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1.
Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men.
Rubinow, KB, Vaisar, T, Chao, JH, Heinecke, JW, Page, ST
Journal of clinical lipidology. 2018;(4):1072-1082
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Abstract
BACKGROUND Exogenous testosterone decreases serum concentrations of high-density lipoprotein cholesterol (HDL-C) in men, but whether this alters cardiovascular risk is uncertain. OBJECTIVE To investigate the effects of testosterone and estradiol on HDL particle concentration (HDL-Pima) and metrics of HDL function. METHODS We enrolled 53 healthy men, 19 to 55 years of age, in a double-blinded, placebo-controlled, randomized trial. Subjects were rendered medically castrate using the GnRH receptor antagonist acyline and administered either (1) placebo gel, (2) low-dose transdermal testosterone gel (1.62%, 1.25 g), (3) full replacement dose testosterone gel (1.62%, 5 g) or (4) full replacement dose testosterone gel together with an aromatase inhibitor for 4 weeks. At baseline and end of treatment, serum HDL total macrophage and ABCA1-specific cholesterol efflux capacity (CEC), HDL-Pima and size, and HDL protein composition were determined. RESULTS Significant differences in serum HDL-C were observed with treatment across groups (P = .01 in overall repeated measures ANOVA), with increases in HDL-C seen after both complete and partial testosterone deprivation. Medical castration increased total HDL-Pima (median [interquartile range] 19.1 [1.8] nmol/L at baseline vs 21.3 [3.1] nmol/L at week 4, P = .006). However, corresponding changes in total macrophage CEC and ABCA1-specific CEC were not observed. Change in serum 17β-estradiol concentration correlated with change in total macrophage CEC (β = 0.33 per 10 pg/mL change in serum 17β-estradiol, P = .03). CONCLUSIONS Testosterone deprivation in healthy men leads to a dissociation between changes in serum HDL-C and HDL CEC. Changes in serum HDL-C specifically due to testosterone exposure may not reflect changes in HDL function.
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Will 68Ga PSMA-radioligands be the only choice for nuclear medicine in prostate cancer in the near future? A clinical update.
Cuccurullo, V, di Stasio, GD, Evangelista, L, Ciarmiello, A, Mansi, L
Revista espanola de medicina nuclear e imagen molecular. 2018;(2):103-109
Abstract
Prostate Cancer (PCa) represents the most common malignant tumor in men but according to the European Association of Urology (EAU) guidelines, a mass screening for PCa diagnosis should not be performed due to over-diagnosis and over-treatment related problems. An early clinical diagnosis is possible, mainly based on digital rectal examination and Prostatic Specific Agent (PSA) testing. However, the only mandatory test to define the presence of PCa is ultrasound guided-biopsy, obtained on multiple samples, which has also a high prognostic value. In this context, diagnostic imaging plays an important role as confirmed by EAU that in a 2016 update of their guidelines on PCa stated the importance of Positron Emission Tomography (PET) with 11C- or 18F-choline combined with computed tomography (CT) to identify local relapse, lymph node involvement and metastatic spread at all stages. Consequently, in 2017, the European Association of Nuclear Medicine (EANM) together with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published new guidelines for 68Ga-Prostate Specific Membrane Antigen (PSMA) PET/CT to help physicians in the recommendation, execution and interpretation of PET/CT scans in patients with PCa. Thus, the aim of this 'evidence paper' is to define the current diagnostic algorithm in PCa in order to increase the general level of confidence in approaching such a crucial topic.
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Elucidating the Structures of Amyloid Oligomers with Macrocyclic β-Hairpin Peptides: Insights into Alzheimer's Disease and Other Amyloid Diseases.
Kreutzer, AG, Nowick, JS
Accounts of chemical research. 2018;(3):706-718
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Abstract
In the more than a century since its identification, Alzheimer's disease has become the archetype of amyloid diseases. The first glimpses of the chemical basis of Alzheimer's disease began with the identification of "amyloid" plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with "cross-β" structure in 1968. Further efforts led to the discovery of the β-amyloid peptide, Aβ, as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils. At this point, a three-decade-long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer's disease. Along the way, an alternative model began to emerge in which small aggregates of Aβ, called "oligomers", rather than fibrils, are the culprits that lead to neurodegeneration in Alzheimer's disease. This Account describes what is known about the structures of the fibrils and details our research group's efforts to understand the structural, biophysical, and biological properties of the oligomers in amyloid diseases. β-Sheets are the building blocks of amyloid fibrils and oligomers. Amyloid fibrils generally consist of extended networks of parallel β-sheets. Amyloid oligomers appear to be more compact enclosed structures, some of which are thought to be composed of antiparallel β-sheets comprising β-hairpins. β-Hairpins are special because their twisted shape, hydrophobic surfaces, and exposed hydrogen-bonding edges impart a unique propensity to form compact assemblies. Our laboratory has developed macrocyclic β-sheets that are designed to mimic β-hairpins formed by amyloidogenic peptides and proteins. The β-hairpin mimics contain two β-strand peptide fragments linked together at their N- and C-termini by two δ-linked ornithine turn mimics to create a macrocycle. An N-methyl group is installed on one of the β-strands to prevent uncontrolled aggregation. These design features facilitate crystallization of the β-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form. During the past few years, our laboratory has elucidated the X-ray crystallographic structures of oligomers formed by β-hairpin mimics derived from Aβ, α-synuclein, and β2-microglobulin. Out of these three amyloidogenic peptides and proteins, the Aβ β-hairpin mimics have provided the most insight into amyloid oligomers. Our studies have revealed a previously undiscovered mode of self-assembly, whereby three Aβ β-hairpin mimics assemble to form a triangular trimer. The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers. Some of the dodecamers pack in the crystal lattice to form annular porelike assemblies. Some of the β-hairpin mimics and triangular trimers assemble in solution to form oligomers that recapitulate the crystallographically observed oligomers. These oligomers exhibit toxicity toward neuronally derived cells, recapitulating the toxicity of the oligomers formed by full-length amyloidogenic peptides and proteins. These findings are significant, because they address a gap in understanding the molecular basis of amyloid diseases. We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer's disease, Parkinson's disease, and other amyloid diseases.
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N-Terminal Cu-Binding Motifs (Xxx-Zzz-His, Xxx-His) and Their Derivatives: Chemistry, Biology and Medicinal Applications.
Gonzalez, P, Bossak, K, Stefaniak, E, Hureau, C, Raibaut, L, Bal, W, Faller, P
Chemistry (Weinheim an der Bergstrasse, Germany). 2018;(32):8029-8041
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Abstract
Peptides and proteins with N-terminal amino acid sequences NH2 -Xxx-His (XH) and NH2 -Xxx-Zzz-His (XZH) form well-established high-affinity CuII -complexes. Key examples are Asp-Ala-His (in serum albumin) and Gly-His-Lys, the wound healing factor. This opens a straightforward way to add a high-affinity CuII -binding site to almost any peptide or protein, by chemical or recombinant approaches. Thus, these motifs, NH2 -Xxx-Zzz-His in particular, have been used to equip peptides and proteins with a multitude of functions based on the redox activity of Cu, including nuclease, protease, glycosidase, or oxygen activation properties, useful in anticancer or antimicrobial drugs. More recent research suggests novel biological functions, mainly based on the redox inertness of CuII in XZH, like PET imaging (with 64 Cu), chelation therapies (for instance in Alzheimer's disease and other types of neurodegeneration), antioxidant units, Cu transporters and activation of biological functions by strong CuII binding. This Review gives an overview of the chemical properties of Cu-XH and -XZH motifs and discusses the pros and cons of the vastly different biological applications, and how they could be improved depending on the application.
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Lactotripeptides Supplementations Alleviate the Decrease in Maximal Isometric Force After High-Intensity Eccentric Exercise: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.
Tagawa, K, Ra, SG, Choi, Y, Maeda, S
American journal of physical medicine & rehabilitation. 2018;(5):370-374
Abstract
OBJECTIVE The aim of the study was to investigate whether lactotripeptides supplementations alleviate the decrease in the maximal isometric force, an indirect marker of muscle damage, after eccentric exercise (ECC). DESIGN Twenty-two young men performed 50 ECC of the elbow flexors using an isokinetic dynamometer. The subjects were randomly assigned to either the placebo or lactotripeptides group and were each given a 4.5 mg/d placebo or lactotripeptides thrice on the exercise day and the day after. Maximal isometric force and brachial arterial diameter were assessed before and 2 days after the ECC. RESULTS The interaction of time and group on maximal isometric force was significant (P < 0.05); maximal isometric force was significantly decreased in both groups after ECC (P < 0.005). The interaction of brachial arterial diameter was significant (P < 0.05); brachial arterial diameter was significantly increased in only the lactotripeptides group (P < 0.005). In addition, the change in maximal isometric force was significantly related to the change in brachial arterial diameter after adjusting for body weight and change in range of motion (P < 0.05). CONCLUSIONS The present results suggest that lactotripeptides supplementation alleviates the decrease in the maximal isometric force via an increase in brachial arterial diameter after ECC.
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Surface-driven first-step events of nanoscale self-assembly for molecular peptide fibers: An experimental and theoretical study.
Forte, G, Messina, GML, Zamuner, A, Dettin, M, Grassi, A, Marletta, G
Colloids and surfaces. B, Biointerfaces. 2018;:148-155
Abstract
New experimental results are reported on the self-assembling behavior of EAK16-II, the first discovered ionic self-complementary peptide, incubated at ultralow concentration (10-6 M) at neutral pH onto differently charged surfaces. It is found that strongly negatively charged surfaces promote the self-assembly of flat, micrometer-long mono-molecular fibers of side-on assembled sequences, lying onto a continuous monolayer of flat-on EAK16-II molecules. These results suggest that the monomolecular EAK16-II self-assembly is driven by the peculiar matching condition between peptide and surface electrostatic properties. Molecular Mechanics simulations of the basic bimolecular interactions confirmed the experimental inferences, showing that the flat-on state is the most stable arrangement for two interacting EAK16-II sequences onto strongly negatively charged surfaces, where indeed EAK16-II β-sheet conformation is stabilized, while the weak electrostatic interactions with mildly charged substrates promote an "entangled" EAK16-II geometry. Molecular Dynamics simulations further showed that the mobility and diffusional freedom of the peptides from the surfaces are ruled by the relative strength of peptide-surface electrostatic interactions, so that desorption probability for the peptide sequences is negligible from strongly-charged surfaces and high from mildly-charged surfaces. Furthermore, it has been found that an oligopeptide sequence lying onto two flat-on EAK16-II molecules, gains a remarkable lateral mobility, while remaining weakly bound to the surface, thus allowing the further molecular self-alignment responsible for the micrometer-long fiber formation. The reported results pave the way to the understanding and control of the subtle peptide-surface structural motifs matching enabling the formation of micrometer-long, but nanometer-wide monomolecular fibers.
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Methanobactins: Maintaining copper homeostasis in methanotrophs and beyond.
Kenney, GE, Rosenzweig, AC
The Journal of biological chemistry. 2018;(13):4606-4615
Abstract
Methanobactins (Mbns) are ribosomally produced, post-translationally modified natural products that bind copper with high affinity and specificity. Originally identified in methanotrophic bacteria, which have a high need for copper, operons encoding these compounds have also been found in many non-methanotrophic bacteria. The proteins responsible for Mbn biosynthesis include several novel enzymes. Mbn transport involves export through a multidrug efflux pump and re-internalization via a TonB-dependent transporter. Release of copper from Mbn and the molecular basis for copper regulation of Mbn production remain to be elucidated. Future work is likely to result in the identification of new enzymatic chemistry, opportunities for bioengineering and drug targeting of copper metabolism, and an expanded understanding of microbial metal homeostasis.
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Interactions mediated by a public good transiently increase cooperativity in growing Pseudomonas putida metapopulations.
Becker, F, Wienand, K, Lechner, M, Frey, E, Jung, H
Scientific reports. 2018;(1):4093
Abstract
Bacterial communities have rich social lives. A well-established interaction involves the exchange of a public good in Pseudomonas populations, where the iron-scavenging compound pyoverdine, synthesized by some cells, is shared with the rest. Pyoverdine thus mediates interactions between producers and non-producers and can constitute a public good. This interaction is often used to test game theoretical predictions on the "social dilemma" of producers. Such an approach, however, underestimates the impact of specific properties of the public good, for example consequences of its accumulation in the environment. Here, we experimentally quantify costs and benefits of pyoverdine production in a specific environment, and build a model of population dynamics that explicitly accounts for the changing significance of accumulating pyoverdine as chemical mediator of social interactions. The model predicts that, in an ensemble of growing populations (metapopulation) with different initial producer fractions (and consequently pyoverdine contents), the global producer fraction initially increases. Because the benefit of pyoverdine declines at saturating concentrations, the increase need only be transient. Confirmed by experiments on metapopulations, our results show how a changing benefit of a public good can shape social interactions in a bacterial population.
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Methanobactins: from genome to function.
Dassama, LM, Kenney, GE, Rosenzweig, AC
Metallomics : integrated biometal science. 2017;(1):7-20
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Abstract
Methanobactins (Mbns) are ribosomally produced, post-translationally modified peptide (RiPP) natural products that bind copper with high affinity using nitrogen-containing heterocycles and thioamide groups. In some methanotrophic bacteria, Mbns are secreted under conditions of copper starvation and then re-internalized as a copper source for the enzyme particulate methane monooxygenase (pMMO). Genome mining studies have led to the identification and classification of operons encoding the Mbn precursor peptide (MbnA) as well as a number of putative transport, regulatory, and biosynthetic proteins. These Mbn operons are present in non-methanotrophic bacteria as well, suggesting a broader role in and perhaps beyond copper acquisition. Genetic and biochemical studies indicate that specific operon-encoded proteins are involved in Mbn transport and provide insight into copper-responsive gene regulation in methanotrophs. Mbn biosynthesis is not yet understood, but combined analysis of Mbn structures, MbnA sequences, and operon content represents a powerful approach to elucidating the roles of specific biosynthetic enzymes. Future work will likely lead to the discovery of unique pathways for natural product biosynthesis and new mechanisms of microbial metal homeostasis.
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Functional oligopeptide as a novel strategy for drug delivery.
Ji, Y, Qiao, H, He, J, Li, W, Chen, R, Wang, J, Wu, L, Hu, R, Duan, J, Chen, Z
Journal of drug targeting. 2017;(7):597-607
Abstract
Oligopeptides, a type of short peptide, which consist of 2-20 amino acids, exhibit a variety of biological functions in drug delivery systems, such as specific targeting, cell penetration, self-assembled capacity and responsiveness to the environment. In this review, we aim to highlight the importance of functional oligopeptides for nanomedical applications and put forward the views on the future development direction of oligopeptide medicines. Oligopeptides have gained wide attentions due to their inherent properties, but the lack of understanding the mechanisms of in vivo transport behavior is the biggest problem and challenge at the present stage. Therefore, it is an important direction for the future clinical research to systematically evaluate its metabolic behavior and safety in vivo.