Caroline Addison Carvalho Xavier de Medeiros

Effect of telmisartan on levels of IL-1, TNF-α, down-regulated COX-2, MMP-2, MMP-9 and RANKL/RANK in an experimental periodontitis model.

Aim The aim of this study was to evaluate the effect of telmisartan (TELM) on inflammation, oxidation and the expression of matrix metalloproteinases (MMPs) and the expression RANKL/RANK/OPG in the periodontal tissue of a rat model for ligature-induced periodontitis. Materials and methods Male Wistar albino rats were randomly divided into five groups of 10 rats each: (i) non-ligated, given water; (ii) ligated, given water; (iii) ligated, given 1 mg/kg TELM; (iv) ligated, given 5 mg/kg TELM; and (v) ligated, given 10 mg/kg TELM. All groups were treated with saline or TELM for 10 days. Periodontal tissue was analysed by histopathology; by the immunohistochemical examination of COX-2, MMP-2, MMP-9 and the RANKL/RANK/OPG pathway; and by ELISA analysis of the levels of IL-1β, IL-10, TNF-α, myeloperoxidase (MPO), malonaldehyde (MDA) and glutathione (GSH). Results Treatment with 10 mg/kg TELM resulted in reduced concentrations of MPO, MDA (p < 0.05) and the pro-inflammatory cytokine IL-1β (p < 0.05); reduced expression of MMP-2, MMP-9, RANK, RANKL and COX-2; and an increase in OPG. The levels of TNF-α were significantly reduced in all TELM-treated groups. Conclusions These findings confirm the involvement of TELM in reducing the inflammatory response, oxidative stress and bone loss in ligature-induced periodontitis in rats.

Carvedilol decrease IL-1β and TNF-α, inhibits MMP-2, MMP-9, COX-2, and RANKL expression, and up-regulates OPG in a rat model of periodontitis.

Periodontal diseases are initiated primarily by Gram-negative, tooth-associated microbial biofilms that elicit a host response that causes osseous and soft tissue destruction. Carvedilol is a β-blocker used as a multifunctional neurohormonal antagonist that has been shown to act not only as an anti-oxidant but also as an anti-inflammatory drug. This study evaluated whether Carvedilol exerted a protective role against ligature-induced periodontitis in a rat model and defined how Carvedilol affected metalloproteinases and RANKL/RANK/OPG expression in the context of bone remodeling. Rats were randomly divided into 5 groups (n = 10/group): (1) non-ligated (NL), (2) ligature-only (LO), and (3) ligature plus Carvedilol (1, 5 or 10 mg/kg daily for 10 days). Periodontal tissue was analyzed for histopathlogy and using immunohistochemical analysis characterized the expression profiles of MMP-2, MMP-9, COX-2, and RANKL/RANK/OPG and determined the presence of IL-1β, IL-10 and TNF-α, myeloperoxidase (MPO), malonaldehyde (MDA) and, glutathione (GSH). MPO activity in the group with periodontal disease was significantly increased compared to the control group (p<0.05). Rats treated with 10 mg/kg Carvedilol presented with significantly reduced MPO and MDA concentrations (p<0.05) in addition to presenting with reduced levels of the pro-inflammatory cytokines IL-1 β and TNF-α (p<0.05). IL-10 levels in Carvedilol-treated rats remained unaltered. Immunohistochemical analysis demonstrated reduced expression of MMP-2, MMP-9, RANK, RANKL, COX-2, and OPG in rats treated with 10 mg/kg Carvedilol. This study demonstrated that Carvedilol affected bone formation/destruction and anti-inflammatory activity in a rat model of periodontitis.

Olmesartan decreased levels of IL-1β and TNF-α, down-regulated MMP-2, MMP-9, COX-2, RANK/RANKL and up-regulated SOCs-1 in an intestinal mucositis model.

Methotrexate (MTX) is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukaemia and other malignancies. The efficacy of methotrexate is often limited by mucositis and intestinal injury, which are major causes of morbidity in children and adults. The aim of this study was to evaluate the effect of olmesartan (OLM), an angiotensin II receptor antagonist, on an Intestinal Mucositis Model (IMM) induced by MTX in Wistar rats. IMM was induced via intraperitoneal (i.p.) administration of MTX (7 mg/kg) for three consecutive days. The animals were pre-treated with oral OLM at 0.5, 1 or 5 mg/kg or with vehicle 30 min prior to exposure to MTX. Small intestinal homogenates were assayed for levels of the IL-1β, IL-10 and TNF-α cytokines, malondialdehyde and myeloperoxidase activity. Additionally, immunohistochemical analyses of MMP-2, MMP-9, COX-2, RANK/RANKL and SOCS-1 and confocal microscopy analysis of SOCS-1 expression were performed. Treatment with MTX + OLM (5 mg/kg) resulted in a reduction of mucosal inflammatory infiltration, ulcerations, vasodilatation and haemorrhagic areas (p<0.05) as well as reduced concentrations of MPO (p<0.001) and the pro-inflammatory cytokines IL-1β (p<0.001) and TNF-a (p<0.01), and increase anti-inflammatory cytocine IL-10 (p<0.05). Additionally, the combined treatment reduced expression of MMP-2, MMP-9, COX-2, RANK and RANKL(p<0.05) and increased cytoplasmic expression of SOCS-1 (p<0.05). Our findings confirm the involvement of OLM in reducing the inflammatory response through increased immunosuppressive signalling in an IMM. We also suggest that the beneficial effect of olmesartan treatment is specifically exerted during the damage through blocking inflammatory cytocines.

Azilsartan increases levels of IL-10, down-regulates MMP-2, MMP-9, RANKL/RANK, Cathepsin K and up-regulates OPG in an experimental periodontitis model.

Aims The aim of this study was to evaluate the effects of azilsartan (AZT) on bone loss, inflammation, and the expression of matrix metallo proteinases (MMPs), receptor activator of nuclear factor κB ligand (RANKL), receptor activator of nuclear factor κB (RANK), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2), and cathepsin K in periodontal tissue in a rat model of ligature-induced periodontitis. Materials and Methods Male Wistar albino rats were randomly divided into 5 groups of 10 rats each: (1) nonligated, water; (2) ligated, water; (3) ligated, 1 mg/kg AZT; (4) ligated, 5 mg/kg AZT; and (5) ligated, 10 mg/kg AZT. All groups were treated with saline or AZT for 10 days. Periodontal tissues were analyzed by histopathology and immunohistochemical detection of MMP-2, MMP-9, COX-2, RANKL, RANK, OPG, and cathepsin K. Levels of IL-1β, IL-10, TNF-α, myeloperoxidase (MPO), and glutathione (GSH) were determined by ELISA. Results Treatment with 5 mg/kg AZT resulted in reduced MPO (p<0.05) and IL-1β (p<0.05), increased levels of IL-10 (p<0.05), and reduced expression of MMP-2, MMP-9, COX-2, RANK, RANKL, cathepsin K, and increased expression of OPG. Conclusions These findings reveal that AZT increases anti-inflammatory cytokines and GSH and decreases bone loss in ligature-induced periodontitis in rats.

Quality of Life, Family Support, and Comorbidities in Institutionalized Elders With and Without Symptoms of Depression

The institutionalization of elders can decrease the health status and quality of life in this population. The aim of this study was to analyze the socio-demographic, quality of life, family support, and comorbidities variables in institutionalized elders with and without symptoms of depression. This was a cross-sectional study in institutions for long permanence for the elderly in the State of Rio Grande do Norte, Brazil. Two institutionalized elderly groups were compared (138 elders: 69 with and 69 without depressive symptoms). The instruments used were: mini-mental state examination, geriatric depression scale in the reduced version, socio-demographic questionnaire, quality of life (World Health Organization Quality of Life abbreviated-WHOQOL-bref), and inventory of perception of family support. Elders with depressive symptoms had inferior quality of life than those without depressive symptoms. Other factors that negatively influenced the quality of life in this population include: low economic conditions, occurrence of comorbidities, and deficient family assistance. These results have important implications in the decision making process with regard to strategies for improving the health status of institutionalized elders.

Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis

Aim To evaluate the effects of metformin (Met) on inflammation, oxidative stress, and bone loss in a rat model of ligature-induced periodontitis. Materials & methods Male albino Wistar rats were divided randomly into five groups of twenty-one rats each, and given the following treatments for 10 days: (1) no ligature + water, (2) ligature + water, (3) ligature + 50 mg/kg Met, (4) ligature + 100 mg/kg Met, and (5) ligature + 200 mg/kg Met. Water or Met was administered orally. Maxillae were fixed and scanned using Micro-computed Tomography (μCT) to quantitate linear and bone volume/tissue volume (BV/TV) volumetric bone loss. Histopathological characteristics were assessed through immunohistochemical staining for MMP-9, COX-2, the RANKL/RANK/OPG pathway, SOD-1, and GPx-1. Additionally, confocal microscopy was used to analyze osteocalcin fluorescence. UV-VIS analysis was used to examine the levels of malondialdehyde, glutathione, IL-1β and TNF-α from gingival tissues. Quantitative RT-PCR reaction was used to gene expression of AMPK, NF-κB (p65), and Hmgb1 from gingival tissues. Significance among groups were analysed using a one-way ANOVA. A p-value of p<0.05 indicated a significant difference. Results Treatment with 50 mg/kg Met significantly reduced concentrations of malondialdehyde, IL-1β, and TNF-α (p < 0.05). Additionally, weak staining was observed for COX-2, MMP-9, RANK, RANKL, SOD-1, and GPx-1 after 50 mg/kg Met. OPG and Osteocalcin showed strong staining in the same group. Radiographically, linear measurements showed a statistically significant reduction in bone loss after 50 mg/kg Met compared to the ligature and Met 200 mg/kg groups. The same pattern was observed volumetrically in BV/TV and decreased osteoclast number (p<0.05). RT-PCR showed increased AMPK expression and decreased expression of NF-κB (p65) and HMGB1 after 50 mg/kg Met. Conclusions Metformin, at a concentration of 50 mg/kg, decreases the inflammatory response, oxidative stress and bone loss in ligature-induced periodontitis in rats.

Protective effect of dexamethasone on 5-FU-induced oral mucositis in hamsters

Oral mucositis (OM) is an important side effect of cancer treatment, characterized by ulcerative lesions in the mucosa of patients undergoing radiotherapy or chemotherapy, which has marked effects on patient quality of life and cancer therapy continuity. Considering that few protocols have demonstrated efficacy in preventing this side effect, the aim of this study was to examine the effect of dexamethasone (DEX) on OM induced by 5-fluorouracil (5-FU) in hamsters by studying signaling pathways. OM was induced in hamsters by 5-FU followed by mechanical trauma (MT) on day 4. On day 10, the animals were euthanized. The experimental groups included saline, MT, 5-FU, and DEX (0.25, 0.5, or 1 mg/kg). Macroscopic, histopathological, and immunohistochemical analyses as well as immunofluorescence experiments were performed on the oral mucosa of the animals. The oral mucosal samples were analyzed by enzyme-linked immunosorbent assays, and quantitative real-time polymerase chain reaction (qPCR). DEX (0.5 or 1 mg/kg) reduced inflammation and ulceration of the oral mucosa of hamsters. In addition, DEX (1 mg/kg) reduced the cytokine levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and macrophage migration inhibitory factor (MIF). DEX (1 mg/kg) also reduced the immunoexpression of cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-2, transforming growth factor (TGF)-β, MIF, Smad 2/3, Smad 2/3 phosphorylated and NFκB p65 in the jugal mucosa. Finally, DEX (1 mg/kg) increased interleukin-1 receptor-associated kinase 3 (IRAK-M), glucocorticoid-induced leucine zipper (GILZ), and mitogen-activated protein kinase (MKP1) gene expression and reduced NFκB p65 and serine threonine kinase (AKt) gene expression, relative to the 5-FU group. Thus, DEX improved OM induced by 5-FU in hamsters.

Telmisartan Modulates the Oral Mucositis Induced by 5-Fluorouracil in Hamsters

Oral mucositis (OM) is a common adverse effect resulting from cancer therapy. The OM it has implications that may compromise oncologic treatment and decrease the patient’s quality of life. The therapeutic options to prevent or treat the symptoms of OM are scarce; there is no effective therapy that improves the symptoms. Based on the need for further research for the treatment of OM, the present study objective was to evaluate the effect of telmisartan (TELM) on the OM induced by 5-fluorouracil (5-FU), using as animal model Golden Syrian hamsters. 5-FU followed by mechanical trauma on day 4 was used to induce OM in hamsters. Euthanasia occurred on the day 10. The experiments were constituted by the groups saline, mechanical trauma, 5-FU, and TELM in three doses (1, 5, or 10 mg/kg). Macroscopic, histopathological, and immunohistochemical analyses as well as immunofluorescence experiments were performed on the oral mucosa of the animals. The samples also were used for analysis enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reactions (qPCR). TELM (5 or 10 mg/kg) was able to reduce the inflammatory ulceration and infiltration in the oral mucosa of the animals, decreasing the levels of the cytokines TNF-α and IL-1β. These treatments was minimize the immunostaining for cyclooxygenase-2, matrix metalloproteinase-9, transforming growth factor-β, and smad 2/3. The nuclear transcription factor kappa B (NFκB) p65 and inducible nitric oxide synthase were reduced in the oral mucosa. Finally, TELM (10 mg/kg) increased the PPARγ gene expression and reduced STAT1 and NFκB p65 gene expression relative to the 5-FU group. Therefore, TELM prevents the OM produced by 5-FU on animal model.