RESUMEN
Toll-like receptor 4 (TLR4) acts as a double-edged sword in the occurrence and development of periodontitis. While the activation of TLR4 in macrophages aids in clearing local pathogens, it can also disrupt innate immune responses, upsetting microecological balance and accelerating the destruction of periodontal bone tissues. To date, the effects of TLR4 on osteogenesis and osteoclastogenesis in periodontitis have not been comprehensively studied. In this study, we investigated the development of periodontitis in the Tlr4-/- mice by ligating their second molars with silk threads. Compared to wild-type (WT) mice, Tlr4-/- mice demonstrated increased resistance to periodontitis-associated bone destruction, as evidenced by decreased bone resorption and enhanced bone regeneration. Mechanistically, the deletion of Tlr4 not only inhibited osteoclast formation by reducing the expression of NFATc1, CTSK and TRAP, but also enhanced osteogenic abilities through increased expression of OCN, OPN and RUNX2. In conclusion, TLR4 tips the balance of osteoclastogenesis and osteogenesis, thereby promoting periodontal bone destruction in periodontitis.
Asunto(s)
Ratones Noqueados , Osteoblastos , Osteoclastos , Osteogénesis , Periodontitis , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Periodontitis/inmunología , Periodontitis/genética , Periodontitis/patología , Osteoclastos/fisiología , Osteoclastos/inmunología , Ratones , Osteoblastos/metabolismo , Osteoblastos/inmunología , Ratones Endogámicos C57BL , Masculino , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Humanos , Pérdida de Hueso Alveolar/inmunología , Pérdida de Hueso Alveolar/patologíaRESUMEN
N6-methyladenosine (m6A) is a form of posttranscriptional modification that plays important roles in cancer including oral squamous cell carcinoma (OSCC). Most studies to date have focused on a limited number of regulators and oncogenic pathways, thus failing to provide comprehensive insight into the dynamic effects of m6A modification. In addition, the role of m6A modification in shaping immune cell infiltration in OSCC has yet to be clarified. This study was designed to assess m6A modification dynamics in OSCC and to understand how such modifications influence clinical immunotherapeutic treatment outcomes. m6A modification patterns linked with 23 m6A regulators were analyzed in 437 OSCC patients from TCGA and GEO cohorts. These patterns were then quantified through m6A score based on algorithms derived from a principal component analysis (PCA) approach. The m6A modification patterns of OSCC samples were grouped into two clusters based on the m6A regulators expression, and immune cell infiltration was linked with the 5-year survival outcomes of patients in these clusters. 1575 genes associated with OSCC patient prognosis were identified and used to re-cluster these samples into two groups. Patients in clusters exhibiting higher levels of m6A regulator expression exhibited poorer overall survival (OS), whereas patients with high m6A scores survived for longer (p < 0.001). The overall mortality rates in the groups of patients with low and high m6A scores were 55% and 40%, respectively, and the m6A score distributions in clusters of patients grouped by m6A modification patterns and gene expression further supported the link between a high m6A score and better prognostic outcomes. Immunophenoscore (IPS) values for patients in different m6A score groups suggested that the use of PD-1-specific antibodies or CTLA-4 inhibitors alone or in combination would yield superior treatment outcomes in patients in the high-m6A score group relative to the low-m6A score group. m6A modification patterns are relevant to heterogeneity in OSCC. Detailed analyses of m6A modification patterns may thus offer novel insight regarding immune cell infiltration within the OSCC tumor microenvironment, guiding novel efforts to provide patients with more effective immunotherapeutic interventions.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Metilación , Microambiente Tumoral , PronósticoRESUMEN
<p><b>OBJECTIVE</b>To investigate the polymorphisms of 15 STR loci of Han population in Yan'an.</p><p><b>METHODS</b>Blood samples were obtained from 100 unrelated Han individuals in Yan'an. DNA templates were screened by AmpF/STR Identifiler kit and ABI3100Avant DNA analyzer.</p><p><b>RESULTS</b>The allele frequencies of 15 STR loci ranged from 0.005 to 0.550, and the genotype frequencies ranged from 0.010 to 0.310. The combined match probability was 2.5x10(-17) and combined EPP was 0.999999999.</p><p><b>CONCLUSIONS</b>The 15 STR loci used in this study were highly polymorphic in Han population in Yan'an and suitable for population study and forensic cases in this region.</p>