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1.
Pediatr Hematol Oncol ; 38(3): 227-238, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33205673

RESUMEN

Bone marrow minimal residual disease (MRD) is the strongest predictor of relapse in children with acute lymphoblastic leukemia (ALL). 6-mercaptopurine (6MP) in ALL therapy has wide inter-individual variation in disposition and is strongly influenced by polymorphisms in the thiopurine methyltransferase (TPMT) gene. In 952 patients treated according to the NOPHO ALL2008 protocol, we explored the association between thiopurine disposition, TPMT genotypes and MRD levels after consolidation therapy with 6MP, high-dose methotrexate (HD-MTX), asparaginase, and vincristine. The levels of the cytotoxic DNA-incorporated thioguanine were significantly higher on day 70-79 in G460A/A719G TPMT heterozygous (TPMTHZ) compared to TPMT wild type (TPMTWT) patients (mean: 230.7 vs. 149.7 fmol/µg DNA, p = 0.002). In contrast, TPMT genotype did not associate with the end of consolidation MRD levels irrespective of randomization of the patients to fixed dose (25 mg/m2/day) or 6MP escalation (up to 50 or 75 mg/m2/day) during consolidation therapy.


Asunto(s)
Antineoplásicos/uso terapéutico , Mercaptopurina/uso terapéutico , Metiltransferasas/genética , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/uso terapéutico , Niño , Quimioterapia de Consolidación , Femenino , Humanos , Masculino , Metotrexato/uso terapéutico , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Vincristina/uso terapéutico
2.
Exp Eye Res ; 179: 142-149, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30439349

RESUMEN

Retinal ischemia remains a major cause of blindness in the world with few acute treatments available. Recent emphasis on retinal vasculature and the ophthalmic artery's vascular properties after ischemia has shown an increase in vasoconstrictive functionality, as previously observed in cerebral arteries following stroke. Specifically, endothelin-1 (ET-1) receptor-mediated vasoconstriction regulated by the MEK/ERK1/2 pathway. In this study, the ophthalmic artery of rats was occluded for 2 h with the middle cerebral artery occlusion model. MEK/ERK1/2 inhibitor U0126 was administered at 0, 6, and 24 h following reperfusion and the functional properties of the ophthalmic artery were evaluated at 48 h post reperfusion. Additionally, retinal function was evaluated at day 1, 4, and 7 after reperfusion. Occlusion of the ophthalmic artery led to a significant increase of endothelin-1 mediated vasoconstriction which can be attenuated by U0126 treatment, most evident at higher ET-1 concentrations of 10-7 M (Emax151.0 ±â€¯22.0% of 60 mM K+), vs non-treated ischemic arteries Emax 212.1 ±â€¯14.7% of 60 mM K+). Retinal function also deteriorated following ischemia and was improved with treatment with a-wave amplitudes of 725 ± 36 µV in control, 560 ± 21 µV in non-treated, and 668 ± 73 µV in U0126 treated at 2 log cd*s/m2 luminance in the acute stages (1 days post-ischemia). Full spontaneous retinal recovery was observed at day 7 regardless of treatment. In conclusion, this is the first study to show a beneficial in vivo effect of U0126 on vascular contractility following ischemia in the ophthalmic artery. Coupled with the knowledge obtained from cerebral vasculature, these results point towards a novel therapeutic approach following ischemia-related injuries to the eye.


Asunto(s)
Infarto de la Arteria Cerebral Media/fisiopatología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Arteria Oftálmica/fisiopatología , Retina/fisiopatología , Animales , Butadienos/farmacología , Electrorretinografía , Inhibidores Enzimáticos/farmacología , Inmunohistoquímica , Isquemia/fisiopatología , Masculino , Microscopía Fluorescente , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Músculo Liso Vascular/fisiología , Miografía , Nitrilos/farmacología , Ratas , Ratas Wistar , Vasoconstricción/fisiología
3.
Purinergic Signal ; 14(1): 83-90, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29290027

RESUMEN

The P2X7 receptor is a frequently studied member of the purinergic receptor family signalling via channel opening and membrane pore formation. Fluorescent imaging is an important molecular method for studying cellular receptor expression and localization. Fusion of receptors to fluorescent proteins might cause major functional changes and requires careful functional evaluation such as has been done for the rat P2X7 receptor. This study examines fusion constructs of the human P2X7 receptor. We assessed surface expression, channel opening with calcium influx, and pore formation using YO-PRO-1 dye uptake in response to BzATP stimulation in transfected cells. We found that tagging at the N-terminal of the human P2X7 receptor with the enhanced green fluorescent protein (eGFP) disturbed channel opening and pore formation despite intact surface expression. A triple hemagglutinin (3HA) fused to the N-terminal also disrupted pore formation but not channel opening showing that even a small tag alters the normal function of the receptor. Together, this suggests that in contrast to what has been observed for the rat P2X7 receptor, the human P2X7 receptor contains N-terminal motifs important for signalling that prevent the construction of a functionally active fusion protein.


Asunto(s)
Canales de Calcio/metabolismo , Colorantes Fluorescentes/farmacología , Proteínas Fluorescentes Verdes/farmacología , Receptores Purinérgicos P2X7/metabolismo , Transducción de Señal/fisiología , Humanos , Transducción de Señal/efectos de los fármacos
4.
Brain ; 140(6): 1657-1668, 2017 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-28460015

RESUMEN

The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways. In conclusion, our data show that decreased P2Y11 signalling plays an important role in the development of narcolepsy with cataplexy.


Asunto(s)
Narcolepsia/genética , Narcolepsia/fisiopatología , Receptores Purinérgicos P2/genética , Transducción de Señal/genética , Adulto , Cataplejía/genética , Cataplejía/fisiopatología , Exones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Linaje
5.
Scand Cardiovasc J ; 52(6): 340-343, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30481075

RESUMEN

OBJECTIVES: The purinergic system has not been investigated in detail following ischemia/reperfusion (I/R) injury in the heart. In the present study, we focus on both release and response to extracellular adenosine triphosphate (ATP). Pannexin (Panx) channels have been shown to be involved in ATP release from myocytes and can activate P2X1 and P2Y2 receptors on the coronary artery. DESIGN: We applied a well-characterized I/R model in rats, with 24 hours of reperfusion. Panx expression in the myocardial tissue was measured with quantitative polymerase chain reaction (qPCR) and flow cytometry. ATP release was detected in situ using luminescence and the vascular response to nucleotides determined in a wire myograph. RESULTS: Here, we show that Panx expression is increased after experimental myocardial I/R, leading to an increase in extracellular ATP release, which could be inhibited by probenecid. Functional studies revealed that the P2Y2 receptor-dependent contraction is reduced in the coronary artery after I/R, which might be a response to the increased ATP levels. CONCLUSION: We, therefore, conclude that the regulation of the arterial purinergic system minimizes coronary contractions following ischemia.


Asunto(s)
Adenosina Trifosfato/metabolismo , Conexinas/metabolismo , Vasos Coronarios/metabolismo , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Vasoconstricción , Animales , Conexinas/genética , Vasos Coronarios/fisiopatología , Modelos Animales de Enfermedad , Infarto del Miocardio/genética , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/fisiopatología , Proteínas del Tejido Nervioso/genética , Comunicación Paracrina , Ratas Sprague-Dawley , Receptores Purinérgicos P2Y2/metabolismo , Transducción de Señal
7.
Purinergic Signal ; 12(3): 427-37, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27246167

RESUMEN

The P2Y11 receptor is a member of the purinergic receptor family. It has been overlooked, somewhat due to the lack of a P2ry11 gene orthologue in the murine genome, which prevents the generation of knockout mice, which have been so helpful for defining the roles of other P2Y receptors. Furthermore, some of the studies reported to date have methodological shortcomings, making it difficult to determine the function of P2Y11 with certainty. In this review, we discuss the lack of a murine "P2Y11-like receptor" and highlight the limitations of the currently available methods used to investigate the P2Y11 receptor. These methods include protein recognition with antibodies that show very little specificity, gene expression studies that completely overlook the existence of a fusion transcript between the adjacent PPAN gene and P2RY11, and agonists/antagonists reported to be specific for the P2Y11 receptor but which have not been tested for activity on numerous other adenosine 5'-triphosphate (ATP)-binding receptors. We suggest a set of criteria for evaluating whether a dataset describes effects mediated by the P2Y11 receptor. Following these criteria, we conclude that the current evidence suggests a role for P2Y11 in immune activation with cell type-specific effects.


Asunto(s)
Receptores Purinérgicos P2 , Animales , Humanos
8.
Prostate ; 75(2): 126-40, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25327291

RESUMEN

BACKGROUND: Elevated levels of endogenous or exogenous estrogens during fetal life can induce permanent disturbances in prostate growth and predispose to precancerous lesions. Recent studies have indicated that also early anti-androgen exposure may affect prostate cancer risk. METHODS: We examined the influence of perinatal exposure to mixtures of anti-androgenic and estrogenic chemicals on prostate development. Wistar rats were exposed from gestation day 7 to postnatal day 22 to a mixture of 8 anti-androgenic compounds (AAMix), a mixture of four estrogenic compounds (EMix), or paracetamol or a mixture of all 13 compounds (TotalMix) in mixture ratios reflecting human exposure levels. RESULTS: Ventral prostate weights were reduced by the TotalMix and AAMix in pre-pubertal rats. Histological changes in prostate appeared with increasing age and indicated a shift from the normal age-dependent epithelial atrophy towards hyperplasia. These lesions showed similarities to pre-cancerous lesions in humans. Increased proliferation was observed already in pre-puberty and it was hypothesized that this could be associated with reduced ERß signaling, but no clear conclusions could be made from gene expression studies on ERß-related pathways. The influences of the estrogenic chemicals and paracetamol on prostate morphology were minor, but in young adulthood the estrogen mixture reduced ventral prostate mRNA levels of Igf1 and paracetamol reduced the mRNA level ofPbpc3. CONCLUSIONS: Mixtures of endocrine disrupters relevant for human exposure was found to elicit persistent effects on the rat prostate following perinatal exposure, suggesting that human perinatal exposure to environmental chemicals may increase the risk of prostate cancer later in life.


Asunto(s)
Antagonistas de Andrógenos/toxicidad , Disruptores Endocrinos/toxicidad , Próstata/efectos de los fármacos , Próstata/patología , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/patología , Animales , Animales Recién Nacidos , Femenino , Masculino , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/fisiología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas Wistar
9.
Pharmacol Rep ; 71(5): 926-928, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31450027

RESUMEN

BACKGROUND: Narcolepsy with cataplexy is a neurological sleep disorder, which is believed to arise from the autoimmune destruction of hypocretin-producing neurons. The purinergic receptor P2Y11 is associated with narcolepsy in genome-wide association studies, and P2RY11 sequencing has further revealed eight rare missense mutations associated with the disease. Some of these mutations alter the signaling properties of P2Y11, but for some, no functional effects have been discovered so far. METHODS: This study examined the surface expression of the eight narcolepsy-associated P2Y11 mutations using an in vitro surface expression assay. RESULTS: The assay showed excellent discrimination between cells transfected with tagged wild type and the untagged P2Y11 receptor, proving complete specificity towards the 3HA-N-tag used for the assay. Our results show a decreased surface expression of the R307W P2Y11 mutant and a surface expression similar to wild type for the other seven mutants. CONCLUSION: Based on the present findings, alteration in surface expression is not likely to play a role in how P2Y11 influences narcolepsy pathogenesis. This is important because intact surface expression increases the usefulness of P2Y11 as a future drug target.


Asunto(s)
Expresión Génica , Narcolepsia/genética , Receptores Purinérgicos P2/genética , Variación Genética , Células HEK293 , Humanos , Mutación , Neuronas/metabolismo , Orexinas/metabolismo , Transfección
10.
J Vis Exp ; (140)2018 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-30346386

RESUMEN

Retinal pericytes play an important role in many diseases of the eye. Immunohistochemical staining techniques of retinal vessels and microvascular pericytes are central to ophthalmological research. It is vital to choose an appropriate method of visualizing the microvascular pericytes. We describe retinal microvascular pericyte immunohistochemical staining in cryo-sections, whole-mounts, and hypotonic isolated vasculature using antibodies for platelet-derived growth factor receptor ß (PDGFRß) and nerve/glial antigen 2 (NG2). This allows us to highlight advantages and shortcomings of each of the three tissue preparations for the visualization of the retinal microvascular pericytes. Cryo-sections provide transsectional visualization of all retinal layers but contain only a few occasional transverse cuts of the microvasculature. Whole-mount provides an overview of the entire retinal vasculature, but visualization of the microvasculature can be troublesome. Hypotonic isolation provides a method to visualize the entire retinal vasculature by the removal of neuronal cells, but this makes the tissue very fragile.


Asunto(s)
Técnicas Histológicas/métodos , Inmunohistoquímica/métodos , Pericitos/inmunología , Retina/diagnóstico por imagen , Vasos Retinianos/inmunología , Animales , Humanos , Ratas , Retina/metabolismo
11.
Front Immunol ; 9: 1159, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29937766

RESUMEN

Adenosine triphosphate (ATP) is known to induce cell death in T lymphocytes at high extracellular concentrations. CD4+ and CD8+ T lymphocytes have a differential response to ATP, which in mice is due to differences in the P2X7 receptor expression levels. By contrast, we observed that the difference in human CD4+ and CD8+ T lymphocyte response toward the synthetic ATP-analog BzATP is not explained by a difference in human P2X7 receptor expression. Rather, the BzATP-induced human P2X7 receptor response in naïve and immune-activated lymphocyte subtypes correlated with the expression of another ATP-binding receptor: the human P2Y11 receptor. In a recombinant expression system, the coexpression of the human P2Y11 receptor counteracted BzATP-induced human P2X7 receptor-driven lactate dehydrogenase release (a marker of cell death) and pore formation independent of calcium signaling. A mutated non-signaling human P2Y11 receptor had a similar human P2X7 receptor-inhibitory effect on pore formation, thus demonstrating that the human P2X7 receptor interference was not caused by human P2Y11 receptor signaling. In conclusion, we demonstrate an important species difference in the ATP-mediated cell death between mice and human cells and show that in human T lymphocytes, the expression of the human P2Y11 receptor correlates with human P2X7 receptor-driven cell death following BzATP stimulation.


Asunto(s)
Adenosina Trifosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2/metabolismo , Linfocitos T/fisiología , Animales , Señalización del Calcio , Muerte Celular , Células Cultivadas , Difosfonatos/farmacología , Humanos , Ratones , Naftalenosulfonatos/farmacología , Agonistas del Receptor Purinérgico P2Y/farmacología , Receptor Cross-Talk , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2X7/genética , Transgenes/genética
12.
Eur J Pharmacol ; 829: 85-92, 2018 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-29653090

RESUMEN

The main purpose of this study was to compare in vitro pharmacological properties of human αCGRP (CGRP) and a recently discovered metabolically stable CGRP analogue, SAX, in isolated rat and human artery segments. In rat, CGRP and SAX induced similar vasodilatory responses in isolated mesenteric artery with the potency of SAX being lower than that of CGRP (vasodilatory pEC50 8.2 ±â€¯0.12 and 9.0 ±â€¯0.11, respectively). A corresponding difference in receptor binding affinity of SAX and CGRP was determined in rat cerebral membranes (pKi 8.3 ±â€¯0.19 and 9.3 ±â€¯0.14, respectively). CGRP and SAX-induced vasodilation was antagonised with similar potencies by the CGRP receptor antagonist BIBN4096BS supporting a uniform receptor population for the agonists. In human tissue, SAX and CGRP induced similar pharmacological responses with different potencies in subcutaneous artery (vasodilatory pEC50 8.8 ±â€¯0.18 and 9.5 ±â€¯0.13, respectively) and human recombinant receptors (cAMP signalling pEC50 9.1 ±â€¯0.16 and 10.2 ±â€¯0.19). Like in the rat mesenteric artery, both SAX and CGRP-responses were inhibited by the CGRP receptor antagonist BIBN4096BS with similar antagonistic potencies. In conclusion, all pharmacological characteristics of SAX and CGRP in human and rat sources points towards action via a uniform BIBN4096BS sensitive receptor population with the potency of SAX being 5-10 fold lower than that of CGRP.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/química , Péptido Relacionado con Gen de Calcitonina/farmacología , Vasodilatadores/química , Vasodilatadores/farmacología , Animales , Encéfalo/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Bovinos , Estabilidad de Medicamentos , Humanos , Membranas/efectos de los fármacos , Membranas/metabolismo , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Albúmina Sérica Bovina/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatadores/metabolismo
13.
J Chem Neuroanat ; 78: 25-33, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27515691

RESUMEN

Focus on the purinergic receptor P2Y11 has increased following the finding of an association between the sleep disorder narcolepsy and a genetic variant in P2RY11 causing decreased gene expression. Narcolepsy is believed to arise from an autoimmune destruction of the hypothalamic neurons that produce the neuropeptide hypocretin/orexin. It is unknown how a decrease in expression of P2Y11 might contribute to an autoimmune reaction towards the hypocretin neurons and the development of narcolepsy. To advance narcolepsy research it is therefore extremely important to determine the neuroanatomical localization of P2Y11 in the brain with particular emphasis on the hypocretin neurons. In this article we used western blot, staining of blood smears, and flow cytometry to select two antibodies for immunohistochemical staining of macaque monkey brain. Staining was seen in neuron-like structures in cortical and hypothalamic regions. Rats do not have a gene orthologue to the P2Y11 receptor and therefore rat brain was used as negative control tissue. The chromogenic signal observed in macaque monkey brain in neurons was not considered reliable, because the antibodies stained rat brain in a similar distribution pattern. Hence, the neuroanatomical localization of the P2Y11 receptor remains undetermined due to the lack of specific P2Y11 antibodies for brain immunohistochemistry.


Asunto(s)
Cerebelo/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Receptores Purinérgicos P2/metabolismo , Animales , Inmunohistoquímica/métodos , Macaca , Ratas
14.
ALTEX ; 30(3): 319-30, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23861077

RESUMEN

This paper evaluates in vivo predictability of a battery of in vitro tests covering developmental toxicity and embryotoxicity of five widely used conazole fungicides. The conazoles were investigated in the embryonic stem cell test, and data were compared to in vivo embryotoxicity data. The same conazoles were evaluated on the basis of data from a battery of cell assays for endocrine activity, including assays for AR, ER, AhR, and sex hormone synthesis, and data were compared to in vivo developmental toxicity data. Overall, the ranking of the five conazole fungicides based on in vitro data were in reasonably good agreement with available in vivo effects. Ketoconazole and epoxiconazole are the most potent embryotoxic compounds, whereas prochloraz belongs to the most potent developmental toxicants. In conclusion, a rough prediction of the ranking of these conazole fungicides for in vivo toxicity data was possible by a holistic evaluation of data from a panel of cell-based assays.


Asunto(s)
Antifúngicos/clasificación , Antifúngicos/toxicidad , Alternativas a las Pruebas en Animales , Animales , Antifúngicos/química , Línea Celular , Humanos , Ratones , Valor Predictivo de las Pruebas , Pruebas de Toxicidad/métodos , Pruebas de Toxicidad/normas
15.
Reprod Toxicol ; 42: 180-91, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24036065

RESUMEN

Perinatal exposure to endocrine disrupting chemicals with estrogenic activity can adversely affect reproductive development, but few studies evaluating estrogen-sensitive endpoints have been performed in Wistar rats. Therefore, time-mated Wistar rats (n=10) were gavaged during gestation and lactation with 0, 5, 15 or 50µg/kg bw/day of ethinyl estradiol. This potent estrogen was found to induce an increased number of nipples and reduced ovary weight in female offspring. Malformations of female genitalia were found in young as well as adult offspring, as an increased AGD was seen at birth and a deeper urethral slit length was seen in adulthood. In prepubertal male offspring, estrogen-regulated gene expression in ventral prostate was increased dose-dependently and a decreased ventral prostate weight was seen at 15µg/kg. Female external sexual characteristics and prostate development were found to be targets for exposure to estrogenic compounds and may be of interest in studies on estrogenic environmental compounds.


Asunto(s)
Anomalías Inducidas por Medicamentos , Estrógenos/toxicidad , Etinilestradiol/toxicidad , Canal Anal/anomalías , Animales , Peso Corporal/efectos de los fármacos , Femenino , Masculino , Intercambio Materno-Fetal , Pezones/anomalías , Tamaño de los Órganos/efectos de los fármacos , Ovario/efectos de los fármacos , Ovario/crecimiento & desarrollo , Embarazo , Ratas , Ratas Wistar , Uretra/anomalías , Vagina/anomalías
16.
Mol Cell Endocrinol ; 361(1-2): 106-15, 2012 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-22526026

RESUMEN

Eleven environmental relevant chemicals were investigated for their ability to affect adipogenesis in vitro, biomarker release from adipocytes and PPARα and γ activation. We found that butylparaben stimulated adipogenesis in 3T3-L1 adipocytes and increased release of leptin, adiponectin and resistin from the cells. Butylparaben activated PPARγ as well, which may be a mediator of the adipogenic effect. Polychlorinated biphenyl (PCB)153 also stimulate adipogenesis and biomarker release, but did not affect PPARs. The data indicates that PPARγ activating chemicals often stimulate adipocyte differentiation although PPARγ activation is neither a requirement nor a guarantee for stimulation. Four out of the eleven chemicals (bisphenol A, mono-ethylhexyl phthalate, butylparaben, PCB 153) caused increased adipogenesis. The release of adipocyte-secreted hormones was sometimes but not always correlated with the effect on adipocyte differentiation. Eight chemicals were able to cause increased leptin release. These findings strengthen the hypothesis that chemicals can interfere with pathways related to obesity development.


Asunto(s)
Adipogénesis/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Contaminación de Alimentos/análisis , PPAR gamma/metabolismo , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Animales , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Leptina/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , PPAR alfa/metabolismo , Resistina/metabolismo , Coloración y Etiquetado
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