The adiponectin receptor agonist AdipoAI attenuates periodontitis in diabetic rats by inhibiting gingival fibroblast-induced macrophage migration.

BACKGROUND AND PURPOSE: Low-grade inflammation, a common feature of both diabetes and periodontitis, partly accounts for the complexity and refractoriness of diabetes-associated periodontitis. Adiponectin (APN), the most abundant adipokine in human blood, has been widely reported to have anti-inflammatory functions. Herein, we investigated the ability of an APN receptor agonist, AdipoAI, to alleviate diabetes-associated periodontitis. Furthermore, we revealed the possible mechanism underlying its anti-inflammatory effects. EXPERIMENTAL APPROACH: The maxillary first molar of Zucker diabetic fatty (ZDF) rats was ligated to construct a diabetes-associated periodontitis model, and rats were administered AdipoAI by gavage. We examined diabetes-related indexes, pathological changes in insulin target organs, alveolar bone resorption and systemic and local inflammation. In vitro, transwell assays were used to evaluate monocyte/macrophage migration induced by human gingival fibroblasts (hGFs) with/without AdipoAI treatment. Additionally, we examined chemokine expression levels in hGFs and hGF-induced monocyte/macrophage migration upon siRNA knockdown of Adiponectin receptor expression. Expression of Adipo1/Adipo2 receptors and inflammation-related signalling pathways were examined by IHC and WB, followed by confirmation with an NF-κB P65 inhibitor (BAY 11-7082). KEY RESULTS: AdipoAI lowered fasting blood glucose and serum insulin in ZDF rats and alleviated inflammation in insulin target tissues. Locally, AdipoAI reduced alveolar bone absorption and gingival inflammation. Mechanistically, AdipoAI inhibited hGF-induced monocyte/macrophage migration by reducing CCL2 secretion. In hGFs, AdipoAI attenuated LPS-induced activation of NF-κB P65 and CCL2 expression, which was dependent on the Adipo receptor 1. CONCLUSION AND IMPLICATIONS: AdipoAI, with its ability to alleviate inflammatory damage in tissues, is a candidate for diabetes-associated periodontitis treatment.

Immediate loaded fixed complete dentures supported by implants in patients with a history of periodontitis: A retrospective cohort study of 2 to 7 years.

STATEMENT OF PROBLEM: The outcome of implant-supported fixed complete dentures in edentulous patients with a history of periodontitis is unclear. PURPOSE: The purpose of this retrospective clinical study was to assess the clinical outcomes of immediate loaded fixed complete dentures in individuals with a history of periodontitis and to analyze risk factors related to implant failure. MATERIAL AND METHODS: A total of 642 implants (146 prostheses) in 119 patients were included. The follow-up period ranged from 2 to 7 years. Implant survival rates, marginal bone loss, mechanical complications, biologic complications, and patient satisfaction were evaluated. The Pearson chi-square test, independent samples t test, and multivariate generalized estimating equation were performed for statistical analysis (α=.05). RESULTS: Eleven implants in 9 patients failed, leading to overall survival rates of 98.3% at the implant level and 92.4% at the patient level. The mean ±standard deviation marginal bone loss was 0.62 ±0.86 mm, and marginal bone loss did not differ significantly between axial and tilted implants (P>.05). Mechanical complications were detected in 55 (37.7%) definitive prostheses; biologic complications were detected in 318 (49.5%) implants. Smokers had a significantly lower survival rate than nonsmokers (odds ratio: 6.880, P=.013). Bruxers had a significantly higher incidence of mechanical complications than nonbruxers (P<.001). CONCLUSIONS: The immediate loaded fixed complete denture supported by implants is a suitable treatment option for edentulous patients with a history of periodontitis, with high survival implant rates. Smoking is a risk factor for implant failure. Bruxism may increase the incidence of mechanical complications with implant-supported fixed complete dentures, and the overall biologic complication incidence is comparatively high.

THE CONTENT OF ZINC AND CADMIUM IN BLOOD AND ORAL FLUID IN GENERALIZED PERIODONTITIS IN PEOPLE EXPOSED TO ADVERSE ENVIRONMENTAL FACTORS.

OBJECTIVE: The aim: To study the content of trace elements (cadmium and zinc) in the blood and oral fluid in people with generalized periodontitis and work and live permanently in adverse environmental conditions. PATIENTS AND METHODS: Materials and methods: In order to study the prevalence of periodontal diseases in adults living in areas with high level of soil contamination with heavy metal salts and working in the workplace with occupational hazards, there were studied 163 people who did not have somatic diseases, namely: 133 employees of Burshtyn Thermal Power Plant (TPP) and 30 persons who do not work at Burshtyn TPP. RESULTS: Results: The results of biochemical examination of blood and oral fluid in persons with generalized periodontitis of the I, II degree of severity and being exposed to adverse environmental factors, show changes in the trace element spectrum of blood and oral fluid, namely: a decrease in amount of zinc and an increase in amount of cadmium, which may indicate the disorder of microelement metabolism under conditions of chronic influence of small doses of salts of heavy metals. CONCLUSION: Conclusions: As a result of the performed study, a violation of micronutrient metabolism in biological fluids (blood and oral fluid) was found in persons exposed to adverse environmental factors.

Chronic Porphyromonas gingivalis lipopolysaccharide induces adverse myocardial infarction wound healing through activation of CD8+ T cells.

Oral and gum health have long been associated with incidence and outcomes of cardiovascular disease. Periodontal disease increases myocardial infarction (MI) mortality by sevenfold through mechanisms that are not fully understood. The goal of this study was to evaluate whether lipopolysaccharide (LPS) from a periodontal pathogen accelerates inflammation after MI through memory T-cell activation. We compared four groups [no MI, chronic LPS, day 1 after MI, and day 1 after MI with chronic LPS (LPS + MI); n = 68 mice] using the mouse heart attack research tool 1.0 database and tissue bank coupled with new analyses and experiments. LPS + MI increased total CD8+ T cells in the left ventricle versus the other groups (P < 0.05 vs. all). Memory CD8+ T cells (CD44 + CD27+) were 10-fold greater in LPS + MI than in MI alone (P = 0.02). Interleukin (IL)-4 stimulated splenic CD8+ T cells away from an effector phenotype and toward a memory phenotype, inducing secretion of factors associated with the Wnt/ß-catenin signaling that promoted monocyte migration and decreased viability. To dissect the effect of CD8+ T cells after MI, we administered a major histocompatibility complex-I-blocking antibody starting 7 days before MI, which prevented effector CD8+ T-cell activation without affecting the memory response. The reduction in effector cells diminished infarct wall thinning but had no effect on macrophage numbers or MertK expression. LPS + MI + IgG attenuated macrophages within the infarct without effecting CD8+ T cells, suggesting these two processes were independent. Overall, our data indicate that effector and memory CD8+ T cells at post-MI day 1 are amplified by chronic LPS to potentially promote infarct wall thinning.NEW & NOTEWORTHY Although there is a well-documented link between periodontal disease and heart health, the mechanisms are unclear. Our study indicates that in response to circulating periodontal endotoxins, memory CD8+ T cells are activated, resulting in an acceleration of macrophage-mediated inflammation after MI. Blocking activation of effector CD8+ T cells had no effect on the macrophage numbers or wall thinning at post-MI day 1, indicating that this response was likely due in part to memory CD8+ T cells.

AT1 and AT2 Receptor Knockout Changed Osteonectin and Bone Density in Mice in Periodontal Inflammation Experimental Model.

BACKGROUND: The aim of this study was to evaluate the role of AT1 and AT2 receptors in a periodontal inflammation experimental model. METHODS: Periodontal inflammation was induced by LPS/Porphyromonas gingivalis. Maxillae, femur, and vertebra were scanned using Micro-CT. Maxillae were analyzed histopathologically, immunohistochemically, and by RT-PCR. RESULTS: The vertebra showed decreased BMD in AT1 H compared with WT H (p < 0.05). The femur showed increased Tb.Sp for AT1 H and AT2 H, p < 0.01 and p < 0.05, respectively. The Tb.N was decreased in the vertebra (WT H-AT1 H: p < 0.05; WT H-AT2 H: p < 0.05) and in the femur (WT H-AT1 H: p < 0.01; WT H-AT2 H: p < 0.05). AT1 PD increased linear bone loss (p < 0.05) and decreased osteoblast cells (p < 0.05). RANKL immunostaining was intense for AT1 PD and WT PD (p < 0.001). OPG was intense in the WT H, WT PD, and AT2 PD when compared to AT1 PD (p < 0.001). AT1 PD showed weak immunostaining for osteocalcin compared with WT H, WT PD, and AT2 PD (p < 0.001). AT1 H showed significantly stronger immunostaining for osteonectin in fibroblasts compared to AT2 H (p < 0.01). CONCLUSION: AT1 receptor knockout changed bone density, the quality and number of bone trabeculae, decreased the number of osteoblast cells, and increased osteonectin in fibroblasts.

Gram-positive bacteria cell wall-derived lipoteichoic acid induces inflammatory alveolar bone loss through prostaglandin E production in osteoblasts.

Periodontitis is an inflammatory disease associated with severe alveolar bone loss and is dominantly induced by lipopolysaccharide from Gram-negative bacteria; however, the role of Gram-positive bacteria in periodontal bone resorption remains unclear. In this study, we examined the effects of lipoteichoic acid (LTA), a major cell-wall factor of Gram-positive bacteria, on the progression of inflammatory alveolar bone loss in a model of periodontitis. In coculture of mouse primary osteoblasts and bone marrow cells, LTA induced osteoclast differentiation in a dose-dependent manner. LTA enhanced the production of PGE2 accompanying the upregulation of the mRNA expression of mPGES-1, COX-2 and RANKL in osteoblasts. The addition of indomethacin effectively blocked the LTA-induced osteoclast differentiation by suppressing the production of PGE2. Using ex vivo organ cultures of mouse alveolar bone, we found that LTA induced alveolar bone resorption and that this was suppressed by indomethacin. In an experimental model of periodontitis, LTA was locally injected into the mouse lower gingiva, and we clearly detected alveolar bone destruction using 3D-µCT. We herein demonstrate a new concept indicating that Gram-positive bacteria in addition to Gram-negative bacteria are associated with the progression of periodontal bone loss.

Glycogen synthase kinase-3ß (GSK-3ß) deficiency inactivates the NLRP3 inflammasome-mediated cell pyroptosis in LPS-treated periodontal ligament cells (PDLCs).

Bacterial infection caused cell pyroptosis and gingival inflammation contributes to periodontitis progression, and lipopolysaccharide (LPS) is the main infectious agent of gram-negative bacteria, which is reported to be closely associated with gingival inflammation and periodontitis. In this study, the primary human periodontal ligament cells (PDLCs) were isolated, cultured, and exposed to LPS treatment, and the results suggested that LPS suppressed cell viability and promoted pro-inflammatory cytokines' (IL-1ß, IL-18, IL-6, and TNF-α) generation and secretion in the PDLCs and its supernatants in a time- and concentration-dependent manner. Also, we noticed that LPS upregulated NLRP3, Gasdermin D, and cleaved caspase-1 to trigger pyroptotic cell death in the PDLCs. Further experiments identified that glycogen synthase kinase-3ß (GSK-3ß) was upregulated by LPS treatment, and inhibition of GSK-3ß by its inhibitor (GSKI) or GSK-3ß downregulation vectors was effective to restore normal cellular functions in LPS-treated PDLCs. Mechanistically, blockage of GSK-3ß restrained NLRP3-meidated cell pyroptosis and inflammation, resulting in the recovery of cell viability and inhibition of cell death in PDLCs treated with LPS, which further ameliorated periodontitis progression. Finally, we collected the serum from periodontitis patients and healthy volunteers, and the clinical data supported that those pro-inflammatory cytokines were also upregulated in patients' serum but not in the healthy participants. Taken together, we concluded that targeting the GSK-3ß/NLRP3 pathway mediated cell pyroptosis was effective to attenuate LPS-induced cell death and inflammation in PDLCs, and this study firstly investigated this issue, which broadened our knowledge in this field.

Low-intensity Pulsed Ultrasound regulates alveolar bone homeostasis in experimental Periodontitis by diminishing Oxidative Stress.

Periodontitis is a widespread oral disease that results in the loss of alveolar bone. Low-intensity pulsed ultrasound (LIPUS), which is a new therapeutic option, promotes alveolar bone regeneration in periodontal bone injury models. This study investigated the protective effect of LIPUS on oxidative stress in periodontitis and the mechanism underlying this process. Methods: An experimental periodontitis model was induced by administering a ligature. Immunohistochemistry was performed to detect the expression levels of oxidative stress, osteogenic, and osteoclastogenic markers in vivo. Cell viability and osteogenic differentiation were analyzed using the Cell Counting Kit-8, alkaline phosphatase, and Alizarin Red staining assays. A reactive oxygen species assay kit, lipid peroxidation MDA assay kit, and western blotting were used to determine oxidative stress status in vitro. To verify the role of nuclear factor erythroid 2-related factor 2 (Nrf2), an oxidative regulator, during LIPUS treatment, the siRNA technique and Nrf2-/- mice were used. The PI3K/Akt inhibitor LY294002 was utilized to identify the effects of the PI3K-Akt/Nrf2 signaling pathway. Results: Alveolar bone resorption, which was experimentally induced by periodontitis in vivo, was alleviated by LIPUS via activation of Nrf2. Oxidative stress, induced via H2O2 treatment in vitro, inhibited cell viability and suppressed osteogenic differentiation. These effects were also alleviated by LIPUS treatment via Nrf2 activation. Nrf2 silencing blocked the antioxidant effect of LIPUS by diminishing heme oxygenase-1 expression. Nrf2-/- mice were susceptible to ligature-induced periodontitis, and the protective effect of LIPUS on alveolar bone dysfunction was weaker in these mice. Activation of Nrf2 by LIPUS was accompanied by activation of the PI3K/Akt pathway. The oxidative defense function of LIPUS was inhibited by exposure to LY294002 in vitro. Conclusions: These results demonstrated that LIPUS regulates alveolar bone homeostasis in periodontitis by attenuating oxidative stress via the regulation of PI3K-Akt/Nrf2 signaling. Thus, Nrf2 plays a pivotal role in the protective effect exerted by LIPUS against ligature-induced experimental periodontitis.

Inflammation has synergistic effect with nicotine in periodontitis by up-regulating the expression of α7 nAChR via phosphorylated GSK-3ß.

Periodontitis is the leading cause of adult tooth loss, and those who smoke are at an increased risk of developing periodontitis. α7 nicotinic acetylcholine receptor (α7 nAChR) is proposed to mediate the potential synergistic effect of nicotine and inflammation in smoking-related periodontitis. However, this has not been experimentally demonstrated. We isolated and cultured human periodontal ligament stem cells (PDLSCs) from healthy and inflamed tissues. PDLSCs were treated with either inflammatory factors or nicotine. We measured expression of genes that are associated with osteogenic differentiation and osteoclast formation using RT-qPCR and Western blot analyses. Besides, immunohistochemical staining, micro-CT analysis and tartaric acid phosphatase staining were used to measure α7 nAChR expression and function. Inflammation up-regulated α7 nAChR expression in both periodontal ligament tissues and PDLSCs. The up-regulated α7 nAChR contributed to the synergistic effect of nicotine and inflammation, leading to a decreased capability of osteogenic differentiation and increased capability of osteoclast formation-induction of PDLSCs. Moreover, the inflammation-induced up-regulation of α7 nAChR was partially dependent on the level of phosphorylated GSK-3ß. This study provides experimental evidence for the pathological development of smoking-related periodontitis and sheds new light on developing inflammation and α7 nAChR-targeted therapeutics to treat and prevent the disease.

Calcitriol suppresses lipopolysaccharide-induced alveolar bone damage in rats by regulating T helper cell subset polarization.

BACKGROUND: Although the immunomodulatory properties of calcitriol in bone metabolism have been documented for decades, its therapeutic role in the management of periodontitis remains largely unexplored. In this study, we hypothesized that calcitriol suppresses lipopolysaccharide (LPS)-induced alveolar bone loss by regulating T helper (Th) cell subset polarization. METHODS: To test this hypothesis, we determined the effect of calcitriol intervention on the development of LPS-induced periodontitis in rats in terms of bone loss (micro-CT analysis), local inflammatory infiltration levels, the number of osteoclasts (hematoxylin and eosin staining) and the level of osteoclastogenesis (tartrate-resistant acid phosphatase method). Furthermore, immunohistochemistry was used to assess the expression levels of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) as well as the cytokine levels of interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-17, and IL-10 throughout the LPS-injected region. Finally, the polarization potential of Th cells in peripheral blood was analyzed using flow cytometry. RESULTS: Calcitriol intervention decreased alveolar bone loss in response to LPS injection and inflammatory cell infiltration. Analysis of osteoclast number and RANKL and OPG expression showed that bone resorption activity was largely suppressed in response to calcitriol administration, along with decreased IL-17 levels but increased IL-4 and IL-10 levels in periodontal tissues (the LPS-injected region). Similarly, the percentages of Th2 and Treg cells in peripheral blood increased, but the percentages of Th1 and Th17 cells decreased in rats receiving calcitriol. CONCLUSION: Our findings suggest that calcitriol can be used to inhibit bone loss in experimental periodontitis, likely via the regulation of local and systemic Th cell polarization.

Anti-inflammatory effects of shikonin in human periodontal ligament cells.

CONTEXT: Shikonin (SHI), an active component extracted from Radix Arnebiae, has been reported to possess anti-inflammatory properties in various cells. However, its effect on lipopolysaccharide (LPS)-stimulated human periodontal ligament cells (hPDLCs) is unknown. OBJECTIVE: To investigate the effects of SHI on the expression of inflammatory related cytokines in LPS-stimulated hPDLCs. MATERIALS AND METHODS: The effects of SHI (0.125, 0.25, 0.5, 1, and 2 µg/mL) on hPDLCs proliferation for 1, 3 and 7 days were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), matrix metalloproteinase-2 (MMP-2), MMP-9 and cyclooxygenase-2 (COX-2) were detected in hPDLCs following SHI treatment (0.25 and 0.5 µg/mL) using Quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR). The signaling pathways triggered by SHI in hPDLC were evaluated using western blotting. RESULTS: LD50 of SHI is 1.7 µg/mL (day 1) and 1.1 µg/mL (day 3 and 7) in hPDLCs. No morphological changes were observed when hPDLCs were treated with LPS only (1 µg/mL) or LPS with SHI (0.25 and 0.5 µg/mL). Data from qRT-PCR suggests that SHI attenuates LPS-induced increases of IL-1, IL-6, TNF-α, MMP-2, MMP-9 and COX-2 in hPDLCs. Down-regulation of phosphorylated extracellular signal-regulated kinase (ERK) and nuclear factor-κB (NF-κB), and up-regulation of I-κB, were observed in LPS-stimulated hPDLCs after exposed to SHI at 0.25 or 0.5 µg/mL. DISCUSSION AND CONCLUSIONS: SHI possesses anti-inflammatory effects in LPS-stimulated hPDLCs via phospho-ERK and NF-κB/I-κB signaling pathways; this suggests that SHI may hold potential as an anti-inflammatory agent against periodontitis.

Effects of nicotine administration in rats on MMP2 and VEGF levels in periodontal membrane.

BACKGROUND: Nicotine is associated with increased incidence of periodontal disease and poor response to therapy. This article aimed at identifying the expression of matrix metalloproteinases 2 (MMPs2) and vascular endothelial growth factor (VEGF) proteins on extracellular matrix, fibrous distribution and angiogenetic development in periodontitis caused by nicotine effects on periodontal membrane. MATERIALS AND METHODS: In this experimental study, rats were divided into nicotine and control groups. While the rats in the nicotine group (n = 6) were administered 2 mg/kg nicotine sulphate for 28 days, the animals in the control group (n = 6) were only administered 1.5 mL physiologic saline solution subcutaneously for 28 days. RESULTS: Histological sections were prepared and immunohistochemically stained for MMP2 and VEGF. The sections stained with Trichrome-Masson were observed under light microscope. VEGF and MMP2 immunoreactivity of periodontal gingiva and dentin was assessed by immunohistochemical staining. CONCLUSIONS: Nicotine reduces MMP production, disrupts collagen synthesis and causes periodontitis. We observed that nicotine increases periodontitis by disrupting periodontal membrane and prevents tooth to anchor in dental alveoli by disrupting epithelial structure.

Lactate Dehydrogenase and ß-Glucuronidase as Salivary Biochemical Markers of Periodontitis Among Smokers and Non-Smokers.

OBJECTIVES: This study aimed to establish lactate dehydrogenase (LDH) and ß-glucuronidase as salivary biomarkers of periodontitis among smokers and non-smokers. METHODS: This cross-sectional case-control study was conducted at the Aligarh Muslim University, Aligarh, India, between January and June 2017. A total of 200 participants were divided into four groups based on their periodontal and smoking statuses. Unstimulated mixed saliva samples were collected to estimate LDH and ß-glucuronidase levels. In addition, total protein was estimated using Lowry's method. RESULTS: There was a significant increase in enzyme activity in the periodontitis groups compared to the non-periodontitis groups (P <0.001). However, significantly lower enzyme activity was observed among smokers, irrespective of periodontal status (P <0.001). Nevertheless, a receiver operating characteristic curve analysis indicated the diagnostic potential of both enzymes to be fair-to-excellent. CONCLUSION: Although smoking was found to significantly alter enzyme activity, LDH and ß-glucuronidase were reliable salivary biomarkers of periodontitis among both smokers and non-smokers.

Anti-inflammatory effect of ATB-352, a H2S -releasing ketoprofen derivative, on lipopolysaccharide-induced periodontitis in rats.

Periodontal disease is the most common cause of tooth loss in humans, is an inflammatory disease initiated by oral microbial biofilm. Given the involvement of the inflammatory pathway in this type of pathology, the main pharmacological strategy for the treatment of periodontitis, is the inhibition of the inflammatory process in order to prevent tissue destruction and bone resorption, a condition associated with a painful state. To do this, the best class of drugs are Non-steroidal anti-inflammatory drugs (NSAIDs), however, the presence of side effects, especially at the gastrointestinal tract, limits their use for long-term therapy. Recently, some evidence shows that derivatives of NSAIDs capable of releasing hydrogen sulphide exhibit lower collateral effects, particularly at the gastric level. In fact, H2S is an endogenous gaseous mediator with a cytoprotective role at the gastric level. In this study, we have compared the protective effects of ketoprofen with ATB-352, a hydrogen sulfide-releasing derivative of ketoprofen, in an experimental model of periodontitis in rat. Periodontitis was induced by a single intragingival injection of 1 µl LPS (10 µg/µl), Our results show that 14 h after intragingival injection of LPS, there was a high tissue damage associated with bone resorption, and in gingivomucosal tissues there was a significant expression of NF-kb p65 and pro-inflammatory cytokine as well as a higher expression of COX-2 and iNOS, activation of the apoptotic process, and also increased levels of NGF expression, often associated with a higher nociceptive perception. Treatment with ATB-352 at the dose of 20mg\kg, was able to reduce the inflammatory process associated with intragingival LPS injection and also had a positive effect on bone resorption and tissue damage.

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing.

Chronic inflammatory diseases, such as periodontal disease, associate with adverse wound healing in response to myocardial infarction (MI). The goal of this study was to elucidate the molecular basis for impaired cardiac wound healing in the setting of periodontal-induced chronic inflammation. Causal network analysis of 168 inflammatory and extracellular matrix genes revealed that chronic inflammation induced by a subseptic dose of Porphyromonas gingivalis lipopolysaccharide (LPS) exacerbated infarct expression of the proinflammatory cytokine Ccl12. Ccl12 prevented initiation of the reparative response by prolonging inflammation and inhibiting fibroblast conversion to myofibroblasts, resulting in diminished scar formation. Macrophage secretion of Ccl12 directly impaired fibronectin and collagen deposition and indirectly stimulated collagen degradation through upregulation of matrix metalloproteinase-2. In post-MI patients, circulating LPS levels strongly associated with the Ccl12 homologue monocyte chemotactic protein 1 (MCP-1). Patients with LPS levels ≥ 1 endotoxin units (EU)/ml (subseptic endotoxemia) at the time of hospitalization had increased end diastolic and systolic dimensions compared with post-MI patients with < 1 EU/ml, indicating that low yet pathological concentrations of circulating LPS adversely impact post-MI left ventricle (LV) remodeling by increasing MCP-1. Our study provides the first evidence to our knowledge that chronic inflammation inhibits reparative fibroblast activation and generates an unfavorable cardiac-healing environment through Ccl12-dependent mechanisms.

Effects of Cinnamoyloxy-mammeisin from Geopropolis on Osteoclast Differentiation and Porphyromonas gingivalis-Induced Periodontitis.

Bone-loss-related diseases such as rheumatoid arthritis, osteomyelitis, osteoporosis, and periodontitis are associated with high rates of morbidity worldwide. These disorders are characterized by an imbalance between the formation and activity of osteoblasts and osteoclasts, leading to bone loss. In this context, we evaluated the effect of cinnamoyloxy-mammeisin (CNM), an anti-inflammatory coumarin found in Melipona scutellaris geopropolis, on key targets related to bone remodeling. In the present study we investigated the in vitro effects of CNM on osteoclast differentiation and M-CSF+RANKL-induced osteoclastogenic marker expression. Additionally, the interference of CNM treatment on osteoclast activity was evaluated by zymography and resorption area. Finally, we assessed the capacity of the compound to mitigate alveolar bone loss in vivo in experimental murine periodontitis induced by Porphyromonas gingivalis. We observed that treatment with CNM impaired osteoclast differentiation, as evidenced by a reduced number of tartrate-resistant acid-phosphatase-positive multinucleated cells (TRAP+) as well as the expression of osteoclastogenic markers upon M-CSF+RANKL-induced stimulation. Similarly, we observed reduced gelatinolytic and resorption capacity in M-CSF+RANKL-induced cells in vitro. Lastly, CNM attenuated alveolar bone loss in an experimental murine periodontitis model. These findings indicate that CNM may be considered a promising treatment for bone loss diseases.

Lidocaine Prevents Oxidative Stress-Induced Endothelial Dysfunction of the Systemic Artery in Rats With Intermittent Periodontal Inflammation.

BACKGROUND: Periodontal inflammation causes endothelial dysfunction of the systemic artery. However, it is unknown whether the use of local anesthetics during painful dental procedures alleviates periodontal inflammation and systemic endothelial function. This study was designed to examine whether the gingival or systemic injection of lidocaine prevents oxidative stress-induced endothelial dysfunction of the systemic artery in rats with intermittent periodontal inflammation caused by lipopolysaccharides (LPS). METHODS: Some rats received 1500 µg LPS injections to the gingiva during a week interval from the age of 8 to 11 weeks (LPS group). Lidocaine (3 mg/kg), LPS + lidocaine (3 mg/kg), LPS + lidocaine (1.5 mg/kg), and LPS + lidocaine (3 mg/kg, IP) groups simultaneously received gingival 1.5 or 3 mg/kg or IP 3 mg/kg injection of lidocaine on the same schedule as the gingival LPS. Isolated aortas or mandibles were subjected to the evaluation of histopathologic change, isometric force recording, reactive oxygen species, and Western immunoblotting. RESULTS: Mean blood pressure and heart rate did not differ among the control, LPS, LPS + lidocaine (3 mg/kg), and lidocaine (3 mg/kg) groups. LPS application reduced acetylcholine (ACh, 10 to 10 mol/L)-induced relaxation (29% difference at ACh 3 × 10 mol/L, P = .01), which was restored by catalase. Gingival lidocaine (1.5 and 3 mg/kg) dose dependently prevented the endothelial dysfunction caused by LPS application (24.5%-31.1% difference at ACh 3 × 10 mol/L, P = .006 or .001, respectively). Similar to the gingival application, the IP injection of lidocaine (3 mg/kg) restored the ACh-induced dilation of isolated aortas from rats with the LPS application (27.5% difference at ACh 3 × 10 mol/L, P < .001). Levels of reactive oxygen species were double in aortas from the LPS group (P < .001), whereas the increment was abolished by polyethylene glycol-catalase, gingival lidocaine (3 mg/kg), or the combination. The LPS induced a 4-fold increase in the protein expression of tumor necrosis factor-α in the periodontal tissue (P < .001), whereas the lidocaine (3 mg/kg) coadministration partly reduced the levels. Lidocaine application also decreased the protein expression of the nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox, which was enhanced by the gingival LPS (5.6-fold increase; P < .001). CONCLUSIONS: Lidocaine preserved the aortic endothelial function through a decrease in arterial reactive oxygen species produced by nicotinamide adenine dinucleotide phosphate oxidase and periodontal tumor necrosis factor-α levels in rats with periodontal inflammation. These results suggest the beneficial effect of the gingival application of local anesthetics on the treatment of periodontal diseases on endothelial function of systemic arteries.

Low-level laser and antimicrobial photodynamic therapy on experimental periodontitis in rats submitted to chemotherapy by 5-fluorouracil.

PURPOSE: The aim of this study was to evaluate the effects of low-level laser therapy (LLLT) and antimicrobial photodynamic therapy (aPDT) as adjuvant to mechanical treatment of experimental periodontitis (EP) in adult rats submitted to 5-fluorouracil (5-FU) chemotherapy. METHODS: EP was induced through ligature around the left mandibular first molar for 7 days. The ligature was removed and the animals separated into groups: EP, no treatment; 5FU, systemic administration of 5-FU (80 and 40 mg/kg); 5FU/scaling and root planing (SRP), systemic application of 5-FU and SRP; 5FU/SRP/LLLT, systemic application of 5-FU, SRP, and LLLT (660 nm, 0.035 W; 29.4 J/cm2); and 5FU/SRP/aPDT, systemic application of 5-FU, SRP, and aPDT (methylene blue irrigation and LLLT). The animals were euthanized 7, 15, and 30 days after treatments. Histological sections from mandibles were processed for histomorphometric and immunohistochemical analysis (TRAP, RANKL, OPG, TNF-α, IL-6, IL-10). The alveolar bone loss (BL) area in the furcation region of the mandibular first molar was analyzed histometrically. RESULTS: There was less bone loss in 5FU/SRP/aPDT compared with 5FU at 7 days (p < 0.05). The immunohistochemical analysis showed no significant difference for TRAP and osteoprotegerin, but lower RANKL immunolabeling was observed in the 5FU/SRP/LLLT and 5FU/SRP/aPDT groups compared with the 5FU group at 15 days. There was lower TNF-α and IL-6 immunolabeling in the 5FU/SRP/LLLT and 5FU/SRP/aPDT groups and higher IL-10 immunolabeling in 5FU/SRP/aPDT at 30 days. CONCLUSION: LLLT and aPDT adjuvant to SRP minimized the effects of 5-FU on periodontal disease. Furthermore, aPDT promoted greater benefits in bone loss control and inflammatory response.

Implant maintenance treatment and peri-implant health.

Data sourcesMedline (PubMed), Embase, Cochrane Central Register of Controlled Trials and Cochrane Oral Health Group Trials Register databases and a manual search of the Journal of Dental Research, Journal of Clinical Periodontology, Journal of Periodontology and the International Journal of Periodontics and Restorative Dentistry from January 2014 to February 2015.Study selectionProspective, retrospective, randomised or not, case-controlled or case series trials showing the incidence or recurrence of peri-implant disease plus or minus PIMT over more than six months.Data extraction and synthesisThree reviewers independently selected studies and abstracted data with two reviewers assessing study quality using the Newcastle-Ottawa Scale (NOS). A multivariate binomial regression was used to examine the data.ResultsThirteen studies were included with ten contributing to the meta-analysis. The average quality assessment score (NOS) was 5.3 out of a possible nine, only one paper achieved eight. At patient level mucositis ranged from 18.5-74.2% and peri-implantitis from 8-28%, with significant effects being seen for treatment (z= -14.36, p<0.001). Mucositis was affected by history of periodontitis and mean PIMT at implant and patient levels, respectively. For peri-implantitis there were also significant effects of treatment (z = -16.63, p<0.001). Increased peri-implantitis was observed for patients with a history of periodontal disease. (z=3.76, p<0.001). Implants under PIMT have 0.958 the incident event compared to those with no PIMT.ConclusionsWithin the limitations of the present systematic review it can be concluded that implant therapy must not be limited to placement and restoration of dental implants, but to the implementation of PIMT to potentially prevent biological complications and heighten the long-term success rate. Although it must be tailored to a patients risk profiling, our findings suggest reason to claim a minimum recall PIMT interval of five to six months. Additionally, it must be stressed that even in the establishment of PIMT, biological complications might occur. Hence, patient-, clinical-, and implant-related factors must be thoroughly explored.

Anti-inflammatory effect of the Salvia sclarea L. ethanolic extract on lipopolysaccharide-induced periodontitis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia sclarea L., clary, is an aromatic plant traditionally used in folk medicine for the treatment of various diseases and conditions. Although it has been primarily used as a stomachic, there are data on traditional use of S. sclarea as an agent against gingivitis, stomatitis and aphthae. AIM OF THE STUDY: The aim of the study was to examine the effect of the S. sclarea ethanolic extract on the lipopolysaccharide (LPS)-induced periodontitis in rats from the immunological and histopathological standpoint. MATERIAL AND METHODS: Periodontal inflammation in rats was induced by repeated injections of LPS from Escherichia coli into the interdental papilla between the first and second right maxillary molars. The extract was administered two times a day by oral gavage (200mg/kg body weight). The inflammatory status was assessed by the measurements of proinflammatory cytokines interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) of gingival tissues and descriptive analysis of histological sections of periodontium. Chemical characterization of the extract was determined using high performance liquid chromatography system (HPLC). Antioxidant activity of the extract was estimated with two in vitro complementary methods: 2,2-diphenyl-1-picrylhydrazyl and ß-carotene/linoleic acid models. RESULTS: Treatment with S. sclarea extract, compared to the untreated group of the rats, significantly diminished the process of inflammation decreasing the levels of IL-1ß, IL-6 and TNF-α, reducing the gingival tissue lesions and preserving bone alveolar resorption. Considerably smaller number of inflammatory cells and larger number of fibroblasts was noticed. The administration of the extract three days earlier did not have significant preventive effects. Rosmarinic acid was the predominant compound in the extract. The extract showed strong antioxidant effects in both test systems. CONCLUSIONS: S. sclarea extract manifested anti-inflammatory effect in LPS-induced periodontitis suggesting that it may have a role as a therapeutic agent in periodontal diseases. Having in mind that overproduction of reactive oxygen species is connected to periodontitis, the strong antioxidant capacity may be contributable to anti-inflammatory properties of the extract.