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1.
J Bone Miner Metab ; 38(5): 648-657, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32350616

RESUMO

INTRODUCTION: Lactoferrin has recently been reported for its potent bone growth effects. However, the effects of lactoferrin on the healing process of fragility fracture have not yet been studied, so the purpose of this study is to investigate whether oral administration of lactoferrin can promote the fracture healing in an OVX animal model. MATERIALS AND METHODS: Three months after bilateral ovariectomy, all rats underwent unilateral tibial osteotomy and were then randomly divided into control group and bovine lactoferrin (bLF) group. At 4 and 8 weeks post-fracture, animals were sacrificed, and the fractured tibiae and serum samples were collected for evaluation. RESULTS: Our results showed that bLF treatment not only accelerated the bone growth at an early stage of OPF healing but also shortened the remolding process of OPF healing. When compared to control group, bLF treatment induced a significant rise in callus BMD (by 35.0% at 4 weeks and by 39.7% at 8 weeks; both p < 0.05) consistent with enhanced biomechanical strength of the callus, with ultimate force increased by 3.39-fold at 4 weeks (p < 0.05) and 1.95-fold at 8 weeks (p < 0.05). Besides, bLF administration resulted in a substantial increase in serum levels of BALP and a significant decrease in serum levels of TRAP 5b and TNF-α. Moreover, both the RANKL/OPG mRNA ratio and the expression of TNF-α in the callus of bLF-treated group were markedly lower than those in the control group. CONCLUSIONS: At a dose of 85mg/kg/day orally administrated bLF potently promoted the bone healing following tibial fracture in OVX rats.


Assuntos
Consolidação da Fratura/efeitos dos fármacos , Lactoferrina/administração & dosagem , Lactoferrina/farmacologia , Ovariectomia , Absorciometria de Fóton , Administração Oral , Fosfatase Alcalina/sangue , Animais , Fenômenos Biomecânicos/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Calo Ósseo/diagnóstico por imagem , Calo Ósseo/efeitos dos fármacos , Calo Ósseo/patologia , Feminino , Humanos , Lactoferrina/sangue , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Ratos Sprague-Dawley , Fosfatase Ácida Resistente a Tartarato/sangue , Tíbia/efeitos dos fármacos , Tíbia/patologia , Fator de Necrose Tumoral alfa/sangue , Microtomografia por Raio-X
2.
Int J Nanomedicine ; 15: 3039-3056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32431500

RESUMO

Background: Electrospinning is a widely used technology that can produce scaffolds with high porosity and surface area for bone regeneration. However, the small pore sizes in electrospun scaffolds constrain cell growth and tissue-ingrowth. In this study, novel drug-loading core-shell scaffolds were fabricated via electrospinning and freeze drying to facilitate the repair of tibia bone defects in rabbit models. Materials and Methods: The collagen core scaffolds were freeze-dried containing icariin (ICA)-loaded chitosan microspheres. The shell scaffolds were electrospun using collagen, polycaprolactone and hydroxyapatite materials to form CPH composite scaffolds with the ones containing ICA microspheres named CPHI. The core-shell scaffolds were then cross-linked by genipin. The morphology, microstructure, physical and mechanical properties of the scaffolds were assessed. Rat marrow mesenchymal stem cells from the wistar rat were cultured with the scaffolds. The cell adhesion and proliferation were analysed. Adult rabbit models with tibial plateau defects were used to evaluate the performance of these scaffolds in repairing the bone defects over 4 to 12 weeks. Results: The results reveal that the novel drug-loading core-shell scaffolds were successfully fabricated, which showed good physical and chemical properties and appropriate mechanical properties. Furthermore, excellent cells attachment was observed on the CPHI scaffolds. The results from radiography, micro-computed tomography, histological and immunohistochemical analysis demonstrated that abundant new bones were formed on the CPHI scaffolds. Conclusion: These new core-shell composite scaffolds have great potential for bone tissue engineering applications and may lead to effective bone regeneration and repair.


Assuntos
Regeneração Óssea , Flavonoides/farmacologia , Tíbia/efeitos dos fármacos , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Regeneração Óssea/efeitos dos fármacos , Quitosana/química , Colágeno/química , Durapatita/química , Flavonoides/administração & dosagem , Flavonoides/química , Masculino , Teste de Materiais , Células-Tronco Mesenquimais/citologia , Microesferas , Poliésteres/química , Porosidade , Coelhos , Ratos Wistar , Tíbia/diagnóstico por imagem , Microtomografia por Raio-X
3.
Drug Discov Ther ; 14(2): 77-83, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32378649

RESUMO

Tacrolimus, a calcineurin inhibitor, affects bone metabolism and increases the risk of fracture due to marked bone loss. Bisphosphonates increase the bone mineral density (BMD) in osteoporosis patients. Menatetrenone has less positive effects on BMD but reduces the risk of fracture by improving bone quality. In this study, we investigated the effectiveness of the combined administration of risedronate and menatetrenone against bone loss induced by tacrolimus. Wistar rats were divided into four groups: [1] control, [2] tacrolimus at 1.5 mg/kg, [3] tacrolimus + risedronate at 1.0 mg/kg, and [4] tacrolimus + risedronate + menatetrenone at 20 mg/kg. After the drugs were administered for 4 weeks, bone histomorphometric analysis was performed and bone strength was evaluated using a three point bending method. BMD was measured using quantitative computed tomography. Tacrolimus significantly reduced the BMD and strength properties of the lower limb bones. These tacrolimusinduced decreases were suppressed by risedronate treatment. The combined administration of risedronate and menatetrenone more significantly improved bone strength properties than risedronate alone. Bone histomorphometric analysis revealed a significant increase in bone resorption with tacrolimus. Risedronate alone significantly suppressed the tacrolimus-induced increase in bone resorption but simultaneously reduced bone formation. On the other hand, the combined administration of risedronate and menatetrenone suppressed the tacrolimus-induced increase in bone resorption, in addition to the significant risedronate-induced decrease in bone formation. This study suggests that the combined administration of risedronate and menatetrenone improves bone strength in tacrolimus-treated rats by preventing and ameliorating the risedronate-induced suppression of bone formation.


Assuntos
Doenças Ósseas Metabólicas/tratamento farmacológico , Imunossupressores/efeitos adversos , Ácido Risedrônico/uso terapêutico , Tacrolimo/efeitos adversos , Vitamina K 2/análogos & derivados , Animais , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/induzido quimicamente , Quimioterapia Combinada , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Masculino , Osteogênese/efeitos dos fármacos , Ratos Wistar , Tíbia/efeitos dos fármacos , Tíbia/fisiologia , Vitamina K 2/uso terapêutico
4.
Poult Sci ; 99(5): 2633-2644, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32359599

RESUMO

This experiment studied the effect of broiler breeder nutritional strategies on uniformity, carcass traits, tibia parameters, and behavior during rearing and prebreeder periods (up to 22 wk of age). One-day-old pullets (n = 384) were randomly assigned to 4 treatments arranged as a 2 × 2 factorial, with 2 fiber levels (control vs. fibrous diet, 15% diluted in AMEn and nutrient content) and 2 vitamin C feed inclusions (0 vs. 200 mg/kg). At 6, 15, and 22 wk, blood sampling was carried out (4 birds/replicate) to determine serum alkaline phosphatase (ALP) levels, and behavior was observed by visual scan sampling. At 22 wk, carcass traits, tibia parameters, and intestinal morphology were assessed (2 birds/replicate), and tail- and wing-feather integrity of all birds were scored. Fibrous diet did not modify BW uniformity, mortality, or tibia growth when compared with control diet. Pullets fed the fibrous diet had lower tibia breaking strength, elastic modulus, and ash content values (P < 0.05). They also had lower ALP serum level at 6 and 22 wk (P < 0.05), their breast muscle was less developed (18.5 vs. 19.8%, P < 0.05), and their abdominal fat deposition was higher (1.14 vs. 0.87%, P < 0.05). At 15 and 22 wk, they performed, on average, 97% less grasping feather pecking and 45% less non-food object pecking behaviors, and their wing-feather score was lower (P < 0.05) at 22 wk. Tail- and wing-feather scores of the control treatments were reduced by vitamin C inclusion (tail: 0.30 vs. 1.15, P < 0.05; wing: 0.98 vs. 1.26, P < 0.05) at 22 wk. In conclusion, fibrous diet improves carcass traits (reduces breast muscle and increases abdominal fat deposition), deteriorates bone mineral deposition and thus skeletal strength, and reduces stereotypic behaviors, improving wing-feather integrity. Vitamin C inclusion improves tail- and wing-feather integrity of lower in feed allowance.


Assuntos
Ácido Ascórbico/metabolismo , Peso Corporal , Galinhas/fisiologia , Fibras na Dieta/metabolismo , Longevidade , Comportamento Estereotipado , Tíbia/química , Ração Animal/análise , Animais , Ácido Ascórbico/administração & dosagem , Peso Corporal/efeitos dos fármacos , Dieta/veterinária , Fibras na Dieta/administração & dosagem , Suplementos Nutricionais/análise , Feminino , Longevidade/efeitos dos fármacos , Distribuição Aleatória , Reprodução , Comportamento Estereotipado/efeitos dos fármacos , Tíbia/efeitos dos fármacos
5.
Nat Commun ; 11(1): 1578, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221289

RESUMO

PARP1 and PARP2 dual inhibitors, such as olaparib, have been recently FDA approved for the treatment of advanced breast and ovarian cancers. However, their effects on bone mass and bone metastasis are unknown. Here we show that olaparib increases breast cancer bone metastasis through PARP2, but not PARP1, specifically in the myeloid lineage, but not in the cancer cells. Olaparib treatment or PARP1/2 deletion promotes osteoclast differentiation and bone loss. Intriguingly, myeloid deletion of PARP2, but not PARP1, increases the population of immature myeloid cells in bone marrow, and impairs the expression of chemokines such as CCL3 through enhancing the transcriptional repression by ß-catenin. Compromised CCL3 production in turn creates an immune-suppressive milieu by altering T cell subpopulations. Our findings warrant careful examination of current PARP inhibitors on bone metastasis and bone loss, and suggest cotreatment with CCL3, ß-catenin inhibitors, anti-RANKL or bisphosphonates as potential combination therapy for PARP inhibitors.


Assuntos
Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Reabsorção Óssea/patologia , Neoplasias da Mama/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocina CCL3/deficiência , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Feminino , Deleção de Genes , Humanos , Camundongos Knockout , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoclastos/patologia , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Poli(ADP-Ribose) Polimerases/deficiência , Regiões Promotoras Genéticas/genética , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , beta Catenina/metabolismo
6.
PLoS One ; 15(3): e0230240, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187215

RESUMO

It has been demonstrated in numerous studies that bee pollen supplementation shows numerous positive effects on health. However, its impact on bones is largely unknown. The purpose of this study was to investigate the effect of bee pollen supplementation on the tibia biomechanical properties and bone morphometric measures using Japanese quail as an animal model. The experiment was arranged in a 2x2x2 factorial design, with sex, quail line (meat-type or egg-lying type), and bee pollen inclusion (0 or 10 g/kg of feed) as factors. The quails were one-day-old at the beginning of the experiment, they were euthanized after 42 days. Our study showed for the first time unfavorable effects of bee pollen on bones properties. Bee pollen supplementation negatively affected bone structure, irrespective of quails' sex or line type. Bone length (P < 0.001), weight (P < 0.01), and mean relative wall thickness (P < 0.01) and mineralization (P < 0.05) were reduced by bee pollen treatment. For female quails, irrespective of line type, the decrease of yield load (P < 0.001), ultimate load (P < 0.01), yield stress (P < 0.001) and ultimate stress (P < 0.05) was noted. Analysis of growth plate in bone metaphysis showed that bee pollen supplementation slowed the process of bone maturation irrespective of sex (P < 0.05). On contrary, dietary bee pollen positively affected bone homeostasis of trabecular bone in bone metaphysis as bone mineral density increased in experimental groups (P < 0.05). In males, this was the result of the increase of trabecular thickness (P < 0.01), in females due to the reduction of trabecular space (P < 0.001). In conclusion, our results demonstrate that bee pollen (1.0%, 10 g/kg of feed) supplementation caused significant negative effects on the mechanical endurance of the tibia of quails, while showed beneficial effects on trabecular bone histomorphometry.


Assuntos
Abelhas/metabolismo , Densidade Óssea/efeitos dos fármacos , Desenvolvimento Ósseo/efeitos dos fármacos , Pólen/metabolismo , Tíbia/efeitos dos fármacos , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Coturnix , Dieta , Suplementos Nutricionais , Feminino , Masculino , Carne , Codorniz
7.
Ann Agric Environ Med ; 27(1): 66-75, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32208582

RESUMO

OBJECTIVE: The aim of the study was to determine the effect of nesfatin-1 on bone properties in female rats in the conditions of developing osteopenia induced by ovariectomy (OVX). MATERIAL AND METHODS: The experiment was performed on 21 female Wistar rats assigned to 3 groups receiving intraperitoneally physiological saline (SHO, OVX-PhS) and nesfatin-1 in dose 2 µg/kg BW of (OVX-NES) once a day for 8 wks. At the end of the experiment, the rats were scanned using the DXA method to determine the body composition, tBMC, and tBMD. The isolated femora and tibia were tested with the DXA method for BMD and BMC, and with the pQCT method for separate analysis of the cortical and trabecular bone tissue. The bone strength parameters were also determined. The immunohistochemical method was used for determination of nesfatin-1 localization in growth cartilage. Bone metabolism markers (osteocalcin, bALP, and NTx) were identified using an ELISA kit. RESULTS: OVX exerts a negative effect on bone tissue. The nesfatin-1 administration influenced positively the DXA parameters of tibia. TvBMD and TbvBMD measured by pQCT in metaphysis of bones were significantly higher in the OVX-NES group than in OVX-PhS. No differences were found in the values of bone strength parameters between SHO and OVX-NES females. Extra- and intracellular immunohistochemical reaction for nesfatin-1 was observed in all zones of growth cartilage, with the strongest reaction detected in the calcifying zone. Nesfatin-1 administration caused a significant increase in the osteocalcin and bALP concentration in relation to the OVX-PhS animals. CONCLUSIONS: The results of the experiment indicate that nesfatin-1 exerts a protective effect on bone tissue properties and can be used in the prevention of osteoporosis.


Assuntos
Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Nucleobindinas/farmacologia , Absorciometria de Fóton , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Animais , Doenças Ósseas Metabólicas/diagnóstico por imagem , Doenças Ósseas Metabólicas/metabolismo , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Osteocalcina/metabolismo , Ovariectomia , Ratos Wistar , Tíbia/diagnóstico por imagem , Tíbia/efeitos dos fármacos
8.
PLoS One ; 15(3): e0230379, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32203558

RESUMO

Individuals with chronic kidney disease have elevated levels of oxidative stress and are at a significantly higher risk of skeletal fracture. Advanced glycation end products (AGEs), which accumulate in bone and compromise mechanical properties, are known to be driven in part by oxidative stress. The goal of this study was to study effects of N-acetylcysteine (NAC) on reducing oxidative stress and improving various bone parameters, most specifically mechanical properties, in an animal model of progressive CKD. Male Cy/+ (CKD) rats and unaffected littermates were untreated (controls) or treated with NAC (80 mg/kg, IP) from 30 to 35 weeks of age. Endpoint measures included serum biochemistries, assessments of systemic oxidative stress, bone morphology, and mechanical properties, and AGE levels in the bone. CKD rats had the expected phenotype that included low kidney function, elevated parathyroid hormone, higher cortical porosity, and compromised mechanical properties. NAC treatment had mixed effects on oxidative stress markers, significantly reducing TBARS (a measure of lipid peroxidation) while not affecting 8-OHdG (a marker of DNA oxidation) levels. AGE levels in the bone were elevated in CKD animals and were reduced with NAC although this did not translate to a benefit in bone mechanical properties. In conclusion, NAC failed to significantly improve bone architecture/geometry/mechanical properties in our rat model of progressive CKD.


Assuntos
Acetilcisteína/administração & dosagem , Antioxidantes/administração & dosagem , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Tíbia/efeitos dos fármacos , Animais , Caseínas/administração & dosagem , Caseínas/efeitos adversos , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/etiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Modelos Animais de Doenças , Progressão da Doença , Produtos Finais de Glicação Avançada/análise , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Mutação , Proteínas Nucleares/genética , Estresse Oxidativo/efeitos dos fármacos , Hormônio Paratireóideo/sangue , Ratos , Tíbia/química , Tíbia/diagnóstico por imagem , Tíbia/patologia , Microtomografia por Raio-X
9.
Poult Sci ; 99(2): 734-743, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32029158

RESUMO

In poultry production, vaccination is an effective measure to protect chickens from diseases. Vaccination, however, is a stressor that may induce stress responses that interfere with the growth and development of chickens. The interaction between the skeletal and immune systems on bone quality has gained more attention. In the present study, the influence of high frequency vaccinations on the bone development of layer pullets was investigated. Thirty 35-day-old SPF White Leghorn layer pullets were obtained and randomly subjected to the following treatments: vaccinated against Newcastle disease (ND) with LoSota vaccine once at 35-day-old (V1, control); 4 times at 35, 49, 63, and 77 d of age (V4); and 7 times at 35, 42, 49, 56, 63, 70, and 77 d of age (V7). The body weight and organ index of the spleen, thymus, and tibia were recorded. The antibody titer and serum and the tibia calcium and phosphorus concentrations were measured. The transcription levels of the IL-6, IL-17, TNF-α, receptor activator of NF-κB ligand (RANKL), and osteoprotegerin (OPG) genes were determined in spleen, thymus, and the tibia. The results showed that V7 decreased body weight and increased the ND antibody titer, compared to V1-chickens. The expression levels of IL-6, IL-17, and TNF-α were upregulated in spleen, thymus, and the tibia of V7 chickens. In the tibia, RANKL was upregulated, while OPG was downregulated by V7 treatment. The results indicate that high frequency vaccination induces immune stress and impairs bone development. The results suggest that the augmented cytokine expression in immune organs and the tibia is associated with activation of the OPG/RANKL pathway, which, in turn, enhances osteoclastogenesis. The appropriate frequency of vaccination should support optimal bone development and full immunoprotection in layer pullets.


Assuntos
Desenvolvimento Ósseo/fisiologia , Galinhas/fisiologia , Osteogênese , Estresse Fisiológico/imunologia , Vacinação/veterinária , Animais , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Desenvolvimento Ósseo/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Feminino , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/metabolismo , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos , Tíbia/efeitos dos fármacos , Tíbia/metabolismo
10.
Ecotoxicol Environ Saf ; 190: 110126, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31918251

RESUMO

Tetramethyl thiuram disulfide (thiram) is a dithiocarbamate pesticide used for crop protection and storage. But, it's widespread utilization is associated with deleterious growth plate cartilage disorder in broilers termed as avian tibial dyschondroplasia (TD). TD results in non-mineralized and less vascularized proximal tibial growth plate cartilage causing lameness and poor growth performance. This study investigated the therapeutic potential of puerarin against thiram toxicity in TD affected chickens. One-day-old broiler chickens (n = 240) were alienated into three equal groups i.e. control, TD and puerarin (n = 80) and were offered standard feed. Additionally, TD and puerarin groups were offered thiram at 50 mg/kg of feed from 4 to 7 days for TD induction followed by puerarin therapy at 120 mg/kg to puerarin group only from 8 to 18 days for TD treatment. Thiram feeding to TD and puerarin group chickens caused lameness, mortality, and increased the aspartate aminotransferase (AST), alanine aminotransferase (ALT), malondialdehyde (MDA) levels and growth plate (GP) size and upregulated HIF-1α expression. Besides, the production parameters, alkaline phosphatase (ALP), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels and the expressions of TIMP-3 and BCL-2 were decreased (p < 0.05). Puerarin alleviated lameness, enhanced angiogenesis and growth performance and serum and antioxidant enzymes, decreased apoptosis and recuperated GP width by significantly downregulating HIF-1α and upregulating the TIMP-3 and BCL-2 mRNA and protein expressions in puerarin group chickens (p < 0.05). In conclusion, the toxic effects associated with thiram can be mitigated using puerarin.


Assuntos
Fungicidas Industriais/toxicidade , Isoflavonas/farmacologia , Osteocondrodisplasias/veterinária , Tiram/toxicidade , Vasodilatadores/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas/metabolismo , Glutationa Peroxidase/metabolismo , Lâmina de Crescimento/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Malondialdeído/metabolismo , Neovascularização Patológica/induzido quimicamente , Doenças das Aves Domésticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Tíbia/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-3/metabolismo
11.
BMC Genomics ; 21(1): 50, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941444

RESUMO

BACKGROUND: The Tibial dyschondroplasia (TD) in fast-growing chickens is mainly caused by improper blood circulation. The exact mechanism underlying angiogenesis and vascularization in tibial growth plate of broiler chickens remains unclear. Therefore, this research attempts to study genes involved in the regulation of angiogenesis in chicken red blood cells. Twenty-four broiler chickens were allotted into a control and thiram (Tetramethyl thiuram disulfide) group. Blood samples were collected on day 2, 6 (8- and 14-days old chickens) and 15 (23 days old chickens). RESULTS: Histopathology and hematoxylin and eosin (H&E) results showed that angiogenesis decreased on the 6th day of the experiment but started to recover on the 15th day of the experiment. Immunohistochemistry (IHC) results confirmed the expressions of integrin alpha-v precursor (ITGAV) and clusterin precursor (CLU). Transcriptome sequencing analysis evaluated 293 differentially expressed genes (DEGs), of which 103 up-regulated genes and 190 down-regulated genes were enriched in the pathways of neuroactive ligand receptor interaction, mitogen-activated protein kinase (MAPK), ribosome, regulation of actin cytoskeleton, focal adhesion, natural killer cell mediated cytotoxicity and the notch signalling pathways. DEGs (n = 20) related to angiogenesis of chicken erythrocytes in the enriched pathways were thromboxane A2 receptor (TBXA2R), interleukin-1 receptor type 1 precursor (IL1R1), ribosomal protein L17 (RPL17), integrin beta-3 precursor (ITGB3), ITGAV, integrin beta-2 precursor (ITGB2), ras-related C3 botulinum toxin substrate 2 (RAC2), integrin alpha-2 (ITGA2), IQ motif containing GTPase activating protein 2 (IQGAP2), ARF GTPase-activating protein (GIT1), proto-oncogene vav (VAV1), integrin alpha-IIb-like (ITGA5), ras-related protein Rap-1b precursor (RAP1B), tyrosine protein kinase Fyn-like (FYN), tyrosine-protein phosphatase non-receptor type 11 (PTPN11), protein patched homolog 1 (PTCH1), nuclear receptor corepressor 2 (NCOR2) and mastermind like protein 3 (MAML3) selected for further confirmation with qPCR. However, commonly DEGs were sarcoplasmic/endoplasmic reticulum calcium ATPase 3 (ATP2A3), ubiquitin-conjugating enzyme E2 R2 (UBE2R2), centriole cilia and spindle-associated protein (CCSAP), coagulation factor XIII A chain protein (F13A1), shroom 2 isoform X6 (SHROOM2), ras GTPase-activating protein 3 (RASA3) and CLU. CONCLUSION: We have found potential therapeutic genes concerned to erythrocytes and blood regulation, which regulated the angiogenesis in thiram induced TD chickens. This study also revealed the potential functions of erythrocytes. 1. Tibial dyschondroplasia (TD) in chickens were more on day 6, which started recovering on day 15. 2. The enriched pathway observed in TD chickens on day 6 was ribosome pathway, on day 15 were regulation of actin cytoskeleton and focal adhesion pathway. 3. The genes involved in the ribosome pathways was ribosomal protein L17 (RPL17). regulation of actin cytoskeleton pathway were Ras-related C3 botulinum toxin substrate 2 (RAC2), Ras-related protein Rap-1b precursor (RAP1B), ARF GTPase-activating protein (GIT1), IQ motif containing GTPase activating protein 2 (IQGAP2), Integrin alpha-v precursor (ITGAV), Integrin alpha-2 (ITGA2), Integrin beta-2 precursor (ITGB2), Integrin beta-3 precursor (ITGB3), Integrin alpha-IIb-like (ITGA5). Focal adhesion Proto-oncogene vav (Vav-like), Tyrosine-protein kinase Fyn-like (FYN).


Assuntos
Galinhas/genética , Osteocondrodisplasias/veterinária , Doenças das Aves Domésticas/induzido quimicamente , Tiram/toxicidade , Tíbia/efeitos dos fármacos , Animais , Ontologia Genética , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/genética , Osteocondrodisplasias/induzido quimicamente , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/metabolismo , Doenças das Aves Domésticas/patologia , Tíbia/patologia , Transcriptoma/efeitos dos fármacos
12.
Food Chem Toxicol ; 136: 110954, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31707033

RESUMO

Due to the growing number of applications of cadmium oxide nanoparticles (CdO NPs), there is a concern about their potential deleterious effects. The objective of our study was to investigate the effect of CdO NPs on the immune response, renal and intestine oxidative stress, blood antioxidant defence, renal fibrotic response, bone density and mineral content. Six-week-old female ICR mice were exposed to CdO NPs for 6 weeks by inhalation (particle size: 9.82 nm, mass concentration: 31.7 µg CdO/m3, total deposited dose: 0.195 µg CdO/g body weight). CdO NPs increased percentage of thymus CD3e+CD8a+ cells and moderately enhanced splenocyte proliferation and production of cytokines and chemokines. CdO NPs elevated pro-fibrotic factors (TGF-ß2, α-SMA and collagen I) in the kidney, and concentrations of AGEs in the intestine. The ratio of GSH and GSSG in blood was slightly reduced. Exposure to CdO NPs resulted in 10-fold higher Cd concentration in tibia bones. No differences were found in bone mass density, mineral content, bone area values, bone concentrations of Ca, P, Mg and Ca/P ratio. Our findings indicate stimulation of immune/inflammatory response, oxidative stress in the intestine, starting fibrotic response in kidneys and accumulation of CdO NPs in bones of mice.


Assuntos
Compostos de Cádmio/toxicidade , Fibrose/induzido quimicamente , Imunidade Celular/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Óxidos/toxicidade , Tíbia/efeitos dos fármacos , Administração por Inalação , Animais , Compostos de Cádmio/administração & dosagem , Citocinas/metabolismo , Feminino , Intestinos/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Linfonodos/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos ICR , Óxidos/administração & dosagem , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
13.
Clin Oral Investig ; 24(3): 1239-1247, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31317257

RESUMO

OBJECTIVES: Metoprolol is a cardioselective competitive beta-1 adrenergic receptor antagonist with antihypertensive properties, devoid of intrinsic sympathomimetic activity. Various studies have suggested the effect of beta-blockers on bone remodeling. We aimed to investigate whether metoprolol affects bone remodeling by altering anti-inflammatory and pro-inflammatory cytokines. MATERIALS AND METHODS: Surgical defects of 3 mm diameter were created in tibiae of 72 Sprague-Dawley rats. Rats were randomly assigned to a control group without metoprolol treatment (n = 36), and a test group treated with 0.1 mg/kg/day metoprolol (n = 36). Six rats from each group were sacrificed at days 0, 1, 3, 5, 7, and 14. The percentages of cells, which showed positive immunohistochemical staining for IL-1ß, IL-6, IL-10, and RANKL, were assessed in the defect area. Differences in percentages of stained cells within each of the test and control groups over various time intervals were tested using one-way ANOVA test. A P value of < 0.05 was considered statistically significant. RESULTS: No significant differences in IL-1ß, IL-10, IL-6, and RANKL expressions were found between test and control groups at the same interval. Significant reduction was observed at different time intervals in the same group (P < 0.05). CONCLUSION: Metoprolol did not reduce bone-active cytokine: IL-1ß, IL-6, and RANKL. It also did not elevate IL-10 expression levels. Thus, it does not appear to decrease osteoclastogenesis. CLINICAL RELEVANCE: Results from this animal model help us understand any effect of metoprolol on bone healing by potential contribution to different real-world clinical research.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Remodelação Óssea/efeitos dos fármacos , Metoprolol/administração & dosagem , Tíbia/efeitos dos fármacos , Animais , Injeções Intraperitoneais , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Projetos Piloto , Ligante RANK/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tíbia/patologia
14.
Life Sci ; 241: 117132, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837327

RESUMO

INTRODUCTION: This study aimed to verify the effects of cigarette smoke exposure in bone mineralization and fibrillar matrix composition as well as in bone healing after tibial fracture induction. METHODS: C57Bl/6 Mice were assigned according to exposure and surgery: C room air; F room air and tibia open osteotomy; CS cigarette smoke; FCS cigarette smoke and tibia open osteotomy. In order to study fracture healing we performed, under anesthesia, a bone injury through a tibial shaft osteotomy. Bone samples were obtained to evaluate bone histomorphometry, trabecular morphology and volume, trabecular collagen types composition and presence of inflammatory cytokines and growth factors. RESULTS: CS exposure significantly reduced the thickness of bone trabeculae associated with decrease in mineralizing surface and mineral deposition rate, leading a lower bone formation rate and longer mineralization time. Resorption surface and osteoclastic surface were greater in the CS group, attesting increased resorptive action. There was a decrease in type I collagen deposition and genes expression in the CS and FCS groups compared to C group and in contrast there was an increase in type V collagen deposition and genes expression in the CS, FC and FSC groups compared to C group. Also, CS exposure induced a decrease in bone forming cytokines and an increase in inflammatory associated cytokines, and these changes were intensified under fracture conditions. CONCLUSION: Cigarette smoke exposure alters bone matrix composition and worsens bone mineralization, leading to bone fragility by increasing collagen V synthesis and deposition and impairing collagen I fibril forming and assembling. And these deleterious effects contributed to the worsening in fracture healing after tibia osteotomy.


Assuntos
Calcificação Fisiológica/efeitos dos fármacos , Fumar Cigarros/efeitos adversos , Osteogênese/efeitos dos fármacos , Fumaça/efeitos adversos , Tíbia/patologia , Fraturas da Tíbia/patologia , Animais , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tíbia/efeitos dos fármacos , Tíbia/lesões , Tíbia/metabolismo , Fraturas da Tíbia/etiologia , Fraturas da Tíbia/metabolismo
15.
Toxicol Lett ; 321: 122-130, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31874197

RESUMO

Our previous studies confirmed that prenatal caffeine exposure (PCE) could induce susceptibility to osteoarthritis in adult offspring rats due to poor chondrocyte differentiation, but its mechanism remains to be further investigated. This study aimed to explore whether subchondral bone dysplasia mediates susceptibility to osteoarthritis in adult offspring rats induced by PCE. Pregnant Wistar rats were treated with caffeine (120 mg/kg.d) or saline from gestational day (GD) 9 to 20. The female offspring were euthanized to collect femurs at GD20, postnatal week (PW) 6, and PW28 (non-ovariectomy and ovariectomy groups) to detect osteoarthritis-like phenotype, subchondral bone mass, ossification center development, and other evidence. The results showed that PCE increased the Mankin score of pathological articular cartilage, but decreased articular cartilage thickness and subchondral bone mass, which were more obvious after ovariectomy. Meanwhile, the correlation analysis results demonstrated that the Mankin score of articular cartilage was significantly negatively correlated with subchondral bone mass, and the thickness of articular cartilage was significantly positively correlated with subchondral bone mass. Further, the length and area of the primary and secondary ossification centers, the number of osteoblasts, and the related genes' expression of osteogenic differentiation (e.g., Runx2, BSP, ALP, and OCN) were all significantly decreased in the PCE group before and after birth. Taken together, PCE induced susceptibility to osteoarthritis in adult female offspring, which was likely related to the subchondral bone dysplasia and reduction of subchondral bone mass production due to developmental disorder of primary and secondary ossification centers caused by osteoblast differentiation disability before and after birth.


Assuntos
Doenças do Desenvolvimento Ósseo/induzido quimicamente , Cafeína/toxicidade , Cartilagem Articular/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Osteoartrite/induzido quimicamente , Osteogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/metabolismo , Doenças do Desenvolvimento Ósseo/patologia , Cartilagem Articular/patologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Idade Gestacional , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese/genética , Ovariectomia , Gravidez , Ratos Wistar , Fatores Sexuais , Tíbia/efeitos dos fármacos , Tíbia/metabolismo , Tíbia/patologia
16.
Int J Mol Sci ; 20(23)2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816823

RESUMO

Patients with inflammatory bowel disease (IBD) often present poor bone health and are 40% more at risk of bone fracture. Studies have implicated autophagy in IBD pathology and drugs used to treat IBD stimulate autophagy in varying degrees, however, their effect on the skeleton is currently unknown. Here, we have utilised the dextran sulphate sodium (DSS) model of colitis in mice to examine the effects of the thiopurine drug azathioprine on the skeleton. Ten-week-old male mice (n = 6/group) received 3.0% DSS in their drinking water for four days, followed by a 14-day recovery period. Mice were treated with 10 mg/kg/day azathioprine or vehicle control. Histopathological analysis of the colon from DSS mice revealed significant increases in scores for inflammation severity, extent, and crypt damage (p < 0.05). Azathioprine provided partial protection to the colon, as reflected by a lack of significant difference in crypt damage and tissue regeneration with DSS treatment. MicroCT of vehicle-treated DSS mice revealed azathioprine treatment had a significant detrimental effect on the trabecular bone microarchitecture, independent of DSS treatment. Specifically, significant decreases were observed in bone volume/tissue volume (p < 0.01), and trabecular number (p < 0.05), with a concurrent significant increase in trabecular pattern factor (p < 0.01). Immunohistochemical labelling for LC3 revealed azathioprine to induce autophagy in the bone marrow. Together these data suggest that azathioprine treatment may have a deleterious effect on IBD patients who may already be at increased risk of osteoporotic bone fractures and thus will inform on future treatment strategies for patient stratification.


Assuntos
Azatioprina/efeitos adversos , Doenças Inflamatórias Intestinais/patologia , Tíbia/patologia , Animais , Autofagia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Osso Esponjoso/efeitos dos fármacos , Osso Esponjoso/patologia , Colo/patologia , Sulfato de Dextrana , Doenças Inflamatórias Intestinais/induzido quimicamente , Masculino , Camundongos Endogâmicos C57BL , Fenótipo , Tíbia/efeitos dos fármacos
17.
PLoS Genet ; 15(12): e1008530, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31841498

RESUMO

Vitamin D is important for normal skeletal homeostasis, especially in growing children. There are no previous genome-wide association (GWA) studies exploring genetic factors that influence vitamin D metabolism in early childhood. We performed a GWA study on serum 25-hydroxyvitamin D (25(OH)D) and response to supplementation in 761 healthy term-born Finnish 24-month-old children, who participated in a randomized clinical trial comparing effects of 10 µg and 30 µg of daily vitamin D supplementation from age 2 weeks to 24 months. Using the Illumina Infinium Global Screening Array, which has been optimized for imputation, a total of 686085 markers were genotyped across the genome. Serum 25(OH)D was measured at the end of the intervention at 24 months of age. Skeletal parameters reflecting bone strength were determined at the distal tibia at 24 months using peripheral quantitative computed tomography (pQCT) (data available for 648 children). For 25(OH)D, two strong GWA signals were identified, localizing to GC (Vitamin D binding protein) and CYP2R1 (Vitamin D 25-hydroxylase) genes. The GWA locus comprising the GC gene also associated with response to supplementation. Further evidence for the importance of these two genes was obtained by comparing association signals to gene expression data from the Genotype-Tissue Expression project and performing colocalization analyses. Through the identification of haplotypes associated with low or high 25(OH)D concentrations we used a Mendelian randomization approach to show that haplotypes associating with low 25(OH)D were also associated with low pQCT parameters in the 24-month-old children. In this first GWA study on 25(OH)D in this age group we show that already at the age of 24 months genetic variation influences 25(OH)D concentrations and determines response to supplementation, with genome-wide significant associations with GC and CYP2R1. Also, the dual association between haplotypes, 25(OH)D and pQCT parameters gives support for vertical pleiotropy mediated by 25(OH)D.


Assuntos
Colestanotriol 26-Mono-Oxigenase/genética , Família 2 do Citocromo P450/genética , Tíbia/diagnóstico por imagem , Proteína de Ligação a Vitamina D/genética , Vitamina D/análogos & derivados , Vitamina D/administração & dosagem , Desenvolvimento Infantil , Pré-Escolar , Feminino , Finlândia , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Masculino , Análise da Randomização Mendeliana , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto , Tíbia/efeitos dos fármacos , Tíbia/crescimento & desenvolvimento , Tomografia Computadorizada por Raios X , Vitamina D/sangue , Vitamina D/farmacocinética
18.
Biomed Res Int ; 2019: 4575424, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781616

RESUMO

Background: Upper partial fibulectomy has been preliminarily proved to have the efficacy for pain alleviation and improvement of function in patients with mild to moderate medial compartment knee osteoarthritis (KOA). However, the previous studies lack the control group with other treatments. The aim of this prospective, randomized controlled study is to compare the clinical and biomechanical effects between upper partial fibulectomy and drug conservative treatment on improvement of clinical pain, function, and gait for patients with mild to moderate medial knee osteoarthritis (KOA) and further discuss its biomechanical mechanism. Methods: From August 2016 to February 2017, 49 and 48 patients with mild to moderate medial KOA were allocated to fibulectomy and drug groups. We assessed the patients' visual analog scale (VAS) pain score, Hospital for Special Surgery (HSS) knee score, limb alignment, passive flexion/extension range of motion (ROM) of the knee, and 3D gait kinematics and kinetics parameters before and after intervention. Repeated-measures ANOVA with Dunnett's post hoc assessment and multivariate analysis of variance were applied for intragroup and intergroup comparisons, respectively. Results: The improvement in the fibulectomy group on the VAS pain score, HSS knee score, walking speed, and walking knee range of motion (ROM) was statistically better than that in the drug group. The decreased overall peak knee adduction moment (KAM) (decreased by 16.1%) and hip-knee-ankle (HKA) angle (decreased by 0.99° from a more varus alignment to a more neutral alignment) of the affected and operated side 1 year after surgery were observed in the fibulectomy group. Conclusion: This research demonstrated that as a biomechanical intervention, upper partial fibulectomy can be a better choice in pain relief and function and gait improvement than drug conservative treatment for patients with early-stage knee OA. The long-term clinical outcomes, indication, and rationale for the improvement in clinical symptoms should be investigated further.


Assuntos
Articulação do Joelho/cirurgia , Ligamento Colateral Médio do Joelho/cirurgia , Osteoartrite do Joelho/tratamento farmacológico , Osteoartrite do Joelho/cirurgia , Idoso , Fenômenos Biomecânicos/efeitos dos fármacos , Fenômenos Biomecânicos/fisiologia , Tratamento Conservador , Feminino , Marcha/fisiologia , Humanos , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/fisiopatologia , Masculino , Ligamento Colateral Médio do Joelho/efeitos dos fármacos , Ligamento Colateral Médio do Joelho/fisiopatologia , Pessoa de Meia-Idade , Osteoartrite do Joelho/fisiopatologia , Amplitude de Movimento Articular/efeitos dos fármacos , Tíbia/efeitos dos fármacos , Tíbia/fisiopatologia , Tíbia/cirurgia , Resultado do Tratamento , Caminhada
19.
Environ Sci Pollut Res Int ; 26(36): 36322-36332, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31713825

RESUMO

The widespread use of thiram has raised concerns for health and its toxic effects, but the underlying toxicity mechanism on platelets and bones is poorly defined. Here, we found a significant increase in the number of platelets in chickens with the thiram intake, due to the increased expression of thrombopoietin mRNA in the dysfunction liver. Furthermore, the decreased vascular distribution and cell death of chondrocytes in the tibial growth plates (TGPs) were observed, resulting in bone growth inhibition, which is associated with the abnormal activation of platelets leading to the extraordinary decrease of vascular endothelial growth factor A (VEGFA) and angiopoietin-1 protein were released and their corresponding receptors VEGFR2 and Tie-2 expressions were also reduced in the TGPs. Taken together, these findings revealed that thiram has an adverse effect on bones and platelets, which may have a high risk of thrombosis and osteoarthritis.


Assuntos
Galinhas/sangue , Galinhas/crescimento & desenvolvimento , Lâmina de Crescimento/efeitos dos fármacos , Praguicidas/toxicidade , Tiram/toxicidade , Proteínas Angiogênicas/metabolismo , Animais , Lâmina de Crescimento/irrigação sanguínea , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Contagem de Plaquetas , Trombopoetina/metabolismo , Tíbia/efeitos dos fármacos , Tíbia/crescimento & desenvolvimento
20.
Biomed Pharmacother ; 120: 109205, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31634777

RESUMO

Osteoporosis is a chronic disease whose symptoms include a reduction in bone strength, osteopenia, and damage to the bone microstructure. Ferulic acids are natural polyphenols present in various fruits that suppress the fusion and apoptosis of mature osteoclasts. Rats were divided into sham, control (osteoporosis), 10 mg/kg body weight ferulic acid, 20 mg/kg body weight ferulic acid, and 30 mg/kg body weight ferulic acid treatment groups. Osteoporosis was induced in neonatal by administration of dexamethasone (glucocorticoids). Bone mineral density (BMD), osteocalcin and alkaline phosphatase (ALP) levels, bone mechanical parameters, and mRNA and protein levels of sirtuin1 (SIRT1) and nuclear factor kappa-B (NF-κB) in the osteoporotic neonatal rats were assessed. Histopathological analysis was also conducted. Treatment with 20 and 30 mg/kg body weight ferulic acid increased BMD by 25% and 141.7%, respectively, but reduced ALP and osteocalcin levels. Furthermore, treatment with 20 or 30 mg/kg body weight ferulic acid significantly reduced the pixel intensity and significantly increased the peak load and ultimate stiffness. Ferulic acid significantly increased the mRNA and protein levels of SIRT1 and reduced those of NF-κB. Finally, the histopathological analysis showed that ferulic acid increased BMD. In summary, ferulic acid exhibited protective effects against osteoporosis in neonatal rats.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Densidade Óssea/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Dexametasona , Glucocorticoides , NF-kappa B/metabolismo , Osteoporose/prevenção & controle , Sirtuína 1/metabolismo , Tíbia/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Ativação Enzimática , NF-kappa B/genética , Osteoporose/induzido quimicamente , Osteoporose/enzimologia , Osteoporose/patologia , Ratos , Transdução de Sinais , Sirtuína 1/genética , Tíbia/enzimologia , Tíbia/patologia
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