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关键词： AP1-S1   AP1-B1   AP1-G1   AP1-M1   Prognosis   HLA-loss   Immunological regulation  

摘要： The clathrin adaptor protein 1 (AP1) plays a pivotal role in the endocytosis of cell surface proteins and transportation between the golgi apparatus and lysosomes. Despite its critical functions, the implications of AP1 dysregulation in human cancers have yet to be elucidated. The structural analysis of AP1 subunits was conducted utilizing data from the Protein Data Bank (PDB), which is composed of four subunits: AP1-S1, AP1-B1, AP1-G1, and AP1-M1. Notably, the expression levels of AP1 subunits exhibit significant variability between tumor and normal tissues across different cancer types using data from the CPTAC, GEO, and TCGA databases. Kaplan-Meier (K-M) curve analysis has revealed that certain AP1 subunits are correlated with patient prognosis in various cancers. For instance, the AP1-S1 subunit is related to poor survival outcomes in head and neck squamous carcinoma, clear cell renal cell carcinoma, and lung adenocarcinoma. Furthermore, the aberrant expression of AP1-S1 demonstrated a negative correlation with immune cells infiltration, particularly in lung adenocarcinoma. Concurrently, a significant negative relationship between AP1-S1 and HLA molecules was observed, indicating a potential mechanism for AP1-induced HLA degradation. In vitro experiments demonstrated that the knockdown of AP1-S1 led to an upregulation of HLA-B protein expression and inhibited the viability, migration, and invasion capabilities of tumor cells in lung adenocarcinoma cell lines, specifically A549 and H1299. Immunohistochemical staining further revealed the abnormal expression of AP1-S1 in lung adenocarcinoma specimens. Through a comprehensive pan-cancer multi-omics analysis and experimental validation, this study explored the prognostic significance of four AP1 subunits. Additionally, it examined the regulatory relationship between AP1S1 and HLA-B, which may play a role in immune escape. Additionally, the research identified AP1-S1 as a valuable biomarker and a potential target for

关键词： IL-20 family   Neuroinflammation   Neurodegenerative diseases   Cytokines   Therapeutic targets  

摘要： The IL-20 cytokine family, comprising IL-19, IL-20, IL-22, IL-24, and IL-26, has emerged as a critical player in the pathogenesis of neurodegenerative diseases due to its multiple roles in inflammation, tissue repair, and immune modulation. These cytokines signal through IL-20 receptor complexes (IL-20RA/IL-20RB and IL-22RA1/IL20RB), triggering diverse immune processes. Recent evidence highlights their significant contributions to neuroinflammation and neurodegeneration in central nervous system disorders. IL-20 family cytokines impact microglial activation, which, when dysregulated, exacerbates neuronal damage. Specifically, IL-20 and IL-24 are linked to elevated pro-inflammatory markers in glial cells, promoting neurodegeneration. In contrast, IL-22 exhibits dual functionality, exerting protective and pathological roles depending on the inflammatory milieu. Key mechanisms involve the regulation of blood-brain barrier integrity, oxidative stress, and autophagy. IL-22 and IL-24 also protect neurons by enhancing antioxidant defenses and maintaining epithelial barrier function, while their dysregulation contributes to blood-brain barrier disruption and protein aggregate accumulation, hallmark features of Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Elevated IL-22 levels in Alzheimer's disease and IL-19's regulatory role in multiple sclerosis suggest they may serve as potential biomarkers and therapeutic targets. IL-26's role in amplifying inflammatory cascades further underscores the complexity of this cytokine family in neurodegenerative pathology. Therapeutically, strategies targeting IL-20 cytokines include monoclonal antibodies, receptor modulation, and recombinant cytokine administration. These approaches aim to mitigate neuroinflammation, restore immune balance, and protect neuronal integrity. This review underscores the IL-20 family's emerging relevance in neurodegenerative diseases, highlighting its potential for novel diagnostic and thera

摘要： Abdominal aortic aneurysm (AAA) is a common degenerative disease of the abdominal aorta, which can result in extremely high mortality owing to the rupture of the abdominal aorta. The activation of IL-7R has been shown to modulate the inflammatory responses, which play an important role in the progression of AAAs. However, the mechanism of IL-7/IL-7R axis in AAAs is still unclear. This study aims to investigate the effects of IL-7R on AAAs and the underlying mechanisms involved. Wild-type C57BL/6 and IL-7R knockout mice were used as experimental subjects. ELISA analysis, histological staining, western blotting and qPCR were performed to explore effects of IL-7R deficiency in the formation and development of elastase-induced AAAs. Transwell, CCK8, and immunofluorescence assays detected the migration and polarization of RAW264.7 macrophages in vitro. We demonstrated that IL-7R was elevated in mice with AAAs. Blocking IL-7R can inhibit the formation of AAAs and reduce aortic dilatation, elastic layer degradation, and inflammatory cell infiltration. Knockout of IL-7R suppressed the migration, infiltration and M1 polarization of macrophages. Moreover, inhibition of the NF-κB signaling pathway by BAY 11-7082 attenuated the macrophage-mediated inflammatory responses caused by IL-7R overexpression. In short, this study showed that IL-7R promotes the infiltration and migration of macrophages by regulating M1 macrophage polarization, possibly in part via activation of the NF-κB pathway, which may be associated with the development of AAAs.

摘要： The major histocompatibility complex (MHC) encompasses a group of genes critical for immune system regulation. In humans, these molecules are referred to as human leukocyte antigens (HLA) due to their initial discovery in human leukocytes. Class I molecules present antigens to CD8 + T cells, while Class II molecules present to CD4 + T cells. Here we report a patient who had a background of parental consanguinity and a family history suggestive of immunodeficiency. He presented with clinical symptoms including fever, septic arthritis, recurrent moniliasis. Preliminary diagnostic tests revealed hypogammaglobulinemia and CD4 lymphopenia. Further immunological assessment indicated extremely low expression levels of HLA molecules: HLA ABC at 5% and HLA DR at 0%. Genetic analysis showed a mutation in the regulatory factor X5 (RFX5) gene, leading to a combined immunodeficiency diagnosis. Consequently, hematopoietic stem cell transplantation (HSCT) was planned. Regulatory factor X5plays a pivotal role in immune function by transactivating genes critical for the expression of MHC Class I and Class II molecules, as well as beta- 2-microglobulin (B2M). MHC Class I transcription is controlled indirectly by RFX5, and the RFX5 gene mutation in the patient likely caused the markedly reduced expression of HLA ABC in addition to HLA DR. Combined HLA-ABC and HLA-DR expression analyses via flow cytometry may serve as a valuable diagnostic tool for identifying RFX5-related immunodeficiency at an early stage, facilitating timely genetic testing and appropriate clinical management.

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： Oleanolic acid   Mesangial proliferative glomerulonephritis   Mesangial cells proliferation   Inflammatory response   Network pharmacology   IL-17/ERK/AKT pathway  

摘要： Background: Mesangial proliferative glomerulonephritis (MsPGN) is a common form of glomerulonephritis characterized by mesangial cell proliferation and inflammatory responses. However, current clinical treatment options for MsPGN are rather limited. Oleanolic acid (OA), a natural pentacyclic triterpenoid compound, exhibits anti-tumor and anti-inflammatory properties and has been proven to have renal protective effects. We speculate that OA could potentially serve as an alternative therapy for MsPGN. Objective: This study aimed to investigate the therapeutic efficacy and mechanism of OA against MsPGN. Methods: Tail vein injection of anti-Thy1 antibody was used to establish the MsPGN model, followed by a comprehensive assessment of the effects of OA on renal function, histopathological changes, and inflammatory responses in anti-Thy1 nephritis rats. Subsequently, network pharmacology was employed to predict the key targets and pathways of OA in treating MsPGN. Finally, in vivo and in vitro experiments were conducted to validate the results of network pharmacology. Results: OA significantly improved renal function, and attenuated mesangial cell proliferation and inflammatory reactions in anti-Thy1 nephritis rats. Network pharmacology analysis identified TNF-alpha, IL-6, IL-1 beta, MAPK3, and AKT1 as key targets of OA in the treatment of MsPGN, and involved the IL-17 signaling pathway. Additionally, we observed increased phosphorylation levels of ERK and AKT, as well as activation of downstream inflammatory responses, in both anti-Thy1 nephritis rats and mesangial cells stimulated with IL-17. In contrast, treatment with OA and the ERK inhibitor PD98059 reversed these effects. Furthermore, we identified IL17RA within this pathway as a potential target of OA. Conclusions: Our study demonstrates that OA can modulate the IL-17/ERK/AKT signaling pathway, thereby improving anti-Thy1 antibody-induced MsPGN. This establishes a theoretical basis for OA to potentially serve as a

关键词： Interleukin 11   PTGS2   PGE2   Granulosa cell   Cattle  

摘要： Ovulation is a highly organized and multifaceted series of events, which parallels with inflammatory processes. Prostaglandins (PGs) have been shown to play an important role in the modulation of ovulation. Our previous study revealed that Interleukin 11 (IL-11) signaling is critical in regulating steroidogenesis in bovine granulosa cells (GCs). However, the precise roles of IL-11 in the regulation of PGs remain unclear. In the present study, we investigated the effects and underlying molecular mechanisms of IL-11 on the production of PGs in primary bovine GCs. At LH-induced levels, we observed that 10 ng/mL IL-11 significantly increased prostaglandin E2 (PGE2) production via upregulating the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), while IL11 treatment did not affect the production of prostaglandin F2 alpha (PGF2 alpha). Furthermore, 10 ng/mL IL-11 treatment activated the phosphorylation of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3), which was accompanied by STAT3 nuclear translocation. Additionally, these effects were inhibited by the addition of the STAT3-specific inhibitor C188-9. Specifically, C188-9 treatment blocked the IL-11-induced STAT3 nuclear translocation, downregulated the mRNA and protein expression levels of PTGS2, and ultimately led to a reduction in PGE2 production induced by 10 ng/mL IL-11. Our findings elucidate the cellular and molecular mechanisms by which IL-11 regulates PGE2 expression through the JAK1/STAT3 signaling pathway in bovine GCs in the presence of LH, contributing to a better understanding of the ovulatory process.

关键词： AGT/AGTR1a/IL-1 beta axis   extracellular matrix metabolism   osteoarthritis   renin-angiotensin system   SEMA6D  

摘要： The tissue-localized renin-angiotensin system (tRAS) plays a pivotal role in the crosstalk between cardiovascular factors and osteoarthritis (OA). Semaphorin 6D (SEMA6D), a cardiovascular neuroeffector, may contribute to chondrocyte homeostasis;however, its cartilage-specific functions remain unclear. Chondrocytes with altered SEMA6D expression were established via gene transfection. RNA sequencing was performed to identify SEMA6D-related genes and pathways, with preliminary validation in human OA samples. Furthermore, biochemical methods were employed to investigate the role of the AGT/AGTR1a/IL-1 beta axis in mediating SEMA6D-associated extracellular matrix metabolism (ECM). An AAV5-based lentiviral vector was used to generate OA rat models overexpressing SEMA6D, followed by radiological and histological analyses. SEMA6D overexpression significantly enhanced ECM homeostasis, marked by increased Aggrecan, COL2A1 and decreased COL10A1, MMP13, and Runx2 expression. These SEMA6D-induced genes were enriched in the tRAS pathway, with AGT, AGTR1a, and IL-1 beta identified as critical targets. Furthermore, the AGT/AGTR1a/IL-1 beta axis activated ECM degradation in chondrocytes, while SEMA6D overexpression effectively suppressed this signaling. In the OA rat model, elevated SEMA6D expression significantly reduced cartilage degradation. SEMA6D confers chondroprotective effects in OA by modulating the tRAS pathway, likely through inhibition of the AGT/AGTR1a/IL-1 beta axis, thereby regulating ECM metabolism and chondrocyte hypertrophy. These findings enhance our understanding of cardiovascular influences on cartilage health and reveal tissue-specific regulatory mechanisms in OA.

摘要： A tumor cell subpopulation of tumor-initiating cells (TIC) or "cancer stem cells" is associated with therapeutic resistance, as well as both local and distant recurrences. Signal transducer and activator of transcription (STAT) activity is elevated in TICs in claudin-low models of human triple-negative breast cancer, which enables enrichment of TICs using a STAT-responsive reporter. Lineage tracing of TICs as they undergo cell state changes could enable a better understanding of the molecular phenotypes of TIC and uncover strategies to selectively target TICs. In this study, we developed a STAT-responsive lineage-tracing system and used it in conjunction with the original reporter to enrich for cells with enhanced mammosphere-forming potential. This approach was able to detect TICs in some, but not all, basal-like triple-negative breast cancer xenograft models, indicating that STAT signaling has both TIC-related and TIC-independent functions. Single-cell RNA sequencing (RNA-seq) of reporter-tagged xenografts and clinical samples identified a common IFN/STAT1-associated transcriptional state in TICs that was previously linked to inflammation and macrophage differentiation. Surprisingly, most of the identified genes were not present in previously published TIC signatures derived using bulk RNA-seq. Finally, bone marrow stromal cell antigen-2 was identified as a cell surface marker of this state that functionally regulated TIC frequency. These results suggest that TICs may exploit the IFN/STAT1 signaling axis to promote their activity and that targeting this pathway may help eliminate TICs. Significance: Coupling single-cell transcriptomics with tumor-initiating cell enrichment identified IFN response gene expression not previously reported in bulk RNA-sequencing-derived signatures and proposed IFN/STAT1 signaling as a candidate therapeutic target in breast cancer.