sequences in these E. coli strains was superior to that of the commonly used conjugative transfer system E. coli ET12567 (pUZ8002). For optimizing expression of foreign BGCs, the chassis strain S. coelicolor A3(2)-2023 was generated by deleting four endogenous BGCs followed by introducing multiple recombinase-mediated cassette exchange (RMCE) sites in the S. coelicolor A3(2) chromosome. Additionally, modular RMCE cassettes (Cre-lox, Vika-vox, Dre-rox, and phiBT1-attP) were constructed for integrating BGCs into the chassis strain. Micro-HEP was tested using BGCs for the anti-fibrotic compound xiamenmycin and griseorhodins. Two to four copies of the xim BGC were integrated by RMCE, with increasing copy number associated with increasing yield of xiamenmycin. The grh BGC was also efficiently expressed, and the new compound griseorhodin H was identified. Conclusion We demonstrated that our Micro-HEP system enables the efficient expression of foreign BGCs, facilitating the discovery of new NPs and increasing yields. Graphical Abstract

In this study, a Bacillus velezensis SDU strain capable of producing poly-γ-glutamate (γ-PGA) was newly identified from the rhizosphere soil of Baimiao taro. The strain is a glutamate-independent strain and can produce polyglutamic acid in a culture medium completely free of glutamate. The hydrolyzed product of the polyglutamic acid produced is D-glutamic acid. The molecular weight of γ-PGA, estimated via the Mark–Houwink equation, was 1390 kDa. Furthermore, the molecular weight measured by Waters gel permeation chromatography with multi-angle laser light scattering (GPC–MALLS) was 1167 kDa. The production of γ-PGA and its antioxidant and tyrosine inhibition properties were investigated. The γ-PGA production reached 23.1 g/L, and the productivity was 0.77 g L−1 h−1. Specifically, γ-PGA exhibited superoxide anion (·O2−) radical scavenging activity and tyrosinase inhibitory activity. This study introduces a promising strain and a highly efficient application method for γ-PGA, which can be broadly utilized in the pharmaceutical, food, and cosmetic industries.