IUBMB Life最新文献

A Disintegrin and metalloprotease (ADAM) family encompasses a diverse array of widely expressed proteases functioning in pathological processes. ADAM15 stands out as a pivotal mediator in multiple tumor types, responding to immune checkpoint inhibitors (ICI) significantly. By promoting pro-angiogenic genes, potentiating integrin binding as well as modulating the inflammatory response, ADAM15 orchestrates cellular adhesion and migration, thereby fostering tumor progression. Despite these compelling insights, the intricate roles of ADAM15 in prediction, immune modulation, and therapeutic targeting among malignant disorders remain largely unexplored. To decipher the pan-cancer landscape of ADAM15, we integrated data from multiple databases. Immunohistochemical profiles of ADAM15 were retrieved from the human protein atlas (HPA) database. Furthermore, the tumor immune estimation resource (TIMER) and the ESTIMATE (Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data) algorithm were harnessed to dissect the immune infiltration patterns and immune checkpoint genes associated with ADAM15. The tumor immune single-sample gene set enrichment analysis (TISMO) was employed to explore the impact of ADAM15 on the tumor immune microenvironment. Additionally, drug sensitivity analysis and subsequent molecular docking studies were conducted to identify potential therapeutic compounds targeting ADAM15. These findings were rigorously validated through reverse transcription-polymerase chain reaction (RT-PCR), western blotting (WB), and immunohistochemistry (IHC) by cell lines and clinical samples from hepatocellular carcinoma (HCC) as well as colon adenocarcinoma (COAD). Our comprehensive analysis revealed that ADAM15 is markedly upregulated in diverse cancer types. IHC, WB, and RT-PCR assays of HCC and COAD confirmed these findings. Notably, elevated ADAM15 correlates with adverse prognosis in pan-cancer, positioning it as a promising novel biomarker. Drug sensitivity profiling unveiled a positive and statistically significant association between ADAM15 and AZD-8055 and Nitazoxanide, whereas a negative correlation was observed with Oxaliplatin and Ponatinib. These findings were further corroborated by molecular docking simulations, highlighting the potential of these compounds as therapeutic targets for ADAM15-driven cancers. Our study underscores the multifaceted role of ADAM15 in cancer progression, immune evasion, and response to therapy. By elucidating the intricate interplay between ADAM15 and the tumor microenvironment (TME), we have identified novel diagnostic biomarkers and potential therapeutic avenues.

Hemophilia is an inherited disorder characterized by impaired blood clotting caused by mutations in the genes responsible for producing coagulation factor (F) VIII (hemophilia A, HA) or FIX (hemophilia B, HB). Current treatment primarily relies on replacement therapy, involving frequent and costly infusions of FVIII or FIX concentrates. While effective, these treatments come with the risk of developing neutralizing antibodies (inhibitors) against the infused factor. In recent years, non-factor replacement therapies have emerged as innovative treatment options, offering enhanced efficacy especially for patients with inhibitors. Despite their advantages, these approaches still fall short of providing a definitive, long-term cure. Since hemophilia is a monogenic disease, it presents an excellent opportunity for cell and gene therapy approaches aimed at achieving durable treatment and potentially a cure. Over the past three decades, remarkable advancements have been made in hemophilia gene therapy, culminating in the approval of Valoctocogene roxaparvovec (ROCTAVIAN, AAV-FVIII) and Etranacogene dezaparvovec (HEMGENIX, AAV-FIX) for patients with severe HA and HB, respectively. Nevertheless, gene therapy poses questions regarding its long-term efficacy and safety. This review synthesizes findings from clinical trials, addresses persistent challenges in hemophilia gene therapy, and underscores the biological constraints and limitations inherent to viral vector-based approaches.

Methylglyoxal (MGO) is endogenously produced under physiological conditions as a by-product of glycolysis and by autooxidation of glucose and lipid peroxidation. The digestive system can also take up MGO from exogenous sources, especially from ultra-processed foods. MGO is a highly reactive molecule, able to react with macromolecules forming covalent adducts resulting in advanced glycation end-products formation. MGO can also enter the nucleus and react with nucleic acids with the formation of MGO-nucleic acid adducts. The intestinal epithelium is continuously exposed to dietary and endogenous stimuli, including MGO, but the potential harmful role of MGO at the intestinal level has been poorly investigated. Therefore, the aim of the study was to further investigate the effects of MGO in intestinal cells and the molecular mechanisms involved, with particular attention to epigenetic regulatory enzymes such as histone deacetylases (HDAC), ten-eleven translocation (TET) family enzymes, and DNA methyltransferases (DNMT). Our results demonstrate that MGO exposure induces alterations in intestinal barrier function in differentiated Caco-2 cells monolayers. Moreover, MGO treatment induces cell apoptosis associated with an increase in cytosolic and mitochondrial reactive oxygen species. MGO-induced oxidative stress was associated with activation of the NFκB pathway and increased levels of proinflammatory molecules such as TNF-α and antioxidant enzymes (superoxide dismutase 1 [SOD1] and catalase). The increased expression of γH2AX suggests damage to DNA in MGO-treated cells. A decrease in HDAC1/2 expression, consistent with the increase in acetylated histone H4 levels, and an inhibition of the expression of TET (TET1, TET2) proteins was observed in MGO-treated cells. These results suggest that MGO may also disrupt epigenetic homeostasis mechanisms, offering further insight into the pathways through which MGO causes cellular damage in intestinal cells.

This study aimed to identify a novel prognostic signature derived from an EGFR Tyrosine kinase inhibitors (TKI-resistant) macrophage subpopulation and to evaluate its clinical and therapeutic relevance in HCC. We utilized single-cell RNA sequencing data from HCC patients. An EGFR-TKI resistance score was calculated across all cell types. Macrophages, which exhibited the highest resistance score, were sub-clustered to identify the most resistant subpopulation. Marker genes from this sub-cluster were intersected with differentially expressed genes (DEGs) from the TCGA-LIHC cohort. A robust prognostic model was constructed. The model's performance was rigorously validated, and the signature was further characterized through multi-omics analysis and its correlation with immune checkpoint blockade (ICB) response and drug sensitivity. scRNA-seq analysis unequivocally identified macrophages as possessing the highest EGFR-TKI resistance score. We identified seven key prognostic genes: SLC41A3, DCAF13, PPM1G, NDC80, FAM83D, FUCA2, and UQCRH. A risk model built on these seven genes effectively stratified patients into high- and low-risk groups with significantly different overall survival (OS) in the TCGA cohort, a finding successfully validated in the independent GSE76427 cohort. A clinical nomogram integrating the risk score demonstrated excellent predictive accuracy, with AUC values for 1-, 3-, and 5-year OS of 0.816, 0.781, and 0.799, respectively. The low-risk group was associated with a favorable immune-infiltrated phenotype and was predicted to be more sensitive to immunotherapy. Conversely, the high-risk group exhibited distinct genomic features and was predicted to be more sensitive to specific targeted agents, including Navitoclax and Sorafenib. We identified and validated a novel 7-gene prognostic signature derived from a subpopulation of EGFR-TKI-resistant macrophages. This signature accurately predicts patient survival, offers insights into the molecular mechanisms of therapy resistance in HCC, and provides a promising tool for improved patient stratification and the development of personalized treatment strategies.