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Biomolecules, Volume 9, Issue 2 (February 2019)

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Cover Story (view full-size image) In eukaryotic cells, liquid–liquid phase separation of ribonucleoproteins (RNPs) drives regulated [...] Read more.
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Open AccessReview Mechanisms of Spindle Positioning: Lessons from Worms and Mammalian Cells
Biomolecules 2019, 9(2), 80; https://doi.org/10.3390/biom9020080
Received: 8 January 2019 / Revised: 13 February 2019 / Accepted: 18 February 2019 / Published: 25 February 2019
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Abstract
Proper positioning of the mitotic spindle is fundamental for specifying the site for cleavage furrow, and thus regulates the appropriate sizes and accurate distribution of the cell fate determinants in the resulting daughter cells during development and in the stem cells. The past [...] Read more.
Proper positioning of the mitotic spindle is fundamental for specifying the site for cleavage furrow, and thus regulates the appropriate sizes and accurate distribution of the cell fate determinants in the resulting daughter cells during development and in the stem cells. The past couple of years have witnessed tremendous work accomplished in the area of spindle positioning, and this has led to the emergence of a working model unravelling in-depth mechanistic insight of the underlying process orchestrating spindle positioning. It is evident now that the correct positioning of the mitotic spindle is not only guided by the chemical cues (protein–protein interactions) but also influenced by the physical nature of the cellular environment. In metazoans, the key players that regulate proper spindle positioning are the actin-rich cell cortex and associated proteins, the ternary complex (Gα/GPR-1/2/LIN-5 in Caenorhabditis elegans, Gαi/Pins/Mud in Drosophila and Gαi1-3/LGN/NuMA in humans), minus-end-directed motor protein dynein and the cortical machinery containing myosin. In this review, I will mainly discuss how the abovementioned components precisely and spatiotemporally regulate spindle positioning by sensing the physicochemical environment for execution of flawless mitosis. Full article
(This article belongs to the Special Issue Cytoskeleton and Regulation of Mitosis)
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Open AccessArticle Saturated Fatty Acid Activates T Cell Inflammation Through a Nicotinamide Nucleotide Transhydrogenase (NNT)-Dependent Mechanism
Biomolecules 2019, 9(2), 79; https://doi.org/10.3390/biom9020079
Received: 16 January 2019 / Revised: 19 February 2019 / Accepted: 19 February 2019 / Published: 25 February 2019
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Abstract
Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated [...] Read more.
Circulating fatty acids (FAs) increase with obesity and can drive mitochondrial damage and inflammation. Nicotinamide nucleotide transhydrogenase (NNT) is a mitochondrial protein that positively regulates nicotinamide adenine dinucleotide phosphate (NADPH), a key mediator of energy transduction and redox homeostasis. The role that NNT-regulated bioenergetics play in the inflammatory response of immune cells in obesity is untested. Our objective was to determine how free fatty acids (FFAs) regulate inflammation through impacts on mitochondria and redox homeostasis of peripheral blood mononuclear cells (PBMCs). PBMCs from lean subjects were activated with a T cell-specific stimulus in the presence or absence of generally pro-inflammatory palmitate and/or non-inflammatory oleate. Palmitate decreased immune cell expression of NNT, NADPH, and anti-oxidant glutathione, but increased reactive oxygen and proinflammatory Th17 cytokines. Oleate had no effect on these outcomes. Genetic inhibition of NNT recapitulated the effects of palmitate. PBMCs from obese (BMI >30) compared to lean subjects had lower NNT and glutathione expression, and higher Th17 cytokine expression, none of which were changed by exogenous palmitate. Our data identify NNT as a palmitate-regulated rheostat of redox balance that regulates immune cell function in obesity and suggest that dietary or therapeutic strategies aimed at increasing NNT expression may restore redox balance to ameliorate obesity-associated inflammation. Full article
(This article belongs to the Special Issue Mitochondrial Diseases)
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Open AccessArticle Silver Nanoparticle-Induced Phosphorylation of Histone H3 at Serine 10 Involves MAPK Pathways
Biomolecules 2019, 9(2), 78; https://doi.org/10.3390/biom9020078
Received: 31 January 2019 / Revised: 15 February 2019 / Accepted: 18 February 2019 / Published: 22 February 2019
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Abstract
The phosphorylation of histone H3 at serine 10 (p-H3S10) has been shown to be closely correlated with mitotic chromosome condensation. We previously reported that intracellular silver nanoparticles (AgNPs) release Ag ions that alter actin filament dynamics, leading to the activation of Aurora kinases [...] Read more.
The phosphorylation of histone H3 at serine 10 (p-H3S10) has been shown to be closely correlated with mitotic chromosome condensation. We previously reported that intracellular silver nanoparticles (AgNPs) release Ag ions that alter actin filament dynamics, leading to the activation of Aurora kinases and the formation of p-H3S10 through a mechanism clearly different from that occurring during mitosis. In the present study, we examined other mechanisms underlying the induction of p-H3S10 formation by AgNPs. We observed that the early formation of p-H3S10 induced by AgNPs occurred via the activation of mitogen-activated protein kinase (MAPK) pathways, specifically the Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. The late AgNP-induced p-H3S10 formation occurred via the activation of the entire MAPK cascade. On the other hand, p-H3S10 formation was not due to DNA damage induced by AgNPs, or the activation of the kinases ataxia telangiectasia-mutated (ATM) and ATM-Rad3-related (ATR). Several studies have compared the mechanism of AgNP toxicity to a Trojan horse-type molecular pathway. We observed different effects of AgNO3 (Ag+) and AgNPs on cells, and only the JNK inhibitor suppressed the temporary AgNO3-induced formation of p-H3S10. These results strongly indicate that AgNP-induced p-H3S10 formation does not rely solely on one signaling pathway, but rather may involve two or more pathways. Full article
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Open AccessArticle Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level
Biomolecules 2019, 9(2), 77; https://doi.org/10.3390/biom9020077
Received: 7 January 2019 / Revised: 10 February 2019 / Accepted: 10 February 2019 / Published: 22 February 2019
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Abstract
Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less [...] Read more.
Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessReview The Health Beneficial Properties of Rhodomyrtus tomentosa as Potential Functional Food
Biomolecules 2019, 9(2), 76; https://doi.org/10.3390/biom9020076
Received: 1 February 2019 / Revised: 15 February 2019 / Accepted: 18 February 2019 / Published: 21 February 2019
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Abstract
Rhodomyrtus tomentosa (Aiton) Hassk. is a flowering plant belonging to the family Myrtaceae, native to southern and southeastern Asia. It has been used in traditional Vietnamese, Chinese, and Malaysian medicine for a long time for the treatment of diarrhea, dysentery, gynecopathy, stomachache, and [...] Read more.
Rhodomyrtus tomentosa (Aiton) Hassk. is a flowering plant belonging to the family Myrtaceae, native to southern and southeastern Asia. It has been used in traditional Vietnamese, Chinese, and Malaysian medicine for a long time for the treatment of diarrhea, dysentery, gynecopathy, stomachache, and wound healing. Moreover, R. tomentosa is used to make various food products such as wine, tea, and jam. Notably, R. tomentosa has been known to contain structurally diverse and biologically active metabolites, thus serving as a potential resource for exploring novel functional agents. Up to now, numerous phenolic and terpenoid compounds from the leaves, root, or fruits of R. tomentosa have been identified, and their biological activities such as antioxidant, antibacterial, anti-inflammatory, and anticancer have been evidenced. In this contribution, an overview of R. tomentosa and its health beneficial properties was focused on and emphasized. Full article
Open AccessReview Testosterone in Males as Enhanced by Onion (Allium Cepa L.)
Biomolecules 2019, 9(2), 75; https://doi.org/10.3390/biom9020075
Received: 29 December 2018 / Revised: 9 February 2019 / Accepted: 20 February 2019 / Published: 21 February 2019
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Abstract
Testosterone (17β-Hydroxyandrost-4-en-3-one) is the main sex hormone in males. Maintaining and enhancing testosterone level in men is an incessant target for many researchers. Examples of such research approaches is to utilize specific types of food or dietary supplements as a safe and easily [...] Read more.
Testosterone (17β-Hydroxyandrost-4-en-3-one) is the main sex hormone in males. Maintaining and enhancing testosterone level in men is an incessant target for many researchers. Examples of such research approaches is to utilize specific types of food or dietary supplements as a safe and easily reached means. Here, specifically, since 1967 until now, many research studies have revealed the effect of onion on testosterone; however, this link has yet to be collectively reviewed or summarized. To accomplish this contribution, we searched the Scopus, Web of Science, and PubMed databases for full articles or abstracts (published in English language) from April 1967 through December 2018 using the keywords “onion” versus “testosterone”. In addition, a number of related published articles from the same databases were included to improve the integrity of the discussion, and hence the edge of the future directions. In summary, there is an evidence that onions enhance testosterone level in males. The mechanisms by which this occurs is mainly by increasing the production of luteinizing hormone, enhancing the antioxidant defense mechanism in the tests, neutralizing the damaging effects of the generated free radicals, ameliorating insulin resistance, promoting nitric oxide production, and altering the activity of adenosine 5′-monophosphate -activated protein kinase. However, this effect requires further approval in humans, mainly by conducting clinical trials. Full article
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Open AccessEditorial Introduction to Peptidyl-Prolyl cis/trans Isomerase (PPIase) Series
Biomolecules 2019, 9(2), 74; https://doi.org/10.3390/biom9020074
Received: 8 February 2019 / Accepted: 11 February 2019 / Published: 20 February 2019
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Abstract
About 30 years after the discovery of peptidyl-prolyl cis/trans isomerases (PPIases), research on this group of proteins has become somewhat calmer than it used to be, but it still generates lots of interest [...] Full article
Open AccessArticle The Effect of Cytochalasans on the Actin Cytoskeleton of Eukaryotic Cells and Preliminary Structure–Activity Relationships
Biomolecules 2019, 9(2), 73; https://doi.org/10.3390/biom9020073
Received: 21 January 2019 / Revised: 14 February 2019 / Accepted: 14 February 2019 / Published: 19 February 2019
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Abstract
In our ongoing search for new bioactive fungal metabolites, two new cytochalasans were isolated from stromata of the hypoxylaceous ascomycete Hypoxylon fragiforme. Their structures were elucidated via high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. Together with 23 additional cytochalasans [...] Read more.
In our ongoing search for new bioactive fungal metabolites, two new cytochalasans were isolated from stromata of the hypoxylaceous ascomycete Hypoxylon fragiforme. Their structures were elucidated via high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy. Together with 23 additional cytochalasans isolated from ascomata and mycelial cultures of different Ascomycota, they were tested on their ability to disrupt the actin cytoskeleton of mammal cells in a preliminary structure–activity relationship study. Out of all structural features, the presence of hydroxyl group at the C7 and C18 residues, as well as their stereochemistry, were determined as important factors affecting the potential to disrupt the actin cytoskeleton. Moreover, reversibility of the actin disrupting effects was tested, revealing no direct correlations between potency and reversibility in the tested compound group. Since the diverse bioactivity of cytochalasans is interesting for various applications in eukaryotes, the exact effect on eukaryotic cells will need to be determined, e.g., by follow-up studies involving medicinal chemistry and by inclusion of additional natural cytochalasans. The results are also discussed in relation to previous studies in the literature, including a recent report on the anti-Biofilm activities of essentially the same panel of compounds against the pathogenic bacterium, Staphylococcus aureus. Full article
(This article belongs to the Special Issue Biology, Biotechnology and Bioprospecting of Microbial Biomolecules)
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Open AccessArticle Protecting Group-Free Synthesis of Glycopolymer-Type Amphiphilic Macromonomers and Their Use for the Preparation of Carbohydrate-Decorated Polymer Particles
Biomolecules 2019, 9(2), 72; https://doi.org/10.3390/biom9020072
Received: 27 December 2018 / Revised: 9 February 2019 / Accepted: 9 February 2019 / Published: 19 February 2019
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Abstract
Polymer particles modified with carbohydrates on their surfaces are of significant interest, because their specific recognition abilities to biomolecules are valuable for developing promising materials in biomedical fields. Carbohydrate-decorated core-shell polymer particles are expected to be efficiently prepared by dispersion polymerization using a [...] Read more.
Polymer particles modified with carbohydrates on their surfaces are of significant interest, because their specific recognition abilities to biomolecules are valuable for developing promising materials in biomedical fields. Carbohydrate-decorated core-shell polymer particles are expected to be efficiently prepared by dispersion polymerization using a glycopolymer-based amphiphilic macromonomer as both a polymeric steric stabilizer and a monomer. To create glycopolymer-type macromonomers, we propose a new strategy combining living cationic polymerization of an alkynyl-functionalized vinyl ether (VE), and the click reaction for the preparation of glycopolymers having a polymerizable terminal group, and investigate their dispersion copolymerization with styrene for generating carbohydrate-decorated polymer particles. This study deals with (i) the synthesis of block copolymer-type amphiphilic macromonomers bearing a methacryloyl group at the α-terminus, and pendant alkynyl groups by living cationic polymerization of alkynyl-substituted VE (VEEP), (ii) the derivatization of maltose-carrying macromonomers by click chemistry of the pendant alkynyl groups of the precursor macromonomers with maltosyl azide without any protecting/deprotecting processes, and (iii) the preparation of maltose-decorated (Mal-decorated) polymer particles through the dispersion copolymerization of glycopolymer-type macromonomers with styrene in polar media. Moreover, this study concerns the specific interactions of the resultant polymer particles with the lectin concanavalin A (Con A). Full article
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Open AccessFeature PaperArticle Molecular Crowding Tunes Material States of Ribonucleoprotein Condensates
Biomolecules 2019, 9(2), 71; https://doi.org/10.3390/biom9020071
Received: 31 December 2018 / Revised: 5 February 2019 / Accepted: 5 February 2019 / Published: 19 February 2019
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Abstract
Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to a changing cellular environment. RNP condensation is largely governed by promiscuous attractive inter-chain interactions mediated by low-complexity domains (LCDs). Using an archetypal disordered [...] Read more.
Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to a changing cellular environment. RNP condensation is largely governed by promiscuous attractive inter-chain interactions mediated by low-complexity domains (LCDs). Using an archetypal disordered RNP, fused in sarcoma (FUS), here we study how molecular crowding impacts the RNP liquid condensation. We observe that the liquid–liquid coexistence boundary of FUS is lowered by polymer crowders, consistent with an excluded volume model. With increasing bulk crowder concentration, the RNP partition increases and the diffusion rate decreases in the condensed phase. Furthermore, we show that RNP condensates undergo substantial hardening wherein protein-dense droplets transition from viscous fluid to viscoelastic gel-like states in a crowder concentration-dependent manner. Utilizing two distinct LCDs that broadly represent commonly occurring sequence motifs driving RNP phase transitions, we reveal that the impact of crowding is largely independent of LCD charge and sequence patterns. These results are consistent with a thermodynamic model of crowder-mediated depletion interaction, which suggests that inter-RNP attraction is enhanced by molecular crowding. The depletion force is likely to play a key role in tuning the physical properties of RNP condensates within the crowded cellular space. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessArticle Effects of Winter Flounder Antifreeze Protein on the Growth of Ice Particles in an Ice Slurry Flow in Mini-Channels
Biomolecules 2019, 9(2), 70; https://doi.org/10.3390/biom9020070
Received: 5 January 2019 / Revised: 1 February 2019 / Accepted: 1 February 2019 / Published: 18 February 2019
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Abstract
The control of ice growth in ice slurry is important for many fields, including (a) the cooling of the brain during cardiac arrest, (b) the storage and transportation of fresh fish and fruits, and (c) the development of distributed air-conditioning systems. One of [...] Read more.
The control of ice growth in ice slurry is important for many fields, including (a) the cooling of the brain during cardiac arrest, (b) the storage and transportation of fresh fish and fruits, and (c) the development of distributed air-conditioning systems. One of the promising methods for the control is to use a substance such as antifreeze protein. We have observed and report here growth states of ice particles in both quiescent and flowing aqueous solutions of winter flounder antifreeze proteins in mini-channels with a microscope. We also measured ice growth rates. Our aim was to improve the levels of ice growth inhibition by subjecting the antifreeze protein solution both to preheating and to concentrating by ultrafiltration. We have found that the ice growth inhibition by the antifreeze protein decreased in flowing solutions compared with that in quiescent solutions. In addition, unlike unidirectional freezing experiments, the preheating of the antifreeze protein solution reduced the ice growth inhibition properties. This is because the direction of flow, containing HPLC6 and its aggregates, to the ice particle surfaces can change as the ice particle grows, and thus the probability of interaction between HPLC6 and ice surfaces does not increase. In contrast to this, ultrafiltration after preheating the solution improved the ice growth inhibition. This may be due to the interaction between ice surfaces and many aggregates in the concentrates. Full article
(This article belongs to the Special Issue Antifreeze Protein: New Insight from Different Approaches)
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Open AccessArticle Surface-Degradable Drug-Eluting Stent with Anticoagulation, Antiproliferation, and Endothelialization Functions
Biomolecules 2019, 9(2), 69; https://doi.org/10.3390/biom9020069
Received: 5 December 2018 / Revised: 29 January 2019 / Accepted: 6 February 2019 / Published: 18 February 2019
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Abstract
Drug-eluting stents (DES) have been widely applied for saving the life of patients with coronary artery diseases (CADs). However, conventional polymers such as polylactic acid (PLA) and poly (lactic-co-glycolic acid) (PLGA), which are widely applied for drug-eluting stents studies, have serious bulk erosion [...] Read more.
Drug-eluting stents (DES) have been widely applied for saving the life of patients with coronary artery diseases (CADs). However, conventional polymers such as polylactic acid (PLA) and poly (lactic-co-glycolic acid) (PLGA), which are widely applied for drug-eluting stents studies, have serious bulk erosion problems, like high local acidity and poor mechanical properties. Instead, we chose surface erosion polymer poly (1, 3-trimethylene carbonate) (PTMC) as a drug carrier in this study. Here, we fabricated and characterized a novel durable-polymer drug-eluting 316 L stainless steel (SS) stent, in which the inner surface was coated with a Ti–O film using the magnetron sputtering method to promote the growth of endothelial cells (ECs). On the outer layer of the stent, first, a Ti–O film was deposited and, then, on top of it a rapamycin-loaded PTMC coat was deposited using the ultrasonic atomization spray method. This dual coating inhibited the migration and expansion of smooth muscle cells (SMCs). The drug coating also inhibited the adhesion/activation of platelets. In tests on dogs, it was found the novel stent promoted re-endothelialization and reduced restenosis, in contrast to the plain SS stent. Thus, the novel stent may have promise for use in treating patients with CAD. Full article
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Open AccessReview Chrysophanol: A Natural Anthraquinone with Multifaceted Biotherapeutic Potential
Biomolecules 2019, 9(2), 68; https://doi.org/10.3390/biom9020068
Received: 29 December 2018 / Revised: 5 February 2019 / Accepted: 7 February 2019 / Published: 18 February 2019
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Abstract
Chrysophanol is a unique anthraquinone having broad-spectrum therapeutic potential along with ecological importance. It is the first polyketide that has been reported to be biosynthesized in an organism-specific manner. The traditional Chinese and Korean medicinal systems provide evidence of the beneficial effects of [...] Read more.
Chrysophanol is a unique anthraquinone having broad-spectrum therapeutic potential along with ecological importance. It is the first polyketide that has been reported to be biosynthesized in an organism-specific manner. The traditional Chinese and Korean medicinal systems provide evidence of the beneficial effects of chrysophanol on human health. The global distribution of chrysophanol encountered in two domains of life (bacteria and eukaryota) has motivated researchers to critically evaluate the properties of this compound. A plethora of literature is available on the pharmacological properties of chrysophanol, which include anticancer, hepatoprotective, neuroprotective, anti-inflammatory, antiulcer, and antimicrobial activities. However, the pharmacokinetics and toxicity studies on chrysophanol demand further investigations for it to be used as a drug. This is the first comprehensive review on the natural sources, biosynthetic pathways, and pharmacology of chrysophanol. Here we reviewed recent advancements made on the pharmacokinetics of the chrysophanol. Additionally, we have highlighted the knowledge gaps of its mechanism of action against diseases and toxicity aspects. Full article
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Open AccessReview Getting the Akt Together: Guiding Intracellular Akt Activity by PI3K
Biomolecules 2019, 9(2), 67; https://doi.org/10.3390/biom9020067
Received: 11 January 2019 / Revised: 11 February 2019 / Accepted: 12 February 2019 / Published: 16 February 2019
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Abstract
Intracellular signaling pathways mediate the rapid response of cells to environmental cues. To control the fidelity of these responses, cells coordinate the activities of signaling enzymes with the strength, timing, and localization of the upstream stimuli. Protein kinase Akt links the PI3K-coupled receptors [...] Read more.
Intracellular signaling pathways mediate the rapid response of cells to environmental cues. To control the fidelity of these responses, cells coordinate the activities of signaling enzymes with the strength, timing, and localization of the upstream stimuli. Protein kinase Akt links the PI3K-coupled receptors to cellular anabolic processes by phosphorylating multiple substrates. How the cells ensure that Akt activity remains proportional to upstream signals and control its substrate specificity is unclear. In this review, I examine how cell-autonomous and intrinsic allosteric mechanisms cooperate to ensure localized, context-specific signaling in the PI3K/Akt axis. Full article
(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)
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Open AccessArticle Genome-Wide Identification and Characterization of SQUAMOSA—Promoter-Binding Protein (SBP) Genes Involved in the Flowering Development of Citrus Clementina
Biomolecules 2019, 9(2), 66; https://doi.org/10.3390/biom9020066
Received: 25 December 2018 / Revised: 7 February 2019 / Accepted: 7 February 2019 / Published: 14 February 2019
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Abstract
SQUAMOSA-promoter binding protein (SBP)-box genes encode a family of plant-specific transcription factors that play vital roles in plant growth and development. In this study, 15 SBP-box genes were identified and isolated from Citrus clementina (CclSBPs), where 10 of these genes were [...] Read more.
SQUAMOSA-promoter binding protein (SBP)-box genes encode a family of plant-specific transcription factors that play vital roles in plant growth and development. In this study, 15 SBP-box genes were identified and isolated from Citrus clementina (CclSBPs), where 10 of these genes were predicted to be putative targets of Citrus clementina microRNA156 (CclmiR156). The 15 CclSBP genes could be classified into six groups based on phylogenetic analysis, diverse intron–exon structure, and motif prediction, similar to the SQUAMOSA promoter binding protein-like (SPL) gene family of Populus trichocarpa and Arabidopsis thaliana. Furthermore, CclSBPs classified into a group/subgroup have similar gene structures and conserved motifs, implying their functional redundancy. Tissue-specific expression analysis of CclSBPs demonstrated their diversified expression patterns. To further explore the potential role of CclSBPs during floral inductive water deficits, the dynamic changes of the 15 CclSBPs were investigated during floral inductive water deficits, and the results showed that some CclSBPs were associated with floral induction. Among these genes, CclSBP6 was not homologous to the Arabidopsis SBP-box gene family, and CclSBP7 was regulated by being alternatively spliced. Therefore, CclSBP6 and CclSBP7 were genetically transformed in Arabidopsis. Overexpression of the two genes changed the flowering time of Arabidopsis. Full article
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Open AccessArticle The Role of Buffers in Wild-Type HEWL Amyloid Fibril Formation Mechanism
Biomolecules 2019, 9(2), 65; https://doi.org/10.3390/biom9020065
Received: 14 January 2019 / Revised: 4 February 2019 / Accepted: 5 February 2019 / Published: 14 February 2019
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Abstract
Amyloid fibrils, highly ordered protein aggregates, play an important role in the onset of several neurological disorders. Many studies have assessed amyloid fibril formation under specific solution conditions, but they all lack an important phenomena in biological solutions—buffer specific effects. We have focused [...] Read more.
Amyloid fibrils, highly ordered protein aggregates, play an important role in the onset of several neurological disorders. Many studies have assessed amyloid fibril formation under specific solution conditions, but they all lack an important phenomena in biological solutions—buffer specific effects. We have focused on the formation of hen egg-white lysozyme (HEWL) fibrils in aqueous solutions of different buffers in both acidic and basic pH range. By means of UV-Vis spectroscopy, fluorescence measurements and CD spectroscopy, we have managed to show that fibrillization of HEWL is affected by buffer identity (glycine, TRIS, phosphate, KCl-HCl, cacodylate, HEPES, acetate), solution pH, sample incubation (agitated vs. static) and added excipients (NaCl and PEG). HEWL only forms amyloid fibrils at pH = 2.0 under agitated conditions in glycine and KCl-HCl buffers of high enough ionic strength. Phosphate buffer on the other hand stabilizes the HEWL molecules. Similar stabilization effect was achieved by addition of PEG12000 molecules to the solution. Full article
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Open AccessReview Palm Oil in Lipid-Based Formulations and Drug Delivery Systems
Biomolecules 2019, 9(2), 64; https://doi.org/10.3390/biom9020064
Received: 29 November 2018 / Revised: 7 February 2019 / Accepted: 7 February 2019 / Published: 13 February 2019
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Abstract
Palm oil is natural oil packed with important compounds and fatty acids ready to be exploited in lipid-based formulations and drug delivery. Palm oil and palm kernel oil contain long-chain and medium-chain triglycerides, respectively, including phytonutrients such as tocotrienol, tocopherol and carotenes. The [...] Read more.
Palm oil is natural oil packed with important compounds and fatty acids ready to be exploited in lipid-based formulations and drug delivery. Palm oil and palm kernel oil contain long-chain and medium-chain triglycerides, respectively, including phytonutrients such as tocotrienol, tocopherol and carotenes. The exploitation of these compounds in a lipid-based formulation would be able to address hydrophobicity, lipophilicity, poor bioavailability and low water-solubility of many current drugs. The utilisation of palm oil as part of the drug delivery system seemed to improve the bioavailability and solubility of the drug, stabilising emulsification of formulation between emulsifier and surfactant, promoting enhanced drug permeability and performance, as well as extending the shelf-life of the drug. Despite the complexity in designing lipid-based formulations, palm oil has proven to offer dynamic behaviour in providing versatility in drug design, form and delivery. However, the knowledge and application of palm oil and its fractions in lipid-based formulation are scarce and interspersed. Therefore, this study aims to focus on the research and outcomes of using palm oil in lipid-based formulations and drug delivery systems, due to the importance of establishing its capabilities and benefits. Full article
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Open AccessArticle The Effect of Buffers on Weak Acid Uptake by Vesicles
Biomolecules 2019, 9(2), 63; https://doi.org/10.3390/biom9020063
Received: 18 December 2018 / Revised: 7 February 2019 / Accepted: 8 February 2019 / Published: 13 February 2019
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Abstract
The assessment of weak acid membrane permeability (Pm) frequently involves large unilamellar vesicles. It relies on measurements of the intravesicular pH drop, ΔpHin, in response to a sudden augmentation of external acid concentration. However, ΔpHin may be [...] Read more.
The assessment of weak acid membrane permeability (Pm) frequently involves large unilamellar vesicles. It relies on measurements of the intravesicular pH drop, ΔpHin, in response to a sudden augmentation of external acid concentration. However, ΔpHin may be primarily governed by non-instantaneous protonation and deprotonation reactions of (i) the acid itself, (ii) the buffer molecules, and (iii) the fluorescent pH reporter dye. Moreover, buffer concentration and acid gradient also serve as determinants of ΔpHin, as we show here. The uniexponential time constant (τ) of ΔpHin(t) is an invalid measure of Pm as Arrhenius plots of Pm and τ reveal different activation energies for acid influx. We calculate Pm by fitting a mathematical model to experimental stopped-flow traces. The model takes into account not only the time course of total internal buffer capacity but also (i) water self-dissociation, (ii) volume changes due to acid induced osmotic water flow, and (iii) the spontaneous membrane proton leak. It allows extracting a Pm of 30.8 ± 3.5 μm/s for formic acid for 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) vesicles. Full article
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Open AccessArticle Relationship between Circulating Serpina3g, Matrix Metalloproteinase-9, and Tissue Inhibitor of Metalloproteinase-1 and -2 with Chronic Obstructive Pulmonary Disease Severity
Biomolecules 2019, 9(2), 62; https://doi.org/10.3390/biom9020062
Received: 25 January 2019 / Revised: 5 February 2019 / Accepted: 6 February 2019 / Published: 13 February 2019
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Abstract
Chronic obstructive pulmonary disease (COPD) is influenced by genetic and environmental factors. A protease-antiprotease imbalance has been suggested as a possible pathogenic mechanism for COPD. Here, we examined the relationship between circulating serpina3g, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 and -2 [...] Read more.
Chronic obstructive pulmonary disease (COPD) is influenced by genetic and environmental factors. A protease-antiprotease imbalance has been suggested as a possible pathogenic mechanism for COPD. Here, we examined the relationship between circulating serpina3g, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 and -2 (TIMP-1 and -2, respectively) and severity of COPD. We included 150 stable COPD patients and 35 control subjects in the study. The COPD patients were classified into four groups (I, II, III, and IV), according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines based on the severity of symptoms and the exacerbation risk. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in the all patients than in control subjects. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in groups III and IV than in groups I and II. A negative correlation between serpina3g, MMP-9, and TIMP-1 and -2 levels and the forced expiratory volume in 1 s (FEV1) was observed. MMP-9 concentration and the MMP-9/TIMP-1 ratio were higher in patients with emphysema than in other phenotypes (both with p < 0.01). The findings of this study suggest that circulating serpina3g, MMP-9, and TIMP-1 and -2 levels may play an important role in airway remodeling in COPD pathogenesis. Disrupted protease-antiprotease imbalance in patients with COPD is related to the presence of airway injury. MMP-9 concentration and the MMP-9/TIMP-1 ratio are the best predictors of emphysema in COPD patients. Full article
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Open AccessArticle Light-Induced Protein Clustering for Optogenetic Interference and Protein Interaction Analysis in Drosophila S2 Cells
Biomolecules 2019, 9(2), 61; https://doi.org/10.3390/biom9020061
Received: 11 December 2018 / Revised: 30 January 2019 / Accepted: 30 January 2019 / Published: 12 February 2019
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Abstract
Drosophila Schneider 2 (S2) cells are a simple and powerful system commonly used in cell biology because they are well suited for high resolution microscopy and RNAi-mediated depletion. However, understanding dynamic processes, such as cell division, also requires methodology to interfere with protein [...] Read more.
Drosophila Schneider 2 (S2) cells are a simple and powerful system commonly used in cell biology because they are well suited for high resolution microscopy and RNAi-mediated depletion. However, understanding dynamic processes, such as cell division, also requires methodology to interfere with protein function with high spatiotemporal control. In this research study, we report the adaptation of an optogenetic tool to Drosophila S2 cells. Light-activated reversible inhibition by assembled trap (LARIAT) relies on the rapid light-dependent heterodimerization between cryptochrome 2 (CRY2) and cryptochrome-interacting bHLH 1 (CIB1) to form large protein clusters. An anti-green fluorescent protein (GFP) nanobody fused with CRY2 allows this method to quickly trap any GFP-tagged protein in these light-induced protein clusters. We evaluated clustering kinetics in response to light for different LARIAT modules, and showed the ability of GFP-LARIAT to inactivate the mitotic protein Mps1 and to disrupt the membrane localization of the polarity regulator Lethal Giant Larvae (Lgl). Moreover, we validated light-induced co-clustering assays to assess protein-protein interactions in S2 cells. In conclusion, GFP-based LARIAT is a versatile tool to answer different biological questions, since it enables probing of dynamic processes and protein-protein interactions with high spatiotemporal resolution in Drosophila S2 cells. Full article
(This article belongs to the Special Issue Cytoskeleton and Regulation of Mitosis)
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Open AccessReview The ROMP: A Powerful Approach to Synthesize Novel pH-Sensitive Nanoparticles for Tumor Therapy
Biomolecules 2019, 9(2), 60; https://doi.org/10.3390/biom9020060
Received: 29 November 2018 / Revised: 19 December 2018 / Accepted: 11 February 2019 / Published: 12 February 2019
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Abstract
Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery [...] Read more.
Fast clearance, metabolism, and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects, despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo models of cancer. The specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. This paper deals with the synthesis of the polymeric nanoparticle platform, which was produced by Ring-Opening Metathesis Polymerization (ROMP), able to release anti-cancer drugs in dispersion, such as histone deacetylase inhibitors, into mesothelioma tumors. The core-shell nanoparticles (NPs) have stealth properties due to their poly(ethylene oxide) shell and can be viewed as universal nano-carriers on which any alkyne-modified anti-cancer molecule can be grafted by click chemistry. A cleavage reaction of the chemical bond between NPs and drugs through the contact of NPs with a medium presenting an acidic pH, which is typically a cancer tumor environment or an acidic intracellular compartment, induces a controlled release of the bioactive molecule in its native form. In our in vivo syngeneic model of mesothelioma, a highly selective accumulation of the particles in the tumor was obtained. The release of the drugs led to an 80% reduction of tumor weight for the best compound without toxicity. Our work demonstrates that the use of theranostic nanovectors leads to an optimized delivery of epigenetic inhibitors in tumors, which improves their anti-tumor properties in vivo. Full article
(This article belongs to the Special Issue Nanoparticles for Cancer Therapy)
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Open AccessTechnical Note Compression of Large Sets of Sequence Data Reveals Fine Diversification of Functional Profiles in Multigene Families of Proteins: A Study for Peptidyl-Prolyl cis/trans Isomerases (PPIase)
Biomolecules 2019, 9(2), 59; https://doi.org/10.3390/biom9020059
Received: 21 December 2018 / Revised: 21 January 2019 / Accepted: 30 January 2019 / Published: 11 February 2019
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Abstract
In this technical note, we describe analyses of more than 15,000 sequences of FK506-binding proteins (FKBP) and cyclophilins, also known as peptidyl-prolyl cis/trans isomerases (PPIases). We have developed a novel way of displaying relative changes of amino acid (AA)-residues at a given sequence [...] Read more.
In this technical note, we describe analyses of more than 15,000 sequences of FK506-binding proteins (FKBP) and cyclophilins, also known as peptidyl-prolyl cis/trans isomerases (PPIases). We have developed a novel way of displaying relative changes of amino acid (AA)-residues at a given sequence position by using heat-maps. This type of representation allows simultaneous estimation of conservation level in a given sequence position in the entire group of functionally-related paralogues (multigene family of proteins). We have also proposed that at least two FKBPs, namely FKBP36, encoded by the Fkbp6 gene and FKBP51, encoded by the Fkbp5 gene, can form dimers bound via a disulfide bridge in the nucleus. This type of dimer may have some crucial function in the regulation of some nuclear complexes at different stages of the cell cycle. Full article
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Open AccessArticle Triterpene Derivatives as Relevant Scaffold for New Antibiofilm Drugs
Biomolecules 2019, 9(2), 58; https://doi.org/10.3390/biom9020058
Received: 15 January 2019 / Revised: 30 January 2019 / Accepted: 30 January 2019 / Published: 11 February 2019
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Abstract
New medicines for the treatment of bacterial biofilm formation are required. For this reason, this study shows the in vitro activity of betulinic acid (BA), ursolic acid (UA) and their twenty derivatives against planktonic and biofilm cells (gram-positive bacterial pathogens: Enterococcus faecalis, [...] Read more.
New medicines for the treatment of bacterial biofilm formation are required. For this reason, this study shows the in vitro activity of betulinic acid (BA), ursolic acid (UA) and their twenty derivatives against planktonic and biofilm cells (gram-positive bacterial pathogens: Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis). We evaluated the antibiofilm activity (through the crystal violet method), as well as the antibacterial activity via absorbance (OD600) at concentrations of 5, 25 and 100 µM. Likewise, the cytotoxicity of all compounds was evaluated on a kidney African green monkey (VERO) cell line at the same concentration, by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) methodology. We verified for the first time whether different groups at carbon 3 (C-3) of triterpenes may interfere in the antibiofilm activity with minimal or no antibacterial effect. After the screening of 22 compounds at three distinct concentrations, we found antibiofilm activity for eight distinct derivatives without antibiotic effect. In particular, the derivative 2f, with an isopentanoyl ester at position C-3, was an antibiofilm activity against S. aureus without any effect upon mammalian cells. Full article
(This article belongs to the Special Issue Evaluation and formulation of Bioactive Terpenes)
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Open AccessArticle Evaluation of Physicians’ Knowledge and Attitudes Towards Biosimilars in Russia and Issues Associated with Their Prescribing
Biomolecules 2019, 9(2), 57; https://doi.org/10.3390/biom9020057
Received: 15 October 2018 / Revised: 4 February 2019 / Accepted: 5 February 2019 / Published: 11 February 2019
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Abstract
Physician awareness and perceptions towards biosimilars are important factors in their adoption to clinical practice. Our objectives were to assess levels of knowledge and attitudes towards biosimilars and key policies on their use among Russian physicians, define the level of interest in new [...] Read more.
Physician awareness and perceptions towards biosimilars are important factors in their adoption to clinical practice. Our objectives were to assess levels of knowledge and attitudes towards biosimilars and key policies on their use among Russian physicians, define the level of interest in new information on biosimilars, and determine what evidence drives treatment decisions in Russia. Physicians with awareness of biologics across different specialties and regions of Russia completed an online survey. A Likert and other rating scales were used to collect opinions, which were summarized descriptively. Responses of subgroups of respondents were compared using t-tests. Among 206 respondents (n = 51 rheumatologists; n = 53 gastroenterologists; n = 50 hematologists; n = 52 oncologists), 66% had positive impressions regarding the introduction of biosimilars in Russia. Overall, 80% lacked understanding of the differences between biosimilars and generics. In all, 67% supported prescribing biologics by distinguishable names and were negative about tender policies limiting choice of therapies for patients. The majority believed in mandatory publication of clinical trial results on biosimilars (94%), agreed biosimilars should be subject to rigorous post-marketing surveillance (98%), and expressed willingness to learn more about biosimilars (94%). Biosimilar education among Russian physicians is required, which may help shape balanced and evidence-based policies for biosimilars in Russia. Full article
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Open AccessReview Formulations of Curcumin Nanoparticles for Brain Diseases
Biomolecules 2019, 9(2), 56; https://doi.org/10.3390/biom9020056
Received: 14 December 2018 / Revised: 30 January 2019 / Accepted: 1 February 2019 / Published: 8 February 2019
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Abstract
Curcumin is a polyphenol that is obtained from Curcuma longa and used in various areas, such as food and textiles. Curcumin has important anti-inflammatory and antioxidant properties that allow it to be applied as treatment for several emerging pathologies. Remarkably, there are an [...] Read more.
Curcumin is a polyphenol that is obtained from Curcuma longa and used in various areas, such as food and textiles. Curcumin has important anti-inflammatory and antioxidant properties that allow it to be applied as treatment for several emerging pathologies. Remarkably, there are an elevated number of publications deriving from the terms “curcumin” and “curcumin brain diseases”, which highlights the increasing impact of this polyphenol and the high number of study groups investigating their therapeutic actions. However, its lack of solubility in aqueous media, as well as its poor bioavailability in biological systems, represent limiting factors for its successful application. In this review article, the analysis of its chemical composition and the pivotal mechanisms for brain applications are addressed in a global manner. Furthermore, we emphasize the use of nanoparticles with curcumin and the benefits that have been reached as an example of the extensive advances in this area of health. Full article
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Open AccessReview Phosphatases in Mitosis: Roles and Regulation
Biomolecules 2019, 9(2), 55; https://doi.org/10.3390/biom9020055
Received: 17 December 2018 / Revised: 31 January 2019 / Accepted: 1 February 2019 / Published: 7 February 2019
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Abstract
Mitosis requires extensive rearrangement of cellular architecture and of subcellular structures so that replicated chromosomes can bind correctly to spindle microtubules and segregate towards opposite poles. This process originates two new daughter nuclei with equal genetic content and relies on highly-dynamic and tightly [...] Read more.
Mitosis requires extensive rearrangement of cellular architecture and of subcellular structures so that replicated chromosomes can bind correctly to spindle microtubules and segregate towards opposite poles. This process originates two new daughter nuclei with equal genetic content and relies on highly-dynamic and tightly regulated phosphorylation of numerous cell cycle proteins. A burst in protein phosphorylation orchestrated by several conserved kinases occurs as cells go into and progress through mitosis. The opposing dephosphorylation events are catalyzed by a small set of protein phosphatases, whose importance for the accuracy of mitosis is becoming increasingly appreciated. This review will focus on the established and emerging roles of mitotic phosphatases, describe their structural and biochemical properties, and discuss recent advances in understanding the regulation of phosphatase activity and function. Full article
(This article belongs to the Special Issue Cytoskeleton and Regulation of Mitosis)
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Open AccessArticle Combination Anthelmintic/Antioxidant Activity Against Schistosoma Mansoni
Biomolecules 2019, 9(2), 54; https://doi.org/10.3390/biom9020054
Received: 10 December 2018 / Revised: 29 January 2019 / Accepted: 31 January 2019 / Published: 5 February 2019
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Abstract
Schistosomiasis is a major neglected tropical disease. Treatment for schistosomiasis with praziquantel (PZQ), which is effective against the parasite, by itself is not capable to counteract infection-associated disease lesions including hepatic fibrosis. There is a pressing need for novel therapies. Due to their [...] Read more.
Schistosomiasis is a major neglected tropical disease. Treatment for schistosomiasis with praziquantel (PZQ), which is effective against the parasite, by itself is not capable to counteract infection-associated disease lesions including hepatic fibrosis. There is a pressing need for novel therapies. Due to their biological properties, antioxidant biomolecules might be useful in treating and reverting associated pathological sequelae. Here, we investigated a novel therapy approach based on a combination of anthelmintic drugs with antioxidant biomolecules. We used a host-parasite model involving Bioamphalaria glabrata and newly transformed schistosomula (NTS) of Schistosoma mansoni. For in vitro drug screening assays, was selected several antioxidants and evaluated not only antischistosomal activity but also ability to enhance activity of the anthelmintic drugs praziquantel (PZQ) and artesunate (AS). The morphological alterations induced by compounds alone/combined were assessed on daily basis using an inverted and automated microscope to quantify NTS viability by a fluorometric-based method. The findings indicated that not only do some antioxidants improve antischistosomal activity of the two anthelmintics, but they exhibit activity per se, leading to high mortality of NTS post-exposure. The combination index (CI) of PZQ + Mel (CI = 0.80), PZQ + Resv (CI = 0.74), AS + Resv (CI = 0.34), AS + NAC (CI = 0.89), VDT + Flav (CI = 1.03) and VDT + Resv (CI = 1.06) reveal that they display moderate to strong synergism. The combination of compounds with discrete mechanisms of action might provide a valuable adjunct to contribution for treatment of schistosomiasis-associated disease. Full article
(This article belongs to the Special Issue Multidrug Combinations)
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Open AccessArticle Oxygen Availability during Growth Modulates the Phytochemical Profile and the Chemo-Protective Properties of Spinach Juice
Biomolecules 2019, 9(2), 53; https://doi.org/10.3390/biom9020053
Received: 31 December 2018 / Revised: 22 January 2019 / Accepted: 22 January 2019 / Published: 4 February 2019
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Abstract
Fruits and vegetables are a good source of potentially biologically active compounds. Their regular consumption in the human diet can help reduce the risk of developing chronic diseases such as cardiovascular diseases and cancer. Plants produce additional chemical substances when subject to abiotic [...] Read more.
Fruits and vegetables are a good source of potentially biologically active compounds. Their regular consumption in the human diet can help reduce the risk of developing chronic diseases such as cardiovascular diseases and cancer. Plants produce additional chemical substances when subject to abiotic stress or infected by microorganisms. The phytochemical profile of spinach leaves (Spinacia oleracea L.), which is a vegetable with widely recognized health-promoting activity, has been affected by applying root hypoxic and re-oxygenation stress during plant growth. Leaf juice at different sampling times has been subject to liquid chromatography mass spectrometry (LC-MSn) analysis and tested on the human colorectal adenocarcinoma cell line HT29 by using the Comet assay. The cells were previously treated with H2O2 to simulate the presence of an oxidative stress (as in colon cancer condition) and the leaf juice application resulted in a significant antioxidant and protective in vitro effect. The duration of the hypoxic/re-oxygenation stress imposed on the plant reflects the antioxidant leaf juice content. After hypoxic stress (24 h) and reoxygenation (2 h), we show a decrease (50%) of the relative abundance of the principal identified antioxidant molecules but a higher antioxidant activity of the spinach juice on HT29 cells (20%). Data shows a complex relation between plant growing conditions and the modulation of secondary metabolites content in leaf juice that results in different chemo-protective activities in colon cancer cells. Full article
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Open AccessReview Biological Actions of the Hsp90-binding Immunophilins FKBP51 and FKBP52
Biomolecules 2019, 9(2), 52; https://doi.org/10.3390/biom9020052
Received: 27 November 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 1 February 2019
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Abstract
Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins are characterized by the additional presence of tetratricopeptide-repeats (TPR) through which they bind to the 90-kDa heat-shock protein (Hsp90), and via this chaperone, immunophilins contribute to [...] Read more.
Immunophilins are a family of proteins whose signature domain is the peptidylprolyl-isomerase domain. High molecular weight immunophilins are characterized by the additional presence of tetratricopeptide-repeats (TPR) through which they bind to the 90-kDa heat-shock protein (Hsp90), and via this chaperone, immunophilins contribute to the regulation of the biological functions of several client-proteins. Among these Hsp90-binding immunophilins, there are two highly homologous members named FKBP51 and FKBP52 (FK506-binding protein of 51-kDa and 52-kDa, respectively) that were first characterized as components of the Hsp90-based heterocomplex associated to steroid receptors. Afterwards, they emerged as likely contributors to a variety of other hormone-dependent diseases, stress-related pathologies, psychiatric disorders, cancer, and other syndromes characterized by misfolded proteins. The differential biological actions of these immunophilins have been assigned to the structurally similar, but functionally divergent enzymatic domain. Nonetheless, they also require the complementary input of the TPR domain, most likely due to their dependence with the association to Hsp90 as a functional unit. FKBP51 and FKBP52 regulate a variety of biological processes such as steroid receptor action, transcriptional activity, protein conformation, protein trafficking, cell differentiation, apoptosis, cancer progression, telomerase activity, cytoskeleton architecture, etc. In this article we discuss the biology of these events and some mechanistic aspects. Full article
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Open AccessArticle Electrocardiographic and Seasonal Patterns Allow Accurate Differentiation of Tako-Tsubo Cardiomyopathy from Acute Anterior Myocardial Infarction: Results of a Multicenter Study and Systematic Overview of Available Studies
Biomolecules 2019, 9(2), 51; https://doi.org/10.3390/biom9020051
Received: 31 December 2018 / Revised: 27 January 2019 / Accepted: 28 January 2019 / Published: 30 January 2019
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Abstract
Background. Though several studies about prevalence, etiology, clinical characteristics, preceding events, clinical management, and outcome of Tako-Tsubo cardiomyopathy (TTC) exist, the current knowledge of TTC remains limited. Objective. In 2006, TTC was classified among the acquired forms of cardiomyopathy. On the [...] Read more.
Background. Though several studies about prevalence, etiology, clinical characteristics, preceding events, clinical management, and outcome of Tako-Tsubo cardiomyopathy (TTC) exist, the current knowledge of TTC remains limited. Objective. In 2006, TTC was classified among the acquired forms of cardiomyopathy. On the basis of pathophysiological implications, we analyzed whether the presence of ST-segment elevation in lead -aVR (i.e., ST-segment depression in aVR) and the simultaneous absence of ST-segment elevation in lead V1 allow a reliable differentiation of TTC from acute anterior ST-segment elevation myocardial infarction (STEMI). A further investigative feature is the seasonal variation of TTC. Since acute cardiovascular events exhibit definite chronobiological patterns, various small studies have tried to evaluate whether this is also the case for TTC. Because results are conflicting, we also conducted a multicenter study and analyzed the findings in context with a systematic overview of available studies. Methods. We compared the ECG patterns of 115 patients with TTC, who were admitted to five large acute cardiac care centers associated with university hospitals in Southwestern Germany between January 2001 and June 2011, with those of 100 patients with acute anterior ST-segment elevation myocardial infarction (STEMI) treated in one of these centers. In addition, we performed a computer-assisted MEDLINE search of the literature from January 2000 to September 2011 and analyzed the chronobiological patterns of available TTC cases, including our TTC cohort. Results. Testing the predefined diagnostic criteria was superior to any other electrocardiographic finding and differentiated TTC from anterior STEMI with a sensitivity of 73%, a specificity of 84%, a positive predictive value of 63%, and a negative predictive value of 89%. Beyond that, the onset of TTC showed a clear variation as a function of season and month. While events occurred most frequently during summer (38.4%, p < 0.01), the event rate was the lowest in autumn (16.4%) and winter (21.9%). Chronobiological analyses on a monthly basis identified a significant annual rhythmic pattern in TTC, which peaked in August (11.9%; p < 0.01) and had its nadir in November (6.3%). Conclusions. Our data illustrate that the ST-segment changes in leads aVR and V1 represent a simple and accurate ECG criterion to differentiate TTC from anterior STEMI in patients who are admitted within 12 h of symptom onset. Similarly, the results of our seasonal analysis indicate a distinct chronobiological variation in TTC occurrence. TTC, thereby, differs from major acute cardiovascular diseases, especially acute myocardial infarction (AMI), which is characterized by winter peaks and troughs in summer. If these results are confirmed in large independent cohorts, they may yield diagnostic implications, changing the regular invasive AMI management in TTC patients. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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