Modulating the sEH/EETs Axis Restrains Specialized Proresolving Mediator Impairment and Regulates T Cell Imbalance in Experimental Periodontitis.

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.

Soluble epoxide hydrolase inhibition enhances production of specialized pro-resolving lipid mediator and promotes macrophage plasticity.

BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFA) are lipid mediators that are rapidly inactivated by soluble epoxide hydrolase (sEH). Uncontrolled and chronic inflammatory disorders fail to sufficiently activate endogenous regulatory pathways, including the production of specialized pro-resolving mediators (SPMs). Here, we addressed the relationship between SPMs and the EET/sEH axis and explored the effects of sEH inhibition on resolving macrophage phenotype. EXPERIMENTAL APPROACH: Mice were treated with a sEH inhibitor, EETs, or sEH inhibitor + EETs (combination) before ligature placement to induce experimental periodontitis. Using RT-qPCR, gingival samples were used to examine SPM receptors and osteolytic and inflammatory biomarkers. Maxillary alveolar bone loss was quantified by micro-CT and methylene blue staining. SPM levels were analysed by salivary metabolo-lipidomics. Gingival macrophage phenotype plasticity was determined by RT-qPCR and flow cytometry. Effects of sEH inhibition on macrophage polarization and SPM production were assessed with bone marrow-derived macrophages (BMDMs). KEY RESULTS: Pharmacological inhibition of sEH suppressed bone resorption and the inflammatory cytokine storm in experimental periodontitis. Lipidomic analysis revealed that sEH inhibition augmented levels of LXA4, RvE1, RvE2, and 4-HDoHE, concomitant with up-regulation of LTB4R1, CMKLR1/ChemR23, and ALX/FPR2 SPM receptors. Notably, there is an impact on gingival macrophage plasticity was affected suggesting an inflammation resolving phenotype with sEH inhibition. In BMDMs, sEH inhibition reduced inflammatory macrophage activation, and resolving macrophages were triggered to produce SPMs. CONCLUSION AND IMPLICATIONS: Pharmacological sEH inhibition increased SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders.

High doses of zoledronic acid induce differential effects on femur and jawbone microstructure.

OBJECTIVES: The aim of this study is to investigate the long-term effects on jaw and femur bone induced by oncologic doses of zoledronic acid in a young rat model. MATERIAL AND METHODS: Six 12-week-old male Wistar rats received zoledronic acid (0.6 mg/kg) and six control rats received saline solution in the same volume. Compounds were administered intraperitoneally in five doses every 28 days. Euthanasia was performed 150 days after therapy onset. After animal sacrifice, their mandibles and femurs were scanned ex vivo using a high-resolution (14 µm) micro-computed tomography. Morphometric bone parameters were calculated using CT-Analyzer (Bruker, Belgium) between the first and second mandibular molars and in the distal femur metaphysis and epiphysis. RESULTS: The treatment group as compared to the controls showed a significantly (p < .05) increased bone quantity (↑BV/TV, ↓Po[Tot], ↑Tb.Th), bone density (↑TMD, ↑BMD), and osteosclerosis of the trabecular bone (↓Tb.Sp, ↓Conn.Dn, ↓Tb.Pf, ↓SMI) in all anatomical sites. Bone remodeling suppression due to zoledronic acid treatment was more pronounced (p < .05) in the femoral metaphysis relative to the mandible and epiphysis. The exploratory linear discriminant analysis showed that for the mandible, it was mainly the bone quantity-related morphometric indices (BV/TV and Tb.Th), while for the femoral epiphysis and metaphysis, it was bone structure-related (Tb.Pf and Tb.N), which are of primary importance to study the treatment effect. CONCLUSION: High doses of bisphosphonates can differently affect the bone quantity, density, and structure in long bones and jawbones. In the metaphysis, bone changes were primarily concentrated in the region of the growth plate. Future studies may consider the use of bone morphometric indices to evaluate the effect of bisphosphonates.

Tomographic study of Jaw bone changes in patients with bisphosphonate-related osteonecrosis.

BACKGROUND: Bisphosphonates (BP) are synthetic pyrophosphate-like substances with antiresorptive properties and specifically affect osteoclastic activity. In 2007, the American Association of Oral and Maxillofacial Surgeons (AAOMS) defined diagnostic criteria for Osteonecrosis of the Jaws Associated with Bisphosponates (BRONJ). BRONJ is mainly diagnosed by clinical features, but the detection of early bone changes by imaging may help prevent and better understand the disease. The objective of this study was to evaluate maxillary changes in CBCT in patients using BP. MATERIAL AND METHODS: All included patients were diagnosed with osteonecrosis and received bisphosphonate drugs in the last ten years. All imaging examinations were obtained by I-CAT and 3D Accuitomo. The multiplanar reconstructions were analyzed by an examiner without knowledge of the clinical aspects and location of the lesions. RESULTS: The study sample consisted of 21 patients, the majority of the sample represented patients with cancer (76.2%), the other patients had osteoporosis (23.8%). Only four patients (19.04%) received alendronate, while intravenous bisphosphonates, such as zoledronate and pamidronate, represented the treatment of most of our sample. Most of our patients presented stage 1 and 2 MRONJ (85.7%), whose lesions were mainly observed in the mandible (52.4%). Fifty-seven percent of the patients had at least one bone change. CONCLUSIONS: In BRONJ, bone changes vary between exposed and non-exposed areas and one aspect of the study was: persistent extraction cavities in the BRONJ lesion region and high frequency of periodontal ligament space widening in areas that are not involved in BRONJ lesions. This reflects the very important role of dental and periodontal diseases in the pathophysiology of BRONJ. Thus, preventive measures should be prioritized for patients exposed to anti-resorptive drugs. Key words:Cone-Beam computed tomography, osteonecrosis, bisphosphonate-associated osteonecrosis of the jaw.

Auditing of the prescription of antimicrobials in a dental school: perspective to rational use / Auditoria da prescrição de antibacterianos em uma faculdade de odontologia: perspectiva para o uso racional

Objective: To audit the prescriptions of antimicrobials in the School of Dentistry of the Federal University of Goiás in order to identify the most prescribed ones, which doses were used for prophylactic and therapeutic measures and the patients' clinical pictures that justified the prescriptions. Methods: From the patients' records and prescriptions the following information was collected: prescribed antibiotic; dose; duration of treatment; patients' clinical pictures and medical histories; dental clinic where the patient was treated and clinical procedure performed. Results: Seven hundred and eighteen patients' records were analyzed and 180 antimicrobial prescriptions were identified. The results showed that the Emergency Clinic was responsible for the highest number of prescriptions. When we consider the type of antimicrobial prescribed, the amoxicillin, amoxicillin in association with clavulanate acid or in association with metronidazole represent the majority of the prescriptions. Conclusion: The treatment of dentistry emergencies was responsible for the highest number of prescriptions and amoxicillin was the most prescribed antibiotic. Variations regarding duration of treatment and the moment of the prescription were identified.

Objetivo: O objetivo deste estudo foi avaliar as prescrições de antibacterianos na Faculdade de Odontologia da Universidade Federal de Goiás para identificar os medicamentos mais prescritos, as doses utilizadas para medidas profiláticas e terapêuticas e as indicações clínicas que justificaram a prescrição. Material e método: As seguintes informações foram extraídas dos prontuários odontológicos e prescrições dos pacientes: antibiótico prescrito, dose, duração do tratamento, indicação clínica e o procedimento clínico realizado. Resultados: Setecentos e dezoito prontuários foram analisados e 180 prescrições de antibacterianos foram identificadas. Os resultados mostraram que a Clínica de Emergência emitiu o maior número de prescrições. Quando consideramos o tipo de antibacteriano, a amoxicilina, amoxicilina em associação com ácido clavulanato ou em associação com o metronidazol, corresponderam a maior parte das prescrições. Conclusões: A maioria das prescrições ocorreu no tratamento de emergências odontológicas e amoxicilina foi o antibacteriano mais prescrito. Foram identificadas variações na duração do tratamento e no momento da prescrição.