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1.
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
2.
Sci Rep ; 8(1): 3680, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29487404

RESUMO

Tibial dyschondroplasia (TD) is the most-prevalent leg disorder in fast-growing chickens; it is intractable and characterized by abnormal endochondral bone formation of proximal tibial growth-plates (TGPs). Previous studies have shown that bone is a highly vascularized tissue dependent on the coordinated coupling between angiogenesis and osteogenesis, but the underlying mechanisms of bone formation and bone remodeling are poorly defined in TD chickens. Here, we observed that inhibition of vasculogenesis and angiogenesis remarkably impaired vascular invasion in the hypertrophic chondrocyte zone of the TGPs, resulting in the massive death of chondrocytes due to a shortage of blood vessels and nutrients. Moreover, the balance of the OPG (osteoprotegerin)/RANKL (receptor activator of nuclear factor-kB ligand) system is also severely disrupted during the osteogenesis process while coupling with angiogenesis, both of which eventually lead to abnormal endochondral bone formation in TD chickens. Thus, the process of vascular formation in endochondral bone appears to initiate the pathological changes in TD, and improvement of this process during coupling with osteogenesis may be a potential therapeutic approach to treat this intractable disease.


Assuntos
Lâmina de Crescimento/patologia , Osteocondrodisplasias/patologia , Tíbia/patologia , Animais , Galinhas , Lâmina de Crescimento/irrigação sanguínea , Lâmina de Crescimento/metabolismo , Osteocondrodisplasias/metabolismo , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Tíbia/irrigação sanguínea , Tíbia/metabolismo
3.
Sci Rep ; 7(1): 9089, 2017 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-28831181

RESUMO

Tibial dyschondroplasia (TD) is an intractable poultry problem that is characterized by the appearance of non-vascularized and non-mineralized cartilage masses in tibial growth plates (TGPs). However, the role of angiogenesis inhibition in the occurrence of TD remains unknown. In this study, we found that, compared to low-altitude Arbor Acres chickens (AACs), high-altitude Tibetan chickens showed higher tibial vascular distributions that were accompanied by up-regulation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor A (VEGFA) and VEGF receptors. These observations provide insights into hypoxia-induced angiogenesis, which may be related to the absence of TD in high-altitude native Tibetan chickens. Importantly, hypoxia experiments also showed that during hypoxia, tibial angiogenesis was enhanced, which was due to pro-angiogenic factor up-regulation (including VEGFA, VEGFR1, VEGFR2, and IL-8), in AACs. Moreover, we observed that thiram-induced TD could strongly inhibit tibial angiogenesis in the hypertrophic zone through coordinated down-regulation of HIF-1α and pro-angiogenic factors, leading to a disruption in the blood supply to the TGP. Taken together, these findings reveal that the occurrence of TD is highly associated with inhibition of tibial angiogenesis through down-regulated expression of HIF-1α, VEGFA and VEGF receptors, which results in suppression of TGP development.


Assuntos
Osteocondrodisplasias/veterinária , Doenças das Aves Domésticas/induzido quimicamente , Transdução de Sinais , Tiram/efeitos adversos , Tíbia/irrigação sanguínea , Doença da Altitude/genética , Doença da Altitude/metabolismo , Animais , Galinhas , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Osteocondrodisplasias/induzido quimicamente , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Tíbia/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
BMC Genomics ; 14: 276, 2013 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-23617778

RESUMO

BACKGROUND: Tibial dyschondroplasia (TD) is a common skeletal disorder in broiler chickens. It is characterized by the presence of a non-vascularized and unmineralized cartilage in the growth plate. Previous studies have investigated differential expression of genes related to cartilage development during latter stages of TD. The aim of our study was to identify differentially expressed genes (DEGs) in the growth plate of broiler chickens, which were associated with early stage TD. We induced TD using tetramethylthiuram disulfide (thiram) for 1, 2, and 6 days and determined DEGs with chicken Affymetrix GeneChip assays. The identified DEGs were verified by quantitative polymerase chain reaction (qPCR) assays. RESULTS: We identified 1630 DEGs, with 82, 1385, and 429 exhibiting at least 2.0-fold changes (P < 0.05) at days 1, 2, and 6, respectively. These DEGs participate in a variety of biological processes, including cytokine production, oxidation reduction, and cell surface receptor linked signal transduction on day 1; lipid biosynthesis, regulation of growth, cell cycle, positive and negative gene regulation, transcription and transcription regulation, and anti-apoptosis on day 2; and regulation of cell proliferation, transcription, dephosphorylation, catabolism, proteolysis, and immune responses on day 6. The identified DEGs were associated with the following pathways: neuroactive ligand-receptor interaction on day 1; synthesis and degradation of ketone bodies, terpenoid backbone biosynthesis, ether lipid metabolism, JAK-STAT, GnRH signaling pathway, ubiquitin mediated proteolysis, TGF-ß signaling, focal adhesion, and Wnt signaling on day 2; and arachidonic acid metabolism, mitogen-activated protein kinase (MAPK) signaling, JAK-STAT, insulin signaling, and glycolysis on day 6. We validated seven DEGs by qPCR. CONCLUSIONS: Our findings demonstrate previously unrecognized changes in gene transcription associated with early stage TD. The DEGs we identified by microarray analysis will be used in future studies to clarify the molecular pathogenic mechanisms of TD. From these findings, potential pathways involved in early stage TD warrant further investigation.


Assuntos
Osteocondrodisplasias/genética , Doenças das Aves Domésticas/genética , Animais , Galinhas/genética , Regulação para Baixo , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/patologia , Carne , Osteocondrodisplasias/induzido quimicamente , Osteocondrodisplasias/metabolismo , Análise Serial de Proteínas , Tiram , Tíbia/patologia , Transcriptoma
6.
ACS Med Chem Lett ; 3(9): 764-8, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900545

RESUMO

3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (4) was identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this communication, some of the structure-activity relationship of the azaquinolone analogues leading to 4 is discussed. The focus is on how changes at the amide functionality affected the biochemical potency, cellular potency, metabolic properties, and solubility of this class of JNK inhibitors. Optimization of these properties led to the identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat and mouse TNF-α challenge models.

7.
Vaccine ; 28(32): 5220-7, 2010 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-20538095

RESUMO

To identify linear B-cell epitopes of urease B (UreB), a series of 19 partially overlapping fragments of the UreB gene were expressed. Three MAbs against UreB of Helicobacter pylori (H. pylori), A1H10, A3C10, and B3D9, were tested for their reactivity to the truncated proteins by Western blot and enzyme-linked immunosorbent assay (ELISA). Three linear B-cell epitopes were identified covering a stretch of 15 amino acid (aa) residues and localized in the aa regions 158-172, 181-195, and 349-363 of UreB. ELISA also showed that the three synthetic peptides containing epitope sequences (UP32: GGGTGPADGTNATTI, UP35: WMLRAAEEYSMNLGF, and UP38: TLHDMGIFSITSSDS) were recognized by the corresponding MAbs and H. pylori positive sera from H. pylori infected patients. Mice immunized with glutathione S-transferase (GST) fusion peptides showed that epitope-specific antibodies were capable of inhibiting urease enzymatic activity. These results should be useful in clinical applications and highlight the potential importance of these epitopes as the targets for development of epitope-based vaccines against H. pylori.


Assuntos
Anticorpos Neutralizantes/imunologia , Proteínas de Bactérias/imunologia , Epitopos de Linfócito B/imunologia , Helicobacter pylori/enzimologia , Urease/imunologia , Animais , Anticorpos Monoclonais/imunologia , Mapeamento de Epitopos , Feminino , Helicobacter pylori/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C
8.
Mol Cancer Ther ; 9(1): 134-44, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20053779

RESUMO

Targeting the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway represents a promising anticancer strategy. Recently, we have reported a novel class of potent and selective non-ATP-competitive MEK1/2 inhibitors with a unique structure and mechanism of action. RO5068760 is a representative of this class showing significant efficacy in a broad spectrum of tumors with aberrant mitogen-activated protein kinase pathway activation. To understand the relationship between systemic exposures and target (MEK1/2) inhibition as well as tumor growth inhibition, the current study presents a detailed in vivo characterization of efficacy, pharmacokinetics, and pharmacodynamics of RO5068760 in multiple xenograft tumor models. For inhibition of MEK1/2 as measured by the phosphorylated ERK levels, the estimated EC(50)s in plasma were 1.36 micromol/L (880 ng/mL) and 3.35 micromol/L (2168 ng/mL) in LOX melanoma and HT-29 colorectal cancer models, respectively. A similar EC(50) (1.41 micromol/L or 915 ng/mL) was observed in monkey peripheral blood lymphocytes. To achieve tumor growth inhibition (>or=90%), an average plasma drug concentration of 0.65 or 5.23 micromol/L was required in B-RafV600E or K-Ras mutant tumor models, respectively, which were remarkably similar to the IC(90) values (0.64 or 4.1 micromol/L) determined in vitro for cellular growth inhibition. With equivalent in vivo systemic exposures, RO5068760 showed superior efficacy in tumors harboring B-RafV600E mutation. The plasma concentration time profiles indicate that constant p-ERK suppression (>50%) may not be required for optimal efficacy, especially in highly responsive tumors. This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen.


Assuntos
Imidazolidinas/farmacologia , Imidazolidinas/farmacocinética , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , Fenilbutiratos/farmacologia , Fenilbutiratos/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazolidinas/sangue , Imidazolidinas/química , Macaca fascicularis , Camundongos , Camundongos Nus , Fenilbutiratos/sangue , Fenilbutiratos/química , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/química
9.
Vet J ; 179(3): 430-6, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18406640

RESUMO

This study investigated the effect of exogenous insulin-like growth factor (IGF)-1 on the proliferation and differentiation of osteoblastic cells from Chinese Holstein cattle and the resultant bone nodule formation and mineralisation in vitro. The osteoblastic cells were isolated and cultured, then identified using Giemsa and alkaline phosphatase (ALP) staining methods. The effect of different concentrations of IGF-1 on cell growth was assessed by MTT assay. The ALP activity and osteocalcin (OC) concentration in the osteoblastic cells were measured by a colorimetric assay and a radioimmmunoassay, respectively. Calcium nodules were observed using alizarin red S stain, while the content of matrix calcium was determined by atomic absorption spectrophotometry. Cell proliferation in the cultures was stimulated by IGF-1 at concentrations ranging from 1 to 200ng/mL, with the maximum effect observed at 100ng/mL. This effect was observed from day 1 and peaked at day 5, but decreased at day 7. At concentrations of 10ng/mL and 100ng/mL, IGF-1 significantly induced ALP activity, OC level, matrix calcium content, and nodule formation of the osteoblastic cells by 20-180% (P<0.05 or P<0.01), compared to controls. The results suggested that IGF-1 is an anabolic agent for the proliferation, differentiation, mineralisation and calcium content of dairy cow osteoblasts, and could therefore act as a potential treatment for the metabolic bone diseases in these animals.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Osteoblastos/efeitos dos fármacos , Animais , Densidade Óssea/fisiologia , Desenvolvimento Ósseo/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Calcificação Fisiológica/fisiologia , Bovinos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Osteoblastos/fisiologia
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