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关键词： LPS-induced septic acute lung injury   Ethyl Caffeate   Network pharmacology   Transcriptomics   Inflammation   Apoptosis  

摘要： Background: Septic acute lung injury (Septic-ALI, SA) is a severe complication of sepsis with limited clinical treatment options. Ethyl Caffeate (EC) is a phenolic compound isolated from Ilex latifolia Thunb (I. latifolia) of the Aquifoliaceae family. Purpose: This study aimed to investigate the potential mechanisms of EC in treating SA by integrating network pharmacology and transcriptomics. Methods: We used network pharmacology to predict the potential pathways and targets of EC and validated these predictions using the GEO database, molecular docking and MDS. Subsequently, LPS-induced inflammation models in RAW cells and a mouse model of SA were established to evaluate the therapeutic effects of EC. Cell transcriptomic sequencing, along with ELISA, qRT-PCR, and Western blot analyses, were performed on both cellular and animal models to validate the key pathways and targets. Results: EC targeted TNF-alpha and MMP9, significantly alleviating LPS-induced SA through the TNF-alpha/NF-kappa B/MMP9 axis. Specifically, network pharmacology and molecular docking suggested that EC may target TNF, MMP9, EGFR, PRKACA, and MAPK3. Transcriptomic analyses, MDS and in vitro and in vivo experiments showed that EC primarily reduced the expression of p-p65 and p-I kappa B alpha in the TNF pathway by inhibiting TNF-alpha, thereby down-regulating the expression of downstream effector molecules MMP9 and MMP14, and improving lung tissue damage, cell apoptosis, and inflammation levels in mice. Conclusion: This study was the first to integrate network pharmacology and transcriptomic results, revealing the mechanism by which EC ameliorated SA through the TNF-alpha/NF-kappa B/MMP9 axis. Furthermore, experimental validation identified TNF-alpha and MMP9 as two core targets of EC, providing a valuable reference for the clinical treatment of SA.

关键词： Cytokines and Chemokines   Animal Models   Adaptive immunity  

关键词： Bladder cancer   Bioinformatic analysis   MiR-125b   Apoptosis   IL-6/IL-6R/STAT3 pathway  

摘要： Bladder cancer (BLCA) is an aggressive malignancy characterized by limited therapeutic options and a poor prognosis. Research has indicated that abnormally expressed miRNAs play a significant role in the pathogenesis of BLCA, although the specific mechanisms remain unclear. MiR-125b plays a tumor suppressor role in a variety of cancers and affects the biological processes of cancer cells such as proliferation, invasion, migration and apoptosis by regulating different signaling pathways. Elucidation of the molecular mechanisms underlying miR125b may provide clinical therapeutic strategies for bladder cancer. Here, miR-125b was downregulated whereas its targets IL-6R and STAT3 were upregulated in BLCA, as evidenced by bioinformatics analysis. Kaplan-Meier analysis confirmed that miR-125b serves as an independent prognostic factor linked to overall survival (OS) in patients with bladder cancer. Furthermore, overexpression of miR-125b significantly inhibited BLCA cell proliferation, migration, and invasion, while promoting apoptosis, as evidenced by an increased Bax/Bcl-2 ratio and activated cleaved caspase-3. Further investigations demonstrated that miR-125b directly targets and downregulates both IL-6R and STAT3. In a xenograft model, miR-125b overexpression effectively inhibited tumor growth in bladder cancer by blocking IL-6/IL-6R and STAT3 signaling pathways. Collectively, these findings broaden our understanding of the mechanism by which miR-125b acting as a BLCA suppressor in apoptotic regulation by targeting the IL-6/IL-6R/STAT3 signaling pathway, providing novel insights regarding the design of novel miRNA based therapeutic strategies against BLCA.

关键词： Achilles tendon   Kager's fat pad   rupture   thickness  

摘要： BACKGROUND: Acute Achilles tendon ruptures (ATR) are among the most common sports-related injuries. The aim of this study was to evaluate the correlation between Achilles tendon (AT) and Kager's fat pad (KFP) thickness with clinical and functional out-comes, measured using the Achilles Tendon Rupture Score (ATRS) and the Foot and Ankle Outcome Score (FAOS), in patients treated with open surgical repair for acute ATR. METHODS: This retrospective study included 42 patients who underwent surgery for ATR at our institution between January 2017 and December 2021. All patients were treated using the open surgical Krackow suture technique. ATRS, FAOS, and Visual Analogue Scale (VAS) scores were recorded one year postoperatively. AT and KFP thicknesses were measured via ultrasonography by an independent radiologist at one-year follow-up. RESULTS: The mean age of the patients was 45.38 +/- 9.68 years, with 22 male patients (52.4%). The mean ATRS was 65.17 +/- 24.46, the mean FAOS was 76.14 +/- 16.75, and the mean VAS score was 3.02 +/- 1.44. The mean AT thickness on the operated side was 15.54 +/- 2.89 mm, compared to 14.58 +/- 2.28 mm on the contralateral side (p=0.009). The mean KFP thickness on the operated side was 8.42 +/- 2.99 mm, compared to 6.32 +/- 2.67 mm on the contralateral side (p=0.005). A strong correlation was found between ATRS and FAOS (r=0.742, p<0.001). For AT thickness, there were moderate negative correlations with both ATRS and FAOS (r=-0.544, p=0.013;r=-0.451, p=0.003, respectively). For KFP thickness, a moderate negative correlation was found with ATRS (r=-0.506, p=0.001). CONCLUSION: AT and KFP thicknesses had no significant direct effect on ATRS and FAOS. However, ATRS and FAOS scores fol-lowing open surgical repair of acute ATR were correlated with each other and with functional outcomes. Despite its specific complica-tions, open surgical repair of acute ATR is an effective option for patients eligible for surgery.

关键词： Crohn's disease   Persistence   Ustekinumab   Second-line therapy  

摘要： BackgroundAnti-TNF treatment failure in Crohn's disease is common, and the literature on the selection of subsequent treatment is scant. Ustekinumab may be associated with high persistence rates and it appears to be effective in perianal *** objective: persistence, clinical, and biologic remission with ustekinumab. Secondary objectives: Persistence of the first biologic therapy, reasons for change of treatment, need for dose optimization, surgery, hospitalizations, and adverse events with ***, observational, single-center study from a prospective database of Crohn's disease adult patients receiving ustekinumab after failure of anti-TNF or vedolizumab. A sub-analysis was performed to evaluate ustekinumab persistence after the approval of risankizumab and *** duration with ustekinumab was 27.65 months (SD 18.27) and persistence was 86.76%. Clinical remission was 40.63% at week 4, 54.35% at week 8, 54.9% at year 1, 76.92% at year 4, and 100% at year 5. Persistence with ustekinumab was longer than with anti-TNF: year 1, 93.2 vs 72.06%;year 2, 89.4 vs 45.59%;and year 3, 86.1 vs 30.88%. Just over one-third (36.76%) of patients required dose optimization. Nine (13.24%) patients stopped treatment due to primary non-response [1 (1.47%)], loss of response [5(7.35%)], and adverse events [3 (4.41%)]. Eleven (16.18%) patients needed surgery and hospitalization. After the approval of upadacitinib and risankizumab, ustekinumab persistence was 80.88%. Seven (70%) of the patients with perianal disease achieved clinical remission and 4 (40%) completed fistula *** may have better persistence as a second-line treatment compared to anti-TNF and may be effective in perianal disease.

摘要： Multicellular cytokine networks drive intestinal inflammation and colitis-associated cancer (CAC). Interleukin-22 (IL-22) exerts both protective and pathogenic effects in the intestine, but the mechanisms that regulate this balance remain unclear. Here, we identify that IL-22 directly induces responsiveness to the IL-6 family cytokine oncostatin M (OSM) in intestinal epithelial cells (IECs) by activating STAT3 and upregulating the OSM receptor. In turn, OSM synergizes with IL-22 to sustain STAT3 activation in IECs and promote proinflammatory epithelial adaptation and immune cell chemotaxis to the inflamed intestine. Conditional deletion of the OSM receptor in IECs protects mice from both colitis and CAC, and pharmacological blockade of OSM attenuates established CAC. Thus, IL-22 and OSM form a pathogenic circuit that drives inflammation and tumorigenesis. Our findings reveal a previously unknown mechanism by which OSM supports intestinal pathology and highlight the IL-22-OSM axis as a promising therapeutic target for inflammatory bowel disease and CAC.

关键词： Lupus   Genetic   Juvenile-onset   SLE   HLA   Haplotype   Disease activity   Complement   C4  

摘要： Objective: Systemic lupus erythematosus (SLE) is a systemic autoimmune/inflammatory disease with a strong genetic component. Genetic burden is higher in children when compared to patients with adult-onset SLE, contributing to earlier disease expression and more severe phenotypes. The human leukocyte antigen (HLA) cluster on chromosome 6p21.3 is among the most variable genomic regions, representing a major risk-factor for SLE in adults. Its impact on juvenile-onset (j)SLE remains largely unstudied. Methods: High-resolution sequencing of HLA class I (A, B, C), class II (DRB1, DQA1, DQB1) and class III (complement C2) was undertaken in the multi-ancestral UK JSLE Cohort including participants of Caucasian (n = 151, 48.8 %), Asian (n = 108, 35.0 %) and African/Caribbean (n = 50, 16.2 %) descent. Considering ancestral variation, clinical associations were tested at the level of alleles (2-field resolution), associated HLA protein sequences (antigen binding domains, 4-field resolution), and extended haplotypes (DRh). Results: Although important ancestral recombination was reported for HLA-DR2 and-DR3 haplotypes, risk associated with jSLE was conserved at related alleles (DR2h: DRB1*15:01, DQA*01:02, DQB1*06:02;DR3h: C*07:02 [Asian], B*08:01, C2 rs9332730 [Asian], DRB1*03:01). HLA-DR7 haplotypes (DRB1*07:01, OR = 0.44, 95 % CI:0.27-0.72, p = 0.0004;DQA1*02:01, OR = 0.34, 95 % CI:0.21-0.56, p = 1.8 x 10(-6)) protect Asians from jSLE development. Among 23 clinical variables recorded, the main association was found between low levels of complement C4 in Caucasian carriers of HLA-DR3h. This was not the case in Asians due to recombination with HLA-C*07:02 and integration of the C2 rs9332730 minor allele. Low C4 serum levels associated with HLA-DQA1*01:02 (DR2h) in Caucasians after excluding HLA-DR3h carriers from the analysis. An association between low white blood cell counts and HLA-A*03:01P was observed across ancestries. Conclusion: Genetic variation in the HLA cluster asso

关键词： Transfection   Small interfering RNA   Luminescence   SARS CoV 2   Protein extraction   Phosphorylation   Viral transmission and infection   Protein translation  

摘要： Protein kinase R (PKR) expression is induced by interferons. This protein is activated by double-stranded (ds) RNAs or RNAs containing duplex regions, produced after different stimuli, such as after viral infections, leading to the phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2 alpha), and subsequently inhibiting cellular and viral protein translation. This function may lead to different effects such as to impairing the replication of RNA viruses by inhibiting viral protein translation, and to modulating the innate immune responses after viral infections by affecting the translation of effector proteins. In this work, we identify, for the first time, an interaction of IFN alpha inducible protein 27 (IFI27) with PKR-activating protein (PACT or PRKRA) and with PKR, showing that the interaction of IFI27 with PACT is likely mediated by dsRNAs or RNAs containing duplex regions, and that the interaction of IFI27 with PKR is PACT-dependent. Interestingly, using IFI27 knocked-down, knocked-out and overexpressing tumour-derived, established cells, we show that these interactions trigger a potentiation of the activity of PKR and, therefore, a decrease in protein translation. Moreover, we find that IFI27 increases PKR function in cells infected with different RNA viruses such as Severe Acute Respiratory virus 2 (SARS-CoV-2), and Vesicular Stomatitis virus (VSV), and in cells transfected with the dsRNA analog poly(I:C), suggesting a broad effect of IFI27 on PKR activation. Moreover, we show that IFI27 expression increases the formation of stress granules (SGs) at the cell cytoplasm, correlating with the increased PKR activation mediated by IFI27, as it has been shown that the translational arrest induced by activated PKR leads to the formation of SGs. Mechanistically, we describe that this ability of IFI27 to activate PKR is dependent on its interaction with PACT. Further understanding of the regulation of PKR activity will allow us to develop new

摘要： Objectives: Transmembrane serine protease 2 (TMPRSS2) plays a key role in the entry of viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and influenza A into host cells, and its elevated expression is a risk factor for the spread of viral infection. However, TMPRSS2 expression and the factors related to its induction in oral keratinocytes and fibroblasts remain largely unknown. Here, we examined TMPRSS2 expression and factors related to its induction in oral mucosal cells. Methods: TMPRSS2 expression was examined in oral keratinocytes (RT7) and fibroblasts (GT1). Subsequently, TMPRSS2 induction in was analyzed in both cell types following transfection of nucleic acid and inflammatory cytokines, such as interleukin (IL)-1 beta. Finally, the effects of IL-1 beta on STAT1 activation related to double- stranded RNA (dsRNA)-induced TMPRSS2 expression were examined. Results: RT7 and GT1 cells exhibited constitutive TMPRSS2 mRNA and protein expression. Transfection with Poly(I:C) (as a dsRNA) and poly (dA:dT) (as a double- stranded DNA [dsDNA]) increased TMPRSS2 expression. TMPRSS2 expression was also increased by IL-1 beta, but not IFN-gamma or TNF-alpha, while the combination of IL-1 beta and transfected Poly(I:C) caused a dramatic increase in TMPRSS2 expression as compared to each alone in both cell types. IL-1 beta also enhanced transfected Poly(I:C)activated STAT1 related to TMPRSS2 expression. Conclusions: TMPRSS2-expressing oral keratinocytes and fibroblasts are targets of SARS-CoV-2 and influenza A virus. TMPRSS2 expression, in cooperation with IL-1 beta, plays an important role in promoting infection during virus invasion in oral mucosal cells.

关键词： memory   PIRCHE   SLA   swine   xenotransplantation  

摘要： Swine-derived kidneys are a promising alternative organ source for transplantation, but compatibility in the major histocompatibility complex remains an immunological barrier. Furthermore, in repeat transplantations, CD4+ memory T cells can lead to a more rapid immune response against repeated exposure to the same antigens. Several studies have shown that HLA and SLA proteins share overlapping B cell epitopes due to structural or electrostatic similarities, but the role of overlapping T cell epitopes has not been fully explored. This study aims to computationally analyse the potential risk of memory T cell activation in subsequent human-after-swine and swine-after-human transplantation by evaluating shared T cell epitopes between the two graft sources. We show that while HLA and SLA demonstrate striking structural similarities, their linear protein sequences are very distinct, which translates to disparate HLA- and SLA-derived peptidomes and T cell epitopes. By applying the PIRCHE-II Tmem analysis to a simulated panel of recipients receiving repeat transplantations from a human kidney and from a swine xenograft, we observed a median of 1 shared T cell epitope in the cross-species context, compared to a median of 17 shared between two human-derived kidneys. This suggests that a swine xenograft exposes a low risk of T cell memory against a later human donor, and that xenotransplantation may provide an opportunity to receive a graft for highly HLA-sensitised recipients.