RESUMO
Introduction: Current therapeutic strategies, including immune checkpoint blockade (ICB), exhibit limited efficacy in treating hepatocellular carcinoma (HCC). Nanoparticles, particularly those that can accumulate specifically within tumors and be activated by sonodynamic therapy (SDT), can induce immunogenic cell death (ICD); however, ICD alone has not achieved satisfactory therapeutic effectiveness. This study investigates whether combining ICB with ICD induced by nanoparticle-mediated SDT could enhance anti-tumor immunity and inhibit HCC growth. Methods: We developed an iron-based micelle nanodelivery system encapsulating the Near-Infrared Dye IR-780, which was surface-modified with a cyclic tripeptide composed of arginine-glycine-aspartic acid (cRGD). This led to the synthesis of targeted IR780@FOM-cRGD nanoparticles. These nanoparticles were specifically engineered to kill tumor cells under sonication, activate immunogenic cell death (ICD), and be used in conjunction with immune checkpoint blockade (ICB) for the treatment of hepatocellular carcinoma (HCC). Results: The synthesized IR780@FOM-cRGD nanoparticles had an average diameter of 28.23±1.750 nm and a Zeta potential of -23.95±1.926. Confocal microscopy demonstrated that IR780@FOM-cRGD could target HCC cells while minimizing toxicity to healthy cells. Upon sonodynamic activation, these nanoparticles consumed significant amounts of oxygen and generated substantial reactive oxygen species (ROS), effectively killing tumor cells and inhibiting the proliferation, invasion, and migration of H22 cells. Hemolysis assays confirmed the in vivo safety of the nanoparticles, and in vivo fluorescence imaging revealed significant accumulation in tumor tissues. Mouse model experiments showed that combining ICB(which induced by Anti-PD-L1) with ICD (which induced by IR780@FOM-cRGD), could effectively activated anti-tumor immunity and suppressed tumor growth. Discussion: This study highlights the potential of IR780@FOM-cRGD nanoparticles to facilitate tumor eradication and immune activation when used in conjunction with Anti-PD-L1 therapy. This combination represents a non-invasive, efficient, and targeted approach for the treatment of hepatocellular carcinoma (HCC). By integrating sonodynamic therapy with immunotherapy, this strategy promises to substantially improve the effectiveness of traditional treatments in combating HCC, offering new avenues for clinical application and therapeutic innovation.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animais , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/imunologia , Camundongos , Nanopartículas/química , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/imunologia , Linhagem Celular Tumoral , Antígeno B7-H1/imunologia , Humanos , Indóis/química , Indóis/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/química , Terapia por Ultrassom/métodos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Morte Celular Imunogênica/efeitos dos fármacos , Micelas , Terapia Combinada/métodos , Camundongos Endogâmicos BALB C , Imunoterapia/métodosRESUMO
As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy.
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Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.
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COVID-19/complicações , COVID-19/virologia , Glucose/metabolismo , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Proteínas de Membrana/metabolismo , SARS-CoV-2 , Animais , Biomarcadores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Jejum , Expressão Gênica , Gluconeogênese/efeitos dos fármacos , Gluconeogênese/genética , Interações Hospedeiro-Patógeno , Humanos , Hiperglicemia/sangue , Fígado/metabolismo , Fígado/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Especificidade de Órgãos/genéticaRESUMO
The prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention.
Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Proteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Fosfoproteínas/metabolismo , Animais , Apolipoproteína B-100/metabolismo , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Resistência à Insulina , Fígado/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Fosfoproteínas/genética , TranscriptomaRESUMO
BACKGROUND: Complex aberration in lung is rare, which may increase risk of vascular injury and cause ligation of wrong pulmonary vein or bronchus by mistake during lung surgery, and result in sever complication like pulmonary congestion or atelectasis. CASE SUMMARY: A 44-year-old female was admitted for a ground glass nodule (24 mm in diameter) in her right upper lobe. Video-assisted thoracoscopic (VATS) right upper lobectomy with lymph nodes dissection was performed. During operation, we simultaneously identified extremely rare aberrations of right preeparterial bronchus, right upper lobe vein behind pulmonary artery and right middle lobe vein drained into left atrium in this patient. The patient was well recovered and discharged at the postoperative-day 4. CONCLUSION: Preoperatively, three-dimensional reconstruction can help to identify inconspicuous variation of pulmonary vessels and bronchus effectively. During lung surgery, if anatomic aberration is suspected, careful dissection of vessels and bronchus will help to confirm whether there is an aberration or not.