Complex Pharmacology of Free Fatty Acid Receptors

G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or “free” fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential

Palmaria palmata (Dulse) as an unusual maritime aetiology of hyperkalemia in a patient with chronic renal failure: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hyperkalemia is rare in individuals with normal renal function, regardless of dietary intake. This is due to the ability of the kidneys to adapt to increasing serum potassium concentrations. In patients with renal compromise, potassium homeostasis can become impaired. <it>Palmaria palmata </it>(dulse) is an edible seaweed known to be very rich in potassium. We report a case of hyperkalemia precipitated by the consumption of dulse by a patient with known renal disease.</p> <p>Case Presentation</p> <p>A 66-year-old Caucasian woman with diabetes and chronic renal disease presented to our emergency department with nausea, vomiting, and worsening malaise, which had been present for less than a day. She had undergone electrocardiogram monitoring, which showed bradycardia, and periods of asystole. Our patient denied any other symptoms. Laboratory analysis revealed a serum potassium level of 8.6 mmol/L (normal range 3.5 to 4.9 mmol/L). Although our patient was taking some medications known to influence renal function, the only recent change that she could recount was that she had consumed approximately 200 g of dulse within the preceding 24 hours. A diagnosis of hyperkalemia was made, and the patient was treated successfully, and discharged home in her pre-morbid state.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first published report of hyperkalemia due to dulse consumption. Dulse is high in potassium, with concentrations upwards of 34 times greater than that found in bananas. Caution should be taken in prescribing medications with potential adverse renal effects for patients with known renal impairment. In such instances, renal function should be monitored closely. Patients should be counseled to avoid dietary sources high in potassium, with particular attention paid to unusual geographical dietary variations.</p

Variation in carbon isotope discrimination in Cleistogenes squarrosa (Trin.) Keng: patterns and drivers at tiller, local, catchment, and regional scales

Understanding the patterns and drivers of carbon isotope discrimination in C4 species is critical for predicting the effects of global change on C3/C4 ratio of plant community and consequently on ecosystem functioning and services. Cleistogenes squarrosa (Trin.) Keng is a dominant C4 perennial bunchgrass of arid and semi-arid ecosystems across the Mongolian plateau of the Eurasian steppe. Its carbon isotope discrimination (13Δ) during photosynthesis is relatively large among C4 species and it is variable. Here the 13Δ of C. squarrosa and its potential drivers at a nested set of scales were examined. Within cohorts of tillers, 13Δ of leaves increased from 5.1‰ to 8.1‰ from old to young leaves. At the local scale, 13Δ of mature leaves varied from 5.8‰ to 8.4‰, increasing with decreasing grazing intensity. At the catchment scale, 13Δ of mature leaves varied from 6.2‰ to 8.5‰ and increased with topsoil silt content. At the regional scale, 13Δ of mature leaves varied from 5.5‰ to 8.9‰, increasing with growing-season precipitation. At all scales, 13Δ decreased with increasing leaf nitrogen content (Nleaf). Nleaf was positively correlated with grazing intensity and leaf position along tillers, but negatively correlated with precipitation. The presence of the correlations across a range of different environmental contexts strongly implicates Nleaf as a major driver of 13Δ in C. squarrosa and, possibly, other C4 species

Dissociation of Motor Task-Induced Cortical Excitability and Pain Perception Changes in Healthy Volunteers

Background: There is evidence that interventions aiming at modulation of the motor cortex activity lead to pain reduction. In order to understand further the role of the motor cortex on pain modulation, we aimed to compare the behavioral (pressure pain threshold) and neurophysiological effects (transcranial magnetic stimulation (TMS) induced cortical excitability) across three different motor tasks. Methodology/Principal Findings Fifteen healthy male subjects were enrolled in this randomized, controlled, blinded, cross-over designed study. Three different tasks were tested including motor learning with and without visual feedback, and simple hand movements. Cortical excitability was assessed using single and paired-pulse TMS measures such as resting motor threshold (RMT), motor-evoked potential (MEP), intracortical facilitation (ICF), short intracortical inhibition (SICI), and cortical silent period (CSP). All tasks showed significant reduction in pain perception represented by an increase in pressure pain threshold compared to the control condition (untrained hand). ANOVA indicated a difference among the three tasks regarding motor cortex excitability change. There was a significant increase in motor cortex excitability (as indexed by MEP increase and CSP shortening) for the simple hand movements. Conclusions/Significance: Although different motor tasks involving motor learning with and without visual feedback and simple hand movements appear to change pain perception similarly, it is likely that the neural mechanisms might not be the same as evidenced by differential effects in motor cortex excitability induced by these tasks. In addition, TMS-indexed motor excitability measures are not likely good markers to index the effects of motor-based tasks on pain perception in healthy subjects as other neural networks besides primary motor cortex might be involved with pain modulation during motor training

Gut microbiota functions: metabolism of nutrients and other food components

The diverse microbial community that inhabits the human gut has an extensive metabolic repertoire that is distinct from, but complements the activity of mammalian enzymes in the liver and gut mucosa and includes functions essential for host digestion. As such, the gut microbiota is a key factor in shaping the biochemical profile of the diet and, therefore, its impact on host health and disease. The important role that the gut microbiota appears to play in human metabolism and health has stimulated research into the identification of specific microorganisms involved in different processes, and the elucidation of metabolic pathways, particularly those associated with metabolism of dietary components and some host-generated substances. In the first part of the review, we discuss the main gut microorganisms, particularly bacteria, and microbial pathways associated with the metabolism of dietary carbohydrates (to short chain fatty acids and gases), proteins, plant polyphenols, bile acids, and vitamins. The second part of the review focuses on the methodologies, existing and novel, that can be employed to explore gut microbial pathways of metabolism. These include mathematical models, omics techniques, isolated microbes, and enzyme assays

Metabolomic Profiling Reveals Mitochondrial-Derived Lipid Biomarkers That Drive Obesity-Associated Inflammation

Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to “Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome

Spike-timing-dependent plasticity in lower-limb motoneurons after human spinal cord injury

Recovery of lower-limb function after spinal cord injury (SCI) likely depends on transmission in the corticospinal pathway. Here, we examined whether paired corticospinal-motoneuronal stimulation (PCMS) changes transmission at spinal synapses of lower-limb motoneurons in humans with chronic incomplete SCI and aged-matched controls. We used 200 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the leg representation of the motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the tibialis anterior (TA) muscle 2 ms before antidromic potentials evoked in motoneurons by electrical stimulation of the common peroneal nerve (PCMS+) or when antidromic potentials arrived 15 or 28 ms before corticospinal volleys (PCMS-) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the TA muscle before and after each stimulation protocol. After PCMS+, the size of MEPs elicited by TMS and electrical stimulation increased for up to 30 min in control and SCI participants. Notably, this was accompanied by increases in TA electromyographic activity and ankle dorsiflexion force in both groups, suggesting that this plasticity has functional implications. After PCMS-, MEPs elicited by TMS and electrical stimulation were suppressed if afferent input from the common peroneal nerve reduced TA MEP size during paired stimulation in both groups. In conclusion, PCMS elicits spike-timing-dependent changes at spinal synapses of lower-limb motoneurons in humans and has potential to improve lower-limb motor output following SCI. Approaches that aim to enhance corticospinal transmission to lower-limb muscles following spinal cord injury (SCI) are needed. We demonstrate that paired corticomotoneuronal stimulation (PCMS) can enhance plasticity at spinal synapses of lower-limb motoneurons in humans with and without SCI. We propose that PCMS has potential for improving motor output in leg muscles in individuals with damage to the corticospinal tract