Endochondral ossification is essential for the development of appendicular bones, physiological bone remodelling and fracture healing. Recent studies have identified mesenchymal stromal cell-derived FABP5+ septoclasts (SCs) as key mediators for the growth and repair of long bones, particularly in cartilage matrix degradation and growth plate remodelling via the secretion of matrix metalloproteinases. Our previous study has shown that soluble epoxide hydrolase (sEH) inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), promotes long bone growth and bone repair by enhancing H-type vessel-coupled osteogenesis. However, whether TPPU treatment regulates SC activity, thereby promoting long-bone growth and fracture healing, remains unclear. Here, our in vitro and in vivo results showed that TPPU treatment promoted long-bone growth in newborn mice and regulated the hypertrophic layer in the growth plate, with a reduced ratio of hypertrophic cartilage (HC) to proliferative cartilage (PC) width. Furthermore, TPPU treatment enhanced SC activity, as evidenced by elevated expression of MMP9 and FABP5 in the metaphysis near the growth plate. Simultaneously, TPPU induced FABP5+ SC-like cells to degrade chondrocytes in co-cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs). Mechanistically, TPPU enhanced the crosstalk of co-cultured HUVECs and hDPSCs to activate the NOTCH signalling pathway in hDPSCs by upregulating HIF-1α expression in HUVECs. Furthermore, TPPU enhanced fracture healing by inducing more FABP5+ SCs and MMP9 secretion at the fracture site. Collectively, these findings highlight sEH as a promising therapeutic target that regulates endochondral ossification through inducing SC activity, offering new opportunities for bone development and repair.

Background: Periodontitis is increasingly recognized as a contributing risk factor for Alzheimer's disease (AD). Our previous research demonstrated that periodontitis activates brain glial cells and upregulates the innate immune protein interferon-induced transmembrane protein 3 (IFITM3), leading to β-amyloid (Aβ) deposition. However, the underlying mechanisms remain unclear. Methods: In vitro , primary mouse glial cells were treated as follows: Control, Porphyromonas gingivalis ( Pg) , Pg +siRNA-IRF7, and Pg +pirinixic acid group. Glial activation and interferon pathway gene expression were analyzed by quantitative reverse transcription polymerase chain reaction(RT-qPCR) and Immunofluorescence. Secreted IFN-β was measured by ELISA. Neurons were then exposed to conditioned media from these glial cultures, and neuronal IFITM3 and Aβ levels were assessed via immunofluorescence. In vivo , a periodontitis model was established in C57BL/6J mice via silk ligation and Pg topical application, and the impact of periodontitis on intracranial neuroinflammation was assessed. Neuroinflammatory changes were compared with those of age-matched APP/PS1 mice. Hippocampal and cortical expression of IRF1-9, IFNs, IFITM3, and inflammatory genes was quantified by RT-qPCR. Finally, mouse periodontitis models were treated with PBS or pirinixic acid, and AD-like brain pathology was evaluated by RT-qPCR and immunohistochemistry. Results: In vitro , Pg significantly upregulated IRF7, IFN-β, and IFITM3 expression in glial cells, with markedly more pronounced effects observed in astrocytes than in microglia. Knockdown of Irf7 or treatment with pirinixic acid effectively attenuated Pg -induced astrocyte activation, reduced IFN-β levels in the culture supernatant, and subsequently suppressed neuronal IFITM3 upregulation and Aβ accumulation. Database analysis revealed that Toll-like receptor 4 (TLR4) is widely expressed in astrocytes, and Pg treatment significantly upregulated the gene levels of Tlr4 and Ticam1/Ticam2 . In vivo , periodontitis induced neuroinflammation and Aβ deposition in the brains of mice, with hippocampal expression patterns of PPAR-α and IRF7 closely resembling those observed in APP/PS1 transgenic mice. Furthermore, pirinixic acid treatment markedly ameliorated periodontitis-induced neuroinflammation. Conclusion: These findings further substantiate the pathological link between periodontitis and AD, highlighting the importance of periodontitis prevention and treatment in AD management. Moreover, we identify the IRF7-IFN-β-IFITM3-Aβ axis as a novel molecular pathway and a potential therapeutic target for AD via the oral-brain axis.

Background/purpose Tuft cells (TCs) activate type II immunity by interleukin-25 (IL-25) and stimulate proliferation and mucus secretion of goblet cells to defense worms. TCs have been identified in the striated ducts of submandibular glands. Sjögren's disease (SjD) has been linked to type II immunity, with increased IL-25 expression, yet the role of TCs in this context remains and their association with SjD and contribution to IL-25 production are unknown. Materials and methods Labial gland biopsies from SjD patients and patients with labial gland cysts were collected for histological staining. Immunofluorescence was employed to detect the expression and localization of DCLK1, KRT19, and IL-25. C57BL/10 mice and NOD.B10 mice were selected to measure salivary flow rate. RT-qPCR was used to detect the gene expression of POU2F3, DCLK1, and IL-25 in the submandibular glands. Results DCLK1-positive TCs were detected in labial gland from SjD patients and the submandibular glands of NOD.B10 mice. DCLK1 and IL-25 proteins were strongly expressed in striated ducts adjacent to lymphoid foci in both SjD patient and NOD.B10 mice, showing a positive correlation with the degree of lymphoid infiltration and ductal dilation with colocalization. TC markers, including DCLK1 and POU2F3 were significantly upregulated, concomitant with reduced salivary flow and increased lymphoid infiltration. Conclusion TCs are closely associated with salivary gland pathology and lymphoid infiltration in SjD. TCs-derived IL-25 implies their involvement in the pathological process of SjD. This work underscores the promise of TCs as a promising target for both understanding and treating SjD pathogenesis.

Primary Sjögren’s disease (pSjD) is a chronic autoimmune disease. Clinically, sialography and lip gland biopsy in patients with pSjD show characteristic ductal dilations. However, the roles of the immune responses in ductal dilation remain unknown. We show that Th2 cells and their core cytokine IL-4 promote salivary duct dilatation in human and experimental SjD. Specifically, striated duct dilation is accompanied by periductal lymphocyte infiltration, which is correlated with increased IL-4 levels. In vivo, IL-4 neutralization reduced ductal dilation. Mechanistically, IL-4 induces the formation of cyst-like structures in cultured embryonic submandibular glands of mice. At the molecular level, IL-4 activates SHH signaling pathway in striated duct epithelial cells, upregulating SNAI1 and suppressing Cadherin 1 expression. This process disrupts interepithelial adhesion, leading to ductal dilation. Thus, IL-4 drives salivary gland ductal dilation that interferes with salivary gland function in SjD. Our findings should have implications for a potential therapeutic target in clinical pSjD.

Abstract The functional interdependence between type 2 immunity and the nervous system plays a critical role in maintaining tissue homeostasis and promoting repair across multiple organs. These systems act in concert through bidirectional crosstalk to preserve systemic physiological equilibrium. The nervous system, including its peripheral components, releases neuropeptides and neurotransmitters in response to signals from type 2 immune cells, such as T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s), thereby inducing cytokine production and immunomodulatory effects. Conversely, type 2 immune cells and their cytokines can sensitize peripheral nociceptors and regulate neurotransmitter release, forming a reciprocal feedback loop. This review summarizes the molecular mechanisms underlying type 2 neuroimmune interactions and their roles in physiological homeostasis and tissue repair across multiple organ systems, including the nervous system, skin, gastrointestinal tract, respiratory tract, and oral cavity. In addition, we highlight current controversies and knowledge gaps to identify critical molecular targets that confer specificity to type 2 neuroimmune interactions, and to propose emerging conceptual frameworks and research directions for the clinical management of related disorders.

Perineural invasion (PNI) has significant implications for the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Lissencephaly-1 (LIS1) plays a crucial role in neural development and is highly expressed in HNSCC, showing a positive correlation with tumor invasion. However, the precise role of LIS1 in PNI and its underlying molecular mechanisms are not well understood. The study employed bioinformatics analysis and immunohistochemistry to investigate the gene expression of LIS1 in HNSCC tissues. Transwell assays, wound healing assays, and co-culture models were used to evaluate the PNI capacity of HNSCC cells in vitro. A microfluidic chip was designed to study the interactions between the tumor and Schwann cells. RNA sequencing analysis provided insights into the signaling pathways involved in LIS1. Mechanistic investigations were performed using RT-qPCR and Western blotting. Additionally, a murine sciatic nerve invasion model was established to assess the effects of LIS1 on tumor invasion and PNI in vivo. Analysis of the TIMER and GEPIA2 databases revealed elevated levels of LIS1 mRNA in HNSCC tissues compared to those in adjacent normal tissues. Clinicopathological evaluation confirmed that LIS1 expression was enriched in the tumor cytoplasm and positively correlated with PNI. HNSCC cells overexpressing LIS1 demonstrated enhanced PNI capacity. Co-culture experiments revealed that LIS1 expression in tumor cells stimulated the proliferation and migration of SCs. RNA sequencing analysis identified the regulatory effects of LIS1 on PHGDH, PSAT1, and PSPH, which activate the serine pathway. Subsequent investigations demonstrated that serine, acting on Schwann cells through the NMDAR/AKT signaling pathway, promotes tumor PNI. In vivo experiments using nude mice supported the role of LIS1 in promoting the PNI capacity through the serine pathway. Our findings indicate that LIS1 expression in HNSCC is pivotal for facilitating communication between tumor cells and Schwann cells through the serine/NMDAR/AKT axis, thereby promoting perineural invasion of HNSCC. Our study identified LIS1 as a potential predictive marker of perineural invasion and underscored its significance as a therapeutic target for HNSCC treatment.

Neutrophils, as the rapid response cells of the innate immune system, play a critical role in defending against acute infections and are intricately involved in the bidirectional regulation of neurodegenerative and chronic inflammatory disorders. Emerging evidence indicates neutrophils in the pathogenesis of Alzheimeru2019s disease (AD) and periodontitis through releasing inflammatory mediators, formation of neutrophil extracellular traps (NETs), and modulation of the local microenvironment. These cells could act as a crucial connection bridging the pathological processes in the brain and the oral cavity. This review explores the presence and functional roles of neutrophils in AD, provides a comprehensive overview of their mechanisms in periodontitis, and summarizes associated clinical detection indicators. Furthermore, it outlines potential neutrophil-mediated pathways that connect periodontitis and AD. By integrating findings from single-cell sequencing, animal models, and clinical data, this review offers new perspectives for early diagnosis and therapeutic intervention in periodontitis to potentially delay the progression of AD. It also highlights the dynamic role of neutrophils as a mechanistic bridge between the two diseases and discusses targeted diagnostic and treatment strategies focused on neutrophil modulation.

Periodontitis is a risk factor linked to Alzheimer’s disease (AD), and characterized by amyloid-beta (Aβ) pathology. Mounting evidence suggests a contributory role of periodontitis in the onset and progression of AD. Type I interferons are upregulated in Porphyromonas gingivalis (Pg)-induced periodontitis in murine models. Colonization of Pg has been identified in the brains of patients with AD. Recently, interferon-induced transmembrane protein 3 (IFITM3), an inflammation-induced innate immunity protein, was identified as a novel γ-secretase modulatory protein for Aβ production in AD. However, whether periodontitis triggers an increase in type I interferons in the brain, subsequently inducing AD-like pathology by eliciting the innate immune response of glial cells and activating the IFITM3-Aβ axis, remains unclear. Additionally, the question of whether colonization of Pg in brain induces innate immune in astrocytes and microglia remains unanswered. We assessed the impact of Pg-induced periodontitis on cognitive impairment in C57BL/6J and APP/PS1 mice using behavioral tests. The effects of Periodontitis/Pg on microglia and astrocytes were measured using quantitative reverse transcriptase PCR (qRT-PCR), western blotting, and histological staining. Pg-induced periodontitis led to cognitive impairment in C57BL/6J mice and exacerbated a cognitive decline in APP/PS1 mice. Furthermore, Pg-induced periodontitis elevated the levels of interferon (IFN)-β, IFITM3, and Aβ deposition in the brains of both C57BL/6J and APP/PS1 mice. We also identified Pg DNA, glial activation, and the expression of inflammatory mediators in the brain of a Pg-induced periodontitis model. Additionally, our findings confirmed astrocytes as the primary responders to Pg-induced innate immunity and inflammation both in vitro and in vivo. Periodontitis also induces an increase in IFITM3 expression in periodontal tissue, salivary glands. We define a previously unidentified link between periodontitis and cognitive decline, and provide new evidence linking oral pathogenic bacteria-induced innate immunity and neuroinflammation to AD pathogenesis and cognitive decline, partly through increased blood-brain barrier (BBB) permeability, triggered neuroinflammation, and elevated IFITM3 in glial cells for Aβ deposition. Moreover, periodontitis exacerbates innate immunity and cognitive impairment in AD mice, underscoring the importance of preventive and therapeutic strategies for periodontal disease in AD patients.

Macrophage immunomodulation has emerged as a novel intervention and therapeutic strategy for temporomandibular joint osteoarthritis (TMJOA), potentially serving as a key approach for reducing synovial inflammation and promoting cartilage repair. The soluble epoxide hydrolase inhibitor (sEHi), TPPU, has shown potential therapeutic effects against inflammatory diseases and osteogenesis by elevating endogenous Epoxyeicosatrienoic acids (EETs). However, it remains largely unknown whether TPPU can reduce inflammation and cartilage degradation in the TMJOA. In vivo, the effects of TPPU on articular cartilage and synovial tissue pathology were assessed using H E, Masson, Safranin-O/Fast Green staining and immunohistochemistry in a mouse model of TMJOA induced by unilateral anterior crossbite (UAC). RNA-seq and Western Blot was employed to investigate the key signal pathway of TPPU on M1 macrophage polarization. Subsequently, a co-culture system of macrophages and ATDC5 chondrocytes was established, and the influence of TPPU-treated macrophages on chondrogenesis was evaluated through Alcian Blue staining and RT-qPCR. In vivo, we observed that in UAC-induced TMJOA mice, TPPU significantly reduced the infiltration of inflammatory cells in the synovium and the positive expression of inflammatory factors TNF-α and IL-1β. It also mitigated the degradation of cartilage matrix and increased the positive expression of chondrogenic markers SOX9 and COL II. In vitro experiments revealed that TPPU inhibited the polarization of M1 macrophages, reduced inflammatory responses, and subsequently increased the expression of chondrogenic markers (SOX9 and COLII) in chondrocytes. RNA-seq data indicated that the NF-κB/IL-17 pathway as a putative target following TPPU treatment in macrophages. Further experiments confirmed that the addition of TPPU to macrophages inhibited the reduction in chondrogenesis induced by IL-17 and NF-κB agonists in the co-cultured cells. Our study elucidates a novel role of TPPU in inhibiting M1 macrophage polarization and modulating inflammatory immune responses via the EETs/NF-κB/IL-17 axis, thereby inhibiting cartilage damage in TMJOA.

Background Revascularization and restoration of normal pulp-dentin complex are important for tissue-engineered pulp regeneration. Recently, a unique periodontal tip-like endothelial cells subtype (POTCs) specialized to dentinogenesis was identified. We have confirmed that TPPU, a soluble epoxide hydrolase (sEH) inhibitor targeting epoxyeicosatrienoic acids (EETs) metabolism, promotes bone growth and regeneration by angiogenesis and osteogenesis coupling. We hypothesized that TPPU could also promote revascularization and induce POTCs to contribute to pulp-dentin complex regeneration. Here, we in vitro and in vivo characterized the potential effect of TPPU on the coupling of angiogenesis and odontogenesis and investigated the relevant mechanism, providing new ideas for pulp-dentin regeneration by targeting sEH. Methods In vitro effects of TPPU on the proliferation, migration, and angiogenesis of dental pulp stem cells (DPSCs), human umbilical vein endothelial cells (HUVECs) and cocultured DPSCs and HUVECs were detected using cell counting kit 8 (CCK8) assay, wound healing, transwell, tube formation and RT-qPCR. In vivo, Matrigel plug assay was performed to outline the roles of TPPU in revascularization and survival of grafts. Then we characterized the VEGFR2 + POTCs around odontoblast layer in the molar of pups from C57BL/6 female mice gavaged with TPPU. Finally, the root segments with DPSCs mixed with Matrigel were implanted subcutaneously in BALB/c nude mice treated with TPPU and the root grafts were isolated for histological staining. Results In vitro, TPPU significantly promoted the migration and tube formation capability of cocultured DPSCs and HUVECs. ALP and ARS staining and RT-qPCR showed that TPPU promoted the osteogenic and odontogenic differentiation of cultured cells, treatment with an anti-TGF-β blocking antibody abrogated this effect. Knockdown of HIF-1α in HUVECs significantly reversed the effect of TPPU on the expression of angiogenesis, osteogenesis and odontogenesis-related genes in cocultured cells. Matrigel plug assay showed that TPPU increased VEGF/VEGFR2-expressed cells in transplanted grafts. TPPU contributed to angiogenic-odontogenic coupling featured by increased VEGFR2 + POTCs and odontoblast maturation during early dentinogenesis in molar of newborn pups from C57BL/6 female mice gavaged with TPPU. TPPU induced more dental pulp-like tissue with more vessels and collagen fibers in transplanted root segment. Conclusions TPPU promotes revascularization of dental pulp regeneration by enhancing migration and angiogenesis of HUVECs, and improves odontogenic differentiation of DPSCs by TGF-β. TPPU boosts the angiogenic–odontogenic coupling by enhancing VEGFR2 + POTCs meditated odontoblast maturation partly via upregulating HIF-1α, which contributes to increasing pulp-dentin complex for tissue-engineered pulp regeneration.

OBJECTIVE:Craniofacial and oral malformations (COMs) represent an important class of human developmental disorders with profound implications on the anatomical structure, appearance, and various physiological functions. In this study, we aimed to define the spectrum of COMs and analysis its features or possible influencing factors to improve the surveillance and control of the disease. MATERIALS AND METHODS:We organized a multicenter survey of COMs from 19 hospitals in 14 provinces. The clinical data of COM cases were collected from the electronic medical records system, cleaned and aggregated for analysis. RESULTS:A total of 90,895 COM cases with 76 types of diseases were identified from 34,649,545 hospital population. The four most common COMs were supernumery teeth (62.64%), cleft lip and palate (28.53%), microdontia (2.86%), and tooth agenesis (1.70%). The remaining 72 diseases were detected in 3881 cases and were considered to be rare COMs. Moreover, 84.72% of rare COMs also manifested as other malformations or dysfunctions of the bone, skin and other tissues. CONCLUSIONS:COMs exhibit age and gender distribution patterns, have multiple types, and significant dental malformations. The diagnostic criteria and registration practices for COMs influence their reported prevalence and temporal trends, necessitating future improvements.

Improving the microenvironment to augment endogenous regenerative potential has emerged as a fundamental concept for stimulating and expediting periodontal tissue repair and regeneration. Previous studies have demonstrated that TPPU, a soluble epoxide hydrolase inhibitor (sEHi), mediates the suppression of inflammatory bone loss in periodontitis models. However, the underlying mechanisms remain largely elusive. In this study, we constructed a human umbilical vein endothelial cell (HUVEC) and periodontal ligament stem cell (PDLSC) coculture system in vitro and tested the anti-inflammatory effect of TPPU under inflammatory conditions. The roles of HIF-1α and Endomucin (EMCN) in the anti-inflammatory effects of TPPU were analyzed. The effects of TPPU on osteogenesis and osteoclastogenesis in cocultured cells were examined. The in vivo periodontitis model further verified the effects of TPPU on inhibiting neutrophil adhesion and inflammation and inhibiting osteoclasts. Our in vitro experiments demonstrated that TPPU enhances the interaction between mesenchymal stem cells and vascular endothelial cells to enhance anti-inflammatory and osteogenic differentiation effects and revealed a new anti-inflammatory mechanism of TPPU involving the upregulation of EMCN in endothelial cells to prevent lymphocyte recruitment. We also confirmed that TPPU inhibits osteoclast activity. Our in vivo findings showed that TPPU inhibits osteoclast activity and neutrophil adhesion and enhances periodontal tissue repair and regeneration. TPPU promotes local regeneration in periodontitis by inhibiting inflammation and bone resorption. Thus, targeting soluble epoxide hydrolase represents an endogenous regenerative strategy for periodontitis treatment.

Extracellular vesicles (EVs) have recently received increasing attention as essential mediators of communication between tumor cells and their microenvironments. Tumor-associated macrophages (TAMs) play a proangiogenic role in various tumors, especially head and neck squamous cell carcinoma (HNSCC), and angiogenesis is closely related to tumor growth and metastasis. This research focused on exploring the mechanisms by which EVs derived from TAMs modulate tumor angiogenesis in HNSCC. Our results indicated that TAMs infiltration correlated positively with microvascular density in HNSCC. Then we collected and identified EVs from TAMs. In the microfluidic chip, TAMs derived EVs significantly enhanced the angiogenic potential of pHUVECs and successfully induced the formation of perfusable blood vessels. qPCR and immunofluorescence analyses revealed that EVs from TAMs transferred miR-21-5p to endothelial cells (ECs). And targeting miR-21-5p of TAMs could effectively inhibit TAM-EVs induced angiogenesis. Western blot and tube formation assays showed that miR-21-5p from TAM-EVs downregulated LATS1 and VHL levels but upregulated YAP1 and HIF-1α levels, and the inhibitors of YAP1 and HIF-1α could both reduce the miR-21-5p enhanced angiogenesis in HUVECs. The in vivo experiments further proved that miR-21-5p carried by TAM-EVs promoted the process of tumor angiogenesis via YAP1/HIF-1α axis in HNSCC. Conclusively, TAM-derived EVs transferred miR-21-5p to ECs to target the mRNA of LATS1 and VHL, which inhibited YAP1 phosphorylation and subsequently enhanced YAP1-mediated HIF-1α transcription and reduced VHL-mediated HIF-1α ubiquitination, contributing to angiogenesis in HNSCC. These findings present a novel regulatory mechanism of tumor angiogenesis, and miR-21-5p/YAP1/HIF-1α might be a potential therapeutic target for HNSCC.

Objective: Oral ulcers are a lesion in the oral mucosa that impacts chewing or drinking. Epoxyeicosatrienoic Acids (EETs) have enhanced angiogenic, regenerative, anti-inflammatory, and analgesic effects. The present study aims to evaluate the effects of 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea (TPPU), a soluble epoxide hydrolase inhibitor for increasing EETs level, on the healing of oral ulcers.Methods: The chemically-induced oral ulcers were established in Sprague Dawley rats. The ulcer area was treated with TPPU to evaluate the healing time and pain threshold of ulcers. The expression of angiogene-sis and cell proliferation-related protein in the ulcer area was detected using immunohistochemical stain-ing. The effects of TPPU on migration and angiogenesis capability were measured with scratch assay and tube formation.Results: Compared with the control group, TPPU promoted wound healing of oral ulcers with a shorter healing time, and raised pain thresholds. Immunohistochemical staining showed that TPPU increased the expression of angiogenesis and cell proliferation-related protein with reduced inflammatory cell infiltration in the ulcer area. TPPU enhanced cell migration and tube-forming potential in vitro.Conclusions: The present results support the potential of TPPU with multiple biological effects for the treatment of oral ulcers by targeting soluble epoxide hydrolase.

Type H vessels have recently been identified to modulate osteogenesis. Epoxyeicostrioleic acids (EETs) have an essential contribution to vascular homeostasis. However, whether increased EETs with soluble epoxide hydrolase (sEH) inhibitor TPPU enhance the coupling of angiogenesis and osteogenesis remains largely unknown. The effects of TPPU on cross-talk between co-cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs), and on long bone growth and calvarial defect repair in mice were investigated in vitro and in vivo. TPPU enhanced osteogenic differentiation of co-cultured HUVECs and hDPSCs in vitro and increased type H vessels, and long bone growth and bone repair of calvarial defect. Mechanistically, TPPU promoted cell proliferation and angiogenesis, reclined cell apoptosis, and significantly increased CD31hi EMCNhi endothelial cells (ECs) and SLIT3 and HIF-1α expression levels in co-cultured HUVECs and hDPSCs. Knockdown of Slit3 in hDPSCs or Hif-1α in HUVECs impaired the formation of CD31hi EMCNhi ECs and reversed TPPU-induced osteogenesis. We defined a previously unidentified effect of TPPU coupling angiogenesis and osteogenesis. TPPU induced type H vessels by upregulating the expression of hDPSCs-derived SLIT3, which resulted in the activation of ROBO1/YAP1/HIF-1α signalling pathway in ECs. Targeting metabolic pathways of EETs represents a new strategy to couple osteogenesis and angiogenesis, sEH is a promising therapeutic target for bone regeneration and repair.

阿尔茨海默病(Alzheimer's disease,AD)是继癌症、心血管病、脑血管病之后威胁老年人健康的第四大原发病.AD的病因尚不清楚.牙周病是最常见的菌群失调引起的口腔慢性炎症性疾病,也是AD的重要危险因素.流行病学证据显示,牙周病患者AD的患病风险显著增加,但其具体机制仍未可知.慢性神经炎症与AD的病理生理学相关,全身炎症可诱发和加剧中枢神经系统免疫反应参与AD,牙周病同样可以引发机体慢性炎症.已经有研究表明,牙周病可能通过引发神经炎症参与AD发病.然而,目前仍缺乏关于牙周病通过神经免疫途径参与AD发病机制的系统评价.因此,本文总结了牙周病和AD之间已知的相互作用,并强调了对牙周病通过神经免疫和神经炎症途径参与AD发病机制的见解,以期为牙周病与AD的相关机制研究提供更多的思路.

The role of periosteum rich in a variety of bone cells and growth factors in the treatment of bone defects has gradually been discovered. However, due to the limited number of healthy transplantable periosteum, there are still major challenges in the clinical treatment of critical-size bone defects. Various techniques for preparing biomimetic periosteal scaffolds that are similar in composition and structure to natural periosteal scaffold have gradually emerged. This article reviews the current preparation methods of biomimetic periosteal scaffolds based on various biomaterials, which are mainly divided into natural periosteal materials and various polymer biomaterials. Several preparation methods of biomimetic periosteal scaffolds with different principles are listed, their strengths and weaknesses are also discussed. It aims to provide a more systematic perspective for the preparation of biomimetic periosteal scaffolds in the future.

Inflammation-induced autophagy is a double-edged sword. Dysfunction of autophagy impairs the differentiation capacity of mesenchymal stem cells and enhances inflammation-induced bone loss. Tooth extraction with periodontal and/or endodontic lesions exacerbates horizontal and vertical resorption of alveolar bone during the healing period. Alveolar socket preservation (ASP) procedure following tooth extraction has important clinical implications for future prosthodontic treatments. Studies have shown that epoxyeicosatrienoic acids (EETs) have significant anti-inflammatory effects and participate in autophagy. However, whether EETs can minimize alveolar bone resorption and contribute to ASP by regulating autophagy levels under inflammatory conditions remain elusive. Here, we figured out that LPS-induced inflammatory conditions increased the inflammatory cytokine and inhibited osteogenic differentiation of human dental pulp stem cells (hDPSCs), and led to excessive autophagy of hDPSCs. Moreover, we identified that increased EETs levels using TPPU, a soluble epoxide hydrolase inhibitor, reversed these negative outcomes. We further demonstrated the potential of TPPU to promote early healing of extraction sockets and ASP, and speculated that it was related to autophagy. Taken together, these results suggest that targeting inhibition of soluble epoxide hydrolase using TPPU plays a protective role in the differentiation and autophagy of mesenchymal stem cells and provides potential feasibility for applying TPPU for ASP, especially under inflammatory conditions.

Interleukin-9 (IL-9)-producing CD4+ T helper cells (Th9) have been implicated in allergy/asthma and anti-tumor immunity, yet molecular insights on their differentiation from activated T cells, driven by IL-4 and transforming growth factor-beta (TGF-β), is still lacking. Here we show opposing functions of two transcription factors, D-binding protein (DBP) and E2F8, in controlling Th9 differentiation. Specifically, TGF-β and IL-4 signaling induces phosphorylation of the serine 213 site in the linker region of the Smad3 (pSmad3L-Ser213) via phosphorylated p38, which is necessary and sufficient for Il9 gene transcription. We identify DBP and E2F8 as an activator and repressor, respectively, for Il9 transcription by pSmad3L-Ser213. Notably, Th9 cells with siRNA-mediated knockdown for Dbp or E2f8 promote and suppress tumor growth, respectively, in mouse tumor models. Importantly, DBP and E2F8 also exhibit opposing functions in regulating human TH9 differentiation in vitro. Thus, our data uncover a molecular mechanism of Smad3 linker region-mediated, opposing functions of DBP and E2F8 in Th9 differentiation.

OBJECTIVE:Sjögren's syndrome (SS) is a systemic autoimmune disease, and T cells play an important role in the initiation and perpetuation of the disease. In this study, we developed an immunotherapy for NOD/LtJ mice with SS-like symptoms by combining a transient depletion of CD4+ T cells with the administration of autoantigen-specific peptide Ro480. METHODS:NOD/LtJ mice were treated with single anti-CD4 monoclonal antibody (mAb) followed 2 days later by a series of 6 intraperitoneal injections of Ro480-494 every other day. Salivary flow rates were determined pre- and posttreatment once a week. Mice were euthanized 6 weeks after the initial anti-CD4 mAb treatment, salivary glands (SGs) were collected for analyses of histologic disease scores and inflammatory cell infiltration, polymerase chain reaction determination of genes was conducted, and flow cytometry analysis including major histocompatibility complex class II tetramer staining of immune cells was performed. In addition, adoptive transfer of Treg cells was administrated to investigate the function of the newly generating Treg cells in vivo. RESULTS:The combination of anti-CD4 mAb with autoantigen-specific peptide Ro480 generated SSA/Ro antigen-specific Treg cells in vivo, which can suppress interferon-γ production of CD4+ T cells and inflammation infiltration in SGs and maintain the function of SGs. CONCLUSION:Our findings provide a new approach to generating antigen-specific Treg cells in vivo for SS treatment, which may have implications for potential therapy for patients with SS.