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Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short-acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription-quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases.
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Reabsorção Óssea , Periodontite , Humanos , Animais , Camundongos , Microtomografia por Raio-X , Periodontite/metabolismo , Inflamação , Eicosanoides , Epóxido Hidrolases/metabolismoRESUMO
Chronic inflammation poses challenges to effective cancer treatment. Although anti-inflammatory therapies have shown short-term benefits, their long-term implications may be unfavorable because they fail to initiate the necessary inflammatory responses. Recent research underscores the promise of specialized pro-resolving mediators, which play a role in modulating the cancer microenvironment by promoting the resolution of initiated inflammatory processes and restoring tissue hemostasis. This review addresses current insights into how inflammation contributes to cancer pathogenesis and explores recent strategies to resolve inflammation associated with cancer.
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BACKGROUND: Periodontal diseases are chronic inflammatory conditions that require early screening for effective long-term management. Oral neutrophil counts (ONCs) correlate with periodontal inflammation. This study investigates a point-of-care test using a neutrophil enzyme activity (NEA) colorimetric strip for measuring periodontal inflammation. METHODS: This prospective study had two phases. Phase 1 validated the relationship between ONCs and periodontal inflammation with 90 participants. Phase 2 examined the test's applicability in a real-world setting through a multicentre clinical trial with 375 participants at four sites. ONCs were quantified in oral rinses using laboratory-based methods, and the NEA strip was used for ONC stratification. Clinical measures included bleeding on probing (BoP), probing depth (PD) and clinical attachment loss (CAL). RESULTS: ONCs were significantly elevated in patients with Grade B periodontitis and deep periodontal pockets (PD ≥ 5 mm, CAL ≥ 5 mm). The NEA strip accurately classified patients into high or low ONC categories, showing 80% sensitivity, 82.5% specificity and an AUC of 0.89. It also assessed the effectiveness of periodontal therapy in reducing ONC and inflammation. The test was user-friendly, with no reported discomfort among patients. CONCLUSION: The NEA strip is a user-friendly and rapid screening tool for detecting high ONCs associated with periodontal inflammation and for evaluating the effectiveness of periodontal therapy.
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Inflammation plays a significant role in carcinogenesis and tumor growth. The current study was designed to test the hypothesis that resolvin E1 (RvE1) and overexpression of the receptor for RvE1 (ERV1) will prevent and/or reverse tumor generation in a gain-of-function mouse model of tumor seeding with lung cancer cells. To measure the impact of enhanced resolution of inflammation on cancer pathogenesis, ERV1-overexpressing transgenic (TG) and wild-type FVB mice were given an injection of 1 × 106 LA-P0297 cells subcutaneously and were treated with RvE1 (100 ng; intraperitoneally) or placebo. To assess the impact of RvE1 as an adjunct to chemotherapy, ERV1-TG and wild-type FVB mice were treated with cisplatin or cisplatin + RvE1. RvE1 significantly prevented tumor growth and reduced tumor size, cyclooxygenase-2, NF-κB, and proinflammatory cytokines in TG animals as compared to wild-type animals. A significant decrease in Ki-67, vascular endothelial growth factor, angiopoietin (Ang)-1, and Ang-2 was also observed in TG animals as compared to wild-type animals. Tumor-associated neutrophils and macrophages were significantly reduced by RvE1 in transgenics (P < 0.001). RvE1 administration with cisplatin led to a significant reduction of tumor volume and reduced cyclooxygenase-2, NF-κB, vascular endothelial growth factor-A, Ang-1, and Ang-2. These data suggest that RvE1 prevents inflammation and vascularization, reduces tumor seeding and tumor size, and, when used as an adjunct to chemotherapy, enhances tumor reduction at significantly lower doses of cisplatin.
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Neoplasias Pulmonares , Fator A de Crescimento do Endotélio Vascular , Angiopoietinas/uso terapêutico , Animais , Cisplatino/farmacologia , Ciclo-Oxigenase 2 , Citocinas , Modelos Animais de Doenças , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácido Eicosapentaenoico/farmacologia , Xenoenxertos , Inflamação/patologia , Antígeno Ki-67 , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , NF-kappa B/metabolismoRESUMO
The long noncoding RNA (lncR) ANRIL in the human genome is an established genetic risk factor for atherosclerosis, periodontitis, diabetes, and cancer. However, the regulatory role of lncR-ANRIL in bone and adipose tissue metabolism remains unclear. To elucidate the function of lncRNA ANRIL in a mouse model, we investigated its ortholog, AK148321 (referred to as lncR-APDC), located on chr4 of the mouse genome, which is hypothesized to have similar biological functions to ANRIL. We initially revealed that lncR-APDC in mouse bone marrow cells (BMSCs) and lncR-ANRIL in human osteoblasts (hFOBs) are both increased during early osteogenesis. Subsequently, we examined the osteogenesis, adipogenesis, osteoclastogenesis function with lncR-APDC deletion/overexpression cell models. In vivo, we compared the phenotypic differences in bone and adipose tissue between APDC-KO and wild-type mice. Our findings demonstrated that lncR-APDC deficiency impaired osteogenesis while promoting adipogenesis and osteoclastogenesis. Conversely, the overexpression of lncR-APDC stimulated osteogenesis, but impaired adipogenesis and osteoclastogenesis. Furthermore, KDM6B was downregulated with lncR-APDC deficiency and upregulated with overexpression. Through binding-site analysis, we identified miR-99a as a potential target of lncR-APDC. The results suggest that lncR-APDC exerts its osteogenic function via miR-99a/KDM6B/Hox pathways. Additionally, osteoclasto-osteogenic imbalance was mediated by lncR-APDC through MAPK/p38 and TLR4/MyD88 activation. These findings highlight the pivotal role of lncR-APDC as a key regulator in bone and fat tissue metabolism. It shows potential therapeutic for addressing imbalances in osteogenesis, adipogenesis, and osteoclastogenesis.
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MicroRNAs , RNA Longo não Codificante , Humanos , Camundongos , Animais , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Osso e Ossos/metabolismo , Osteogênese/genética , Tecido Adiposo/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Histona Desmetilases com o Domínio JumonjiRESUMO
OBJECTIVE: This study aimed to investigate the correlation between the expression levels of C3b and C4b in human gingival tissue (GT) and gingival crevicular fluid (GCF) and disease severity in human periodontitis and to determine whether C3b and C4b are significant site-specific complementary diagnostic markers for periodontitis. BACKGROUND: A variety of biomarkers that have potential for informing diagnoses of periodontitis have been proposed. The complement components C3b and C4b were found to be positively correlated with disease severity. The therapeutic effect of targeting C3b and C4b on inflammatory bone loss in experimental periodontitis models has been studied. However, studies on the diagnostic potential of the gingival C3b and C4b expression levels for periodontitis are scarce. METHODS: The expression levels of C3b and C4b in the GT and GCF were investigated via immunohistochemistry and enzyme-linked immunosorbent assay, respectively. The correlation between the expression levels of C3b and C4b and disease severity with probing depth as well as the clinical attachment level were determined. To evaluate the diagnostic accuracy of the C3b and C4b expression levels at the periodontitis sites, the receiver operating characteristic (ROC) curve, cut-off point, area under the ROC curve, sensitivity, and specificity were analyzed. RESULTS: The expression levels of C3b and C4b in human GT and GCF were significantly positively correlated with periodontitis severity. The expression levels of combined C3b + C4b in the GT can significantly differentiate the disease status at the tissue level (p < .0001). Similarly, the expression levels of C3b + C4b in GCF can statistically distinguish periodontitis sites from healthy ones (p < .0001). CONCLUSIONS: Locally deposited C3b and C4b were positively correlated with periodontitis severity and recognized as site-specific diagnostic biomarkers for clinicopathological features in periodontitis. The association between the C3b and C4b network and periodontitis may be further understood and provide a basis for the development of novel screening as well as diagnostic and therapeutic strategies for periodontitis.
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Periodontite , Humanos , Periodontite/diagnóstico , Periodontite/metabolismo , Gengiva/metabolismo , Líquido do Sulco Gengival/química , Biomarcadores/metabolismo , Ensaio de Imunoadsorção EnzimáticaRESUMO
AIMS: To use experimental periodontitis models in rats to investigate the correlation between local expression of the complement components C3b and C4b in periodontal tissues and disease severity, and to assess the therapeutic effects of targeting C3b/C4b on inflammatory bone loss. MATERIALS AND METHODS: The gingival expression of C3, C3b, and C4b in animal experimental periodontitis models were analysed immunohistochemically. The therapeutic effects of the C3b/C4b inhibitor (SB002) on ligation-induced experimental periodontitis was examined using biochemical, histological, and immunohistochemical analyses. RESULTS: The gingival expression levels of C3, C3b, and C4b were positively correlated with the severity of periodontitis. Moreover, both single and multiple injections of the C3b/C4b inhibitor had preventive and therapeutic effects on alveolar bone loss in ligation-induced experimental periodontitis with no associated adverse consequences. CONCLUSIONS: The association between C3b/C4b and periodontitis may provide a basis for the development of novel therapeutic strategies for periodontitis and other inflammatory diseases.
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Complemento C4b , Periodontite , Ratos , Animais , Complemento C4b/metabolismo , Complemento C3b/metabolismo , Convertases de Complemento C3-C5/metabolismo , Inflamação , Periodontite/complicações , Periodontite/tratamento farmacológicoRESUMO
OBJECTIVES: This study aimed to evaluate the impact of chlorhexidine (CHX) gel on inflammation-induced periodontal tissue destruction, osteoclastogenesis, subgingival microbiota, and on the modulation of the RANKL/OPG as well as inflammatory mediators during bone remodeling in vivo. MATERIALS AND METHODS: Ligation- and LPS injection-induced experimental periodontitis were created to investigate the effect of topical application of CHX gel in vivo. Alveolar bone loss, osteoclast number and gingival inflammation was evaluated by micro-CT, histological, immunohistochemistry and biochemical analysis. The composition of the subgingival microbiota was characterized by 16S rRNA gene sequencing. RESULTS: Data shows significant decreases in the alveolar bone destruction in rats from ligation-plus-CHX gel group compared to ligation group. In addition, significant decreases in the number of osteoclasts on bone surface and the protein level of receptor activator of nuclear factor κB ligand (RANKL) in gingival tissue were observed in rats from ligation-plus-CHX gel group. Moreover, data shows significantly decreased inflammatory cell infiltration and decreased expression of cyclooxygenase (COX-2) and inducible NO synthase (iNOS) in gingival tissue from ligation-plus-CHX gel group versus ligation group. Assessment of the subgingival microbiota revealed changes in rats with CHX gel application treatment. CONCLUSION: HX gel presents protective effect on gingival tissue inflammation, osteoclastogenesis, RANKL/OPG expression, inflammatory mediators, and alveolar bone loss in vivo, which may have a translational impact on the adjunctive use in the management of inflammation-induced alveolar bone loss.
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Perda do Osso Alveolar , Periodontite , Ratos , Animais , Clorexidina , Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/prevenção & controle , RNA Ribossômico 16S , Ratos Wistar , Periodontite/tratamento farmacológico , Inflamação , Mediadores da InflamaçãoRESUMO
Chronic inflammatory diseases are the major cause of morbidity and mortality in the aging population worldwide. Chronic inflammation reflects a deficiency in the resolution phase of the acute inflammatory response, which then fails to engage the adaptive immune system accordingly. Resolution of inflammation is a tightly regulated biological pathway that sequentially aids in eliminating the inducing agent and orchestrates clearance of effete immune cells to promote the return to tissue homeostasis. The lipid mediators of resolution of inflammation comprise a family of specialized pro-resolving mediators (SPMs). The synthesis of SPMs occurs via enzymatic conversion of essential omega-6 (n-6) and omega-3 (n-3) fatty acids. SPMs have anti-inflammatory, pro-resolving and tissue regenerating properties. A large number of in vitro and in vivo studies have unveiled the mechanism of action of many SPMs. Here, we focus on the actions of SPMs in health and chronic disease models as well as their potential as therapeutic agents in ongoing and future clinical trials.
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Ácidos Graxos Ômega-3 , Inflamação , Idoso , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Ácidos Docosa-Hexaenoicos , Eicosanoides , Ácidos Graxos Ômega-3/uso terapêutico , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismoRESUMO
AIM: The goal was to use a deep convolutional neural network to measure the radiographic alveolar bone level to aid periodontal diagnosis. MATERIALS AND METHODS: A deep learning (DL) model was developed by integrating three segmentation networks (bone area, tooth, cemento-enamel junction) and image analysis to measure the radiographic bone level and assign radiographic bone loss (RBL) stages. The percentage of RBL was calculated to determine the stage of RBL for each tooth. A provisional periodontal diagnosis was assigned using the 2018 periodontitis classification. RBL percentage, staging, and presumptive diagnosis were compared with the measurements and diagnoses made by the independent examiners. RESULTS: The average Dice Similarity Coefficient (DSC) for segmentation was over 0.91. There was no significant difference in the RBL percentage measurements determined by DL and examiners ( p=.65 ). The area under the receiver operating characteristics curve of RBL stage assignment for stages I, II, and III was 0.89, 0.90, and 0.90, respectively. The accuracy of the case diagnosis was 0.85. CONCLUSIONS: The proposed DL model provides reliable RBL measurements and image-based periodontal diagnosis using periapical radiographic images. However, this model has to be further optimized and validated by a larger number of images to facilitate its application.
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Aprendizado Profundo , Periodontite , Humanos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Periodontite/diagnósticoRESUMO
OBJECTIVES: Chronic inflammatory diseases, including diabetes and cardiovascular disease, are heterogeneous and often co-morbid, with increasing global prevalence. Uncontrolled type 2 diabetes (T2D) can result in severe inflammatory complications. As neutrophils are essential to normal and aberrant inflammation, we conducted RNA-seq transcriptomic analyses to investigate the association between neutrophil gene expression and T2D phenotype. As specialized pro-resolving lipid mediators (SPM) act to resolve inflammation, we further surveyed the impact of neutrophil receptor binding SPM resolvin E1 (RvE1) on isolated diabetic and healthy neutrophils. METHODS: Cell isolation and RNA-seq analysis of neutrophils from N = 11 T2D and N = 7 healthy individuals with available clinical data was conducted. Additionally, cultured neutrophils (N = 3 T2D, N = 3 healthy) were perturbed with increasing RvE1 doses (0 nM, 1 nM, 10 nM, or 100 nM) prior to RNA-seq. Data was evaluated through a bioinformatics pipeline including pathway analysis and post hoc false discovery rate (FDR)-correction. RESULTS: We observed significant differential expression of 50 genes between T2D and healthy neutrophils (p < 0.05), including decreased T2D gene expression in inflammatory- and lipid-related genes SLC9A4, NECTIN2, and PLPP3 (p < 0.003). RvE1 treatment induced dose-dependent differential gene expression (uncorrected p < 0.05) across groups, including 59 healthy and 216 T2D neutrophil genes. Comparing T2D to healthy neutrophils, 1097 genes were differentially expressed across RvE1 doses, including two significant genes, LILRB5 and AKR1C1, involved in inflammation (p < 0.05). CONCLUSIONS: The neutrophil transcriptomic database revealed novel chronic inflammatory- and lipid-related genes that were differentially expressed between T2D cells when compared to controls, and cells responded to RvE1 dose-dependently by gene expression changes. Unraveling the mechanisms regulating abnormalities in diabetic neutrophil responses could lead to better diagnostics and therapeutics targeting inflammation and inflammation resolution.
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Diabetes Mellitus Tipo 2/imunologia , Inflamação/genética , Neutrófilos/fisiologia , 20-Hidroxiesteroide Desidrogenases/genética , Adulto , Idoso , Antígenos CD/genética , Células Cultivadas , Diabetes Mellitus Tipo 2/genética , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Nectinas/genética , Fosfatidato Fosfatase/genética , Análise de Sequência de RNA , Trocadores de Sódio-Hidrogênio/genética , TranscriptomaRESUMO
INTRODUCTION: Corticotomy is widely used in clinical practice to accelerate tooth movement and shorten the duration of orthodontic treatment. It is effective, but an invasive surgery is needed to induce alveolar bone osteopenia that enable rapid tooth movement. In this study, we discovered the potential of 6-shogaol as a more patient-friendly non-invasive alternative to induce transient osteopenia and accelerate tooth movement. MATERIALS AND METHODS: The effects of 6-shogaol on the bone marrow macrophages (BMM) proliferation and osteoclast differentiation, and bone resorption were determined in vitro. Sprague-Dawley rats were distributed into three groups: CON, IPinj or Localinj and euthanized at day 28. Micro-CT, histology, immunohistological, and TUNEL analysis were performed to evaluate the tooth movement acceleration effect of 6-shogaol. RESULTS: In vitro, 6-shogaol promotes osteoclast differentiation and functional demineralization of alveolar bone. RANKL-induced mRNA expression of osteoclastic-specific genes was significantly higher in the presence of 6-shogaol. A dose-dependent increase in the area of TRAP-positive cells was observed with 6-shogaol treatment. F-actin ring formation and increased bone resorption confirmed that osteoclasts treated with 6-shogaol were mature and functional. 6-shogaol stimulated JNK activation and NFATc1 expression during osteoclast differentiation. In vivo, 6-shogaol promotes alveolar bone transient osteopenia and accelerates orthodontic tooth movement. Alveolar bone mass was reduced, more osteoclasts were observed in bone resorption lacunae on the compression side, and the expression of RANKL and sclerostin were higher than the control group. In conclusion, our results suggest that 6-shogoal accelerates tooth movement by inducing osteopenia by a mechanism similar to surgically induced bone injury.
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Reabsorção Óssea , Técnicas de Movimentação Dentária , Animais , Catecóis , Humanos , Fatores de Transcrição NFATC , Osteoclastos , Ratos , Ratos Sprague-DawleyRESUMO
Periodontitis is a complex disease: (a) various causative factors play a role simultaneously and interact with each other; and (b) the disease is episodic in nature, and bursts of disease activity can be recognized, ie, the disease develops and cycles in a nonlinear fashion. We recognize that various causative factors determine the immune blueprint and, consequently, the immune fitness of a subject. Normally, the host lives in a state of homeostasis or symbiosis with the oral microbiome; however, disturbances in homeostatic balance can occur, because of an aberrant host response (inherited and/or acquired during life). This imbalance results from hyper- or hyporesponsiveness and/or lack of sufficient resolution of inflammation, which in turn is responsible for much of the disease destruction seen in periodontitis. The control of this destruction by anti-inflammatory processes and proresolution processes limits the destruction to the tissues surrounding the teeth. The local inflammatory processes can also become systemic, which in turn affect organs such as the heart. Gingival inflammation also elicits changes in the ecology of the subgingival environment providing optimal conditions for the outgrowth of gram-negative, anaerobic species, which become pathobionts and can propagate periodontal inflammation and can further negatively impact immune fitness. The factors that determine immune fitness are often the same factors that determine the response to the resident biofilm, and are clustered as follows: (a) genetic and epigenetic factors; (b) lifestyle factors, such as smoking, diet, and psychosocial conditions; (c) comorbidities, such as diabetes; and (d) local and dental factors, as well as randomly determined factors (stochasticity). Of critical importance are the pathobionts in a dysbiotic biofilm that drive the viscious cycle. Focusing on genetic factors, currently variants in at least 65 genes have been suggested as being associated with periodontitis based on genome-wide association studies and candidate gene case control studies. These studies have found pleiotropy between periodontitis and cardiovascular diseases. Most of these studies point to potential pathways in the pathogenesis of periodontal disease. Also, most contribute to a small portion of the total risk profile of periodontitis, often limited to specific racial and ethnic groups. To date, 4 genetic loci are shared between atherosclerotic cardiovascular diseases and periodontitis, ie, CDKN2B-AS1(ANRIL), a conserved noncoding element within CAMTA1 upstream of VAMP3, PLG, and a haplotype block at the VAMP8 locus. The shared genes suggest that periodontitis is not causally related to atherosclerotic diseases, but rather both conditions are sequelae of similar (the same?) aberrant inflammatory pathways. In addition to variations in genomic sequences, epigenetic modifications of DNA can affect the genetic blueprint of the host responses. This emerging field will yield new valuable information about susceptibility to periodontitis and subsequent persisting inflammatory reactions in periodontitis. Further studies are required to verify and expand our knowledge base before final cause and effect conclusions about the role of inflammation and genetic factors in periodontitis can be made.
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Gengivite , Doenças Periodontais , Periodontite , Estudo de Associação Genômica Ampla , Humanos , InflamaçãoRESUMO
Periodontitis is an infectious-inflammatory disease that results from loss of balance between the commensal microbiome and the host response. The hyper-inflammatory, uncontrolled inflammatory immune lesion promotes tissue damage and impedes effective bacterial clearance. In this review, the relationship between the microbiome and the inflammatory/immune response is explored in the context of a bi-directional pathogenesis; bacteria induce inflammation and inflammation modifies the growth environment causing shifts in the composition of the microbiome. Resolution of inflammation is an active, receptor-mediated process induced by specialized pro-resolving lipid mediators. Inflammatory disease may, therefore, be the result of failure of resolution. Failure to resolve inflammation coupled with resultant microbiome changes is hypothesized to drive development of periodontitis. Re-establishment of microbiome/host homeostasis by specialized pro-resolving lipid mediator therapy suggests that microbiome dysbiosis, the host hyperinflammatory phenotype, and periodontitis can be reversed.
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Periodontite Crônica , Microbiota , Disbiose , Humanos , Inflamação , Mediadores da InflamaçãoRESUMO
The last decade has witnessed unparalleled advances in our understanding of the complexity of the oral microbiome and the compositional changes that occur in subgingival biofilms in the transition from health to gingivitis and to destructive periodontal disease. The traditional view, which has held sway for the last 2 decades, that disease is characterized by the outgrowth of a consortium, or consortia, of a limited number of potentially pathogenic organisms, has given way to an alternative paradigm. In this new view, the microbiological changes associated with disease represent whole-scale alterations to the overall microbial population structure and to the functional properties of the entire community. Thus, and in common with other microbially mediated diseases of the gastrointestinal tract, the normally balanced, symbiotic, and generally benign commensal microbiome of the tooth-associated biofilm undergoes dysbiosis to a potentially deleterious microbiota. Coincident with progress in defining the microbiology of these diseases, there have been equally important advances in our understanding of the inflammatory systems of the periodontal tissues, their control, and how inflammation may contribute both to the development of dysbiosis and, in a deregulated state, the destructive disease process. One can therefore speculate that the inflammatory response and the periodontal microbiome are in a bidirectional balance in oral health and a bidirectional imbalance in periodontitis. However, despite these clear insights into both sides of the host/microbe balance in periodontal disease, there remain several unresolved issues concerning the role of the microbiota in disease. These include, but are not limited to, the factors which determine progression from gingivitis to periodontitis in a proportion of the population, whether dysbiosis causes disease or results from disease, and the molecular details of the microbial stimulus responsible for driving the destructive inflammatory response. Further progress in resolving these issues may provide significant benefit to diagnosis, treatment, and prevention.
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Microbiota , Doenças Periodontais , Periodontite , Disbiose , Humanos , PeriodontoRESUMO
Programming of inflammation resolution is governed by a class of specialized pro-resolving lipid mediators (SPMs) that act in concert to modulate epithelial, endothelial, and immune cell function for restoration of homeostasis. The resolution circuits are altered in obesity and associated morbidities, including type 2 diabetes mellitus (T2D), through reduced production and/or action of SPMs, which can be rescued by therapeutic SPM delivery or up-regulation of SPM receptors. Resolvin E1 (RvE1), an eicosapentaenoic acid derivative, has potent pro-resolving and insulin-sensitizing actions mediated by BLT1 and ERV1 receptors in the vasculature and metabolic organs. Nonetheless, the RvE1-mediated increase in protective adipokines such as adiponectin in white adipose tissues, the enhancement of monocyte patrolling function in the vasculature, as well as the macrophage-clearing functions improve metabolic control in obese-prone conditions. RvE1-enhanced resolving function in obesity prevents dysbiosis of the gut microflora and increased gut permeability. These functions suggest that RE1 has therapeutic potential for immunometabolic alterations associated with T2D in patients with reduced inflammation resolving capacity. SPM profiling in individuals at risk for T2D and associated complications will help to advance personalized disease management and precision medicine.
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Diabetes Mellitus Tipo 2/imunologia , Ácido Eicosapentaenoico/análogos & derivados , Lipídeos/química , Animais , Ácido Eicosapentaenoico/imunologia , Humanos , Lipídeos/imunologiaRESUMO
Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-α or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-α induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes.
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Redutases do Citocromo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Neutrófilos/metabolismo , Receptores do Leucotrieno B4/metabolismo , Adulto , Células Cultivadas , Cromatografia Líquida , Redutases do Citocromo/imunologia , Diabetes Mellitus Tipo 2/imunologia , Ácido Eicosapentaenoico/imunologia , Ácido Eicosapentaenoico/metabolismo , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Fagocitose/imunologia , Reação em Cadeia da Polimerase , Receptores do Leucotrieno B4/imunologia , Espectrometria de Massas em Tandem , TranscriptomaRESUMO
BACKGROUND: Historically, inflammatory periodontal diseases (gingivitis and periodontitis) have been recognized as being primarily of bacterial origin. Bacteria are necessary for disease development, but the presence of specific bacteria does not guarantee progression to periodontitis. Periodontitis is a multifactorial disease; specific bacteria are associated with disease, but may not be the target of treatment. Gingivitis and periodontitis are inflammatory conditions associated with bacterial overgrowth. AIM: To analyse evidence for established thought that specific bacteria directly participate in the pathogenesis of periodontitis and question the long-held tenet that penetration of the periodontal connective tissues by bacteria and their products is a significant phase in the initial development of periodontitis. METHODS: The literature was searched for studies on initiation of gingivitis and periodontitis by specific pathogens. The search results were insufficient for a systematic review and have been summarized in a commentary instead. RESULTS: There is very little evidence in the literature to support the commonly held concept that specific bacteria initiate periodontitis. CONCLUSION: We present evidence for a paradigm supporting the central role of inflammation, rather than specific microbiota, in the early pathogenesis of periodontitis, and discuss whether controlling the inflammation can influence the character and composition of the periodontal infection.
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Bactérias , Gengivite , Doenças Periodontais , Periodontite , Gengivite/microbiologia , Humanos , Doenças Periodontais/microbiologia , Periodontite/microbiologia , PeriodontoRESUMO
Periodontitis is a biofilm-induced inflammatory disease characterized by dysbiosis of the commensal periodontal microbiota. It is unclear how natural regulation of inflammation affects the periodontal biofilm. Promoters of active resolution of inflammation, including resolvin E1 (RvE1), effectively treat inflammatory periodontitis in animal models. The goals of this study were 1) to compare periodontal tissue gene expression in different clinical conditions, 2) to determine the impact of local inflammation on the composition of subgingival bacteria, and 3) to understand how inflammation impacts these changes. Two clinically relevant experiments were performed in rats: prevention and treatment of ligature-induced periodontitis with RvE1 topical treatment. The gingival transcriptome was evaluated by RNA sequencing of mRNA. The composition of the subgingival microbiota was characterized by 16S rDNA sequencing. Periodontitis was assessed by bone morphometric measurements and histomorphometry of block sections. H&E and tartrate-resistant acid phosphatase staining were used to characterize and quantify inflammatory changes. RvE1 treatment prevented bone loss in ligature-induced periodontitis. Osteoclast density and inflammatory cell infiltration in the RvE1 groups were lower than those in the placebo group. RvE1 treatment reduced expression of inflammation-related genes, returning the expression profile to one more similar to health. Treatment of established periodontitis with RvE1 reversed bone loss, reversed inflammatory gene expression, and reduced osteoclast density. Assessment of the rat subgingival microbiota after RvE1 treatment revealed marked changes in both prevention and treatment experiments. The data suggest that modulation of local inflammation has a major role in shaping the composition of the subgingival microbiota.
Assuntos
Disbiose/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Inflamação/tratamento farmacológico , Periodontite/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/uso terapêutico , Inflamação/genética , Masculino , Ratos , Ratos WistarRESUMO
Periodontal health is defined by absence of clinically detectable inflammation. There is a biological level of immune surveillance that is consistent with clinical gingival health and homeostasis. Clinical gingival health may be found in a periodontium that is intact, i.e. without clinical attachment loss or bone loss, and on a reduced periodontium in either a non-periodontitis patient (e.g. in patients with some form of gingival recession or following crown lengthening surgery) or in a patient with a history of periodontitis who is currently periodontally stable. Clinical gingival health can be restored following treatment of gingivitis and periodontitis. However, the treated and stable periodontitis patient with current gingival health remains at increased risk of recurrent periodontitis, and accordingly, must be closely monitored. Two broad categories of gingival diseases include non-dental plaque biofilm-induced gingival diseases and dental plaque-induced gingivitis. Non-dental plaque biofilm-induced gingival diseases include a variety of conditions that are not caused by plaque and usually do not resolve following plaque removal. Such lesions may be manifestations of a systemic condition or may be localized to the oral cavity. Dental plaque-induced gingivitis has a variety of clinical signs and symptoms, and both local predisposing factors and systemic modifying factors can affect its extent, severity, and progression. Dental plaque-induced gingivitis may arise on an intact periodontium or on a reduced periodontium in either a non-periodontitis patient or in a currently stable "periodontitis patient" i.e. successfully treated, in whom clinical inflammation has been eliminated (or substantially reduced). A periodontitis patient with gingival inflammation remains a periodontitis patient (Figure 1), and comprehensive risk assessment and management are imperative to ensure early prevention and/or treatment of recurrent/progressive periodontitis. Precision dental medicine defines a patient-centered approach to care, and therefore, creates differences in the way in which a "case" of gingival health or gingivitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys. Thus, case definitions of gingival health and gingivitis are presented for both purposes. While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing. Here we classify gingival health and gingival diseases/conditions, along with a summary table of diagnostic features for defining health and gingivitis in various clinical situations.