RESUMO
OBJECTIVE: To compare the initial stress distribution and displacement on mandibular dentition using extra and inter-radicular mini-implants for arch distalization, by means of finite element analysis. METHODS: For this study, two finite element models of the mandible were designed. The models consisted of periodontal ligament (PDL) and alveolar bone of all teeth until second molars. In the Case 1, bilateral extra-radicular buccal-shelf stainless steel mini-implants (10.0-mm length; 2.0-mm diameter) were placed between first and second permanent molars. In the Case 2, bilateral inter-radicular stainless steel mini-implants (10.0-mm length; 1.5-mm diameter) were placed between second premolar and first permanent molar. Power hook was attached between canine and first premolar at a fixed height of 8mm. In the two cases, 200g of distalization force was applied. ANSYS v. 12.1 software was used to analyze and compare von Mises stress and displacement in the mandibular dentition, PDL and bone. RESULTS: Higher stresses were observed in mandibular dentition with the inter-radicular implant system. The amount of von Mises stress was higher for cortical bone (85.66MPa) and cancellous bone (3.64MPa) in Case 2, in comparison to cortical bone (41.93MPa) and cancellous bone (3.43MPa) in Case 1. The amount of arch distalization was higher for mandible in Case 1 (0.028mm), in comparison to Case 2 (0.026mm). CONCLUSION: Both systems were clinically safe, but extra-radicular implants showed more effective and controlled distalization pattern, in comparison to inter-radicular implants, in Class III malocclusion treatment.
Assuntos
Implantes Dentários , Aço Inoxidável , Análise de Elementos Finitos , Dente Molar/cirurgia , Ligamento Periodontal , Dente Pré-Molar/cirurgiaRESUMO
ABSTRACT Objective: To compare the initial stress distribution and displacement on mandibular dentition using extra and inter-radicular mini-implants for arch distalization, by means of finite element analysis. Methods: For this study, two finite element models of the mandible were designed. The models consisted of periodontal ligament (PDL) and alveolar bone of all teeth until second molars. In the Case 1, bilateral extra-radicular buccal-shelf stainless steel mini-implants (10.0-mm length; 2.0-mm diameter) were placed between first and second permanent molars. In the Case 2, bilateral inter-radicular stainless steel mini-implants (10.0-mm length; 1.5-mm diameter) were placed between second premolar and first permanent molar. Power hook was attached between canine and first premolar at a fixed height of 8mm. In the two cases, 200g of distalization force was applied. ANSYS v. 12.1 software was used to analyze and compare von Mises stress and displacement in the mandibular dentition, PDL and bone. Results: Higher stresses were observed in mandibular dentition with the inter-radicular implant system. The amount of von Mises stress was higher for cortical bone (85.66MPa) and cancellous bone (3.64MPa) in Case 2, in comparison to cortical bone (41.93MPa) and cancellous bone (3.43MPa) in Case 1. The amount of arch distalization was higher for mandible in Case 1 (0.028mm), in comparison to Case 2 (0.026mm). Conclusion: Both systems were clinically safe, but extra-radicular implants showed more effective and controlled distalization pattern, in comparison to inter-radicular implants, in Class III malocclusion treatment.
RESUMO Objetivo: Comparar a distribuição da tensão inicial e o deslocamento na dentição inferior usando mini-implantes extra e inter-radiculares para distalização da arcada, por meio da análise de elementos finitos. Métodos: Dois modelos de elementos finitos da mandíbula foram criados, os quais consistiram de ligamento periodontal (PDL) e osso alveolar de todos os dentes até os segundos molares. No Caso 1, mini-implantes extra-radiculares de aço inoxidável (10,0 mm de comprimento; 2,0 mm de diâmetro) foram colocados bilateralmente na buccal-shelf entre o primeiro e o segundo molares permanentes. No Caso 2, mini-implantes de aço inoxidável inter-radiculares (comprimento de 10,0 mm; diâmetro de 1,5 mm) foram colocados bilateralmente entre o segundo pré-molar e o primeiro molar permanentes. Um Power hook foi preso entre o canino e o primeiro pré-molar a uma altura fixa de 8mm. Nos dois casos, foi aplicada força de distalização de 200g. O software ANSYS v. 12.1 foi usado para analisar e comparar a tensão de von Mises e o deslocamento na dentição inferior, ligamento periodontal e osso. Resultados: Maiores tensões foram observadas na dentição inferior com o sistema de implantes inter-radiculares. A quantidade de tensões de von Mises foi maior para osso cortical (85,66MPa) e osso esponjoso (3,64MPa) no Caso 2, em comparação com osso cortical (41,93MPa) e osso esponjoso (3,43MPa) no Caso 1. A quantidade de distalização da arcada inferior foi maior no Caso 1 (0,028 mm), em comparação com o Caso 2 (0,026 mm). Conclusão: Ambos os sistemas foram clinicamente seguros, mas os implantes extra-radiculares mostraram um padrão de distalização mais eficaz e controlado, em comparação com os implantes inter-radiculares, para tratamento da má oclusão de Classe III.
RESUMO
Shiga toxigenic Escherichia coli (STEC) is one of the most important food-borne zoonotic bacterial pathogens responsible for causing gastrointestinal infections, haemorrhagic colitis and haemolytic uremic syndrome. The present study was aimed to isolate and characterize STEC from neonatal dairy calves, animal handlers and their surrounding environment and to establish the genetic relationship among isolates by multilocus sequence typing (MLST). A total number of 115 samples were collected and processed for the isolation of E. coli. The occurrence rate of E. coli was 92.2% (106/115), of which, 18 were typed as STEC. Antibacterial susceptibility analysis revealed 11 (61.1%) strains as multiple drug-resistant (MDR). MLST analysis has delineated 16 sequence types (STs) including nine novel STs. Among STs, ST58 dominated with three strains and was recovered from the environment and neonatal calves. Strains from neonatal calves and humans showed genetic relatedness with significant bootstrap support values indicative of zoonotic transmission potentiality. Analysis of 211 global isolates belonging to 61 STs indicated predominant STs (ST 21, ST 33 and ST 3416) that can be either host-specific (ST 33 and ST 3416) or can be shared among human and bovine hosts (ST 21). The MLST analysis indicates genetic relatedness among isolates and the results predispose inter-host transmission and zoonotic spread.
Assuntos
Infecções por Escherichia coli , Proteínas de Escherichia coli , Escherichia coli Shiga Toxigênica , Animais , Antibacterianos , Zoonoses Bacterianas , Bovinos/microbiologia , Farmacorresistência Bacteriana Múltipla , Infecções por Escherichia coli/veterinária , Proteínas de Escherichia coli/genética , Humanos , Tipagem de Sequências Multilocus , Escherichia coli Shiga Toxigênica/classificação , Escherichia coli Shiga Toxigênica/efeitos dos fármacosRESUMO
Ultraviolet B (UVB) radiation is known as a culprit in skin carcinogenesis. We have previously reported that bucillamine (N-[2-mercapto-2-methylpropionyl]-L-cysteine), a cysteine derivative with antioxidant and anti-inflammatory capacity, protects against UVB-induced p53 activation and inflammatory responses in mouse skin. Since MAPK signaling pathways regulate p53 expression and activation, here we determined bucillamine effect on UVB-mediated MAPK activation in vitro using human skin keratinocyte cell line HaCaT and in vivo using SKH-1 hairless mouse skin. A single low dose of UVB (30 mJ cm-2 ) resulted in increased JNK/MAPK phosphorylation and caspase-3 cleavage in HaCaT cells. However, JNK activation and casaspe-3 cleavage were inhibited by pretreatment of HaCaT cells with physiological doses of bucillamine (25 and 100 µm). Consistent with these results, bucillamine pretreatment in mice (20 mg kg-1 ) inhibited JNK/MAPK and ERK/MAPK activation in skin epidermal cells at 6-12 and 24 h, respectively, after UVB exposure. Moreover, bucillamine attenuated UVB-induced Ki-67-positive cells and cleaved caspase-3-positive cells in mouse skin. These findings demonstrate that bucillamine inhibits UVB-induced MAPK signaling, cell proliferation and apoptosis. Together with our previous report, we provide evidence that bucillamine has a photoprotective effect against UV exposure.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cisteína/análogos & derivados , Queratinócitos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Pele/efeitos dos fármacos , Raios Ultravioleta , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cisteína/farmacologia , Ativação Enzimática , Feminino , Humanos , Queratinócitos/enzimologia , Queratinócitos/efeitos da radiação , Camundongos , Camundongos Pelados , Transdução de Sinais/efeitos dos fármacos , Pele/enzimologia , Pele/efeitos da radiaçãoRESUMO
The antiangiogenic therapy for prostate cancer with Nintedanib, a potent inhibitor of important growth factor receptors, has been proven to delay tumor progression and arrest tumor growth; thus, the aim herein is to evaluate Nintedanib effects on tumor cells, besides angiogenesis and apoptosis processes, metalloproteinases and hypoxia factor in an animal model. Nintedanib promoted growth inhibition and cell death in a dose-dependent manner, showing no tumor selectivity. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) were treated with Nintedanib (10 mg/kg/day) in different stages of tumor development and the ventral prostate was examined for protein levels by means of immunohistochemistry and Western blotting and apoptosis evaluation. In vitro antiproliferative activity of Nintedanib was also assessed in nine human tumor cell lines. Early Nintedanib treatment has shown decreased levels of FGF-2, VEGFR-1, MMP-9 and HIF-1α and a significantly increased apoptosis of epithelial cells. Furthermore, late Nintedanib treatment decreased FGF-2, VEGFR-1 and FGFR-3 levels. Importantly, even after treatment discontinuation, treated animals displayed a significant decrease in VEGFR-1 as well as MMP-9. Although Nintedanib treatment in late stages of tumor growth has shown some good results, it is noteworthy that the drug presents the best tissue response when administered in the early stages of disease development. Nintedanib treatment has shown to be a promising approach for prostate cancer therapy, especially in the early stages of the disease, interfering in different carcinogenesis progression pathways.
Assuntos
Adenocarcinoma/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Apoptose , Hipóxia/patologia , Indóis/uso terapêutico , Próstata/patologia , Neoplasias da Próstata/irrigação sanguínea , Neoplasias da Próstata/tratamento farmacológico , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/patologia , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Indóis/farmacologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estadiamento de Neoplasias , Neoplasias da Próstata/patologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: In recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model. METHODS: Both androgen-independent (LNCaP) and androgen-dependent (PC3) PCa cell lines were treated with a range of Nintedanib doses for 72 h, and effect on cell growth and expression of angiogenesis associated VEGF receptors was analyzed. In pre-clinical efficacy evaluation, male TRAMP mice starting at 8 and 12 weeks of age were orally-fed with vehicle control (10% Tween 20) or Nintedanib (10 mg/Kg/day in vehicle control) for 4 weeks, and sacrificed immediately after 4 weeks of drug treatment or sacrificed 6-10 weeks after stopping drug treatments. At the end of treatment schedule, mice were sacrificed and ventral lobe of prostate was excised along with essential metabolic organ liver, and subjected to histopathological and extensive molecular evaluations. RESULTS: The total cell number decreased by 56-80% in LNCaP and 45-93% in PC3 cells after 72 h of Nintedanib treatment at 2.5-25 µM concentrations. In pre-clinical TRAMP studies, Nintedanib led to a delay in tumor progression in all treatment groups; the effect was more pronounced when treatment was given at the beginning of the glandular lesion development and continued till study end. A decreased microvessel density and VEGF immunolocalization was observed, besides decreased expression of Androgen Receptor (AR), VEGFR-1 and FGFR-3 in some of the treated groups. No changes were observed in the histological liver analysis. CONCLUSIONS: Nintedanib treatment was able to significantly decrease the growth of PCa cell lines and also delay growth and progression of PCa lesions to higher grades of malignancy (without inducing any hepatotoxic effects) in TRAMP mice. Furthermore, it was observed that Nintedanib intervention is more effective when administered during the early stages of neoplastic development, although the drug is capable of reducing cell proliferation even after treatment interruption.
Assuntos
Adenocarcinoma/prevenção & controle , Antineoplásicos/farmacologia , Indóis/farmacologia , Neoplasias da Próstata/prevenção & controle , Animais , Animais Geneticamente Modificados , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos EndogâmicosRESUMO
Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore, hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant-1 and GDC-0449) in BCC cells. Silibinin (25-100 µm) treatment for 48 h strongly inhibited growth and induced death in ASZ001, Sant-1-resistant (ASZ001-Sant-1) and GDC-0449-resistant (ASZ001-GDC-0449) BCC cells. Furthermore, colony-forming ability of ASZ001, ASZ001-Sant-1 and ASZ001-GDC-0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated EGFR (Tyrosine 1173) and total EGFR in ASZ001-Sant-1 cells, key signaling molecules responsible for BCC resistance toward hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated Akt (Serine 473), phosphorylated ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli-1 level but increased the SUFU expression in ASZ001-Sant-1-resistant cells. Silibinin treatment of ASZ001-Sant-1-resistant cells also decreased bcl-2 but increased cleaved caspase 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitor-resistant BCC cells.
Assuntos
Carcinoma Basocelular/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silibina/farmacologia , Neoplasias Cutâneas/patologia , Antineoplásicos/farmacologia , Carcinoma Basocelular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Cutâneas/metabolismoRESUMO
PURPOSE: To evaluate the toxic effects and associated mechanisms in corneal tissue exposed to the vesicating agent, nitrogen mustard (NM), a bifunctional alkylating analog of the chemical warfare agent sulfur mustard. METHODS: Toxic effects and associated mechanisms were examined in maximally affected corneal tissue using corneal cultures and human corneal epithelial (HCE) cells exposed to NM. RESULTS: Analysis of ex vivo rabbit corneas showed that NM exposure increased apoptotic cell death, epithelial thickness, epithelial-stromal separation, and levels of vascular endothelial growth factor, cyclooxygenase 2, and matrix metalloproteinase-9. In HCE cells, NM exposure resulted in a dose-dependent decrease in cell viability and proliferation, which was associated with DNA damage in terms of an increase in p53 ser15, total p53, and H2A.X ser139 levels. NM exposure also induced caspase-3 and poly ADP ribose polymerase cleavage, suggesting their involvement in NM-induced apoptotic death in the rabbit cornea and HCE cells. Similar to rabbit cornea, NM exposure caused an increase in cyclooxygenase 2, matrix metalloproteinase-9, and vascular endothelial growth factor levels in HCE cells, indicating a role of these molecules and related pathways in NM-induced corneal inflammation, epithelial-stromal separation, and neovascularization. NM exposure also induced activation of activator protein 1 transcription factor proteins and upstream signaling pathways including mitogen-activated protein kinases and Akt protein kinase, suggesting that these could be key factors involved in NM-induced corneal injury. CONCLUSIONS: Results from this study provide insight into the molecular targets and pathways that could be involved in NM-induced corneal injuries laying the background for further investigation of these pathways in vesicant-induced ocular injuries, which could be helpful in the development of targeted therapies.