Search

Abstract Background Colorectal cancer (CRC) is a prevalent malignancy worldwide, with increasing incidence and mortality rates. Although treatment options have improved, CRC remains a leading cause of death due to metastasis. Early intervention can significantly improve patient outcomes, making it crucial to understand the molecular mechanisms underlying CRC metastasis. In this study, we performed bioinformatics analysis to identify potential genes associated with CRC metastasis. Methods We downloaded and integrated gene expression datasets (GSE89393, GSE100243, and GSE144259) from GEO database. Differential expression analysis was conducted, followed by Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The hub gene SERPINA3 was selected for further in vitro functional studies. Additionally, the role of miR-137-3p/miR-296-5p/ Serpin family A member 3 (SERPINA3) in CRC cell function was investigated using in vitro assays. Results Analysis of the gene expression datasets revealed differentially expressed genes (DEGs) associated with CRC metastasis. GO analysis showed enrichment in biological processes such as blood coagulation regulation and wound healing. Cellular component analysis highlighted extracellular matrix components and secretory granules. Molecular function analysis identified activities such as serine-type endopeptidase inhibition and lipoprotein receptor binding. KEGG analysis revealed involvement in pathways related to complement and coagulation cascades, cholesterol metabolism, and immune responses. The common DEGs among the datasets were further investigated. We identified SERPINA3 as a hub gene associated with CRC metastasis. SERPINA3 exerted enhanced effects on migration, proliferation and epithelial-mesenchymal transition (EMT) and inhibitory effects on caspase-3/-9 activities in HT29 and SW620 cells. MiR-137-3p overexpression increased activities of caspase-3/-9, decreased migration and proliferation, and also repressed EMT in HT29 cells, which were obviously attenuated by SERPINA3 enforced overexpression. Consistently, SERPINA3 enforced overexpression also largely reversed miR-296-5p mimics-induced increased in activities of caspase-3/-9, decrease in migration, proliferation and EMT in HT29 cells. Conclusion Through bioinformatics analysis, we identified potential genes associated with CRC metastasis. The functional studies focusing on SERPINA3/miR-137-3p/miR-296-5p further consolidated its role in regulating CRC progression. Our findings provide insights into novel mechanisms underlying CRC metastasis and might contribute to the development of effective treatment strategies. However, the role of SERPINA3/miR-137-3p/miR-296-5p signaling in CRC still requires further investigation.

Trade-in (TON) and trade-old-for-remanufactured (TOR) programs are commonly used to boost consumer demand and recycle old products, and can generate significant economic benefits from disassembling or reusing old products. However, the influence of channel structures on the TON and TOR optimal decisions of closed-loop supply chains (CLSCs) is rarely discussed. To explore the impact of the implementation of the TOR program on the optimal pricing and demand strategy, enterprise profit, environment, and social welfare when the enterprise has applied the TON program, we develop four models with different power structures and market decisions to maximize enterprise profits based on consumer utility and the Stackelberg game: (1) manufacturer-led model with TON (Model M); (2) retailer-led model with TON (Model R); (3) manufacturer-led model with TON and TOR (Model TM); (4) retailer-led model with TON and TOR (Model TR). The manufacturer-led models may benefit consumers more and stimulate the replacement consumers’ demand for TON and TOR programs. Both TON and TOR demand for the Model TM are considerable. However, when the retailer is in the driver’s seat, the retailer can profit more due to government subsidies for the TOR programs. Our analysis provides insights into the choice of corporate power structures, reducing environmental impacts and improving social welfare. This paper studies for the first time the influence of different power structures and government subsidies on TON and TOR programs in CLSCs. Future research could consider the impact of old products quality or multi-period models on TON and TOR programs.

Abstract Background Chronic pelvic pain (CPP) is a common symptom of endometriosis. Women with endometriosis are also at a high risk of suffering from anxiety, depression, and other psychological disorders. Recent studies indicate that endometriosis can affect the central nervous system (CNS). Changes in the functional activity of neurons, functional magnetic resonance imaging signals, and gene expression have been reported in the brains of rat and mouse models of endometriosis. The majority of the studies thus far have focused on neuronal changes, whereas changes in the glial cells in different brain regions have not been studied. Methods Endometriosis was induced in female mice (45-day-old; n = 6–11/timepoint) by syngeneic transfer of donor uterine tissue into the peritoneal cavity of recipient animals. Brains, spines, and endometriotic lesions were collected for analysis at 4, 8, 16, and 32 days post-induction. Sham surgery mice were used as controls (n = 6/timepoint). The pain was assessed using behavioral tests. Using immunohistochemistry for microglia marker ionized calcium-binding adapter molecule-1 (IBA1) and machine learning “Weka trainable segmentation” plugin in Fiji, we evaluated the morphological changes in microglia in different brain regions. Changes in glial fibrillary acidic protein (GFAP) for astrocytes, tumor necrosis factor (TNF), and interleukin-6 (IL6) were also evaluated. Results We observed an increase in microglial soma size in the cortex, hippocampus, thalamus, and hypothalamus of mice with endometriosis compared to sham controls on days 8, 16, and 32. The percentage of IBA1 and GFAP-positive area was increased in the cortex, hippocampus, thalamus, and hypothalamus in mice with endometriosis compared to sham controls on day 16. The number of microglia and astrocytes did not differ between endometriosis and sham control groups. We observed increased TNF and IL6 expression when expression levels from all brain regions were combined. Mice with endometriosis displayed reduced burrowing behavior and hyperalgesia in the abdomen and hind-paw. Conclusion We believe this is the first report of central nervous system-wide glial activation in a mouse model of endometriosis. These results have significant implications for understanding chronic pain associated with endometriosis and other issues such as anxiety and depression in women with endometriosis. Graphical Abstract

The landscape diversity index (LDI) is an important level in biodiversity conservation, and its scale dependence has an important role in regional landscape planning and biological conservation. The aim of this study is to analyze in depth the effects of spatial scale changes in the classification of different landscape components on LDI and to explore the thresholds of LDI. The classification of landscape components was accomplished in the ArcMap environment using fusion and merging tools, and the LDI thresholds and scale changes were quantitatively assessed by LDI values. The results show that there are differences in LDI values for different classifications, and the threshold for LDI without considering scale changes can be interpreted as: 0.4215 ≤ LDI ≤ 1.9754. The grain sizes suitable for landscape diversity analysis are 160m and 1280 m, and the effective amplitude range of the I, II and III land type is 9~31 km, while the effective amplitude of three land use types is 20∼31 km, relatively lagging behind. However, when considering amplitude changes, the LDI threshold can be interpreted as 0.3027 ≤ LDI ≤ 2.0947, which is suitable for large-scale regional landscape diversity studies when the grain size is large. In conclusion, the essence of landscape diversity change with scale is caused by changes in the number and area of landscape components, and the threshold analysis should not only take into account the grain size and amplitude, but also consider the landscape background of the study area.

Soil water–salt variations at different spatiotemporal scales and their influencing factors are essential for regional vegetation restoration and management. However, the study of soil water–salt of the alpine area has not taken into account the effect of topography, especially in the long time series. This work investigated the spatiotemporal characteristics of water and salt in topsoil from 2000 to 2021, using regression analysis of on-site data and MODIS products. The heterogeneity and trends of soil water–salt in various topographic factors (elevation, slope, and aspect) were also explored by selecting the maximum area of each gradient factor as the constrained condition with the help of ArcGIS software. The results revealed that 1) the models applied to SWC (soil water content), EC (electrical conductivity), and pH utilizing vegetation indices were suitable for estimating the spatiotemporal variations of soil water–salt. 2) Soil water–salt exhibited local aggregation characteristics with an upward trend in SWC and a downward trend in EC and pH as a whole. 3) Mean annual SWC peaked at 3,400–3,800 m with increasing elevation and trended downward with increasing slope. The aspect of mean annual SWC was characterized by lower values in the southwest and south and higher values in the north, while the results for pH were reversed. The slope had a greater influence on EC than on SWC and pH. 4) The trend change of SWC, EC, and pH fluctuated at 2000–2,400 m and >4,600 m with a clear inflection point at 4°–8° and 20°–24°, respectively. In summary, the effects of topography responded to the distribution and trends of soil water–salt. The results have significant implications for implementing ecological improvements in regions with complicated topography and can serve as a reference for formulating future ecological policies.

There are many participating companies involved in the supply chain system. In order to achieve multi-enterprise, multi-resource-oriented service product information sharing, it is necessary to have the ability to match transactions in a highly credible environment. In the current supply chain system, the core enterprise generally builds a centralized supply chain resource-sharing platform to realize knowledge sharing, and the security of the system completely depends on the core enterprise. In addition, the cost of trust establishment is very high. It is urgent to establish a reasonable trust mechanism. On this basis, the factors affecting knowledge sharing and the problems to solve are analyzed, and the plan and factors of using blockchain technology to build a knowledge-sharing platform are proposed. Finally, the conceptual model of the blockchain-based knowledge-sharing platform is designed, and its business process and economic model are emphasized to provide ideas for breaking through the bottleneck of the supply chain system.

The plant-specific SHI-related sequence (SRS) family of transcription factors plays a vital role in growth regulation, plant development, phytohormone biosynthesis, and stress response. However, the genome-wide identification and role in the abiotic stress-related functions of the SRS gene family were not reported in white sweet clover (Melilotus albus). In this study, nine M. albus SRS genes (named MaSRS01-MaSRS09) were identified via a genome-wide search method. All nine genes were located on six out of eight chromosomes in the genome of M. albus and duplication analysis indicated eight segmentally duplicated genes in the MaSRS family. These MaSRS genes were classified into six groups based on their phylogenetic relationships. The gene structure and motif composition results indicated that MaSRS members in the same group contained analogous intron/exon and motif organizations. Further, promoter region analysis of MaSRS genes uncovered various growth, development, and stress-responsive cis-acting elements. Protein interaction networks showed that each gene has both functions of interacting with other genes and members within the family. Moreover, real-time quantitative PCR was also performed to verify the expression patterns of nine MaSRS genes in the leaves of M. albus. The results showed that nine MaSRSs were up- and down-regulated at different time points after various stress treatments, such as salinity, low-temperature, salicylic acid (SA), and methyl jasmonate (MeJA). This is the first systematic study of the M. albus SRS gene family, and it can serve as a strong foundation for further elucidation of the stress response and physiological improvement of the growth functions in M. albus.

In the mammary gland, genetic circuits controlled by estrogen, progesterone, and prolactin, act in concert with pathways regulated by members of the epidermal growth factor family to orchestrate growth and morphogenesis during puberty, pregnancy and lactation. However, the precise mechanisms underlying the crosstalk between the hormonal and growth factor pathways remain poorly understood. We have identified the CUB and zona pellucida-like domain-containing protein 1 (CUZD1), expressed in mammary ductal and alveolar epithelium, as a novel mediator of mammary gland proliferation and differentiation during pregnancy and lactation. Cuzd1-null mice exhibited a striking impairment in mammary ductal branching and alveolar development during pregnancy, resulting in a subsequent defect in lactation. Gene expression profiling of mammary epithelium revealed that CUZD1 regulates the expression of a subset of the EGF family growth factors, epiregulin, neuregulin-1, and epigen, which act in an autocrine fashion to activate ErbB1 and ErbB4 receptors. Proteomic studies further revealed that CUZD1 interacts with a complex containing JAK1/JAK2 and STAT5, downstream transducers of prolactin signaling in the mammary gland. In the absence of CUZD1, STAT5 phosphorylation in the mammary epithelium during alveologenesis was abolished. Conversely, elevated expression of Cuzd1 in mammary epithelial cells stimulated prolactin-induced phosphorylation and nuclear translocation of STAT5. Chromatin immunoprecipitation confirmed co-occupancy of phosphorylated STAT5 and CUZD1 in the regulatory regions of epiregulin, a potential regulator of epithelial proliferation, and whey acidic protein, a marker of epithelial differentiation. Collectively, these findings suggest that CUZD1 plays a critical role in prolactin-induced JAK/STAT5 signaling that controls the expression of key STAT5 target genes involved in mammary epithelial proliferation and differentiation during alveolar development.

Endometriosis, defined as growth of the endometrial cells outside the uterus, is an inflammatory disorder that is associated with chronic pelvic pain and infertility in women of childbearing age. Although the estrogen-dependence of endometriosis is well known, the role of progesterone in development of this disease remains poorly understood. In this study, we developed a disease model in which endometriosis was induced in the peritoneal cavities of immunocompetent female mice, and maintained with exogenous estrogen. The endometriosis-like lesions that were identified at a variety of ectopic locations exhibited abundant blood supply and extensive adhesions. Histological examination revealed that these lesions had a well-organized endometrial architecture and fibrotic response, resembling those recovered from clinical patients. In addition, an extensive proliferation, inflammatory response, and loss of estrogen receptor alpha (ERα) and progesterone receptor (PR) expression were also observed in these lesions. Interestingly, administration of progesterone before, but not after, lesion induction suppressed lesion expansion and maintained ERα and PR expressions. These progesterone-pretreated lesions exhibited attenuation in KI67, CD31, and pro-inflammatory cytokine expression as well as macrophage infiltration, indicating that progesterone ameliorates endometriosis progression by inhibiting cell proliferation, inflammation and neovascularization. Our studies further showed that suppression of global DNA methylation by application of DNA methyltransferase inhibitor to female mice bearing ectopic lesions restrained lesion expansion and restored ERα and PR expression in eutopic endometrium and ectopic lesions. These results indicate that epigenetic regulation of target gene expression via DNA methylation contributes, at least in part, to progesterone resistance in endometriosis.

During placenta development, a succession of complex molecular and cellular interactions between the maternal endometrium and the developing embryo ensures reproductive success. The precise mechanisms regulating this maternal-fetal crosstalk remain unknown. Our study revealed that the expression of Rac1, a member of the Rho family of GTPases, is markedly elevated in mouse decidua on days 7 and 8 of gestation. To investigate its function in the uterus, we created mice bearing a conditional deletion of the Rac1 gene in uterine stromal cells. Ablation of Rac1 did not affect the formation of the decidua but led to fetal loss in mid gestation accompanied by extensive hemorrhage. To gain insights into the molecular pathways affected by the loss of Rac1, we performed gene expression profiling which revealed that Rac1 signaling regulates the expression of Rab27b, another GTPase that plays a key role in targeting vesicular trafficking. Consequently, the Rac1-null decidual cells failed to secrete vascular endothelial growth factor A, which is a critical regulator of decidual angiogenesis, and insulin-like growth factor binding protein 4, which regulates the bioavailability of insulin-like growth factors that promote proliferation and differentiation of trophoblast cell lineages in the ectoplacental cone. The lack of secretion of these key factors by Rac1-null decidua gave rise to impaired angiogenesis and dysregulated proliferation of trophoblast cells, which in turn results in overexpansion of the trophoblast giant cell lineage and disorganized placenta development. Further experiments revealed that RAC1, the human ortholog of Rac1, regulates the secretory activity of human endometrial stromal cells during decidualization, supporting the concept that this signaling G protein plays a central and conserved role in controlling endometrial secretory function. This study provides unique insights into the molecular mechanisms regulating endometrial secretions that mediate stromal-endothelial and stromal-trophoblast crosstalk critical for placenta development and establishment of pregnancy.

BackgroundEndometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development.Methods and findingsEpigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression.ConclusionsHAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.

The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2(d/d)), the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2(d/d) mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs) in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy.

Metagenomic sequencing of the microbial soil community was used to assess the effect of various nitrogen fertilizer treatments in combination with constant rice straw return to the soil in the tiller layer of Northeast China’s black paddy soil used for rice production. Here, we investigated changes in the composition, diversity, and structure of soil microbial communities in the soil treated with four amounts of nitrogen fertilizers (53, 93, 133, and 173 kg/ha) applied to the soil under a constant straw return of 7500 kg/ha, with a control not receiving N. The relationships between soil microbial community structure and soil physical and chemical properties were determined. The results showed that the available K content of the soil significantly (p < 0.05) increased in soil receiving the lowest N-fertilizer dose. When applied at high amounts, N-fertilizer changed the Chao1 and ACE indices of the soil microorganisms (p < 0.05), and the treatments resulted in significant differences in the β-diversity of the soil microorganisms. By NMDS analysis it was demonstrated that the treatment significantly affected the structure of the soil microbial communities. Redundancy analysis showed that the main physicochemical drivers behind these differences were total nitrogen, total potassium, ammonium nitrogen, total phosphorus, and available potassium. The soil microbial communities in the control treatment were negatively correlated with nitrate and ammonium nitrogen; the lowest N-fertilizer treatment produced positive correlations with total nitrogen, total potassium, and total phosphorus and negative correlations with ammonium nitrogen; the highest dose negatively correlated with total nitrogen, available potassium, available phosphorus, total phosphorus, and pH. This study showed that moderate N fertilizer application is an effective way to increase soil microbial diversity and improve soil quality. This experiment provides technical support for the application of the alternative fertilizer technology of straw return to the field and provides a theoretical basis for rational fertilization of paddy fields in a cold climate.

It has been found that the traditionally used electromagnetic wave instruments have limitations in detection depths, as well as a lack of directionality. Therefore, those types of instruments cannot meet the needs of geo-steering applications. However, azimuth electromagnetic wave instruments have shown the ability to quickly acquire effective geo-steering information using a tilt coil design method, which can potentially provide accurate guidance for decision-making in drilling direction adjustments. In this study, a design method for an azimuth electromagnetic wave detection instrument for underground coal mining was proposed. The relationships between the structural parameters of the instrument and installation angles of the coils and the response signals were obtained in this study using simulations. Then, by choosing reasonable instrument spacings, coil installation angles, and transmitting frequencies, the detection performances of the instrument were successfully improved. Also, the basic parameter selections of the proposed logging-while-drilling azimuth electromagnetic wave logging instrument were determined to be suitable for underground coal-mining purposes. It was also found that the symmetric compensation of the instrument was sensitive to the interface responses, and the anti-symmetric compensation was sensitive to the anisotropic responses. In addition, a method of detecting the interface positions and azimuth of coal-seam interfaces using azimuth electromagnetic waves, as well as the potential for the application of the instrument for the detection of low-resistivity anomalies in coal goafs, were effectively demonstrated. The results of this study provided theoretical references for future coal-seam boundary detections and explorations, and also added insight into the development processes of coal-seam bedding. [ABSTRACT FROM AUTHOR]

Glass fiber reinforced plastic (GFRP) composites have been applied to the manufacture of missile shields and unmanned aerial vehicle (UAV) shells. It is of great significance to explore the ablation characteristics of different lasers for these composites. Currently, most existing studies on the ablation characteristics of lasers for Glass fiber reinforced plastic composites are conducted under a single laser output mode, such as continuous wave (CW) laser or pulsed laser. However, the ablation characteristics of combined lasers for Glass fiber reinforced plastic composites have not been clarified. Therefore, the ablation characteristics of single lasers (continuous wave, millisecond (ms) pulsed, or nanosecond (ns) pulsed laser) and combined laser (CW/ms or CW/ns combined pulsed lasers) were investigated by experimental and simulation methods in this study. Additionally, the ablation mechanisms of Glass fiber reinforced plastic under different laser irradiation conditions were compared and analyzed. The results demonstrated that the ablation rates of single lasers for Glass fiber reinforced plastic composites were all within an order of magnitude of 10 μg/J, which was not significantly correlated with the light source system. The ablation efficiency of the single laser was determined by the incident laser energy. The continuous wave laser was found to be the optimal light source for the ablation and destruction of Glass fiber reinforced plastic composites. Nevertheless, there were some obstacles in the ablation process of continuous wave lasers. Applying pulsed lasers during the irradiation of the continuous wave laser may generate a synergistic effect. Under the conditions in this study, the CW/ns pulsed combined laser increased the ablation efficiency by 53.8%.

In the context of the new normal economy, the supply-side reform has become the main idea of a macroeconomic policy that stimulates economic growth. The economic development patterns of all enterprises need to be improved in the context of supply-side reform. One of the most important issues is the change in the supply chain of enterprises. In the supply chain, the integrated model problem of supply, manufacture, and sales is the most important research area in the supply chain. In this paper, an integrated model including suppliers, manufacturers, and distributors is established. This model contains linear equation of state and neural network nonlinear model. This paper presents the objective function and constraints of the supply chain, such as inventory cost, supply cost, production level and so on. For the integration model of supply chain, the simulated annealing method was used to optimize and the initial conditions were empirically analyzed on the background of Liaohua Company. [ABSTRACT FROM AUTHOR]

The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2d/d), the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2d/d mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs) in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy. [ABSTRACT FROM AUTHOR]

During pregnancy, progesterone inhibits the growth-promoting actions of estrogen in the uterus. However, the mechanism for this is not clear. The attenuation of estrogen-mediated proliferation of the uterine epithelium by progesterone is a prerequisite for successful implantation. Our study reveals that progesterone-induced expression of the basic helix-loop-helix transcription factor Hand2 in the uterine stroma suppresses the production of several fibroblast growth factors (FGFs) that act as paracrine mediators of mitogenic effects of estrogen on the epithelium. In mouse uteri lacking Hand2, continued induction of these FGFs in the stroma maintains epithelial proliferation and stimulates estrogen-induced pathways, resulting in impaired implantation. Thus, Hand2 is a critical regulator of the uterine stromal-epitheliat communication that directs proper steroid regulation conducive for the establishment of pregnancy. [ABSTRACT FROM AUTHOR]

Phosphorus (P) is an important nutrient affecting nodulation and nitrogen fixation in soybeans. To further investigate the relationship of phosphorus with soybean nodulation and nitrogen fixation, the seedling grafting technique was applied in this study to prepare dual-root soybean systems for a sand culture experiment. From the unfolded cotyledon stage to the initial flowering stage, one side of each dual-root soybean system was irrigated with nutrient solution containing 1 mg/L, 31 mg/L, or 61 mg/L of phosphorus (phosphorus-application side), and the other side was irrigated with a phosphorus-free nutrient solution (phosphorus-free side), to study the effect of local phosphorus supply on nodulation and nitrogen fixation in soybean. The results are described as follows: (1) Increasing the phosphorus supply increased the nodules weight, nitrogenase activity, ureide content, number of bacteroids, number of infected cells, and relative expression levels of nodule nitrogen fixation key genes (GmEXPB2, GmSPX5, nifH, nifD, nifK, GmALN1, GmACP1, GmUR5, GmPUR5, and GmHIUH5) in root nodules on the phosphorus-application side. Although the phosphorus-application and phosphorus-free sides demonstrated similar changing trends, the phosphorus-induced increases were more prominent on the phosphorus-application side, which indicated that phosphorus supply systematically regulates nodulation and nitrogen fixation in soybean. (2) When the level of phosphorus supply was increased from 1 mg/L to 31 mg/L, the increase on the P– side root was significant, and nodule phosphorus content increased by 57.14–85.71% and 68.75–75.00%, respectively; ARA and SNA were 218.64–383.33% and 11.41–16.11%, respectively, while ureide content was 118.18–156.44%. When the level of phosphorus supply was increased from 31mg/L to 61mg/L, the increase in the regulation ability of root and nodule phosphorus content, ARA, SNA, and ureide content were low for roots, and the value for nodules was lower than when the phosphorus level increased from 1 mg/L to 31 mg/L. (3) A high-concentration phosphorus supply on one side of a dual-root soybean plant significantly increased the phosphorus content in the aboveground tissues, as well as the roots and nodules on both sides. In the roots on the phosphorus-free side, the nodules were prioritized for receiving the phosphorus transported from the aboveground tissues to maintain their phosphorus content and functionality.

A critical role of progesterone (P) during early pregnancy is to induce differentiation of the endometrial stromal cells into specialized decidual cells that support the development of the implanting embryo. The P-induced signaling pathways that participate in the formation and function of the decidual cells remain poorly understood. We report here that the expression of the bone morphogenetic protein 2 (BMP2), a morphogen belonging to the TGFβ superfamily, is induced downstream of P action in the mouse uterine stroma during decidualization. To determine the function of BMP2 during this differentiation process, we employed a primary culture system in which undifferentiated stromal cells isolated from pregnant mouse uterus undergo decidualization. When recombinant BMP2 was added to these stromal cultures, it markedly advanced the differentiation program. We also found that siRNA-mediated silencing of BMP2 expression in these cells efficiently blocked the differentiation process. Gene expression profiling experiments identified Wnt4 as a downstream target of BMP2 regulation in stromal cells undergoing decidualization. Attenuation of Wnt4 expression by siRNAs greatly reduced stromal differentiation in vitro, indicating that it is a key mediator of BMP2-induced decidualization. We also observed a remarkable induction in the expression of BMP2 in human endometrial stromal cells during decidualization in vitro in response to steroids and cAMP. Addition of BMP2 to these cultures led to a robust enhancement of Wnt4 expression and stimulated the differentiation process. Collectively, our studies uncovered a unique conserved pathway involving BMP2 and Wnt4 that mediates P-induced stromal decidualization in the mouse and the human. [ABSTRACT FROM AUTHOR]

During early pregnancy, steroid hormones estrogen (E) and progesterone (P) regulate a complex series of interactions between the implanting embryo and the uterus by controlling the proliferation and differentiation of uterine epithelium and stroma in a timely manner. To identify the steroid-regulated genes that control these functions, we performed messenger RNA profiling of mouse uterine tissues at the time of implantation. Our analysis revealed that the expression of the transcription factor CCAAT/enhancer- binding protein β (C/EBPβ) is rapidly induced in the pregnant uterus at the time of blastocyst attachment. The expression of C/EBPβ increased further during the decidualization phase of pregnancy and was localized in the proliferating as well as the decidualized stromal cells surrounding the implanted embryo. Administration of E or P to ovariectomized females induced C/EBPβ expression in both uterine epithelium and stroma, showing a dual regulation of this gene by these hormones. The female C/EBPβ-null mice are infertile. We, therefore, assessed steroid-hormone-dependent responses in the uteri of these mice. We observed that E-induced proliferation of uterine epithelial cells is markedly compromised in the absence of C/EBPβ. Most strikingly, there was a complete lack of response of the C/EBPβ-deficient uteri to an artificial deciduogenic stimulus, indicating a critical role of this transcription factor in regulating the decidualization program. Further analysis revealed defects in steroid-induced stromal cell proliferation and differentiation in C/EBPβ-null uteri. Collectively, our studies established that C/EBPβ is a key mediator of steroid responsiveness of the epithelium and stroma in the mouse uterus. [ABSTRACT FROM AUTHOR]

Background and objective Survivin, a member of the inhibitor of apoptosis (IAP) protein family, has been demonstrated as a potential new target for apoptosis-based therapy in cancer and lymphoma. The aim of this study is to investigate effects and mechanisms of survivin siRNA transfection on lung adenocarcinoma cell lines SPCA1 and SH77. Methods A siRNA plasmid expression vector and pSi scrambled against survivin were constructed and transfected into SPCA1 and SH77 cells with Lipofectamine 2000. The proliferations of lung adenocarcinoma SPCA1 and SH77 cells were detected by MTT. The apoptotic rate and cell cycle were detected by flow cytometer. The activity of survivin mRNA and protein expression were analyzed with RT-PCR and Western blot. Results Survivin siRNA reduced the proliferation of SPCA1 and SH77 cells. Cell cycle was inhibited in G0/G1. Expressions of survivin siRNA mRNA and protein were reduced in transfected cells compared with the control cells. Conclusion siRNA targeted against survivin can effectively suppress SPCA1 and SH77 cells proliferation and significantly induce SPCA1 and SH77 cells apoptosis.

Background and objective The spider venom may inspire new drugs to treat cancer. The aim of this study is to investigate the effects and mechanisms of spider venom on lung adenocarcinoma cell A549. Methods The proliferation of lung adenocarcinoma A549 cells was detected by MTT. The apoptosis rate was observed with MTT assay and flow cytometer. The activity of catalase was detected by colorimetry. The malondialdehyde (MDA) content was determined by improved thiobarbituric acid fluorometric method. The expression of P38MAPK protein was analyzed with Western blot. Results Spider venom can remarkably inhibite the proliferation of lung adenocarcinoma A549 cells, increased activity of catalase and MDA content, down-regulated expression of P38MAPK compared with the control group. Conclusion The reduced proliferation of lung adenocarcinoma A549 cells by spider venom is may be associated with the increased of activity of catalase and MDA content and decreased expression of P38MAPK.

The peptide hormone prolactin (PRL) and certain members of the epidermal growth factor (EGF) family play central roles in mammary gland development and physiology, and their dysregulation has been implicated in mammary tumorigenesis. Our recent studies have revealed that the CUB and zona pellucidalike domain-containing protein 1 (CUZD1) is a critical factor for PRL-mediated activation of the transcription factor STAT5 in mouse mammary epithelium. Of note, CUZD1 controls production of a specific subset of the EGF family growth factors and consequent activation of their receptors. Here, we found that consistent with this finding, CUZD1 overexpression in nontransformed mammary epithelial HC11 cells increases their proliferation and induces tumorigenic characteristics in these cells. When introduced orthotopically in mouse mammary glands, these cells formed adenocarcinomas, exhibiting elevated levels of STAT5 phosphorylation and activation of the EGF signaling pathway. Selective blockade of STAT5 phosphorylation by pimozide, a small-molecule inhibitor, markedly reduced the production of the EGF family growth factors and inhibited PRLinduced tumor cell proliferation in vitro. Pimozide administration to mice also suppressed CUZD1-driven mammary tumorigenesis in vivo. Analysis of human MCF7 breast cancer cells indicated that CUZD1 controls the production of the same subset of EGF family members in these cells as in the mouse. Moreover, pimozide treatment reduced the proliferation of these cancer cells. Collectively, these findings indicate that overexpression of CUZD1, a regulator of growth factor pathways controlled by PRL and STAT5, promotes mammary tumorigenesis. Blockade of the STAT5 signaling pathway downstream of CUZD1 may offer a therapeutic strategy for managing these breast tumors. [ABSTRACT FROM AUTHOR]

The progesterone receptor (PR) plays a critical role during ovulation. Mice lacking the PR gene are anovulatory due to a failure in the rupture of the preovulatory follicles. The pathways that operate downstream of PR to control ovulation are poorly understood. Using gene expression profiling, we identified peroxisome proliferator-activated receptor γ(PPARγ) as a target of regulation by PR in the granulosa cells of the preovulatory follicles during the ovulatory process. To investigate the function of PPARγ during ovulation, we created a conditional knockout mouse in which this gene was deleted via Cre-Lox-mediated excision in granulosa cells. When these mutant mice were subjected to gonadotropin-induced superovulation, the preovulatory follicles failed to rupture and the number of eggs released from the mutant ovaries declined drastically. Gene expression analysis identified endothelin-2, interleukin-6, and cyclic GMP-dependent protein kinase II as novel targets of regulation by PPARγ in the ovary. Our studies also suggested that cycloxygenase 2-derived metabolites of long-chain fatty acids function as endogenous activating ligands of PPARγ in the preovulatory follicles. Collectively, these studies revealed that PPARγ is a key mediator of the biological actions of PR in the granulosa cells and activation of its downstream pathways critically controls ovulation. [ABSTRACT FROM AUTHOR]