RESUMO
The in vivo functions of SerpinB2 in tumor cells and tumor-associated macrophages (TAMs) during breast cancer development and metastasis remain elusive. SerpinB2-deficient MMTV-PyMT mice (PyMTSB2-/-) were previously produced to explore the biological roles of SerpinB2 in breast cancer. Compared with MMTV-PyMT wild-type (PyMTWT) mice, PyMTSB2-/- mice showed delayed tumor progression and reduced CK8 + tumor cell dissemination to lymph nodes. RNA-Seq data revealed significantly enriched genes associated with inflammatory responses, especially upregulated M1 and downregulated M2 macrophage marker genes in PyMTSB2-/- tumors. Decreased CD206+M2 and increased NOS2+M1 markers were detected in the primary tumors and metastatic lymph nodes of PyMTSB2-/- mice. In an in vitro study, SerpinB2 knockdown decreased the sphere formation and migration of MDA-MB-231 cells and suppressed protumorigenic M2 polarization of RAW264.7 cells. The combination of low SerpinB2, high NOS2, and low CD206 expression was favorable for survival in patients with breast cancer, as assessed in the BreastMark dataset. Our study demonstrates that SerpinB2 deficiency delays mammary tumor development and metastasis in PyMTWT mice, along with reduced sphere formation and migration abilities of tumor cells and decreased macrophage protumorigenic polarization.
Assuntos
Neoplasias da Mama , Inibidor 2 de Ativador de Plasminogênio , Animais , Feminino , Humanos , Camundongos , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Macrófagos/metabolismo , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/genética , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Inibidor 2 de Ativador de Plasminogênio/genética , Inibidor 2 de Ativador de Plasminogênio/metabolismo , Inibidor 2 de Ativador de Plasminogênio/deficiência , Células RAW 264.7 , Macrófagos Associados a Tumor/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.
Assuntos
COVID-19 , Receptor para Produtos Finais de Glicação Avançada , SARS-CoV-2 , Humanos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/patologia , COVID-19/complicações , COVID-19/virologia , Animais , Camundongos , Inflamação/metabolismo , Inflamação/patologia , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/metabolismo , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Grupo de Alta Mobilidade/genética , Masculino , Pulmão/patologia , Pulmão/metabolismo , Pulmão/imunologia , FemininoRESUMO
Background: Osteoarthritis (OA), the most prevalent form of arthritis, is a degenerative joint disease marked by the progressive deterioration of articular cartilage, leading to clinical manifestations such as joint pain. Objective: This study investigated the effects of Curcuma longa L. extract (CL) containing curcumin, demethoxycurcumin, and bisdemethoxycurcumin on monosodium iodoacetate (MIA)-induced OA rats. Design: Sprague-Dawley rats with MIA-induced OA received CL supplementation at doses of 5, 25, and 40 mg/kg body weight. Results: CL extract administration suppressed mineralisation parameters and morphological modifications and decreased arachidonate5-lipoxygenase and leukotriene B4 levels in articular cartilage. Additionally, it decreased serum prostaglandin E2, NO, and glycosaminoglycanlevels as well as the protein expression of phosphorylated inhibitor kappa B-alpha, phosphorylated p65, cyclooxygenase-2, and inducible nitric oxide synthase in the cartilage of MIA-injected rats. Furthermore, it also reduced matrix metalloproteinases and elevated SMAD family member 3 phosphorylation, tissue inhibitor of metalloproteinases, aggrecan, collagen type I, and collagen type II levels in the articular cartilage of MIA-induced OA rats. Conclusions: This study's findings suggest that CL supplementation helps prevent OA development and is an effective therapy for OA.