RESUMEN
BACKGROUND: Although sodium glucose cotransporter 2 (SGLT2) inhibitors have many beneficial effects for type 2 diabetes, including decreased cardiovascular death, recent reports that they increased glucagon through SGLT2 inhibition raised some concern. Troglitazone, Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, was reported to increase SGLT2 in renal proximal tubule cells, but its role on pancreatic alpha cells have not been reported. We investigated the effect of troglitazone on SGLT2 expression in alpha cells and subsequent glucagon regulation in hyperglycemia. METHODS: An Alpha TC1-6 cell line was cultured in control (5 mM) or hyperglycemia (HG, 15 mM) for 72 h. We applied troglitazone with or without PPARγ antagonist (GW9662 10 µM). To investigate the involvement of PI3K/Akt pathway, we applied troglitazone with or without Wortmanin. We measured sodium glucose transporter 2 (SGLT2) and glucagon (GCG) mRNA and protein expression. PPAR gamma, PI3K and Akt protein were also measured. RESULTS: Exposure of alpha TC cells to HG for 72 h increased glucagon mRNA and protein expression. HG decreased SGLT2 mRNA and protein expression. Troglitazone significantly reversed HG-induced reduction of SGLT2 expression and increase of glucagon secretion. PPARγ antagonist (GW9662 10 µM) decreased the expression of SGLT2 and increased glucagon as HG did. Hyperglycemia increased PI3K and pAkt expression in alpha cells. Wortmanin (PI3K inhibitor, 1 µM) reversed HG-induced SGLT2 decrease and glucagon increase. Troglitazone treatment decreased PI3K and pAkt expression in HG. CONCLUSION: In conclusion, PPARγ agonist, troglitazone improved glucose transport SGLT2 dysfunction and subsequent glucagon dysregulation in alpha cell under hyperglycemia. Those effects were through the involvement of PI3K/pAkt signaling pathway. This study may add one more reason for the ideal combination of PPARγ agonist and SGLT2 inhibitor in clinical practice.
Asunto(s)
Cromanos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Células Secretoras de Glucagón/metabolismo , Glucagón/metabolismo , Hiperglucemia/fisiopatología , PPAR gamma/agonistas , Transportador 2 de Sodio-Glucosa/metabolismo , Tiazolidinedionas/farmacología , Animales , Células Cultivadas , Células Secretoras de Glucagón/efectos de los fármacos , Células Secretoras de Glucagón/patología , Glucosa/farmacología , Hipoglucemiantes/farmacología , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , TroglitazonaRESUMEN
We present a screening-level exposure-assessment method which integrates exposure from all plausible exposure pathways as a result of indoor residential use of cleaning products. The exposure pathways we considered are (i) exposure to a user during product use via inhalation and dermal, (ii) exposure to chemical residues left on clothing, (iii) exposure to all occupants from the portion released indoors during use via inhalation and dermal, and (iv) exposure to the general population due to down-the-drain disposal via inhalation and ingestion. We use consumer product volatilization models to account for the chemical fractions volatilized to air (fvolatilized ) and disposed down the drain (fdown-the-drain ) during product use. For each exposure pathway, we use a fate and exposure model to estimate intake rates (iR) in mg/kg/d. Overall, the contribution of the four exposure pathways to the total exposure varies by the type of cleaning activities and with chemical properties. By providing a more comprehensive exposure model and by capturing additional exposures from often-overlooked exposure pathways, our method allows us to compare the relative contribution of various exposure routes and could improve high-throughput exposure assessment for chemicals in cleaning products.
Asunto(s)
Contaminantes Atmosféricos/análisis , Contaminación del Aire Interior/análisis , Exposición a Riesgos Ambientales/análisis , Productos Domésticos/análisis , Administración Cutánea , Monitoreo del Ambiente/métodos , Humanos , Inhalación , Modelos Biológicos , Piel/química , VolatilizaciónRESUMEN
Exposure to fine particulate matter (PM2.5 ) is a major contributor to the global human disease burden. The indoor environment is of particular importance when considering the health effects associated with PM2.5 exposures because people spend the majority of their time indoors and PM2.5 exposures per unit mass emitted indoors are two to three orders of magnitude larger than exposures to outdoor emissions. Variability in indoor PM2.5 intake fraction (iFin,total ), which is defined as the integrated cumulative intake of PM2.5 per unit of emission, is driven by a combination of building-specific, human-specific, and pollutant-specific factors. Due to a limited availability of data characterizing these factors, however, indoor emissions and intake of PM2.5 are not commonly considered when evaluating the environmental performance of product life cycles. With the aim of addressing this barrier, a literature review was conducted and data characterizing factors influencing iFin,total were compiled. In addition to providing data for the calculation of iFin,total in various indoor environments and for a range of geographic regions, this paper discusses remaining limitations to the incorporation of PM2.5 -derived health impacts into life cycle assessments and makes recommendations regarding future research.
Asunto(s)
Contaminación del Aire Interior/análisis , Exposición a Riesgos Ambientales/análisis , Monitoreo del Ambiente , Material Particulado/análisis , HumanosRESUMEN
UNLABELLED: Consumer products and building materials emit a number of semivolatile organic compounds (SVOCs) in the indoor environment. Because indoor SVOCs accumulate in dust, we explore the use of dust to determine source strength and report here on analysis of dust samples collected in 30 US homes for six phthalates, four personal care product ingredients, and five flame retardants. We then use a fugacity-based indoor mass balance model to estimate the whole-house emission rates of SVOCs that would account for the measured dust concentrations. Di-2-ethylhexyl phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) were the most abundant compounds in these dust samples. On the other hand, the estimated emission rate of diethyl phthalate is the largest among phthalates, although its dust concentration is over two orders of magnitude smaller than DEHP and DiNP. The magnitude of the estimated emission rate that corresponds to the measured dust concentration is found to be inversely correlated with the vapor pressure of the compound, indicating that dust concentrations alone cannot be used to determine which compounds have the greatest emission rates. The combined dust-assay modeling approach shows promise for estimating indoor emission rates for SVOCs. PRACTICAL IMPLICATIONS: The combined dust-assay modeling approach in this study can be used to predict the source strength of indoor released compounds, integrating emissions from consumer products, building materials, and other home furnishings. Our findings show that estimated emission rates are closely related to not only the level of compounds on dust, but also the vapor pressure of the compound. Thus, a fugacity-based indoor mass balance model and measured dust concentrations can be used to estimate the whole-house emission rates from all sources in actual indoor settings, when individual sources of emissions are unknown.
Asunto(s)
Contaminación del Aire Interior/análisis , Polvo/análisis , Modelos Químicos , Compuestos Orgánicos Volátiles/análisis , California , Preescolar , Femenino , Humanos , Maryland , Pennsylvania , EmbarazoRESUMEN
This study investigates the protective effects of GamiHyangsa-Yukgunja (GHY, a popular herbal medicine formula) on indomethacin-induced gastric mucosal lesions and morphological change in rats. Subcutaneous injection of indomethacin (25 mg/kg) produced the following gastric morphological alterations: mucosa hemorrhagic infarct, mucosa cell necrosis, leukocyte infiltration, mucosa hemorrhagic erosion, and gastric pit disappearance. Tissue damages were accompanied by increased oxidative stress, lipid peroxidation, and decreases in superoxide dismutase (SOD), and catalase (CAT) activities, and glutathione (GSH) concentrations. Our results show that pretreatment of the rats with orally administered GHY extract (3.3 ml/kg/day) significantly reduced gastric lesion formation and caused the amelioration of several pathological changes in the above-mentioned gastric mucosal lesions. Concomitantly, GHY-pretreatment increased gastric mucosal SOD and CAT activities and GSH concentrations. We therefore propose that GHY exerts a prophylactic effect on the indomethacin-induced gastric mucosal lesions by enhancing antioxidant defense systems.
Asunto(s)
Antioxidantes/farmacología , Medicamentos Herbarios Chinos/farmacología , Indometacina/farmacología , Oxidantes/farmacología , Plantas Medicinales , Estómago/patología , Animales , Antioxidantes/metabolismo , Catalasa/metabolismo , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Oxidación-Reducción , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Estómago/efectos de los fármacos , Superóxido Dismutasa/metabolismoRESUMEN
Within a few minutes of T-cell activation, transcription of a set of genes including c-fos and c-jun is activated. For maximal induction of c-jun, at least two major signal pathways are required. One can be triggered by T-cell receptor engagement or phorbol esters and the other by anti-CD28 engagement. The c-jun promoter region between -117 and -50 contains binding sites for the transcription factors Spl, CTF, ATF/CREB, and MEF2. In this study, we sought to map the sequences in the c-jun promoter responsible for CD28-mediated induction in activated Jurkat T cell by point mutational analysis. We found that mutation of the c-jun MEF2 site strongly reduces CD28 induction of the promoter in Jurkat T cells and that MEF2D is the major binding molecule to the c-jun MEF2 site in Jurkat T cells. Mutation of the c-jun ATF site also partially reduced CD28 induction of the promoter. In addition, pretreatment with an endolysomotropic agent NH4Cl, an acidic sphingomyelinase inhibitor, completely inhibited the activation of the c-jun promoter by anti-CD28 antibody treatment, whereas pretreatment with wortmannin, a PI3-kinase inhibitor, did not affect the induction of the c-jun promoter. These results suggest that CD28 signaling leading to the c-jun promoter involves acidic sphingomyelinase, but not PI3-kinase, to activate factors binding to the MEF2 and ATF sites.
Asunto(s)
Antígenos CD28/fisiología , Proteínas de Unión al ADN/fisiología , Regulación de la Expresión Génica/inmunología , Genes jun/inmunología , Células Jurkat/metabolismo , Regiones Promotoras Genéticas/inmunología , Factores de Transcripción/fisiología , Sitios de Unión/genética , Humanos , Células Jurkat/inmunología , Proteínas de Dominio MADS , Factores de Transcripción MEF2 , Factores Reguladores Miogénicos , Fosfatidilinositol 3-Quinasas/fisiología , Secuencias Reguladoras de Ácidos Nucleicos/genética , Transducción de Señal/inmunología , Esfingomielina Fosfodiesterasa/fisiologíaRESUMEN
This article describes the first report of phakomatous choristoma of the eyelid in Korea. A six-month-old boy underwent excision of a congenital inferonasal orbital mass arising from the left lower lid. A dermoid cyst was suspected, however a diagnosis of phakomatous choristoma was made following conventional histology. An immunohistochemical study of this rare benign congenital tumor was conducted. The cuboidal epithelial cells comprising this choristoma showed strongly positive cytoplasmic staining with S-100 protein and vimentin. They also showed focally positive staining with a neuron-specific enolase, while they showed no immunoreactivity to cytokeratin or epithelial membrane antigen. The results of the immunohistochemical study support the conclusion that this tumor is of lenticular anlage origin.
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Coristoma/diagnóstico , Enfermedades de los Párpados/diagnóstico , Cristalino , Biomarcadores , Coristoma/metabolismo , Diagnóstico Diferencial , Células Epiteliales/patología , Enfermedades de los Párpados/metabolismo , Humanos , Lactante , Queratinas/metabolismo , Masculino , Mucina-1/metabolismo , Fosfopiruvato Hidratasa/metabolismo , Proteínas S100/metabolismo , Tomografía Computarizada por Rayos X , Vimentina/metabolismoRESUMEN
Juvenile xanthogranuloma is a xanthomatous and granulomatous condition that frequently arises before 1 year of age and mainly occurs on the head and trunk. We report a rare solitary juvenile xanthogranuloma on the right palm of a 10-year-old girl, present for one year. This solitary involvement of the palm has been reported only twice before.