TET3-mediated DNA demethylation modification activates SHP2 expression to promote endometrial cancer progression through the EGFR/ERK pathway.

OBJECTIVE: Src homology phosphotyrosin phosphatase 2 (SHP2) has been implicated in the progression of several cancer types. However, its function in endometrial cancer (EC) remains unclear. Here, we report that the ten-eleven translocation 3 (TET3)-mediated DNA demethylation modification is responsible for the oncogenic role of SHP2 in EC and explore the detailed mechanism. METHODS: The transcriptomic differences between EC tissues and control tissues were analyzed using bioinformatics tools, followed by protein-protein interaction network establishment. EC cells were treated with shRNA targeting SHP2 alone or in combination with isoprocurcumenol, an epidermal growth factor receptor (EGFR) signaling activator. The cell biological behavior was examined using cell counting kit-8, colony formation, flow cytometry, scratch assay, and transwell assays, and the median inhibition concentration values to medroxyprogesterone acetate/gefitinib were calculated. The binding of TET3 to the SHP2 promoter was verified. EC cells with TET3 knockdown and combined with SHP2 overexpression were selected to construct tumor xenografts in mice. RESULTS: TET3 and SHP2 were overexpressed in EC cells. TET3 bound to the SHP2 promoter, thereby increasing the DNA hydroxymethylation modification and activating SHP2 to induce the EGFR/extracellular signal-regulated kinase (ERK) pathway. Knockdown of TET3 or SHP2 inhibited EC cell malignant aggressiveness and impaired the EGFR/ERK pathway. Silencing of TET3 inhibited the tumorigenic capacity of EC cells, and ectopic expression of SHP2 or isoprocurcumenol reversed the inhibitory effect of TET3 knockdown on the biological activity of EC cells. CONCLUSION: TET3 promoted the DNA demethylation modification in the SHP2 promoter and activated SHP2, thus activating the EGFR/ERK pathway and leading to EC progression.

Platelet-rich plasma-derived extracellular vesicles inhibit NF-κB/NLRP3 pathway-mediated pyroptosis in intervertebral disc degeneration via the MALAT1/microRNA-217/SIRT1 axis.

BACKGROUND: Intervertebral disc degeneration (IDD) is a main contributor to lower back pain, and compression stress-induced apoptosis of nucleus pulposus (NP) cells and extracellular matrix (ECM) degradation has been implicated in the IDD progression. The functions of platelet-rich plasma (PRP)-derived extracellular vesicles (PRP-EVs) in regulating these biological processes remain unclear in IDD. Here, we aimed to investigate the key role of long noncoding RNA (lncRNA) MALAT1 incorporated in PRP-EVs in IDD. METHODS: Tert-butyl hydroperoxide (TBHP)-induced damage in NP cells was treated with PRP-EVs extracted from healthy volunteers, followed by MTT, EdU, TUNEL, and Western blot assays. IDD mice were also treated with PRP-EVs. Histomorphological and pathological changes were evaluated. The pyroptosis of cells and the degradation of ECM were detected by ELISA and immunohistochemistry. We screened the differentially expressed lncRNAs in NP cells after PRP-EVs treatment by microarray analysis. The downstream targets of MALAT1 in NP cells were predicted and validated by rescue experiments. FINDINGS: TBHP induction reduced cell proliferation and exacerbated pyroptosis and ECM degradation, and PRP-EVs inhibited TBHP-induced cell damage. PRP-EVs-treated mice with IDD had reduced Thompson scores, increased NP tissue content, and restored ECM. PRP-EVs upregulated MALAT1 expression in vivo and in vitro, whereas MALAT1 downregulation exacerbated NP cell pyroptosis and ECM degradation. MALAT1 upregulated SIRT1 expression by downregulating microRNA (miR)-217 in NP cells. SIRT1 blocked the NF-κB/NLRP3 pathway-mediated pyroptosis, thereby alleviating IDD. INTERPRETATION: PRP-EVs deliver MALAT1 to regulate miR-217/SIRT1, thereby controlling NP cell pyroptosis in IDD.

A study on the level of NLRP3 inflammasome in patients with premature rupture of membranes.

OBJECTIVE: In this study, we investigated the levels of interleukin-1ß (IL-1ß), IL-18, and the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome in patients with premature rupture of membranes (PROMs). METHODS: We selected 60 pregnant women at the Fourth Hospital of Baotou between January 2019 and July 2021. These women were divided into three distinct groups: the preterm PROM group with 20 cases, term PROM (TPROM) group with 20 cases, and a control group with 20 cases consisting of normal full-term pregnancies without PROM. Peripheral blood was collected from all participants. Using enzyme-linked immunosorbent assay, the levels of IL-1 and IL-18 in the plasma were assessed. Additionally, the proportions of NLRP3, apoptosis-associated speck-like protein (ASC), and caspase-1-positive macrophages were also evaluated. RESULTS: The ratios of NLRP3, ASC, IL-1ß, and IL-18 concentrations, along with the presence of caspase-1-positive macrophages, were notably greater in the PROM groups in comparison with the control group (p < .05). In the TPROM group and control group, the proportions of IL-1ß and IL-18 levels were found to be lower than NLRP3, ASC, and caspase-1-positive macrophages levels (p < .05). CONCLUSION: The concentrations of IL-1ß and IL-18, as well as the ratios of NLRP3, ASC, and caspase-1-positive macrophages, were elevated in patients with PROM compared to the control group. This suggests a potential correlation between the excessive activation of NLRP3 and the development of PROM.

Meta-analysis of randomised controlled trials comparing unipolar with bipolar hemiarthroplasty for displaced femoral-neck fractures.

PURPOSE: Unipolar and bipolar hemiarthroplasty (HA) are used to treat displaced femoral-neck fractures. However, which type is best for treating displaced femoral-neck fractures in elderly patients remains a subject for debate. Our aim was to review randomised controlled trials to establish which type provides superior clinical outcome for this patient population. METHODS: We searched PubMed, Embase and Cochrane Register of Controlled Trials databases and Web of Science for randomised controlled trials (RCTs) comparing unipolar with bipolar HA to treat femoral-neck fracture in the elderly. Risk ratios (RRs) and mean differences (MDs) from each trial were pooled using random-effects or fixed-effects models depending on study heterogeneity. Analysis was performed using RevMan5.2 from the Cochrane Collaboration. RESULTS: A total of 1,100 patients from nine studies were assessed in this meta-analysis. Results showed no significant differences in function score [MD = -0.14, 95% confidence interval (CI) -2.42-2.13], mortality (RR = 0.97, 95% CI 0.65-1.46), dislocation (RR = 1.33, 95% CI 0.53-3.34), deep infection (RR = 0.79, 95% CI 0.35-1.79), acetabular erosion (RR = 1.99, 95% CI 0.61-6.52), operating time (MD = 2.14, 95% CI -9.85 to14.14), blood loss (MD = 13.40, 95% CI -49.60 to 76.39) and length of hospital stay (MD = 0.12, 95% CI -0.49 to 0.73) between unipolar and bipolar HA. CONCLUSIONS: Unipolar and bipolar HA achieved similar clinical outcomes in patients with displaced femoral-neck fractures.