Exogenous hydrogen sulfide prevents necroptosis by inhibiting p38MAPK pathway activation in JEG-3 trophoblast cells: A role in preeclampsia.

Setting 7 subsection in abstract Objectives: Necroptosis, a form of programmed cell death, can occur in the placenta of patients with preeclampsia (PE). Hydrogen sulfide (H2S) can inhibit necroptosis of human umbilical vein endothelial cells under the high-glucose-induced injury. Whether H2S can protect trophoblasts against necroptosis underlying PE has not been elucidated. This study was aimed to explore the protective role of H2S in trophoblast cells against necroptosis underlying PE. DESIGN: This is an in vitro experimental study. PARTICIPANTS: A total of 10 pregnant women with severe preeclampsia (PE) and 10 matched control normotensive pregnant women were included. The placenta tissues were extracted from participators. The human JEG-3 trophoblasts were commercially available. METHODS: The expression and localization of necrotic proteins were assayed in human placenta samples and the effect of necrotic cell death on the proliferation and apoptosis of human JEG-3 trophoblasts was evaluated. The component expressions of inflammatory cytokine and p38MAPK signaling pathway were measured in samples pretreated with or without NaHS (H2S donor) and SB203580 (p38 inhibitor). RESULTS: RIPA1, RIPA3, and p-p38 levels were significantly higher in PE placental tissue, whereas cystathionine-ß-synthase expression was decreased. In JEG-3 trophoblasts, necroptosis increased apoptotic cell numbers, suppressed cell proliferation, increased inflammatory cytokine expression, and increased p38MAPK activation, which can be prevented by NaHS. LIMITATIONS: In the present study, we did not provide sufficient evidence that necroptosis was a part of the pathogenesis of preeclampsia. CONCLUSIONS: we proposed the putative role of necroptosis in early-onset PE, reflected by the blockage of caspase-8/3 and increased expression of RIPA1, and RIPA3 in PE placenta tissues. Furthermore, we demonstrated that exogenous H2S protected cytotrophoblasts against CER-induced necroptosis via the p38MAPK pathway.

A Cellular Senescence-Related Signature Predicts Cervical Cancer Patient Outcome and Immunotherapy Sensitivity.

Cervical cancer (CC) is one of the most prevalent gynecological malignancies. The rate of mortality and morbidity among patients with CC is high. Cellular senescence is involved in tumorigenesis as well as in the cancer progression. However, the involvement of cellular senescence in CC development is still unclear and requires further investigation. In this study, we retrieved data on cellular senescence-related genes (CSRGs) from the "CellAge" Database. We used the TCGA-CESC and CGCI-HTMCP-CC datasets as the training and validation sets, respectively. Finally, a signature was constructed using "univariate" and "Least Absolute Shrinkage and Selection Operator" (LASSO) Cox regression analysis, which contains eight CSRGs. Using this signature, we calculated the risk scores of all patients in the training and validation cohorts and categorized them into the low-risk group (LR-G) and the high-risk group (HR-G). Results showed that, compared to patients in the HR-G, those in the LR-G demonstrated a more positive clinical prognosis, more abundant immune cell infiltrations, and a more active immune response. The signature could also modulate the expression of SASP factors. In vitro studies showed an increased expression of SERPINE1 and IL-1α genes included in the signature in CC cells and tissues. Our findings help to deepen our insights into the etiology of CC, which could be beneficial for prognostic prediction and immunotherapy in clinical practice.

Single-cell RNA sequencing of peripheral blood reveals immune cell dysfunction in premature ovarian insufficiency.

Background: Premature ovarian insufficiency (POI) is one of the most common causes of female infertility and the etiology is highly heterogeneous. Most cases are idiopathic and the pathogenesis remains unclear. Previous studies proved that the immune system plays a crucial role in POI. However, the precise role of immune system remains unclear. This study aimed to analyze the characteristics of peripheral blood mononuclear cells (PBMC) from patients with POI by single-cell RNA sequencing (scRNA-seq) and to explore the potential involvement of immune response in idiopathic POI. Methods: PBMC was collected from three normal subjects and three patients with POI. PBMC was subjected to scRNA-seq to identify cell clusters and differently expressed genes (DEGs). Enrichment analysis and cell-cell communication analysis were performed to explore the most active biological function in the immune cells of patients with POI. Results: In total, 22 cell clusters and 10 cell types were identified in the two groups. Compared with normal subjects, the percentage of classical monocytes and NK cells was decreased, the abundance of plasma B cells was increased, and CD4/CD8 ratio was significantly higher in POI. Furthermore, upregulation of IGKC, IFITM1, CD69, JUND and downregulation of LYZ, GNLY, VCAN, and S100A9 were identified, which were enriched in NK cell-mediated cytotoxicity, antigen processing and presentation, and IL-17 signaling pathway. Among them, IGHM and LYZ were respectively the most significantly upregulated and downregulated genes among all cell clusters of POI. The strength of cell-cell communication differed between the healthy subjects and patients with POI, and multiple signaling pathways were assessed. The TNF pathway was found to be unique in POI with classical monocytes being the major target and source of TNF signaling. Conclusions: Dysfunction of cellular immunity is related to idiopathic POI. Monocytes, NK cells, and B cells, and their enriched differential genes may play a role in the development of idiopathic POI. These findings provide novel mechanistic insight for understanding the pathogenesis of POI.

A Cellular Senescence-Related Signature Predicts Cervical Cancer Patient Outcome and Immunotherapy Sensitivity.

Cervical cancer (CC) is among the most prevalent gynaecological malignancy. The rate of mortality and morbidity of patients with CC is high. Cellular senescence is involved in tumorigenesis as well as cancer progression. However, the involvement of cellular senescence in CC development is still unclear and requires further investigation. We retrieved data on cellular senescence-related genes (CSRGs) from the "CellAge" Database. We used TCGA-CESC and the CGCI-HTMCP-CC datasets as the training and validation sets, respectively. Eight CSRGs signatures based on the data extracted from these sets were constructed using "univariate" and "Least Absolute Shrinkage and Selection Operator Cox regression analyses". Using this model, we calculated the risk scores of all patients in the training and validation cohort and categorised these patients into the low-risk group (LR-G) and the high-risk group (HR-G). Finally, compared to patients in the HR-G, CC patients in the LR-G demonstrated a more positive clinical prognosis; the expression of senescence-associated secretory phenotype (SASP) markers and immune cell infiltration was higher, and these patients had more active immune responses. In vitro studies showed increased SERPINE1 and IL-1α ((genes included in the signature) expression in CC cells and tissues. The eight-gene prognostic signatures could modulate the expression of SASP factors and the tumour immune micro-environment (TIME). It could be used as a reliable biomarker for predicting the patient's prognosis and response to immunotherapy in CC.