Phospholipase Cε hydrolyzes perinuclear phosphatidylinositol 4-phosphate to regulate cardiac hypertrophy.

Phospholipase Cε (PLCε) is a multifunctional enzyme implicated in cardiovascular, pancreatic, and inflammatory functions. Here we show that conditional deletion of PLCε in mouse cardiac myocytes protects from stress-induced pathological hypertrophy. PLCε small interfering RNA (siRNA) in ventricular myocytes decreases endothelin-1 (ET-1)-dependent elevation of nuclear calcium and activation of nuclear protein kinase D (PKD). PLCε scaffolded to muscle-specific A kinase-anchoring protein (mAKAP), along with PKCε and PKD, localizes these components at or near the nuclear envelope, and this complex is required for nuclear PKD activation. Phosphatidylinositol 4-phosphate (PI4P) is identified as a perinuclear substrate in the Golgi apparatus for mAKAP-scaffolded PLCε. We conclude that perinuclear PLCε, scaffolded to mAKAP in cardiac myocytes, responds to hypertrophic stimuli to generate diacylglycerol (DAG) from PI4P in the Golgi apparatus, in close proximity to the nuclear envelope, to regulate activation of nuclear PKD and hypertrophic signaling pathways.

The association between dairy product consumption and cognitive function in the National Health and Nutrition Examination Survey.

The present cross-sectional study sought to determine the potential relationships between the intake of dairy foods (total dairy products, milk and cheese) and cognitive function through information garnered in the National Health and Nutrition Examination Surveys (1988-94 and 1999-2002). Cognitive measures of vasomotor speed, coding speed and immediate memory recall were assessed from a simple reaction time task (SRTT), symbol-digit substitution test (SDST) and serial digit learning task, respectively, in adults 20-59 years of age. A summation of the percentile rank scores on each of the three tests provided a measure of overall cognitive function. In adults 60 years of age and above, a story recall test and a digit-symbol substitution test (DSST) were utilised to determine cognitive function in an elderly population. The results indicated that cognitive scores for the SRTT were not different between consumers and non-consumers of dairy foods. However, there were associations observed between 20- and 59-year-old consumers of total dairy foods and a higher SDST percentile score (53.2 (SE 1.3) to 49.4 (SE 2.0)) and a calculated global cognitive percentile score (53.3 (SE 1.1) to 50.2 (SE 1.4)) compared with non-consumers. A similar significant association was observed with cheese consumers. In adults over 60 years of age, an association between total dairy product consumption and higher DSST percentile scores (51.5 (SE 1.9) to 46.2 (se 3.0)) was also observed. These findings highlight the need for additional research on how dairy products may affect cognition and by what mechanisms, through its nutrients or other components.

Tumor necrosis factor-alpha-mediated regulation of the inositol 1,4,5-trisphosphate receptor promoter.

Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, has been implicated as a central mediator in multiple homeostatic and pathologic processes. Signaling cascades downstream of its cellular cognate receptors, as well as the resultant transcriptional responses have received intense interest in regards to how such signals impact cellular physiology. Notably, TNF-alpha was shown to potentiate neuronal Ca(2+) signaling by enhancing type-1 inositol 1,4,5-trisphosphate receptor (IP(3)R) steady-state mRNA levels. In the present study, we sought to determine the promoter region ultimately responsive to TNF-alpha exposure. We report that a sequence encompassing a specificity protein 1 (SP-1) binding site is necessary for TNF-alpha regulation. Electrophoretic mobility shift analysis demonstrated specific binding to this sequence, while site-directed mutagenesis of this site abrogated both JNK-mediated regulation as well as transcription factor binding. Expression of a dominant-negative SP-1 eliminated both the enhanced promoter activity and the elevated IP(3)R-mediated Ca(2+) signals observed with TNF-alpha exposure. Overall, these data delineate a key pathway by which TNF-alpha in a neuronal environment modulates IP(3)R expression and intracellular Ca(2+) homeostasis.

Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice.

Inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta, appear integral in initiating and/or propagating Alzheimer's disease (AD)-associated pathogenesis. We have previously observed a significant increase in the number of mRNA transcripts encoding the pro-inflammatory cytokine TNF-alpha, which correlated to regionally enhanced microglial activation in the brains of triple transgenic mice (3xTg-AD) before the onset of overt amyloid pathology. In this study, we reveal that neurons serve as significant sources of TNF-alpha in 3xTg-AD mice. To further define the role of neuronally derived TNF-alpha during early AD-like pathology, a recombinant adeno-associated virus vector expressing TNF-alpha was stereotactically delivered to 2-month-old 3xTg-AD mice and non-transgenic control mice to produce sustained focal cytokine expression. At 6 months of age, 3xTg-AD mice exhibited evidence of enhanced intracellular levels of amyloid-beta and hyperphosphorylated tau, as well as microglial activation. At 12 months of age, both TNF receptor II and Jun-related mRNA levels were significantly enhanced, and peripheral cell infiltration and neuronal death were observed in 3xTg-AD mice, but not in non-transgenic mice. These data indicate that a pathological interaction exists between TNF-alpha and the AD-related transgene products in the brains of 3xTg-AD mice. Results presented here suggest that chronic neuronal TNF-alpha expression promotes inflammation and, ultimately, neuronal cell death in this AD mouse model, advocating the development of TNF-alpha-specific agents to subvert AD.

Dairy and blood pressure: a fresh look at the evidence.

The Dietary Guidelines for Americans, 2010 indicated there is moderate evidence for an association between the consumption of dairy foods and lower blood pressure in adults; however, it also stated that more evidence was needed, especially in clinical trials, to fully delineate a causal relationship. The purpose of this review is to provide background by examining the historical literature and the evidence reviewed by the 2010 Dietary Guidelines Advisory Committee, to examine the gaps in knowledge indicated by that committee, and to determine if recently published evidence is sufficient to elucidate or dismiss an association between dairy foods and blood pressure maintenance. Examination of the newly published literature, together with evaluation of the evidence as a whole, shows that the preponderance of evidence indicates dairy foods are beneficially associated with blood pressure; however, additional research is necessary to identify the mechanism of action of dairy foods. New evidence should come from carefully designed clinical trials that examine not only blood pressure outcomes but also the ability of dairy foods to affect the vasculature.

Effects of low-fat dairy intake on blood pressure, endothelial function, and lipoprotein lipids in subjects with prehypertension or stage 1 hypertension.

OBJECTIVE: This randomized crossover trial assessed the effects of 5 weeks of consuming low-fat dairy (one serving/day each of 1% fluid milk, low-fat cheese, and low-fat yogurt) versus nondairy products (one serving/day each of apple juice, pretzels, and cereal bar) on systolic and diastolic blood pressures (SBP and DBP), vascular function (reactive hyperemia index [RHI] and augmentation index), and plasma lipids. METHODS: Patients were 62 men and women (mean age 54.5 years, body mass index 29.2 kg/m(2)) with prehypertension or stage 1 hypertension (mean resting SBP/DBP 129.8 mmHg/80.8 mmHg) while not receiving antihypertensive medications. A standard breakfast meal challenge including two servings of study products was administered at the end of each treatment period. RESULTS: Dairy and nondairy treatments did not produce significantly different mean SBP or DBP in the resting postprandial state or from premeal to 3.5 hours postmeal (SBP, 126.3 mmHg versus 124.9 mmHg; DBP, 76.5 mmHg versus 75.7 mmHg), premeal (2.35 versus 2.20) or 2 hours postmeal (2.33 versus 2.30) RHI, and premeal (22.5 versus 23.8) or 2 hours postmeal (12.4 versus 13.2) augmentation index. Among subjects with endothelial dysfunction (RHI ≤ 1.67; n = 14) during the control treatment, premeal RHI was significantly higher in the dairy versus nondairy condition (2.32 versus 1.50, P = 0.002). Fasting lipoprotein lipid values were not significantly different between treatments overall, or in subgroup analyses. CONCLUSION: No significant effects of consuming low-fat dairy products, compared with low-fat nondairy products, were observed for blood pressures, measures of vascular function, or lipid variables in the overall sample, but results from subgroup analyses were consistent with the hypothesis that dairy foods might improve RHI in those with endothelial dysfunction.

Influence of dairy product and milk fat consumption on cardiovascular disease risk: a review of the evidence.

Although evidence has linked the consumption of saturated fat (SF) to increased LDL levels and an increased risk of the development of cardiovascular disease (CVD), recent findings have indicated that the link between CVD and SF may be less straightforward than originally thought. This may be due to the fact that some food sources high in SF contain an array of saturated and unsaturated fatty acids, each of which may differentially affect lipoprotein metabolism, as well as contribute significant amounts of other nutrients, which may alter CVD risk. The purpose of this review is to examine the published research on the relationship between milk fat containing dairy foods and cardiovascular health. The findings indicate that the majority of observational studies have failed to find an association between the intake of dairy products and increased risk of CVD, coronary heart disease, and stroke, regardless of milk fat levels. Results from short-term intervention studies on CVD biomarkers have indicated that a diet higher in SF from whole milk and butter increases LDL cholesterol when substituted for carbohydrates or unsaturated fatty acids; however, they may also increase HDL and therefore might not affect or even lower the total cholesterol:HDL cholesterol ratio. The results from the review also indicate that cheese intake lowers LDL cholesterol compared with butter of equal milk fat content. In addition, the review highlights some significant gaps in the research surrounding the effects of full-fat dairy on CVD outcomes, pointing to the need for long-term intervention studies.

Vitamin D intake and status are associated with lower prevalence of metabolic syndrome in U.S. adults: National Health and Nutrition Examination Surveys 2003-2006.

BACKGROUND: Previous reports have shown that metabolic syndrome and some metabolic syndrome components are associated with serum 25-hydroxyvitamin D [25(OH)D]. METHODS: Using the National Health and Nutrition Examination Surveys (NHANES), 2003-2006, we evaluated the associations of vitamin D intake (n=3543) and vitamin D status [25(OH)D; n=3529], with the prevalence of metabolic syndrome and its components in adults 20 years and older. Exclusion criteria included nonfasted subjects, those pregnant and/or lactating, and, for intake analyses, those with unreliable 24-h recall records. Subjects were separately classified into quartiles of vitamin D intake (both including and excluding supplements) and serum 25(OH)D. Logistic regression was used to determine odds ratios (OR) for metabolic syndrome after adjusting for multiple confounders. RESULTS: Those in the highest quartile of serum 25(OH)D had 60% lower odds for metabolic syndrome as compared to those in the lowest quartile [OR=0.40; 95% confidence interval (CI) 0.27, 0.59]. Elevated waist circumference (OR=0.57; 95% CI 0.39, 0.84), low high-density lipoprotein cholesterol (HDL-C) (OR=0.54; 95% CI 0.39, 0.75), and high homeostasis model assessment of insulin resistance (HOMA-IR) (OR=0.40; 95% CI 0.29, 0.55) were the main components associated with serum 25(OH)D. Compared with the lowest vitamin D intake quartile (excluding supplements), those in the highest intake quartile had 28% lower odds for metabolic syndrome (OR=0.72; 95% CI 0.58, 0.90). No components of metabolic syndrome were significantly associated with dietary intake of vitamin D with supplements included or excluded. CONCLUSIONS: We conclude that higher 25(OH)D, and, to a lesser degree, greater dietary vitamin D intake, are associated with reduced prevalence of metabolic syndrome.

Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction.

Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory molecule, which upon engagement with its cognate receptors on target cells, triggers downstream signaling cascades that control a number of cellular processes related to cell viability, gene expression, ion homeostasis, and synaptic integrity. In the central nervous system (CNS), TNF-alpha is produced by brain-resident astrocytes, microglia, and neurons in response to numerous intrinsic and extrinsic stimuli. This review will summarize the key events that lead to TNF-alpha elaboration in the CNS, and the effects that these inflammatory signals impart on neuronal signaling in the context of homeostasis and neuropathology.

Impaired TNF-alpha control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neurons.

The misguided control of inflammatory signaling has been previously implicated in the pathogenesis of several neurological disorders, including Alzheimer's disease (AD). Induction of tumor necrosis factor-alpha (TNF-alpha), a central mediator of neuroinflammation, occurs commensurate with the onset of early disease in 3xTg-AD mice, which develop both amyloid plaque and neurofibrillary tangle pathologies in an age- and region-dependent pattern. Herein, we describe regulation inherent to 3xTg-AD neurons, which results in the loss of TNF-alpha mediated enhancement of inositol 1,4,5 trisphosphate (IP3R)-mediated Ca2+ release. This modulation also leads to significant down-regulation of IP3R signaling following protracted cytokine exposure. Through the experimental isolation of each AD-related transgene, it was determined that expression of the PS1M146V transgene product is responsible for the loss of the TNF-alpha effect on IP3R-mediated Ca2+ release. Furthermore, it was determined that the suppression of TNF-alpha receptor expression occurred in the presence of the presenilin transgene. Our findings attribute this familial AD mutation to suppressing a Ca2+-regulated signal cascade potentially intended to "inform" neurons of proximal neuroinflammatory events and trigger compensatory responses for protection of neural transmission.

Tumor necrosis factor-alpha potentiates intraneuronal Ca2+ signaling via regulation of the inositol 1,4,5-trisphosphate receptor.

Inflammatory events have long been implicated in initiating and/or propagating the pathophysiology associated with a number of neurological diseases. In addition, defects in Ca2+-handling processes, which shape membrane potential, influence gene transcription, and affect neuronal spiking patterns, have also been implicated in disease progression and cognitive decline. The mechanisms underlying the purported interplay that exists between neuroinflammation and Ca2+ homeostasis have yet to be defined. Herein, we describe a novel neuron-intrinsic pathway in which the expression of the type-1 inositol 1,4,5-trisphosphate receptor is regulated by the potent pro-inflammatory cytokine tumor necrosis factor-alpha. Exposure of primary murine neurons to tumor necrosis factor-alpha resulted in significant enhancement of Ca2+ signals downstream of muscarinic and purinergic stimulation. An increase in type-1 inositol 1,4,5-trisphosphate receptor mRNA and protein steady-state levels following cytokine exposure positively correlated with this alteration in Ca2+ homeostasis. Modulation of Ca2+ responses arising from this receptor subtype and its downstream effectors may exact significant consequences on neuronal function and could underlie the compromise in neuronal activity observed in the setting of chronic neuroinflammation, such as that associated with Parkinson disease and Alzheimer disease.