Oxidatively-modified and glycated proteins as candidate pro-inflammatory toxins in uremia and dialysis patients

End stage renal disease (ESRD) patients accumulate blood hallmarks of protein glycation and oxidation. It is now well established that these protein damage products may represent a heterogeneous class of uremic toxins with pro-inflammatory and pro-oxidant properties. These toxins could be directly involved in the pathogenesis of the inflammatory syndrome and vascular complications, which are mainly sustained by the uremic state and bioincompatibility of dialysis therapy. A key underlying event in the toxicity of these proteinaceous solutes has been identified in scavenger receptor-dependent recognition and elimination by inflammatory and endothelial cells, which once activated generate further and even more pronounced protein injuries by a self-feeding mechanism based on inflammation and oxidative stress-derived events. This review examines the literature and provides original information on the techniques for investigating proteinaceous pro-inflammatory toxins. We have also evaluated therapeutic - either pharmacological or dialytic - strategies proposed to alleviate the accumulation of these toxins and to constrain the inflammatory and oxidative burden of ESRD.     

The fatty acid profiles in a drop of blood from a fingertip correlate with physiological, dietary and lifestyle parameters in volunteers

Limited data are available on the fatty acid (FA) composition of circulating lipids and the associations with diet, physiological and pathological conditions, due to the complexity and costs of the analytical process. The aim of our study was to evaluate the FA composition in 108 healthy subjects and to correlate the data with gender, pregnancy, dietary habits, lifestyle, and short-term controlled intake of n-3 FA, using an innovative analytical approach for the collection and processing of blood samples. Ten subjects were also supplemented with n-3 polyunsaturated FA as smoked salmon or capsules for 3 weeks. The resulting blood FA composition was affected by gender, pregnancy, diet and smoking. The data indicate that this new analytical methodology is suitable for assessing associations between circulating FA and various parameters in large population groups, and is applicable to epidemiological studies and in the assessment of the effects of controlled FA supplementation in clinical studies.     

Evidence that dams promote biotic differentiation of zooplankton communities in two Brazilian reservoirs

Hydrobiologia - Human activities may change beta diversity—the spatial variation in species composition—in different ways. Positive and negative trends in beta diversity are referred as...     

A species-specific qPCR assay provides novel insight into range expansion of the Mediterranean monk seal (Monachus monachus) by means of eDNA analysis

Biodiversity and Conservation - The monk seal is the most endangered pinniped worldwide and the only one found in the Mediterranean, where its distribution and abundance have suffered a drastic...     

Stimulation of TLRs by LMW-HA induces self-defense mechanisms in vaginal epithelium

The innate immune system is present throughout the female reproductive tract and functions in synchrony with the adaptive immune system to provide protection in a way that enhances the chances for fetal survival, while protecting against potential pathogens. Recent data show that activation of Toll-like receptor (TLR)2 and 4 by low-molecular weight hyaluronic acid (LMW-HA) in the epidermis induces secretion of the antimicrobial peptide β-defensin 2. In the present work, we show that LMW-HA induces vaginal epithelial cells to release different antimicrobial peptides, via activation of TLR2 and TLR4. Further, we found that LMW-HA favors repair of vaginal epithelial injury, involving TLR2 and TLR4, and independently from its classical receptor CD44. This wound-healing activity of LMW-HA is dependent from an Akt/phosphatidylinositol 3 kinase pathway. Therefore, these findings suggest that the vaginal epithelium is more than a simple physical barrier to protect against invading pathogens: on the contrary, this surface acts as efficient player of innate host defense, which may modulate its antimicrobial properties and injury restitution activity, following LMW-HA stimulation; this activity may furnish an additional protective activity to this body compartment, highly and constantly exposed to microbiota, ameliorating the self-defense of the vaginal epithelium in both basal and pathological conditions.     

No association between leptin levels and sleep duration or quality in obese adults

Previous research in lean subjects has found lower leptin levels associated with shorter sleep duration. Since leptin levels are higher and some of the actions of leptin are impaired in obese individuals, one cannot assume that sleep will be similarly associated with leptin in obese individuals. The aim of this paper was to examine the cross-sectional association between habitual sleep duration and quality and plasma leptin levels in a sample of 80 obese men and premenopausal women aged 18-50 years. Leptin levels (ng/ml) were assayed on a fasting blood sample taken in the morning. We calculated a relative leptin level by dividing leptin by body fat percentage. Sleep duration and sleep efficiency were measured by 2 weeks of wrist actigraphy and respiratory disturbance index (RDI), a measure of sleep disordered breathing, was assessed by a portable screening device on a single night. Mean leptin levels and body fat percentage were higher in women than men (P < 0.001), however, mean RDI was higher in men (P = 0.01). There were no significant associations between relative leptin level and any of the sleep measures, including sleep duration, sleep efficiency, and sleep disordered breathing. There was also no difference between men and women in the association between sleep and leptin. In conclusion, contrary to what has been reported in other studies, measures of sleep duration and quality were not associated with leptin levels in our sample of obese adults.     

Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement.     

Impaired striatal Akt signaling disrupts dopamine homeostasis and increases feeding

Background

The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address “food-abuse” disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and dysregulation of higher order circuitry involved in feeding. Dopamine (DA) rich brain structures, such as striatum, provide motivation stimuli for feeding. In these central circuitries, DA dysfunction is posited to contribute to obesity pathogenesis. We identified a mechanistic link between metabolic dysregulation and the maladaptive behaviors that potentiate weight gain. Insulin, a hormone in the periphery, also acts centrally to regulate both homeostatic and reward-based HF feeding. It regulates DA homeostasis, in part, by controlling a key element in DA clearance, the DA transporter (DAT). Upon HF feeding, nigro-striatal neurons rapidly develop insulin signaling deficiencies, causing increased HF calorie intake.

Methodology/Principal Findings

We show that consumption of fat-rich food impairs striatal activation of the insulin-activated signaling kinase, Akt. HF-induced Akt impairment, in turn, reduces DAT cell surface expression and function, thereby decreasing DA homeostasis and amphetamine (AMPH)-induced DA efflux. In addition, HF-mediated dysregulation of Akt signaling impairs DA-related behaviors such as (AMPH)-induced locomotion and increased caloric intake. We restored nigro-striatal Akt phosphorylation using recombinant viral vector expression technology. We observed a rescue of DAT expression in HF fed rats, which was associated with a return of locomotor responses to AMPH and normalization of HF diet-induced hyperphagia.

Conclusions/Significance

Acquired disruption of brain insulin action may confer risk for and/or underlie “food-abuse” disorders and the recalcitrance of obesity. This molecular model, thus, explains how even short-term exposure to “the fast food lifestyle” creates a cycle of disordered eating that cements pathological changes in DA signaling leading to weight gain and obesity.     

Cardiovascular actions of rattlesnake bradykinin ([Val1,Thr6]bradykinin) in the anesthetized South American rattlesnake Crotalus durissus terrificus

Incubation of heat-denatured plasma from the rattlesnake Crotalus atrox with trypsin generated a bradykinin (BK) that contained two amino acid substitutions (Arg1 --> Val and Ser6 --> Thr) compared with mammalian BK. Bolus intra-arterial injections of synthetic rattlesnake BK (0.01-10 nmol/kg) into the anesthetized rattlesnake, Crotalus durissus terrificus, produced a pronounced and concentration-dependent increase in systemic vascular conductance (Gsys). This caused a fall in systemic arterial blood pressure (Psys) and an increase in blood flow. Heart rate and stroke volume also increased. This primary response was followed by a significant rise in Psys and pronounced tachycardia (secondary response). Pretreatment with N(G)-nitro-L-arginine methyl ester reduced the NK-induced systemic vasodilatation, indicating that the effect is mediated through increased NO synthesis. The tachycardia associated with the late primary and secondary response to BK was abolished with propranolol and the systemic vasodilatation produced in the primary phase was also significantly attenuated by pretreatment, indicating that the responses are caused, at least in part, by release of cathecholamines and subsequent stimulation of beta-adrenergic receptors. In contrast, the pulmonary circulation was relatively unresponsive to BK.