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关键词： Gastric cancer stem cells   Clofoctol   SerpinE1/beta-catenin   RanBP2   Necroptosis  

摘要： Gastric cancer stem cells (GCSCs) play a crucial role in the initiation, progression, recurrence and therapeutic resistance, contributing to a poor prognosis. Consequently, GCSCs are deemed to be a potential therapeutic target for gastric cancer (GC). Although beta-catenin is a well-recognized therapeutic target for GC and several inhibitors have demonstrated potent anti-tumor effects, there is a dearth of therapeutic agents targeting beta-catenin for clinical therapy. In this study, we carried out high-throughput screening of clinically approved drugs to identify effective inhibitors of beta-catenin. The results revealed that the antibiotic drug, clofoctol (CFT) effectively reduced the beta-catenin level, attenuated stemness traits both in vitro and in vivo, and induced necroptosis of GCSCs. Further analyzing of downstream genes and targeted proteins, we found that CFT inhibited GCSCs viability by binding to the SUMO E3 ligase RanBP2, thereby suppressing the SerpinE1/beta-catenin axis and activating TNF-mediated necroptosis. These results indicate that CFT may exert potent therapeutic effects against GC by targeting beta-catenin and inhibiting the viability of GCSCs.

关键词： 枝睾阔盘吸虫   脂肪酸结合蛋白   原核表达   多克隆抗体   ELISA  

摘要： 对枝睾阔盘吸虫（Eurytremacladorchis）的脂肪酸结合蛋白（FABP）进行原核表达与鉴定，并制备鼠抗EcFABP多克隆抗体。方法 通过PCR技术扩增了含开放阅读框（ORF）的EcFABP序列，构建重组表达质粒pET-28a-EcFABP。IPTG诱导EcFABP重组蛋白表达并进行最佳诱导时间优化。将纯化后的重组蛋白与弗氏佐剂等比例乳化后免疫BALB/c小鼠，制备多克隆抗体，经ELISA检测其抗体效价。同时采用Western blot检测多克隆抗体特异性，qPCR技术检测第42 d小鼠脾细胞因子（IL-4、IL-10、IL-12、IFN-γ）的转录水平。扩增出枝睾阔盘吸虫FABP基因ORF大小为402 bp，编码133个氨基酸，理论分子量约为15 kDa。SDS-PAGE和Western blot结果表明，本试验成功表达并纯化出EcFABP包涵体重组蛋白。间接ELISA法检测鼠源多克隆抗体，效价为1 256 000。Western blot结果表明，鼠抗EcFABP抗体可以与重组蛋白发生特异性反应。重组蛋白可诱导小鼠体内4种脾细胞因子表达上调，产生Th1和Th2两种类型的免疫反应。本试验成功制备了具有免疫原性的EcFABP蛋白及其鼠源多克隆抗体，为进一步研究枝睾阔盘吸虫FABP蛋白的功能及相关的诊断检测方法奠定了基础。

关键词： Miocene  

摘要： Records from the Miocene il-Blata section in Malta offer insights into the depositional environments of the Central Mediterranean following an Early Miocene restriction of the Mesopotamian Seaway (c. 20 Ma). Inorganic and organic stable carbon isotope values suggest relatively steady depositional environments, whereas authigenic iron dolomite abundances exhibiting substantial delta O-18 and delta C-13 variations at a sequence scale indicate dynamic sedimentation conditions leading to differential diagenesis. Petrographically, the dolomitic levels exhibit matrix-selective dolomitization, occasional silicification and phosphatization, and textural indicators pointing to subsurface microbial influences. These features collectively point to complex shallow burial diagenesis. In addition, the presence of framboidal pyrite and gypsum infilling foraminiferal chambers, along with the absence of large planktonic foraminifera, suggests the development of palaeoenvironmental stress imposed by a density-stratified water column affecting the pore waters. Towards the top of the studied succession, a shift from organic to siliceous deposits reflects water column perturbations possibly linked to changes in oceanic circulation associated with a temporary re-opening of the Mesopotamian Seaway. This study not only underscores the hydrochemical controls exerted by North African terrigenous fluxes over the Mediterranean, but also highlights the intricate interplay between shifting depositional environments and shallow burial diagenetic processes in shaping the geochemical and textural fabrics of authigenic mineral assemblages.

关键词： Chagas disease   HLA-DRB1   cardiomyopathy   cross-reactivity   T-cells  

摘要： Introduction Human infection with the protozoan Trypanosoma cruzi causes Chagas disease, which may lead to a deadly dilated cardiomyopathy resulting from T-cell-mediated inflammation. We found that specific HLA-DRB1 alleles (*0103, *0402, *1301, and *1302) that display the DERAA motif are linked to this severe clinical manifestation of Chagas *** We employed computational analysis, in vitro functional assays, and single-cell RNA sequencing to determine the response of CD4+ T cells from indeterminate (IND) and cardiac (CCC) Chagas patients to peptides selected on DERAA-bearing *** We observed that these alleles display binding affinity towards host-derived peptides with sequence similarity to parasite-derived proteins. These peptides can activate and induce proliferation of CD4+ T-cells from CCC, but not IND. Importantly, the magnitude of this response correlated with the severity of ventricular dysfunction and increased production of soluble factors associated with myocardial fibrosis. Analysis of differentially expressed genes (DEGs) in activated CD4+ T-cells from individuals with the DERAA-DRB1 alleles demonstrated a high expression of cytotoxic, chemotactic and proapoptotic genes, linking these cells with pathogenic functions. Finally, we observed the upregulation of genes that code for the host proteins that contain the potentially pathogenic peptides in the cardiac tissue of CCC, suggesting their involvement in *** Our findings highlight the ability of CD4+ T-cells from CCC patients to recognize and react to foreign and self-peptides, thereby emphasizing the importance of HLA-DRB1 alleles in the presentation of potentially pathogenic antigens and in the amplification of CCC pathology.

摘要： Keloids are common pathological scars resulting from previous trauma or inflammation. Interferon-gamma (IFN-gamma) has shown significant therapeutic effects when used alone or in combination with other agents. While IFN-gamma has been found to regulate ferroptosis in tumor cells, its ability to regulate ferroptosis in keloid fibroblasts (KFs) is unclear. Here, we have demonstrated a direct causal relationship between IFN-gamma levels and ferroptosis in KFs. To explore the intrinsic mechanism, we performed genome-wide RNA and proteomics sequencing and found that serpine2 was the most significantly downregulated gene in KFs after exogenous overexpression of IFN-gamma. Serpine2, which belongs to a family of serine protease inhibitors, has been shown to play an important role in fibrotic diseases. Therefore, we hypothesized that serpine2 is a downstream gene in the regulation of ferroptosis in KFs by IFN-gamma. Our results showed that serpine2 overexpression promotes collagen synthesis, which in turn promotes the proliferation, migration, and invasive functions of KFs. We further demonstrated that serpine2 overexpression promoted system Xc- transporter expression, cystine uptake, and glutathione synthesis, enhanced GPX4 activity;and inhibited reactive oxygen species generation. This resulted in a reduction in intracellular lipid peroxidation and the levels of its metabolite malondialdehyde, as well as inhibited ferroptosis in KFs. IFN-gamma reversed these effects of serpine2 overexpression. These results were largely confirmed in in vivo keloid models too. These findings imply that IFN-gamma not only directly induces ferroptosis in KFs but also enhances their sensitivity to ferroptosis by inhibiting the synthesis of SLC7A11 and SLC3A2 through downregulation of serpine2. In summary, we suggest that the serpine2-system Xc- axis is a promising therapeutic target for the treatment of keloids.

关键词： Harmaline   Pain   Oxidative stress   Inflammation   Nrf-2   Nitric oxide   COX-inhibition  

摘要： Harmaline, a naturally occurring beta-carboline alkaloid found in plants such as Peganum harmala and Banisteriopsis caapi, exhibits various pharmacological activities, including antioxidant and neuroprotective properties. Its free radical-scavenging ability contributes to cellular protection against oxidative stress. Based on these properties, the present study aimed to explore the antinociceptive and anti-inflammatory effects of harmaline using acetic acid-induced writhing and carrageenan-induced paw edema mice models. Mice were treated with acetic acid to induce writhing, and carrageenan was administered to induce paw edema. Following carrageenan administration, the animals were euthanized, and paw tissues were harvested for biochemical analysis. Harmaline significantly reduced the frequency of acetic acid-induced writhing and attenuated carrageenan-induced inflammation, as indicated by a decrease in paw thickness. Biochemical analysis revealed that harmaline (5 mg/kg) reduced lipid peroxidation and preserved GSH levels in paw tissues, highlighting its antioxidant effects. Furthermore, harmaline treatment lowered IL-1 beta levels and upregulated Nrf-2, indicating modulation of inflammatory and antioxidant signaling. Pre-treatment with substance P and L-arginine reversed harmaline's effects on writhing and paw edema, suggesting the involvement of cyclo-oxygenase and nitric oxide pathways. These pre-treatments also reversed the harmaline-induced reduction in TBARS and IL-1 beta levels, as well as elevation of GSH and Nrf-2 levels, further supporting the involvement of these pathways. Overall, this study demonstrates that harmaline effectively alleviates pain and inflammation through the inhibition of COX and nitric oxide pathways, alongside the activation of Nrf-2-antioxidant signaling. These findings support harmaline's potential as a therapeutic agent for pain and inflammation, warranting further research into its clinical applications.

关键词： lower-grade glioma   prognosis   NK cells   CD56(dim) NK   HLA-I   anti-tumour immunity   transcriptional signature   deconvolution  

摘要： Background: Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. Methods: Here, we explored the transcriptional landscape of HLA-I molecules across various solid cancer transcriptomes from The Cancer Genome Atlas (TCGA) database and assessed the impact of HLA-I expression on the clinical significance of tumour-infiltrating CD56(dim) and CD56(bright) NK cells. Results: Our analysis revealed that high HLA-I expression correlated with reduced patient survival in the TCGA lower-grade glioma (LGG) cohort, with this association varying by histopathological subtype. We then estimated the relative abundance of 23 immune and stromal cell signatures in LGG transcriptomes using a cellular deconvolution approach, which revealed that LGG patients with low HLA-I expression and high CD56(dim) NK cell abundance had better survival outcomes compared to those with high HLA-I expression and low CD56(dim) NK cell abundance. Furthermore, HLA-I expression was positively correlated with various inhibitory NK cell receptors and negatively correlated with activating NK cell receptors, particularly those within the killer cell lectin-like receptor (KLR) gene family. High co-expression of HLA-E and NKG2A predicted poor survival outcomes in LGG patients, whereas low HLA-E and high NKG2C/E abundance predicted more favourable outcomes, suggesting a potential modulatory role of HLA-I on the tumour-infiltrating cytotoxic CD56(dim) NK cell subset. Conclusions: Overall, our study unveils a potential role for deregulated HLA-I expression in modulating the clinical impact of glioma-infiltrating CD56(dim) NK cells. These findings lay the foundation for future in-depth experimental studies to investigate the underlying mechanisms.

关键词： apoptosis inhibitor of macrophage   CD5L   foamy macrophage   Mycobacterium avium   lipid metabolism   interleukin 10  

摘要： Non-tuberculous mycobacteria infections, including Mycobacterium avium, are increasingly recognized as a growing public health concern, even among immunocompetent individuals. These infections are a significant cause of chronic pulmonary disease, and they are characterized by the formation of foamy macrophages (FMs) that facilitate bacterial persistence. Previously, we reported that apoptosis inhibitor of macrophage (AIM), a protein secreted by macrophages, promotes lipid droplet accumulation in M. avium-infected macrophages. However, the precise role of AIM in modulating immune responses remains unclear. This study aimed to elucidate the effect of AIM on FM formation, bacterial burden, and immune response in M. avium-infected mice by comparing AIM knockout (KO) mice with wild-type mice. Histological analysis revealed a reduction in FM formation in AIM KO mice, accompanied by decreased lipid droplet accumulation and altered expression of lipid metabolism-related genes. Furthermore, AIM KO mice exhibited a reduced bacterial load in the lungs, highlighting decreased cytokine production, including IL-1 beta, compared to wild-type mice. In addition, the analysis of the immune cells of AIM KO mice using flow cytometry revealed an increase in M1 macrophages and IFN-gamma-producing T cells, as well as a decrease in M2 macrophages and interleukin 10 (IL-10)-producing T cells. The reduced expression of CD36 and PD-L1 in macrophages from AIM KO mice further supports the skewing toward an M1 phenotype. In vitro experiments with bone marrow-derived macrophages (BMDMs) confirmed reduced bacterial growth and lipid droplet formation in AIM KO BMDMs, which was restored by AIM and IL-10 treatment. These findings suggest that AIM contributes to the promotion of FM formation by establishing an immunosuppressive environment that promotes the establishment of M. avium through IL-10 production.

关键词： Palmoplantar psoriasis   IL 23   IL 17   drug survival   switch  

摘要： BackgroundThe aim of this study is to confront the effectiveness of anti-IL 17 versus anti-IL 23 mAb in treating palmoplantar psoriasis by comparing the incidence of patients that required a therapy switch to another mAb class. Furthermore, we calculated the mean time intercurrent the beginning therapy with mAbs and the necessity to switch class due to *** design and methodsWe enrolled 116 patients with moderate to severe palmoplantar psoriasis. Patients with the pustular variant were excluded from this study. We performed statistical analysis to calculate the incidence of therapy switch in anti-IL 17 and anti-IL 23 mAb *** results of both univariate and multivariate statistical analysis demonstrated that patients in therapy with anti-IL 23 mAb have a lower incidence of therapy switch compared to patients in therapy with anti-IL 17 drugs. The median switch time is 105 months. No other significant factors predictive of therapy switch were *** real-life evidence confirms the reduced necessity of therapy switch in patients with palmoplantar psoriasis treated with anti-IL 23 antibodies, compared to those treated with IL 17 inhibitors.

关键词： DILI   Hepatotoxicity   liver injury   medications   HLA   risk   prediction  

摘要： IntroductionDrug-induced liver injury is an important adverse effect and can be caused by various medications, including novel therapeutic agents. The risk stratification of patients susceptible to DILI is a growing *** coveredThe current article highlights new studies on risk stratification regarding risk factors of DILI, prediction of liver injury, and predictors of severe outcomes. Studies on patient demographic and genetic risk factors are discussed, in addition to the potential role of concomitant medications that may affect the risk of *** opinionAlthough much is known about patient risk factors for DILI, a better combination of these factors into risk scores is needed to predict which patients are particularly susceptible. Knowledge of these risk factors might determine drug treatment in the near future, as well as the need for routine monitoring of liver tests.