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关键词： Ovarian cancer   Tumor microenvironment   Macrophage polarization   IL-33   TRIM28  

摘要： The tumor microenvironment provides optimal condition for the growth of ovarian cancer. Macrophages display a highly functional plasticity to respond various signals. Switching macrophages' phenotype is a potential therapeutic strategy for the treatment of cancer. We used RNA-sequencing(RNA-Seq) and Chromatin immunoprecipitation-sequencing(ChIP-Seq) analyses in bone-marrow-derived macrophages (BMDMs) from wildtype (WT) and its receptor interleukin-1 receptor like-1 (IL1RL1 or ST2) knockout(ST2-/-) mice revealed that the interaction between IL-33 and TRIM28, which plays an antioxidant role, regulates glycolysis in BMDMs by promoting the PI3K/Akt pathway in ST2-independent manner, thereby reducing M2 polarization of macrophages is a way to inhibit ovarian cancer growth.

关键词： 粪拟杆菌   过敏性哮喘   卵清蛋白特异性免疫球蛋白E   细胞因子   肠道菌群  

摘要： 目的： 利用优化的小鼠过敏性哮喘模型，体内评价一株粪拟杆菌IM01的抗哮喘功能及对肠道菌群的影响。方法： 对比不同激发方式优化卵清蛋白（OVA）诱导的哮喘小鼠模型。将雌性BALB/c小鼠随机分为磷酸盐缓冲溶液、OVA模型组和IM01干预组。IM01干预组经口给予1×109菌落形成单位/只IM01活菌，连续21d，第22天采集肺部组织。检测血清OVA特异性免疫球蛋白E（IgE）及肺白细胞介素（IL）-4、IL-5、IL-13水平，并进行肺组织苏木精-伊红染色和粪便16S rRNA基因测序分析。结果：OVA雾化激发方式建模更优；口服IM01显著降低哮喘小鼠血清IgE及肺部IL-4、IL-5、IL-13水平，减轻肺病理炎性细胞浸润；IM01调节肠道菌群结构（增高有益菌/降低有害菌丰度）。结论： IM01经口干预可缓解哮喘小鼠肺部炎症及病理损伤，并调节肠道菌群组成。

关键词： coal dust exposure   dyslipidemia   lipid metabolism   FMO3 (flavin monooxygenase 3)   IL-6 (interleukin-6)  

摘要： Background: This study aims to investigate the impact of coal dust (silicon dioxide) exposure on dyslipidemia and its underlying mechanisms, with a focus on the association between coal dust exposure and hepatic metabolic disorders. Methods: Clinical data were collected from 5433 coal mine workers to compare the incidence of dyslipidemia between the dust-exposed group and the non-exposed group. A mouse model of silicon dioxide exposure was established to observe hepatic fat accumulation and pathological changes. Liver tissue sequencing was performed to screen for key differential genes. In vitro cell experiments were utilized to identify the molecular mechanisms underlying hepatocyte metabolic abnormalities induced by silicon dioxide exposure. Results: Clinical data revealed that 69.2% of miners in the dust-exposed group developed dyslipidemia, which was higher than the 30.7% in the non-exposed group. Animal data showed that silicon dioxide exposure led to hepatic fat deposition and pathological damage, with the degree of injury positively correlated with exposure time. Liver sequencing identified a significant upregulation of the FMO3 (flavin monooxygenase 3) gene in mouse liver tissue following silicon dioxide exposure, accompanied by enhanced inflammatory responses. Mechanistic studies demonstrated that silicon dioxide activates Kupffer cells to secrete IL-6 (interleukin-6), which induces high expression of FMO3 in hepatocytes through the PKC/YY1 signaling pathway, thereby disrupting lipid metabolism. Conclusions: Silicon dioxide exposure can promote the upregulation of FMO3 expression in hepatocytes by activating Kupffer cells to release IL-6 via the PKC/YY1 pathway, ultimately leading to lipid metabolic disorders and dyslipidemia

关键词： ATF6 alpha   normal human dermal fibroblasts   skin   UPR   UVB-induced senescence  

摘要： Skin aging is influenced by both intrinsic and extrinsic factors, particularly UV radiation, and is characterized by an accumulation of senescent cells. Remarkably, exposure to UV can trigger senescence in different skin cell types, including dermal fibroblasts. However, the molecular mechanisms underlying UV-induced senescence and the impact of the related senescence-associated secretory phenotype (SASP) on the homeostasis of the overlying epidermis remain poorly understood. Here, we identified that both chronological aging and photoaging induce the unfolded protein response (UPR) in human dermal samples. We demonstrated that silencing ATF6 alpha disrupts the establishment of the UVB-induced senescent phenotype by preventing the onset of several senescent biomarkers and alters the composition of the SASP, consequently affecting its impact on the increased proliferation of keratinocytes embedded in reconstructed human epidermis. Moreover, we found that ATF6 alpha partially mediates IL8 expression involved in the hyperproliferation of cultured keratinocytes. Together, our findings highlight the importance of the ATF6 alpha/IL8 axis in regulating the homeostasis of neighboring cells during skin photoaging, thus suggesting ATF6 alpha as a potentially promising target for senotherapeutic interventions.

关键词： Tocilizumab   Interleukin-6   COVID-19   Viral pneumonia   Acute respiratory distress syndrome   Randomized controlled trial  

摘要： Background The objective of this clinical trial is to evaluate the efficacy and safety of IL-6 driven personalized treatment strategy with tocilizumab in patients with severe COVID-19 pneumonia. Trial design Randomized, controlled, open-label, single-center trial of a tocilizumab treatment strategy in adult patients hospitalized with severe COVID-19 pneumonia and IL-6 serum levels > 40 pg/mL. Methods Patients were randomized 1:1 to receive standard of care (SOC) or SOC plus one dose of tocilizumab. The primary outcome was death or need for invasive mechanical ventilation (IMV) within 28 days after randomization. Secondary outcomes included ICU admission, days on IMV and hospital stay. A meta-analysis of clinical trials to evaluate the effect of tocilizumab on mortality and need of IMV in patients with COVID-19 pneumonia was performed. Results Sixty-two patients were included: 30 in the SOC arm and 32 in the standard-treatment plus tocilizumab arm. The primary outcome occurred in 12.9% in the tocilizumab arm and 32.3% in the SOC arm(p = 0.068). There was a trend towards fewer days on IMV (7.5 vs 19.5 days, p = 0.073) and a shorter hospital stay (4 vs 8 days, p = 0.134) in the tocilizumab group. No serious adverse events were reported. The meta-analysis revealed a RR for death or IMV of 0.83 (95% CI: 0.77-0.89) in patients receiving tocilizumab, compared to patients receiving SOC. Conclusion Tocilizumab could be effective to prevent death or IMV in patients with severe COVID-19 pneumonia and high IL-6 serum levels. Safety profile of tocilizumab does not arise major concern in patients with severe COVID19.

关键词： IL-18BP   fibrosis   MASH   hepatic stellate cell   APB-R3   IFNγ  

摘要： Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by inflammation and fibrosis, with enhanced interleukin-18 (IL-18) signaling. IL-18-binding protein (IL-18BP) neutralizes IL-18, but its therapeutic potential in MASH is unclear. We find elevated IL-18BP and IL-18 levels in patients with MASH and mice, with free IL-18 correlating with disease severity. IL-18 stimulates interferon-gamma (IFNg) production in CD4 T cells, increasing hepatic IL-18BP. IL-18BP-deficient mice show worsened liver inflammation and fibrosis. We develop a human IL-18BP biologics (APB-R3) and inject it to mice to evaluate its pharmacologic efficacy. APB-R3 significantly improves MASH in reducing fibrosis and inflammation and inhibits hepatic stellate cell activation via the cGMP pathway. This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis, and our engineered IL-18BP biologics can become a promising therapeutic candidate for curing MASH.

关键词： ECs pyroptosis   DR   circTHADA   CASP1   ceRNA network  

摘要： Our study aimed to elucidate the mechanism by which circTHADA competitively adsorbs miR-494-3p to regulate CASP1-mediated endothelial cell (EC) pyroptosis in diabetic retinopathy (DR). To be specific, we used high glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs) as DR cell models and streptozotocin (STZ)-treated mice as DR mouse models. The expression levels of circTHADA, miR-494-3p, CASP1, NLRP3, GSDMD-N and IL-1 beta were detected and flow cytrometry was applied to measure cell pyroptosis rate and dual luciferase reporter assays were utilized to determine the direct binding sites. As a result, exacerbated EC pyroptosis in DR was detected in DR cell and mouse models. Based on differentially expressed circRNA profiles by microarray and experimental verification, circTHADA was filtered and identified to regulate CASP1-mediated EC pyroptosis. miR-494-3p was then proven to be involved in circTHADA-mediated ceRNA network by bioinformatics analysis and experimental verification. Further gain- and loss-of-function experiments and rescue experiments revealed the function of the circTHADA/miR-494-3p/CASP1 axis in pyroptosis.