Maternal diets affected ceramides and fatty acids in brain regions of neonatal rats with prenatal ethanol exposure.

Objectives: Ceramide (Cer), known as apoptotic markers, increases with prenatal ethanol (EtOH) exposure, resulting in neuroapoptosis. Whether maternal nutrition can impact Cer concentrations in brain, via altering plasma and brain fatty acid compositions have not been examined. This study compared a standard chow with a formulated semi-purified energy dense (E-dense) diet on fatty acid composition, Cer concentrations, and apoptosis in plasma and brain regions (cortex, cerebellum, and hippocampus) of pups exposed to EtOH during gestation. Methods: Pregnant Sprague-Dawley rats were randomized into four groups: chow (n = 6), chow + EtOH (20% v/v) (n = 7), E-dense (n = 6), and E-dense + EtOH (n = 8). At postnatal day 7, representing the peak brain growth spurt in rats, lipids, and apoptosis were analyzed by gas chromatography and a fluorometric caspase-3 assay kit, respectively. Results: Maternal E-dense diet increased total fatty acid concentrations (p < 0.0001), including docosahexaenoic acid (DHA) (p < 0.0001) in plasma, whereas DHA concentrations were decreased in the cerebellum (p < 0.03) of pups than those from chow-fed dams. EtOH-induced Cer elevations in the hippocampus of pups born to dams fed chow were reduced by an E-dense diet (p < 0.02). No significant effects of maternal diet quality and EtOH were observed on caspase-3 activity. No significant correlations existed between plasma/brain fatty acids and Cer concentrations. Discussions: Maternal diet quality affected fatty acid compositions and Cer concentrations of pups with prenatal EtOH exposure, differently. Maternal nutrition has the potential to prevent or alleviate some of the adverse effects of prenatal EtOH exposure.

Fatty acid compositions of immature and mature testis are differently responsive to dietary docosahexasenoic acid during development in rats exposed to prenatal ethanol.

BACKGROUND: Ethanol (EtOH) exposure impairs, but docosahexaenoic acid (DHA) supports testis functions. This study investigated whether dietary DHA and prenatal EtOH exposure affected fatty acid profiles equally in immature and mature testis during developmental stages. METHODS: Female rats were exposed to ± EtOH (3g/kg BW, twice a day via gavage) throughout pregnancy, while consuming a diet supplemented ± DHA (1.4%, w/w). Pups were continued on their mother's diet after weaning with testes collected for fatty acid analysis at different stages of reproductive development, at gestational day 20 (GD20) and postnatal day (PD) 4, 21, 49, and 90, to present fetal, neonatal, weaning, prepubertal and adult stages, respectively. RESULTS: Regardless of EtOH exposure, dietary DHA significantly increased in testis DHA at all ages, with testis at weaning and prepuberty being more responsive to the diet (p<0.0002). Immature testis at GD20 and PD4 contained more DHA than n-6 docosapentaenoic acid (n-6 DPA) compared to mature testis while being well responsive to the maternal DHA diet through gestation and lactation. The level of n-6 very long chain fatty acids and (VLCFA) and n-6 DPA, distinctively increased from weaning and prepuberty, respectively, and were not reduced by the DHA diet at prepuberty and adulthood. Prenatal EtOH minimally affected testis fatty acids during development. CONCLUSION: Immature and mature testis responds differently to dietary DHA. The age around sexual maturity might be a critical time for dietary intervention as testis was more responsive to diet at this time point. The increase in DPA and n-6 VLCFA in matured testis while not affected by dietary DHA, indicates their critical roles in male reproductive function in rodents.

Saskatoon berry supplementation prevents cardiac remodeling without improving renal disease in an animal model of reno-cardiac syndrome.

Saskatoon berry (SKB) may have the potential to counter reno-cardiac syndrome owing to its antioxidant capacity. Here, we investigated the renal and cardiovascular effects of SKB-enriched diet in a rat model of reno-cardiac disease. Two groups of wild-type rats (+/+) and two groups of Hannover Sprague-Dawley (Han:SPRD-Cy/+) rats were given either regular diet or SKB diet (10% w/w total diet) for 8 weeks. Body weight, kidney weight, kidney water content, and left ventricle (LV) weight were measured. Blood pressure (BP) was measured by the tail-cuff method. Echocardiography was performed to assess cardiac structure and function. Serum creatinine and malondialdehyde (MDA) were also measured. Han:SPRD-Cy/+ rats had significantly higher kidney weight, kidney water content, LV weight, BP, and creatinine compared with wild-type rats (+/+). The SKB diet supplementation did not reduce kidney weight, kidney water content, BP, and LV weight in Han:SPRD-Cy/+ rats. The SKB diet also resulted in higher systolic BP in Han:SPRD-Cy/+rats. Han:SPRD-Cy/+rats showed cardiac structural remodeling (higher LV wall thickness) without any cardiac functional abnormalities. Han:SPRD-Cy/+ rats also had significantly higher creatinine whereas the concentration of MDA was not different. The SKB diet supplementation reduced cardiac remodeling and the concentration of MDA without altering the concentration of creatinine in Han:SPRD-Cy/+ rats. In conclusion, Han:SPRD-Cy/+ rats developed significant renal disease, high BP, and cardiac remodeling by 8 weeks without cardiac functional impairment. The SKB diet may be useful in preventing cardiac remodeling and oxidative stress in Han:SPRD-Cy/+rats. PRACTICAL APPLICATIONS: Saskatoon berry (SKB) is widely consumed as fresh fruit or processed fruit items and has significant commercial value. It may offer health benefits due to the presence of bioactives such as anthocyanins. SKB has very good culinary flavors, and it is an economically viable fruit crop in many parts of the world. The disease-modifying benefits of SKB are mainly ascribed to the antioxidant nature of its bioactive content. Polycystic kidney disease is a serious condition that can lead to renal and cardiac abnormalities. Here, we showed that SKB supplementation was able to mitigate cardiac remodeling and lower the level of a marker of oxidative stress in an animal model of reno-cardiac syndrome. Our study suggests that SKB possesses beneficial cardioprotective properties. Further evidence from human studies may help in increasing the consumption of SKB as a functional food.

Docosahexaenoic Acid: Outlining the Therapeutic Nutrient Potential to Combat the Prenatal Alcohol-Induced Insults on Brain Development.

Brain development is markedly affected by prenatal alcohol exposure, leading to cognitive and behavioral problems in the children. Protecting neuronal damage from prenatal alcohol could improve neural connections and functioning of the brain. DHA, a n-3 (ω-3) long-chain PUFA, is involved in the development of neurons. Insufficient concentrations of DHA impair neuronal development and plasticity of synaptic junctions and affect neurotransmitter concentrations in the brain. Alcohol consumption during pregnancy decreases the maternal DHA status and reduces the placental transfer of DHA to the fetus, resulting in less DHA being available for brain development. It is important to know whether DHA could induce beneficial effects on various physiological functions that promote neuronal development. This review will discuss the current evidence for the beneficial role of DHA in protecting against neuronal damage and its potential in mitigating the teratogenic effects of alcohol.

A pilot study on the effect of early provision of dietary docosahexaenoic acid on testis development, functions, and sperm quality in rats exposed to prenatal ethanol.

BACKGROUND: Prenatal ethanol (EtOH) exposure is associated with adverse effect on the male reproductive function. Dietary docosahexaenoic acid (DHA) is known to improve testis function and sperm parameters, thereby male fertility. This study piloted whether dietary DHA influences testis development and function in rats exposed to prenatal EtOH. METHODS: Pregnant female Sprague-Dawley rats (n = 30) received either EtOH (3 g/kg, twice a day, n = 14) or dextrose (n = 16) throughout pregnancy. Moreover, they were fed either diet supplemented with (Cont + DHA, n = 8, EtOH + DHA, n = 6) or without DHA (1.4% w/w of total fatty acids) (Cont, EtOH, n = 8 each), with pups being continued on their mothers' diet after weaning. Tissues were collected at gestational day (GD) 20, postnatal day (PD) 4, 21, 49 and 90 for analyzing testicular developmental markers and sperm parameters, and plasma for testosterone. RESULTS: Dietary DHA increased serum testosterone at GD20 (p < .05) and sperm normal morphology at PD90 (p < .0001) compared to the group without DHA supplementation. Dietary DHA also increased the height of germinal epithelium at peripuberty, PD49 (p < .03). The EtOH exposure induced a marked decline in the testicular gene expression of StAR at PD49 (p < .02) than those of non-EtOH treated group. CONCLUSIONS: These findings indicate that dietary DHA may positively contribute to male fertility by impacting sperm normal morphology likely by increasing fetal testosterone level. Prenatal EtOH exposure did not adversely affect the overall testis developmental markers during development and sperm parameters in adulthood.

DHA supplementation during prenatal ethanol exposure alters the expression of fetal rat liver genes involved in oxidative stress regulation.

Prenatal ethanol (EtOH) exposure is known to induce adverse effects on fetal brain development. Docosahexaenoic acid (DHA) has been shown to alleviate these effects by up-regulating antioxidant mechanisms in the brain. The liver is the first organ to receive enriched blood after placental transport. Therefore, it could be negatively affected by EtOH, but no studies have assessed the effects of DHA on fetal liver. This study examined the effects of maternal DHA intake on DHA status and gene expression of key enzymes of the glutathione antioxidant system in the fetal liver after prenatal EtOH exposure. Pregnant Sprague-Dawley dams were intubated with EtOH for the first 10 days of pregnancy, while being fed a control or DHA-supplemented diet. Fetal livers were collected at gestational day 20, and free fatty acids and phospholipid profile, as well as glutathione reductase (GR) and glutathione peroxidase-1 (GPx1) gene expressions, were assessed. Prenatal EtOH exposure increased fetal liver weight, whereas maternal DHA supplementation decreased fetal liver weight. DHA supplementation increased fetal liver free fatty acid and phospholipid DHA independently of EtOH. GR and GPx1 messenger RNA (mRNA) expressions were significantly increased and decreased, respectively, in the EtOH-exposed group compared with all other groups. Providing DHA normalized GR and GPx1 mRNA expression to control levels. This study shows that maternal DHA supplementation alters the expression of fetal liver genes involved in the glutathione antioxidative system during prenatal EtOH exposure. The fetal liver may play an important role in mitigating the signs and symptoms of fetal alcohol spectrum disorders in affected offspring.

Vascular and cardiac effects of grape powder in the spontaneously hypertensive rat.

BACKGROUND: We previously reported that resveratrol, a polyphenol found in red grapes, attenuated changes in small artery geometry and stiffness, as well as cardiac hypertrophy and cardiac function in the spontaneously hypertensive rat (SHR). However, in addition to resveratrol, grapes contain a variety of bioactive polyphenols such as catechins, anthocyanins, and flavonoids. Therefore, we investigated the effects of grape consumption in SHR. METHODS: Wistar-Kyoto (WKY) rats and SHR were treated with freeze-dried grape powder for 10 weeks. Dilatory, geometry, and stiffness properties of mesenteric small arteries were assessed by pressurized myography. Left ventricular mass index and cardiac function were assessed by two-dimensional guided M-mode and pulse-wave Doppler echocardiography. RESULTS: Elevated blood pressure in SHR was associated with remodeling and impaired endothelium-dependent relaxation of small arteries. Augmented left ventricular mass index (reflecting hypertrophy) and diminished cardiac function were also evident in SHR. Although grape treatment failed to affect cardiac dysfunction, it elicited a significant reduction in blood pressure, improved arterial relaxation, increased vascular compliance, and attenuated cardiac hypertrophy. CONCLUSIONS: Treatment with whole grape powder conferred mild vascular and cardiac benefits in SHR. Therefore, dietary grape consumption may be a feasible and salutary adjunct to pharmacological treatment of human hypertension.

Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats.

We hypothesized that a low-dose resveratrol will reverse cardiovascular abnormalities in rats fed a high-fat (HF) diet. Obese prone (OP) and obese resistant (OR) rats were fed an HF diet for 17 weeks; Sprague-Dawley rats fed laboratory chow served as control animals. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Assessments included echocardiography, blood pressure, adiposity, glycemia, insulinemia, lipidemia, and inflammatory and oxidative stress markers. Body weight and adiposity were significantly higher in OP rats when compared to OR rats. Echocardiographic measurements showed prolonged isovolumic relaxation time in HF-fed OP and OR rats. Treatment with resveratrol significantly improved diastolic function in OP but not in OR rats without affecting adiposity. OP and OR rats had increased blood pressure which remained unchanged with treatment. OP rats had elevated fasting serum glucose and insulin, whereas OR rats had increased serum glucose and normal insulin concentrations. Resveratrol treatment significantly reduced serum glucose while increasing serum insulin in both OP and OR rats. Inflammatory and oxidative stress markers, serum triglycerides and low-density lipoprotein were higher in OP rats, which were significantly reduced with treatment. In conclusion, HF induced cardiac dysfunction in both OP and OR rats. Treatment reversed abnormalities in diastolic heart function associated with HF feeding in OP rats, but not in OR rats. The beneficial effects of resveratrol may be mediated through regression of hyperglycemia, oxidative stress and inflammation.

Resveratrol prevents norepinephrine induced hypertrophy in adult rat cardiomyocytes, by activating NO-AMPK pathway.

Increased adrenergic drive is a major factor influencing the development of pathological cardiac hypertrophy, a stage which precedes overt heart failure. We examined the effect of resveratrol, a polyphenol (found predominantly in grapes), in preventing norepinephrine induced hypertrophy of adult cardiomyocyte, and the role of nitric oxide (NO) and adenosine monophosphate kinase (AMPK) in the effects of resveratrol. Cardiomyocytes isolated from adult rats were pretreated, or not, with resveratrol and then exposed to norepinephrine for 24h. In other experiments cardiomyocytes were also treated with different pharmacological inhibitors of NO synthase, AMPK and sirtuin for elucidating the signaling pathways underlying the effect of resveratrol. In order to validate the role of these signaling molecules in the in vivo settings, we also examined hearts from resveratrol treated spontaneously hypertensive rats (SHR), a genetic model of essential hypertension. Cardiomyocyte hypertrophy was determined by morphometry and (3)H-phenylalanine incorporation assay. NO levels and AMPK activity were measured using a specific assay kit and western blot analysis respectively. In vitro, resveratrol prevented the norepinephrine-induced increase in cardiomyocytes size and protein synthesis. Pharmacological inhibition of NO-AMPK signaling abolished the anti-hypertrophic action of resveratrol. Consistent with the in vitro findings, the anti-hypertrophic effect of resveratrol in the SHR model was associated with increases in NO and AMPK activity. This study demonstrates that NO-AMPK signaling is linked to the anti-hypertrophic effect of resveratrol in adult cardiomyocytes in vitro, and in the SHR model in vivo.

Resveratrol and small artery compliance and remodeling in the spontaneously hypertensive rat.

BACKGROUND: Small arteries from the spontaneously hypertensive rat (SHR) exhibit abnormal stiffness and geometry. This study investigated the effects of resveratrol, a polyphenol found in foods such as red grapes, on small arteries in SHR. METHODS: Wistar-Kyoto (WKY) rats and SHR were treated with resveratrol (2.5 mg/kg/day) for 10 weeks. Mesenteric small artery segments (third-order branches) were mounted in a pressure myograph, and vascular geometry and mechanical properties were calculated from lumen and media dimensions measured at incremental intraluminal pressures. Systolic blood pressure was measured by tail-cuff plethysmography. RESULTS: Increased compliance and reduced wall component stiffness were observed in SHR arteries vs. WKY arteries. Though resveratrol did not prevent lowering of wall component stiffness, it did attenuate, at least in part, the increased compliance of SHR arteries. In contrast, resveratrol increased compliance and reduced wall component stiffness in WKY arteries. SHR arteries exhibited remodeling that consisted of narrowed lumens, thickened media widths, and augmented media-to-lumen ratios. Resveratrol partially attenuated the remodeling process and also abolished exaggerated ERK signaling and expression of proliferating cell nuclear antigen (a marker of proliferation) in SHR arteries. The latter effects might be related to the ability of resveratrol to alleviate oxidative stress in SHR and enhance protein kinase G (PKG) activity. Elevated blood pressure in 20-week-old SHR was unaffected by resveratrol. CONCLUSIONS: The ability of resveratrol to limit the increase in compliance of SHR arteries is likely related to inhibitory effects on remodeling and pro-growth ERK signaling rather than blood pressure or arterial wall component stiffness.

Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure.

BACKGROUND: Cardiac hypertrophy is a compensatory enlargement of the heart in response to stress such as hypertension. It is beneficial in reducing stress placed on the heart. However, when the stress is of a chronic nature, it becomes pathological and leads to cardiac dysfunction and heart failure. Current treatments for hypertension and heart failure have proven beneficial but are not highly specific and associated with side effects. Accordingly, there is an important need for alternative strategies to provide safe and effective treatment. METHODS: Ten-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with resveratrol (2.5 mg/kg/day) for a period of 10 weeks. Systolic blood pressure, and cardiac structure and function were measured in all groups at different time points of resveratrol treatment. Oxidative stress was also determined in all groups after 10 weeks of resveratrol treatment. RESULTS: SHRs were characterized with high blood pressure and concentric hypertrophy from 15 weeks of age. Cardiac functional abnormalities were also evident in SHR from 15 weeks onwards. Resveratrol treatment significantly prevented the development of concentric hypertrophy, and systolic and diastolic dysfunction in SHR without lowering blood pressure. Resveratrol also significantly reduced the oxidative stress levels of cardiac tissue in SHR. CONCLUSIONS: Resveratrol treatment was beneficial in preventing the development of concentric hypertrophy and cardiac dysfunction in SHR. The cardioprotective effect of resveratrol in SHR may be partially mediated by a reduction in oxidative stress. Thus, resveratrol may have potential in preventing cardiac impairment in patients with essential hypertension.