Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling. Here, we focused on the role of Semaphorin 3A (Sema3A), expressed by sensory nerves, in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement (OTM) model. Firstly, bone formation was activated after the 3rd day of OTM, coinciding with a decrease in sensory nerves and an increase in pain threshold. Sema3A, rather than nerve growth factor (NGF), highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM. Moreover, in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells (hPDLCs) within 24 hours. Furthermore, exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload. Mechanistically, Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway, maintaining mitochondrial dynamics as mitochondrial fusion. Therefore, Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation, both as a pain-sensitive analgesic and a positive regulator for bone formation.
Humans ; Bone Remodeling ; Cell Differentiation ; Osteogenesis ; Semaphorin-3A/pharmacology* ; Trigeminal Ganglion/metabolism*

Objective : To investigate the correlation between the expression level of YTHDF1 in oral squamous cell carcinoma ( OSCC) and clinicopathologic features and its potential prognostic value． Methods : The expression of YTHDF1 in 132 OSCC tissues and 66 paracancerous tissues was detected by immunohistochemistry (IHC) ，and the expression of YTHDF1 protein in OSCC cell lines was detected by Western blot．The correlation between YTHDF1 and clinicopathological features was analyzed by chi-square test．Kaplan-Meier and Cox factors were used to analyze the factors affecting the survival time of the patients and draw the survival curves of the YTHDF1 gene to evaluate its potential clinical significance. Results : The expression of YTHDF1 in OSCC tissues was higher than that in para- cancerous tissues (P＜0. 001) ，and the expression of YTHDF1 protein increased in OSCC cell lines compared with normal oral epithelial keratinocytes (P ＜0. 001) ．The expression of YTHDF1 was correlated with the TNM stage and T stage of patients with OSCC (P＜0. 05) ，and the patients with high expression of YTHDF1 had a shorter sur- vival time compared with those with low expression (P ＜0. 001) ． Conclusion High expression of YTHDF1 may be associated with poor patient prognosis and YTHDF1 may be able to serve as a target for OSCC treatment.

BACKGROUND: One of the most important treatment modalities for non-small cell lung cancer (NSCLC) is immune checkpoint inhibitor. Nevertheless, a small percentage of patients do not respond well to these therapies, highlighting the significance of identifying important CD8+ T cell subsets for immunotherapy and creating trustworthy biomarkers. The purpose of this study is to assess the potential utility of TIM3+CD8+ T cells as new biomarkers by examining their expressions in various areas of the NSCLC tumor microenvironment. METHODS: Based on biopsy techniques, tumor tissue samples were obtained from patients with NSCLC and categorized into tumor central and non-central regions. Using flow cytometry, the infiltration of TIM3+CD8+ T cells and the surface expression of programmed cell death 1 (PD-1) on these cells were examined, and their correlations with the effectiveness of immunotherapy were assessed. RESULTS: The non-central region of tumor tissues had considerably larger infiltration of TIM3+CD8+ T lymphocytes compared to the non-central region (P<0.0001). This pattern was found in both subgroups with tumor diameters ≥3 cm or <3 cm (P<0.01). In comparison to TIM3-CD8+ T cells, TIM3+CD8+ T cells showed higher levels of PD-1 (P<0.001), with more PD-1+TIM3+CD8+ T cells invading the non-central region (P<0.01). Clinical responders to immunotherapy had considerably lower infiltration levels of TIM3+CD8+ T cells in the tumor non-central region compared to non-responders, with lower levels correlated with better clinical outcomes (P<0.01), while no correlation was identified in the tumor central region (P>0.05). According to reciever operating characteristic (ROC) curve analysis, TIM3+CD8+ T cells in the tumor non-central region had an area under the curve (AUC) of 0.9375 for predicting the effectiveness of immunotherapy, which was considerably higher than that of TIM3+CD8+ T cells in the tumor central region and programmed cell death ligand 1 (PD-L1) [tumor proportion score (TPS)]. CONCLUSIONS In the tumor microenvironment of NSCLC, TIM3+CD8+ T cells show regional distribution patterns. The expression of this cell population in the non-central region of the tumor microenvironment may be a biomarker for predicting the effectiveness of immunotherapy.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Lung Neoplasms/metabolism* ; Hepatitis A Virus Cellular Receptor 2/immunology* ; Tumor Microenvironment/immunology* ; CD8-Positive T-Lymphocytes/metabolism* ; Male ; Female ; Middle Aged ; Aged ; Adult ; Programmed Cell Death 1 Receptor/metabolism* ; Immunotherapy ; Clinical Relevance

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.

Bone formation and deposition are initiated by sensory nerve infiltration in adaptive bone remodeling.Here,we focused on the role of Semaphorin 3A(Sema3A),expressed by sensory nerves,in mechanical loads-induced bone formation and nerve withdrawal using orthodontic tooth movement(OTM)model.Firstly,bone formation was activated after the 3rd day of OTM,coinciding with a decrease in sensory nerves and an increase in pain threshold.Sema3A,rather than nerve growth factor(NGF),highly expressed in both trigeminal ganglion and the axons of periodontal ligament following the 3rd day of OTM.Moreover,in vitro mechanical loads upregulated Sema3A in neurons instead of in human periodontal ligament cells(hPDLCs)within 24 hours.Furthermore,exogenous Sema3A restored the suppressed alveolar bone formation and the osteogenic differentiation of hPDLCs induced by mechanical overload.Mechanistically,Sema3A prevented overstretching of F-actin induced by mechanical overload through ROCK2 pathway,maintaining mitochondrial dynamics as mitochondrial fusion.Therefore,Sema3A exhibits dual therapeutic effects in mechanical loads-induced bone formation,both as a pain-sensitive analgesic and a positive regulator for bone formation.