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1.
Mol Hum Reprod ; 30(7)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38870534

RESUMO

Acephalic spermatozoa syndrome (ASS) is a severe teratospermia with decaudated, decapitated, and malformed sperm, resulting in male infertility. Nuclear envelope protein SUN5 localizes to the junction between the sperm head and tail. Mutations in the SUN5 gene have been identified most frequently (33-47%) in ASS cases, and its molecular mechanism of action is yet to be explored. In the present study, we generated Sun5 knockout mice, which presented the phenotype of ASS. Nuclear membrane protein LaminB1 and cytoskeletal GTPases Septin12 and Septin2 were identified as potential partners for interacting with SUN5 by immunoprecipitation-mass spectrometry in mouse testis. Further studies demonstrated that SUN5 connected the nucleus by interacting with LaminB1 and connected the proximal centriole by interacting with Septin12. The binding between SUN5 and Septin12 promoted their aggregation together in the sperm neck. The disruption of the LaminB1/SUN5/Septin12 complex by Sun5 deficiency caused separation of the Septin12-proximal centriole from the nucleus, leading to the breakage of the head-to-tail junction. Collectively, these data provide new insights into the pathogenesis of ASS caused by SUN5 deficiency.


Assuntos
Proteínas de Membrana , Camundongos Knockout , Membrana Nuclear , Septinas , Cabeça do Espermatozoide , Cauda do Espermatozoide , Animais , Humanos , Masculino , Camundongos , Infertilidade Masculina/metabolismo , Infertilidade Masculina/genética , Lamina Tipo B/metabolismo , Lamina Tipo B/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Membrana Nuclear/metabolismo , Septinas/metabolismo , Septinas/genética , Cabeça do Espermatozoide/metabolismo , Cabeça do Espermatozoide/patologia , Cauda do Espermatozoide/metabolismo , Espermatozoides/metabolismo , Teratozoospermia/metabolismo , Teratozoospermia/genética
2.
J Nanobiotechnology ; 22(1): 296, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38811964

RESUMO

BACKGROUND: Combination therapy involving immune checkpoint blockade (ICB) and other drugs is a potential strategy for converting immune-cold tumors into immune-hot tumors to benefit from immunotherapy. To achieve drug synergy, we developed a homologous cancer cell membrane vesicle (CM)-coated metal-organic framework (MOF) nanodelivery platform for the codelivery of a TLR7/8 agonist with an epigenetic inhibitor. METHODS: A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining. RESULTS: In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model. CONCLUSION: MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.


Assuntos
Receptor 7 Toll-Like , Receptor 8 Toll-Like , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Camundongos , Feminino , Humanos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Nanopartículas/química , Fatores de Transcrição/metabolismo , Camundongos Endogâmicos BALB C , Proteínas de Ciclo Celular/metabolismo , Imunoterapia/métodos , Epigênese Genética/efeitos dos fármacos , Proteínas que Contêm Bromodomínio
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