SHP2 participates in decidualization by activating ERK to maintain normal nuclear localization of progesterone receptor.

In brief: The establishment and maintenance of embryo implantation and pregnancy require decidualization of endometrial stromal cells. This paper reveals that SHP2 ensures the correct subcellular localization of progesterone receptor, thereby safeguarding the process of decidualization. Abstract: Decidualization is the process of conversion of endometrial stromal cells into decidual stromal cells, which is caused by progesterone production that begins during the luteal phase of the menstrual cycle and then increases throughout pregnancy dedicated to support embryonic development. Decidualization deficiency is closely associated with various pregnancy complications, such as recurrent miscarriage (RM). Here, we reported that Src-homology-2-containing phospho-tyrosine phosphatase (SHP2), a key regulator in the signal transduction process downstream of various receptors, plays an indispensable role in decidualization. SHP2 expression was upregulated during decidualization. SHP2 inhibitor RMC-4550 and shRNA-mediated SHP2 reduction resulted in a decreased level of phosphorylation of ERK and aberrant cytoplasmic localization of progesterone receptor (PR), coinciding with reduced expression of IGFBP1 and various other target genes of decidualization. Solely inhibiting ERK activity recapitulated these observations. Administration of RMC-4550 led to decidualization deficiency and embryo absorption in mice. Moreover, reduced expression of SHP2 was detected in the decidua of RM patients. Our results revealed that SHP2 is key to PR's nuclear localization, thereby indispensable for decidualization and that reduced expression of SHP2 might be engaged in the pathogenesis of RM.

A cross-sectional study of the association between heavy metals and pan-cancers associated with sex hormones in NHANES 1999-2018.

Given the complexity of tumorigenesis, numerous studies have also shown that excessive exposure to heavy metals increases the risk of cancers and disrupts the secretion of sex hormones. However, the specific effects of heavy metals on cancers remain to be proven. To confirm the association between heavy metals and pan-cancer sex hormone levels among adults, 94,337 individuals from the National Health and Nutrition Examination Survey were assessed. We examined the associations between pan-cancers associated with sex hormones (ovarian, testicular, breast, and prostate cancers) and heavy metals in blood/urine. The methods (the WQS (weighted quantile sums) and SVYGLM (survey generalized linear model) regressions) were used to evaluate the association between sex hormone-related cancers and each metal category by incorporating covariates. To evaluate the overall effect of heavy metals and detect the dose-response relationship between the prevalence of pan-cancers associated with sex hormones and heavy metals, RCS (restricted cubic splines) were applied. Environmental exposure to heavy metals may be associated with pan-cancers associated with sex hormones in adults in the USA. Prostate cancer was inversely associated with blood cadmium while positively associated with blood lead, urinary tin, and thallium. Breast cancer was inversely associated with blood lead. Ovarian cancer was positively associated with blood cadmium. We also found a non-linear dose-response relationship between pan-cancers associated with sex hormones and heavy metals, which was non-parametric, using RCS models. The OR for breast cancer decreased along with the increase in lead concentration under approximately 20 µg/dl, while the OR for prostate cancer increased between urine thallium levels of approximately 0.17-1.1 ng/ml. Pan-cancers associated with sex hormones are associated with exposure to heavy metals. Considering the design of the NHANES study, further studies need to be conducted on other nationally representative surveys.

Associations of dietary antioxidant micronutrients with the prevalence of obesity in adults.

Background: Antioxidant micronutrients have a therapeutic potential for clinical treatment of obesity. NO research, however, has examined the connection between the complex level of dietary antioxidants and obesity. Materials and methods: We mainly aimed to investigate the relationship between a combination of antioxidants and obesity using the database of the national health and nutrition examination survey (NHANES). This cross-sectional study contains a survey of 41,021 people (≥18 years) in total ranging from 2005 to 2018. Multivariate logistic and weighted quantile sum (WQS) regression were performed to investigate the associations between these antioxidants, both individually and collectively, and the prevalence of obesity. The restricted cubic spline (RCS) regression was also utilized to analyze the linearity of these associations. Results: According to multivariate logistic models, we found that the levels of most antioxidants in the highest quartile were independently related to a lower prevalence of obesity, while a reverse result was observed in selenium (p for trend <0.05). The WQS index revealed that a total of the 11 antioxidants is negatively related to the prevalence of obesity and abdominal obesity (all p<0.001), and iron/vitamin C have the greatest weight in the negative associations between antioxidant complex and obesity, as well as abdominal obesity. In addition, the RCS regression showed that retinol, vitamin A, α-carotene, ß-carotene, ß-cryptoxanthin, vitamin C, iron, and copper all had a non-linear association with obesity. Threshold effect analysis demonstrated that the inflection points of retinol, vitamin A, α-carotene, ß-carotene, ß-cryptoxanthin, vitamin C, iron, and cooper were 235.57, 374.81, 58.89, 891.44, 30.70, 43,410.00, 11,240.00, and 990.00 µg/day, respectively. Conclusion: Our study found that a high level of a complex of 11 dietary antioxidants is related to a lower prevalence of obesity and abdominal obesity, among this inverse associations iron and vitamin C have the greatest weight.

Polycystic ovary syndrome: Identification of novel and hub biomarkers in the autophagy-associated mRNA-miRNA-lncRNA network.

Introduction: Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder prevalent among women of reproductive age. Recent studies show that autophagy participated in the pathogenesis of PCOS, including anovulation, hyperandrogenism, and metabolic disturbances. This study was designed to screen autophagy-related genes (ATGs) that may play a pivotal role in PCOS, providing potential biomarkers and identifying new molecular subgroups for therapeutic intervention. Methods: Gene expression profiles of the PCOS and control samples were obtained from the publicly available Gene Expression Omnibus database. The gene lists of ATGs from databases were integrated. Then, the weighted gene co-expression network analysis was conducted to obtain functional modules and construct a multifactorial co-expression network. Gene Ontology and KEGG pathway enrichment analyses were performed for further exploration of ATG's function in the key modules. Differentially expressed ATGs were identified and validated in external datasets with the Limma R package. To provide guidance on PCOS phenotyping, the dysfunction module consists of a co-expression network mapped to PCOS patients. A PCOS-Autophagy-related co-expression network was established using Cytoscape, followed by identifying molecular subgroups using the Limma R package. ps. RNA-sequencing analysis was used to confirm the differential expression of hub ATGs, and the diagnostic value of hub ATGs was assessed by receiver operating characteristic curve analysis. Results: Three modules (Brown, Turquoise, and Green) in GSE8157, three modules (Blue, Red, and Green) in GSE43264, and four modules (Blue, Green, Black, and Yellow) in GSE106724 were identified to be PCOS-related by WGCNA analysis. 29 ATGs were found to be the hub genes that strongly correlated with PCOS. These hub ATGs were mainly enriched in autophagy-related functions and pathways such as autophagy, endocytosis, apoptosis, and mTOR signaling pathways. The mRNA-miRNA-lncRNA multifactorial network was successfully constructed. And three new molecular subgroups were identified via the K-means algorithm. Discussion: We provide a novel insight into the mechanisms behind autophagy in PCOS. BRCA1, LDLR, MAP1B, hsa-miR-92b-3p, hsa-miR-20b-5p, and NEAT1 might play a considerably important role in PCOS dysfunction. As a result, new potential biomarkers can be evaluated for use in PCOS diagnosis and treatment in the future.

Novel Hub genes co-expression network mediates dysfunction in a model of polycystic ovary syndrome.

BACKGROUND: This study aimed to integrate DNA methylation, miRNA, and mRNA microarray data to construct a gene co-expression network for polycystic ovarian syndrome (PCOS). METHODS: The weighted gene co-expression network analysis (WGCNA) was conducted to construct a PCOS-related co-expression network by using the GEO public datasets. We performed Gene Ontology and KEGG pathway enrichment analyses for a further exploration of gene function in networks. Finally, the dysfunction module consisting of a co-expression network was mapped to the PCOS patients and tried to provide guidance to the PCOS phenotyping. RESULTS: Three modules (Midnightbule, Pink, and Red) were identified to be PCOS-related by WGCNA analysis. These module-related genes were enriched in cell response to stimulus, PI3K-Akt signaling pathway, insulin biological process, signaling pathway, and cytokine-cytokine receptor interaction biological processes. The multiple-factor network, including miRNA-lncRNA and DNA methylation-mRNA interaction, was closely associated with PCOS dysfunction. CONCLUSION: Our study render a novel insight into the mechanisms and might provide candidate biomarkers and therapeutic targets for the classification of PCOS dysfunction.

The effects of laser stimulation at acupoint ST36 on anxiety-like behaviors and anterior cingulate cortex c-Fos expression in a rat post-traumatic stress disorder model.

Post-traumatic stress disorder (PTSD) is a mental disorder that is linked with the onset of multiple anxiety-like behaviors. This study was designed to assess how these behaviors and anterior cingulate cortex (ACC) c-Fos expression were impacted by 10.6-µm laser stimulation at acupoint ST36 a rat model of PTSD. A rat model of PTSD was prepared via prolonged exposure of animals to a stressor, followed by a 7-day period during which animals were allowed to rest undisturbed in their cages. Rats were randomized into four experimental groups (n = 12/group): the control, PTSD, LS, and sham LS groups. Control group animals were not subjected to SPS procedures prior to behavioral testing. LS and sham LS animals were administered LS treatment at bilateral ST36 acupoints or non-acupoints, respectively, for a 7-day period. Animals were then assessed for performance in elevated plus maze (EPM) tests and open-field tests (OFT), and their plasma corticosterone levels were measured. In addition, c-Fos-positive nuclei in the ACC were detected via immunohistochemical staining. Relative to sham LS treatment and PTSD model control rats, LS was associated with increased time spent in both open EPM test arms and in the central area in the OFT (P < 0.05). The PTSD model group exhibited a significant reduction in ACC c-Fox expression, while LS treatment significantly increased this expression (P < 0.001). In addition, a correlation was detected between anxiety-like behaviors and altered ACC neuronal activation. The results of this study indicate that LS at acupoint ST36 can have a previously unreported effect on anxiety-like behaviors in the context of PTSD, with ACC neuronal activation potentially being implicated as a driver of this effect.

Metabolite Changes in the Aqueous Humor of Patients With Retinal Vein Occlusion Macular Edema: A Metabolomics Analysis.

Macular edema (ME) is the main cause of visual impairment in patients with retinal vein occlusion (RVO). The degree of ME affects the prognosis of RVO patients, while it lacks objective laboratory biomarkers. We aimed to compare aqueous humor samples from 28 patients with retinal vein occlusion macular edema (RVO-ME) to 27 age- and sex-matched controls by ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry, so as to identify the key biomarkers and to increase the understanding of the mechanism of RVO-ME at the molecular level. Through univariate and multivariate statistical analyses, we identified 60 metabolites between RVO-ME patients and controls and 40 differential metabolites in mild RVO-ME [300 µm ≤ central retinal thickness (CRT) < 400 µm] patients compared with severe RVO-ME (CRT ≥ 400 µm). Pathway enrichment analysis showed that valine, leucine, and isoleucine biosynthesis; ascorbate and aldarate metabolism; and pantothenate and coenzyme A biosynthesis were significantly altered in RVO-ME in comparison with controls. Compared with mild RVO-ME, degradation and biosynthesis of valine, leucine, and isoleucine; histidine metabolism; beta-alanine metabolism; and pantothenate and coenzyme A biosynthesis were significantly changed in severe RVO-ME. Furthermore, the receiver operating characteristic (ROC) curve analysis revealed that adenosine, threonic acid, pyruvic acid, and pyro-L-glutaminyl-l-glutamine could differentiate RVO-ME from controls with an area under the curve (AUC) of >0.813. Urocanic acid, diethanolamine, 8-butanoylneosolaniol, niacinamide, paraldehyde, phytosphingosine, 4-aminobutyraldehyde, dihydrolipoate, and 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide had an AUC of >0.848 for distinguishing mild RVO-ME from severe RVO-ME. Our study expanded the understanding of metabolomic changes in RVO-ME, which could help us to have a good understanding of the pathogenesis of RVO-ME.

Ultrawide Color Gamut Perovskite and CdSe/ZnS Quantum-Dots-Based White Light-Emitting Diode with High Luminous Efficiency.

We demonstrate excellent color quality of liquid-type white light-emitting diodes (WLEDs) using a combination of green light-emitting CsPbBr3 and red light-emitting CdSe/ZnS quantum dots (QDs). Previously, we reported red (CsPbBr1.2I1.8) and green (CsPbBr3) perovskite QDs (PQDs)-based WLEDs with high color gamut, which manifested fast anion exchange and stability issues. Herein, the replacement of red PQDs with CdSe/ZnS QDs has resolved the aforementioned problems effectively and improved both stability and efficiency. Further, the proposed liquid-type device possesses outstanding color gamut performance (132% of National Television System Committee and 99% of Rec. 2020). It also shows a high efficiency of 66 lm/W and an excellent long-term operation stability for over 1000 h.