RESUMEN
BACKGROUND/OBJECTIVES: Maternal obesity increases risk for childhood obesity, but molecular mechanisms are not well understood. We hypothesized that primary umbilical vein endothelial cells (HUVEC) from infants of overweight and obese mothers would harbor transcriptional patterns reflecting offspring obesity risk. SUBJECTS/METHODS: In this observational cohort study, we recruited 13 lean (pre-pregnancy body mass index (BMI) <25.0 kg m-2) and 24 overweight-obese ('ov-ob', BMI⩾25.0 kg m-2) women. We isolated primary HUVEC, and analyzed both gene expression (Primeview, Affymetrix) and cord blood levels of hormones and adipokines. RESULTS: A total of 142 transcripts were differentially expressed in HUVEC from infants of overweight-obese mothers (false discovery rate, FDR<0.05). Pathway analysis revealed that genes involved in mitochondrial and lipid metabolism were negatively correlated with maternal BMI (FDR<0.05). To test whether these transcriptomic patterns were associated with distinct nutrient exposures in the setting of maternal obesity, we analyzed the cord blood lipidome and noted significant increases in the levels of total free fatty acids (lean: 95.5±37.1 µg ml-1, ov-ob: 124.1±46.0 µg ml-1, P=0.049), palmitate (lean: 34.5±12.7 µg ml-1, ov-ob: 46.3±18.4 µg ml-1, P=0.03) and stearate (lean: 20.8±8.2 µg ml-1, ov-ob: 29.7±17.2 µg ml-1, P=0.04), in infants of overweight-obese mothers. CONCLUSIONS: Prenatal exposure to maternal obesity alters HUVEC expression of genes involved in mitochondrial and lipid metabolism, potentially reflecting developmentally programmed differences in oxidative and lipid metabolism.
Asunto(s)
Células Endoteliales de la Vena Umbilical Humana/metabolismo , Metabolismo de los Lípidos/genética , Madres , Obesidad/genética , Complicaciones del Embarazo/genética , Cordón Umbilical/citología , Adulto , Estudios de Cohortes , Femenino , Desarrollo Fetal , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Lactante , Inflamación/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Mitocondrias/metabolismo , Obesidad/metabolismo , Obesidad/patología , Obesidad/prevención & control , Embarazo , Complicaciones del Embarazo/metabolismo , Complicaciones del Embarazo/patología , Efectos Tardíos de la Exposición PrenatalRESUMEN
The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30â mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30â mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30â mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20â mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15â mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30â mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4â min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5â mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.
Asunto(s)
Hidrazinas/farmacología , Hidrazonas/farmacología , Hipnóticos y Sedantes/farmacología , Actividad Motora/efectos de los fármacos , Receptores de GABA/efectos de los fármacos , Tiofenos/farmacología , Animales , Hidrazinas/química , Hidrazonas/química , Masculino , Ratones , Receptores de GABA/fisiología , Tiofenos/químicaRESUMEN
The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.
Asunto(s)
Animales , Masculino , Ratones , Hidrazinas/farmacología , Hidrazonas/farmacología , Hipnóticos y Sedantes/farmacología , Actividad Motora/efectos de los fármacos , Receptores de GABA/efectos de los fármacos , Tiofenos/farmacología , Hidrazinas/química , Hidrazonas/química , Receptores de GABA/fisiología , Tiofenos/químicaRESUMEN
Analisaram-se a etiologia e as características clínicas da doença-diarréica em 161 lactentes pertencentes a famílias de baixas condiçöes sócio-econômicas na cidade de Recife. O estudo foi realizado no Hospital Geral de Pediatria do Instituto Materno Infantil de Pernambuco. Acompanhou-se a evoluçäo clínica do quadro diarréico de 128 lactentes. Conclue-se que a doença diarréica é predominantemente de etiologia bacteriana no grupo estudado