Molecular docking study and antireabsorptive activity of a semi-synthetic coumarin derivative from Platymiscium floribundum in the ligature-induced periodontitis in rats: the involvement of heme oxygenase-1.

OBJETIVE: This study aimed to evaluate the anti-resorptive activity of a semi-synthetic coumarin derivative from Platymiscium floribundum, named 6,7-dimethoxy-3-nitrocoumarin. MATERIAL AND METHODS: Molecular docking studies were performed to test the binding performance of the derivative against targets associated with alveolar bone loss (TNF-α, IL-1ß, and catalase) and a target considered an antioxidant defense (HO-1) during periodontitis. Periodontitis was induced by placing a nylon ligature around the second molars. The rats received for 11 days 6,7-dimethoxy-3-nitrocoumarin (0.01, 0.1, or 1 mg/kg) or vehicle. We investigated by RT-qPCR analysis (TNF-α, IL-1ß, and HO-1 mRNA expression levels) and by colorimetric assay (catalase activity) the mechanism of action mediated by 6,7-dimethoxy-3-nitrocoumarin. The in vivo toxicity of 6,7-dimethoxy-3-nitrocoumarin was evaluated. RESULTS: 6,7-Dimethoxy-3-nitrocoumarin (0.1 or 1 mg/kg) reduced alveolar bone loss (1.05 ± 0.24), when compared to vehicle-treated group (3.05 ± 0.30). The interactions of 6,7-dimethoxy-3-nitrocoumarin and the four targets (TNF-α, IL-1ß, catalase, and HO-1) showed firm bonds above 6.0 kcal/mol. 6,7-dimethoxy-3-nitrocoumarin (1 mg/kg) lowered mRNA expression levels of TNF-α (2.33 ± 0.56) and IL-1ß (19.87 ± 2.9), while it increased both the mRNA expression levels of HO-1 (43.40 ± 1.05) and the catalase activity (46.42 ± 4.59), when compared to vehicle-treated group (46.29 ± 8.43; 37.83 ± 4.38; 1.58 ± 0.11; 8.93 ± 1.86, respectively). The animals did not show any signs of toxicity. CONCLUSION: 6,7-Dimethoxy-3-nitrocoumarin decreased inflammatory bone loss in the ligature-induced periodontitis in rats, and the activation of the HO-1 pathway may contribute, at least partially, to its protective effects by reducing TNF-α and IL-1ß mRNA levels and increasing catalase activity. CLINICAL RELEVANCE: 6,7-Dimethoxy-3-nitrocumarin could be used as an adjunct to subgingival instrumentation during active and supportive periodontal treatment.

Bone morphogenetic proteins in biomineralization of two endodontic restorative cements.

To assess the effect of biodentine (BD) and MTA-angelus (MTA) on biocompatibility, BMP2, BMP4, and osteocalcin (OC) expression. Subcutaneously implanted tubes of four groups (MTA, BD, Control, and Sham) were kept over 15, 30, and 60 days; histological analyses were performed using H&E and Von Kossa; ELISA quantified IL-1ß and IL-8 expression; and qRT-PCR verified gene expression of BMPs and OC. Sham showed slight changes in profile/intensity of inflammatory infiltrate in all periods. Control had an inflammatory score significantly higher than Sham at 15 days (p < .05). BD revealed a similar inflammatory response to Sham, without significant changes over periods. MTA group exhibited an increase in chronic inflammatory profile at 30 days, with significant reduction at 60 days, when compared to Sham (p < .05). At 30/60 days, experimental groups presented birefringent areas. At 30/60 days, BD and MTA significantly increase IL-1ß compared to Control, whereas an increase in IL-8 was observed only in BD. At 30/60 days, BD produces an expression of BMP2 whereas MTA influenced BMP4 and OC. Materials tested are biocompatible and they have osteoinductive activity; the materials influenced the expression of the tested mediators differently, suggesting different affinities with the substrate and the dental substrates.

A semi-synthetic flavonoid from Bauhinia pulchella stem attenuates inflammatory osteolysis in periodontitis in rats: Impact on cytokine levels, oxidative stress, and RANK/RANKL/OPG pathway.

OBJECTIVES: Many species of theBauhinia genus have been widely used in folk medicine as analgesic, anti-inflammatory and antioxidant agents. (-)-Fisetinidol palmitate is a semi-syntetic flavonoid obtained from the ethanolic extract of the stem of Bauhinia pulchella. This study aimed to evaluate the antiresorptive effect of the semi-syntetic (-)-fisetinidol palmitate in ligature-induced periodontitis in rats. Also, it evaluated the mechanism of action of (-)-fisetinidol palmitate and its toxicity. DESIGN: Periodontitis was inducedvia a nylon thread ligature (3.0) around the second upper left molars. Rats were treated (oral gavage) once a day for 11 days with (-)-fisetinidol palmitate (0.01 or 0.1 mg/kg) or saline vehicle. RESULTS: (-)-Fisetinidol palmitate (0.1 mg/kg) reduced alveolar bone loss, increased bone alkaline phosphatase (BALP), superoxide dismutase (SOD), and catalase (CAT) activity; also, it decreased IL1-ß, IL-8/CINC-1, nitrite/nitrate levels and myeloperoxidase activity. (-)-Fisetinidol palmitate reduced the mRNA levels of IL1-ß, IL-6, RANK, and RANK-L, while it increased the OPG ones. No statistical differences (P > 0.05) were observed in the transaminases (ALT, AST) and Total Alkaline Phosphatase (TALP) levels among groups. (-)- CONCLUSIONS: Fisetinidol palmitate did not result in any signs of toxicity and had anti-resorptive effects in a pre-clinical trial of periodontitis, showing antioxidant activity with the involvement of the RANK/RANKL/OPG pathway.

Protective effect of Platymiscium floribundum Vog. in tree extract on periodontitis inflammation in rats.

Periodontitis is an immuno-inflammatory disease, which can lead to tooth loss. This study aimed to investigate the efficacy of Platymiscium floribundum Vog., a Brazilian tree which has been used in folk medicine as an anti-inflammatory agent, in a pre-clinical trial of periodontitis in rats. Periodontitis was induced by placing a sterilized nylon (3.0) thread ligature around the cervix of the second left upper molar of the rats, which received (per os) P. floribundum extract (0.1, 1 or 10 mg/kg) or vehicle 1h before periodontitis-challenge and once daily during 11 days. Treatment with P. floribundum (10mg/kg) decreased alveolar bone loss, MPO activity nitrite/nitrate levels, oxidative stress, TNF-α, IL1-ß, IL-8/CINC-1, and PGE2 gingival levels, and transcription of TNF-α, IL1-ß, COX-2, iNOS, RANK, and RANKL genes, while elevated both BALP serum levels and IL-10 gingival levels. The animals did not show signs of toxicity throughout the experimental course. These findings show that P. floribundum has anti-inflammatory and anti-resorptive properties in a pre-clinical trial of periodontitis, representing an interesting biotechnological tool.

Stemodia maritima L. Extract Decreases Inflammation, Oxidative Stress, and Alveolar Bone Loss in an Experimental Periodontitis Rat Model.

Periodontitis is very prevalent worldwide and is one of the major causes of tooth loss in adults. About 80% of the worldwide population use medicinal plants for their health care. Stemodia maritima L. (S. maritima) antioxidant and antimicrobial effects in vitro as well as anti-inflammatory properties. Herein, the potential therapeutic effect of S. maritima was assessed in rats subjected to experimental periodontitis (EP). EP was induced in female Wistar rats by nylon thread ligature around 2nd upper left molars for 11 days. Animals received (per os) S. maritima (0.2; 1 or 5 mg/kg) or vehicle (saline + DMSO) 1 h before ligature and then once daily for 11 days. The naive group had no manipulation. After this time-point, the animals were terminally anesthetized, and the maxillae were removed for morphometric and histological analyzes (HE). Gingival tissues were dissected to cytokine levels detection (TNF-α, IL1-ß, CINC-1, and IL-10), enzymes superoxide dismutase (SOD), and catalase (CAT) analysis, as well as gene expression (TNF-α, IL-1ß, RANK, and iNOS) by qRT-PCR. Systemic parameters (weight variation, plasma levels of hepatic enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatinine, total alkaline phosphatase (TALP), and bone alkaline phosphatase (BALP) were performed. Histological analysis of the stomach, liver, kidney, and heart was also performed. S. maritima (5 mg/kg) decreased alveolar bone loss, TNF-α and CINC-1 gingival levels, oxidative stress, and transcription of TNF-α, IL1-ß, RANK, and iNOS genes. It elevated both BALP activity and IL-10 gingival levels. The animals showed no any signs of toxicity. In conclusion, S. maritima reduced pro-inflammatory cytokine production, oxidative stress, and alveolar bone loss in a pre-clinical trial of periodontitis. S. maritima is a potential tool for controlling the development of periodontitis.

Disodium chlodronate prevents bone resorption in experimental periodontitis in rats.

BACKGROUND: Periodontitis is a chronic disease characterized by alveolar bone loss and inflammatory changes. We studied the effect of disodium chlodronate (CD), a bisphosphonate used in metastatic and metabolic bone disease as a bone resorbing drug, in an experimental periodontitis model (EPD) focusing on anti-resorptive and anti-inflammatory parameters. METHODS: A nylon thread ligature was placed around the left maxillary molars of 72 male Wistar rats who were sacrificed after 7 or 11 days. Groups were treated daily with CD (1, 5, or 25 mg/kg/sc) starting at day 0 until day 7 (prophylactic CD) or from day 5 until day 11 (curative CD) after periodontitis induction. Non-treated group (NT) consisted of rats subjected to periodontitis that received no pharmacological treatment. Alveolar bone loss (ABL) was measured as the distance between the cuspid tips and the alveolar bone. The right jaw was used as control. The hemiarcades were processed for histopathologic analysis. RESULTS: In NT group there was significant ABL, severe mononuclear cells influx, and increase in osteoclast numbers. Prophylactic CD treatment decreased the ABL 25.8%, 61.6%, and 75.5% as compared to NT for the 1, 5, and 25 mg/kg CD doses, respectively. Curative CD treatment decreased the ABL 20%, 62%, and 69% as compared to NT for the 1, 5 and 25 mg/kg CD doses, respectively. Both prophylactic and curative CD decreased histological changes, as compared to NT rats (P <0.01). CONCLUSIONS: CD has both bone sparing and anti-inflammatory activity in EPD in rats when administered as a pretreatment or in an ongoing process. The possibility of using CD as an alternative treatment in human periodontitis should be considered.

Bloqueio seletivo da ciclooxigenase tipo 2 inibe a reabsorção óssea inflamatória em ratos / Selective blocking of type 2 cyclooxygenase inhibits inflammatory bone loss in rats

Objetivo - Considerando que as prostaglandinas participam na reabsorção óssea inflamatória e que não se dispõe de modelos in vivo que permitam quantificar macroscopicamente a perda óssea, decidiu-se investigar se um inibidor seletivo da ciclooxigenase do tipo 2 (meloxicam-MLX) seria capaz de alterar a perda óssea alveolar em um modelo de periodontite, bem como comparar seus efeitos sobre a mucosa gástrica em relação aos de um inibidor não seletivo de ciclooxigenase (indometacina-IND). Métodos - Quarenta e oito ratos Wistar foram submetidos à indução da doença periodontal experimental (DPE) através da colocação de um fio de náilon nos molares superiores. A perda óssea foi avaliada em uma hemiarcada como a distância entre a junção amelocementária e o osso alveolar. A outra hemiarcada foi processada para análise histopatológica. Avaliaram-se a curva ponderal e o leucograma. Grupos de animais foram tratados (sc) com IND (n = 6; 0,5, 1 ou 2mg/kg) ou MLX (n=6; 0,75, 1,5 ou 3 mg/kg). Realizou-se análise macroscópica da mucosa gástrica. Resultados - Observou-se no grupo não tratado significante perda óssea, influxo celular, aumento no número de osteoclastos e perda ponderal. IND e MLX reduziram a perda óssea, as alterações histopatológicas, influxo celular e perda ponderal. Os estômagos dos animais tratados com IND (1 e 2mg/kg) apresentaram hemorragia e úlceras, enquanto os animais tratados com MLX exibiram petéquias isoladas apenas com a maior dose (3mg/kg). Conclusão - A inibição de COX preveniu a perda óssea nesse modelo de doença periodontal. MLX apresentou eficácia similar e menor dano à mucosa gástrica do que IND. MLX apresentou melhor relação risco/benefício do que inibidores não seletivos de COX