Periodontitis In Diabetes Research Articles

Polyphenol-mediated redox-active hydrogel with H2S gaseous-bioelectric coupling for periodontal bone healing in diabetes.

Excessive oxidative response, unbalanced immunomodulation, and impaired mesenchymal stem cell function in periodontitis in diabetes makes it a great challenge to achieve integrated periodontal tissue regeneration. Here, a polyphenol-mediated redox-active algin/gelatin hydrogel encapsulating a conductive poly(3,4-ethylenedioxythiopene)-assembled polydopamine-mediated silk microfiber network and a hydrogen sulfide sustained-release system utilizing bovine serum albumin nanoparticles is developed. This hydrogel is found to reverse the hyperglycemic inflammatory microenvironment and enhance functional tissue regeneration in diabeticperiodontitis. Polydopamine confers the hydrogel with anti-oxidative and anti-inflammatory activity. Theslow, sustained release of hydrogen sulfide from the bovine serum albumin nanoparticles recruits mesenchymal stem cells and promotes subsequent angiogenesis and osteogenesis. Moreover, poly(3,4-ethylenedioxythiopene)-assembled polydopamine-mediated silk microfiber confers the hydrogel with good conductivity, which enables it to transmit endogenous bioelectricity, promote cell arrangement, and increase the inflow of calcium ion. In addition, the synergistic effects of hydrogen sulfide gaseous-bioelectric coupling promotes bone formation by amplifying autophagy in periodontal ligament stem cells and modulating macrophage polarization via lipid metabolism regulation. This study provides innovative insights into the synergistic effects of conductivity, reactive oxygen species scavenging, and hydrogen sulfide on the periodontium in a hyperglycemic inflammatory microenvironment, offering a strategy for the design of gaseous-bioelectric biomaterials to promote functional tissue regeneration in immune-related diseases.

High glucose condition aggravates inflammatory response induced by Porphyromonas gingivalis in THP-1 macrophages via autophagy inhibition

BackgroundPorphyromonase gingivalis (P. gingivalis) is a type of bacteria that causes periodontitis, which is strongly correlated with systemic diseases such as diabetes. However, the effect of hyperglycemia on periodontitis are unclear. The present study examined the effects of high glucose levels on the response to P. gingivalis infection.ResultsThe expression of P. gingivalis-induced interleukin-1β (IL-1β) and inflammasomes increased as the glucose concentration increased. High glucose conditions suppressed P. gingivalis–induced autophagy in human acute monocytic leukemia cell line (THP-1) macrophages. Zingerone increased autophagy and alleviated P. gingivalis-induced inflammatory response in THP-1 macrophages under high glucose conditions. In addition, P. gingivalis- induced inflammation in bone marrow-derived macrophages of diabetic mice was higher than in wild-type mice, but a zingerone treatment decreased the levels. Alveolar bone loss due to a P. gingivalis infection was significantly higher in diabetic mice than in wild-type mice.ConclusionsHigh-glucose conditions aggravated the inflammatory response to P. gingivalis infection by suppressing of autophagy, suggesting that autophagy induction could potentially to treat periodontitis in diabetes. Zingerone has potential use as a treatment for periodontal inflammation induced by P. gingivalis in diabetes patients.

Cascade Reactions Catalyzed by Gold Hybrid Nanoparticles Generate CO Gas Against Periodontitis in Diabetes.

The treatment ofdiabetic periodontitis poses a significant challenge due to the presence of local inflammation characterized by excessive glucose concentration, bacterial infection, and high oxidative stress. Herein, mesoporous silica nanoparticles (MSN) are embellished with gold nanoparticles (Au NPs) and loaded with manganese carbonyl to prepare a carbon monoxide (CO) enhanced multienzyme cooperative hybrid nanoplatform (MSN-Au@CO). The Glucose-like oxidase activity of Au NPs catalyzes the oxidation of glucose to hydrogen peroxide (H2O2) and gluconic acid，and then converts H2O2 to hydroxyl radicals (•OH) by peroxidase-like activity to destroy bacteria. Moreover, CO production in response to H2O2, together with Au NPs exhibited a synergistic anti-inflammatory effect in macrophages challenged by lipopolysaccharides. The underlying mechanism can be the induction of nuclear factor erythroid 2-related factor 2 to reduce reactive oxygen species, and inhibition of nuclear factor kappa-B signaling to diminish inflammatory response. Importantly, the antibacterial and anti-inflammation effects of MSN-Au@CO are validated in diabetic rats with ligature-induced periodontitis by showing decreased periodontal bone loss with good biocompatibility. To summarize, MSN-Au@CO is fabricate to utilize glucose-activated cascade reaction to eliminate bacteria, and synergize with gas therapy to regulate the immune microenvironment, offering a potential direction for the treatment of diabetic periodontitis.

Dysregulation of CXCL1 Expression and Neutrophil Recruitment in Insulin Resistance and Diabetes-Related Periodontitis in Male Mice.

The mechanism for the increased risks for periodontitis in the gingival tissues due to insulin resistance and diabetes is unclear. We investigated how insulin action in gingival fibroblasts modulates the progression of periodontitis in resistance and diabetes. Insulin upregulated the lipopolysaccharide-induced neutrophil chemoattractant, CXCL1, production in gingival fibroblasts via insulin receptors and Akt activation. Enhancing CXCL1 expression in the gingiva normalized diabetes and insulin resistance-induced delays in neutrophils recruitment and periodontitis. Targeting dysregulation of CXCL1 in fibroblasts is potentially therapeutic for periodontitis and may also improve wound healing in insulin resistance and diabetes.

Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging

Hyperglycemia induces chronic low-grade inflammation (inflammaging), which is a newly identified contributor to diabetes-related tissue lesions, including the inflammatory bone loss in periodontitis. It is also a secondary senescent pattern mediated by an increased burden of senescent cells and senescence-associated secretory phenotype (SASP). Macrophage is a key SASP-spreading cell and may contribute to the maintenance of SASP response in the periodontal microenvironment. Using a transgenic diabetic model (BLKS/J-Leprdb/leprdb mice) we identified striking senescence of the periodontium in young (18-wk)-diabetic mice accompanied by amassed p16+-macrophages and enhanced early SASP response. Exposed to high glucose in vitro, bone marrow-derived macrophage (BMDM) revealed a strong GLUT1 mRNA response driving the elevated-glucose uptake. GLUT1 is a representative and facilitative glucose transporter in macrophages with potential roles in hyperglycemia-induced inflammation. In this study, both GLUT1 and the downstream GTPase Rheb expression upregulated in the gingiva of diabetic mice with impaired condition. Furthermore, SASP release and p16/p21 signaling were proven to be triggered by mTOR phosphorylation in BMDM and antagonized by restricting glucose uptake in GLUT1−/− BMDM. Taken together, our findings suggest that elevated-GLUT1 sensor responded to high glucose is important for macrophage senescence and SASP response, generated as a result of hyperglycemia, and it is a potential molecular mechanism for the exacerbation of periodontitis in diabetes.

628-P: Insulin's Regulation of CXCL1 Expression Is Critical for Neutrophil Recruitments and the Development of Periodontitis and Poor Wound Healing in Diabetes

A major cause of poor wound healing and periodontitis in diabetes is defective immune response to infections. Insulin signaling via the PI3K/Akt pathway is selectively inhibited in the gingival and wound fibroblasts of diabetic rodents and patients. To determine how loss of insulin actions in gingival fibroblasts can affect periodontitis development, myofibroblast insulin receptors (IR) were deleted by crossbreeding IRβ-flox/flox mice with SM22-Cre C57BL/6 (SMIRKO) mice, which were fed with regular diet (RD), while wild type (WT) littermates were fed with high-fat diet (HFD) for 10 weeks. To induce periodontitis, 7-0 silk ligatures were tied around maxillary molars for 4, 7 or 14 days. When mice were sacrificed to assess alveolar bone loss, immune cell populations and inflammatory cytokine expression in the gingiva was assessed. Gingival IRβ expression in SMIRKO and HFD-fed mice was decreased by 70% and 50%, respectively, with comparable reductions in insulin-induced (100nM) phosphorylation of Akt (pAkt). Ligature-induced alveolar bone loss in SMIRKO and HFD-fed mice was greater by 70% and 40%, respectively, as compared to RD-fed WT mice. Post-ligature time course analysis showed that while neutrophil recruitment was delayed significantly, macrophages and lymphocyte numbers were elevated in both SMIRKO and HFD-fed mice. Similarly, neutrophil-recruiting factors CXCL1 and 2 expression were decreased in the gingiva, whereas TNFα and IL-1β expression were elevated. Gingival myofibroblasts from SMIRKO and HFD-fed mice showed dramatic reductions of IRβ expression and insulin-induced pAkt with parallel lowering of E.coli LPS-induced CXCL1 expression via downregulation of TLR2, compared to RD-fed mice. These data provided the first evidence that insulin action is critical for neutrophil recruitment during infection by enabling CXCL1 expression in gingival myofibroblasts, which is inhibited in diabetes. Disclosure T. Shinjo: None. Q. Li: None. A. Ishikado: Employee; Self; SunStar Inc. Employee; Spouse/Partner; SunStar Inc. K. Park: None. R. St-Louis: None. H. Yokomizo: None. J. Fu: None. M. Yu: None. H. Wang: None. H. Hasturk: None. T.E. Van Dyke: None. G.L. King: Research Support; Self; Sanofi. Funding Sunstar Foundation; Iacocca Family Foundation

479-P: Combination of Trans-resveratrol and Hesperetin Corrects Unscheduled Increased Glucose Metabolism Driving Dysfunction of Human Periodontal Ligament Fibroblasts in Hyperglycemia In Vitro

Dysfunction of human periodontal ligament fibroblasts (PDLFs) contributes to increased prevalence and severity of periodontitis in diabetes. Hyperglycemia induces multiple pathways of metabolic dysfunction: mitochondrial dysfunction, hexosamine and protein kinase C pathway activation and increased formation of methylglyoxal (MG) in human periodontal ligament fibroblasts in vitro. We recently showed that increased glucose metabolism driving metabolic dysfunction in hyperglycemia is produced by glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis, increasing HK2 activity. In this study we investigated correction of this by combination of resveratrol and hesperetin (tRES-HESP) which induces expression of glyoxalase 1 (Glo1) and protects against increased MG. Human PDLFs were incubated in primary culture with 8 mM or 25 mM glucose for 3 days with and without 10 µM tRES-HESP. Glucose consumption and flux of MG formation was measured by enzymatic assay. Activity of glyoxalase 1 (Glo1) was measured by spectrophotometric assay. HK2 protein was determined by Western blotting. The flux of glucose consumption in high glucose concentration cultures of PDLFs was increased, compared to low glucose concentration control (10,658 ± 1,141 vs. 5,923 ± 706 nmol/106 cells/day, n = 3; +80%, P<0.01). Flux of formation of MG was increased similarly: 9.74 ± 0.42 v 6.79 ± 0.47 nmol/106 cells/day, n = 3; +44%, P<0.001). Glo1 activity was decreased in high glucose culture: 485 ± 78 vs. 946 ± 99 mU/mg protein (-49%, P<0.001). HK2 protein was increased: +32% at day 3 (P<0.05). tRES-HESP corrected increased glucose consumption and MG formation, and decreased Glo1 activity in high glucose concentration cultures. tRES-HESP offers a new therapy to prevent diabetic periodontitis. Disclosure N. Rabbani: None. A.A. Ashour: None. M. Xue: None. P. Thornalley: None.

The Effect of Sticopus Hermanii-Hyperbaric Oxygen Therapy to Inflammatory Response of Diabetic Periodontitis

Periodontitis is a major risk factor in the oral cavity in chronic diabetes mellitus. The level of IL-1β as inflammatory cytokine increased in patients with type 2 diabetes and periodontitis, while IL-10 is an anti-inflammatory cytokine, may mediate periodontitis in diabetes. Stichopus hermanii (SH) have been known to have anti-inflammation property. Hyperbaric Oxygen Therapy (HBOT) thas been used as adjuvant therapy in diabetes wound healing. Purpose: To examine the effect of combination SH and HBOT to the expression of inflammatory response of IL-1β and IL-10 on diabetic periodontitis rats. Methods :Thirty male Wistar rats were divided to normal (K-0), diabetic-periodontitis (K-1), and treatment group of SH (K-2), HBOT (K-3), and SH-HBOT (K-4).Experimental diabetic was induced by single dose 65 mg/kg of BW intraperitoneal. The Sticopus hermanii gel 3% by topical application in sulcus gingiva and HBOT 2,4 ATA 3x30 minutes interval 5 minute for 7 days. After 52 days the animals were decapitated and the expression of IL-1β and IL-10 were examined by immunohistochemistry. Data were analyzed with ANOVA and LSD. Results : The expression of IL-1β were raised in K-1 group (10.68±1.50) (p< 0.05), while IL-10 were not raised (8.00 ±1.95) compare to normal group (7.25 ± 0.85) (p>0.05). Treatment with SH in K-2 group resulted in decreased of IL-1β expression (10.00± 1.09) while the expression of IL-10 were raised (8.33 ± 2.60) compare to K-1 (7.25 ± 0.85) (p<0.05). Treatment with HBOT in K-3 group resulted in decreased of IL-10 expression (8.333±0,81) while the expression of IL- 10 were raised (10.67±1.03) compare to K-1 (p<0.05). Treatment with SH-HBOT in K-4 group showed the most decreasing expression of IL-1β (6.50±2.44) and increasing expression of IL-10 (14.83±1.47) compare to K-1 (p<0.05). Conclusions : Combination of SH-HBOT decreased the expression of IL-1β and increased the expression of IL-10 on diabetic periodontitis diabetes rats

Role of poly(ADP-ribose) polymerase activation in the pathogenesis of periodontitis in diabetes.

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. 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 2weeks. 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. 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. 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.

Mitochondrial dysfunction is involved in the aggravation of periodontitis by diabetes.

To elucidate whether mitochondrial dysfunction contributes to aggravated periodontitis in diabetes. Sixty-four wistar rats were randomly assigned into four groups: control, periodontitis, diabetes, and diabetic periodontitis. Two weeks after induction of diabetes, periodontitis was induced by silk ligation for 2weeks and thereafter evaluated by assessing alveolar bone loss and apoptosis of periodontium cells. Mitochondrial oxidative stress was detected by MitoSOX staining. Mitochondrial function was determined by measuring ATP production, and by assessing mitochondrial DNA copy number, activities of electron transport chain complexes, and biogenesis with real-time PCR. Significantly severer bone loss, enhanced periodontium cell apoptosis, and mitochondrial oxidative stress were found in the rats with diabetic periodontitis than the others. Furthermore, diabetic rats with periodontitis presented severer mitochondrial dysfunction than lean rats with periodontitis, as reflected by compromised ATP production, decreased mitochondrial DNA copy number, reduced gene expression of electron transport chain complex I subunits, and impaired mitochondrial biogenesis (p<0.05). Multiple regression analysis further indicated a close correlation between these mitochondrial events and bone loss in diabetic periodontitis. Mitochondrial dysfunction was positive correlated to aggravated periodontitis in diabetes and might represent a therapeutic target for diabetic periodontitis.

Gingival crevicular fluid levels of protease‐activated receptors type 1 and type 2 in diabetic patients with periodontitis

Protease activated receptor type 1 (PAR1 ) seems to play a role in periodontal repair, while PAR2 is associated with periodontal inflammation. As diabetes is a known risk factor for periodontal disease, the aim of this study was to evaluate the influence of type 2 diabetes on PAR1 and PAR2 mRNA expression in the gingival crevicular fluid of patients with chronic periodontitis before and after non-surgical periodontal treatment. Gingival crevicular fluid samples and clinical parameters consisting of measuring probing depth, clinical attachment level, bleeding on probing and plaque index were collected from systemically healthy patients and patients with type 2 diabetes and chronic periodontitis, at baseline and after non-surgical periodontal therapy. PAR1 and PAR2 , as well as the presence of the proteases RgpB gingipain and neutrophil proteinase-3 were assessed by quantitative polymerase chain reaction in the gingival crevicular fluid. The periodontal clinical parameters significantly improved after periodontal therapy (p<0.01). Diabetes led to increased expression of PAR1 in gingival crevicular fluid, and in the presence of chronic periodontitis, it significantly decreased the expression of PAR1 and PAR2 (p<0.05). Moreover, non-surgical periodontal treatment in diabetics resulted in increased expression of PAR1 and PAR2 (p<0.05), and decreased expression of RgpB gingipain and proteinase-3 (p<0.05). The present data demonstrated that diabetes was associated with an altered expression of PAR1 and PAR2 in the gingival crevicular fluid cells of subjects with chronic periodontitis. Future studies are necessary to elucidate the effects of PAR1 upregulation in periodontally healthy sites and PAR2 downregulation in chronic periodontitis sites on the increased susceptibility and severity of periodontitis in diabetes.

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

To review the evidence for the molecular and cellular processes that may potentially link periodontal disease and diabetes. The pathogenic roles of cytokines and metabolic molecules (e.g. glucose, lipids) are explored and the role of periodontal bacteria is also addressed. Paradigms for bidirectional relationships between periodontitis and diabetes are discussed and opportunities for elaborating these models are considered. Database searches were performed using MeSH terms, keywords, and title words. Studies were evaluated and summarized in a narrative review. Periodontal microbiota appears unaltered by diabetes and there is little evidence that it may influence glycaemic control. Small-scale clinical studies and experiments in animal models suggest that IL-1β, TNF-α, IL-6, OPG and RANKL may mediate periodontitis in diabetes. The AGE-RAGE axis is likely an important pathway of tissue destruction and impaired repair in diabetes-associated periodontitis. A role for locally activated pro-inflammatory factors in the periodontium, which subsequently impact on diabetes, remains speculative. There is substantial information on potential mechanistic pathways which support a close association between diabetes and periodontitis, but there is a real need for longitudinal clinical studies using larger patient groups, integrated with studies of animal models and cells/tissues in vitro.

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

To review the evidence for the molecular and cellular processes that may potentially link periodontal disease and diabetes. The pathogenic roles of cytokines and metabolic molecules (e.g. glucose, lipids) are explored and the role of periodontal bacteria is also addressed. Paradigms for bidirectional relationships between periodontitis and diabetes are discussed and opportunities for elaborating these models are considered. Database searches were performed using MeSH terms, keywords, and title words. Studies were evaluated and summarized in a narrative review. Periodontal microbiota appears unaltered by diabetes and there is little evidence that it may influence glycaemic control. Small-scale clinical studies and experiments in animal models suggest that IL-1b, TNF-a, IL-6, OPG and RANKL may mediate periodontitis in diabetes. The AGE-RAGE axis is likely an important pathway of tissue destruction and impaired repair in diabetes-associated periodontitis. A role for locally activated pro-inflammatory factors in the periodontium, which subsequently impact on diabetes, remains speculative. There is substantial information on potential mechanistic pathways which support a close association between diabetes and periodontitis, but there is a real need for longitudinal clinical studies using larger patient groups, integrated with studies of animal models and cells/tissues in vitro.

The comparison of IL-6, elastase and α-PI expressions in human chronic periodontitis with type 2 diabetes mellitus

Diabetes mellitus is an important risk factor of periodontal diseases. It is one of the main contributing factors for periodontal disease and also limiting factor for periodontal treatments such as implant therapy. Although diabetes itself does not cause periodontitis, periodontal disease progresses more rapidly and leads to more tooth losses in patients with poorly controlled blood glucose. Severe periodontitis has been associated with an increased risk of poor glycemic control and, in turn untreated advanced periodontal disease can deteriorate the metabolic control of diabetes. Various pathogenetic factors have been suggested to explain the increased prevalence and severity of periodontitis in diabetes.1) Reduced polymorphonuclear leukocyte(PMN) function has been found in patients with diabetes. This impairment of function was noted in assays of PMN chemotaxis, adherence and phagocytosis. Studies of PMN defects suggest that this dysfunction could lead to impaired host resistance to infection. Gingival fibroblasts from diabetic patients synthesize less collagen compared to non-diabetic subjects. In addition to decreased collagen production, crevicular fluid collagenolytic activity also was increased in diabetic patients. This increased crevicular fluid collagenase activity appears to be primarily of neutrophil origin. Non-enzymatic glycosylation process results in increased cross-linking between collagen molecules. This cross-linking of collagen significantly contributes to reduced solubility and de-

MMP-2, MMP-8 Expression in gingival tissue of Chronic Periodontitis associated to Type 2 Diabetes Mellitus

Diabetes mellitus(DM) in itself does not cause periodontitis. However, there are epidemiologic evidences that diabetes predisposes and accelerates the irreversible periodontal destruction. Severe periodontitis has been associated with an increased risk of poor glycemic control and, in turn, untreated advanced periodontal disease can deteriorate the metabolic control of diabetes 1-4) . Accumulation of plaque is not related directly to the early onset and rapid progression of periodontal tissue destruction in diabetes. Various pathogenic factors have been suggested to explain the increased prevalence and severity of periodontitis in diabetes. An exaggerated inflammatory response to potential periodontopathogenic bacterial virulence factors, such as lipopolysaccharide(LPS), may influence the periodontitis in diabetes. Moreover, an impaired recruitment and cellular function of polymorphonuclear leukocytes(PMNLs) has been linked to extensive periodontal tissue destruction 1-3) .1) Structual studies on diabetic patients have revealed vascular changes in gingiva and other tissues, a thickening of subendotherial basement membrane and, paradoxically, an increased permeability of basement membrane to virulent pathogenic microflora and to its potential vilurent factors 5-7) . Futhermore, a prolonged exposure to hyperglycemia can be primary factor responsible for the formation of non-enzymatic advanced glycosylation end-products(AGEs), demonstrated recently in periodontal tissues of diabetic patients. AGEs are further responsible for