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1.
Chemosphere ; 246: 125808, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31918107

RESUMO

This study evaluated the acute developmental toxicity of six priority phthalic acid esters (PAEs) including dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), di-n-octyl phthalate (DNOP), and benzyl butyl phthalate (BBP) in zebrafish embryos. A novel alcian blue and alizarin red double staining was performed to detect skeletal development of zebrafish larvae. Results revealed that all six PAEs could induce different developmental abnormalities in zebrafish larvae, including abnormal movement, decreased heart rate, spinal curvature, and pericardial edema. The bone development of zebrafish larvae exposed to PAEs was also affected by PAEs acute exposure. Among PAEs, DBP, and BBP even at low doses can cause mortality in zebrafish, implying their higher toxicity. Contrarily, DEHP and DNOP showed minor effects on the developmental morphology of zebrafish larvae. However, the gene expression levels of skeleton-related genes showed the upregulation of the runx2b and shha genes after DEHP and DBP exposure. Taken together, the strict use and release of PAEs in the environment should be supervised by the government for ecological and environmental safety.


Assuntos
Morfogênese/efeitos dos fármacos , Ácidos Ftálicos/toxicidade , Esqueleto/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Animais , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Ésteres/toxicidade , Larva , Ácidos Ftálicos/metabolismo , Esqueleto/efeitos dos fármacos , Peixe-Zebra/fisiologia
2.
Nano Lett ; 19(5): 2985-2992, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30983358

RESUMO

As a newly noninvasive emerging modality, NIR-II fluorescence imaging (1000-1700 nm) has many advantages over conventional visible and NIR-I imaging (700-900 nm). Unfortunately, only a few NIR-II fluorophores are suitable for bone imaging. Here, we report an NIR-II fluorophore based on DSPE-mPEG encapsulated rare earth doped nanoparticles (RENPs@DSPE-mPEG), which shows inherent affinity to bone without linking any targeting ligands, and thus, it provides an alternative noninvasive and nonradiation strategy for skeletal system mapping and bone disease diagnoses. Interestingly, within the NIR-II window, imaging at a longer wavelength (1345 nm) provides a higher resolution and signal-to-noise ratio than imaging at 1064 nm, even though the quantum yield at 1064 nm is 2-fold higher than that at 1345 nm. Besides bone imaging, RENPs@DSPE-mPEG show an imaging application in blood vessels and lymph nodes. Importantly, RENPs@DSPE-mPEG can be internalized by circulating white blood cells. This finding may open a window to increase efficient nanoparticle delivery in the fields such as immunotherapy and improve the diagnostic and therapeutic efficacy of cancer-targeted nanoparticles in clinical applications.


Assuntos
Osso e Ossos/diagnóstico por imagem , Metais Terras Raras/química , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Vasos Sanguíneos/diagnóstico por imagem , Vasos Sanguíneos/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/efeitos dos fármacos , Metais Terras Raras/farmacologia , Nanopartículas/química , Neoplasias/patologia , Neoplasias/terapia , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacologia , Esqueleto/efeitos dos fármacos , Trombose/diagnóstico por imagem , Trombose/patologia
3.
Int Immunopharmacol ; 62: 277-286, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30036771

RESUMO

Two Epimedium-derived isomeric flavonoids, CIT and IT, had the therapeutic effect in osteopenic rats. However, it is difficult to expound their activity differences in anti-osteoporosis. This paper contrasted their anti-osteoporosis activity from the perspective of their affinity to OPG/RANKL protein targets. Molecular docking indicated that both of CIT and IT could interact with the hydrophobic pockets of OPG/RANKL, while CIT was easier and more stable to combine with RANKL. On the contrary, compared with CIT, IT was more inclined to combine with OPG and stay away from combining with RANKL. Subsequently, whether the interaction between isomeric flavonoids and OPG/RANKL targets promoted or suppressed bone resorption was undefined and which was validated by zebrafish embryo and ovariectomized rats in this paper. Compared with IT, the staining area and cumulative optical density of zebrafish skeleton were significantly increased after the treatment of CIT (0.1 µM, p < 0.05). Furthermore, CIT mainly reflected a more significant role in upregulating OPG (p < 0.05), downregulating RANKL (p < 0.05), reducing serum AKP and TRACP level (p < 0.05), enhancing bone biomechanical properties (p < 0.05), increasing bone mineral density (p < 0.05) and improving trabecular bone microarchitecture (p < 0.05) in osteoporotic rats. In conclusion, the combination of isomeric flavonoids (CIT/IT) and OPG/RANKL targets attenuated the excitation effects of OPG or RANKL on RANKL. Because CIT was more firmly combined with RANKL than IT, CIT had stronger anti-osteoporosis effect by inhibiting bone resorption.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Epimedium/química , Flavonoides/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Animais , Densidade Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Feminino , Flavonoides/química , Flavonoides/isolamento & purificação , Simulação de Acoplamento Molecular , Osteoporose/metabolismo , Osteoprotegerina/genética , Ovariectomia , Ligação Proteica , Ligante RANK/genética , Ratos Sprague-Dawley , Esqueleto/efeitos dos fármacos , Esqueleto/metabolismo , Estereoisomerismo , Peixe-Zebra
4.
Birth Defects Res ; 110(15): 1157-1187, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29921029

RESUMO

Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings.


Assuntos
Desenvolvimento Ósseo/fisiologia , Osso e Ossos/efeitos dos fármacos , Embriologia/métodos , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Modelos Animais de Doenças , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Desenvolvimento Embrionário/efeitos dos fármacos , Feto , Humanos , Mamíferos , Organogênese , Primatas/anatomia & histologia , Coelhos/anatomia & histologia , Roedores/anatomia & histologia , Esqueleto/diagnóstico por imagem , Esqueleto/efeitos dos fármacos
5.
J Am Acad Orthop Surg ; 26(10): 343-352, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29659378

RESUMO

Achieving fracture union is highly dependent on the initial inflammatory phase of fracture healing, which is influenced by both the local and systemic inflammatory environments. The rapidly emerging field of osteoimmunology involves the study of the interactions between the immune system and the skeletal system. Recent research has advanced the current state of knowledge regarding the effects of the surrounding soft-tissue injury, fracture hematoma, and the method of fracture fixation on the inflammatory phase of fracture healing. Acute systemic inflammation, as seen in patients with polytrauma, and chronic systemic inflammation, as seen in patients with diabetes or rheumatoid arthritis, affects the inflammatory phase of fracture healing. The use of NSAIDs can influence early fracture healing. Understanding the effects of standard orthopaedic interventions on the local and systemic inflammatory responses and early fracture healing is important for optimizing fracture union.


Assuntos
Consolidação da Fratura/imunologia , Inflamação/imunologia , Esqueleto/imunologia , Lesões dos Tecidos Moles/imunologia , Anti-Inflamatórios não Esteroides/farmacologia , Fenômenos Biomecânicos , Consolidação da Fratura/efeitos dos fármacos , Consolidação da Fratura/fisiologia , Humanos , Inflamação/fisiopatologia , Esqueleto/efeitos dos fármacos , Esqueleto/fisiopatologia , Lesões dos Tecidos Moles/fisiopatologia
6.
Reprod Toxicol ; 77: 143-153, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29522798

RESUMO

Rats were treated orally with ayahuasca (AYA) on gestation days (GD) 6-20 at doses corresponding to one-(1X) to eight-fold (8X) the average dose taken by a human adult in a religious ritual, and the pregnancy outcome evaluated on GD21. Rats treated with 4X and 8X doses died during the treatment period (44 and 52%), and those that survived showed kidney injury. Rats surviving the 8X dose showed neuronal loss in hippocampal regions and in the raphe nuclei, and those from the 2X dose neuronal loss in CA1. Delayed intrauterine growth, induced embryo deaths and increased occurrence of foetal anomalies were observed at the 8X dose. At non-lethal doses, AYA enhanced embryolethality and the incidence of foetal soft-tissue and skeleton anomalies. This study suggested that AYA is developmentally toxic and that its daily use by pregnant women may pose risks for the conceptus.


Assuntos
Banisteriopsis , Bebidas/toxicidade , Alucinógenos/toxicidade , Preparações de Plantas/toxicidade , Teratogênios/toxicidade , Anormalidades Induzidas por Medicamentos , Anormalidades Múltiplas/induzido quimicamente , Animais , Encéfalo/anormalidades , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Retardo do Crescimento Fetal , Rim/anormalidades , Rim/efeitos dos fármacos , Fígado/anormalidades , Fígado/efeitos dos fármacos , Masculino , Troca Materno-Fetal , Neurônios/efeitos dos fármacos , Gravidez , Ratos Wistar , Esqueleto/anormalidades , Esqueleto/efeitos dos fármacos , Testículo/anormalidades , Testículo/efeitos dos fármacos , Ureter/anormalidades , Ureter/efeitos dos fármacos , Útero/anormalidades , Útero/efeitos dos fármacos
7.
Ann Agric Environ Med ; 25(1): 60-65, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29575874

RESUMO

INTRODUCTION: Growth hormone deficiency (GHD) is one of the main indications for growth hormone therapy. One characteristic of this disease is bone age delay in relation to the chronological age. Pituitary dysfunction negatively affects the growth and development of the jaws and teeth of the child. The secretion of endocrine glands regulates growth, development, and gender differentiation. It also controls the growth of bones and teeth, regulates metabolism of calcium and phosphate, proteins, lipids and carbohydrates. The primary role in the endocrine system is played by the pituitary gland which is responsible for the production of somatotropin [1]. Dysfunction of the pituitary gland has a negative effect on the growth and development of long bones in the body, and may have an adverse effect on the development of maxilla, mandible and dentition of a child. There is some information in the literature that dental age is delayed in short stature children; the replacement of deciduous teeth by permanent teeth is also delayed, and newly erupted permanent teeth often require orthodontic treatment. Applying hormonal therapy positively affects the process of replacement of dentition [2, 3, 4, 5, 6]. OBJECTIVES: The aim of the study was to assess bone and dental age, as well as analyze the state of dentition in children diagnosed with GH deficiency treated with growth hormone, depending on the duration of treatment. MATERIAL AND METHODS: The study material consisted of 110 children (27 males, 83 females), hospitalized for somatotropin hypopituitarism in the Department of Paediatric Endocrinology and Diabetology at the Medical University of Lublin, Poland. The mean birth age was 13 years (156 months) with a standard deviation of 2 years and 6 months (30 months). 47 children (43%) started treatment with the growth hormone (group starting treatment) and 63 children (57%) whose treatment was started 2-3 years previously (group in the course of treatment). The control group consisted of 41 generally healthy children (15males, 25 females) with ENT problems, such as hypoacusis and a condition after nasal injury, hospitalized in the Department of Paediatric Otolaryngology at the Medical University of Lublin, Poland. The mean age was 11 years and 5 months (137 months) with standard deviation of 2 years and 5 months (29 months). Informed consent was obtained from the parents. The study was approved by the Bioethical Committee at the Medical University of Lublin (Resolution No. KE-0254 /216 /2012).


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Esqueleto/crescimento & desenvolvimento , Dente/crescimento & desenvolvimento , Adolescente , Criança , Feminino , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Polônia , Esqueleto/efeitos dos fármacos , Dente/efeitos dos fármacos
8.
Calcif Tissue Int ; 102(5): 607-618, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29470611

RESUMO

Osteoporosis in rheumatic diseases is a very well-known complication. Systemic inflammation results in both generalized and localized bone loss and erosions. Recently, increased knowledge of inflammatory process in rheumatic diseases has resulted in the development of potent inhibitors of the cytokines, the biologic DMARDs. These treatments reduce systemic inflammation and have some effect on the generalized and localized bone loss. Progression of bone erosion was slowed by TNF, IL-6 and IL-1 inhibitors, a JAK inhibitor, a CTLA4 agonist, and rituximab. Effects on bone mineral density varied between the biological DMARDs. Medications that are approved for the treatment of osteoporosis have been evaluated to prevent bone loss in rheumatic disease patients, including denosumab, cathepsin K, bisphosphonates, anti-sclerostin antibodies and parathyroid hormone (hPTH 1-34), and have some efficacy in both the prevention of systemic bone loss and reducing localized bone erosions. This article reviews the effects of biologic DMARDs on bone mass and erosions in patients with rheumatic diseases and trials of anti-osteoporotic medications in animal models and patients with rheumatic diseases.


Assuntos
Antirreumáticos/farmacologia , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Humanos , Esqueleto/efeitos dos fármacos
9.
J Cell Physiol ; 233(8): 5696-5715, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29323712

RESUMO

Bisphosphonates are considered the most effective drugs for controlling adult and pediatric osteolytic diseases. Although they have been used successfully for many years, several side effects, such as osteonecrosis of the jaw, delayed dental eruption, atypical femoral fracture, and alterations to the bone growth system, have been described. After an overview of nitrogenous bisphosphonate, the purpose of this article is to describe their mechanisms of action and current applications, review the preclinical and clinical evidence of their side effects in the skeleton ("what we know"), and describe current recommendations for preventing and managing these effects ("what we can do"). Finally, promising future directions on how to limit the occurrence of these side effects will be presented.


Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Esqueleto/efeitos dos fármacos , Animais , Humanos , Osteonecrose/induzido quimicamente
10.
J Cell Physiol ; 233(4): 3540-3551, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29044507

RESUMO

TIEG knockout (KO) mice exhibit a female-specific osteopenic phenotype and altered expression of TIEG in humans is associated with osteoporosis. Gene expression profiling studies identified sclerostin as one of the most highly up-regulated transcripts in the long bones of TIEG KO mice relative to WT littermates suggesting that TIEG may regulate SOST expression. TIEG was shown to substantially suppress SOST promoter activity and the regulatory elements through which TIEG functions were identified using promoter deletion and chromatin immunoprecipitation assays. Knockdown of TIEG in IDG-SW3 osteocyte cells using shRNA and CRISPR-Cas9 technology resulted in increased SOST expression and delayed mineralization, mimicking the results obtained from TIEG KO mouse bones. Given that TIEG is an estrogen regulated gene, and as changes in the hormonal milieu affect SOST expression, we performed ovariectomy (OVX) and estrogen replacement therapy (ERT) studies in WT and TIEG KO mice followed by miRNA and mRNA sequencing of cortical and trabecular compartments of femurs. SOST expression levels were considerably higher in cortical bone compared to trabecular bone. In cortical bone, SOST expression was increased following OVX only in WT mice and was suppressed following ERT in both genotypes. In contrast, SOST expression in trabecular bone was decreased following OVX and significantly increased following ERT. Interestingly, a number of miRNAs that are predicted to target sclerostin exhibited inverse expression levels in response to OVX and ERT. These data implicate important roles for TIEG and estrogen-regulated miRNAs in modulating SOST expression in bone.


Assuntos
Proteínas de Ligação a DNA/deficiência , Estrogênios/farmacologia , Glicoproteínas/metabolismo , Osteócitos/efeitos dos fármacos , Esqueleto/metabolismo , Fatores de Transcrição/deficiência , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Proteínas Morfogenéticas Ósseas/metabolismo , Osso e Ossos/metabolismo , Feminino , Marcadores Genéticos/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos Knockout , Osteócitos/metabolismo , Ovariectomia/métodos , Esqueleto/efeitos dos fármacos
11.
An Acad Bras Cienc ; 89(1 Suppl 0): 635-647, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28562829

RESUMO

The development of DBA/2J mouse strain embryos is nearly 12 h - or 6 somite pairs - delayed as compared to the outbred NMRI mouse embryos of the same age on gestation days (GD) 8-12. To evaluate inter-strain differences in susceptibility to teratogens, dams were treated with methylnitrosourea (MNU, 5 mg/kg body weight i.p.) on defined gestation days (NMRI: GD 9, 91/2 or 10; DBA/2J: GD 10 or 101/2). Skeletal anomalies produced by MNU on both mouse strains varied with the GD of treatment. The pattern of anomalies produced by MNU on a given GD markedly differed between the two mouse strains, yet they were similar -with a few exceptions- when exposures at equivalent embryonic stages are compared. Findings from this study indicated that strain-dependent differences in the developmental stage of mouse embryos of the same gestational age occur, a possibility that has been often neglected when inter-strain differences in susceptibility to developmental toxicants are interpreted.


Assuntos
Embrião de Mamíferos/anormalidades , Desenvolvimento Embrionário/efeitos dos fármacos , Metilnitrosoureia/toxicidade , Esqueleto/anormalidades , Somitos/anormalidades , Teratogênios/toxicidade , Animais , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos DBA , Gravidez , Esqueleto/efeitos dos fármacos , Esqueleto/embriologia , Somitos/efeitos dos fármacos , Somitos/embriologia
12.
Toxicology ; 381: 1-9, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28214531

RESUMO

Chlormequat Chloride (CCC), a widely used plant growth regulator, could decrease body weight in animals; however, the mechanism has not been well studied. This study was designed to evaluate the skeletal development toxicity of CCC on pubertal male Sprague-Dawley (SD) rats and to investigate whether CCC impacts the development of chondrocyte, osteoblast and osteoclast through growth hormone (GH) and insulin like growth factor 1 (IGF-I). Rats from 23 to 70 on postnatal days were exposed to CCC daily by gavage at doses of 0, 75, 150, and 300mg/kg bw/d. The results showed that the size of femurs and tibias, bone mineral density and biomechanical parameters were significantly decreased in the 300mg/kg bw/d group compared with the control group. The concentration of osteocalcin (OCN) and C-terminal telopeptide of type I collagen (CTX-I) in blood in the 150mg/kg bw/d group was also changed. The mRNA expression ratio of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in 150 and 300mg/kg bw/d group was increased. Histological analysis of proximal and distal epiphyseal plates of the right femurs showed that both the proliferative zone and hypertrophic zone narrowed in CCC-treated groups. The concentration of IGF-I in blood was reduced with an increase in exposure doses of CCC. The mRNA expression of growth hormone receptor (GHR) in tibia was decreased in the CCC-treated group. The results indicated that CCC might indirectly impact the formation and activation of chondrocytes, osteoblasts and osteoclasts because of the decline of GHR and IGF-I, leading to skeletal development damage.


Assuntos
Clormequat/toxicidade , Condrócitos/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Esqueleto/efeitos dos fármacos , Animais , Peso Corporal , Densidade Óssea/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno Tipo I/sangue , Relação Dose-Resposta a Droga , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Hormônio do Crescimento/metabolismo , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteocalcina/sangue , Osteoclastos/metabolismo , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Peptídeos/sangue , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Somatotropina/genética , Receptores da Somatotropina/metabolismo , Esqueleto/crescimento & desenvolvimento , Tíbia/efeitos dos fármacos , Tíbia/metabolismo
13.
Toxicol Sci ; 155(2): 485-496, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28077779

RESUMO

Recent studies from mammalian, fish, and in vitro models have identified bone and cartilage development as sensitive targets for dioxins and other aryl hydrocarbon receptor ligands. In this study, we assess how embryonic 2,3,7,8-tetrachlorochlorodibenzo-p-dioxin (TCDD) exposure impacts axial osteogenesis in Japanese medaka (Oryzias latipes), a vertebrate model of human bone development. Embryos from inbred wild-type Orange-red Hd-dR and 3 transgenic medaka lines (twist:EGFP, osx/sp7:mCherry, col10a1:nlGFP) were exposed to 0.15 nM and 0.3 nM TCDD and reared until 20 dpf. Individuals were stained for mineralized bone and imaged using confocal microscopy to assess skeletal alterations in medial vertebrae in combination with a qualitative spatial analysis of osteoblast and osteoblast progenitor cell populations. Exposure to TCDD resulted in an overall attenuation of vertebral ossification characterized by truncated centra, and reduced neural and hemal arch lengths. Effects on mineralization were consistent with modifications in cell number and cell localization of transgene-labeled osteoblast and osteoblast progenitor cells. Endogenous expression of osteogenic regulators runt-related transcription factor 2 (runx2) and osterix (osx/sp7), and extracellular matrix genes osteopontin (spp1), collagen type I alpha I (col1), collagen type X alpha I (col10a1), and osteocalcin (bglap/osc) was significantly diminished at 20 dpf following TCDD exposure as compared with controls. Through global transcriptomic analysis more than 590 differentially expressed genes were identified and mapped to select pathological states including inflammatory disease, connective tissue disorders, and skeletal and muscular disorders. Taken together, results from this study suggest that TCDD exposure inhibits axial bone formation through dysregulation of osteoblast differentiation. This approach highlights the advantages and sensitivity of using small fish models to investigate how xenobiotic exposure may impact skeletal development.


Assuntos
Oryzias/embriologia , Osteogênese/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Esqueleto/efeitos dos fármacos , Animais , Calcificação Fisiológica/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Microscopia Confocal , Doenças Musculoesqueléticas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Esqueleto/metabolismo , Transativadores/efeitos dos fármacos
14.
Biom J ; 58(1): 186-205, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26250444

RESUMO

In addition to getting a preliminary assessment of efficacy, phase II trials can also help to determine dose(s) that have an acceptable toxicity profile over repeated cycles as well as identify subgroups with particularly poor toxicity profiles. Correct modeling of the dose-toxicity relationship in patients receiving multiple cycles of the same dose in oncology trials is crucial. A major challenge lies in taking advantage of the conditional nature of data collection, that is each cycle is observed conditional on having no previous toxicities on earlier cycles. We develop a novel and parsimonious model for the probability of toxicity during a kth cycle of therapy, conditional on not seeing toxicity in any of the k-1 previous cycles using a Markov model, hereafter we refer to these probabilities as conditional probabilities of toxicity. Our model allows the conditional probability of toxicity to depend on randomized dose group, cumulative dose from prior cycles, a measure of how consistently a patient responds to the same dose exposure and individual risk factors influencing the ability to tolerate the treatment regimen. Simulations studying finite sample properties of the model are given. Finally, the approach is demonstrated in a phase II trial studying two dose levels of ifosfamide plus doxorubicin and granulocyte colony-stimulating factor in soft tissue sarcoma patients over four cycles. The Markov model provides correct estimates of the probabilities of toxicity in finite sample simulations. It also correctly models the data from the phase II clinical trial, and identifies particularly high cumulative toxicity in females.


Assuntos
Antineoplásicos/efeitos adversos , Biometria/métodos , Ensaios Clínicos Fase II como Assunto , Cadeias de Markov , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Calibragem , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Ifosfamida/efeitos adversos , Masculino , Análise Multivariada , Sarcoma/tratamento farmacológico , Esqueleto/efeitos dos fármacos , Resultado do Tratamento
15.
Chem Res Toxicol ; 28(5): 1060-9, 2015 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-25853276

RESUMO

Human and natural activities release many pollutants in the marine environment. The mixture of pollutants can affect many organisms concurrently. We used Paracentrotus lividus as a model to analyze the effects on signal transduction pathways and stress gene expression in embryos exposed continuously to double stress, i.e., cadmium (Cd) from fertilization and UVB at cleavage (Cd/UVB-embryos). By microscopical inspection, we evaluated embryonic morphology after 72 h of development. Tissue-specific markers were used to assess mesoderm differentiation by immunofluorescence. We analyzed p38MAPK, ERK1/2, and JNK activation by Western blot and mRNA profiles of Pl-MT, Pl-14-3-3epsilon, and Pl-jun genes by real-time quantitative polymerase chain reaction (qPCR) and the localization of their transcripts by whole mount in situ hybridization (WMISH). We found that the Cd/UVB combined exposure induced morphological malformations in 76% of pluteus embryos, mainly affecting the development of the skeleton, including the normal branching of skeletal roads. In Cd/UVB-embryos, p38MAPK was activated 1 h after UVB exposure and a remarkable overexpression of the Pl-MT, Pl-14.3.3epsilon, and Pl-jun genes 24 h after UVB exposure. Pl-MT and Pl-14.3.3epsilon mRNAs were misexpressed as they were localized in a position different from that observed in wild-type embryos, i.e., the intestine. On the contrary, Pl-jun mRNA has remained localized in the skeletogenic cells despite their displacement in exposed embryos. In conclusion, Cd/UVB exposure affected skeletal patterning producing alternative morphologies in which p38MAPK activation and Pl-MT, Pl-14.3.3epsilon, and Pl-jun gene overexpression seem linked to a protective role against the stress response induced by Cd/UVB.


Assuntos
Cádmio/toxicidade , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos da radiação , Paracentrotus/embriologia , Paracentrotus/efeitos da radiação , Animais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/embriologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/efeitos da radiação , Paracentrotus/efeitos dos fármacos , Paracentrotus/genética , RNA Mensageiro/genética , Esqueleto/anormalidades , Esqueleto/efeitos dos fármacos , Esqueleto/embriologia , Esqueleto/efeitos da radiação , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Artigo em Inglês | MEDLINE | ID: mdl-25737366

RESUMO

We previously demonstrated that monohydroxylated polycyclic aromatic hydrocarbons (OHPAHs), which are metabolites of polycyclic aromatic hydrocarbons (PAHs), act on calcified tissue and suppress osteoblastic and osteoclastic activity in the scales of teleost fish. The compounds may possibly influence other calcified tissues. Thus, the present study noted the calcified spicules in sea urchins and examined the effect of both PAHs and OHPAHs on spicule formation during the embryogenesis of sea urchins. After fertilization, benz[a]anthracene (BaA) and 4-hydroxybenz[a]anthracene (4-OHBaA) were added to seawater at concentrations of 10(-8) and 10(-7) M and kept at 18 °C. The influence of the compound was given at the time of the pluteus larva. At this stage, the length of the spicule was significantly suppressed by 4-OHBaA (10(-8) and 10(-7) M). BaA (10(-7) M) decreased the length of the spicule significantly, while the length did not change with BaA (10(-8) M). The expression of mRNAs (spicule matrix protein and transcription factors) in the 4-OHBaA (10(-7) M)-treated embryos was more strongly inhibited than were those in the BaA (10(-7) M)-treated embryos. This is the first study to demonstrate that OHPAHs suppress spicule formation in sea urchins.


Assuntos
Benzo(a)Antracenos/toxicidade , Calcificação Fisiológica/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hemicentrotus/efeitos dos fármacos , Esqueleto/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Hemicentrotus/embriologia , Hemicentrotus/crescimento & desenvolvimento , Hemicentrotus/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Hidroxilação , Japão , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Larva/metabolismo , Concentração Osmolar , Oceano Pacífico , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo , RNA Mensageiro/metabolismo , Esqueleto/embriologia , Esqueleto/crescimento & desenvolvimento , Esqueleto/metabolismo , Testes de Toxicidade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
J Neurol Sci ; 50(1): 29-55, 1981 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7229658

RESUMO

The administration of a single dose of vitamin A to pregnant hamsters, early during the morning of their 8th day of gestation, induces types I and II Arnold--Chiari malformation (ACM), as well as various types of axial skeletal-dysraphic disorders known to be associated with the human disease. This new model provides a means of carrying comparative studies between the axial skeletal defects and neurological anomalies of this complex developmental malformation with those which characterize the other induced disorders related to it. Study of this experimental model has demonstrated that the basichondrocranium of fetuses with ACM is shorter than normal and slightly elevated (lordotic) in relation to the axis of the vertebral column. The shortness of the basichondrocranium of these fetuses is caused by the underdevelopment of the occipital bone specially noticeable in its basal component (basioccipital). This basic defect has resulted in a short and small posterior cerebral fossa which is inadequate to contain the developing nervous structures of that region. The developing cerebellum is displaced downward to an anomalous position just above the foramen magnum; and, the developing medulla is compressed or crowded into the small posterior cerebral fossa of affected fetuses. The lordotic elevation of the basichondrocranium is also responsible for the reduction of the pontine flexure and the increased angle of the cervical flexure of the hindbrain found in these fetuses. All of these neurological anomalies, which are characteristic and diagnostic of clinical ACm as well, are considered here to be secondary to the axial skeletal defects rather than primary abnormalities, as is generally believed. The peculiar type of protrusion of the odontoid process into the cranial cavity found in fetuses with ACM, as well as in those with cranioschisis aperta and occulta, is also considered to be caused by the slight depression of the underdeveloped basioccipital and therefore, comparable to the so-called basilar impression often described in clinical ACM. This study has emphasized various developmental features which are closely related with the morphogenesis of ACM, including: the somitic origin of the occipital bone, and the late growth of the cerebellum which is predominantly postnatal in almost all experimental animals. It has been pointed out that some developmental defects involving the occipital bone and the caudal vertebral column, such as those which characterize ACM type II, may be more closely related than previously recognized. It has been also pointed out that the so-called cerebellar herniation into the cervical spinal canal described in the human disease represents a late addition to this disorder which is related to the relatively late growth of the cerebellum...


Assuntos
Malformação de Arnold-Chiari/embriologia , Animais , Malformação de Arnold-Chiari/induzido quimicamente , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Cricetinae , Modelos Animais de Doenças , Feminino , Meningomielocele/induzido quimicamente , Gravidez , Esqueleto/efeitos dos fármacos , Esqueleto/embriologia , Vitamina A/toxicidade
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