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关键词： IL-10   Colorectal cancer liver metastasis   Breast cancer liver metastasis   Other cancer liver metastasis   Research progress  

摘要： Liver metastasis can occur in a wide range of cancers and have a significant impact on patient survival and prognosis. Once liver metastasis occurs, patients often lose the opportunity for surgery, and although a small percentage of patients can undergo hepatic resection to prolong survival, the benefit is not great. There were also many factors affecting liver metastasis, including reprogramming of the primary tumor metabolism, disturbances in the immune microenvironment and immune cells, alterations in the gut microbiota, and epigenetic changes. Interleukin-10 (IL-10) has a dual role as a cytokine that has been found in recent years to be pro-inflammatory as well as pro-liver metastasis. IL-10 exerts pro-metastatic effects mainly by regulating the polarization of tumor macrophages in the tumor microenvironment, especially by promoting the polarization of M2 macrophages. However, the role of IL-10 in tumorigenesis and progression remains controversial and the molecular mechanism involved in promoting liver metastasis is currently unclear. In view of the increasing role of IL-10 in promoting liver metastasis, this review summarizes the role of IL-10 in liver metastasis of colorectal cancer, breast cancer and other tumors in recent years, and provides ideas for subsequent clinical practice and basic research.

关键词： Bruton's tyrosine kinase inhibitor   diffuse large B-cell lymphoma   IL-10   natural killer group 2 member D   phosphorylated STAT3  

摘要： The aim of this study is to explore the role of the IL-10/STAT3 pathway in the upregulation of natural killer group 2, member D (NKG2D) ligands (MICA and ULBP2) induced by Bruton's tyrosine kinase (BTK) inhibitors in non-germinal center B-cell-like diffuse large B-cell lymphoma cells. The expression levels of NKG2D ligands and the IL-10/STAT3 pathway in SUDHL4, U2932, and OCI-LY3 cells were analyzed using western blotting. After stimulation of the B-cell receptor signaling pathway with IgM antibodies, the expression levels of NKG2D ligands, as well as IL-10 and phosphorylated STAT3 (p-STAT3) were significantly reduced. In contrast, treatment with ibrutinib produced effects opposite to those induced by IgM antibodies. Additionally, treatment of U2932 and OCI-LY3 cells with the STAT3 inhibitor (STAT3-IN-1) led to an increase in NKG2D ligand expression and a decrease in IL-10 levels. When IL-10 neutralizing antibodies were introduced, p-STAT3 levels decreased, and NKG2D ligand expression increased. Similar outcomes were observed when the BTK inhibitors ACP-196 and BGB-3111 were administered. Our findings suggest that the IL-10/STAT3 pathway plays a key role in the upregulation of NKG2D ligands induced by BTK inhibitors in U2932 and OCI-LY3 cells.

关键词： Propolis alcoholic extract   Osteoblast   Hypoxia   Cell proliferation  

摘要： Numerous studies have demonstrated the significant role of propolis in various biological processes, including inflammation and the repair of endothelial and bone tissues. The cascade of inflammation, proliferation, and tissue remodeling characterizes the injury site. Remarkable progress has been made in the field of alternative medicine with the utilization of propolis. In this study, we specifically investigated the effects of alcoholic extract of propolis on cell adhesion, survival, remodeling, and differentiation pathways in osteoblasts. Our findings revealed the activation of survival proteins such as AKT, ERK, and phosphorylated ERK during the adhesion phase, while interleukins, specifically IL-6 and TNF, exhibited increased expression during cell differentiation. Furthermore, treatment with propolis extract led to enhanced activity of metalloproteinases (MMP9 and MMP2) and HIF-1 alpha, a crucial activator of angiogenesis and bone remodeling. It was observed that the alcoholic propolis extract stimulated cell proliferation, differentiation, and repair, with key molecules involved in these processes including pro-inflammatory factors IL-6 and TNF alpha, as well as HIF-1, MMP2, and BMP7 proteins. Collectively, these factors induced an initial state of proliferation followed by differentiation and repair. Therefore, the alcoholic extract of propolis holds promise as a potential therapeutic agent, particularly in cases involving tissue repair. Nevertheless, further comprehensive in vitro and in vivo studies targeting this area are necessary to advance our understanding.

摘要： [This corrects the article DOI: 10.1007/s10616-024-00698-z.].

关键词： Photobiomodulation   Spinal cord injury   Autophagy   Inflammation   TLR2  

摘要： After spinal cord injury (SCI), peripherally derived macrophages infiltrated the injury area to exert inflammatory effects, causing barriers to the repair of spinal cord injury. Our previous study confirmed that photobiomodulation (PBM) could promote the motor function recovery and inhibit the secretion of inflammatory cytokines after SCI, moreover, PBM also has a role in promoting autophagy, but the mechanism is not clear. Therefore, we aimed to investigate whether PBM promotes autophagy by regulating the inflammatory response of macrophages, which in turn regulates functional repair after SCI. Male C57/BL6 mice were used to prepare a model of clamped spinal cord injury, and PBM irradiation was performed for 28 consecutive days, which showed that motor function of the mice was improved. We observed that autophagy proteins (LC3, Beclin-1 and P62) were inhibited and inflammasome-related proteins (NLRP3, Caspase-1 and IL-1 beta) expression was significantly enhanced in SCI mice. We analyzed the RNA sequencing (RNA-seq) of SCI, SCI+PBM treated mice in combination with autophagy database. The results showed 25 differentially expressed genes (DEGs). Protein-protein interaction (PPI) network and Hub gene analysis revealed TLR2 as a key molecule in the regulation of autophagy levels by PBM after SCI. We performed preliminary analysis in macrophages cultured in vitro and observed that PBM suppressed the expression of TLR2 and inflammasome-related proteins in M1-type macrophages and promoted the expression of autophagy proteins. Subsequently, we used an agonist of TLR2 (CU-T12-9) to up regulate TLR2 expression and observed that macrophage autophagy was inhibited and inflammatory response was enhanced. After PBM irradiation, the effect of CU-T12-9 was counteracted. Taken together, PBM promotes autophagy and attenuates the inflammatory response by regulating TLR2, a key molecule of autophagy in spinal cord injury.

关键词： Bladder cancer   Cytoskeleton reorganization   TNF-alpha   METTL3   CLASP2   IQGAP1  

摘要： Background: Bladder cancer (BCa) metastasis is a multi-step process triggered by cytoskeleton reorganization. However, the regulation mechanism of cytoskeleton reorganization in BCa remains ambiguous. This study elucidated the influence of tumor necrosis factor-alpha (TNF-alpha) in cytoskeleton remodeling during BCa metastasis and its possible mechanisms. Methods: Colony formation, scratch, transwell, and the nude mouse model were adopted to evaluate the growth and metastasis. Molecular expression was assessed by immunohistochemical staining, quantitative real-time PCR (qRT-PCR), and Western blotting. The N6-methyladenosine (m6A) level was detected by methylated RNA immunoprecipitation (MeRIP). Protein interaction was validated by Co-immunoprecipitation (Co-IP). Immunofluorescence staining was used to identify rearrangement of actin filament fibers (F-actin) and protein colocalization. Results: TNF-alpha facilitated cytoplasmic linker associated protein 2 (CLASP2) and methyltransferase like 3 (METTL3) expression in a dose (10-50 ng/mL)-dependent manner in BCa. CLASP2 high expression suggested a shorter overall survival of BCa patients. CLASP2 deficiency suppressed BCa cell proliferation, migration, and invasion via disrupting F-actin cytoskeleton. Mechanistically, TNF-alpha promoted METTL3-mediated m6A modification of CLASP2 to enhance CLASP2 mRNA stability. Moreover, CLASP2 directly interplayed with IQ motif containing GTPase activating protein 1 (IQGAP1) to regulate F-actin cytoskeleton remodeling. In vivo data demonstrated that inhibition of METTL3/CLASP2 axis delayed lung metastasis in nude mice. Conclusion: TNF-alpha favors BCa cell metastasis, which involves METTL3-mediated m6A modification of CLASP2 that interacts with IQGAP1, thus leading to F-actin cytoskeleton remodeling. Our findings suggest targeting TNF alpha/METTL3/CLASP2/IQGAP1 axis as a potential avenue for promising treatment for BCa.

关键词： Mycobacterium tuberculosis   Tubercular serpiginous–like choroiditis   Molecular mimicry   IL   interleukin   MTB   Mycobacterium tuberculosis   PR   photoreceptor   RHO   rhodopsin   RMSD   root mean square deviation   RPE   retinal pigment epithelium   TB   tuberculosis   TBU   TB uveitis   TLR   Toll-like receptor  

摘要： Purpose: The presentation of posterior ocular tuberculosis (TB) varies greatly along with the need for immunomodulatory therapy to control inflammation. In this study, we explore the potential mechanisms and pathways for autoimmune-related inflammation in ocular TB using molecular mimicry-based mathematical modeling. Design: Computational protein analysis. Methods: Twenty-three TB-related proteins, including ESAT-6 subgroup proteins, and 23 retinal ganglion cells, photoreceptor, and retinal pigment epithelium (RPE) cellular proteins were included in this study. The 3-dimensional structure and sequence of the TB AG proteins were compared to the above-mentioned retinal, photoreceptor, and RPE cellular proteins. All retinal proteins were obtained from the UniProt database. The sequence and 3-dimensional structure of TB-related proteins and retinal proteins were compared with the TM-align server. The interactions of proteins showing significant similarity (template modeling score above 0.5, root mean square deviation [RMSD] value below 5A degrees) with cytokines (interleukin [IL]6, IL10, IL12A, IL12B, TLR2, TLR3, and TLR4) were analyzed. Autoimmune and autoinflammation-related protein-receptor interaction of similar proteins was assessed using the CABS-dock web server. Main Outcome Measures: Template modeling score, structural alignment accuracy using RMSD value, protein-cytokine interaction. Results: We detected a high level of structural similarity between ESAT-6 (EsxA, EsxB) proteins and rhodopsin, HSPA1A, RPE-related BEST-1, ABCC-1, ABCC-4, ABCC-5, SLC47A1, SLC1A5, SLC38A7, SLC6A6, SLC5A6, LAT-1, and SLC16A1 proteins. When we evaluated the likelihood/potential to stimulate an immune response via a cytokine release, TLR-2 (most common), TLR-3, and TLR-4, which are highly susceptible to Mycobacterium tuberculosis ESAT-6 (ESXA and ESXB) proteins, showed a potential receptor-protein interaction with retinal proteins. Moreover, some eye-related proteins had the capacity

关键词： IL-12   Immunotherapy   cancer   uPAR/CD87/PLAUR   Tumor-targeting   Immune-oncology  

摘要： IL-12, also called IL-12p70, is a highly potent, proinflammatory heterodimeric cytokine that can mediate many beneficial anti-tumor effects. In preclinical studies, recombinant IL-12, as well as IL-12 gene therapies, have demonstrated notable anti-tumor results across various tumor types;however, IL-12 clinical benefit has been limited by its poor tolerability at potentially efficacious doses. We have developed a novel approach to mitigate the toxicity of IL-12 by engineering tumor-targeted split IL-12 that preferentially localizes IL-12 activity to the tumor microenvironment. The functionally inactive IL-12 subunits, p35 and p40, are separately fused to antibody fragments targeting a highly expressed tumor-associated antigen, uPAR. The goal of this strategy is to drive assembly and activity of the IL-12 heterodimer into the tumor site through sequential administration of the targeted subunits, reducing systemic exposure and thereby potentially reducing associated toxicities. We use in vitro activity assays along with in vivo pharmacokinetic and pharmacodynamic studies in mice and non-human primates to demonstrate that the split IL-12 anti-uPAR fusions are capable of assembly and activity in vivo. The targeted p35 and p40 subunits are capable of complexing to form IL-12p70 and inducing STAT4 phosphorylation when applied to cultured immune cells, indicating in vitro IL-12 activity. Furthermore, sequential administration of subunits in in vivo mouse models demonstrates rapid serum clearance of IL-12 while extending retention in the tumor. Finally, dosing in non-human primates shows molecules are functionally active in vivo. This is a unique strategy with great clinical promise to harness the therapeutic potential of IL-12 while potentially avoiding the toxicity associated with systemic delivery.

关键词： lupus(1)   B cell(2)   IL-4(3)   TLR7(4)   transcriptomics(5)   autoantibodies(6)  

摘要： TLR7 stimulation of T-bet+CD11c+IgD-CD27- double-negative 2 (DN2) B cells is crucial for autoantibody formation in systemic lupus erythematosus (SLE). Here, we show that administration of IL-4 for five weeks significantly reduced autoantibodies and T-bet+CD11c+ IgD- B cells in autoimmune BXD2 mice treated with R848, a TLR7 agonist. Single-cell transcriptomics analysis indicates that following two doses of in vivo administration, IL-4 redirected development toward follicular, CD23+ germinal center (GC), and DN4-like memory B cells compared to treatment with R848 alone. While IL-4 enhanced genes related to antigen processing and presentation, it also suppressed R848-induced Ki67+ GC B cells in vivo. In vitro stimulation of SLE patient B cells with a DN2 polarizing cocktail revealed that IL-4 reduced the expression of interferon response and DN2 signature genes, promoting a population of CD23+T-bet- DN4 B population. These findings suggest that developmental reprogramming by IL-4 counteracts TLR7-promoted DN2 and GC B cells in SLE.

关键词： Autoimmune diseases   Cytokine   IL-12   IL-23   IL-35  

摘要： In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment.