3-methyl-1H-indol-1-yl dimethylcarbamodithioate attenuates periodontitis through targeting MAPK signaling pathway-regulated mitochondrial function.

Periodontitis, the second most common oral disease, is primarily initiated by inflammatory responses and osteoclast differentiation, in which the MAPK signaling pathway and mitochondrial function play important roles. 3-methyl-1H-indol-1-yl dimethylcarbamodithioate (3o), a hybrid of indole and dithiocarbamate, was first synthesized by our group. It has shown anti-inflammatory activity against lipopolysaccharide-induced acute lung injury. However, it is not known if 3o can exert effects in periodontitis. In vitro study: LPS-induced macrophage inflammation initiation and a receptor activator of nuclear factor κB ligand-stimulated osteoclast differentiation model were established. Cell viability, inflammatory cytokines, osteoclast differentiation, the MAPK signaling pathway, and mitochondrial function before and after treatment with 3o were investigated. In vivo study: Alveolar bone resorption, inflammatory cytokine expression, osteoclast differentiation, and the underlying mechanisms were assessed in mice with periodontitis. Inflammatory cytokine expression and osteoclast differentiation appeared downregulated after 3o treatment. 3o inhibited the MAPK signaling pathway and restored mitochondrial function, including mitochondrial reactive oxygen species, mitochondrial membrane potential, and ATP production. Meanwhile, 3o reduced inflammation activation and bone resorption in mice with periodontitis, reflected by the decreased expression of inflammatory cytokines and osteoclasts, implying that 3o inhibited the MAPK signaling pathway and the mitochondrial oxidative DNA damage marker 8-OHdG. These results highlight the protective role of 3o in periodontitis in mice and reveal an important strategy for preventing periodontitis.

Skeleton-derived extracellular vesicles in bone and whole-body aging: From mechanisms to potential applications.

The skeleton serves as a supportive and protective organ for the body. As individuals age, their bone tissue undergoes structural, cellular, and molecular changes, including the accumulation of senescent cells. Extracellular vesicles (EVs) play a crucial role in aging through the cellular secretome and have been found to induce or accelerate age-related dysfunction in bones and to contribute further via the circulatory system to the aging of phenotypes of other bodily systems. However, the extent of these effects and their underlying mechanisms remain unclear. Therefore, this paper attempts to give an overview of the current understanding of age-related alteration in EVs derived from bones. The role of EVs in mediating communications among bone-related cells and other body parts is discussed, and the significance of bones in the whole-body aging process is highlighted. Ultimately, it is hoped that gaining a clearer understanding of the relationship between EVs and aging mechanisms may serve as a basis for new treatment strategies for age-related degenerative diseases in the skeleton and other systems.

M2 macrophages secrete glutamate-containing extracellular vesicles to alleviate osteoporosis by reshaping osteoclast precursor fate.

Osteoclast precursors (OCPs) are thought to commit to osteoclast differentiation, which is accelerated by aging-related chronic inflammation, thereby leading to osteoporosis. However, whether the fate of OCPs can be reshaped to transition into other cell lineages is unknown. Here, we showed that M2 macrophage-derived extracellular vesicles (M2-EVs) could reprogram OCPs to downregulate osteoclast-specific gene expression and convert OCPs to M2 macrophage-like lineage cells, which reshaped the fate of OCPs by delivering the molecular metabolite glutamate. Upon delivery of glutamate, glutamine metabolism in OCPs was markedly enhanced, resulting in the increased production of α-ketoglutarate (αKG), which participates in Jmjd3-dependent epigenetic reprogramming, causing M2-like macrophage differentiation. Thus, we revealed a novel transformation of OCPs into M2-like macrophages via M2-EVs-initiated metabolic reprogramming and epigenetic modification. Our findings suggest that M2-EVs can reestablish the balance between osteoclasts and M2 macrophages, alleviate the symptoms of bone loss, and constitute a new approach for bone-targeted therapy to treat osteoporosis.

The interaction between the nervous system and the stomatognathic system: from development to diseases.

The crosstalk between the nerve and stomatognathic systems plays a more important role in organismal health than previously appreciated with the presence of emerging concept of the "brain-oral axis". A deeper understanding of the intricate interaction between the nervous system and the stomatognathic system is warranted, considering their significant developmental homology and anatomical proximity, and the more complex innervation of the jawbone compared to other skeletons. In this review, we provide an in-depth look at studies concerning neurodevelopment, craniofacial development, and congenital anomalies that occur when the two systems develop abnormally. It summarizes the cross-regulation between nerves and jawbones and the effects of various states of the jawbone on intrabony nerve distribution. Diseases closely related to both the nervous system and the stomatognathic system are divided into craniofacial diseases caused by neurological illnesses, and neurological diseases caused by an aberrant stomatognathic system. The two-way relationships between common diseases, such as periodontitis and neurodegenerative disorders, and depression and oral diseases were also discussed. This review provides valuable insights into novel strategies for neuro-skeletal tissue engineering and early prevention and treatment of orofacial and neurological diseases.

Hydroxytyrosol prevents periodontitis-induced bone loss by regulating mitochondrial function and mitogen-activated protein kinase signaling of bone cells.

Reactive oxygen species (ROS) overproduction promotes the alveolar bone loss during the development of periodontitis. Mitochondria are the principal source of ROS. Hydroxytyrosol (HT), a natural phenolic compound present in olive oil, is well known for its antioxidant and mitochondrial-protective prosperities. Nonetheless, the impact of HT on periodontitis and its related mechanisms underlying bone cell behavior remains unknown. Osteoclasts differentiated from RAW264.7 model and oxidative stress (OS) induced pre-osteoblast MC3T3-E1 cell injury model were treated with and without HT. Cell viability, apoptosis, differentiation, mitochondrial function along with mitogen-activated protein kinase (MAPK) signaling pathway were investigated. Meanwhile, the effect and related mechanisms of HT on bone loss in mice with periodontitis were also detected. HT inhibited osteoclast differentiation and prevented OS induced pre-osteoblast cells injury via regulating mitochondrial function as well as ERK and JNK signaling pathways. Moreover, HT attenuated the alveolar bone loss, increased bone forming activity, inhibited the osteoclasts differentiation and decreased the level of OS in mice with periodontitis. Our findings, for the first time, revealed a novel function of HT in bone remodeling of periodontitis, and highlighted its therapeutical potential for the prevention/treatment of periodontitis.

Crosstalk between reactive oxygen species and Dynamin-related protein 1 in periodontitis.

Excessive generation of reactive oxygen species (ROS) have great impacts on the development of periodontitis. Dynamin-related protein 1 (Drp1) mediated mitochondrial fission is the main reason and the result of excessive ROS generation. However, whether Drp1 and crosstalk between ROS and Drp1 contribute to the process of periodontitis remains elusive. We herein investigated the role and functional significance of crosstalk between ROS and Drp1 in periodontitis. Firstly, human periodontal ligament cells (hPDLCs) were treated with hydrogen peroxide (H2O2) and ROS inhibitor N-acetyl-cysteine (NAC) or Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1). Cell viability, apoptosis, osteogenic differentiation, expression of Drp1, and mitochondrial function were investigated. Secondly, mice with periodontitis were treated with NAC or Mdivi-1. Finally, gingival tissues were collected from periodontitis patients and healthy individuals to evaluate ROS and Drp1 levels. H2O2 induced cellular injury and inflammation, excessive ROS production, mitochondrial abnormalities, and increased expression of p-Drp1 and Drp1 in hPDLCs, which could be reversed by NAC and Mdivi-1. Moreover, both NAC and Mdivi-1 ameliorated tissue damage and inflammation, and decreased expression of p-Drp1 and Drp1 in mice with periodontitis. More importantly, patients with periodontitis presented significantly higher levels of ROS-induced oxidative damage and p-Drp1 than that in healthy individuals and correlated with clinical parameters. In summary, ROS-Drp1 crosstalk greatly promotes the development of periodontitis. Pharmacological blockade of this crosstalk might be a novel therapeutic strategy for periodontitis.

Nanoscopic wear behavior of dentinogenesis imperfecta type II tooth dentin.

OBJECTIVES: The aim of this study was to investigate the wear behavior of Dentinogenesis imperfecta type II (DGI-II) dentin and elucidate the correlation between its tribological properties and components. METHODS: The mid-coronal dentin of normal and DGI-II teeth were divided into two groups: perpendicular and parallel to the dentin tubules. The microstructure of dentin was detected using atomic force microscopy (AFM). The wear behavior of dentin was evaluated by nanoscratch tests and scanning electron microscopy (SEM). Meanwhile, changes in molecular groups and chemical composition were analyzed by Raman and Energy-Dispersive X-ray (EDX) tests, respectively. Nanohardness was also evaluated. RESULTS: AFM images of DGI-II dentin illustrated a decrease in the number of tubules and the tubule diameter. Nanoscratch test showed a higher friction coefficient and a greater depth-of-scratch in DGI-II dentin. The wear resistance of DGI-II dentin was reduced independent of tubule orientation. EDX results indicated that DGI-II dentin mineral content decreased and Raman spectra results showed DGI-II dentin had a decreased collagen matrix structure stability coupled with hypomineralization. Furthermore, a significant reduction in nanohardness and elastic modulus of DGI-II dentin was observed. Regression analysis revealed a close correlation between dentin components and inferior wear resistance. CONCLUSIONS: All results indicated the wear behavior of DGI-II dentin was significantly deteriorated, presumably caused by the disorder in microstructures and the reduction of chemical composition.