Xiaoli Wang

Objective: To investigate the role and molecular mechanism of the GATA2/ZNF486/JAM2 transcriptional regulatory axis in the invasion and migration of Uterine Corpus Endometrial Carcinoma (UCEC). Methods: We employed reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB) to assess the expression levels of ZNF486, GATA2, and JAM2 in UCEC cell lines. Lentivirus-mediated overexpression and knockdown cell lines were established, and CCK-8, colony formation, Transwell, and wound healing assays were performed to evaluate cell proliferation, invasion, and migration. WB and immunofluorescence were used to detect changes in epithelial-mesenchymal transition (EMT) markers. The direct binding and transcriptional activation of target gene promoters by transcription factors were confirmed through ChIP-qPCR and dual-luciferase reporter assays. Results: ZNF486 was significantly downregulated in UCEC. Its overexpression upregulated E-cadherin, downregulated N-cadherin and Vimentin, and markedly inhibited cell proliferation, invasion, and migration. Mechanistically, ZNF486 directly bound to and transcriptionally activated the JAM2 promoter; knockdown of JAM2 partially attenuated the tumor-suppressive effects of ZNF486. Furthermore, GATA2 was identified as an upstream transcription factor that directly activated ZNF486 transcription; knockdown of ZNF486 abrogated the tumor-suppressive effects induced by GATA2 overexpression. Conclusion: GATA2 inhibits EMT, invasion, and migration in UCEC by transcriptionally activating the ZNF486-JAM2 axis. This pathway provides a potential molecular framework for understanding UCEC progression.

Acute lung injury (ALI) represents a severe respiratory condition. Inflammation is a pivotal factor in the pathogenesis of ALI. Mammalian STE20-like protein kinase 1 (MST1) has emerged as a key regulator of sphingolipid metabolism and a mediator of inflammatory responses. However, the precise role and underlying mechanisms of MST1 in lipopolysaccharide (LPS)-induced ALI remain unclear. This study aimed to investigate the influence of MST1 on the inflammatory response in LPS-induced ALI. An LPS-induced ALI model was established using RAW 264.7 cells and mice. In vivo, lung histopathological changes, wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and inflammatory cytokine levels [interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α)] were assessed. Oxidative stress markers, including superoxide dismutase (SOD) activity and malondialdehyde (MDA) content, were measured. In vitro, MST1 overexpression was induced in RAW 264.7 cells via lentiviral transfection. Cell viability and proliferation were evaluated using the CCK-8 assay. The expression levels of NF-κB and NLRP3 signaling pathways in vitro or in vivo were analyzed using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting analysis. The results showed that inhibition of MST1 expression attenuated lung damage, alleviated inflammation, enhanced antioxidant capacity, and inhibited the activation of NF-κB and NLRP3 pathways in vivo. In contrast, MST1 overexpression promoted cell proliferation and inflammation in vitro, accompanied by the activation of NF-κB and NLRP3 signaling pathways. This study demonstrated that MST1 activation contributed to inflammation in LPS-induced ALI by modulating the NF-κB/NLRP3 signaling pathway. Targeting MST1 may represent a novel approach to the treatment of ALI.

Objective: High-risk human papillomavirus (HR-HPV) screening has increased colposcopy referrals, particularly for women with HR-HPV positivity but no intraepithelial lesion or malignancy (NILM) and those with atypical squamous cells of undetermined significance (ASC-US). A fraction of low-grade squamous intraepithelial lesions (LSILs) is associated with cervical intraepithelial neoplasia grade 2 or worse (CIN2+) during diagnosis. This study evaluated the ability of GYPC methylation (GYPC^m) to distinguish between GYPC^m, HPV genotyping, and their combination and compared the clinical performance of each triage strategy.Methods: To improve cervical screening efficiency, risk stratification based on HPV genotyping and GYPC^m was used as a triage strategy.Results: GYPC^m distinguished between 0.999) and significant differences in specificity (70.5% vs. 21.8%, p < 0.001). The HPV16/18 or GYPC^m triage strategy required the least number of referrals to detect a CIN2 + at 3.9 (3.3–4.6).Conclusion: HPV16/18 or GYPC^m as a triage tool in HPV-positive women with NILM, ASC-US, and LSIL cytology significantly reduced colposcopy referrals while maintaining sensitivity similar to that of HPV16/18 or ASC-US+.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious respiratory disorders caused by a variety of intrapulmonary and extrapulmonary factors. Their incidence is increasing year by year, with high morbidity and mortality rates and lack of effective treatment. Inflammation plays a crucial role in ALI development, with sphingosine kinase 1 (SphK1) being a pivotal enzyme influencing sphingolipid metabolism and participating in inflammatory responses. However, the specific impact and the signaling pathway underlying SphK1 in lipopolysaccharide (LPS)-induced ALI/ARDS are poorly understood. This investigation aimed to explore the influence of SphK1 on inflammation and delve into the mechanistic aspects of inflammation in RAW 264.7 cells during LPS-induced ALI, which is of great importance in providing new targets and strategies for ALI/ARDS treatment. Graphical Abstract

As severe conditions, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) threaten human health. Inflammation and oxidative stress play a vital role in the pathogenesis of ALI/ARDS. Sphingosine kinase 1 (SphK1) significantly contributes to mediating inflammatory responses. Nevertheless, the impact of SphK1 on lipopolysaccharide (LPS)-triggered ALI/ARDS remains largely undetermined. In our current work, we explored the impact of SphK1 on ALI/ARDS using a mouse model. We studied whether it could reduce LPS-triggered inflammatory response and oxidative stress by suppressing SphK1 in ALI/ARDS. The mice were treated with the inhibitor of SphK1 (N,N-dimethylsphingosine, DMS) before intraperitoneal injection of LPS. Moreover, we assessed the survival rate, and several parameters, such as the lung wet/dry (W/D) ratio, myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, and the release of inflammatory cytokines. Western blotting analysis was adopted to evaluate the levels of phosphoinositide 3-kinase (PI3K)/serine/threonine kinase (AKT) pathways. We showed that the inhibitor of SphK1 not only ameliorated LPS-stimulated lung histopathological changes and W/D ratio of lung tissue but also elevated the survival rate, the SOD activity and decreased the MDA content, MPO activity, interleukin-6 (IL-6) and tumor necrosis factor-ɑ (TNF-ɑ) production by regulating the PI3K/AKT signaling pathway in lung tissue. Taken together, SphK1 played an essential role in inflammatory responses and oxidative stress. The underlying mechanism might be linked to the activation and up-regulation of the PI3K/AKT signaling pathway in LPS-triggered ALI/ARDS.

Platelet activation contributes to organs failure in inflammation and plays an important role in endotoxemia. Clopidogrel inhibits platelet aggregation and activation. However, the role of clopidogrel in modulating inflammatory progression of endotoxemia remains largely unexplored. Therefore, we investigated the role of clopidogrel on the activation of platelet and leukocytes in lipopolysaccharide (LPS)‐induced inflammation in mice. Animals were treated with clopidogrel or vehicle before LPS induction. The expression of neutrophil‐platelet aggregates and platelet activation and tissue factor was determined. Immunofluorescence was used to analyze platelet‐leukocyte interactions and tissue factor (TF) expression on leukocytes. Clopidogrel pretreatment markedly decreased lung damage, inhibited platelet‐neutrophil aggregates and TF expression. In addition, clopidogrel reduced thrombocytopenia and affected the number of circulating white blood cell in endotoxemia mice. Moreover, clopidogrel also reduced platelet shedding of CD40L and CD62P in endotoxemic mice. Taken together, clopidogrel played an important role through reducing platelet activation and inflammatory process in endotoxemia.

Oxidative stress and inflammation are hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Resveratrol (trans-3,5,4′-trihydroxystilbene) is known for its antioxidant and anti-inflammatory properties. The study aimed to investigate the effects of resveratrol in a rat model with COPD on the regulation of oxidative stress and inflammation via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α). Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The COPD model was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured. The levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50 mg/kg), compared with the COPD group, alleviation of inflammation and reconstruction in the small airways of the lungs were seen. Resveratrol might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment decreased serum levels of IL-6 and IL-8. Our findings indicate that resveratrol had a therapeutic effect in our rat COPD model, which is related to the inhibition of oxidative stress and inflammatory response. The mechanism may be related to the activation and upgrading of the SIRT1/PGC-1α signaling pathways. Thus resveratrol might be a therapeutic modality in COPD.

Oxidative stress is hypothesized to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD).The study was purposed to investigate the effects of resveratrol (trans-3,5,4'-trihydroxystilbene) in a rat model with COPD on the regulation of oxidative stress via the activation of Sirtuin1 (SIRTl) and proliferator-activated receptor-γ coactivator-1α (PGC-1α).Thirty Wistar rats were randomly divided into three groups: control group, COPD group and resveratrol intervention group. The model of COPD was established by instilling with lipopolysaccharide (LPS) and challenging with cigarette smoke (CS). The pathological changes in lungs were evaluated by hematoxylin and eosin (HE) stain. The levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) in serum were measured by enzyme-linked immunosorbent assay (ELISA). The level of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in both lung tissue homogenate and bronchial alveolar lavage fluid (BALF) were examined by using the commercially available kits. The expression levels of SIRT1 and PGC-1α in the lung tissues were examined by immunohistochemistry as well as real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) and western blotting analysis. After the treatment with resveratrol (50mg/kg), compared with the COPD group, the alleviation of inflammation and the reconstruction in the small airways of lungs were seen, which might be correlated not only with the lower level of MDA and the higher activity of SOD, but also with the upregulation of SIRT1 and PGC-1α expression. Resveratrol treatment also decreased serum levels of IL-6 and IL-8. The results indicated that resveratrol appeared to reduce oxidative stress by altering the levels of MDA and SOD in our rat COPD model, and the possible mechanism of this intervention effect of resveratrol with COPD may be associated with its upregulation of SIRT1and PGC-1α.Thus resveratrol might be a therapeutic modality in COPD.