Antiobesity activity of a sphingosine 1-phosphate analogue FTY720 observed in adipocytes and obese mouse model

Higher levels of body fat are associated with an increased risk for development numerous adverse health conditions. FTY720 is an immune modulator and a synthetic analogue of sphingosine 1-phosphate (S1P), activated S1P receptors and is effective in experimental models of transplantation and autoimmunity. Whereas immune modulation by FTY720 has been extensively studied, other actions of FTY720 are not well understood. Here we describe a novel role of FTY720 in the prevention of obesity, involving the regulation of adipogenesis and lipolysis in vivo and in vitro. Male C57B/6J mice were fed a standard diet or a high fat diet (HFD) without or with FTY720 (0.04 mg/kg, twice a week) for 6 weeks. The HFD induced an accumulation of large adipocytes, down-regulation of phosphorylated AMP-activated protein kinase alpha (p-AMPKalpha) and Akt (p-Akt); down-regulation of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL) and perilipin mRNA as well as up-regulation of phosphorylated HSL (p-HSL, Ser563) and glycogen synthase kinase 3 alpha/beta (p-GSK3alpha/beta). All these effects were blunted by FTY720 treatment, which inhibited adipogenesis and promoted lipolysis. Also, FTY720 significantly decreased lipid accumulation in maturing preadipocytes. FTY720 down-regulated the transcriptional levels of the PPARgamma, C/EBPalpha and adiponectin, which are markers of adipogenic differentiation. FTY720 significantly increased the release of glycerol and the expression of the HSL, ATGL and perilipin, which are regulators of lipolysis. These results show that FTY720 prevented obesity by modulating adipogenesis and lipolysis, and suggest that FTY720 is used for the treatment of obesity.

Sealing ability of MTA-Angelus with propyleneglycol in furcal perforations

This study evaluated the sealing ability of gray MTA-Angelus mixed with propyleneglycol in furcal perforations using a bacterial leakage test. Furcal perforations were created in 30 human mandibular molars using a size 3 round bur. The samples were divided randomly into 2 experimental groups (n=10) according to the mixing agent. In G1, the MTA powder was mixed with propyleneglycol, while distilled water was used in G2. A 3:1 powder-liquid ratio was used for both groups. The MTA was placed in the perforation with an MTA carrier and condensed with hand pluggers. Nonrepaired (n=5) and totally sealed (n=5) perforations served as positive and negative controls, respectively. Bacterial leakage was assessed daily for 30 days in a double-chamber apparatus with Enterococcus faecalis. Data were analyzed using Fisher exact test (p<0.05) for three leakage periods: 1st to 10th day (P1); 11th to 20th day (P2); and 21st to 30th day (P3). The positive control presented leakage in all specimens within the first 24 hours, while no leakage was observed in the negative control during the experimental period. Leakage was observed in five (50%) of the 10 samples of the propyleneglycol group (G1) and seven (70%) of the distilled water group (G2) by the 20th day, without significant difference between the groups in periods P1 and P2 (p=0.137). The leakage was significantly lower for G1 than G2 in period P3 (50% versus 100%, respectively, p=0.016). In this single aerobic bacterial leakage method, the use of propyleneglycol as a vehicle for gray MTAAngelus increased its sealing ability in furcal perforations at the end of the 30-day experimental period.

Este estudo avaliou a capacidade de selamento do MTA-Angelus cinza manipulado com propilenoglicol em perfuracoes de furca usando um teste de infiltracao bacteriana. Perfuracoes de furca foram criadas em 30 molares inferiores usando uma broca esferica numero 3. As amostras foram divididas aleatoriamente em dois grupos experimentais (n=10) de acordo com o agente de manipulacao. Em G1, o po do MTA foi manipulado com propilenoglicol enquanto que a agua destilado foi utilizada no G2. A proporcao po-liquido de 3:1 foi usada para ambos os grupos. O MTA foi colocado na perfuracao com uma porta- MTA e condensado com condensadores manuais. Perfuracoes nao-reparadas (n=5) e totalmente impermeabilizadas (n=5) serviram como controle positivo e negativo, respectivamente. A infiltracao bacteriana foi verificada diariamente durante 30 dias em um aparato de dupla camara com Enterococcus faecalis. Os dados foram analisados pelo teste exato de Fisher (p<0,05) para tres periodos: 1o ao 10o dia (P1), 11o ao 20o dia (P2) e do 21o ao 30o dia (P3). O controle positivo apresentou infiltracao em todas as amostras nas primeiras 24 horas, enquanto nenhuma infiltracao foi observada no controle positivo durante o periodo experimental. Infiltracao foi observada em 5 (50%) das 10 amostras do grupo do propilenoglicol (G1) e 7 (70%) do grupo da agua destilada no 20o dia, sem diferenca significativa entre o grupos nos periodos P1 e P2 (p=0,0137). A infiltracao foi significantemente menor para G1 que para G2 no periodo P3 (50% versus 100%, respectivamente, p=0,016). Neste metodo de infiltracao de apenas uma bacteria aerobica, o uso do propilenoglicol como veiculo para o MTA-Angelus cinza aumentou sua capacidade de selamento em perfuracoes de furca no final do periodo experimental de 30 dias.

Aumento del umbral tusígeno en sujetos sanos con el uso de Levodropropizina / Increase of the cough threshold to capsaicin in healthy adults by administering Levodropropizine

A randomized, prospective, double blind and placebo controlled study was designed to evaluate in 20 non smoker healthy adult volunteers the reproducibility and modification of cough threshold (CT) induced by capsaicin after placebo and Levodropropizine (a new synthetic drug). Adult volonteers of both sexes, mean age 34.9 years old (range: 18-57 years), inhaled increasing concentrations of capsaicin to determine the basal CT: log concentration of capsaicin that induced at least two consecutive coughs. The basal CT was 2.240 µM (+/- 0.060 SE), without differences by sex or age (p: ns), In 11 out of 18 subjects the CT increased from 2.358 (+/- 0,044 SE) on placebo to 2.469 µM (+/- 0.057) after Levodropropizine (p = 0.01). Two subjects were excluded due to intercurrent disease, not related to the study. No significant adverse reactions were reported during the study. Conclusion: Capsaicin induced reproducible controlled cough in 20 healthy volunteers and Levodropropizine given orally increased the cough threshold.

Se diseñó un estudio aleatorio prospectivo, doble ciego cruzado contra placebo, para estudiar la reproducibilidad y las modificaciones del umbral tusígeno (UT) inducido por capsaicina, luego de administrar placebo y Levodropropizina (un nuevo antitusivo sintético). Se determinó el UT basal (logaritmo de la concentración de capsaicina que induce al menos dos toses consecutivas) en 20 voluntarios adultos sanos, no fumadores de ambos sexos con edad promedio de 34,9 años (rango: 18 a 57 años). El promedio del UT basal fue 2,240 µM (+ - 0,060 ES), sin haber diferencias significativas por sexo o edad (p: ns). En 11 de 18 sujetos el UT aumentó de 2,358 µM (+/ - 0,044 ES) con placebo a 2,469 µM (+/- 0,057 ES) con Levodropropizina (p = 0,01). Dos sujetos fueron excluidos por presentar una enfermedad intercurrente no relacionada con el estudio. No hubo efectos adversos significativos. Conclusión: La capsaicina indujo reproduciblemente el reflejo tusígeno en 20 voluntarios sanos, y la Levodropropizina administrada por vía oral aumentó el umbral tusígeno.

Sphingosine mediates FTY720-induced apoptosis in LLC-PK1 cells

FTY720, a synthetic sphingoid base analog, was examined as a new sphingosine kinase inhibitor, which converts endogenous sphingosine into its phosphate form. With 20 micrometer of FTY720, sphingosine accumulated in the LLC-PK1 cells in a time- and dose-dependent manner. The FTY720 treated cells showed a high concentration of fragmented DNA, a high caspase-3 like activity and TUNEL staining cells. It was also found that the sphingosine and sphinganine level increased in a time- and dose-dependent manner within 12 h after the FTY720 treatment. The sphingosine kinase activity was reduced by FTY720 as much as other sphingosine kinase inhibitors, N, N-dimethylsphingosine (DMS), dl-threo-dihydrosphingosine (DHS). The fragmented DNA content as a result of the 20 micrometer of FTY720 treatment and by 5 micrometer of the exogenously added BSA-sphingosine complex indicated typical apoptosis. Under similar conditions, the accumulated sphingosine concentration in all the cells was almost identical even though the sphingosine distribution inside the cells was somewhat different. These results indicate that the FTY720 induced apoptosis is associated with the inhibition of the sphingosine kinase activity and is strongly associated with the successive accumulation of sphingosine.

Skin cleansing in neonates and infants--basics of cleansers.

OBJECTIVE: Using a proper cleanser for bathing neonatal and infant skin is of prime importance considering the anatomical differences with regard to adult skin. Choosing the right cleanser requires knowledge of the composition of a cleanser as well as the properties of the individual ingredients. METHODS: The article discusses the guidelines for cleansing the skin of neonates and infants. The characteristics of an ideal cleanser for pediatric skin have also been enumerated. RESULTS: In India, majority of cleansers recommended for babies do not mention their active ingredients. Their claims of "mildness" have not been substantiated with clinical studies. Cetaphil, a non-soap, lipid-free liquid cleanser, has been clinically proven to be non-irritating by the Chamber Scarification Test. Moreover, Cetaphil also has a pH of less than 7, which does not alter the physiological pH of skin. CONCLUSION: Hence, Cetaphil should definitely be considered while choosing a cleanser for neonates and infants.

Metabolic and pancreatic chances caused in male dogs by testosterone chronic administration

Se estudiaron la citología pancreática y las respuestas glucémica, insulinémica y de ácidos grasos libres séricos que se observan en perros durante la hiperglucemia inducida por la glucosa y en el curso de una hipoglucemia insulínica. Los perros estaban en una de las 3 condiciones siguientes: 1) no tratados, 2) bajo tratamiento con propilenoglicol (controles de vehículo) y 3) bajo tratamiento con propionato de testosterona en su vehículo. Dosis de testosterona: 0.75 mg/Kg peso corporal/día, una vez por día. Ambos tratamientos, intramusculares, duraron 2 semanas. En los páncreas de perros no tratados, los islotes presentaban bordes irregulares con saliencias agudas, y las células B se podían apreciar claramente, con su elevado contenido de gránulos de insulina. Las imágenes negativas de los núcleos de las células B se presentaron en la parte central de dichas. En los páncreas de perros tratados con testosterona, los citoplasmas amarillentos de las células B parecían vacíos, conteniendo sólo unos pocos gránulos beta (pequeña cantidad de insulina almacenada). Parecía que las células B presentaban una gran cantidad de vacuolas. El perfil glucémico en las pruebas de glucosa e insulina, el espacio de glucosa y el tiempo de media vida de la insulina en ciruclación en los perros bajo tratamiento con testosterona en su vehículo fueron simulares a los observados en perros tratados con propilenoglicol sólo, cuando se los estudió de igual modo. Aunque la testosterona no tuvo influencia alguna sobre la secreción de insulina, el espacio de insulina y la velocidad de desaparición de la insulina de la circulación, ella hace que la respuesta hipoglucemiante de la insulina exógena sea apenas mayor que lo normal, aumenta el nivel basal de ácidos grasos libres séricos, acelera la disminución de dichos ácidos durante la prueba de glucosa y favorece su aumento durante el período de recuperación de la hiperglucemia y su rebote durante la hipoglucemia insulínica. Todas estas acciones están relacionadas con la testosterona misma, más allá de las ocasionadas por el vehículo solo