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Periodontal disease is considered one of the diabetic complications with high morbidity and severity. Recent studies demonstrated the involvement of the epigenome on diabetic complications. Histone modifications change chromatin architecture and gene activation. Histone modifications have been reported to alter chromatin structure and regulate gene transcription. In this study, we investigated the impacts of H3 lysine 4 trimethylation (H3K4me3) and specific histone methyltransferases of H3K4 methylation, su(var)3-9, enhancer-of-zeste, and trithorax domain 1A (SETD1A) on periodontal tissue affected by the diabetic condition. We observed the increase in H3K4me3 and SETD1A in gingival tissue of diabetic rats compared with the normal rats. Cultured human fibroblasts (hGFs) confirmed a high glucose-induced increase in H3K4me3 and SETD1A. We further demonstrated that high glucose increased the gene expression of matrix metalloproteinase (MMP) 1 and MMP13, which were canceled by sinefungin, an SETD1A inhibitor. Our investigation suggests that diabetes triggers histone modifications in the gingival tissue, resulting in gingival inflammation. Histone modifications may play crucial roles in the development of periodontal disease in diabetes. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a major cause of mortality worldwide. The initial change in atherosclerosis is intimal thickening due to muscle cell proliferation and migration. A correlation has been observed between periodontal disease and atherosclerosis. Here, we investigated the proliferation and migration of human aortic smooth muscle cells (HASMCs) using Porphyromonas gingivalis-derived LPS (Pg-LPS). To elucidate intracellular signaling, toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) of HASMCs were knocked down, and the role of these molecules in Pg-LPS-stimulated proliferation and migration was examined. The role of mitogen-activated protein kinase (MAPK) in HASMC proliferation and migration was further elucidated by MAPK inhibition. Pg-LPS stimulation increased the proliferation and migration of HASMCs and activated the TLR4/MyD88 pathway. TLR4 knockdown inhibited Pg-LPS stimulated HASMCs proliferation and migration. Pg-LPS stimulation led to the phosphorylation of P38 MAPK, JNK, and ERK, and MyD88 knockdown inhibited the phosphorylation of P38 MAPK and JNK but not ERK. P38 MAPK and SAPK/JNK inhibition did not suppress the proliferation of HASMCs upon Pg-LPS stimulation, but ERK inhibition significantly inhibited proliferation. SAPK/JNK and ERK inhibition suppressed Pg-LPS-stimulated migration of HASMCs. In conclusion, our findings suggest that Pg-LPS may promote atherosclerosis via the activation of MAPK through TLR4. [ABSTRACT FROM AUTHOR]

Aim The aetiology of progressive periodontitis in diabetes has not yet been elucidated. We previously demonstrated that nitrosative stress is increased in diabetic rats with periodontitis. Nitrosative stress induces poly( ADP-ribose) polymerase ( PARP) activation. Here, we demonstrated the involvement of PARP activation in diabetic periodontitis and detailed the therapeutic effects of PARP inhibitor. Materials and Methods Experimental periodontitis was induced by placing a nylon thread ligature. Half of the normal and diabetic rats received the PARP inhibitor, 1,5-isoquinolinediol, for 2 weeks. Gingival PARP activation was detected by immunostaining for poly( ADP-ribose). Periodontitis was evaluated by gingival inflammatory cell infiltration, inflammatory gene expressions and micro- CT analyses. Results Although both periodontitis and the presence of diabetes increased PARP activation in the gingiva, diabetic rats with periodontitis had the highest activation of PARP. Diabetic rats with periodontitis also showed significant increases in monocyte/macrophage invasion into the gingiva, inflammatory gene expressions, nitrotyrosine-positive cells in the gingiva and alveolar bone loss, all of which were suppressed by treatment with the PARP inhibitor. Conclusions These results indicate the involvement of PARP activation in the pathogenesis and aggravation of periodontal disease in diabetes and suggest the therapeutic potential of PARP inhibition for treating periodontal disease, especially in patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: Angiopoietin-like protein 4 (ANGPTL4) is produced in chronic or acute inflammation. Although ANGPTL4 increases in the periodontal ligament fibroblasts during hypoxia, the involvement and role of ANGPTL4 in periodontitis have not been elucidated., Objective: In this study, we investigated whether ligature-induced experimental periodontitis and/or Porphyromonas gingivalis lipopolysaccharides (Pg-LPS) would upregulate ANGPTL4 expression and whether ANGPTL4 would somehow involve in the expression of matrix metalloproteinases (MMPs) which are key molecules in the process of periodontal tissue destruction., Methods: Experimental periodontitis was induced in 6-week-old male Sprague-Dawley rats by placing a nylon suture around the neck of the maxillary second molar. Two weeks after the induction of periodontitis, the periodontal tissue was excised and analyzed by histological/immunohistochemical staining and gene expression analyses. Human gingival fibroblasts (hGFs) were stimulated with Pg-LPS. The gene expression of ANGPTLs and receptors involved in ANGPTL4 recognition were observed. We also confirmed the changes in gene expression of MMPs upon stimulation with human ANGPTL4. Furthermore, we downregulated ANGPTL4 expression by short interfering RNA in hGFs and investigated the effect of Pg-LPS on MMP production., Results: Induction of periodontitis significantly increased the expression of ANGPTL4 in the gingiva. Pg-LPS significantly increased the gene and protein expression of ANGPTL4 in hGFs but not the gene expression of other ANGPTLs or ANGPTL receptors. Recombinant human ANGPTL4 significantly increased MMP13 gene expression in hGFs. We also confirmed that MMP13 expression was increased in the gingiva during experimental periodontitis. Pg-LPS induced MMP13 gene expression in hGFs. These results suggest the pivotal role of ANGPTL4 in periodontitis., Conclusion: Periodontitis increases ANGPTL4 expression in the gingiva, further suggesting that increased ANGPTL4 may be a factor involved in enhancing MMP13 expression., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

β-Aminoisobutyric acid (BAIBA) is a myokine that is secreted from skeletal muscles by the exercise. Recently, increasing evidence has suggested the multifocal physiological activities of BAIBA. In this study, we investigated whether L-BAIBA has protective effects on rat pheochromocytoma (PC12) cells. Cultured PC12 cells were stimulated with L-BAIBA. Western blot analyses revealed that L-BAIBA stimulation significantly increased the phosphorylation of AMPK and Akt. In contrast, no effect was observed on neurite outgrowth by L-BAIBA. To investigate the effects of L-BAIBA on oxidative stress, PC 12 cells were exposed to hydrogen peroxide (H 2 O 2 ) with and without L-BAIBA. Hydrogen peroxide significantly increased reactive oxygen species (ROS) production and apoptosis in PC12 cells. Pretreatment with L-BAIBA suppressed H 2 O 2 -induced ROS production and apoptosis, which was abolished by the inhibition of AMPK by compound C. On the other hand, the inhibitory effects of L-BAIBA on oxidative stress-induced apoptosis were abolished by the inhibition of both AMPK and PI3K/Akt. In conclusion, we demonstrated that L-BAIBA confers protection against oxidative stress in PC12 cells by activating the AMPK and PI3K/Akt pathways. These results suggest that L-BAIBA may play a crucial role on protection of neuron-like cells and become a pharmacological agent to treat neuronal diseases., Competing Interests: The authors declare they have no conflict of interest., (© 2021 The Authors.)