RESUMO
Glycosylation modification of proteins is a common post-translational modification that exists in various organisms and has rich biological functions. It is usually catalyzed by multiple glycosyltransferases located in the Golgi apparatus. ß-1,3-N-acetylglucosaminyltransferases (B3GNTs) are members of the glycosyltransferases and have been found to be involved in the occurrence and development of a variety of diseases including autoimmunity diseases, cancers, neurodevelopment, musculoskeletal system, and metabolic diseases. The functions of B3GNTs represent the glycosylation of proteins is a crucial and frequently life-threatening step in progression of most diseases. In this review, we give an overview about the roles of B3GNTs in tumor, nervous system, musculoskeletal and metabolic diseases, describing the recent results about B3GNTs, in order to provide a research direction and exploration value for the prevention, diagnosis and treatment of these diseases.
Assuntos
Doenças Metabólicas , N-Acetilglucosaminiltransferases , Humanos , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Glicosilação , Glicosiltransferases/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Aging refers to a progressive decline in biological functions, leading to age-related diseases and mortality. The transition metals, including iron, copper, and manganese, play important roles in human physiological and pathological processes. Substantial research has demonstrated that senescent cells accumulate higher levels of transition metals, which in turn accelerates the process of cellular senescence and related diseases through mechanisms such as production of excessive reactive oxygen species (ROS), induction of oxidative stress, DNA damage, and mitochondrial dysfunction. This review article provides a comprehensive overview of the causes of transition metal accumulation in senescent cells, as well as the mechanisms by which it further promotes cellular senescence and related diseases. The aim is to provide insights into anti-aging and treatment of aging-related diseases caused by transition metal accumulation.
Assuntos
Envelhecimento , Senescência Celular , Dano ao DNA , Estresse Oxidativo , Espécies Reativas de Oxigênio , Senescência Celular/fisiologia , Humanos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Animais , Elementos de Transição/metabolismo , Ferro/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Cobre/metabolismo , Manganês/metabolismoRESUMO
Rationale: Spatiotemporal control of pyroptosis has a profound impact on cancer immunotherapy. Owing to the precise spatiotemporal control and reduction in the side effects of ultrasound (US), sonodynamic therapy (SDT) is expected to be a promising mean to activate pyroptosis. Furthermore, the pyroptosis-initiated immune response can be amplified by enhanced lymphocyte infiltration occurring due to extracellular matrix (ECM) depletion. Therefore, it is highly desirable to develop a sonodynamic-immunomodulatory strategy to amplify pyroptosis-mediated tumor immunotherapy by remodeling of the tumor microenvironment, thereby enhancing tumor immunotherapy. Methods: We reported a potent strategy based on a sonosensitizer, which is composed of LY364947-loaded porous coordination network (PCN-224) camouflaged with a red blood cell (RBC) membrane and evaluated pyroptosis activation, collagen depletion, immunocyte infiltration, and adaptive immune response during the pyroptosis-initiated immune response in vitro and in vivo. Results: The sonosensitizer generated reactive oxygen species (ROS) under US irradiation and initiated the caspase-3 apoptotic signaling pathway, which is regarded as the key upstream activator of gasdermin E (GSDME)-mediated pyroptosis. During the subsequent anti-tumor immune response mediated by pyroptosis, LY364947 loosened the ECM structure via collagen depletion, resulting in enhanced T-lymphocyte infiltration and nearly complete eradication of tumors in a mouse model with the formation of immunological memory. Conclusion: Our findings indicate that sonodynamic-immunomodulatory pyroptotic strategy exhibits robust anti-tumor immune efficacy as well as provides novel insights into the role of pyroptosis in cancer immunology.
Assuntos
Piroptose , Microambiente Tumoral , Animais , Camundongos , Imunoterapia , Imunomodulação , Memória Imunológica , Linhagem Celular Tumoral , Espécies Reativas de OxigênioRESUMO
Previously we reported that corneal epithelial barrier function against Pseudomonas aeruginosa was MyD88-dependent. Here, we explored contributions of MyD88-dependent receptors using vital mouse eyes and confocal imaging. Uninjured IL-1R (-/-) or TLR4 (-/-) corneas, but not TLR2 (-/-), TLR5 (-/-), TLR7 (-/-), or TLR9 (-/-), were more susceptible to P. aeruginosa adhesion than wild-type (3.8-fold, 3.6-fold respectively). Bacteria adherent to the corneas of IL-1R (-/-) or TLR5 (-/-) mice penetrated beyond the epithelial surface only if the cornea was superficially-injured. Bone marrow chimeras showed that bone marrow-derived cells contributed to IL-1R-dependent barrier function. In vivo, but not ex vivo, stromal CD11c+ cells responded to bacterial challenge even when corneas were uninjured. These cells extended processes toward the epithelial surface, and co-localized with adherent bacteria in superficially-injured corneas. While CD11c+ cell depletion reduced IL-6, IL-1ß, CXCL1, CXCL2 and CXCL10 transcriptional responses to bacteria, and increased susceptibility to bacterial adhesion (>3-fold), the epithelium remained resistant to bacterial penetration. IL-1R (-/-) corneas also showed down-regulation of IL-6 and CXCL1 genes with and without bacterial challenge. These data show complex roles for TLR4, TLR5, IL-1R and CD11c+ cells in constitutive epithelial barrier function against P. aeruginosa, with details dependent upon in vivo conditions.
Assuntos
Antígeno CD11c/imunologia , Permeabilidade da Membrana Celular , Epitélio Corneano/imunologia , Regulação da Expressão Gênica , Fator 88 de Diferenciação Mieloide/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Animais , Aderência Bacteriana , Medula Óssea/imunologia , Medula Óssea/metabolismo , Medula Óssea/microbiologia , Antígeno CD11c/metabolismo , Células Cultivadas , Epitélio Corneano/metabolismo , Epitélio Corneano/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/microbiologia , Receptores de Interleucina-1/fisiologia , Transdução de Sinais , Receptor 4 Toll-Like/fisiologia , Receptor 5 Toll-Like/fisiologiaRESUMO
Although extensively studied, protein-protein interactions remain highly elusive and are of increasing interest in drug development. We show the assembly of a monoclonal antibody, using multivalent carboxylate ions, into highly-ordered structures. While the presence and function of similar structures in vivo are not known, the results may present a possible unexplored area of antibody structure-function relationships. Using a variety of tools (e.g., mechanical rheology, electron microscopy, isothermal calorimetry, Fourier transform infrared spectroscopy), we characterized the physical, biochemical, and thermodynamic properties of these structures and found that citrate may interact directly with the amino acid residue histidine, after which the individual protein units assemble into a filamentous network gel exhibiting high elasticity and interfilament interactions. Citrate interacts exothermically with the monoclonal antibody with an association constant that is highly dependent on solution pH and temperature. Secondary structure analysis also reveals involvement of hydrophobic and aromatic residues.
Assuntos
Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/metabolismo , Géis/química , Termodinâmica , Animais , Células CHO , Calorimetria/métodos , Ácido Cítrico/química , Cricetulus , Humanos , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Transmissão , Soluções Farmacêuticas , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , TemperaturaRESUMO
BACKGROUND: Progesterone, via its nuclear receptor (PR), exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells. PRINCIPAL FINDINGS: ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to Gâ¢ACA⢠⢠â¢TGTâ¢C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and ß were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs), whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2), a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types. CONCLUSIONS: Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in uterine fibroids and breast cancer.
Assuntos
Perfilação da Expressão Gênica , Genoma Humano/genética , Receptores de Progesterona/metabolismo , Elementos de Resposta/genética , Adulto , Sequência de Bases , Sítios de Ligação/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antagonistas de Hormônios/farmacologia , Humanos , Leiomioma/genética , Leiomioma/metabolismo , Leiomioma/patologia , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mifepristona/farmacologia , Motivos de Nucleotídeos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Perilipina-2 , Matrizes de Pontuação de Posição Específica , Células Tumorais Cultivadas , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVE: To investigate the regulation of early growth response-2 (Egr-2) by transforming growth factor ß3 (TGF-ß3) and its functions in cultured human uterine leiomyoma smooth muscle cells. DESIGN: Laboratory research. SETTING: Academic medical center. PATIENT(S): Primary leiomyoma cells from patients with symptomatic leiomyomata. INTERVENTION(S): Tissue culture followed by RNA and protein analysis. MAIN OUTCOME MEASURE(S): Cell proliferation, alteration in extracellular matrix component expression. RESULT(S): In vivo mRNA levels of Egr-2 were statistically significantly higher in leiomyoma tissues compared with matched myometrial tissues, and showed a statistically significant correlation with TGF-ß3 messenger RNA (mRNA) levels in leiomyoma tissues. In primary leiomyoma smooth muscle cells, TGF-ß3 statistically significantly induced Egr-2 gene expression in a dose-dependent and time-dependent manner. Small interfering RNA (siRNA) knockdown of Egr-2 markedly increased the level of the proliferation marker proliferating cell nuclear antigen and the expression of proto-oncogene c-myc. On the other hand, ablation of Egr-2 stimulated collagen-1A1 and collagen-3A1 transcription and inhibited dermatopontin gene expression. However, the mRNA levels of α-smooth muscle actin and fibronectin were not affected by Egr-2 knockdown. CONCLUSION(S): We demonstrated that TGF-ß3 regulated Egr-2 gene expression and presented evidence that Egr-2 decreases collagen production and stimulates dermatopontin gene expression.