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摘要： Psoriasis is an inflammatory dermatosis that features overproliferation and inflammatory reaction of keratinocytes. A study reported that IL-22 is involved in the pathogenesis of psoriasis by mediating miR-124 to regulate the expression of fibroblast growth factor receptor 2 in keratinocytes. A microRNA may target multiple target genes. Therefore, we speculate that miR-124-3p may also target other downstream genes to affect IL -22-induced keratinocyte function. A possible target gene of miR-124-3p, growth factor receptor-bound protein 2 (GRB2), was screened by analyzing the target gene databases. GRB2 expression was elevated and miR-124-3p expression was decreased in psoriatic lesions compared to psoriatic adjacent normal skins and healthy controls. We performed the following cell experiments in the IL-22-stimulated HaCaT cell model. In keratinocytes transfected with the miR-124-3p mimics, GRB2 expression was significantly lower. We analyzed the regulation of keratinocyte proliferation by GRB2 and miR-124-3p. High levels of GRB2 promoted keratinocyte proliferation and expression of Ki67, PCNA, and K16, which were inhibited by low expression of GRB2. In addition, we found that the effect of GRB2 inhibitors on the proliferation and inflammatory response of keratinocytes was dose-dependent. Finally, we investigated the influence of GRB2 on inflammatory mediators in keratinocytes with the ELISA. After low expression of GRB2, the mRNA expression and secretion of the pro-inflammatory factor were suppressed. When both GRB2 and miR-124-3p were overexpressed, the cellular overproliferation and inflammation caused by GRB2 overexpression were significantly reversed by miR-124-3p. In summary, IL-22-mediated miR-124-3p regulates keratinocyte hyperproliferation and inflammatory response by suppressing GRB2 expression in psoriasis.

关键词： Osteoarthritis   miR-8485   CRLF1   Chondrocytes   IL-1 beta  

摘要： The aim of this study was to investigate the impact of differentially expressed miR-8485 on chondrocyte inflammation in osteoarthritis (OA) and its underlying pathological mechanisms. MiR-8485, which was downregulated in OA, was identified by microarray analysis, and was also found to be decreased in IL-1 beta-induced C28/ I2 cells. miR-8485 down-regulation or IL-1 beta treated of C28/I2 cells induces a decrease in cellular activity, an increase in apoptosis, an elevation in Cleaved caspase-3, MMP13, and ADAMTS5 protein levels, a decrease in Collagen II and Aggrecan levels, and an increase in the levels of pro-inflammatory factors TNF-alpha and IL-6. CRLF1 was identified to be a downstream target gene of miR-8485 using bioinformatics prediction and dual luciferase reporter gene assays. CRLF1 was shown to be increased in IL-1 beta-treated C28/I2 cells, and CRLF1 overexpression partially abrogated the suppressive effect of upregulated miR-8485 on chondrocyte inflammation. In addition, miR-8485 was able to inhibit MAPK/ERK and PI3K/AKT signaling activation by inhibiting CRLF1. In conclusion, miR-8485 was able to inhibit CRLF1 expression and thus inhibit IL-1 beta-triggered inflammation in chondrocytes, potentially through the inhibition of MAPK/ERK and PI3K/AKT signaling pathways.

摘要： Microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) patients are the dominant population in immune checkpoint blockade treatments, while more than half of them could not benefit from single-agent immunotherapy. We tried to identify the biomarker of MSI-H CRC and explore its role and mechanism in anti-PD-1 treatments. Tumor-specific MHC-II was linked to a better response to anti-PD-1 in MSI-H CRC and CD74 promoted assembly and transport of HLA-DR dimers. The characteristic gene was screened by data analysis of single-cell and bulk transcriptome sequencing from public datasets. MSI-H CRC cells co-cultured with peripheral blood mononuclear cells and syngeneic model in C57BL/6 mice were performed to detect the sensitivity to anti-PD-1 treatments respectively. ANXA10 was identified as a characteristic gene of MSI-H CRC and its expression was obviously greater in MSI-H than MSS CRC. ANXA10 significantly sensitized MSI-H CRC to anti-PD-1 treatments in vitro and in vivo. Specifically, ANXA10 promoted HLA-DR dimers in and on the surface of MSI-H CRC by increasing CD74 expression. Besides, this work demonstrated that ANXA10 contributed to better clinical benefits with anti-PD-1 therapy in MSI-H CRC patients. Our results provided a novel molecular marker ANXA10 to identify benefit population of MSI-H CRC for improving efficacy of anti-PD-1 and contributed to selection of treatment strategies.

摘要： Reduced lymphoid enhancer-binding factor 1 (LEF1) expression in patients with adenomyosis during the mid-secretory phase leads to impaired endometrial receptivity, affecting embryo implantation. This study investigated the molecular mechanisms underlying reduced endometrial receptivity in 25 adenomyosis patients and 25 controls. Functional experiments were conducted using human endometrial stromal cells (HESCs) and TERT-immortalized HESCs(T-HESCs), with final validation performed using a mouse model. Western blot and quantitative real-time polymerase chain reaction (RT-qPCR) analyses revealed that patients with adenomyosis showed a marked decrease in LEF1 expression in the stromal cells of the endometrium during the mid-secretory phase. In vitro experiments demonstrated that LEF1 knockdown in stromal cells led to impaired decidualization. Transcriptome sequencing, dual-luciferase reporter assays, and chromatin immunoprecipitation (ChIP) experiments showed that LEF1 could bind to the promoter region of interleukin (IL)-11 and promote its transcription, and IL-11 expression was also found to be downregulated in adenomyosis patients. Overexpression of IL-11 rescued the impaired decidualization caused by decreased LEF1 expression. In the in vitro co-culture model, LEF1/IL-11 knockdown led to a reduction in embryo implantation area, which was partially restored upon IL-11 overexpression. In the adenomyosis mouse model, we observed a decrease in LEF1 expression and a reduction in implantation sites compared to control mice, accompanied by impaired decidualization and receptivity. Notably, supplementation with IL-11 restored the number of implantation sites. The decrease in fertility due to reduced endometrial receptivity in adenomyosis patients is a significant clinical issue in assisted reproductive technology. This research provides insights into one potential molecular mechanism underlying this decreased receptivity, with a specific focus on the reduced expression of L

关键词： EGCG   Asthma   Airway inflammation   TNF-alpha/TNF-R1/NLRP3 signaling pathway  

摘要： (-)-Epigallocatechin-3-gallate (EGCG) is a polyphenol in green tea with potential lung-protective effects. However, the effects of EGCG on airway inflammation in asthma remain unclear. The aim of this study was to investigate the effect and mechanism of EGCG on asthmatic airway inflammation. In this study, the therapeutic effects of EGCG on ovalbumin (OVA)-induced asthmatic mice were tested first. Second, the effects of EGCG on airway inflammation, airway hyperresponsiveness (AHR), airway mucus hypersecretion, cell apoptosis and differential genes were investigated. Finally, the relationships between the effects of EGCG on airway inflammation and the TNF-alpha/TNF-R1/NLRP3 signaling pathway in asthmatic mice were explored. The results showed that EGCG could attenuate AHR, alleviate the symptoms of alveolar wall thickening and inflammatory cell infiltration, decrease the levels of inflammatory cytokines and airway mucus markers, reduce apoptosis and reactive oxygen species (ROS) and increase the mitochondrial membrane potential (MMP) in primary lung cells in asthmatic mice. Additionally, EGCG significantly inhibited the activation of the TNF-alpha/TNF-R1/NLRP3 signaling pathway in the lung tissues of asthmatic mice. The lowest binding free energies of EGCG with TNF-alpha, TNF-R1 and NLRP3 were-11.6,-11.6 and-8.2 kcal/mol, respectively. Moreover, the equilibrium dissociation constant (KD) of EGCG and TNF-R1was 26.05 mu mol/L. EGCG-mediated inhibition of TNF-alpha/TNF-R1/NLRP3 signaling pathway activation was blocked in LPS-induced BEAS-2B and RAW264.7 cells overexpressing TNF-alpha. Consequently, EGCG effectively attenuated AHR and inhibited airway inflammation and airway mucus hyper- secretion in asthmatic mice, and these effects may be closely related to the TNF-alpha/TNF-R1/NLRP3 signaling pathway.

摘要： Osteoarthritis (OA) is a common type of degenerative arthropathy. Previous studies have demonstrated that circular RNAs (circRNAs) are involved in the progression of OA. This study aimed to investigate the role and associated mechanism of circ_0075048 in OA. The expression of circ_0075048 was analyzed based on the Gene Expression Omnibus dataset GSE178724. Human chondrocytes were stimulated with IL-1β to establish an in vitro OA model. Bioinformatic analysis was performed to identify target genes of circ_0075048. The expression of circ_0075048, miR-663b, and LCP1 was detected by quantitative reverse transcription-polymerase chain reaction. The cell viability and apoptosis of C28/I2 cells were determined using Cell Counting Kit-8 assay and flow cytometry. Protein expression was detected using western blotting. The expression of circ_0075048 was up-regulated in IL-1β-induced chondrocytes. circ_0075048 silencing promoted the viability of and inhibited the apoptosis of and extracellular matrix (ECM) production of chondrocytes. circ_0075048 was found to be a sponge of miR-663b and LCP1 was found to be a target of miR-663b. circ_0075048 silencing increased miR-663b expression but decreased LCP1 expression levels in chondrocytes. An miR-663b inhibitor eliminated the protective effect of a circ_0075048 small interfering RNA (siRNA) on chondrocytes. However, an LCP1 siRNA abolished the effect of the miR-663b inhibitor on chondrocytes. circ_0075048 silencing inhibited the apoptosis of and ECM degradation in IL-1β-induced chondrocytes by regulating miR-663b/LCP1 axis.

摘要： The purpose of this study was to determine the levels of IL-17, Bcl-3 and IκBζ gene expression in the gingival crevicular fluid (GCF) of psoriatic and healthy individuals and to compare the clinical periodontal parameters in the patient and control groups. A total of 10 psoriasis patients and 2 healthy patients in the control group were included in the analysis for IL-17, Bcl-3, and IκBζ gene expression in the GCF. Periodontal health, gingival index, plaque index, and mobility (using a periotest device) levels were compared between the groups. While considering the down-expressed patients, the expression level of the Bcl-3 gene showed the most variability among the genes studied in psoriasis disease. IL-17 gene expression levels were significantly higher and up-regulated in all patients compared to the control group. In addition, when comparing IL-17 with Bcl-3, IL-17 gene expression was notably high in all patients except patients 4, 9 and 10. The highest expression levels of the IκBζ gene were observed in the patient sample, except for patients 7 and 8. While plaque index, gingival index, and pocket depth parameters were higher in the psoriasis group, there was no significant difference between the two groups (p = 0.257, p = 0.390, p = 0.240, respectively). In the periotest (mobility) parameter, while the mean value was higher in the psoriasis group significantly (p = 0.030), clinically mean values of two groups were in the same grade according to Miller mobility index. The IκBζ gene showed notable high expression levels in psoriasis patients. It was concluded that psoriasis may be associated with periodontitis. NCT06408454–05/06/2024. Interleukin- 17 (IL-17), Bcl-3, and NF-kappa-B Inhibitor Zeta (IκBζ) Expression Levels in the Psoriasis Patients.

摘要： Fibroblast-like synoviocytes (FLS) are key players in rheumatoid arthritis (RA) by resisting apoptosis via increased autophagy. Elevated synovial aquaporin 1 (AQP1) affects RA FLS behaviors, but its relationship with FLS autophagy is unclear. We aim to clarify that silencing AQP1 inhibits autophagy to exert its anti-RA effects. We studied the effects and mechanisms of AQP1 silencing on autophagy in TNF-α-induced RA FLS and examined the crucial role of autophagy inhibition in its impacts on RA FLS pathogenic behaviors. We explored whether silencing synovial AQP1 relieved rat adjuvant-induced arthritis (AIA) by reducing synovial autophagy. TNF-α stimulation increased AQP1 expression and autophagy levels in RA FLS, with a positive correlation between them. AQP1 silencing inhibited autophagy in TNF-α-stimulated RA FLS, along with suppressing proliferation, promoting apoptosis, and mitigating inflammation. Notably, the inhibitory effects of AQP1 silencing on RA FLS pathogenic behaviors were cancelled by autophagy activation with rapamycin (Rapa) but enhanced by autophagy inhibition using 3-Methyladenine. Mechanistically, silencing AQP1 enhanced the binding of Bcl-2 to Beclin1 by decreasing Beclin1-K63 ubiquitination, thus inhibiting RA FLS autophagy. In vivo, silencing synovial AQP1 relieved the severity and development of rat AIA, alongside reducing Ki67 expression, promoting apoptosis, and decreasing autophagy within AIA rat synovium. Expectedly, the Rapa co-administration nullified the anti-AIA effects of silencing synovial AQP1. These findings reveal that silencing AQP1 inhibits RA FLS pathogenic behaviors and attenuates rat AIA through autophagy inhibition. This study may help clarify the pathogenic role of AQP1 in enhancing autophagy during RA development.

摘要：

Therapeutic human papillomavirus (HPV) DNA vaccine is an attractive option to control existed HPV infection and related lesions. The two early viral oncoproteins, E6 and E7, are continuously expressed in most HPV-related pre- and cancerous cells, and are ideal targets for therapeutic vaccines. We have previously developed an HPV 16 DNA vaccine encoding a modified E7/HSP70 (mE7/HSP70) fusion protein, which demonstrated significant antitumor effects in murine models. In this study, we employed multifaceted approach to enhance the potency of the HPV16 DNA vaccine. Strategies including inserting CpG oligodeoxynucleotide (CpG ODNs) into the vaccine vector backbone, selecting cytokine gene adjuvants, combining plasmids encoding mE6/HSP70 and mE7/HSP70, and utilizing electroporation for vaccination. Our findings revealed that mice immunized with CpG-modified vaccines, coupled with an IL-28B gene adjuvant exhibited heightened antigen-specific CD8⁺ T cell responses. Additionally, the combination of mE6/HSP70 and mE7/HSP70 plasmids synergistically enhanced the specific CD8⁺ T cell response. Furthermore, vaccination with CpG-modified mE7/HSP70 and mE6/HSP70 plasmids, alongside the Interleukin-28B (IL-28B) gene adjuvant, generated substantial preventive and therapeutic antitumor effects against HPV E6- and E7-expressing tumors in C57BL/6 mice. These results suggested that integrating these multiple strategies into an HPV DNA vaccine holds promise for effectively controlling HPV infection and related diseases.

摘要： Interleukin 17A is a pivotal factor in the development and progression of cervical cancer. Common genetic variants of the IL17A gene have been linked to susceptibility to cervical cancer development. However, the observations remained inconsistent, which has been attributed to the lower sample size and differential clinical categorization of patients. In order to ascertain the precise involvement of IL17 in the development of cervical cancer, we conducted a comprehensive meta-analysis of studies that had been previously published. Several literature databases were searched, including PubMed, Google Scholar, and Science Direct. Appropriate published articles were screened and evaluated based on the inclusion and exclusion criteria, and the necessary data were obtained. The CMA v3.3.070 package was used for all analyses. Tenreports met the inclusion criteria for this meta-analysis, including four studies on IL17A levels and seven on IL17A polymorphism (rs2275913). Patients with cervical cancer had elevated IL17A levels compared to controls (standard difference in means = 3.23, p = 0.001). A meta-analysis of IL17A demonstrated that the mutants of both polymorphisms were associated with cervical cancer susceptibility. The trial sequential analysis showed that sufficient investigations have already been conducted for IL17A levels and rs2275913 association studies. Variant of IL17A are associated with an increased risk of developing cervical cancer, and elevated IL17A levels are related to the pathogenesis of cervical cancer.