Digoxin attenuates bisphosphonate related osteonecrosis of the jaws by RORγt-dependent Th17 response in male rats.

OBJECTIVE: The study aimed to evaluate digoxin, an RORγt inhibitor, in Medication-Related Osteonecrosis of the Jaws (MRONJ) in male rats treated with zoledronic acid (ZA). STUDY DESIGN: Forty male Wistar rats were divided into a negative control group (0.1 mL/kg saline), a positive control group (ZA, 0.20 mg/kg), and three test groups treated with ZA and digoxin at 1 (DG1), 2 (DG2), or 4 (DG4) mg/kg. These groups received treatment three times weekly. ZA was administered intravenously on days 0, 7, and 14, followed by extraction of the left lower first molar on day 42, a final ZA dose on day 49, and euthanasia on day 70. Analyses included radiographic, histomorphometric, and immunohistochemical evaluation of the mandibles, western blotting of gingiva, and mechanical tests on femurs. Statistical analysis was performed using ANOVA/Bonferroni tests (P < .05). RESULTS: Digoxin reduced radiolucency of MRONJ (P < .001), inflammatory cells, empty osteocyte lacunae (P < .001), apoptotic osteoclasts (P < .001), and Caspase-3-positive osteocytes (P = .021). ZA increased immunoreactivity for most markers except c-Fos, while digoxin reduced interleukin 17, TNF-α, IL-6, IL-2, FOXP3, c-Jun, NFκB (P < .001), TGF-ß (P = .009), RANKL (P = .035), and OPG (P = .034). Digoxin also reversed RORγt expression (P < .001), increased diarrhea scores (P = .028), renal and cardiac indexes (P < .001), and enhanced femur mechanical properties (P < .013). CONCLUSIONS: Digoxin attenuated MRONJ by inhibiting RORγt and reducing the Th17 response.

Effect of continuous and intermittent sodium alendronate oral dosing on post-extraction alveoli healing in rats.

OBJECTIVE: This study aimed to compare alveolar healing after tooth extraction in two experimental rat models using continuous or discontinuous dosing of sodium alendronate (ALN). DESIGN: Forty-eight male Wistar rats were divided into eight experimental groups (n = 6/group) and administered ALN (2.5, 5.0, or 7.5 mg/kg) by gavage, weekly, either intermittently or following a continuous regimen (2.5, 5.0, or 7.5 mg/kg) before tooth extraction. The positive control rats were administered zoledronic acid (ZA; 0.2 mg/kg, intravenous), whereas negative control rats received sterile saline (0.9% NaCl, gavage). RESULTS: Only the ZA-treated animals showed a larger radiolucent extraction site area compared to the saline group (p = 0.007). Small areas of bone tissue filling the alveoli were visualized in the 7.5 mg/kg continuous ALN group and compared with the saline group (p < 0.001). Increased amounts of empty osteocyte lacunae (p < 0.001) and osteoclasts with signs of apoptosis (p = 0.004) were observed in the continuous ALN groups (2.5, 5.0, and 7.5 mg/kg) compared with the saline group. Increased immunolabeling for TNF-α was observed in the 7.5 mg/kg discontinuous ALN group and all continuous ALN groups compared with the saline group (p < 0.001). The number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts was higher in the two continuous ALN groups (5.0 and 7.5 mg/kg) than in the saline group (p < 0.001). CONCLUSIONS: Continuous administration of ALN impaired post-extraction alveolar bone healing in rats; however, discontinuation of ALN administration before tooth extraction allowed for adequate post-dental extraction alveolar healing.

Gastric toxicity of Alendronate and Methotrexate in Walker 256 carcinosarcoma jaw model / Toxicidade gástrica de Alendronato e Metotrexato em modelo de carcinossarcoma de Walker 256 em mandíbula

Introduction: Experimental animal models represent a key tool used to elucidate the mechanisms of action and toxicity of anticancer drugs. Objective: The purpose was to establish a correlation of neoplastic growth with the combinatorial therapeutic application of sodium alendronate (ALD) and methotrexate (MTX), and to evaluate the gastrointestinal toxicity of these drugs, in the rat Walker 256 carcinosarcoma inoculation model. Methods: Female rats were selected and randomly distributed into 5 groups (n=10): negative control (NC), positive control (PC), MTX-treated group, ALD-treated group, and MTX-ALD-treated group (MTX/ALD). Tumor cells were inoculated as a suspension of 1x106cells/mL into the alveolar cavities produced by exodontia procedures. The following parameters were evaluated: body weight, tumor volume and percentage of tumor inhibition, and gastrointestinal toxicity. Results: The body weight variation was statistically significant between NC animals and PC animals, and between NC animals and ALD-treated group (p<0.01). Tumor volume variation was statistically significant between PC animals, MTX-treated group and MTX/ALD-co-treated group (p<0.05). Analysis of gastric toxicity of MTX-treated group reveled slight reduction of chief (Ch) and parietal (Pr) cellular populations; ALD-treated group exhibited gastric mucosa without histological alterations of Ch cells but intense reduction of Pr cellular population; and MTX/ALD-co-treated group presented reduction of Ch and Pr cellular populations. Conclusions: ALD does not elicit significant antitumor effects on Walker 256 carcinosarcoma cells and decreases antitumor effects of MTX due to toxicity on the gastric epithelium, which is intensified with MTX association.

Introdução: Modelos experimentais em animais representam um instrumento fundamental para elucidar os mecanismos de ação e toxicidade de drogas anticâncer. Objetivo: estabelecer uma correlação do crescimento neoplásico com a aplicação terapêutica combinatória de alendronato de sódio (ALD) e metotrexato (MTX), e avaliar a toxicidade gastrointestinal dessas drogas, no modelo de inoculação de carcinossarcoma de Walker 256 em ratos. Métodos: Ratas fêmeas foram selecionadas e distribuídas aleatoriamente em 5 grupos (n = 10): controle negativo (NC), controle positivo (PC), grupo tratado com MTX, grupo tratado com ALD e grupo tratado com MTX-ALD (MTX/ALD). As células tumorais foram inoculadas como uma suspensão de 1x106 células/mL nas cavidades alveolares produzidas por procedimentos de exodontia. Os seguintes parâmetros foram avaliados: peso corporal, volume tumoral e porcentagem de inibição tumoral e toxicidade gastrointestinal. Resultados: A variação do peso corporal foi estatisticamente significante entre animais NC e animais PC, e entre animais NC e grupo tratado com ALD (p <0,01). A variação do volume tumoral foi estatisticamente significativa entre animais PC, grupo tratado com MTX e grupo tratado com MTX / ALD (p <0,05). A análise da toxicidade gástrica do grupo tratado com MTX revelou uma ligeira redução das populações celulares principais (Ch) e parietais (Pr); o grupo tratado com ALD exibiu mucosa gástrica sem alterações histológicas de células Ch mas intensa redução da população celular Pr; e o grupo tratado com MTX / ALD apresentou redução das populações celulares Ch e Pr. Conclusões: O ALD não provoca efeitos antitumorais significativos nas células do carcinossarcoma Walker 256 e diminui os efeitos antitumorais do MTX devido à toxicidade no epitélio gástrico, que é intensificada com a associação MTX.

Multifocal oral melanoacanthoma associated with Addison's disease and hyperthyroidism: a case report

SUMMARY Oral melanoacanthoma is a mucocutaneous, pigmented, rare, benign, and probably reactive lesion. This paper reports for the first time in the literature a case of multifocal oral melanoacanthoma in a patient diagnosed with Addison's disease and concomitant Graves' disease with hyperthyroidism. The patient presented with oral pigmented lesions, which were hypothesized to be mucosal pigmentation associated with Addison's disease. Due to their unusual clinical pattern, these oral lesions were biopsied and diagnosed as oral melanoacanthoma on histopathology and immunohistochemistry for HMB-45. At the moment of this report, the patient was being treated for her systemic conditions, but the lesions had not regressed. Reactive hyperpigmentation of the skin and mucous membranes may be found in Addison's disease and hyperthyroidism. This case reinforces the hypothesis of a reactive nature for oral melanoacanthoma and highlights the need for investigation of endocrine disorders in patients with multifocal oral melanoacanthoma.

Multifocal oral melanoacanthoma associated with Addison's disease and hyperthyroidism: a case report.

Oral melanoacanthoma is a mucocutaneous, pigmented, rare, benign, and probably reactive lesion. This paper reports for the first time in the literature a case of multifocal oral melanoacanthoma in a patient diagnosed with Addison's disease and concomitant Graves' disease with hyperthyroidism. The patient presented with oral pigmented lesions, which were hypothesized to be mucosal pigmentation associated with Addison's disease. Due to their unusual clinical pattern, these oral lesions were biopsied and diagnosed as oral melanoacanthoma on histopathology and immunohistochemistry for HMB-45. At the moment of this report, the patient was being treated for her systemic conditions, but the lesions had not regressed. Reactive hyperpigmentation of the skin and mucous membranes may be found in Addison's disease and hyperthyroidism. This case reinforces the hypothesis of a reactive nature for oral melanoacanthoma and highlights the need for investigation of endocrine disorders in patients with multifocal oral melanoacanthoma.

Avaliação microscópica, estudo histoquímico e análise de propriedades tensiométricas da pele de tilápia do Nilo / Microscopic evaluation, histochemical study and analysis of tensiometric properties of the Nile Tilapia skin

OBJETIVO: Caracterizar a pele de tilápia do Nilo, uma possível fonte de biomaterial para enxertia, a partir de suas características físicas (resistência à tração), histomorfológicas e da tipificação da composição do colágeno. MÉTODOS: Amostras de pele de tilápia do Nilo foram utilizadas e, para os testes de tração (utilizando a máquina de ensaios universais Instron®), as peles foram submetidas à imersão em soluções de glicerol em crescente concentração. Parte das amostras foi fixada em formol neutro a 10%, processada e corada com o uso da hematoxilina e da eosina, para confecção de lâminas e posterior análise histológica e histoquímica. Todas as etapas foram reproduzidas também em pele humana, doada de cirurgias plásticas, para efeito comparativo. RESULTADOS: A morfologia da pele da tilápia mostrou-se semelhante à da pele humana, com derme profunda formada por espessas fibras colágenas organizadas, em disposição paralela/horizontal e transversal/vertical. A pele de tilápia também apresentou maior composição por colágeno tipo I em relação à pele humana (p=0,015). Nos testes de tração, a carga média suportada pela pele de tilápia foi de 43,9±26,2 N, enquanto a extensão à traçao teve valores médios de 4,4±1,045 cm CONCLUSAO: A pele de tilápia possui características microscópicas semelhantes à estrutura morfológica da pele humana e elevada resistência e extensão à tração em quebra, o que suporta sua possível aplicação como biomaterial. A derme desta pele é composta por feixes organizados de fibras de colágeno denso, predominantemente do tipo I, o que traz considerável importância para seu uso clínico.

OBJECTIVE: To characterize the Nile tilapia skin, a possible source of biomaterial for grafting, from their physical (tensile strength) and histomorphological characteristics, and from collagen classification. METHODS: Samples of Nile tilapia skin were used and, for microtensile tests (by Instron® universal testing machine), were subjected to immersion in glycerol solutions of increasing concentration. Part of the samples was fixed in neutral formalin 10%, processed and prepared using routine staining with hematoxylin and eosin into tissue slides, for further histological and histochemical analysis. All steps were also played in human skin, donated by plastic surgeries, for comparative effects. RESULTS: The morphology of Nile tilapia skin presented similarities with human skin, showing the deep dermis formed by thick organized collagen fibers, on parallel/horizontal and transversal/vertical arrangement. The tilapia skin also presented a larger composition of type I collagen, compared with human skin (p=0.015). On traction tests, the load average supported by tilapia skin was 43.9±26.2 N, while the traction extensile had mean values of 4.44±1.045cm. CONCLUSION: The tilapia skin has microscopic characteristics, similar to the morphological structure of human skin, and high resistance and tensile extension at break, which supports its possible application as biomaterial. The dermis of this skin is composed by organized bundles of dense collagen fibers, predominantly type I ones, which brings considerable importance for its clinical use.