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Aims/Introduction Dental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68‐positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC‐conditioned media on lipopolysaccharide‐stimulated murine macrophage RAW264.7 cells were investigated. Results Diabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68‐positive monocytes/macrophages and the gene expressions of M1 macrophage‐expressed cytokines, tumor necrosis factor‐α and interleukin‐1β, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor‐α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC‐conditioned media significantly increased the gene expressions of interleukin‐10 and CD206 in lipopolysaccharide‐stimulated RAW264.7 cells. Conclusions These results suggest that DPSC transplantation promoted macrophages polarization towards anti‐inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy. Effects of DPSC transplantation on the inflammatory mRNA expressions in sciatic nerves. Transplantation of DPSCs significantly decreased TNF‐α gene expression and increased the CD206 gene expression in the sciatic nerves compared with the vehicle‐injected side in diabetic rats.

Aims/Introduction Orthodontic treatment involves alveolar bone remodeling in response to mechanical loading, resulting in tooth movement through traction‐side bone formation and compression‐side bone resorption. However, there are conflicting reports regarding alveolar bone resorption during the orthodontic treatment of patients with diabetes. Materials and Methods Diabetes was induced in 8‐week‐old C56BL/6J mice using streptozotocin (STZ). Four weeks after the injection of STZ, a mechanical load was applied between the first and second molars on the right side of the upper jaw using the Waldo method with orthodontic elastics in diabetic (DM) and normal (N) mice tooth movement, gene expression, osteoclast counts, alveolar bone residual volume, and bone beam structure were evaluated. Results The duration until spontaneous elastic loss was significantly longer in the DM group, suggesting that tooth movement may be inhibited in the diabetic state. The number of osteoclasts at 7 days after mechanical loading and the alveolar bone resorption were both significantly lower in the DM group. The gene expression levels of vascular endothelial growth factor (VEGF), a protein related to alveolar bone remodeling, and specificity protein 1 (SP1), a transcription factor of the VEGF gene, were significantly lower in the DM group than in the N group on the compression side of mechanical loading. Conclusions Mechanical loading‐induced alveolar bone remodeling is suppressed in the diabetic state. Our results suggest that VEGF is a key molecule involved in impaired bone remodeling under mechanical loading in the diabetic state. Osteoclast counts of normal and diabetic mice at 0, 1, 3, and 7 days after mechanical loading. The number of osteoclasts 7 days after mechanical loading was significantly lower in diabetic mice.

Aims/Introduction Dental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC‐conditioned media (DPSC‐CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats. Eight weeks after the induction of diabetes, DPSC‐CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC‐CM on diabetic polyneuropathy were assessed 4 weeks after DPSC‐CM injection. To confirm the angiogenic effect of DPSC‐CM, the effect of DPSC‐CM on cultured human umbilical vascular endothelial cell proliferation was investigated. Results The administration of DPSC‐CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC‐CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro‐inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC‐CM significantly increased the proliferation of umbilical vascular endothelial cells. Conclusions We showed that DPSC‐CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti‐inflammatory actions. DPSC‐CM could be a novel cell‐free regenerative medicine treatment for diabetic polyneuropathy. We showed the therapeutic efficacy of dental pulp stem cell‐conditioned media (DPSC‐CM) injection into hindlimb skeletal muscles for diabetic polyneuropathy by neuroprotective, angiogenic and anti‐inflammatory actions. As the use of DPSC‐CM will lead to a reduction of the medical costs, maintenance of DPSC‐CM quality by using selected DPSCs with high viability, and freedom from immune incompatibility and tumorigenicity, DPSC‐CM injection could be a novel therapy for diabetic polyneuropathy.

Rotavirus (RV) is considered a major cause of acute viral gastroenteritis in young animals. RV is classified into nine species, five of which have been identified in pigs. Most studies worldwide have highlighted diarrhoea outbreaks caused by RVA, which is considered the most important RV species. In the present study, we described the detection and characterization of porcine RVB as a primary causative agent of diarrhoea outbreaks in pig herds in Brazil. The study showed a high frequency (64/90; 71.1%) of RVB diagnosis in newborn piglets associated with marked histopathological lesions in the small intestines. Phylogenetic analysis of the VP7 gene of wild-type RVB strains revealed a high diversity of G genotypes circulating in one geographic region of Brazil. Our findings suggest that RVB may be considered an important primary enteric pathogen in piglets and should be included in the routine differential diagnosis of enteric diseases in piglets.

Aims/Introduction The association between diabetes and periodontal disease is considered to be bidirectional. However, there is still controversy surrounding the relationship between periodontal disease and type 1 diabetes. We investigated whether insulin improves periodontitis without any local treatments for periodontitis under type 1 diabetes conditions using the ligature‐induced experimental periodontitis model. Materials and Methods Type 1 diabetic rats were induced by streptozotocin injection. Experimental periodontitis was induced by ligature in normal and diabetic rats. Half of the diabetic rats were treated with insulin. Two weeks after the ligature, periodontitis was evaluated. Results Insulin treatment significantly improved inflammatory cell infiltration and inflammatory cytokine gene expression, leading to suppression of alveolar bone loss, in the periodontitis of diabetic rats. Insulin also suppressed the periodontitis‐increased nitric oxide synthase‐positive cells in periodontal tissue of the diabetic rats. Even without induction of periodontitis, diabetic rats showed decreased gingival blood flow and an increased number of nitric oxide synthase‐positive cells in the gingiva and alveolar bone loss compared with normal rats, all of which were ameliorated by insulin treatment. We further confirmed that insulin directly suppressed lipopolysaccharide‐induced inflammatory cytokine expressions in THP‐1 cells. Conclusions There were abnormalities of periodontal tissue even without the induction of periodontitis in streptozotocin‐induced diabetic rats. Insulin treatment significantly ameliorated periodontitis without local periodontitis treatment in diabetic rats. These data suggest the therapeutic impacts of insulin on periodontitis in type 1 diabetes. There was a slight increase in the numbers of inflammatory cells in the gingiva on the periodontitis side of normal rats and on the control side of diabetic rats. The inflammatory cells were markedly increased on the periodontitis side of diabetic rats. Insulin treatment decreased the inflammatory cells in the periodontitis gingiva of diabetic rats.

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.

Aims/Introduction The involvement of glucose‐dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose‐dependent insulinotropic polypeptide receptor‐knockout mice (GIPRKO). We also investigated the anti‐inflammatory effect of GIP in a culture system. Materials and Methods Experimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide‐induced gene expressions in THP‐1 cells were evaluated. Results Periodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor‐α and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac‐1‐positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac‐1‐positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide‐induced tumor necrosis factor‐α and nitric oxide synthase gene expression in a dose‐dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide‐induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway. Conclusions These results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti‐inflammatory effect on periodontitis in addition to its glucose‐lowering effect. Induction of periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue.

Background/Objectives: Oral squamous cell carcinoma (OSCC) often presents at an advanced stage; therefore, the early detection of precursor lesions is crucial. However, the risk assessment of precursor lesions such as oral epithelial dysplasia (OED) remains challenging because of the subjectivity of histopathological grading. We aimed to identify molecular markers that enhance the diagnostic accuracy and prognostic stratification of OSCC and explore the differences in the molecular characterization of OED and OSCC using a few selected markers. Methods: A two-step diagnostic workflow was applied: (1) FISH evaluation of EGFR amplification and CDKN2A deletion to distinguish OED from OSCC and identify EGFR-dependent tumors, and (2) HRAS immunohistochemistry performed exclusively in EGFR-negative OSCCs to stratify EGFR-independent cases. Fluorescence in situ hybridization (FISH) was used to assess seven EGFR/cell cycle-related genes (CCND1, CDKN2A, EGFR, PIK3CA, PTEN, TP53, and 1p36 locus) in 117 formalin-fixed paraffin-embedded samples (66 OED and 51 OSCC) and 10 normal mucosa samples. HRAS expression was evaluated using immunohistochemistry (IHC) in 36 EGFR amplification-negative OSCCs samples. Results:EGFR amplification was frequent in OSCC, whereas CDKN2A deletion was common in OED. The EGFR-amplified/ CDKN2A-intact profile showed high specificity for OSCC and improved diagnostic performance (area under the curve = 0.77) when combined with the Ki-67 labeling index. It also predicted poor disease-free survival (hazard ratio [HR] = 5.08, p = 0.016) and overall survival (HR = 6.10, p = 0.047). Among EGFR-negative OSCCs, HRAS overexpression was associated with advanced-stage disease and a poor prognosis (HR = 6.15, p = 0.043). Conclusions:EGFR amplification was frequent in OSCC, and CDKN2A deletion was prevalent in OED, supporting their use as molecular markers for differential diagnoses. FISH for EGFR/CDKN2A and HRAS IHC can stratify OSCC by diagnosis and prognosis, enabling practical molecular subclassification, including EGFR-negative cases.

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.

Schwann cells play an important role in peripheral nerve function, and their dysfunction has been implicated in the pathogenesis of diabetic neuropathy and other demyelinating diseases. The physiological functions of insulin in Schwann cells remain unclear and therefore define the aim of this study. By using immortalized adult Fischer rat Schwann cells (IFRS1), we investigated the mechanism of the stimulating effects of insulin on the cell proliferation and expression of myelin proteins (myelin protein zero (MPZ) and myelin basic protein (MBP). The application of insulin to IFRS1 cells increased the proliferative activity and induced phosphorylation of Akt and ERK, but not P38-MAPK. The proliferative potential of insulin-stimulated IFRS1 was significantly suppressed by the addition of LY294002, a PI3 kinase inhibitor. The insulin-stimulated increase in MPZ expression was significantly suppressed by the addition of PD98059, a MEK inhibitor. Furthermore, insulin-increased MBP expression was significantly suppressed by the addition of LY294002. These findings suggest that both PI3-K/Akt and ERK/MEK pathways are involved in insulin-induced cell growth and upregulation of MPZ and MBP in IFRS1 Schwann cells.