Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease

Alzheimer's disease (AD) is the most common dementing disorder of late life. Although there might be various different triggering events in the early stages of the disease, they seem to converge on a few characteristic final pathways in the late stages, characterized by inflammation and neurodegeneration. In this review, we revisit the hypothesis that advanced glycation endproducts (AGEs) and their receptor RAGE may play an important role in disease pathogenesis. Accumulation of AGEs in cells and tissues is a normal feature of aging, but is accelerated in AD. In AD, AGEs can be detected in pathological deposits such as amyloid plaques and neurofibrillary tangles. AGEs explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking, glial induction of oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. RAGE and its decoy receptor soluble RAGE, may contribute to or protect against AD pathogenesis by influencing transport of β-amyloid into the brain or by manipulating inflammatory mechanisms. Targeted pharmacological interventions using AGE-inhibitors, RAGE-antagonists, RAGE-antibodies, soluble RAGE or RAGE signalling inhibitors such as membrane-permeable antioxidants may be promising therapeutic strategies to slow down the progression of AD.     

Human movement-related potentials vs desynchronization of EEG alpha rhythm: a high-resolution EEG study

Movement-related potentials (MRPs) and event-related desynchronization (ERD) of alpha rhythm were investigated with an advanced high-resolution electroencephalographic technology (128 channels, surface Laplacian estimate, realistic head modeling). The working hypothesis was that MRPs and alpha ERD reflect different aspects of sensorimotor cortical processes. Both MRPs and alpha ERD modeled the responses of primary sensorimotor (M1-S1), supplementary motor (SMA), and posterior parietal (PP, area 5) areas during the preparation and execution of unilateral finger movements. Maximum responses were modeled in the contralateral M1-S1 during both preparation and execution of the movement. The SMA and PP responses were modeled mainly from the MRPs and alpha ERD, respectively. The modeled ipsilateral M1-S1 responses were larger and stronger in the alpha ERD than MRPs. These results may suggest that alpha ERD reflects changes in the background oscillatory activity in wide cortical sensorimotor areas, whereas MRPs represent mainly increased, task-specific responses of SMA and contralateral M1-S1.     

Arachidonic acid pathway activates multidrug resistance related protein in cultured human lung cells

Primary cultures of human lung cells can serve as a model system to study the mechanisms underlying the effects of irritants in air and to get a deeper insight into the (patho)physiological roles of the xenobiotic detoxification systems. For 99 human lung cancer cases the culture duration for bronchial epithelium and peripheral lung cells (PLC) are given in term of generations and weeks. Using this system, we investigated whether and how prostaglandins (PG) modify multidrug resistance related protein (MRP) function in normal human lung cells. PGF2alpha had no effect on MRP function, whereas PGE2 induced MRP activity in cultured NHBECs. The transport activity study of MRP in NHBEC, PLC, and A549 under the effect of exogenously supplied PGF2alpha (10 microM, 1 day) using single cell fluorimetry revealed no alteration in transport activity of MRP. PG concentrations were within the physiological range. COX I and II inhibitors indomethacin (5, 10 microM) and celecoxib (5, 10 microM) could substantially decrease the transport activity of MRP in NHBEC, PLC, and A549 in 1- and 4-day trials. Prostaglandin E2 did not change cadmium-induced caspase 3/7 activation in NHBECs and had no own effect on caspase 3/7 activity. Cadmium chloride (5, 10 microM) was an effective inducer of caspase 3/7 activation in NHBECs with a fivefold and ninefold rise of activity. In primary human lung cells arachidonic acid activates MRP transport function only in primary epithelial lung cells by prostaglandin E2 but not by F2alpha mediated pathways and this effect needs some time to develop.     

Glycyrrhetinic Acid Accelerates the Clearance of Triptolide through P‐gp In Vitro

Triptolide (TP) is an active ingredient isolated from Tripterygium wilfordii Hook. f. (TWHF), which is a traditional herbal medicine widely used for the treatment of rheumatoid arthritis and autoimmune disease in the clinic. However, its adverse reactions of hepatotoxicity and nephrotoxicity have been frequently reported which limited its clinical application. The aim of this study was to investigate the mechanism of glycyrrhetinic acid (GA) effecting on the elimination of TP in HK‐2 cells and the role of the efflux transporters of P‐gp and multidrug resistance‐associated proteins (MRPs) in this process. An ultra performance liquid chromatography–electrospray ionization–mass spectrometry (UPLC‐ESI‐MS) analytical method was established to determine the intracellular concentration of TP. In order to study the role of efflux transporters of P‐gp and MRPs in GA impacting on the accumulation of TP, the inhibitors of efflux transporters (P‐gp: verapamil; MRPs: MK571) were used in this study. The results showed that GA could enhance the elimination of TP and reduce the TP accumulation in HK‐2 cells. Verapamil and MK571 could increase the intracellular concentration of TP; in addition, GA co‐incubation with verapamil significantly increased the TP cellular concentration compared with the control group. In conclusion, GA could reduce the accumulation of TP in HK‐2 cells, which was related to P‐gp. This is probably one of the mechanisms that TP combined with GA to detoxify its toxicity. Copyright © 2017 John Wiley & Sons, Ltd.     

Analysis and biological properties of amino acid derivates formed by Maillard reaction in foods

Maillard reaction products (MRPs), especially early stage MRPs and melanoidins, are currently gaining a lot of attention due to their reported health-promoting properties and their potential to be used as functional food ingredients. It is often not clear which specific biological function is assigned to which MRP, due to the large amount of MRPs formed during the reaction and difficulties in their purification and identification. This paper provides an overview of amino acid derivatives such as Amadori compounds, carboxymethyllysine, pyrraline, cross-linking products and melanoidins, which can be formed by Maillard reaction in foods, their biological properties and the analytical tools commonly employed for their determination.     

Endogenous bile acid disposition in rat and human sandwich-cultured hepatocytes

We hypothesized that flavonoid-induced glutathione (GSH) efflux through multi-drug resistance proteins (MRPs) and subsequent intracellular GSH depletion is a viable mechanism to sensitize cancer cells to chemotherapies. This concept was demonstrated using chrysin (5-25 μM) induced GSH efflux in human non-small cell lung cancer lines exposed to the chemotherapeutic agent, doxorubicin (DOX). Treatment with chrysin resulted in significant and sustained intracellular GSH depletion and the GSH enzyme network in the four cancer cell types was predictive of the severity of chrysin induced intracellular GSH depletion. Gene expression data indicated a positive correlation between basal MRP1, MRP3 and MRP5 expression and total GSH efflux before and after chrysin exposure. Co-treating the cells for 72 h with chrysin (5-30 μM) and DOX (0.025-3.0 μM) significantly enhanced the sensitivity of the cells to DOX as compared to 72-hour DOX alone treatment in all four cell lines. The maximum decrease in the IC₅₀ values of cells treated with DOX alone compared to co-treatment with chrysin and DOX was 43% in A549 cells, 47% in H157 and H1975 cells and 78% in H460 cells. Chrysin worked synergistically with DOX to induce cancer cell death. This approach could allow for use of lower concentrations and/or sensitize cancer cells to drugs that are typically resistant to therapy.     

Is there a "neural efficiency" in athletes? A high-resolution EEG study

“Neural efficiency” hypothesis posits that cortical activity is spatially focused in experts. Here we tested the hypothesis that compared to non-athletes, elite athletes are characterized by a reduced cortical activation during visuo-motor tasks related to the field of expertise, as a function of movement side. EEG data (56 channels; EB-Neuro) were continuously recorded in the following right-handed subjects: 11 non-athletes, 11 elite fencing athletes, and 11 elite karate athletes. During the EEG recordings, they observed pictures with fencing and karate attacks, and had to quickly click a right (left) keyboard button for the attacks at right (left) monitor side. The EEG data were averaged with respect to the movement onset, and were spatially enhanced by surface Laplacian estimation. The potentials related to the preparation (readiness potential) and initiation (motor potential) of the movements were measured. For the right movement, the potentials overlying supplementary motor and contralateral sensorimotor areas were higher in amplitude in the non-athletes than in the elite karate and fencing athletes. Furthermore, the amplitude of the motor potential over ipsilateral sensorimotor area was higher in the elite karate than fencing athletes, and its distribution over bilateral sensorimotor areas was less asymmetrical in the karate than in the other two groups. For the left movement, these potentials showed no difference between the groups. The present results suggest that “neural efficiency” hypothesis does not fully account for the organization of motor systems in elite athletes. “Neural efficiency” would depend on several factors including side of the movement, hemisphere, and kind of athletes.     

Cryo-EM structure of the small subunit of the mammalian mitochondrial ribosome

The mammalian mitochondrial ribosomes (mitoribosomes) are responsible for synthesizing 13 membrane proteins that form essential components of the complexes involved in oxidative phosphorylation or ATP generation for the eukaryotic cell. The mammalian 55S mitoribosome contains significantly smaller rRNAs and a large mass of mitochondrial ribosomal proteins (MRPs), including large mito-specific amino acid extensions and insertions in MRPs that are homologous to bacterial ribosomal proteins and an additional 35 mito-specific MRPs. Here we present the cryo-EM structure analysis of the small (28S) subunit (SSU) of the 55S mitoribosome. We find that the mito-specific extensions in homologous MRPs generally are involved in inter-MRP contacts and in contacts with mito-specific MRPs, suggesting a stepwise evolution of the current architecture of the mitoribosome. Although most of the mito-specific MRPs and extensions of homologous MRPs are situated on the peripheral regions, they also contribute significantly to the formation of linings of the mRNA and tRNA paths, suggesting a tailor-made structural organization of the mito-SSU for the recruitment of mito-specific mRNAs, most of which do not possess a 5′ leader sequence. In addition, docking of previously published coordinates of the large (39S) subunit (LSU) into the cryo-EM map of the 55S mitoribosome reveals that mito-specific MRPs of both the SSU and LSU are involved directly in the formation of six of the 15 intersubunit bridges.The mammalian mitochondrial genome encodes 37 genes, including two ribosomal RNAs (12S and 16S rRNAs), 22 mitochondrial tRNAs, and 13 polypeptides of the oxidative phosphorylation complexes. All the proteins required for mammalian mitochondrial translation, including mitochondrial ribosomal proteins (MRPs), are encoded in the nuclear genome, translated in the cytoplasm, and then imported into the mitochondrion. Defects in several components of the mammalian mitochondrial translational machinery are involved in a number of human genetic diseases (1–3). Thus, knowledge of the molecular architecture of the mitochondrial translational machinery is important for a better understanding these diseases. Previous low-resolution cryo-EM studies (4–6) have revealed several unique structural features of the mitoribosomes. Because mitochondria are thought to have originated through an early endosymbiotic event between an α-protobacteria and a primitive host cell (7), its ribosomes were proposed to be structurally similar to those of bacteria. However, the overall 3D structure of the mammalian mitoribosome was found to be significantly altered and porous (4) as compared with its bacterial and eukaryotic cytoplasmic counterparts (8–10).The functional 55S mammalian mitoribosome is made up of two unequally sized subunits referred to as the small (SSU, 28S) and large (LSU, 39S) subunits. The LSU is involved in catalyzing the peptidyl-transferase reaction, and the SSU provides the platform for mRNA binding and decoding. Based on cryo-EM studies, partial molecular models of the 39S subunit have been published at 12.1-Å (6) and more recently at ∼5-Å (11) resolution. Here we present the 7-Å cryo-EM structure of the 28S mito-SSU, which is composed of a 12S rRNA molecule and 31 MRPs [numbered S2 to S39, with gaps (12)]. Fifteen of the 31 MRPs are homologous to bacterial ribosomal proteins, most of which (except for MRPs S6 and S12) have accrued mito-specific N-terminal and/or C-terminal amino acid extensions (NTE and CTE, respectively) of varying lengths (Table S1). No homologs for six bacterial ribosomal proteins—S1, S4, S8, S13, S19, and S20—are found in the mito-SSU. We have modeled the complete 12S rRNA, all of the 15 homologous MRPs, and their mito-specific extensions into the cryo-EM density. In addition, we have made an attempt to identify densities for the 16 mito-specific MRPs within the cryo-EM map. Strategic locations of some of the mito-specific MRPs and mito-specific extensions in homologous MRPs on the mito-SSU structure suggest their direct involvement in the recruitment of the unique mitochondrial mRNAs (13).