Damaging effects of a high-fat diet to the brain and cognition: a review of proposed mechanisms.

The prevalence of obesity is growing and now includes at least one-third of the adult population in the United States. As obesity and dementia rates reach epidemic proportions, an even greater interest in the effects of nutrition on the brain have become evident. This review discusses various mechanisms by which a high fat diet and/or obesity can alter the brain and cognition. It is well known that a poor diet and obesity can lead to certain disorders such as type II diabetes, metabolic syndrome, and heart disease. However, long-term effects of obesity on the brain need to be further examined. The contribution of insulin resistance and oxidative stress is briefly reviewed from studies in the current literature. The role of inflammation and vascular alterations are described in more detail due to our laboratory's experience in evaluating these specific factors. It is very likely that each of these factors plays a role in diet-induced and/or obesity-induced cognitive decline.

The Flaw of Medicine: Addressing Racial and Gender Disparities in Critical Care.

The age of modern medicine has ushered in remarkable advances and with them increased longevity of life. The questions are, however: Has everyone benefited from these developments equally? and Do all lives truly matter? The presence of gender and racial health disparities indicates that there is work still left to be done. The first target of intervention may well be the medical establishment itself. The literature presented in this article identifies potential targets for interventions and future areas of exploration.

Two Sides of the Same Coin: Addressing Racial and Gender Disparities Among Physicians and the Impact on the Community They Serve.

The influence of historical cultural norms is evident when analyzing the physician demographics in the United States. To this day, there exists a paucity in diversity as it pertains to gender balance and ethnicity. This phenomenon is particularly concerning when studies support the notion that race and gender concordance are associated with improved outcomes. The literature presented in this article identifies potential targets for interventions on how to attract, train, and retain minority physicians.

Cytochrome P450 (CYP) 2J2 gene transfection attenuates MMP-9 via inhibition of NF-kappabeta in hyperhomocysteinemia.

Hyperhomocysteinemia (HHcy) is associated with atherosclerotic events involving the modulation of arachidonic acid (AA) metabolism and the activation of matrix metalloproteinase-9 (MMP-9). Cytochrome P450 (CYP) epoxygenase-2J2 (CYP2J2) is abundant in the heart endothelium, and its AA metabolites epoxyeicosatrienoic acids (EETs) mitigates inflammation through NF-kappabeta. However, the underlying molecular mechanisms for MMP-9 regulation by CYP2J2 in HHcy remain obscure. We sought to determine the molecular mechanisms by which P450 epoxygenase gene transfection or EETs supplementation attenuate homocysteine (Hcy)-induced MMP-9 activation. CYP2J2 was over-expressed in mouse aortic endothelial cells (MAECs) by transfection with the pcDNA3.1/CYP2J2 vector. The effects of P450 epoxygenase transfection or exogenous supplementation of EETs on NF-kappabeta-mediated MMP-9 regulation were evaluated using Western blot, in-gel gelatin zymography, electromobility shift assay, immunocytochemistry. The result suggested that Hcy downregulated CYP2J2 protein expression and dephosphorylated PI3K-dependent AKT signal. Hcy induced the nuclear translocation of NF-kappabeta via downregulation of IKbetaalpha (endogenous cytoplasmic inhibitor of NF-kappabeta). Hcy induced MMP-9 activation by increasing NF-kappabeta-DNA binding. Moreover, P450 epoxygenase transfection or exogenous addition of 8,9-EET phosphorylated the AKT and attenuated Hcy-induced MMP-9 activation. This occurred, in part, by the inhibition of NF-kappabeta nuclear translocation, NF-kappabeta-DNA binding and activation of IKbetaalpha. The study unequivocally suggested the pivotal role of EETs in the modulation of Hcy/MMP-9 signal.

Memory and hippocampal architecture following short-term midazolam in western diet-treated rats.

The impact of short-term benzodiazepine exposure on cognition in middle-aged or older patients is a highly debated topic among anesthesiologists, critical care physicians and public media. "Western diet" (WD) consumption is linked to impaired cognition as well. The combination of benzodiazepines with substantial exposure to WD might set the stage for increased hippocampal vulnerability for benzodiazepines leading to exaggerated cognitive impairment in the postoperative period. In this study, Fischer 344 rats were fed either WD or standard rodent diet from 5 to 10.5 months of age. Rats were exposed to midazolam or placebo two days prior to an MRI scan using Diffusional Kurtosis Imaging (DKI) to assess brain microstructural integrity, followed by behavioral testing using a water radial arm maze. Hippocampal tissue was collected to assess alterations in protein biochemistry in brain regions associated with learning and memory. Our results showed that rats exposed to the combination of midazolam and WD had significantly delayed time of learning and exhibited spatial memory impairment. Further, we observed an overall increase of kurtosis metrics in the hippocampus and increased expression of the mitochondrial protein VDAC2 in midazolam-treated rats. Our data suggest that both the short-acting benzodiazepine midazolam and WD contribute to negatively affect the brain in middle-aged rats. This study is the first application of DKI on the effects of midazolam and WD exposure, and the findings demonstrate that diffusion metrics are sensitive indicators of changes in the complexity of neurite architecture.

Differential expression of gamma-aminobutyric acid receptor A (GABA(A)) and effects of homocysteine.

BACKGROUND: gamma-Aminobutyric acid (GABA) is a known inhibitory neurotransmitter in the mammalian central nervous system, and homocysteine (Hcy) behaves as an antagonist for GABA(A) receptor. Although the properties and functions of GABA(A) receptors are well studied in mouse neural tissue, its presence and significance in non-neural tissue remains obscure. The aim of the present study was to examine the expression of GABA(A) receptor and its subunits in non-neural tissue. METHODS: The mice were analyzed. The presence of GABA(A) receptor and its subunits was evaluated using Western blot and reverse transcription polymerase chain reaction. RESULTS: We report that GABA(A) receptor protein is abundant in the renal medulla, cortex, heart, left ventricle, aorta and pancreas. Low levels of GABA(A) receptor protein were detected in the atria of the heart, right ventricle, lung and stomach. The mRNA protein expression of GABA(A) receptor subunit shows that alpha1, beta1, beta3 and gamma1 subunits are present only in brain. The mRNA protein expression levels of GABA(A) receptor alpha2, alpha6, beta2 and gamma3 subunits were highly expressed in brain compared to other tested tissue, while GABA(A) receptor gamma2 subunit was expressed only in brain and kidney. Treatment of microvascular endothelial cells with Hcy decreased GABA(A) receptor protein level, which was restored to its baseline level in the presence of GABA(A) receptor agonist, muscimol. The distribution of GABA(A) and GABA(B) receptors in wild type mice was determined and tissue-specific expression patterns were found showing that several receptor subtypes were also expressed in the central nervous system. CONCLUSIONS: Hcy, a GABA(A) agonist, was found to decrease GABA(A) expression levels. These data enlarge knowledge on distribution of GABA receptors and give novel ideas of the effects of Hcy on different organs.

Pulmonary aspiration: new therapeutic approaches in the experimental model.

BACKGROUND: Acute lung injury caused by gastric aspiration is a frequent occurrence in unconscious patients. Acute respiratory distress syndrome in association with gastric aspiration carries a mortality of up to 30% and accounts for up to 20% of deaths associated with anesthesia. Although the clinical condition is well known, knowledge about the exact inflammatory mechanisms is still incomplete. This study was performed to define the role of alveolar macrophages in this inflammatory response. In addition, potentially modifying effects of intratracheally applied nuclear factor kappaB inhibitor pyrrolidine dithiocarbamate were investigated. METHODS: Rat alveolar macrophages were depleted by intratracheal administration of clodronate liposomes, and lung injury was evaluated 6 h after instillation of 0.1N hydrochloric acid. In a second set of experiments, pyrrolidine dithiocarbamate was intratracheally instilled 3 h after hydrochloric acid application, and injury parameters were determined. RESULTS: Depletion of alveolar macrophages resulted in decreased production of inflammatory mediators in acid aspiration (23-80% reduction of messenger RNA or protein of inflammatory mediators; P < 0.05) and consequently also in diminished neutrophil recruitment (36% fewer neutrophils; P < 0.01). Treatment with pyrrolidine dithiocarbamate was highly effective in decreasing neutrophil recruitment (66%; P < 0.01) and vascular permeability (80%; P < 0.001). CONCLUSIONS: These data suggest that alveolar macrophages play an essential role in the inflammatory response of acid-induced lung injury. For the first time, attenuation of acid-induced lung injury with an inhibitor, applied after the onset of injury, is shown.