Impacts of high mobility group box protein 1 gene polymorphisms on morbidity and mortality after living donor liver transplantationTsukiyama, Tanaka, Yamane
et alTranspl Immunol (2025)
Abstract: We investigated the effect of single-nucleotide polymorphisms (SNPs) in the high mobility group box 1 (HMGB1) gene on morbidity and mortality after liver transplantation (LT). Among 120 LT recipients and their living donors, the genotypes of HMGB1, and the SNPs rs2249825, rs1045411, rs1412125, and rs1360485 were determined. There were no significant associations between these four SNPs and the incidence of rejection or mortality. However, the incidence of early allograft dysfunction (EAD) (n = 43), which presents as functional insufficiency within 1 week of LT, was significantly higher in recipients with the GC + CC allele of rs2249825 (n = 17/34) than in those with the GG allele (n = 26/86) (p = 0.044). Although the impact of donor HMGB1 SNPs on the incidence of EAD was not statistically significant, recipients with the GC + CC allele of rs2249825 who received liver grafts from donors with the same genotype had the highest incidence of EAD (p = 0.052). In contrast, the donor TC + CC allele of rs1412125 was an independent risk factor for the development of sepsis (n = 33) in LT recipient (OR = 3.05, 95 % CI = 1.18-7.87, p = 0.021). Thus, the SNPs of the HMGB1 gene in either recipients or donors were not associated with mortality but influenced the incidence of EAD and sepsis, likely being a predictive biomarker for the risk of serious complications after LT.Copyright © 2025. Published by Elsevier B.V.
Hepatic Stellate Cells Activated by Cancer Cell-derived AMIGO2-containing Small Extracellular Vesicles Promote Cancer Cell Migration by Producing IL-8Izutsu, Osaki, Seong
et alAnticancer Res (2025) 45 (4), 1435-1446
Abstract: Our previous studies have demonstrated that amphoterin-induced gene and open reading frame 2 (AMIGO2) functions as a driver gene for liver metastasis, regulating adhesion between cancer cells and liver endothelial cells. AMIGO2-containing small extracellular vesicles (sEVs) derived from gastric cancer (GC) cells were shown to enhance adhesion to hepatic endothelial cells, contributing to pre-metastatic niche formation. However, their role in promoting cancer cell migration into the liver parenchyma remained unclear. This study investigated whether AMIGO2-containing sEVs activate hepatic stellate cells (HSCs) and promote cancer cell migration.AMIGO2-over-expressing and control cell lines (MKN28) were established. sEVs isolated from each cell line were added to human HSCs (TWINT-1). The supernatant collected was added to MKN28 to quantitatively evaluate migration ability and nuclear translocation of NF-kB. A chemokine array identified secreted factors affected by sEV treatment.HSCs were activated by AMIGO2-containing EVs, resulting in increased IL-8 secretion through NF-kB nuclear translocation. This IL-8-rich supernatant significantly enhanced GC cell migration. Neutralizing IL-8 with antibodies suppressed this migration, confirming its pivotal role.AMIGO2-containing sEVs derived from GC cells actively modify the hepatic microenvironment by activating HSCs and inducing IL-8 secretion, which promotes GC cell migration into the liver parenchyma. This process contributes to the formation of a pre-metastatic niche, highlighting AMIGO2-containing sEVs as potential therapeutic targets for preventing liver metastasis.Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
A CXCR4-targeted immunomodulatory nanomedicine for photodynamic amplified immune checkpoint blockade therapy against breast cancerLiu, Chen, Zhang
et alActa Biomater (2025)
Abstract: The therapeutic efficacy of immune checkpoint blockade (ICB) is critically compromised by inadequate T lymphocyte infiltration, low T cell-induced pro-inflammatory responses, and the accumulation of immunosuppressive cells within the tumor microenvironment (TME). In this work, a chimeric peptide-engineered immunomodulatory nanomedicine (designated as CXNP-CeBM) is developed for photodynamic amplified ICB therapy against breast cancer. CXNP-CeBM is composed of a CXCR4-targeting peptide ((C16)2-KLGASWHRPDK) loaded with the photosensitizer of Ce6 and the PD-1/PD-L1 inhibitor of BMS8. CXNP-CeBM specifically recognizes CXCR4 on breast cancer, thus suppressing CXCR4-mediated signaling pathways and enhancing the intracellular delivery of therapeutic agents. The photodynamic therapy (PDT) of CXNP-CeBM damages primary tumor cells to initiate immunogenic cell death (ICD), leading to the release of high mobility group box 1 (HMGB1) and the exposure of calreticulin (CRT). Simultaneously, the interruption of CXCR4 signaling reduces tumor fibrosis, promotes T-cell infiltration, and decreases the number of immunosuppressive cells, thereby enhancing the immunotherapeutic effect of ICB. Treatment with CXNP-CeBM would activate systemic anti-tumor immunity, leading to effective inhibition of both primary and lung metastatic tumors, while maintaining low systemic toxicity. This work provides a reliable strategy for the delivery of multi-synergistic agents, effectively activating breast cancer immunity through a multifaceted mechanism. STATEMENT OF SIGNIFICANCE: Although immune checkpoint blockade (ICB) has shown great potential for malignant tumor therapy, its efficacy is compromised by immunosuppressive microenvironments. Herein, a CXCR4-targeted immunomodulatory nanomedicine (CXNP-CeBM) was constructed for photodynamic amplified ICB therapy of breast cancer. CXNP-CeBM could selectively deliver photosensitizers and PD-1/PD-L1 inhibitors to breast cancer cells that overexpressed the chemokine receptor CXCR4, while interrupting CXCR4 signaling to reduce tumor fibrosis, promote T-cell infiltration, and decrease the number of immunosuppressive cells. Moreover, CXNP-CeBM induced photodynamic therapy to trigger immunogenic cell death while downregulating the PD-L1 level to destroy immune evasion mechanisms, thus activating immunological cascades to treat both primary and lung metastatic tumors. This study provided a multi-synergistic strategy for breast cancer immunotherapy through a multifaceted mechanism.Copyright © 2025. Published by Elsevier Inc.
USP22 promotes angiotensin II-induced podocyte injury by deubiquitinating and stabilizing HMGB1Peng, Huang, Pan
et alCell Signal (2025)
Abstract: Chronic kidney disease (CKD) remains a significant global health burden, with hypertensive nephropathy (HN) being one of its primary causes. Podocyte injury is a key factor in the progression of CKD. However, the molecular mechanisms underlying angiotensin II-induced podocyte injury are not fully understood. Ubiquitin-specific protease 22 (USP22) has been reported to facilitate a range of cellular processes, including cell proliferation and apoptosis. However, the role of USP22 in HN remains unclear.The expression of USP22 was assessed in kidney samples from hypertensive nephropathy patients, angiotensin II-induced hypertensive nephropathy mouse models, and cultured podocytes treated with angiotensin II. Podocyte-specific USP22 knockout mice were used to investigate the effects of USP22 deletion on podocyte injury and inflammation.USP22 expression was significantly upregulated in the kidney of HN patients, angiotensin II-induced mouse models, and cultured podocytes. Podocyte-specific deletion of USP22 markedly reduced angiotensin II-induced podocyte injury and inflammatory responses. Furthermore, we identified high-mobility group box protein 1 (HMGB1) as a protein that interacts with USP22. USP22 deubiquitinated and stabilized HMGB1 through K48-linked ubiquitination. Downregulation of USP22 expression improved kidney function and pathological changes in HN by degrading HMGB1.This study identifies USP22 as a key regulator of angiotensin II-induced podocyte injury and inflammation through its interaction with HMGB1. Our findings revealed that following glomerular injury, damage and shedding of tubular cells also occurred. Targeting the USP22-HMGB1 axis offers a promising therapeutic strategy for treating hypertensive nephropathy and other forms of CKD.Copyright © 2025. Published by Elsevier Inc.
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