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1.
BMC Vet Res ; 13(1): 388, 2017 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-29237458

RESUMEN

BACKGROUND: The use of nutraceuticals is gaining in popularity in human and canine oncology with a relatively limited understanding of the effects in the vastly different tumor types seen in canine oncology. We have previously shown that turmeric root (TE) and rosemary leaf (RE) extracts can work synergistically to reduce neoplastic cell growth, but the mechanisms are poorly understood and require further elucidation. RESULTS: Three different canine cell lines (C2 mastocytoma, and CMT-12 mammary carcinoma, D17 osteosarcoma) were treated with 6.3 µg mL-1 extract individually, or 3.1 µg mL-1 of each extract in combination based on studies showing synergy of these two extracts. Apoptosis, antioxidant effects, cellular accumulation of curcumin, and perturbation of signaling pathways were assessed. The TE + RE combination treatment resulted in Caspase 3/7 activation and apoptosis in all cell lines, beyond the effects of TE alone with the CMT-12 cell line being most susceptible. Both extracts had antioxidant effects with RE reducing reactive oxygen species (ROS) by 40-50% and TE reducing ROS by 80-90%. In addition RE treatment enhanced the c-jun N-terminal kinase (JNK) activity in the C2 cell line and TE + RE exposure increased activated JNK by 4-5 times in the CMT-12 cell line. Upon further examination, it was found that RE treatment caused a significant increase in the cellular accumulation of curcumin by approximately 30% in the C2 and D17 cell lines, and by 4.8-fold in the CMT-12 cell line. This increase in intracellular curcumin levels may play a role in the synergy exhibited when using TE and RE in combination. CONCLUSIONS: The use of RE in combination with TE induces a synergistic response to induce apoptosis which is better than either extract alone. This appears to be related to a variable increased TE uptake in cells and activation of pathways involved in the apoptotic response.


Asunto(s)
Neoplasias Óseas/veterinaria , Enfermedades de los Perros/tratamiento farmacológico , Neoplasias Mamarias Animales/tratamiento farmacológico , Mastocitoma/veterinaria , Osteosarcoma/veterinaria , Fitoterapia/veterinaria , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Rosmarinus , Animales , Neoplasias Óseas/tratamiento farmacológico , Línea Celular Tumoral , Curcuma , Perros , Femenino , Mastocitoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Fitoterapia/métodos
2.
BMC Vet Res ; 12(1): 159, 2016 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-27484718

RESUMEN

BACKGROUND: Adjunctive use of nutraceuticals in human cancer has shown promise, but little work has been done in canine neoplasia. Previous human research has shown that polyphenols and carotenoids can target multiple pathways in vitro and in vivo. These compounds could synergize or antagonize with currently used chemotherapies, either increasing or decreasing the effectiveness of these drugs. Considering the routine and well controlled feeding practices of most dogs, the use of nutraceuticals incorporated into pet food is attractive, pending proof that the extracts are able to improve remission rates. The aim of this study was to examine five feed ingredients for antiproliferative effects, as well as the interaction with toceranib phosphate and doxorubicin hydrochloride, when treating canine neoplastic cell lines in vitro. RESULTS: Screening using MTT proliferation assays showed that green tea, turmeric, and rosemary extracts were the most effective. Turmeric extract (TE) was the most potent and exhibited synergy with a rosemary extract (RE) at concentrations from 1 to 25 µg mL(-1). This combination had an additive or synergistic effect with chemotherapeutic agents at selected concentrations within each cell line. No significant effects on cell viability were observed when the combination therapy was used with normal primary cells. CONCLUSIONS: The use of turmeric and rosemary extracts in combination may be worthwhile to investigate in the pre-clinical and clinical neoplastic considering there are no negative effects on traditional chemotherapy treatment. Further studies into the pharmacokinetics and mechanisms of action of these extracts should be investigated.


Asunto(s)
Alimentación Animal/análisis , Antineoplásicos/farmacología , Dieta/veterinaria , Sinergismo Farmacológico , Extractos Vegetales/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Perros , Doxorrubicina/farmacología , Indoles/farmacología , Pirroles/farmacología
3.
Vet Comp Oncol ; 22(1): 2-11, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37933436

RESUMEN

Quality of life (QOL) in dogs with cancer is a key consideration in the assessment of cancer treatment options. Despite interest in dietary strategies to improve management of oncology patients, there have been very few clinical studies showing the impact of diet on adverse effects of chemotherapy in dogs. This study was a randomised, controlled, double-blinded, multicenter clinical trial to investigate a high-protein, increased-fibre diet supplemented with omega-3 fatty acids, for dogs with cancer undergoing standard-of-care chemotherapy. Client-owned dogs with newly diagnosed grade 2 or higher mast cell tumours (or non-resectable/incompletely resected tumours) or multicentric lymphoma were randomised to receive the test diet (n = 24) or control diet (n = 21) for 8 weeks. Primary outcomes were QOL assessments, faecal scores, and blood concentrations of C-reactive protein and monocyte chemoattractant protein-1. Of 12 QOL parameters, 10 significantly improved from baseline to Week 8 in the test group compared with one in the control group. However, differences between the two groups were only statistically significant for 'frequency of signs of illness' (P = .009). There were no significant differences in the incidence of any adverse events, including gastrointestinal adverse events or clinically significant differences in laboratory parameters or faecal scores between the two groups. The absence of an observed negative impact of the test diet, combined with the magnitude of QOL improvements associated with the diet, suggest that a larger trial is warranted.


Asunto(s)
Alimentación Animal , Enfermedades de los Perros , Ácidos Grasos Omega-3 , Neoplasias , Animales , Perros , Enfermedades de los Perros/tratamiento farmacológico , Ácidos Grasos Omega-3/administración & dosificación , Neoplasias/tratamiento farmacológico , Neoplasias/veterinaria , Calidad de Vida , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos
4.
Vet Comp Oncol ; 19(2): 232-241, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33222403

RESUMEN

Decreased circulating 25-hydroxyvitamin D (25[OH]D) and increased inflammatory marker concentrations have been reported separately in canine cancer. Correlations between the two exist in humans, but little work has examined links in dogs. This study aimed to determine plasma 25(OH)D and inflammatory marker concentrations in healthy dogs and dogs with cancer and to assess correlations in each group. Newly diagnosed dogs with B-cell lymphoma (B-cell, n = 25), T-cell lymphoma (T-cell, n = 9), osteosarcoma (OSA, n = 21), and mast cell tumour (MCT, n = 26) presenting to a tertiary oncology centre, and healthy dogs (n = 25), were enrolled. Plasma samples were analysed for 25(OH)D, C-reactive protein (CRP), haptoglobin (HP), serum amyloid A (SAA), alpha-1-acid glycoprotein (AAG), and 13 chemokines and cytokines. Dogs with B-cell had decreased plasma 25(OH)D (P = .03), and increased plasma CRP, AAG, HP, KC-like and MCP-1 concentrations (P < =.001, .011, <.001, .013 and .009, respectively) compared with healthy dogs. Plasma CRP, HP and SAA concentrations were increased in dogs with OSA compared with healthy dogs (P = .001, .010 and .027, respectively). No differences were noted in dogs with T-cell and MCT. Negative correlations were observed between plasma 25(OH)D concentrations and: AAG concentrations in dogs with T-cell (Rs  = -0.817, P = .007); GM-CSF concentrations (Rs  = -0.569, P = .007) in dogs with OSA; and IL-7 concentrations (Rs  = -0.548, P = .010) in dogs with OSA. Decreased 25(OH)D concentrations and increased concentrations of multiple inflammatory markers were observed in B-cell patients, supporting an association between 25(OH)D and inflammation. The cross-sectional study design meant the timing of changes could not be determined. Prospective cohort studies are warranted.


Asunto(s)
Neoplasias Óseas , Enfermedades de los Perros , Linfoma de Células T , Animales , Perros , Humanos , Biomarcadores , Neoplasias Óseas/veterinaria , Proteína C-Reactiva/análisis , Estudios Transversales , Haptoglobinas/análisis , Linfoma de Células T/veterinaria , Estudios Prospectivos , Vitamina D/análogos & derivados
5.
J Am Vet Med Assoc ; 252(12): 1521-1526, 2018 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-29889635

RESUMEN

OBJECTIVE To quantify vitamin D3 (VitD3) concentrations in commercial dog foods and compare those concentrations with Association of American Feed Control Officials (AAFCO) recommendations and manufacturer-reported concentrations. DESIGN Cross-sectional study. SAMPLE 82 commercial dog foods. PROCEDURES Samples of commercially available dog foods were obtained from owners of healthy dogs in the Guelph, ON, Canada, area and owners of dogs that were patients at the Ontario Veterinary College Health Sciences Centre's Mona Campbell Centre for Animal Cancer. For each food, the VitD3 concentration was determined by high-performance liquid chromatography-tandem mass spectrometry, and adherence to AAFCO and National Research Council recommendations was assessed. Analyzed VitD3 concentrations were compared with manufacturer-reported VitD3 concentrations and between wet and dry foods, among AAFCO nutritional adequacy statements (nutrient profiles vs feeding trials and adult maintenance vs all life stages), between foods sold only by veterinarians and those sold over the counter, and between small and large manufacturers. RESULTS The analyzed VitD3 concentration was below both AAFCO and National Research Council recommendations for one sample and below the assay detection limit for another. Analyzed VitD3 concentrations did not differ significantly from manufacturer-reported VitD3 concentrations or between wet and dry foods, among foods with different AAFCO nutritional adequacy statements, between foods sold only by veterinarians and those sold over the counter, or between foods produced by small and large manufacturers. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that manufacturer-reported VitD3 concentrations were accurate and that dog owners can be confident that VitD3 intake is adequate for AAFCO-compliant commercial dog foods.


Asunto(s)
Alimentación Animal/análisis , Colecalciferol/análisis , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Estudios Transversales , Perros , Guías como Asunto , Valor Nutritivo , Sociedades Veterinarias , Estados Unidos
6.
FEBS Lett ; 580(11): 2609-14, 2006 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-16643902

RESUMEN

The suppressor of cytokine signaling (SOCS) proteins are thought to exert their function through the recruitment of interacting-proteins to the ubiquitin/proteasome degradation pathway. All SOCS proteins bind an Elongin BC E3 ubiquitin ligase complex through the common Socs-box. Here, we show that haem-oxidized IRP2 ubiquitin ligase-1 (HOIL-1), another E3 ubiquitin ligase, interacts with SOCS6. The Ubl domain of HOIL-1 and the SH2 and Socs-box domains of SOCS6 are required for the interaction. HOIL-1 expression stabilizes SOCS6 and induces the ubiquitination and degradation of proteins associated with SOCS6. These data suggest that SOCS proteins may interact with different E3 ubiquitin ligases in addition to a common Elongin BC E3 complex.


Asunto(s)
Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina/metabolismo , Animales , Células COS , Chlorocebus aethiops , Ratones , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Proteínas Supresoras de la Señalización de Citocinas/genética , Factores de Transcripción , Ubiquitina-Proteína Ligasas/genética
7.
J Invest Dermatol ; 130(6): 1514-23, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20182440

RESUMEN

Abnormal fibrillinogenesis is associated with connective tissue disorders (CTDs), including Marfan syndrome (MFS), systemic sclerosis (SSc) and Tight-skin (Tsk) mice. We have previously shown that TGF-beta and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3 are both highly increased in Tsk skin. We investigated the role of CCN3 in abnormal fibrillinogenesis in Tsk mice, MFS, and SSc. Smad3 deletion in Tsk mice decreased CCN3 overexpression, suggesting that TGF-beta mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-beta and Wnt in vitro on CCN3 expression. Disruption of fibrillin-1 assembly by MFS fibrillin decreased CCN3 expression and skin from patients with early diffuse SSc showed a strong correlation between increased CCN3 and fibrillin-1 expression, suggesting that CCN3 regulation by fibrillin-1 extends to these CTDs. Diffuse SSc skin and sera also showed evidence of increased Wnt activity, implicating a Wnt stimulus behind this correlation. CCN3 overexpression markedly repressed fibrillin-1 assembly and also blocked other TGFbeta- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-beta and Wnt for fibrillin fibrillogenesis and profibrotic gene expression.


Asunto(s)
Síndrome de Marfan/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteína Hiperexpresada del Nefroblastoma/metabolismo , Esclerodermia Sistémica/metabolismo , Piel/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Animales , Biopsia , Proteínas CCN de Señalización Intercelular , Estudios de Casos y Controles , Células Cultivadas , Modelos Animales de Enfermedad , Fibrilina-1 , Fibrilinas , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Síndrome de Marfan/patología , Ratones , Ratones Mutantes , Proteínas de Microfilamentos/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Esclerodermia Sistémica/patología , Transducción de Señal/fisiología , Piel/patología , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Proteínas Wnt/antagonistas & inhibidores
8.
J Invest Dermatol ; 128(4): 871-81, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-17943183

RESUMEN

Systemic sclerosis (SSc) is a complex human disorder characterized by progressive skin fibrosis. To better understand the molecular basis of dermal fibrosis in SSc, we analyzed microarray gene expression in skin of the Tight-skin (Tsk) mouse, an animal model where skin fibrosis is caused by an in-frame duplication in fibrillin-1 (Fbn-1). Tsk skin showed increased mRNA levels of several genes involved in Wnt signaling, including Wnt2, Wnt9a, Wnt10b and Wnt11; Dapper homolog antagonist of beta-catenin (DACT1) and DACT2; Wnt-induced secreted protein 2; and secreted frizzled-related protein (SFRP)2 and SFRP4. RNase protection and northern blot confirmed microarray results. Furthermore, Wnt3a markedly stimulated matrix assembly of microfibrillar proteins, including Fbn-1, by cultured fibroblasts, suggesting that Wnts contribute to increased microfibrillar matrices in Tsk skin. Further analysis showed that SFRP4 expression is specifically increased in tissues expressing Tsk-Fbn-1, such as skeletal muscle and skin. The increase in SFRP4 mRNA in Tsk skin started 2 weeks after birth, following the increase in Wnt2 mRNA that occurred at birth. This suggests that SFRP4 may modulate Wnt functions in Tsk skin fibrosis. Lesional skin from SSc patients also showed large increases in SFRP4 mRNA and protein levels in the deep dermis compared to healthy skin, suggesting that the Wnt pathway might regulate skin fibrosis in SSc.


Asunto(s)
Proteínas de Microfilamentos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Esclerodermia Sistémica/etiología , Piel/metabolismo , Proteínas Wnt/metabolismo , Proteína wnt2/metabolismo , Animales , Fibrilina-1 , Fibrilinas , Regulación de la Expresión Génica , Humanos , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas/genética , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/metabolismo , Proteína wnt2/genética
9.
J Biol Chem ; 282(1): 800-8, 2007 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-17099216

RESUMEN

Elastic fibers are complex structures composed of a tropoelastin inner core and microfibril outer mantle guiding tropoelastin deposition. Microfibrillar proteins mainly include fibrillins and microfibril-associated glycoproteins (MAGPs). MAGP-2 exhibits developmental expression peaking at elastic fiber onset, suggesting that MAGP-2 mediates elastic fiber assembly. To determine whether MAGP-2 regulates elastic fiber assembly, we used an in vitro model featuring doxycycline-regulated cells conditionally overexpressing exogenous MAGP-2 and constitutively expressing enhanced green fluorescent protein-tagged tropoelastin. Analysis by immunofluorescent staining showed that MAGP-2 overexpression dramatically increased elastic fibers levels, independently of extracellular levels of soluble tropoelastin, indicating that MAGP-2 stimulates elastic fiber assembly. This was associated with increased levels of matrix-associated MAGP-2. Electron microscopy showed that MAGP-2 specifically associates with microfibrils and that elastin globules primarily colocalize with MAGP-2-associated microfibrils, suggesting that microfibril-associated MAGP-2 facilitates elastic fiber assembly. MAGP-2 overexpression did not change levels of matrix-associated fibrillin-1, MAGP-1, fibulin-2, fibulin-5, or emilin-1, suggesting that microfibrils and other elastic fiber-associated proteins known to regulate elastogenesis do not mediate MAGP-2-induced elastic fiber assembly. Moreover, mutation analysis showed that MAGP-2 does not stimulate elastic fiber assembly through its RGD motif, suggesting that integrin receptor binding does not mediate MAGP-2-induced elastic fiber assembly. Because MAGP-2 interacts with Jagged-1 that controls cell-matrix interaction and cell motility, two key factors in elastic fiber macroassembly, microfibril-associated MAGP-2 may stimulate elastic fiber macroassembly by targeting the release of elastin globules from the cell membrane onto developing elastic fibers.


Asunto(s)
Proteínas Contráctiles/fisiología , Proteínas de la Matriz Extracelular/fisiología , Microfibrillas/metabolismo , Animales , Línea Celular , Membrana Celular/metabolismo , Doxiciclina/farmacología , Elasticidad , Proteínas de la Matriz Extracelular/química , Fibroblastos/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Ratones , Microscopía Electrónica , Microscopía Fluorescente , Plásmidos/metabolismo , Factores de Empalme de ARN , Proteínas Recombinantes/química , Transfección
10.
Curr Opin Rheumatol ; 18(6): 582-7, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17053502

RESUMEN

PURPOSE OF REVIEW: Important recent understandings of fibrillins and fibrillin-associated microfibril proteins suggest new ways these proteins might contribute to tissue fibrosis seen in systemic sclerosis by regulating latent transforming growth factor-beta. This review discusses mutant-fibrillin mouse models of Marfan syndrome and SSc (Tsk mice), and studies suggesting that alterations in microfibrils might contribute to human SSc. RECENT FINDINGS: Fibrillin-1 mutations associated with Marfan syndrome have recently been shown to induce genes activated by TGF-beta. The inhibition of TGF-beta in these mouse models largely reverses phenotypic and pathologic disease manifestations. Recent studies suggest that alterations in the fibrillin-1 structure from mutant Tsk fibrillin cause hypodermal fibrosis and associated changes in dermal gene expression, suggesting stimulation of cytokine-mediating signals. Genetic mutations in fibrillin-1, in a higher frequency in SSc patient populations, and autoantibodies to fibrillin provide potential links to human SSc. SUMMARY: Fibrillin is placed centrally not only as the primary structural component of microfibrils, but also a key regulator of cytokines in the TGF-beta superfamily. Fibrillin may thus communicate alterations in matrix to fibroblast gene expression. These observations complement emerging understandings of the effects of Tsk fibrillin, and genetic and autoimmune studies of human fibrillin on dermal fibrosis.


Asunto(s)
Proteínas de la Matriz Extracelular/metabolismo , Síndrome de Marfan/metabolismo , Proteínas de Microfilamentos/metabolismo , Esclerodermia Sistémica/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Modelos Animales de Enfermedad , Proteínas de la Matriz Extracelular/genética , Fibrilina-1 , Fibrilinas , Regulación de la Expresión Génica , Humanos , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Ratones , Ratones Mutantes , Microfibrillas/genética , Microfibrillas/metabolismo , Proteínas de Microfilamentos/genética , Mutación , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Piel/metabolismo , Piel/patología , Factor de Crecimiento Transformador beta/genética
11.
J Biol Chem ; 279(13): 12249-59, 2004 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-14707129

RESUMEN

Suppressor of cytokine signaling (SOCS) proteins are a family of Src homology 2-containing adaptor proteins. Cytokine-inducible Src homology domain 2-containing protein, SOCS1, SOCS2, and SOCS3 have been implicated in the down-regulation of cytokine signaling. The function of SOCS4, 5, 6, and 7 are not known. KIT receptor signaling is regulated by protein tyrosine phosphatases and adaptor proteins. We previously reported that SOCS1 inhibited cell proliferation in response to stem cell factor (SCF). By screening the other members of SOCS family, we identified SOCS6 as a KIT-binding protein. Using KIT mutants and peptides, we demonstrated that SOCS6 bound directly to KIT tyrosine 567 in the juxtamembrane domain. To investigate the function of this interaction, we constitutively expressed SOCS6 in cell lines. Ectopic expression of SOCS6 in Ba/F3-KIT cell line decreased cell proliferation in response to SCF but not SCF-induced chemotaxis. SOCS6 reduced SCF-induced activation of ERK1/2 and p38 but not activation of AKT or STATs in Ba/F3, murine embryonic fibroblast (MEF), or COS-7 cells. SOCS6 did not impair ERK and p38 activation by other stimuli. These results indicate that SOCS6 binds to KIT juxtamembrane region, which affects upstream signaling components leading to MAPK activation. Our results indicate that KIT signaling is regulated by several SOCS proteins and suggest a putative function for SOCS6 as a negative regulator of receptor tyrosine kinases.


Asunto(s)
Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Transducción de Señal , Secuencia de Aminoácidos , Animales , Anisomicina/farmacología , Células COS , División Celular , Línea Celular , Movimiento Celular , Quimiotaxis , Regulación hacia Abajo , Activación Enzimática , Glutatión Transferasa/metabolismo , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Datos de Secuencia Molecular , Mutación , Péptidos/química , Fosforilación , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/metabolismo , Retroviridae/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Células Madre/metabolismo , Proteínas Supresoras de la Señalización de Citocinas , Factores de Tiempo , Técnicas del Sistema de Dos Híbridos , Tirosina/química , Proteínas Quinasas p38 Activadas por Mitógenos , Dominios Homologos src
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