Polystyrene micro- and nano-particle coexposure injures fetal thalamus by inducing ROS-mediated cell apoptosis.

The adverse effects of plastic on adult animal and human health have been receiving increasing attention. However, its potential toxicity to fetuses has not been fully elucidated. Herein, biodistribution of polystyrene (PS) particles was determined after the maternal mice were orally given PS micro- and/or nano-particles with and without surface modifications during gestational days 1 to 17. The results showed that PS microplastics (MPs) and nanoparticles (NPs) mainly emerged in the alimentary tract, brain, uterus, and placenta in maternal mice, and only the latter infiltrated into the fetal thalamus. PS NPs and carboxyl-modified NPs induced differentially expressed genes mainly enriched in oxidative phosphorylation and GABAergic synapse. Maternal administration of PS particles during gestation led to anxiety-like behavior of the progenies and their γ-aminobutyric acid (GABA) reduction in the prefrontal cortex and amygdala at Week 8. N-Acetylcysteine (NAC), an antioxidant, alleviated PS particles-induced oxidative injury in the fetal brain and rescued the anxiety-like behavior of the progenies. Additionally, PS nanoparticles caused excessive ROS and apoptosis in neuronal cell lines, which were prevented by glutathione supplementation. These results suggested that PS particles produced a negative effect on fetuses by inducing oxidative injury and suppressing GABA synthesis in their brain. The findings contribute to estimating the risk for PS particles to human and animal health.

Characterizing the landscape of cervical squamous cell carcinoma immune microenvironment by integrating the single-cell transcriptomics and RNA-Seq.

BACKGROUND: Cervical squamous cell carcinoma (CSCC), caused by the infection of high-risk human papillomavirus, is one of the most common malignancies in women worldwide. METHODS: RNA expression data, including those from the Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases, were used to identify the expression of RNAs in normal and tumor tissue. Correlation analysis was performed to identify the immune-related long noncoding RNAs (IRLs) and hypoxia-related genes (IRHs) that can influence the activity of the immune system. Prognosis models of immune-related RNAs (IRRs) were used to construct a coexpression network of the immune system. We identified the role of IRRs in immunotherapy by correlation analysis with immune checkpoint genes (ICGs). We then validated the expression data by integrating two single-cell sequencing data sets of CSCC to identify the key immune features. RESULTS: In total, six immune-related gene (IRG), four IRL, and five IRH signatures that can significantly influence the characteristics of the tumor immune microenvironment (TIME) were selected using machine learning methods. The expression level of ICGs was significantly upregulated in GZMB+ CD8+ T-cells and tumor-associated macrophages (TAMs) in tumor tissues. TGFBI+ TAMs are a kind of blood-derived monocyte-derived M0-like TAM linked to hypoxia and a poor prognosis. IFI30+ M1-like TAMs participate in the process of immune-regulation and showed a role in the promotion of CD8+ T-cells and Type 1 T helper (Th1)/Th2 cells in the coexpression network, together with several IRLs, IRGs, and ICGs. CONCLUSIONS: CD16+ monocyte-derived IFI30+ TAMs participated in our coexpression network to regulate the TIME, showing the potential to be a novel immunotherapy target. The enrichment of M0-like TAMs was associated with a worse prognosis in the high-risk score group with IRH signatures. Remarkably, M0-like TAMs in tumor tissues overexpressed TGFBI and were associated with several well-known tumor-proliferation pathways.

Baicalin alleviates endometrial inflammatory injury through regulation of tight junction proteins.

Endometritis is the foremost reason for reduced reproductive performance, which impedes the establishment of pregnancy in ruminants. Baicalin is extensively acknowledged as a tocolytic drug. However, the preventive effect of baicalin on endometrial inflammatory injury remains unclear. The present study aimed to determine the potential benefits of baicalin on endometrial inflammatory injury in animal and cellular models. The results showed that baicalin alleviated the impairment of tight junctions (TJs) and inflammation in the endometrium induced by LPS treatment. Baicalin increased claudin 3 (CLDN3) and tight junction protein 1 (TJP1) levels in a dose-dependent manner in endometrial epithelial cells (EECs) accompanied by autophagy activation with or without LPS treatment. Immunofluorescence staining revealed that baicalin pretreatment prompted MAP1LC3B-positive structures to surround TJ proteins in the cytoplasm and decreased the abnormal aggregation of CLDN3 and TJP1 in the cytosol of EECs. Activation or blockage of autophagy using pharmacologic methods affected the redistribution of TJ proteins by baicalin pretreatment with LPS treatment. The role of autophagy in the modulation of TJ proteins was also confirmed by ATG7 and TFEB overexpression, as evidenced by accelerated redistribution of CLDN3 and TJP1 from the EEC cytosol to the membrane and a loss of membranous CLDN2 in EECs. These data demonstrate that baicalin influences the redistribution of TJ proteins to maintain the barrier function during LPS-induced endometrial inflammatory injury by regulating autophagy and provides a new therapeutic to potentially prevent embryo loss and endometritis.

The involvement of the primo vascular system in local enteritis and its modification by electroacupuncture.

Introduction: The primo vascular system (PVS), an intensive network structure, has been claimed to be representative of the acupuncture meridian. Here, we explored the role of the PVS in local enteritis and its modification by acupuncture. Methods: Chronic cecitis in rabbits was induced by 2,4,6-trinitro-benzene-sulfonic acid (TNBS). The PVS on the cecum was visualized with trypan blue staining, and collected with the help of microsurgical forceps under an optical stereomicroscope. Results: The increased primo vessels (PVs) and primo nodes (PNs) of the PVS on the surface of the cecum were induced by local inflammation, which was positively correlated with the inflammatory cells in the cecal mucosa. Tandem mass tag (TMT) based proteomic analysis revealed that 110 differentiated proteins of the PVS existed between TNBS-treated and control rabbits; 65 proteins were upregulated, while 45 proteins were downregulated. These proteins were mainly enriched in inflammation- and immunity-related processes, such as inflammatory cell proliferation, antigen presentation, and cell adhesion in the proliferated PVS (data are available via ProteomeXchange with the identifiers PXD034280). Importantly, TNBS-induced cecitis, the proliferated PVS and inflammation response-related proteins (CD40, CD45, HLA-DRA1, LAMP1, JAGN1 and FGL1) in the PVS were alleviated or reversed by repetitive electroacupuncture (EA) stimulations. Conclusion: These results suggest that the proliferated PVS and its active inclusions were related to the inflammatory process, which was modified by EA. Our study provides a new avenue for further exploration of the mechanism by which EA exerts anti-inflammatory effects.

Essential Role of CRIM1 on Endometrial Receptivity in Goat.

In domestic ruminants, endometrial receptivity is related to successful pregnancy and economic efficiency. Despite several molecules having been reported in the past regarding endometrial receptivity regulation, much regarding the mechanism of endometrial receptivity regulation remains unknown due to the complex nature of the trait. In this work, we demonstrated that the cysteine-rich transmembrane bone morphogenetic protein (BMP) regulator 1 (CRIM1) served as a novel regulator in the regulation of goat endometrial receptivity in vitro. Our results showed that hormones and IFN-τ increased the expression of CRIM1 in goat endometrial epithelial cells (EECs). Knockdown of CRIM1 via specific shRNA hindered cell proliferation, cell adhesion and prostaglandins (PGs) secretion and thus derailed normal endometrial receptivity. We further confirmed that receptivity defect phenotypes due to CRIM1 interference were restored by ATG7 overexpression in EECs while a loss of ATG7 further impaired receptivity phenotypes. Moreover, our results showed that changing the expression of ATG7 affected the reactive oxygen species (ROS) production. Moreover, mR-143-5p was shown to be a potential upstream factor of CRIM1-regulated endometrial receptivity in EECs. Overall, these results suggest that CRIM1, as the downstream target of miR-143-5p, has effects on ATG7-dependent autophagy, regulating cell proliferation, cell adhesion and PG secretion, and provides a new target for the diagnosis and treatment of early pregnancy failure and for improving the success rates of artificial reproduction.

BCL2L15 Depletion Inhibits Endometrial Receptivity via the STAT1 Signaling Pathway.

In domestic ruminants, endometrial receptivity is critical for a successful pregnancy and economic efficiency. Although the endometrium undergoes major cellular changes during peri-implantation, the precise mechanisms regulating goat endometrial receptivity remain unknown. In this study, we investigated the functional roles and signal transduction of the B-cell lymphoma 2 (Bcl-2)-like protein 15 (BCL2L15) in the regulation of endometrial receptivity in vitro. Our results showed that BCL2L15 was up-regulated in goat endometrial epithelial cells (EECs) under progesterone (P4), estradiol (E2), and interferon-tau (IFN-τ) treatments. Our knockdown of BCL2L15 by specific shRNA that significantly hampered endometrial receptivity. In the absence of BCL2L15, the signal transducer and activator of transcription (STAT)1 and STAT3 pathway were activated. Additionally, pretreatment with the STAT1 inhibitor, fludarabine, restored the effect of silencing BCL2L15 on the endometrial receptivity, but not the STAT3 inhibitor Stattic. Overall, these results suggested that BCL2L15 is the key regulator of endometrial receptivity in goats, regulating the endometrial receptivity through the STAT1 pathway. Understanding the function of BCL2L15-STAT1 in endometrial receptivity is important to the exploration of new targets for the diagnosis and treatment of early pregnancy failure, and improving the success rates for artificial reproduction.