Diabetes-associated Periodontitis Research Articles

SIRT3 alleviates mitochondrial dysfunction and senescence in diabetes-associated periodontitis by deacetylating LRPPRC

SIRT3 alleviates mitochondrial dysfunction and senescence in diabetes-associated periodontitis by deacetylating LRPPRC

Exploring the Logic and Conducting a Comprehensive Evaluation of the Adiponectin Receptor Agonists AdipoRon and AdipoAI's Impacts on Bone Metabolism and Repair-A Systematic Review.

Adiponectin replacement therapy shows promising outcomes in various diseases, especially for bone-related disorders. Challenges in using the complete protein have led to alternative approaches, with AdipoRon and AdipoAI emerging as extensively researched drug candidates. Their influence on models of bone-related disorders has progressed considerably but there has been no review of their effectiveness in modulating bone metabolism and repair. This systematic review seeks to address this knowledge gap. Based on preclinical evidence from PubMed, EMBASE, and COCHRANE, ten studies were included following PRISMA guidelines. The JBI Checklist Critical Appraisal Tool assessed the quality of this systematic review. The studies encompassed various animal models, addressing bone defects, osseointegration, diabetes-associated periodontitis, fracture repair, growth retardation, and diabetes-associated peri-implantitis. AdipoRon and AdipoAI demonstrated effectiveness in modulating bone metabolism and repair through diverse pathways, including the activation of AdipoR1/APPL1, inhibition of F-actin ring formation, suppression of IκB-α phosphorylation, p65 nuclear translocation and Wnt5a-Ror2 signaling pathway, reduction of CCL2 secretion and expression, regulation of autophagy via LC3A/B expression, modulation of SDF-1 production, activation of the ERK-1/2 signaling pathway, modulation of bone integration-related markers and osteokines such as RANKL, BMP-2, OPG, OPN, and Runx2, inhibition of RANKL in osteoblasts, and inhibition of podosome formation via the activation of AMPK. While preclinical studies show promise, human trials are crucial to confirm the clinical safety and effectiveness of AdipoRon and AdipoAI. Caution is necessary due to potential off-target effects, especially in bone therapy with multi-target approaches. Structural biology and computational methods can help predict and understand these effects.

Lysosomal dysfunction-derived autophagy impairment of gingival epithelial cells in diabetes-associated periodontitis with altered protein acetylation

Diabetes-associated periodontitis (DP) presents severe inflammation and resistance to periodontal conventional treatment, presenting a significant challenge in clinical management. In this study, we investigated the underlying mechanism driving the hyperinflammatory response in gingival epithelial cells (GECs) of DP patients. Our findings indicate that lysosomal dysfunction under high glucose conditions leads to the blockage of autophagy flux, exacerbating inflammatory response in GECs. Single-cell RNA sequencing and immunohistochemistry analyses of clinical gingival epithelia revealed dysregulation in the lysosome pathway characterized by reduced levels of lysosome-associated membrane glycoprotein 2 (LAMP2) and V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C) in subjects with DP. In vitro stimulation of human gingival epithelial cells (HGECs) with a hyperglycemic microenvironment showed elevated release of proinflammatory cytokines, compromised lysosomal acidity and blocked autophagy. Moreover, HGECs with deficiency in ATP6V0C demonstrated impaired autophagy and heightened inflammatory response, mirroring the effects of high glucose stimulation. Proteomic analysis of acetylation modifications identified altered acetylation levels in 28 autophagy-lysosome pathway-related proteins and 37 sites in HGECs subjected to high glucose stimulation or siATP6V0C. Overall, our finding highlights the pivotal role of lysosome impairment in autophagy obstruction in DP and suggests a potential impact of altered acetylation of relevant proteins on the interplay between lysosome dysfunction and autophagy blockage. These insights may pave the way for the development of effective therapeutic strategies against DP.

Role of microRNAs in Diabetes-Associated Periodontitis: A Scoping Review.

Diabetes mellitus (DM), a metabolic disorder, exhibits a bidirectional relationship with periodontitis (PD), and recently, microRNAs (miRNAs) were associated with their progression. This review aims to assess the role of miRNAs in the pathogenesis of DM-associated PD and their plausible application as a biomarker for PD in individuals with DM. The search conducted until September 2023 on Medline (Pubmed), Scopus, Embase, and Web of Science using the keywords "microRNA," "miRNA," or "miR," combined with "Diabetes" and "PD" yielded 100 articles. Only research focusing on the role of miRNAs in the pathogenesis of DM-associated PD and their potential application as biomarkers for both conditions were included. Finally, 14 studies were assessed for any bias, and the collected data included study design, sample size, participant groups, age, sample obtained, PD severity, miRNAs examined, clinical and biochemical parameters related to DM and PD, and primary outcomes. In vivo studies indicated altered expression of miRNAs-146a, -146b, -155, -200b, -203, and -223, specifically in the comorbid subjects with both conditions. Animal, ex vivo, and in vitro studies demonstrated altered expression of miRNAs-126, -147, -31, -25-3p, -508-3p, -214, 124-3p, -221, -222, and the SIRT6-miR-216/217 axis. These miRNAs impact innate and adaptive immune mechanisms, oxidative stress, hyperglycemia, and insulin sensitivity, thereby promoting periodontal destruction in DM. miRNA-146a emerges as a reliable biomarker of PD in DM, whereas miRNA-155 is a consistent predictor of PD in subjects without DM. miRNAs exert influence on immuno-inflammation in DM-associated PD. Although they can be biomarkers of PD and DM, their clinical utility is hindered by the absence of standardized tests to evaluate their sensitivity and specificity. Moreover, there has been limited exploration of the role of miRNAs in DM-associated PD through human studies. Future clinical trials are warranted to address this gap, focusing on standardizing sample collection, miRNA sources, and detection methods. This approach will enable the identification of specific miRNAs for DM-associated PD.

Lipotoxicity: The missing link between diabetes and periodontitis?

Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non-alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current invivo, invitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega-3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes-associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis.

Mechanism and application of Lactobacillus in type 2 diabetes-associated periodontitis.

Type 2 diabetes mellitus (T2DM) accelerates the progression of periodontitis through diverse pathways. Abnormal immune responses, excessive activation of inflammation, increased levels of advanced glycation end products, and oxidative stress have defined roles in the pathophysiological process of T2DM-associated periodontitis. Furthermore, in the periodontium of diabetic individuals, there are high levels of advanced glycation end-products and glucose. Meanwhile, progress in microbiomics has revealed that dysbacteriosis caused by T2DM also contributes to the progression of periodontitis. Lactobacillus, owing to its fine-tuning function in the local microbiota, has sparked tremendous interest in this field. Accumulating research on Lactobacillus has detailed its beneficial role in both diabetes and oral diseases. In this study, we summarize the newly discovered mechanisms underlying Lactobacillus-mediated improvement of T2DM-associated periodontitis and propose the application of Lactobacillus in the clinic.

A novel modified-curcumin 2.24 resolves inflammation by promoting M2 macrophage polarization

To assess resolving-like activity by a novel chemically-modified curcumin (CMC2.24) in a “two-hit” model of diabetes-associated periodontitis. Macrophages from rats were cultured in the presence/absence of either Lipopolysaccharide (LPS, 1st hit); or advanced-glycation-end products (AGE, 2nd hit); or both combined. CMC2.24 was added as treatment. The conditioned media were analyzed for MMP-9, cytokines (IL-1β, IL-6, TNF-α), resolvins (RvD1, RvE1, lipoxin A4), and soluble receptor for AGE (sRAGE). The phenotypes of M1/M2 macrophage were analyzed by flow cytometry. Both LPS/AGE-alone, and two-combined, dramatically increased the secretion of MMP-9 by macrophages. CMC2.24 “normalized” the elevated levels of MMP-9 under all conditions. Moreover, CMC2.24 significantly reduced the secretion of IL-1β and IL-6 with a fewer effects on TNF-α. Importantly, CMC2.24 increased RvD1 and sRAGE secretion by macrophages exposed to LPS/AGE; and both treatment groups exhibited increased M2 relative to M1 populations. Furthermore, scatter-diagram showed the macrophages gradually shifted from M1 towards M2 with CMC2.24-treated, whereas LPS/AGE-alone groups remained unchanged. CMC2.24 “normalized” cytokines and MMP-9, but also enhanced RvD1 and sRAGE in macrophages. Crucially, CMC2.24 appears to be a potent inhibitor of the pro-inflammatory M1 phenotype; and a promotor of the pro-resolving M2 phenotype, thus acting like a crucial “switch” to reduce inflammation.

Single-cell transcriptional profiling reveals immunomodulatory properties of stromal and epithelial cells in periodontal immune milieu with diabetes in rats

Periodontitis is the sixth major complication of diabetes. Gingiva, as an important component of periodontal tissues, serves as the first defense barrier against infectious stimuli. However, relatively little is known about cellular heterogeneity and cell-specific changes in gingiva in response to diabetes-associated periodontitis. To characterize molecular changes linking diabetes with periodontitis, we profiled single-cell transcriptome analyses of a total of 45,259 cells from rat gingiva with periodontitis under normoglycemic and diabetic condition. The single-cell profiling revealed that stromal and epithelial cells of gingiva contained inflammation-related subclusters enriched in functions of immune cell recruitment. Compared to normoglycemic condition, diabetes led to a reduction in epithelial basal cells, fibroblasts and smooth muscle cells in gingiva with periodontitis. Analysis of differentially expressed genes indicated that stromal and epithelial populations were reprogrammed towards pro-inflammatory phenotypes promoting immune cell recruitment in diabetes-related periodontitis. In aspect of immune cells, diabetes prominently enhanced neutrophil and M1 macrophage infiltration in periodontitis lesions. Cell-cell communications revealed enhanced crosstalk between stromal/epithelial cells and immune cells mediating by chemokine/chemokine receptor interplay in diabetes-associated periodontitis. Our findings deconvolved cellular heterogeneity of rat gingiva associated with periodontitis and diabetes, uncovered altered immune milieu caused by the disease, and revealed immunomodulatory functions of stromal and epithelial cells in gingival immune niche. The present study improves the understanding of the link between the diabetes and periodontitis and helps in formulating precise therapeutic strategies for diabetes-enhanced periodontitis.

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

Low-grade inflammation, which is a common feature of both diabetes and periodontitis, partly accounts for the complexity and refractory of the 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. The maxillary first molar of Zucker diabetic fatty (ZDF) rats was ligated to construct a diabetes-associated periodontitis model, and the 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 receptors (AdipoRs) expression. Expression of AdipoR1/AdipoR2 and inflammation-related signalling pathways was examined by IHC and WB, which was followed by confirmation with an NF-κB P65 inhibitor (BAY 11-7082). 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 inflammation in gingiva. 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 AdipoR1. AdipoAI, with its ability to alleviate inflammatory damage in tissues, is a candidate for diabetes-associated periodontitis treatment.

Quercetin ameliorates advanced glycation end product-induced wound healing impairment and inflammaging in human gingival fibroblasts

Background/purposeDiabetes mellitus (DM) and periodontal disease are both prevalent and chronic inflammatory disorders that have significant health impact. Many studies have pointed out that advanced glycation end-products (AGEs) in DM induces inflammaging, which is a pre-aging and hyperinflammatory condition, and it has been linked to a greater likelihood in developing periodontitis. Inflammaging in DM has been shown to be driven by AGEs-induced cell senescence, inflammatory cytokines, and oxidative stress, resulting in the degradation of periodontium. Quercetin has shown abilities to decrease inflammation and oxidative stress in a variety of tissues, however, the effect in diabetic periodontitis remains uncertain. Thus, the aim of this study was to investigate its impacts on inflammaging in diabetic periodontitis. Materials and methodsWe examined cell proliferation in human gingival fibroblasts (HGF), wound healing, IL-6 and IL-8 secretions, cellular senescence expression, and the formation of reactive oxygen species (ROS) in response to AGE stimulation with and without Quercetin intervention. Following that, we looked into NF-κβ activity to see if Quercetin mediate its effects via this pro-inflammatory signaling. ResultsQuercetin at 20 μM and below did not have any impact on HGFs’ cell proliferation rate. Quercetin intervention improved the AGEs-impaired wound healing, in addition to the attenuation of AGEs-induced ROS in a dose-dependent pattern. Moreover, Quercetin therapy dose-dependently inhibited AGEs-induced cell senescence activity along with its senescence associated secretion phenotype (SASP) secretions such as IL-6 and IL-8. Western blot analysis indicated that Quercetin was able to reverse the phosphorylation of p65 and Iκβ in AGEs-stimulated HGFs, demonstrating it can modulate NF-κβ pathway. ConclusionAccumulation of AGEs can elicit inflammaging in HGFs, as seen by increased pro-inflammatory cytokines, cell senescence expression and oxidative stress. The results proposed that Quercetin is able to ameliorate inflammaging in diabetic periodontitis and improve wound healing via the suppression of NF-κβ pathway and hence, may be a promising approach for treatment of diabetes-associated periodontitis.

Relationship between circulating senescence-associated secretory phenotype levels and severity of type 2 diabetes-associated periodontitis: A cross-sectional study.

Senescence-associated secretory phenotype (SASP) has recently been found to drive comorbid diabetes and periodontitis by inducing a chronic, low-degree inflammatory state. Here, we sought to explore the relationship between circulating SASP and the severity of type 2 diabetes-associated periodontitis (DP). Eighty patients (middle-aged periodontitis, M-P group; aged periodontitis, A-P group; M-DP group; and A-DP group; n=20) provided gingival epithelium, serum, and periodontal clinical parameters. Circulating levels of 12 DP-related SASP factors were analyzed by immunoassay. Correlation between periodontal clinical parameters and circulating SASP levels was analyzed by Spearman's rank correlation coefficient and back propagation artificial neural network (BPNN). Senescence markers (p16, p21, and HMGB1) in gingiva were determined by immunofluorescence assay. M-DP group had increased serum levels of twelve SASP factors compared with the M-P group (p<0.5). Serum levels of IL-6, IL-4, and RAGE were higher in the A-DP group than the A-P group (p<0.5). The circulating concentrations of certain SASP proteins, including IL-1β, IL-4, MMP-8, OPG, RANKL, and RAGE were correlated with the clinical parameters of DP. BPNN showed that serum SASP levels had considerable predictive value for CAL of DP. Additionally, the DP group had higher expressions of p16, p21, and cytoplasmic-HMGB1 in the gingiva than the P group (p<0.5). Significantly enhanced circulating SASP levels and aggravated periodontal destruction were observed in patients with DP. Importantly, a non-negligible association between serum SASP levels and the severity of DP was found.

Eldecalcitol effectively prevents alveolar bone loss by partially improving Th17/Treg cell balance in diabetes-associated periodontitis.

Background: Diabetes-associated periodontitis (DPD) is an inflammatory and destructive disease of periodontal tissues in the diabetic population. The disease is manifested as more severe periodontal destruction and is more difficult to treat when compared with periodontitis (PD). Eldecalcitol (ELD) is a novel active vitamin D3 analog; however, little clinical evidence is available on its role on improving PD and DPD, and its specific mechanisms remain unclear. In this study, we evaluated the preventative effects of ELD toward PD and DPD and explored its underlying molecular mechanisms. Methods: Experimental PD and DPD mouse models were established by ligation combined with lipopolysaccharide (LPS) from Porphyromonas gingivalis injection in C57BL/6J and C57BLKS/J Iar- + Leprdb/+Leprdb (db/db) mice, respectively. Simultaneously, ELD (0.25μg/kg) was orally administered to mice via an intragastric method. Micro-computed tomography (CT), hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), and tartrate-resistant acid phosphatase (TRAP) staining were used to evaluate alveolar bone alterations in vivo. Flow cytometry, immunofluorescence, and real-time polymerase chain reaction (qRT-PCR) were also used to examine gene expression and probe systemic and local changes in Treg and Th17 cell numbers. Additionally, western blotting and immunofluorescence staining were used to examine changes in STAT3/STAT5 signaling. Results: Micro-CT and HE staining showed that the DPD group had higher alveolar bone loss when compared with the PD group. After applying ELD, alveolar bone loss decreased significantly in both PD and DPD groups, and particularly evident in the DPD group. IHC and TRAP staining also showed that ELD promoted osteoblast activity while inhibiting the number of osteoclasts, and after ELD treatment, the receptor activator of nuclear factor-κB ligand (RANKL) to osteoprotegerin (OPG) ratio decreased. More importantly, this decreasing trend was more obvious in the DPD group. Flow cytometry and qRT-PCR also showed that the systemic Th17/Treg imbalance in PD and DPD groups was partially resolved when animals were supplemented with ELD, while immunofluorescence staining and qRT-PCR data showed the Th17/Treg imbalance was partially resolved in the alveolar bone of both ELD supplemented groups. Western blotting and immunofluorescence staining showed increased p-STAT5 and decreased p-STAT3 levels after ELD application. Conclusion: ELD exerted preventative effects toward PD and DPD by partially rectifying Th17/Treg cell imbalance via STAT3/STAT5 signaling. More importantly, given the severity of DPD, we found ELD was more advantageous in preventing DPD.

Anti-inflammaging effects of vitamin D in human gingival fibroblasts with advanced glycation end product stimulation

Background/purpose:Both periodontal disease and diabetes mellitus (DM) are long-term inflammatory disorders that are highly prevalent and have a significant health impact. Inflammaging, a state of pre-aging and hyperinflammatory state has been acknowledged for its role in DM patients to have heightened risk of periodontitis. Numerous evidences revealed that inflammaging contributed by cell senescence, acceleration of inflammation and oxidative stress participates in the destruction of periodontium in DM. Abilities of vitamin D in suppressing inflammation and oxidative stress have been revealed in a range of tissues, however in DM’s gingival cells, the effect remain undefined. Materials and methods: Under the stimulation of advanced glycation end-products (AGEs), we assessed the cell proliferation in human gingival fibroblast (HGF), IL-6 and IL-8 secretions, cellular senescence expression and generation of reactive oxygen species (ROS) with or without vitamin D intervention. Following that, we examined the expression of Nrf2 and HO-1 to see if vitamin D was able to modulate the anti-oxidant signaling. A knockdown experiment was then conducted to proof the participation of Nrf2 on the secretion of pro-inflammatory IL-6 and IL-8. Results: Following the treatment of vitamin D, AGEs-elicited IL-6 and IL-8 production and cell senescence were dose-dependently repressed. Moreover, vitamin D attenuated AGEs-induced ROS in a dose-dependent pattern. Results from qRT-PCR demonstrated vitamin D reversed the suppression of Nrf2 and HO-1 induced by AGEs. Our findings revealed that the anti-inflammatory and anti-oxidant effect in vitamin D was mediated via the upregulation of Nrf2 expression. Conclusion: These data showed that high levels of AGEs in the gingiva lead to inflammaging reflected by increased pro-inflammatory cytokines, cell senescence expression and oxidative stress. Vitamin D supplementation can reduce oxidative stress and inflammation via the upregulation of Nrf2 signaling and hence, may be a potential approach for treatment of diabetes-associated periodontitis.

Therapeutic Potential of Liraglutide for Diabetes-Periodontitis Comorbidity: Killing Two Birds with One Stone.

Background The relationship between diabetes and periodontitis is bidirectional, and there is now consensus that periodontitis and diabetes are comorbid. There is a quest for a drug that can be used to treat both conditions simultaneously. This study evaluated the anti-inflammatory and osteoprotective effects of liraglutide (LIRA) on periodontitis in diabetic rats. Methods Male Wistar rats (n = 46) were randomly divided into four groups: control group (n = 8), LIRA group (n = 8), diabetes-associated periodontitis+0.9% saline group (diabetic periodontitis (DP)+NaCl group, n = 15), and diabetes-associated periodontitis+LIRA group (DP+LIRA group, n = 15). LIRA treatment lasted for 4 weeks (300 μg/kg/d) after establishment of a rat model of DP. The expression of IL-6, TNF-α, and IL-1β was detected by enzyme-linked immunosorbent assay. The morphological changes of periodontal tissues were observed by hematoxylin–eosin staining. The absorption of alveolar bone and its ultrastructural changes were observed by histomorphometry and microcomputed tomography. The expression of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in alveolar bone was detected by immunohistochemistry. The levels of Runx2 mRNA and ALP mRNA in the gingival epithelium were examined by quantitative real-time polymerase chain reaction. Results LIRA decreased alveolar bone resorption, improved the microstructure of alveolar bone, and reduced periodontal inflammation and damage (P < 0.05). LIRA also reduced blood glucose level and inhibited the secretion of serum IL-6, TNF-α, and IL-1β (P < 0.05). In addition, after treatment with LIRA, the ratio of RANKL/OPG was reduced, and the expression levels of ALP mRNA and Runx2 mRNA were upregulated (P < 0.05). Conclusions LIRA not only controls blood glucose level but also reduces inflammation and bone loss and enhances osteogenic differentiation in diabetes-associated periodontitis. Those indicate that LIRA may be used as a potential medicine for the adjunctive therapy of diabetes-periodontitis comorbidity.

Potential Therapeutic Applications of Natural Compounds in Diabetes-Associated Periodontitis.

Diabetes mellitus (DM) is a major worldwide health burden. DM is a metabolic disease characterized by chronic hyperglycemia, and if left untreated, can lead to various complications. Individuals with uncontrolled DM are more susceptible to periodontitis due to both a hyper-inflammatory host response and an impaired immune response. Periodontitis, on the other hand, may exacerbate DM by increasing both local and systemic inflammatory components of DM-related complications. The current standard for periodontal treatment in diabetes-associated periodontitis (DP) focuses mostly on reducing bacterial load and less on controlling the excessive host response, and hence, may not be able to resolve DP completely. Over the past decade, natural compounds have emerged as an adjunct approach for modulating the host immune response with the hope of curing DP. The anti-oxidant, anti-inflammatory, and anti-diabetic characteristics of natural substances are well-known, and they can be found in regularly consumed foods and drinks, as well as plants. The pathophysiology of DP and the treatment benefits of various bioactive extracts for DP will be covered in this review.

A brief review of vitamin D as a potential target for the regulation of blood glucose and inflammation in diabetes-associated periodontitis.

Diabetes is a metabolic disorder associated with various complications, including periodontitis. The risk of periodontitis is increased in patients with diabetes, while vitamin D deficiency is associated with both diabetes and periodontitis. Thus, there is a need to identify the molecular effects of vitamin D on the regulation of inflammation and glucose in diabetes-associated periodontitis. The Web of Science, Scopus, and PubMed databases were searched for studies of the molecular effects of vitamin D. Molecular effects were reportedly mediated by salivary secretions, interactions of advanced glycation end products (AGEs) with receptors of AGEs (RAGEs), cytokines, and oxidative stress pathways linking diabetes with periodontitis. Vitamin D supplementation attenuates inflammation in diabetes-associated periodontitis by reducing the levels of inflammatory cytokines and numbers of immune cells; it also has antibacterial effects. Vitamin D reduces cytokine levels through regulation of the extracellular signal-related kinase 1/2 and Toll-like receptor 1/2 pathways, along with the suppression of interleukin expression. Glucose homeostasis is altered in diabetes either because of reduced insulin production or decreased insulin sensitivity. These vitamin D-related alterations of glucoregulatory factors may contribute to hyperglycaemia; hyperglycaemia may also lead to alterations of glucoregulatory factors. This review discusses the pathways involved in glucose regulation and effects of vitamin D supplementation on glucose regulation. Further studies are needed to characterise the effects of vitamin D on diabetes-associated periodontitis.

Effect of Salivary Exosomal miR-25-3p on Periodontitis With Insulin Resistance.

Periodontitis is caused by an oral microbial dysbiosis-mediated imbalance of the local immune microenvironment, which is promoted by insulin resistance and obesity. The prevalence and severity of periodontitis is higher in patients with type 2 diabetes than in healthy individuals, possibly because of differences in immune responses. The level of glycemic control also affects the saliva profile, which may further promote periodontal disease in diabetes patients. Therefore, we compared the salivary exosomal miRNA profiles of patients with type 2 diabetes with those of healthy individuals, and we found that exosomal miR-25-3p in saliva is significantly enriched (by approximately 2-fold, p < 0.01) in obese patients with type 2 diabetes. We also identified CD69 mRNA as a miR-25-3p target that regulates both activation of γδ T cells and the inflammatory response. Knockdown of CD69 increased (by approximately 2-fold) interleukin-17A production of γδ T cells in vitro. To evaluate the role of exosomal miRNA on progression of periodontitis, we analyzed regional immune cells in both periodontal tissues and lymph nodes from mice with periodontitis. We found that diet-induced obesity increased the population of infiltrating pro-inflammatory immune cells in the gingiva and regional lymph nodes of these mice. Treatment with miR-25-3p inhibitors prevented the local in vivo inflammatory response in mice with periodontitis and diet-induced obesity. Finally, we showed that suppression of interleukin 17-mediated local inflammation by a miR-25-3p inhibitor alleviated (by approximately 34%) ligature-induced periodontal alveolar bone loss in mice. Taken together, these data suggest that exosomal miR-25-3p in saliva contributes to development and progression of diabetes-associated periodontitis. Discovery of additional miR-25-3p targets may provide critical insights into developing drugs to treat periodontitis by regulating γδ T cell-mediated local inflammation.

A novel adiponectin receptor agonist (AdipoAI) ameliorates type 2 diabetes-associated periodontitis by enhancing autophagy in osteoclasts.

Type 2 diabetes (T2D)-associated periodontitis is severe and refractory in many cases. Considered an inflammatory disease, T2D predisposes to periodontitis by increasing whole-body inflammation. One mechanism of increased inflammation is thatT2D is mediated by loss of production or function of the anti-inflammatory hormone adiponectin. In our previous report, AdipoRon, an adiponectin receptor agonist, and AdipoAI, a newly discovered, more specific agonist, attenuated T2D-associated inflammation by inhibiting osteoclastogenesis and LPS-induced endotoxemia. Autophagy plays an important role during osteoclast differentiation and function. The impact of AdipoAI on osteoclast function and autophagy involved in osteoclastogenesis is not known. Here, we compare AdipoRon and AdipoAI potency, side effects and mechanism of action in T2D-associated periodontitis. The RAW 264.7 cell line was used for in vitro studies. We analyzed the potential cytotoxicity of AdipoAI using the CCK-8 assay. The anti-osteoclastogenic potential of AdipoAI was studied by real-time qPCR and tartrate-resistant acid phosphatase staining. The actions of AdipoAI involved in autophagy were tested by real-time qPCR, western blot and immunofluorescence staining. In the diet-induced obesity model of T2D, we investigated the impact of AdipoAI on fasting blood glucose, alveolar bone loss, and gingival inflammation in mice with experimental periodontitis. AdipoRon inhibited osteoclastogenesis and AdipoAI inhibited osteoclastogenesis at lower doses than AdipoRon without any cytotoxicity. In DIO mice with experimental periodontitis, AdipoAI reduced mouse body weight in 14days, reducing fasting glucose levels, alveolar bone destruction, osteoclast number along the alveolar bone surface, and decreased the expression of pro-inflammatory factors in periodontal tissues. AdipoAI and AdipoRon also enhanced LC3A/B expression when cultured with RANKL.3-Methyladenine, a known autophagy inhibitor, decreased LC3A/B expression and reversed the inhibition of osteoclastogenesis during AdipoAI treatment. Our results demonstrate that AdipoAI ameliorates the severity of T2D-associated periodontitis by enhancing autophagy in osteoclasts at lower doses than AdipoRon without demonstrable side effects. Thus, AdipoAI has pharmaceutical potential for treating diabetes-associated periodontal disease.

Does Chemically Modified Curcumin Control the Progression of Periodontitis? A Systematic Review.

BackgroundRecently, pharmacologic approaches have been seen in utilizing matrix metalloproteinase inhibitors (MMP-I) to prohibit the destruction of connective tissue accompanied by erythrogenic inflammatory diseases such as periodontitis. However, curcumin characteristics have been described to be effective in reducing inflammatory mediators and matrix metalloproteinase (MMP). But, due to its poor solubility and bioavailability, a chemically modified curcumin (CMC 2.24) has been used.ObjectiveThe purpose of this research is to review and analyze the animal attempts which investigate the impact of CMC2.24 on periodontitis.Materials and MethodsOur study was based on reviewing the English preclinical studies using CMC2.24 on an induced periodontal disease which were published up to 2020, only randomized control trials (RCTs) were included. Databases were used from electronic websites including PubMed, ScienceDirect, and Google scholar.ResultsSeven experimental trials involving 162 rats and 8 dogs were included in the present systematic review. Six studies investigated LPS-induced experimental periodontitis, two of them worked on diabetes-associated periodontitis, while one study worked on naturally occurring periodontitis. All included studies revealed that CMC 2.24 reduced alveolar bone loss as well as inhibited the MMP.ConclusionCollectively, we concluded that CMC 2.24 has significant implications in prohibiting the progression of bone loss.

Inhibition of CCL2 by bindarit alleviates diabetes-associated periodontitis by suppressing inflammatory monocyte infiltration and altering macrophage properties

Diabetes-associated periodontitis (DP) aggravates diabetic complications and increases mortality from diabetes. DP is caused by diabetes-enhanced host immune-inflammatory responses to bacterial insult. In this study, we found that persistently elevated CCL2 levels in combination with proinflammatory monocyte infiltration of periodontal tissues were closely related to DP. Moreover, inhibition of CCL2 by oral administration of bindarit reduced alveolar bone loss and increased periodontal epithelial thickness by suppressing periodontal inflammation. Furthermore, bindarit suppressed the infiltration of proinflammatory monocytes and altered the inflammatory properties of macrophages in the diabetic periodontium. This finding provides a basis for the development of an effective therapeutic approach for treating DP.