Galectin-1 suppresses methamphetamine induced neuroinflammation in human brain microvascular endothelial cells: Neuroprotective role in maintaining blood brain barrier integrity.

Methamphetamine (Meth) abuse can lead to the breakdown of the blood-brain barrier (BBB) integrity leading to compromised CNS function. The role of Galectins in the angiogenesis process in tumor-associated endothelial cells (EC) is well established; however no data are available on the expression of Galectins in normal human brain microvascular endothelial cells and their potential role in maintaining BBB integrity. We evaluated the basal gene/protein expression levels of Galectin-1, -3 and -9 in normal primary human brain microvascular endothelial cells (BMVEC) that constitute the BBB and examined whether Meth altered Galectin expression in these cells, and if Galectin-1 treatment impacted the integrity of an in-vitro BBB. Our results showed that BMVEC expressed significantly higher levels of Galectin-1 as compared to Galectin-3 and -9. Meth treatment increased Galectin-1 expression in BMVEC. Meth induced decrease in TJ proteins ZO-1, Claudin-3 and adhesion molecule ICAM-1 was reversed by Galectin-1. Our data suggests that Galectin-1 is involved in BBB remodeling and can increase levels of TJ proteins ZO-1 and Claudin-3 and adhesion molecule ICAM-1 which helps maintain BBB tightness thus playing a neuroprotective role. Galectin-1 is thus an important regulator of immune balance from neurodegeneration to neuroprotection, which makes it an important therapeutic agent/target in the treatment of drug addiction and other neurological conditions.

Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes.

Delta-9-tetrahydrocannabinol (Delta(9)-THC), the main psychoactive component of marijuana, is known to dysregulate various immune responses. Cannabinoid (CB)-1 and -2 receptors are expressed mainly on cells of the central nervous system (CNS) and the immune system. The CNS is the primary target of cannabinoids and astrocytes are known to play a role in various immune responses. Thus we undertook this investigation to determine the global molecular effects of cannabinoids on normal human astrocytes (NHA) using genomic and proteomic analyses. NHA were treated with Delta(9)-THC and assayed using gene microarrays and two-dimensional (2D) difference gel electrophoresis (DIGE) coupled with mass spectrometry (MS) to elucidate their genomic and proteomic profiles respectively. Our results show that the expression of more than 20 translated protein gene products from NHA was differentially dysregulated by treatment with Delta(9)-THC compared to untreated, control NHA.

Endocrine regulation in asymmetric intrauterine fetal growth retardation.

OBJECTIVE: The ponderal index (PI) is a widely accepted measure of disproportionate growth or asymmetrical growth retardation by pediatricians worldwide. Identification of disproportionately grown small for gestational age (SGA) neonates by using the ponderal index as a measure of the nutritional status at birth, is important because they constitute a high-risk group among SGA neonates. Poor nutritional status of the mother could have a direct effect on the organs of the developing fetus and/or affect the endocrine milieu in the maternal feto-placental unit resulting in an increased incidence of intrauterine growth-retarded (IUGR)/SGA births. IUGR is a significant risk factor for adult disease. In this study, we have investigated the endocrine adaptation by the fetus to overcome the growth disadvantage caused due to poor nutritional status of the mother. MATERIALS AND METHODS: We examined the quantitative variations in hormonal and growth factor profiles in paired maternal and cord blood samples obtained from mothers and their neonates who were classified based on their growth status into SGA and appropriate for gestational age (AGA). RESULTS: (1) A total of 24.7% neonates had a PI < 2, indicating a high incidence of asymmetric IUGR in the population studied. (2) Anthropometric parameters measured in the mothers indicate that the mothers giving birth to neonates with a PI < 2 had poor nutritional status, both prior to and during pregnancy. (3) We observed increased levels of placental lactogen and prolactin and decreased levels of insulin in the cord blood of neonates with PI < 2, while lower levels of insulin-like growth factor 1 (IGF-1) and higher levels of epidermal growth factor (EGF) were observed in their mothers. CONCLUSION: Poor maternal nutritional status results in fetal adaptation to a growth restricted environment via the modulation of the pituitary-thyroid axis thereby altering the endocrine milieu, thus affecting fetal growth.

Thyroid hormone dysregulation in intrauterine growth retardation associated with maternal malnutrition and/or anemia.

Data on the effect of maternal malnutrition and/or anemia on thyroid hormone regulation in human fetuses are scarce, and would be of great importance in examining the relevance of Barker's hypothesis, which proposes adaptation of fetuses to undernutrition leading to permanent metabolic and endocrine changes that form the basis of adult diseases. To examine the quantitative variations in thyroid hormone profile of neonates born to malnourished and/or anemic mothers, we quantitated the T3, T4, rT3 and TSH levels in cord blood of neonates and maternal blood of their corresponding mothers that are malnourished and/or anemic. Further, we classified neonates born to each of these groups of mothers into Small for Gestational Age (SGA) or Appropriate for Gestational Age (AGA) based on the intrauterine growth curve for our population, and examined the thyroid hormone profile in these neonates. Our results show that firstly, the effects of malnutrition or anemia on thyroid hormone profile are distinct, secondly, significantly higher levels of cord blood T4 and correspondingly lower levels of T3 and rT3 are observed in the neonates born to anemic and malnourished mothers and thirdly, decreases in cord blood T3 levels were observed in Small for Gestational Age neonates born to anemic mothers. These observations lead us to speculate that alterations in the pituitary-thyroid function result in beneficial adaptations to the hostile intrauterine environment in malnutrition related growth retardation and anemia.

Effect of reduced inspired oxygen on fetal growth and maternal glucose metabolism in rat pregnancy.

The effect of prolonged exposure to a reduced fraction of inspired oxygen ([FiO2] 0.17 for 3 days) on maternal glucose kinetics, placental glucose transporters GLUT1 and GLUT3, and fetal growth was examined in rat pregnancy. Arterial and venous catheters were placed 3 days before the study. [3-(3)H]glucose tracer and deuterium labeling of water were used to measure the rates of glucose turnover and gluconeogenesis (GNG), respectively. Glucose uptake by maternal tissues was measured using [14C]2-deoxyglucose. Exposure to a reduced FiO2 resulted in a significant decrease (mean +/- SE) in fetal weight (room air, 4.02 +/- 0.04 g; 0.17 FiO2, 3.27 +/- 0.6 g, P < .02). There was a significant increase in the maternal-fetal glucose gradient (maternal-fetal glucose ratio: room air, 1.48 +/- 0.11; 0.17 FiO2, 2.26 +/- 0.24, P < .05), but there was no change in the maternal or fetal blood lactate concentration. No significant change in maternal blood pH was observed; however, a significant decrease in the blood partial pressure of O2 (PO2) occurred (room air, 97 +/- 0.5 torr; 0.17 FiO2, 81 +/- 1.8) on day 3. There was no change in the rate of turnover of glucose or GNG in the maternal compartment, nor was there any effect on glucose uptake by the maternal tissues. Placental GLUT1 and GLUT3 mRNA were not different in the control or experimental animals. We conclude that a mild reduction in the FiO2 for 3 days in rat pregnancy results in a significant fetal growth restriction that is not related to any observed alteration in maternal glucose metabolism. The lower glucose concentration in the fetal blood may be the consequence of an increase in fetal glucose metabolism, thereby resulting in an increased maternal-fetal gradient of glucose.