Diabetes and Increased Lipid Peroxidation are Associated with Systemic Inflammation Even in Well-Controlled Patients

Background The effect of the interaction between type 2 diabetes and dyslipidemia on inflammation and lipid peroxidation (LPO) has not been assessed. Aim To investigate whether diabetes coupled with dyslipidemia alters oxidative metabolism leading to increased LPO products and inflammatory status. Methods 100 patients were divided into four groups based upon diabetic and dyslipidemic status: poorly controlled diabetes with dyslipidemia (DM-PC/D), well-controlled diabetes with dyslipidemia (DM-WC/D), normoglycemic individuals with dyslipidemia (NG/D), and normoglycemic individuals without dyslipidemia (NG/ND). Plasma was evaluated for an LPO product (MDA), antioxidant levels and inflammatory cytokines. Results Diabetics presented significantly higher levels of LPO (p \u3c 0.05) and the DM-PC/D had higher levels of proinflammatory cytokines and MDA in the plasma in comparison with normoglycemics (p \u3c 0.05). Interestingly IL1-β, IL-6, and TNF-α in DM-WC/D were not statistically different from those in DM-PC/D. Normoglycemic individuals with dyslipidemia presented significantly increased levels of IL-6 and TNF-α when compared to normoglycemic without dyslipidemia (p \u3c 0.05). MDA levels were also positively correlated with the presence of DM complications (r = 0.42, p \u3c 0.01). Conclusions These findings show that dyslipidemia is associated with an increased inflammatory status, even in well-controlled diabetics and in normoglycemics. Our results suggest that lipid metabolism and peroxidation are important for the development of inflammation, which is elevated in several complications associated with diabetes

Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB

Objective: The aim of this study was to evaluate a possible synergism between AGE-RAGE and TLR4 signaling and the role of p38 MAPK and NF-kB signaling pathways on the modulation of the expression of inflammatory cytokines and proliferation of cells from the innate and adaptive immune response. Material and Methods: T lymphocyte (JM) and monocyte (U937) cell lines were stimulated with LPS and AGE-BSA independently and associated, both in the presence and absence of p38 MAPK and NF-kB inhibitors. Proliferation was assessed by direct counting and viability was assessed by a biochemical assay of mitochondrial function. Cytokine gene expression for RAGe, CCL3, CCR5, IL-6 and TNF-α was studied by RT-PCR and RT-qPCR. Results: RAGE mRNA expression was detected in both cell lines. LPS and AGE-BSA did not influence cell proliferation and viability of either cell line up to 72 hours. LPS and LPS associated with AGE induced expression of IL-6 and TNF-α in monocytes and T cells, respectively. Conclusions: There is no synergistic effect between RAGE and TLR signaling on the expression of IL-6, TNF-α , RAGE, CCR5 and CCL3 by monocytes and lymphocytes. Activation of RAGE associated or not with TLR signaling also had no effect on cell proliferation and survival of these cell types

Avaliação da correlação entre peroxidação lipídica e o perfil de marcadores inflamatórios em pacientes com Diabetes mellitus tipo 2, dislipidemia e periodontite crônica

O presente estudo teve por objetivo avaliar os níveis locais e sistêmicos de peroxidação lipídica (LPO) e sua correlação com o perfil de marcadores inflamatórios, locais e sistêmicos em com Diabetes mellitus (DM) tipo 2, dislipidemia e periodontite crônica, comparando-os a indivíduos sem diabetes. Além disso, buscou-se propor um método validado para avaliar o malondiadeído (MDA) no fluido sulcular gengival de sítios saudáveis e doentes. A amostra foi constituída de 120 pacientes com doença periodontal crônica divididos em 4 grupos: Grupo1 (DM descompensado); Grupo2 (DM compensado); Grupo3 (sem diabetes com dislipidemia); Grupo 4 (sistemicamente saudável). Toda a amostra foi submetida a exame periodontal completo, exame físico e avaliação laboratorial para verificação da glicemia de jejum, hemoglobina glicada (HbA1c), insulina, proteína C-reativa e perfil lipídico. O exame periodontal consistiu na avaliação do índice de placa visível, do índice de sangramento marginal, da posição da margem gengival, da profundidade de sondagem, do sangramento à sondagem e do nível clínico de inserção. Para todos os grupos foram coletadas amostras de fluido sulcular gengival (FSG) (4 sítios sem periodontite e 4 sítios com periodontite) e de sangue para obtenção do plasma sanguíneo. Os níveis de peroxidação lipídica representados pelo MDA, avaliado por HPLC, e pelo LDL oxidado (LDLox), avaliado por ELISA, foram quantificados no fluido sulcular gengival e no plasma. Foram avaliadas ainda as citocinas (IL)-1, -2, - 4, -5, -6, -7, -8, -10, -12, -13 e fator de necrose tumoral α (TNF-α) no FSG e no plasma. Foi possível determinar e validar o método de avaliação no fluido sulcular gengival, com alta precisão, sendo que os coeficientes...The aim of this study is to evaluate the levels of the lipid peroxidation and its correlation with systemic and local inflammatory markers profile in patients with type 2 diabetes mellitus (DM2) dyslipidemia and chronic periodontitis compared to systemically healthy patients. We also aimed to quantify a specific product of the lipid peroxidation process, malondialdehyde (MDA), in gingival crevicular fluid and to describe the validation of this method in this matrix using HPLC. The study sample comprised 120 patients divided into four groups with 30 patients in each group: group 1- diabetes with poor metabolic control with dyslipidemia, group 2- diabetes with good metabolic control, group 3- without diabetes with dyslipidemia and group 4- systemically healthy. All the subjects will go through a complete periodontal examination and physical and laboratory evaluation in order to verify fasting plasma glucose, glycated hemoglobin (HbA1c), lipid profile, insulin and high sensitivity C-reactive protein. Periodontal examination will consist of visible plaque index, gingival bleeding index, bleeding on probing, probing depth (PD) and clinical attachment levels (CAL). Plasma and samples of gingival crevicular fluid (GCF) will be collected in 4 sites without periodontal disease and 4 sites with periodontal disease. The lipid peroxidation levels, evaluated by oxidized LDL (ox LDL) and MDA were measured in GCF and in plasma. Inflammatory cytokines, (IL)-1, -2, -4, -5, -6, -7, -8, -10, -12, -13 and tumor necrosis factor-alpha α (TNF-α) were also evaluated in plasma and GCF. It was possible to validate a HPLC-based method to identify and quantify the MDA in GCF with sensitivity, precision, and accuracy even in small concentrations as observed in healthy... (Complete abstract click electronic access below)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Is rheumatoid arthritis a risk factor for oral bisphosphonate-induced osteonecrosis of the jaws?

Bisphosphonate-related osteonecrosis of the jaws is a relevant side-effect of these drugs that has been generating a great concern through increasing reports, worldwide, of this bone necrosis. Among several BRONJ hypothetical co-factors that could play a role in BRONJ pathogenesis, rheumatoid arthritis (RA) has been included as a relevant risk factor for BRONJ; however, until now the relationship between these diseases has not been fully explained. Thus, the purpose of this paper is to establish hypothetical factors that could link these two diseases, considering mainly inflammatory components and the organism effects of medicines used to treat RA, particularly steroids and methotrexate (MTX). (C) 2011 Elsevier Ltd. All rights reserved

Implantes dentais em pacientes com diabetes mellitus

Dental implants represent a great improvement in Dentistry in respect to rehabilitation of edentulous ridges due to the functional and aesthetic reestablishment with long-term predictability and success. However, the effectiveness of this treatment relies on successful osseointegration during the healing period. In this way, the applicability of dental implants in patients with diabetes mellitus (DM) remains controversial, by the fact that the hyperglycemic status presents a negative effect on the osseointegration. It is not clear yet if the therapy with dental implants is an absolute contraindication to these patients. For this reason, the aim of the present study is to review the literature about the treatment with dental implants in patients with diabetes and to propose a protocol to perform dental implants in patients with diabetes. Diabetes has been considered a relative contraindication to dental implants, as the patients with adequate metabolic control can be treated with this kind of therapy, because inadequate metabolic control can lead to the failure of the treatment. Besides, there are risk factors for the diabetic implant patient that may decrease the success rates of dental implants therapy. In this way, the dentist should understand all the relevant implications before considering the indication of dental implants to patients with diabetes. It is important to have more controlled studies to evaluate the effects of diabetes on the implant-tissue interface and further investigations are necessary in order to elucidate the role of insulin and molecular mechanisms that might interfere on the osseointegration in patients with diabetes.Os implantes osseointegráveis representam um grande avanço da Odontologia, no que diz respeito à reabilitação de áreas edêntulas, uma vez que permite o restabelecimento estético-funcional com previsibilidade e sucesso em longo prazo. No entanto, a efetividade deste tratamento depende do processo de osseointegração, sendo consequentemente dependente do estado de saúde geral do paciente. Sob esse aspecto, a aplicabilidade de implantes em indivíduos portadores de diabetes mellitus (DM) permanece controversa, uma vez que o estado hiperglicêmico pode representar um fator negativo para a osseointegração, conduzindo ao insucesso do tratamento. Além disso, existem fatores de risco inerentes ao diabetes que podem aumentar as taxas de insucesso na terapia com implantes dentários, permanecendo a dúvida se o diabetes seria uma contraindicação absoluta a este tipo de terapia. Dessa forma, o diabetes tem sido considerado uma contraindicação relativa para realização de implantes dentários, de modo que pacientes com controle metabólico adequado são considerados aptos a este tipo de tratamento. Em função desses questionamentos, foi realizada uma revisão da literatura sobre a aplicabilidade de implantes dentais em portadores de diabetes

Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB

Objective: The aim of this study was to evaluate a possible synergism between AGE-RAGE and TLR4 signaling and the role of p38 MAPK and NF-kB signaling pathways on the modulation of the expression of inflammatory cytokines and proliferation of cells from the innate and adaptive immune response. Material and Methods: T lymphocyte (JM) and monocyte (U937) cell lines were stimulated with LPS and AGE-BSA independently and associated, both in the presence and absence of p38 MAPK and NF-kB inhibitors. Proliferation was assessed by direct counting and viability was assessed by a biochemical assay of mitochondrial function. Cytokine gene expression for RAGE, CCL3, CCR5, IL-6 and TNF-alpha was studied by RT-PCR and RT-qPCR. Results: RAGE mRNA expression was detected in both cell lines. LPS and AGE-BSA did not influence cell proliferation and viability of either cell line up to 72 hours. LPS and LPS associated with AGE induced expression of IL-6 and TNF-alpha in monocytes and T cells, respectively. Conclusions: There is no synergistic effect between RAGE and TLR signaling on the expression of IL-6, TNF-alpha, RAGE, CCR5 and CCL3 by monocytes and lymphocytes. Activation of RAGE associated or not with TLR signaling also had no effect on cell proliferation and survival of these cell types.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Doença periodontal em pacientes com Diabetes Mellitus: influência de polimorfismos genéticos?

Currently it is clear that there are several factors that can act as modifiers of diseases, without causing them directly, but having the potential to make these conditions to progress faster and more severe. There is a growing number of studies investigating the relationship between Diabetes Mellitus (DM) and Periodontal Disease (PD), including some studies focusing on the influence of genetic factors in this process. The aim of this study was to verify through a literature review, the influence of genetic polymorphisms in the development of PD in patients with DM. PubMed and BIREME were used as databases and the terms Periodontitis or Periodontal Disease, Polymorphism, Diabetes Mellitus were searched. After a refinement in the literature, five studies were selected and they were related to chronic PD with DM and polymorphisms in cytokine genes, especially interleukin 1 (IL1) e IL6. Polymorphisms were associated with a higher concentration of pro-inflammatory cytokines in the gingival crevicular fluid of diabetic patients when compared to non-diabetic. In conclusion, it is necessary to confirm this association with longitudinal studies that must investigate a larger number of cytokine genes in order to understand the cause-effect relationship between genetic polymorphisms, DM and PD.Nos últimos anos, evidenciou-se que, em muitas patologias, há fatores que não causam diretamente a doença, mas podem modificá-la, tornando o quadro clínico mais grave e a progressão mais rápida. Observa-se um número crescente de estudos investigando a relação entre Diabetes Mellitus (DM) e Doença Periodontal (DP), com alguns enfoques sobre a influência de fatores genéticos nesse processo. Existem polimorfismos genéticos cuja expressão está associada a fatores de risco. Portanto, para que as variantes genéticas afetem a severidade da doença ou a incidência de forma significativa, os polimorfismos genéticos devem agir cumulativamente ou pela interação com outros fatores, como a presença do diabetes. O objetivo deste estudo foi verificar, por meio de revisão sistemática da literatura, a influência de polimorfismos genéticos no perfil inflamatório da DP em pacientes com diabetes. Foram utilizadas as bases de dados BIREME e PubMed com os termos Periodontitis ou Periodontal disease, Polymorphism e Diabetes Mellitus. Realizando-se um refinamento na pesquisa bibliográfica, foram selecionados cinco referências que relacionavam DP crônica com DM e polimorfismos em genes de citocinas, especialmente Interleucina 1 (IL1) e IL6. Estudos associaram a presença de polimorfismos em pacientes portadores de diabetes à maior concentração de citocinas pró-inflamatórias no fluido gengival, quando comparados a pacientes sem diabetes. Conclui-se que, para confirmar essa associação, é necessária a realização de estudos longitudinais, investigando um maior número de genes para compreender melhor as relações causa-efeito entre polimorfismos genéticos, DM e DP

Modulation of Immune Response by RAGE and TLR4 Signalling in PBMCs of Diabetic and Non-Diabetic Patients

Diabetes is associated with increased glucose levels and accumulation of glycated products. It is also associated with impairment in the immune response, such as increased susceptibility to infections. In this study, we assessed the possible interactions between TLR4 and RAGE signalling on apoptosis and on the expression of inflammatory cytokines in PBMC from individuals with and without diabetes. PBMCs were isolated from seven diabetic patients and six individuals without diabetes and stimulated in vitro with bacterial LPS (1 μg/ml) associated or not with BSA-AGE (200 μg/ml). This stimulation was performed for 6 h, both in the presence and in the absence of inhibitors of TLR4 (R. sphaeroides LPS, 20 μg/ml) and RAGE (blocking monoclonal antibody). Apoptosis at early and late stages was assessed by the annexin-V/PI staining using flow cytometry. Regulation of TNF-α and IL-10 gene expression was determined by RT-qPCR. PBMCs from diabetes patients tended to be more resistant apoptosis. There were no synergistic or antagonistic effects with the simultaneous activation of TLR4 and RAGE in PBMCs from either diabetes or non-diabetes group. Activation of TLR4 is more potent for the induction of TNF-α and IL-10; RAGE signalling had a negative regulatory effect on TNF-α expression induced by LPS. TLR and RAGE do not have relevant roles in apoptosis of PBMCs. The activation of TLR has greater role than RAGE in regulating the gene expression of IL-10 and TNF-α.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP