Understanding taste is key for optimizing the palatability of seaweeds and other non-animal-based foods rich in protein. The lingual papillae in the mouth hold taste buds with taste receptors for the five gustatory taste qualities. Each taste bud contains three distinct cell types, of which Type II cells carry various G protein-coupled receptors that can detect sweet, bitter, or umami tastants, while type III cells detect sour, and likely salty stimuli. Upon ligand binding, receptor-linked intracellular heterotrimeric G proteins initiate a cascade of downstream events which activate the afferent nerve fibers for taste perception in the brain. The taste of amino acids depends on the hydrophobicity, size, charge, isoelectric point, chirality of the alpha carbon, and the functional groups on their side chains. The principal umami ingredient monosodium l-glutamate, broadly known as MSG, loses umami taste upon acetylation, esterification, or methylation, but is able to form flat configurations that bind well to the umami taste receptor. Ribonucleotides such as guanosine monophosphate and inosine monophosphate strongly enhance umami taste when l-glutamate is present. Ribonucleotides bind to the outer section of the venus flytrap domain of the receptor dimer and stabilize the closed conformation. Concentrations of glutamate, aspartate, arginate, and other compounds in food products may enhance saltiness and overall flavor. Umami ingredients may help to reduce the consumption of salts and fats in the general population and increase food consumption in the elderly.
MULTIFILE
AimsGenetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM). In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). Mitochondrial dysfunction is thought to be a key driver of pathological remodelling in HCM. Reports of mitochondrial respiratory function and specific disease-modifying treatment options in patients with HCM are scarce.Methods and resultsRespirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration.ConclusionMitochondrial dysfunction is explained by cardiomyocyte architecture disruption and is linked to septal hypertrophy in genotype-negative HCM. Despite severe myocardial remodelling mitochondria were responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in HCM. Mitochondria-targeting therapy may particularly benefit genotype-negative patients with HCM, given the tight link between mitochondrial impairment and septal thickening in this subpopulation.
Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death.
