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Solvent Composition Effects on the Structural Properties of the Aβ42 Monomer from the 3D-RISM-KH Molecular Theory of Solvation.
Blinov, N, Wishart, DS, Kovalenko, A
The journal of physical chemistry. B. 2019;(11):2491-2506
Abstract
Structural characterization of amyloid (A)β peptides implicated in Alzheimer's disease is a challenging problem due to their intrinsically disordered nature and their high propensity for aggregation. Only limited information is currently available from experiments on conformational properties and aggregation pathways of the peptides in cellular environments. In silico modeling complements experimental information, providing atomistic insight into structure and dynamics of different Aβ species. All-atom explicit solvent molecular dynamics (MD) simulations with a properly selected force field can deliver reliable structural and dynamic information. In the case of intrinsically disordered Aβ peptides, enhanced sampling simulations beyond the nanosecond time scale are required to obtain statistically meaningful results even for simple solvent conditions. To overcome the challenges of conformational sampling in crowded cellular environments, alternative approaches have to be used, including postprocessing of MD data. In this study, we employ the statistical-mechanical, three-dimensional reference interaction site model with the Kovalenko-Hirata closure integral equation molecular theory of solvation to describe solvent composition effects on the conformational equilibrium in a structural ensemble of the Aβ42 (covering residues 1-42) monomer based on a statistical reweighting technique. The methodology enables a computationally efficient prediction on how different factors in the cellular environment, such as solvent composition, nonpolar solvation, and macromolecular crowding, affect the structural properties of the monomer. Similarities have been identified between changes in the structural ensemble caused by nonpolar solvation and crowded environments modeled by ionic solution with large negative ions. In particular, both solvent conditions reduce the random coil content and enhance the helical structure content of the monomer. In contrast to the previous studies, which reported increased α-helical content of peptides in crowded environments, this work attributes these structural features to the difference in solvent exposure of hydrophilic residues of the monomer for different secondary structure elements, rather than to (entropic) excluded volume effects.
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An overview of glutaminyl cyclase inhibitors for Alzheimer's disease.
Coimbra, JR, Sobral, PJ, Santos, AE, Moreira, PI, Salvador, JA
Future medicinal chemistry. 2019;(24):3179-3194
Abstract
A diverse range of N-terminally truncated and modified forms of amyloid-β (Aβ) oligomers have been discovered in Alzheimer's disease brains, including the pyroglutamate-Aβ (AβpE3). AβpE3 species are shown to be more neurotoxic when compared with the full-length Aβ peptide. Findings visibly suggest that glutaminyl cyclase (QC) catalyzed the generation of cerebral AβpE3, and therapeutic effects are achieved by reducing its activity. In recent years, efforts to effectively develop QC inhibitors have been pursued worldwide. The inhibitory activity of current QC inhibitors is mainly triggered by zinc-binding groups that coordinate Zn2+ ion in the active site and other common features. Herein, we summarized the current state of discovery and evolution of QC inhibitors as a potential Alzheimer's disease-modifying strategy.
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Reduced Extracellular Matrix Stiffness Prompts SH-SY5Y Cell Softening and Actin Turnover To Selectively Increase Aβ(1-42) Endocytosis.
Kruger, TM, Bell, KJ, Lansakara, TI, Tivanski, AV, Doorn, JA, Stevens, LL
ACS chemical neuroscience. 2019;(3):1284-1293
Abstract
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the extracellular deposition of dense amyloid beta plaques. Emerging evidence suggests that the production of these plaques is initiated by the intracellular uptake and lysosomal preconcentration of the amyloid-beta (Aβ) peptide. All previous endocytosis studies assess Aβ uptake with cells plated on traditional tissue culture plastic; however, brain tissue is distinctly soft with a low-kPa stiffness. Use of an ultrastiff plastic/glass substrate prompts a mechanosensitive response (increased cell spreading, cell stiffness, and membrane tension) that potentially distorts a cell's endocytic behavior from that observed in vivo or in a more physiologically relevant mechanical environment. Our studies demonstrate substrate stiffness significantly modifies the behavior of undifferentiated SH-SY5Y neuroblastoma, where cells plated on soft (∼1 kPa) substrates display a rounded morphology, decreased actin polymerization, reduced adhesion (decreased β1 integrin expression), and reduced cell stiffness compared to cells plated on tissue culture plastic. Moreover, these neuroblastoma on softer substrates display a preferential increase in the uptake of the Aβ(1-42) compared to Aβ(1-40), while both isoforms display a clear stiffness-dependent increase of uptake relative to cells plated on plastic. Considering the brain is a soft tissue that continues to soften with age, this mechanosensitive endocytosis of Aβ has significant implications for understanding age-related neurodegeneration and the mechanism behind Aβ uptake and fibril production. Overall, identifying these physical factors that contribute to the pathology of AD may offer novel avenues of therapeutic intervention.
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4.
B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: The PARADIGM-HF Trial.
Myhre, PL, Vaduganathan, M, Claggett, B, Packer, M, Desai, AS, Rouleau, JL, Zile, MR, Swedberg, K, Lefkowitz, M, Shi, V, et al
Journal of the American College of Cardiology. 2019;(11):1264-1272
Abstract
BACKGROUND Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended. OBJECTIVES The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan. METHODS BNP and NT-proBNP were measured before and after 4 to 6 weeks, 8 to 10 weeks, and 9 months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF. RESULTS Median BNP concentration (before treatment: 202 ng/l [Q1 to Q3: 126 to 335 ng/l]) increased to 235 ng/l (Q1 to Q3: 128 to 422 ng/l) after 8 to 10 weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10 weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan caused a rightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained their prognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with no difference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10 weeks of sacubitril/valsartan were associated with worse outcomes (p = 0.003 and p = 0.005, respectively). CONCLUSIONS Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10 weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).
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Tumour cell blebbing and extracellular vesicle shedding: key role of matrikines and ribosomal protein SA.
Brassart, B, Da Silva, J, Donet, M, Seurat, E, Hague, F, Terryn, C, Velard, F, Michel, J, Ouadid-Ahidouch, H, Monboisse, JC, et al
British journal of cancer. 2019;(4):453-465
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Abstract
BACKGROUND Carcinogenesis occurs in elastin-rich tissues and leads to local inflammation and elastolytic proteinase release. This contributes to bioactive matrix fragment (Matrikine) accumulation like elastin degradation products (EDP) stimulating tumour cell invasive and metastatic properties. We previously demonstrate that EDPs exert protumoural activities through Hsp90 secretion to stabilised extracellular proteinases. METHODS EDP influence on cancer cell blebbing and extracellular vesicle shedding were examined with a videomicroscope coupled with confocal Yokogawa spinning disk, by transmission electron microscopy, scanning electron microscopy and confocal microscopy. The ribosomal protein SA (RPSA) elastin receptor was identified after affinity chromatography by western blotting and cell immunolocalisation. mRNA expression was studied using real-time PCR. SiRNA were used to confirm the essential role of RPSA. RESULTS We demonstrate that extracellular matrix degradation products like EDPs induce tumour amoeboid phenotype with cell membrane blebbing and shedding of extracellular vesicle containing Hsp90 and proteinases in the extracellular space. EDPs influence intracellular calcium influx and cytoskeleton reorganisation. Among matrikines, VGVAPG and AGVPGLGVG peptides reproduced EDP effects through RPSA binding. CONCLUSIONS Our data suggests that matrikines induce cancer cell blebbing and extracellular vesicle release through RPSA binding, favouring dissemination, cell-to-cell communication and growth of cancer cells in metastatic sites.
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Targeting intermediary metabolism enhances the efficacy of BH3 mimetic therapy in hematologic malignancies.
Al-Zebeeby, A, Vogler, M, Milani, M, Richards, C, Alotibi, A, Greaves, G, Dyer, MJS, Cohen, GM, Varadarajan, S
Haematologica. 2019;(5):1016-1025
Abstract
BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-XL (A-1331852) or MCL-1 (A-1210477), in relevant hematologic cancer cell lines. In these models, resistance could not be attributed to either consistent changes in expression levels of the anti-apoptotic proteins or interactions among different pro- and anti-apoptotic BCL-2 family members. Using genetic silencing, pharmacological inhibition and metabolic supplementation, we found that targeting glutamine uptake and its downstream signaling pathways, namely glutaminolysis, reductive carboxylation, lipogenesis, cholesterogenesis and mammalian target of rapamycin signaling resulted in marked sensitization of the chemoresistant cells to BH3 mimetic-mediated apoptosis. Furthermore, our findings highlight the possibility of repurposing widely used drugs, such as statins, to target intermediary metabolism and improve the efficacy of BH3 mimetic therapy.
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SERUM cardiac-specific biomarkers and atrial fibrillation in myotonic dystrophy type I.
Russo, V, Rago, A, Atripaldi, L, Leonardi, S, Papa, AA, Politano, L, Golino, P, Potpara, TS, Nigro, G
Journal of cardiovascular electrophysiology. 2019;(12):2914-2919
Abstract
INTRODUCTION The aim of the present study was to evaluate the role of high-sensitivity cardiac troponin I, N terminal pro-B-type natriuretic peptide (NT-proBNP), creatine kinase-MB mass concentration (CK-MB mass) and copeptin (CP) in predicting incident atrial fibrillation (AF) in myotonic dystrophy type 1 (DM1) patients. MATERIALS AND METHODS The study enrolled 60 consecutive DM1 patients (age 50.3 ± 7.3 years, 34 male) who underwent pacemaker (PM) implantation for cardiac rhythm abnormalities and 60 PM recipients whose age and sex matched served as control group. All DM1 patients underwent a 12-lead electrocardiogram, 2D color Doppler echocardiogram, biomarkers measurements and device interrogation at implantation, 1 month after and every 6 months thereafter for a minimum of 2-year follow-up. RESULTS The study population was divided into two groups according to the presence of AF (AF group vs non-AF group). The AF group was older (47.3 ± 8 vs 38.6 ± 7 years, P = .03) and showed higher serum levels of NT-proBNP (151 ± 38.4 vs 107.3 ± 24.2 pg/mL, P < .001) and CP (18.9 ± 4.5 vs 7 ± 2.3 P < .001) than non-AF Group. NT-proBNP (P < .001) and CP (P < .001) were found to be an independent predictor of AF. Based on the receiver-operating characteristics curve analysis, the cut-off value for NT-proBNP that best predicted AF event in DM1 patients was 123 pg/ml (sensitivity of 83.3% and specificity of 86.5%); the cut-off value for CP that best predicted AF event in DM1 patients was 9 pmol/L (sensitivity of 89% and specificity of 87%). CONCLUSION NT-proBNP and CP represent two independent predictors of AF onset in DM1 population with conduction disturbances underwent PM implantation.
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The effects of collagen peptides on muscle damage, inflammation and bone turnover following exercise: a randomized, controlled trial.
Clifford, T, Ventress, M, Allerton, DM, Stansfield, S, Tang, JCY, Fraser, WD, Vanhoecke, B, Prawitt, J, Stevenson, E
Amino acids. 2019;(4):691-704
Abstract
This study examined whether consuming collagen peptides (CP) before and after strenuous exercise alters markers of muscle damage, inflammation and bone turnover. Using a double-blind, independent group's design, 24 recreationally active males consumed either 20 g day-1 of CP or a placebo control (CON) for 7 days before and 2 days after performing 150 drop jumps. Maximal isometric voluntary contractions, countermovement jumps (CMJ), muscle soreness (200 mm visual analogue scale), pressure pain threshold, Brief Assessment of Mood Adapted (BAM +) and a range of blood markers associated with muscle damage, inflammation and bone turnover C-terminal telopeptide of type 1 collagen (β-CTX) and N-terminal propeptides of type 1 pro-collagen (P1NP) were measured before supplementation (baseline; BL), pre, post, 1.5, 24 and 48 h post-exercise. Muscle soreness was not significantly different in CP and CON (P = 0.071) but a large effect size was evident at 48 h post-exercise, indicative of lower soreness in the CP group (90.42 ± 45.33 mm vs. CON 125.67 ± 36.50 mm; ES = 2.64). CMJ height recovered quicker with CP than CON at 48 h (P = 0.050; CP 89.96 ± 12.85 vs. CON 78.67 ± 14.41% of baseline values; ES = 0.55). There were no statistically significant effects for the other dependent variables (P > 0.05). β-CTX and P1NP were unaffected by CP supplementation (P > 0.05). In conclusion, CP had moderate benefits for the recovery of CMJ and muscle soreness but had no influence on inflammation and bone collagen synthesis.
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Multi-strand β-sheet of Alzheimer Aβ(1-40) folds to β-strip helix: implication for protofilament formation.
Hayward, S, Kitao, A
Journal of biomolecular structure & dynamics. 2019;(8):2143-2153
Abstract
X-ray fiber diffraction experiments on Alzheimer Aβ(1-40) fibrils formed in an assembly process thought to simulate a portion of the pathophysiological process in Alzheimer's disease, indicated protofilaments with tilted β-strands rather than strands oriented perpendicular to the fibril axis as is usually interpreted from cross-β patterns. The protofilament width and tilt angle determined by these experiments were used to predict a β-strip helix model - a β-helix-like structure in which multiple identical polypeptide molecules assemble in-register to form a helical sheet structure such that the outer strands 1 and m join with a register shift t - with m = 11 and t = 22. Starting from untwisted β-sheets comprising 10, 11, and 12 strands, multiple explicit solvent molecular dynamics (MD) simulations were performed to determine whether the sheets form β-strip helices matching the dimensions of the experimentally measured protofilament. In the simulations, the predicted 11-strand sheets curled up to form a closed β-strip helix-like structure with dimensions matching experimental values, whereas the 10- and 12-strand sheets did not form a closed helical structure. The 12-strand structure did, however, show similarity to a cross-β structure determined by a solid-state NMR experiment. The 11-strand β-strip helix resembles a trans-membrane β-barrel which could explain the ability of small oligomers of Aβ(1-40) to form toxic ion channels. A further consequence of opposite sides of the 11-strand strip coming together at a register shift of 22 is end-to-end joins between neighboring β-strip helices, resulting in a protofilament that keeps growing in both directions. Communicated by Ramaswamy H. Sarma.
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Concentration-dependent effects of mercury and lead on Aβ42: possible implications for Alzheimer's disease.
Meleleo, D, Notarachille, G, Mangini, V, Arnesano, F
European biophysics journal : EBJ. 2019;(2):173-187
Abstract
Mercury (Hg) and lead (Pb) are known to be toxic non-radioactive elements, with well-described neurotoxicology. Much evidence supports the implication of metals as potential risk cofactors in Alzheimer's disease (AD). Although the action mechanism of the two metals remains unclear, Hg and Pb toxicity in AD could depend on their ability to favour misfolding and aggregation of amyloid beta proteins (Aβs) that seem to have toxic properties, particularly in their aggregated state. In our study, we evaluated the effect of Hg and Pb both on the Aβ42 ion channel incorporated in a planar lipid membrane made up of phosphatidylcholine containing 30% cholesterol and on the secondary structure of Aβ42 in an aqueous environment. The effects of Hg and Pb on the Aβ42 peptide were observed for its channel incorporated into a membrane as well as for the peptide in solution. A decreasing Aβ42 channel frequency and the formation of large and amorphous aggregates in solution that are prone to precipitate were both dependent on metal concentration. These experimental data suggest that Hg and Pb interact directly with Aβs, strengthening the hypothesis that the two metals may be a risk factor in AD.