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Int. J. Mol. Sci., Volume 19, Issue 7 (July 2018)

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Cover Story (view full-size image) Current knowledge of the pathogenesis and genomic landscape of NK/T-cell lymphoma (ENKTL) is [...] Read more.
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Open AccessArticle The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice
Int. J. Mol. Sci. 2018, 19(7), 2148; https://doi.org/10.3390/ijms19072148
Received: 26 June 2018 / Revised: 13 July 2018 / Accepted: 13 July 2018 / Published: 23 July 2018
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Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for
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Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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Open AccessReview Involvement of Melatonin in the Regulation of the Circadian System in Crayfish
Int. J. Mol. Sci. 2018, 19(7), 2147; https://doi.org/10.3390/ijms19072147
Received: 28 May 2018 / Revised: 3 July 2018 / Accepted: 5 July 2018 / Published: 23 July 2018
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Abstract
Melatonin (MEL) is an ancient molecule, broadly distributed in nature from unicellular to multicellular species. MEL is an indoleamine that acts on a wide variety of cellular targets regulating different physiological functions. This review is focused on the role played by this molecule
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Melatonin (MEL) is an ancient molecule, broadly distributed in nature from unicellular to multicellular species. MEL is an indoleamine that acts on a wide variety of cellular targets regulating different physiological functions. This review is focused on the role played by this molecule in the regulation of the circadian rhythms in crayfish. In these species, information about internal and external time progression might be transmitted by the periodical release of MEL and other endocrine signals acting through the pacemaker. We describe documented and original evidence in support of this hypothesis that also suggests that the rhythmic release of MEL contributes to the reinforcement of the temporal organization of nocturnal or diurnal circadian oscillators. Finally, we discuss how MEL might coordinate functions that converge in the performance of complex behaviors, such as the agonistic responses to establish social dominance status in Procambarus clarkii and the burrowing behavior in the secondary digging crayfish P. acanthophorus. Full article
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Open AccessReview Cartilage Regeneration in Humans with Adipose Tissue-Derived Stem Cells and Adipose Stromal Vascular Fraction Cells: Updated Status
Int. J. Mol. Sci. 2018, 19(7), 2146; https://doi.org/10.3390/ijms19072146
Received: 27 June 2018 / Revised: 18 July 2018 / Accepted: 21 July 2018 / Published: 23 July 2018
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Abstract
Adipose tissue-derived stem cells (ASCs) in the form of stromal vascular fraction (SVF) and cultured expansion have been applied in clinical settings in some countries to treat osteoarthritis (OA) of knees, one of the most common debilitating, incurable disorders. Since the first report
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Adipose tissue-derived stem cells (ASCs) in the form of stromal vascular fraction (SVF) and cultured expansion have been applied in clinical settings in some countries to treat osteoarthritis (OA) of knees, one of the most common debilitating, incurable disorders. Since the first report of successful cartilage-like tissue regeneration with autologous adipose SVF containing ASCs, there has been a gradual increase in the number of publications confirming such results. Thus far, most of the reports have been limited to treatments of OA of knees. Recently, successful applications of adipose SVF in treating OA of ankles and hips have been reported. In addition, several groups have reported modified methods of applying adipose SVF, such as combining bone marrow stimulation with adipose SVF or adding additional extracellular matrix (ECM) in treating OA. Here, we present an updated, systematic review of clinical effectiveness and safety in treating OA of knees, ankles, and one hip since 2016 using ASCs in the form of adipose SVF or in cultured expansion, along with a description and suggestion of potential biological mechanisms of cartilage regeneration. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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Open AccessArticle Early Transcriptomic Response to Phosphate Deprivation in Soybean Leaves as Revealed by RNA-Sequencing
Int. J. Mol. Sci. 2018, 19(7), 2145; https://doi.org/10.3390/ijms19072145
Received: 29 June 2018 / Revised: 17 July 2018 / Accepted: 17 July 2018 / Published: 23 July 2018
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Abstract
Low phosphate (Pi) availability is an important limiting factor affecting soybean production. However, the underlying molecular mechanisms responsible for low Pi stress response and tolerance remain largely unknown, especially for the early signaling events under low Pi stress. Here, a genome-wide transcriptomic analysis
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Low phosphate (Pi) availability is an important limiting factor affecting soybean production. However, the underlying molecular mechanisms responsible for low Pi stress response and tolerance remain largely unknown, especially for the early signaling events under low Pi stress. Here, a genome-wide transcriptomic analysis in soybean leaves treated with a short-term Pi-deprivation (24 h) was performed through high-throughput RNA sequencing (RNA-seq) technology. A total of 533 loci were found to be differentially expressed in response to Pi deprivation, including 36 mis-annotated loci and 32 novel loci. Among the differentially expressed genes (DEGs), 303 were induced and 230 were repressed by Pi deprivation. To validate the reliability of the RNA-seq data, 18 DEGs were randomly selected and analyzed by quantitative RT-PCR (reverse transcription polymerase chain reaction), which exhibited similar fold changes with RNA-seq. Enrichment analyses showed that 29 GO (Gene Ontology) terms and 8 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were significantly enriched in the up-regulated DEGs and 25 GO terms and 16 KEGG pathways were significantly enriched in the down-regulated DEGs. Some DEGs potentially involved in Pi sensing and signaling were up-regulated by short-term Pi deprivation, including five SPX-containing genes. Some DEGs possibly associated with water and nutrient uptake, hormonal and calcium signaling, protein phosphorylation and dephosphorylation and cell wall modification were affected at the early stage of Pi deprivation. The cis-elements of PHO (phosphatase) element, PHO-like element and P responsive element were present more frequently in promoter regions of up-regulated DEGs compared to that of randomly-selected genes in the soybean genome. Our transcriptomic data showed an intricate network containing transporters, transcription factors, kinases and phosphatases, hormone and calcium signaling components is involved in plant responses to early Pi deprivation. Full article
(This article belongs to the Special Issue Ion Transporters and Abiotic Stress Tolerance in Plants)
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Open AccessReview Dynamic DNA Methylation in Plant Growth and Development
Int. J. Mol. Sci. 2018, 19(7), 2144; https://doi.org/10.3390/ijms19072144
Received: 20 June 2018 / Revised: 12 July 2018 / Accepted: 20 July 2018 / Published: 23 July 2018
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Abstract
DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent
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DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent progress in research on the wide variation of DNA methylation in different plants, organs, tissues, and cells; dynamic changes of methylation are also reported during plant growth and development as well as changes in response to environmental stresses. Overall DNA methylation is quite diverse among species, and it occurs in CG, CHG, and CHH (H = A, C, or T) contexts of genes and TEs in angiosperms. Moderately expressed genes are most likely methylated in gene bodies. Methylation levels decrease significantly just upstream of the transcription start site and around transcription termination sites; its levels in the promoter are inversely correlated with the expression of some genes in plants. Methylation can be altered by different environmental stimuli such as pathogens and abiotic stresses. It is likely that methylation existed in the common eukaryotic ancestor before fungi, plants and animals diverged during evolution. In summary, DNA methylation patterns in angiosperms are complex, dynamic, and an integral part of genome diversity after millions of years of evolution. Full article
(This article belongs to the Special Issue DNA Methylation)
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Open AccessReview A History of the Pharmacological Treatment of Bipolar Disorder
Int. J. Mol. Sci. 2018, 19(7), 2143; https://doi.org/10.3390/ijms19072143
Received: 4 June 2018 / Revised: 12 July 2018 / Accepted: 13 July 2018 / Published: 23 July 2018
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Abstract
In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and
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In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and the beginning of the so-called “Psychopharmacological Revolution” in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed. Full article
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Open AccessReview Colletotrichum higginsianum as a Model for Understanding Host–Pathogen Interactions: A Review
Int. J. Mol. Sci. 2018, 19(7), 2142; https://doi.org/10.3390/ijms19072142
Received: 28 June 2018 / Revised: 18 July 2018 / Accepted: 18 July 2018 / Published: 23 July 2018
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Abstract
Colletotrichum higginsianum is a hemibiotrophic ascomycetous fungus that causes economically important anthracnose diseases on numerous monocot and dicot crops worldwide. As a model pathosystem, the Colletotrichum–Arabidopsis interaction has the significant advantage that both organisms can be manipulated genetically. The goal of this review
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Colletotrichum higginsianum is a hemibiotrophic ascomycetous fungus that causes economically important anthracnose diseases on numerous monocot and dicot crops worldwide. As a model pathosystem, the Colletotrichum–Arabidopsis interaction has the significant advantage that both organisms can be manipulated genetically. The goal of this review is to provide an overview of the system and to point out recent significant studies that update our understanding of the pathogenesis of C. higginsianum and resistance mechanisms of Arabidopsis against this hemibiotrophic fungus. The genome sequence of C. higginsianum has provided insights into how genome structure and pathogen genetic variability has been shaped by transposable elements, and allows systematic approaches to longstanding areas of investigation, including infection structure differentiation and fungal–plant interactions. The Arabidopsis-Colletotrichum pathosystem provides an integrated system, with extensive information on the host plant and availability of genomes for both partners, to illustrate many of the important concepts governing fungal–plant interactions, and to serve as an excellent starting point for broad perspectives into issues in plant pathology. Full article
(This article belongs to the Special Issue Plant–Fungal Interactions)
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Open AccessArticle Assembly Mechanism for Aggregation of Amyloid Fibrils
Int. J. Mol. Sci. 2018, 19(7), 2141; https://doi.org/10.3390/ijms19072141
Received: 15 June 2018 / Revised: 10 July 2018 / Accepted: 19 July 2018 / Published: 23 July 2018
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Abstract
The assembly mechanism for aggregation of amyloid fibril is important and fundamental for any quantitative and physical descriptions because it needs to have a deep understanding of both molecular and statistical physics. A theoretical model with three states including coil, helix and sheet
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The assembly mechanism for aggregation of amyloid fibril is important and fundamental for any quantitative and physical descriptions because it needs to have a deep understanding of both molecular and statistical physics. A theoretical model with three states including coil, helix and sheet is presented to describe the amyloid formation. The corresponding general mathematical expression of N molecule systems are derived, including the partition function and thermodynamic quantities. We study the equilibrium properties of the system in the solution and find that three molecules have the extreme value of free energy. The denaturant effect on molecular assemble is also discussed. Furthermore, we apply the kinetic theories to take account of the nucleation and growth of the amyloid in the solution. It has been shown that our theoretical results can be compared with experimental results. Full article
(This article belongs to the Special Issue Amyloid Fibrils and Methods for Their Study)
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Open AccessArticle Effects and Mechanism of Nano-Copper Exposure on Hepatic Cytochrome P450 Enzymes in Rats
Int. J. Mol. Sci. 2018, 19(7), 2140; https://doi.org/10.3390/ijms19072140
Received: 15 June 2018 / Revised: 4 July 2018 / Accepted: 15 July 2018 / Published: 23 July 2018
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Abstract
Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450
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Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals. Full article
(This article belongs to the Section Molecular Toxicology)
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Open AccessReview The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Aging: Implications in Obesity and Cardiovascular Disease
Int. J. Mol. Sci. 2018, 19(7), 2139; https://doi.org/10.3390/ijms19072139
Received: 10 July 2018 / Revised: 19 July 2018 / Accepted: 21 July 2018 / Published: 23 July 2018
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Abstract
Aging has been associated with a series of pathophysiological processes causing general decline in the overall health of the afflicted population. The cumulative line of evidence suggests an important role of oxidative stress in the development and progression of the aging process and
[...] Read more.
Aging has been associated with a series of pathophysiological processes causing general decline in the overall health of the afflicted population. The cumulative line of evidence suggests an important role of oxidative stress in the development and progression of the aging process and metabolic abnormalities, exacerbating adipocyte dysfunction, cardiovascular diseases, and associated complications at the same time. In recent years, robust have established the implication of Na/K-ATPase signaling in causing oxidative stress and alterations in cellular mechanisms, in addition to its distinct pumping function. Understanding the underlying molecular mechanisms and exploring the possible sources of pro-oxidants may allow for developing therapeutic targets in these processes and formulate novel intervention strategies for patients susceptible to aging and associated complications, such as obesity and cardiovascular disease. The attenuation of oxidative stress with targeted treatment options can improve patient outcomes and significantly reduce economic burden. Full article
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Open AccessArticle Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles
Int. J. Mol. Sci. 2018, 19(7), 2138; https://doi.org/10.3390/ijms19072138
Received: 6 July 2018 / Revised: 17 July 2018 / Accepted: 20 July 2018 / Published: 23 July 2018
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Abstract
We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin
[...] Read more.
We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations. Full article
(This article belongs to the collection Bioactive Nanoparticles)
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Open AccessArticle Binding of Organometallic Ruthenium Anticancer Complexes to DNA: Thermodynamic Base and Sequence Selectivity
Int. J. Mol. Sci. 2018, 19(7), 2137; https://doi.org/10.3390/ijms19072137
Received: 14 June 2018 / Revised: 3 July 2018 / Accepted: 4 July 2018 / Published: 23 July 2018
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Abstract
Organometallic ruthenium(II) complexes [(η6-arene)Ru(en)Cl][PF6] (arene = benzene (1), p-cymene (2), indane (3), and biphenyl (4); en = ethylenediamine) are promising anticancer drug candidates both in vitro and in vivo. In
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Organometallic ruthenium(II) complexes [(η6-arene)Ru(en)Cl][PF6] (arene = benzene (1), p-cymene (2), indane (3), and biphenyl (4); en = ethylenediamine) are promising anticancer drug candidates both in vitro and in vivo. In this paper, the interactions between ruthenium(II) complexes and 15-mer single- and double-stranded oligodeoxynucleotides (ODNs) were thermodynamically investigated using high performance liquid chromatography (HPLC) and electrospray ionization mass spectroscopy (ESI-MS). All of the complexes bind preferentially to G8 on the single strand 5′-CTCTCTT7G8T9CTTCTC-3′ (I), with complex 4 containing the most hydrophobic ligand as the most reactive one. To the analogs of I (changing T7 and/or T9 to A and/or C), complex 4 shows a decreasing affinity to the G8 site in the following order: -AG8T- (K: 5.74 × 104 M−1) > -CG8C- > -TG8A- > -AG8A- > -AG8C- > -TG8T- (I) ≈ -CG8A- (K: 2.81 × 104 M−1). In the complementary strand of I, the G bases in the middle region are favored for ruthenation over guanine (G) bases in the end of oligodeoxynucleotides (ODNs). These results indicate that both the flanking bases (or base sequences) and the arene ligands play important roles in determining the binding preference, and the base- and sequence-selectivity, of ruthenium complex in binding to the ODNs. Full article
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Open AccessArticle Development of Convenient System for Detecting Yeast Cell Stress, Including That of Amyloid Beta
Int. J. Mol. Sci. 2018, 19(7), 2136; https://doi.org/10.3390/ijms19072136
Received: 19 June 2018 / Revised: 16 July 2018 / Accepted: 21 July 2018 / Published: 23 July 2018
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(1) Background: As a model eukaryote, the study of stress responses in yeast can be employed for studying human health and disease, and the effects of various drugs that may impact health. “Reporting” of stress in yeast has frequently utilised enzymes like β-galactosidase
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(1) Background: As a model eukaryote, the study of stress responses in yeast can be employed for studying human health and disease, and the effects of various drugs that may impact health. “Reporting” of stress in yeast has frequently utilised enzymes like β-galactosidase that require laborious assays for quantitative results. The use of a stress reporter that can be measured quantitatively and with high sensitivity in living cells in a multi-well plate reader is a more desirable approach; (2) Methods: A multi-copy yeast-Escherichia coli shuttle plasmid containing the HSP42 promoter upstream of the mCherry reporter, along with the URA3 selectable marker was constructed and tested; (3) Results: Under certain stress conditions inducing the heat shock response, transformants containing the plasmid produced red fluorescence that could be readily quantitated in a microtitre plate reader. Stresses that produced red fluorescence included exposure to heat shock, copper ions, oligomeric amyloid beta (Aβ42) and fibrillar Aβ42; (4) Conclusions: Being able to conveniently and quantitatively monitor stresses in whole live populations of yeast offers great opportunities to screen compounds and conditions that cause stress, as well as conditions that alleviate stress. While freshly prepared oligomeric amyloid beta has previously been shown to exhibit high toxicity, fibrils have been generally considered to be non-toxic or of low toxicity. In this study, fibrillar amyloid beta has also been shown to induce stress. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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Open AccessArticle In Planta Preliminary Screening of ER Glycoprotein Folding Quality Control (ERQC) Modulators
Int. J. Mol. Sci. 2018, 19(7), 2135; https://doi.org/10.3390/ijms19072135
Received: 6 June 2018 / Revised: 10 July 2018 / Accepted: 19 July 2018 / Published: 23 July 2018
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Abstract
Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate
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Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate inhibitors in mammals are expensive and cannot be afforded at the preliminary stages of drug development programs. The strong conservation of the ERQC machinery across eukaryotes makes transgenic plants an attractive system for low-cost, easy and fast proof-of-concept screening of candidate ERQC inhibitors. The Arabidopsis thaliana immune response is mediated by glycoproteins, the folding of which is controlled by ERQC. We have used the plant response to bacterial peptides as a means of assaying an ERQC inhibitor in vivo. We show that the treatment of the plant with the iminosugar NB-DNJ, which is a known ER α-glucosidase inhibitor in mammals, influences the immune response of the plant to the bacterial peptide elf18 but not to the flagellin-derived flg22 peptide. In the NB-DNJ-treated plant, the responses to elf18 and flg22 treatments closely follow the ones observed for the ER α-glucosidase II impaired plant, At psl5-1. We propose Arabidopsis thaliana as a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation. Full article
(This article belongs to the Special Issue Glycosylation and Glycoproteins 2018)
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Open AccessCommunication Intrinsic Oncogenic Function of Intracellular Connexin26 Protein in Head and Neck Squamous Cell Carcinoma Cells
Int. J. Mol. Sci. 2018, 19(7), 2134; https://doi.org/10.3390/ijms19072134
Received: 6 May 2018 / Revised: 19 July 2018 / Accepted: 21 July 2018 / Published: 23 July 2018
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Abstract
It has long been known that the gap junction is down-regulated in many tumours. One of the downregulation mechanisms is the translocation of connexin, a gap junction protein, from cell membrane into cytoplasm, nucleus, or Golgi apparatus. Interestingly, as tumours progress and reinforce
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It has long been known that the gap junction is down-regulated in many tumours. One of the downregulation mechanisms is the translocation of connexin, a gap junction protein, from cell membrane into cytoplasm, nucleus, or Golgi apparatus. Interestingly, as tumours progress and reinforce their malignant phenotype, the amount of aberrantly-localised connexin increases in different malignant tumours including oesophageal squamous cell carcinoma, thus suggesting that such an aberrantly-localised connexin should be oncogenic, although gap junctional connexins are often tumour-suppressive. To define the dual roles of connexin in head and neck squamous cell carcinoma (HNSCC), we introduced the wild-type connexin26 (wtCx26) or the mutant Cx26 (icCx26) gene, the product of which carries the amino acid sequence AKKFF, an endoplasmic reticulum-Golgi retention signal, at the C-terminus and is not sorted to cell membrane, into the human FaDu hypopharyngeal cancer cell line that had severely impaired the expression of connexin during carcinogenesis. wtCx26 protein was trafficked to the cell membrane and formed gap junction, which successfully exerted cell-cell communication. On the other hand, the icCx26 protein was co-localised with a Golgi marker, as revealed by immunofluorescence, and thus was retained on the way to the cell membrane. While the forced expression of wtCx26 suppressed both cell proliferation in vitro and tumorigenicity in mice in vivo, icCx26 significantly enhanced both cell proliferation and tumorigenicity compared with the mock control clones, indicating that an excessive accumulation of connexin protein in intracellular domains should be involved in cancer progression and that restoration of proper subcellular sorting of connexin might be a therapeutic strategy to control HNSCC. Full article
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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Open AccessArticle Neuroglobin Regulates Wnt/β-Catenin and NFκB Signaling Pathway through Dvl1
Int. J. Mol. Sci. 2018, 19(7), 2133; https://doi.org/10.3390/ijms19072133
Received: 19 June 2018 / Revised: 6 July 2018 / Accepted: 13 July 2018 / Published: 23 July 2018
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Abstract
Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/β-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined
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Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/β-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined the role of Neuroglobin in regulating Dishevelled-1 and the downstream Wnt/β-Catenin and NFκB signaling pathway. We found that Neuroglobin directly interacts with Dishevelled-1 by co-immunoprecipitation, and the two proteins are co-localized in both cytoplasma and nucleus of SK-N-SH cells. Moreover, the ectopic expression of Neuroglobin promotes the degradation of exogenous and endogenous Dishevelled-1 through the proteasomal degradation pathway. Furthermore, our results showed that Neuroglobin significantly inhibits the luciferase activity of Topflash reporter and the expression of β-Catenin mediated by Dishevelled-1 in SK-N-SH cells. In addition, we also documented that Neuroglobin enhances TNF-α-induced NFκB activation via down-regulating Dishevelled-1. Finally, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assays showed that Neuroglobin is an important neuroprotectant that protects SK-N-SH cells from TNF-α-induced decrease in cell viability. Taken together, these findings demonstrated that Neuroglobin functions as an important modulator of the Wnt/β-Catenin and NFκB signaling pathway through regulating Dishevelled-1. Full article
(This article belongs to the Section Biochemistry)
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Open AccessArticle Identification of Two Auxin-Regulated Potassium Transporters Involved in Seed Maturation
Int. J. Mol. Sci. 2018, 19(7), 2132; https://doi.org/10.3390/ijms19072132
Received: 30 May 2018 / Revised: 18 July 2018 / Accepted: 20 July 2018 / Published: 22 July 2018
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Abstract
The seed is the most important plant reproductive unit responsible for the evolutionary success of flowering plants. Aside from its essential function in the sexual reproduction of plants, the seed also represents the most economically important agricultural product worldwide, providing energy, nutrients, and
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The seed is the most important plant reproductive unit responsible for the evolutionary success of flowering plants. Aside from its essential function in the sexual reproduction of plants, the seed also represents the most economically important agricultural product worldwide, providing energy, nutrients, and raw materials for human nutrition, livestock feed, and countless manufactured goods. Hence, improvements in seed quality or size are highly valuable, due to their economic potential in agriculture. Recently, the importance of indolic compounds in regulating these traits has been reported for Arabidopsis thaliana. The transcriptional and physiological mechanisms involved, however, remain largely undisclosed. Potassium transporters have been suggested as possible mediators of embryo cell size, controlling turgor pressure during seed maturation. In addition, it has been demonstrated that the expression of K+ transporters is effectively regulated by auxin. Here, we provide evidence for the identification of two Arabidopsis K+ transporters, HAK/KT12 (At1g60160) and KUP4 (At4g23640), that are likely to be implicated in determining seed size during seed maturation and, at the same time, show a differential regulation by indole-3-acetic acid and indole-3-acetamide. Full article
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Open AccessArticle Genome-Wide Identification and Characterization of CIPK Family and Analysis Responses to Various Stresses in Apple (Malus domestica)
Int. J. Mol. Sci. 2018, 19(7), 2131; https://doi.org/10.3390/ijms19072131
Received: 23 June 2018 / Revised: 16 July 2018 / Accepted: 17 July 2018 / Published: 22 July 2018
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Abstract
In the CIPK family, the CBL-interacting protein kinases have shown crucial roles in hormone signaling transduction, and response to abiotic stress in plant developmental processes. The CIPK family is characterized by conserved NAF/FISL (Asn-Ala-Phe) and PPI (protein-phosphatase interaction) domains in the C-terminus. However,
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In the CIPK family, the CBL-interacting protein kinases have shown crucial roles in hormone signaling transduction, and response to abiotic stress in plant developmental processes. The CIPK family is characterized by conserved NAF/FISL (Asn-Ala-Phe) and PPI (protein-phosphatase interaction) domains in the C-terminus. However, little data has been reported about the CIPK family in apple. A total of 34 MdCIPK genes were identified from the apple genome in this study and were later divided into two groups according to the CIPK domains, characterized by gene structure and chromosomal distribution, and then mapped onto 17 chromosomes. All MdCIPK genes were expressed in the four apple tissues (leaf, root, flower, and fruit). In addition, the MdCIPK gene expression profile showed that five members among them revealed enhanced expression during the pollen tube growth stages. The MdCIPK4 was the most expressive during the entire fruit development stages. Under stress conditions 21 MdCIPK genes transcript levels were up-regulated in response to fungal and salt treatments. This suggested the possible features of these genes’ response to stresses in apples. Our findings provide a new insight about the roles of CIPK genes in apples, which could contribute to the cloning and functional analysis of CIPK genes in the future. Full article
(This article belongs to the Special Issue Ion Transporters and Abiotic Stress Tolerance in Plants)
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Open AccessArticle High-Content Screening of a Taiwanese Indigenous Plant Extract Library Identifies Syzygium simile leaf Extract as an Inhibitor of Fatty Acid Uptake
Int. J. Mol. Sci. 2018, 19(7), 2130; https://doi.org/10.3390/ijms19072130
Received: 21 June 2018 / Revised: 9 July 2018 / Accepted: 19 July 2018 / Published: 22 July 2018
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Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the recent decades in both developed and developing countries, and is predicted to be the major etiology for liver transplantation in the next decade. Thus, pharmacological strategies to treat NAFLD
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Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the recent decades in both developed and developing countries, and is predicted to be the major etiology for liver transplantation in the next decade. Thus, pharmacological strategies to treat NAFLD are urgently needed. Natural products are considered an excellent source for drug discovery. By utilizing an image-based high-throughput screening with a library containing 3000 Taiwanese indigenous plant extracts, we discovered that the extract of Syzygium simile leaves (SSLE) has an anti-lipid droplet (LD) accumulation effect in hepatic cell lines. Analyses of the expression profile of genes involved in lipid metabolism revealed that SSLE suppressed the mRNA expression of CD36, fatty acid translocase. In agreement with this observation, we showed that SSLE inhibited CD36 protein expression and fatty acid uptake and has only limited effects on pre-formed LDs. Moreover, SSLE reduced LD accumulation and CD36 expression in enterocyte and macrophage cell lines. In conclusion, our findings suggest that SSLE could serve as a potential source for the discovery of novel therapeutic modalities for NAFLD and that the suppression of CD36 expression and fatty acid uptake could contribute to the lipid-lowering effect of SSLE. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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Open AccessArticle Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α Upregulation in PTEN Negative Prostate Cancer Cells
Int. J. Mol. Sci. 2018, 19(7), 2129; https://doi.org/10.3390/ijms19072129
Received: 30 May 2018 / Revised: 13 July 2018 / Accepted: 18 July 2018 / Published: 21 July 2018
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Abstract
The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we
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The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid—a broad acting inhibitor of dicarboxylic acid carriers—strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone. Full article
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Open AccessArticle Comparison of the Anion Inhibition Profiles of the α-CA Isoforms (SpiCA1, SpiCA2 and SpiCA3) from the Scleractinian Coral Stylophora pistillata
Int. J. Mol. Sci. 2018, 19(7), 2128; https://doi.org/10.3390/ijms19072128
Received: 20 June 2018 / Revised: 16 July 2018 / Accepted: 17 July 2018 / Published: 21 July 2018
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Abstract
Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes used by living organisms to accelerate the CO2 hydration/dehydration reaction at rates dramatically high compared to the uncatalyzed reaction. These enzymes have different isoforms and homologues and can be found in the form of
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Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes used by living organisms to accelerate the CO2 hydration/dehydration reaction at rates dramatically high compared to the uncatalyzed reaction. These enzymes have different isoforms and homologues and can be found in the form of cytoplasmic, secreted or membrane-bound proteins. CAs play a role in numerous physiological processes including biomineralization and symbiosis, as is the case in reef-building corals. Previously, molecular and biochemical data have been obtained at the molecular level in the branching coral Stylophora pistillata for two coral isoforms which differ significantly in their catalytic activity and susceptibility to inhibition with anions and sulfonamides. More recently it has been determined that the genome of S. pistillata encodes for 16 CAs. Here, we cloned, expressed, purified and characterized a novel α-CA, named SpiCA3, which is cytoplasmic and ubiquitously expressed in all the cell layers including the calcifying cells. SpiCA3 is the most effective CA among the coral isoforms investigated and the most efficient catalyst known up to date in Metazoa. We also investigated the inhibition profiles of SpiCA3 and compared it with those obtained for the two other isoforms in the presence of inorganic anions and other small molecules known to interfere with metalloenzymes. These results suggest that S. pistillata has adapted its CA isoforms to achieve the physiological functions in different physicochemical microenvironments. Full article
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Open AccessReview Understanding the Role of Dysfunctional and Healthy Mitochondria in Stroke Pathology and Its Treatment
Int. J. Mol. Sci. 2018, 19(7), 2127; https://doi.org/10.3390/ijms19072127
Received: 19 June 2018 / Revised: 12 July 2018 / Accepted: 19 July 2018 / Published: 21 July 2018
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Abstract
Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and
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Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cell transplantation, may hold promise as a stroke therapy, because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria—one that is potentially transferrable into ischemic cells—may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells to critically evaluate the potential of mitochondria-based stem cell therapy for stroke patients. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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Open AccessReview “Sweet Flavonoids”: Glycosidase-Catalyzed Modifications
Int. J. Mol. Sci. 2018, 19(7), 2126; https://doi.org/10.3390/ijms19072126
Received: 14 June 2018 / Revised: 17 July 2018 / Accepted: 19 July 2018 / Published: 21 July 2018
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Abstract
Natural flavonoids, especially in their glycosylated forms, are the most abundant phenolic compounds found in plants, fruit, and vegetables. They exhibit a large variety of beneficial physiological effects, which makes them generally interesting in a broad spectrum of scientific areas. In this review,
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Natural flavonoids, especially in their glycosylated forms, are the most abundant phenolic compounds found in plants, fruit, and vegetables. They exhibit a large variety of beneficial physiological effects, which makes them generally interesting in a broad spectrum of scientific areas. In this review, we focus on recent advances in the modifications of the glycosidic parts of various flavonoids employing glycosidases, covering both selective trimming of the sugar moieties and glycosylation of flavonoid aglycones by natural and mutant glycosidases. Glycosylation of flavonoids strongly enhances their water solubility and thus increases their bioavailability. Antioxidant and most biological activities are usually less pronounced in glycosides, but some specific bioactivities are enhanced. The presence of l-rhamnose (6-deoxy-α-l-mannopyranose) in rhamnosides, rutinosides (rutin, hesperidin) and neohesperidosides (naringin) plays an important role in properties of flavonoid glycosides, which can be considered as “pro-drugs”. The natural hydrolytic activity of glycosidases is widely employed in biotechnological deglycosylation processes producing respective aglycones or partially deglycosylated flavonoids. Moreover, deglycosylation is quite commonly used in the food industry aiming at the improvement of sensoric properties of beverages such as debittering of citrus juices or enhancement of wine aromas. Therefore, natural and mutant glycosidases are excellent tools for modifications of flavonoid glycosides. Full article
(This article belongs to the Special Issue Molecular Transformations of Natural Products)
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Open AccessReview TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections
Int. J. Mol. Sci. 2018, 19(7), 2125; https://doi.org/10.3390/ijms19072125
Received: 18 June 2018 / Revised: 13 July 2018 / Accepted: 16 July 2018 / Published: 21 July 2018
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Abstract
Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS),
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Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders. Full article
(This article belongs to the Special Issue TGF-Beta Super Family Signaling)
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Open AccessReview PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity
Int. J. Mol. Sci. 2018, 19(7), 2124; https://doi.org/10.3390/ijms19072124
Received: 19 June 2018 / Revised: 13 July 2018 / Accepted: 18 July 2018 / Published: 21 July 2018
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Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of
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Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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Open AccessArticle Characterization of a Long Non-Coding RNA, the Antisense RNA of Na/K-ATPase α1 in Human Kidney Cells
Int. J. Mol. Sci. 2018, 19(7), 2123; https://doi.org/10.3390/ijms19072123
Received: 22 June 2018 / Revised: 17 July 2018 / Accepted: 19 July 2018 / Published: 21 July 2018
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Abstract
Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, ATP1A1-AS1, which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult
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Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, ATP1A1-AS1, which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult kidney cells (HK2 cells) and embryonic kidney cells (HEK293 cells). These variants can be detected in both cytosol and nuclear fractions. We also found that the inhibition of DNA methylation has a differential effect on the expression of ATP1A1-AS1 and its sense gene. To investigate the physiological role of this antisense gene, we overexpressed the ATP1A1-AS1 transcripts, and examined their effect on Na/K-ATPase expression and related signaling function in human kidney cells. The results showed that overexpression of the ATP1A1-AS1-203 transcript in HK2 cells reduced the Na/K-ATPase α1 (ATP1A1) gene expression by approximately 20% (p < 0.05), while reducing the Na/K-ATPase α1 protein synthesis by approximately 22% (p < 0.05). Importantly, overexpression of the antisense RNA transcript attenuated ouabain-induced Src activation in HK2 cells. It also inhibited the cell proliferation and potentiated ouabain-induced cell death. These results demonstrate that the ATP1A1-AS1 gene is a moderate negative regulator of Na/K-ATPase α1, and can modulate Na/K-ATPase-related signaling pathways in human kidney cells. Full article
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Open AccessReview The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture
Int. J. Mol. Sci. 2018, 19(7), 2122; https://doi.org/10.3390/ijms19072122
Received: 10 July 2018 / Revised: 17 July 2018 / Accepted: 18 July 2018 / Published: 21 July 2018
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Abstract
Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the
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Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the many different types of blood and immune cells. The new scenario abandons the classical view of a rigidly demarcated lineage tree and replaces it with a much more continuum-like view of the spectrum of fate options open to hematopoietic stem cells and their progeny. This is in contrast to previous lineage diagrams, which envisaged stem cells progressing stepwise through a series of fairly-precisely described intermediate progenitors in order to close down alternative developmental options. Instead, stem and progenitor cells retain some capacity to step sideways and adopt alternative, closely related, fates, even after they have “made a lineage choice.” The stem and progenitor cells are more inherently versatile than previously thought and perhaps sensitive to lineage guidance by environmental cues. Here we examine the evidence that supports these views and reconsider the meaning of cell lineages in the context of a continuum model of stem cell fate determination and environmental modulation. Full article
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Open AccessReview Functions of Rhotekin, an Effector of Rho GTPase, and Its Binding Partners in Mammals
Int. J. Mol. Sci. 2018, 19(7), 2121; https://doi.org/10.3390/ijms19072121
Received: 5 July 2018 / Revised: 13 July 2018 / Accepted: 17 July 2018 / Published: 20 July 2018
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Abstract
Rhotekin is an effector protein for small GTPase Rho. This protein consists of a Rho binding domain (RBD), a pleckstrin homology (PH) domain, two proline-rich regions and a C-terminal PDZ (PSD-95, Discs-large, and ZO-1)-binding motif. We, and other groups, have identified various binding
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Rhotekin is an effector protein for small GTPase Rho. This protein consists of a Rho binding domain (RBD), a pleckstrin homology (PH) domain, two proline-rich regions and a C-terminal PDZ (PSD-95, Discs-large, and ZO-1)-binding motif. We, and other groups, have identified various binding partners for Rhotekin and carried out biochemical and cell biological characterization. However, the physiological functions of Rhotekin, per se, are as of yet largely unknown. In this review, we summarize known features of Rhotekin and its binding partners in neuronal tissues and cancer cells. Full article
(This article belongs to the Special Issue Small GTPases)
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Open AccessReview Non-Coding RNAs in Endometrial Physiopathology
Int. J. Mol. Sci. 2018, 19(7), 2120; https://doi.org/10.3390/ijms19072120
Received: 22 June 2018 / Revised: 12 July 2018 / Accepted: 14 July 2018 / Published: 20 July 2018
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Abstract
The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of
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The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of RNAs involved in different steps of gene regulation. They have been classified, according to their length, into small non-coding RNAs and long non-coding RNAs, or to their function, into housekeeping non-coding RNAs and regulatory non-coding RNAs. Their involvement has been widely demonstrated in all cellular processes, as well as their dysregulation in human pathologies. In this review, we discuss the function of non-coding RNAs in endometrial physiology, analysing their involvement in embryo implantation. Moreover, we explore their role in endometrial pathologies such as endometrial cancer, endometriosis and chronic endometritis. Full article
(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)
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Open AccessReview Vitamins D: Relationship between Structure and Biological Activity
Int. J. Mol. Sci. 2018, 19(7), 2119; https://doi.org/10.3390/ijms19072119
Received: 3 July 2018 / Revised: 17 July 2018 / Accepted: 18 July 2018 / Published: 20 July 2018
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Abstract
The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate
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The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D3 regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D3 that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D3 that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D3, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D3: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D3- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair β-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D. Full article
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