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Int. J. Mol. Sci., Volume 16, Issue 3 (March 2015) – 128 articles , Pages 4362-6620

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798 KiB  
Review
Coronary Artery Calcium Screening: Does it Perform Better than Other Cardiovascular Risk Stratification Tools?
by Irfan Zeb and Matthew Budoff
Int. J. Mol. Sci. 2015, 16(3), 6606-6620; https://doi.org/10.3390/ijms16036606 - 23 Mar 2015
Cited by 37 | Viewed by 7356
Abstract
Coronary artery calcium (CAC) has been advocated as one of the strongest cardiovascular risk prediction markers. It performs better across a wide range of Framingham risk categories (6%–10% and 10%–20% 10-year risk categories) and also helps in reclassifying the risk of these subjects [...] Read more.
Coronary artery calcium (CAC) has been advocated as one of the strongest cardiovascular risk prediction markers. It performs better across a wide range of Framingham risk categories (6%–10% and 10%–20% 10-year risk categories) and also helps in reclassifying the risk of these subjects into either higher or lower risk categories based on CAC scores. It also performs better among population subgroups where Framingham risk score does not perform well, especially young subjects, women, family history of premature coronary artery disease and ethnic differences in coronary risk. The absence of CAC is also associated with excellent prognosis, with 10-year event rate of 1%. Studies have also compared with other commonly used markers of cardiovascular disease risk such as Carotid intima-media thickness and highly sensitive C-reactive protein. CAC also performs better compared with carotid intima-media thickness and highly sensitive C-reactive protein in prediction of coronary heart disease and cardiovascular disease events. CAC scans are associated with relatively low radiation exposure (0.9–1.1 mSv) and provide information that can be used not only for risk stratification but also can be used to track the progression of atherosclerosis and the effects of statins. Full article
(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging)
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<p>Predictive value of coronary artery calcium [<a href="#B4-ijms-16-06606" class="html-bibr">4</a>].</p> Full article ">
1891 KiB  
Article
Activity Analysis and Preliminary Inducer Screening of the Chicken DAZL Gene Promoter
by Lei Zhang, Rui Zhu, Qisheng Zuo, Dong Li, Chao Lian, Beibei Tang, Tianrong Xiao, Yani Zhang and Bichun Li
Int. J. Mol. Sci. 2015, 16(3), 6595-6605; https://doi.org/10.3390/ijms16036595 - 23 Mar 2015
Cited by 6 | Viewed by 6075
Abstract
This study was aimed at identifying the active control area of chicken DAZL gene core promoter, to screen optimum inducers of the DAZL gene, thus to enhance the differentiation of embryonic stem cells into spermatogonial stem cells. Fragments of chicken DAZL gene promoter [...] Read more.
This study was aimed at identifying the active control area of chicken DAZL gene core promoter, to screen optimum inducers of the DAZL gene, thus to enhance the differentiation of embryonic stem cells into spermatogonial stem cells. Fragments of chicken DAZL gene promoter were cloned into fluorescent reporter plasmids and transfected into DF-1 cells. Then Dual-Luciferase® Reporter Assay System was used to identify the activity of the DAZL gene under different inducers. Our studies showed that the DAZL core promoter region for the Suqin yellow chicken was −383 to −39 bp. The dual-luciferase® reporter showed that all-trans retinoic acid (ATRA), a retinoic acid receptor alpha agonist (tamibarotene/Am80), or estradiol (E2) could significantly enhance DAZL transcription. The in vitro inductive culture of chicken ESCs demonstrated that, with ATRA treatment, DAZL transcription peaked at 6 days and then decreased slowly; whereas, DAZL transcription was continuous and peaked at 10 days with Am80 treatment. E2 treatment significantly increased DAZL expression after 8 days. All three treatments were associated with the appearance of male germ cell (MGC)-like cells on day 10. These results provide the optimum inducer screening of the DAZL gene and lay the foundation for further screening of compounds that can induce the differentiation of ESCs into MGCs in vitro. Full article
(This article belongs to the Section Biochemistry)
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<p>(<b>A</b>) The green fluorescent protein (GFP) detection of promoter activity of the chicken Deleted in Azoospermia (<span class="html-italic">DAZL</span>) long promoter fragment in DF-1 cells transfected with positive control <span class="html-italic">pDAZL-EGFP</span>, <span class="html-italic">pEGFP-N1</span>, and negative control <span class="html-italic">pLinker-EGFP</span> (40× magnification); (<b>B</b>) The activity of different promoter regions of the chicken <span class="html-italic">DAZL</span> gene in DF-1 cells; (<b>C</b>) The effect of different inducers on the activity of the chicken <span class="html-italic">DAZL</span> core gene promoter in mouse DF-1 cells. * represents <span class="html-italic">p</span> &lt; 0.05, ** represents <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">Figure 2
<p>Differentiation of chicken embryonic stem cells (ESCs) induced by different <span class="html-italic">DAZL</span> inducers. (<b>A</b>) chicken ESCs with DMEM; (<b>B</b>) chicken ESCs with 10<sup>−5</sup> mol/L l-trans retinoic acid (ATRA) induction; (<b>C</b>) chicken ESCs with 10<sup>−6</sup> mol/L Am800 induction; (<b>D</b>) chicken ESCs with 1 μg/mL E<sub>2</sub> induction. Arrows represent spermatogonial stem cell-like (SSC-like) cells. (400× magnification).</p> Full article ">Figure 3
<p><span class="html-italic">DAZL</span> mRNA expression under ATRA, Am80, and E<sub>2</sub> induction compared with control chicken ESCs. The results are presented as a mean ± SEM of three duplicate runs. Error bars in charts represent the corresponding standard deviations.</p> Full article ">Figure 4
<p>Immunohistochemical detection of DAZL protein expression in chicken ESCs treated with various inducers of germ cell differentiation. (<b>A</b>) chicken ESCs with DMEM; (<b>B</b>) chicken ESCs with 10<sup>−5</sup> mol/L ATRA induction; (<b>C</b>) chicken ESCs with 10<sup>−6</sup> mol/L Am80 induction; (<b>D</b>) chicken ESCs with 1 μg/mL E<sub>2</sub> induction. (400× magnification).</p> Full article ">
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Review
Aminoacyl-tRNA Synthetase Complexes in Evolution
by Svitlana Havrylenko and Marc Mirande
Int. J. Mol. Sci. 2015, 16(3), 6571-6594; https://doi.org/10.3390/ijms16036571 - 23 Mar 2015
Cited by 51 | Viewed by 11438
Abstract
Aminoacyl-tRNA synthetases are essential enzymes for interpreting the genetic code. They are responsible for the proper pairing of codons on mRNA with amino acids. In addition to this canonical, translational function, they are also involved in the control of many cellular pathways essential [...] Read more.
Aminoacyl-tRNA synthetases are essential enzymes for interpreting the genetic code. They are responsible for the proper pairing of codons on mRNA with amino acids. In addition to this canonical, translational function, they are also involved in the control of many cellular pathways essential for the maintenance of cellular homeostasis. Association of several of these enzymes within supramolecular assemblies is a key feature of organization of the translation apparatus in eukaryotes. It could be a means to control their oscillation between translational functions, when associated within a multi-aminoacyl-tRNA synthetase complex (MARS), and nontranslational functions, after dissociation from the MARS and association with other partners. In this review, we summarize the composition of the different MARS described from archaea to mammals, the mode of assembly of these complexes, and their roles in maintenance of cellular homeostasis. Full article
(This article belongs to the Special Issue Functions of Transfer RNAs)
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<p>Occurrence of multi-aminoacyl-tRNA synthetase complexes of different compositions throughout the tree of life. A schematic view of the complexes described in Euryarchaeota, Apicomplexa, Trypanosoma, Fungi, Rhabditina, Crustacea, Insecta, or Vertebrata, is shown. The auxiliary proteins known to have a structural role within the complexes are presented in green. Class I synthetases are in blue; class II in red. Synthetases are indicated according to the one letter symbol of their amino acid substrate. The autonomous editing protein YbaK is in yellow. On the right are represented the complexes described in the literature. The complex isolated from vertebrata is composed of a scaffolding protein (p38), that joins sub-complex I (components circled in red), subcomplex II (components circled in blue), LysRS (K) and AspRS (D). In the complex from Rhabditina, the p43 and MetRS (M) proteins are fused in a single polypeptide. The scaffold protein of the complexes from Apicomplexa and Trypanosma have characteristics of p43 from vertebrates.</p> Full article ">Figure 2
<p>Composition, structural organization and 3D-architecture of the MARS. <b>Left</b>: SDS-PAGE analysis of the MARS from rabbit; <b>Middle</b>: protein:protein interaction map of the MARS, showing two subcomplexes linked by a scaffold protein, p38; <b>Right</b>: low resolution envelope of the MARS determined by SAXS (Small Angle X-ray Scattering). The crystal structure of the 80S ribosome is shown for comparison.</p> Full article ">Figure 3
<p>Schematic comparison of ten aminoacyl-tRNA synthetases from <span class="html-italic">H. sapiens</span> (Hs) with their homologs in <span class="html-italic">E. coli</span> (Ec), <span class="html-italic">S. cerevisiae</span> (Sc) and <span class="html-italic">C. elegans</span> (Ce). Conserved parts are shown in light grey with poorly conserved regions in medium grey. Dark grey boxes represent <span class="html-italic">E. coli</span> specific domains. The number of amino acid residues per polypeptide chain is indicated. Eukaryote specific domains, conserved from yeast to human, are shown in green. Appended domains found only in one or two species are in yellow. Protein–protein and protein–RNA interaction domains are shown in red and blue, respectively: L—leucine-rich domain; GST—glutathion <span class="html-italic">S</span>-transferase-like domain; R'—repeated sequence found in human IleRS; K—lysine-rich domain; R—repeat (WHEP) domain. The names of class I aaRS are highlighted in blue, of class II in red.</p> Full article ">Figure 4
<p>Occurrence of ValRS:EF1A:EF1B complexes or of “free” ValRS in Eukaryota. The conserved catalytic (CAT) and anticodon-binding (ABD) domains are in green. The appended tRNA-binding domain (tRBD) is indicated in red, the protein-binding domain (PBD) only recovered in Deuterostomia, required for association with elongation factor 1, is in yellow.</p> Full article ">
2215 KiB  
Review
Amniotic Fluid Embolism Pathophysiology Suggests the New Diagnostic Armamentarium: β-Tryptase and Complement Fractions C3-C4 Are the Indispensable Working Tools
by Francesco Paolo Busardò, Paola Frati, Simona Zaami and Vittorio Fineschi
Int. J. Mol. Sci. 2015, 16(3), 6557-6570; https://doi.org/10.3390/ijms16036557 - 23 Mar 2015
Cited by 31 | Viewed by 16911
Abstract
Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, [...] Read more.
Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, in order to evaluate the role of immune response in the development of this still enigmatic clinical entity. The following databases (from 1956 to September 2014) Medline, Cochrane Central, Scopus, Web of Science and Science Direct were used, searching the following key words: AFE, pathophysiology, immune/inflammatory response, complement and anaphylaxis. The main key word “AFE” was searched singularly and associated individually to each of the other keywords. Of the 146 sources found, only 19 were considered appropriate for the purpose of this paper. The clinical course is characterized by a rapid onset of symptoms, which include: acute hypotension and/or cardiac arrest, acute hypoxia (with dyspnoea, cyanosis and/or respiratory arrest), coagulopathies (disseminated intravascular coagulation and/or severe hemorrhage), coma and seizures. The pathology still determines a significant morbidity and mortality and potential permanent neurological sequelae for surviving patients. At this moment, numerous aspects involving the pathophysiology and clinical development are still not understood and several hypotheses have been formulated, in particular the possible role of anaphylaxis and complement. Moreover, the detection of serum tryptase and complement components and the evaluation of fetal antigens can explain several aspects of immune response. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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<p>Flow-chart of the papers selected for the purposes of the study.</p> Full article ">Figure 2
<p>The immuno-inflammatory pathogenesis and the target organs. (<b>A</b>) Evidence of fetal squamous cells, lanugo hairs, vernix caseosa, in the pulmonary artery vasculature (Hematoxylin-eosin staining, 200×); (<b>B</b>) AE1/AE3 cytokeratin stains on the lungs showed intense intravascular positivity of fetal squamous cells; (<b>C</b>) Lanugo hairs and nuclei of fetal squamous cells are clearly visible (confocal laser scanning microscope); (<b>D</b>) Mucin fluoresced (in red) in the pulmonary capillary septa (confocal laser scanning microscope); (<b>E</b>) Pulmonary capillary septa: evidence of degranulating mast cells with tryptase-positive material outside the cells (Ab anti-tryptase); (<b>F</b>,<b>G</b>) Degranulating mast cells with tryptase-positive material outside the cells (confocal laser scanning microscope). Figures extracted from cases previously published by Fineschi <span class="html-italic">et al.</span> [<a href="#B12-ijms-16-06557" class="html-bibr">12</a>].</p> Full article ">Figure 3
<p>Histopatological findings. (<b>A</b>) Pulmonary mast cells with anti-tryptase reactions; (<b>B</b>) Degranulating mast cells mast cells present in a bronchial wall (Ab anti-tryptase); (<b>C</b>) Evidence of degranulating mastcells with tryptase-positive material outside the cells (Ab anti-tryptase); (<b>D</b>) Confocal laser scanning microscope: weak expression (head-arrow) of complement C3a in an AFE case. Figures extracted from cases previously published by Fineschi <span class="html-italic">et al.</span> [<a href="#B12-ijms-16-06557" class="html-bibr">12</a>].</p> Full article ">
1382 KiB  
Review
The Potential of the Combination of CRISPR/Cas9 and Pluripotent Stem Cells to Provide Human Organs from Chimaeric Pigs
by Wanyou Feng, Yifan Dai, Lisha Mou, David K. C. Cooper, Deshun Shi and Zhiming Cai
Int. J. Mol. Sci. 2015, 16(3), 6545-6556; https://doi.org/10.3390/ijms16036545 - 23 Mar 2015
Cited by 30 | Viewed by 16098
Abstract
Clinical organ allotransplantation is limited by the availability of deceased human donors. However, the transplantation of human organs produced in other species would provide an unlimited number of organs. The pig has been identified as the most suitable source of organs for humans [...] Read more.
Clinical organ allotransplantation is limited by the availability of deceased human donors. However, the transplantation of human organs produced in other species would provide an unlimited number of organs. The pig has been identified as the most suitable source of organs for humans as organs of any size would be available. Genome editing by RNA-guided endonucleases, also known as clustered regularly interspaced short palindromic repeat (CRISPR/Cas9), in combination with induced pluripotent stem cells (iPSC), may have the potential to enable the creation of human organs from genetically-modified chimaeric pigs. These could potentially provide an unlimited supply of organs that would not be rejected by the recipient’s immune system. However, substantial research is needed to prove that this approach will work. Genetic modification of chimaeric pigs could also provide useful models for developing therapies for various human diseases, especially in relation to drug development. Full article
(This article belongs to the Special Issue Genome Editing)
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<p>Outcome of genome editing used nucleases. Nuclease-induced DNA double-strand breaks (DSBs) can lead to sequence indels (insertion or deletion; black) through non-homologous end-joining (NHEJ) or nucleotide correction (red) through homology-directed repair (HR) in the presence of a donor DNA or a single-strand oligodeoxynucleotide (ssODN). (<b>A</b>) single gene editing; (<b>B</b>) long sequence deletion; and (<b>C</b>) multiple gene editing.</p> Full article ">Figure 2
<p>Schematic representation of (<b>A</b>) ZFN, (<b>B</b>) TALEN, and (<b>C</b>) CRISPR/Cas9. (<b>A</b>) Each ZFN is composed of different zinc-finger proteins (ZFP) at the amino terminus and of the FokI nuclease domain at the carboxyl terminus. Each ZFP recognizes three base pairs; (<b>B</b>) Each transcription activator-like effector nuclease (TALEN) is composed of a transcription activator-like effector (TALE) at the amino terminus and the FokI nuclease domain at the carboxyl terminus. Each TALE repeat is comprised of 33–35 amino acids and recognizes a single base pair through the amino acids at positions 12 and 13, which is called the repeat variable diresidue (RVD, shown in red); and (<b>C</b>) CRISPR/Cas9 is composed of Cas9 protein and a single-chain guide RNA (sgRNA). The guide sequence in the crRNA (shown in black) is complementary to a 20-bp target DNA sequence known as a protospacer, which is next to the 5'-NGG-3'.</p> Full article ">Figure 3
<p>Combination of CRISPR/Cas9 and pluripotent stem cells to provide human organs from chimaeric pigs. Generation of human organs by producing multigene mutations of essential regulators of vascular and lymphatic tissues in the desired organ via rapid and efficient CRISPR/Cas9-mediated genome editing in concert with blastocyst complementation.</p> Full article ">
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Article
Discovery of Benzo[f]indole-4,9-dione Derivatives as New Types of Anti-Inflammatory Agents
by You-Ren Chen, Chih-Hua Tseng, Yeh-Long Chen, Tsong-Long Hwang and Cherng-Chyi Tzeng
Int. J. Mol. Sci. 2015, 16(3), 6532-6544; https://doi.org/10.3390/ijms16036532 - 23 Mar 2015
Cited by 16 | Viewed by 5810
Abstract
Certain benzo[f]indole-4,9-dione derivatives were synthesized and evaluated for their inhibitory effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. Results indicated that (Z)-1-benzyl-4-(hydroxyimino)-1H-benzo[f]indol-9(4H)-one (10) showed [...] Read more.
Certain benzo[f]indole-4,9-dione derivatives were synthesized and evaluated for their inhibitory effects on superoxide anion generation and neutrophil elastase (NE) release in formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-activated human neutrophils. Results indicated that (Z)-1-benzyl-4-(hydroxyimino)-1H-benzo[f]indol-9(4H)-one (10) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 value of 2.78 and 2.74 μM respectively. The action mechanisms of 10 in human neutrophils were further investigated. Our results showed that compound 10 did not alter fMLF-induced phosphorylation of Src (Src family Y416). Notably, phosphorylation of Akt (S473) and mobilization of [Ca2+]i caused by fMLF was inhibited by compound 10. Further structural optimization of 10 is ongoing. Full article
(This article belongs to the Section Biochemistry)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Structures of lapachol, β-lapachone, α-lapachone, and compounds <b>1</b>–<b>5</b>.</p> Full article ">Figure 2
<p>Compound <b>10</b> inhibits phosphorylation of Akt, but not Src, in fMLF-activated human neutrophils. Quantitation of the p-Scr/GADPH (<b>A</b>) and p-Akt/Akt (<b>B</b>) ratios is shown. Representative images from one of three experiments are shown.</p> Full article ">Figure 3
<p>Compound <b>10</b> inhibits fMLF-induced [Ca<sup>2+</sup>]<sub>i</sub> increase in human neutrophils. The traces shown are from three different experiments.</p> Full article ">Figure 4
<p>Synthesis of benzo[<span class="html-italic">f</span>]indole-4,9-dione derivatives <b>8</b>–<b>16</b>.</p> Full article ">
2092 KiB  
Review
Recent Developments of Engineered Translational Machineries for the Incorporation of Non-Canonical Amino Acids into Polypeptides
by Naohiro Terasaka, Yoshihiko Iwane, Anna-Skrollan Geiermann, Yuki Goto and Hiroaki Suga
Int. J. Mol. Sci. 2015, 16(3), 6513-6531; https://doi.org/10.3390/ijms16036513 - 20 Mar 2015
Cited by 30 | Viewed by 12030
Abstract
Genetic code expansion and reprogramming methodologies allow us to incorporate non-canonical amino acids (ncAAs) bearing various functional groups, such as fluorescent groups, bioorthogonal functional groups, and post-translational modifications, into a desired position or multiple positions in polypeptides both in vitro and in vivo [...] Read more.
Genetic code expansion and reprogramming methodologies allow us to incorporate non-canonical amino acids (ncAAs) bearing various functional groups, such as fluorescent groups, bioorthogonal functional groups, and post-translational modifications, into a desired position or multiple positions in polypeptides both in vitro and in vivo. In order to efficiently incorporate a wide range of ncAAs, several methodologies have been developed, such as orthogonal aminoacyl-tRNA-synthetase (AARS)–tRNA pairs, aminoacylation ribozymes, frame-shift suppression of quadruplet codons, and engineered ribosomes. More recently, it has been reported that an engineered translation system specifically utilizes an artificially built genetic code and functions orthogonally to naturally occurring counterpart. In this review we summarize recent advances in the field of ribosomal polypeptide synthesis containing ncAAs. Full article
(This article belongs to the Special Issue Functions of Transfer RNAs)
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Graphical abstract
Full article ">Figure 1
<p>Amino acids described in this review. Sec; selenocysteine, Pyl; pyrrolysine, Y<sup>3i</sup>; 3-iodo-<span class="html-small-caps">l</span>-tyrosine, F<span class="html-italic"><sup>p</sup></span><sup>az</sup>; <span class="html-italic">p</span>-azido-<span class="html-small-caps">l</span>-phenylalanine, K<sup>εac</sup>; ε-<span class="html-italic">N</span>-acetyl-<span class="html-small-caps">l</span>-lysine, Y<span class="html-italic"><sup>o</sup></span><sup>sf</sup>; <span class="html-italic">o</span>-sulfo-<span class="html-small-caps">l</span>-tyrosine, F<span class="html-italic"><sup>p</sup></span><sup>ac</sup>; <span class="html-italic">p</span>-acetyl-<span class="html-small-caps">l</span>-phenylalanine, Sph; (3<span class="html-italic">S</span>,4<span class="html-italic">S</span>)-4-amino-3-hydroxy-6-methylheptanoyl-phenylalanine, <sup>O</sup><sup>H</sup>G; α-glycolic acid, K<sup>tf</sup>; ε-<span class="html-italic">N</span>-trifluoroacetyl-<span class="html-small-caps">l</span>-lysine, Amh; 2-amino-7-aminocarbonylheptanoic acid, Anv; <span class="html-small-caps">l</span>-azidonorvaline, ClAc-<sup>l</sup>Y; <span class="html-italic">N</span>-chloroacetyl-<span class="html-small-caps">l</span>-tyrosine, ClAc-<sup>d</sup>Y; <span class="html-italic">N</span>-chloroacetyl-<span class="html-small-caps">d</span>-tyrosine, ClAc-<sup>l</sup>F; <span class="html-italic">N</span>-chloroacetyl-<span class="html-small-caps">l</span>-phenylalanine, ClAc-<sup>d</sup>F; <span class="html-italic">N</span>-chloroacetyl-<span class="html-small-caps">d</span>-phenylalanine, Fph; <span class="html-italic">N</span>-(5-FAM)-<span class="html-small-caps">l</span>-phenylalanine, K<sup>b</sup>; ε-(6-(biotinoyl)amino)hexanoyl-<span class="html-small-caps">l</span>-lysine.</p> Full article ">Figure 2
<p>(<b>a</b>) General scheme for ribosomal incorporation of non-canonical amino acids (ncAAs) into polypeptides. (1) Engineered tRNA charged with ncAA is prepared by chemical synthesis, aminoacyl-tRNA synthetase (AARS), or ribozymes. (2e) The ncAA-tRNA is recruited to the ribosome by EF-Tu during elongation event. (3e) Peptidyltransfer (PT) reaction between peptidyl-tRNA at the P site and ncAA-tRNA at the A site is catalyzed by ribosome. In engineering of initiation, (2i) ncAA-tRNA<sup>fMet</sup> is involved in an initiation complex by initiation factors (IFs) and (3i) the first peptide bond is formed by PT reaction; (<b>b</b>) Clover leaf structure of tRNA [<a href="#B11-ijms-16-06513" class="html-bibr">11</a>]. Conserved bases are described, circles represent non-conserved bases, and numbers indicate the nucleotide position. Positions 34 to 36 (dark blue) corresponds to the anticodon and position 74 to 76 (red) are universally conserved as CCA. The sequences composing the intron and the extra bases presenting in the variable loop (position noted 47 to 47k) are shown as black line. AAS (magenta), the amino acid-accepting stem; DSL (green), the dihydrouridine stem and loop; ASL (cyan), the anticodon stem and loop; VL (black), the variable loop; TSL (purple), the thymidine stem and loop; Y, pyrimidine; R, purine; H, not G; D, not C. The n bases at position 17, 17a, 20a and 20b are optional bases not present in all tRNAs. Position-1 bases are found in all cytoplasmic mature tRNA<sup>His</sup><sub>GUG</sub> from the three biological domains.</p> Full article ">Figure 3
<p>Coexpression of cyclic peptides bearing various ncAA initiators and ncAA elongators. (<b>a</b>) The initiation table (table<sup>ini</sup>, blue) designates multiple initiators while the elongation table (table<sup>elon</sup>, red) designates various ncAAs as well as cognate amino acids. Some of codon triplets are dual sense, <span class="html-italic">i.e.</span>, designating different amino acids in table<sup>ini</sup> and table<sup>elon</sup>; (<b>b</b>) Schematic illustration of the coexpression. Blue and red tRNAs indicate initiator tRNAs<sup>fMet</sup> and elongator tRNAs<sup>AsnE2</sup>, respectively. The chloroacetylated ncAA initiators react post-translationally with a downstream Cys residue to form macrocyclic structures.</p> Full article ">Figure 4
<p>An orthogonal ribosome–tRNA pair via engineering of the PTC. (<b>a</b>) Schematic illustration of simultaneous expression of two different peptides by orthogonal ribosome–tRNA pairs. The engineered ribosome–tRNA pair (red) has compensatory mutations (C75G in tRNA, G2251C and G2553C in 23S rRNA) in the PTC. Wildtype ribosome–tRNA pair (blue) and engineered pair are mixed with one single mRNA in an <span class="html-italic">in vitro</span> reconstituted translation mixture. Each pair generates two different peptides (blue and red) according to the wildtype (WT)- and orthogonal (OR)-codes, respectively; (<b>b</b>) Illustration of compatibility and orthogonality of the ribosome–tRNA mutant pairs. Line thickness indicates the compatibility of translational activity between each ribosome–tRNA pair; (<b>c</b>) Two genetic codes designed for simultaneous expression of two different peptides from a single mRNA. Wildtype code (WT-code, blue) comprises the wildtype ribosome–tRNA pair, and OR-code (red) comprises the G2251C/G2553C-ribosome–tRNAs-CGA pair.</p> Full article ">
1012 KiB  
Article
Favourable IFNL3 Genotypes Are Associated with Spontaneous Clearance and Are Differentially Distributed in Aboriginals in Canadian HIV-Hepatitis C Co-Infected Individuals
by Nasheed Moqueet, Claire Infante-Rivard, Robert W. Platt, Jim Young, Curtis Cooper, Mark Hull, Sharon Walmsley, Marina B. Klein and The Canadian Co-Infection Study Investigators
Int. J. Mol. Sci. 2015, 16(3), 6496-6512; https://doi.org/10.3390/ijms16036496 - 20 Mar 2015
Cited by 6 | Viewed by 6529
Abstract
Canadian Aboriginals are reported to clear Hepatitis C (HCV) more frequently. We tested the association of spontaneous clearance and three single nucleotide polymorphisms (SNPs) near the Interferon-lambda 3 (IFNL3) gene (rs12979860, rs8099917, functional variant rs8103142) and compared the SNP frequencies between HIV-HCV co-infected [...] Read more.
Canadian Aboriginals are reported to clear Hepatitis C (HCV) more frequently. We tested the association of spontaneous clearance and three single nucleotide polymorphisms (SNPs) near the Interferon-lambda 3 (IFNL3) gene (rs12979860, rs8099917, functional variant rs8103142) and compared the SNP frequencies between HIV-HCV co-infected whites and Aboriginals from the Canadian Co-infection Cohort. HCV treatment-naïve individuals with at least two HCV RNA tests were included (n = 538). A spontaneous clearance case was defined as someone with two consecutive HCV RNA-negative tests, at least six months apart. Data were analyzed using Cox proportional hazards adjusted for sex and ethnicity. Advantageous variants and haplotypes were more common in Aboriginals than Caucasians: 57% vs. 46% had the rs12979860 CC genotype, respectively; 58% vs. 48%, rs8103142 TT; 74% vs. 67%, the rs12979860 C allele; and 67% vs. 64% the TCT haplotype with three favourable alleles. The adjusted Hazard Ratios (95% CI) for spontaneous clearance were: rs12979860: 3.80 (2.20, 6.54); rs8099917: 5.14 (2.46, 10.72); and rs8103142: 4.36 (2.49, 7.62). Even after adjusting for rs12979860, Aboriginals and females cleared HCV more often, HR (95% CI) = 1.53 (0.89, 2.61) and 1.42 (0.79, 2.53), respectively. Our results suggest that favourable IFNL3 genotypes are more common among Aboriginals than Caucasians, and may partly explain the higher HCV clearance rates seen among Aboriginals. Full article
(This article belongs to the Special Issue Viral Hepatitis Research)
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<p>Distribution of favourable IFNL3 genotypes and alleles in Canadian-born Whites and Aboriginals: (<b>a</b>) Frequency of favourable IFNL3 alleles is higher in Aboriginals than Whites; (<b>b</b>) Frequency of favourable IFNL3 genotypes is higher in Aboriginals than Whites. * <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 2
<p>Haplotype distribution in Canadian-born Whites and Aboriginals. Haplotypes containing the favourable alleles at all three SNPs (TCT) are more common in Aboriginals than whites while the opposite is true about haplotypes with the disadvantageous alleles (CTG). TCT = T at rs8103142, C at rs12979860 and T at rs8099917.</p> Full article ">Figure 3
<p>Study and source population: (<b>a</b>) Selection of study population for evaluating the association of IFNL3 genotypes and rates of spontaneous clearance; (<b>b</b>) Selection of study population for comparison of IFNL3 frequency distribution between Canadian Aborginals and Whites.</p> Full article ">
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Article
High-Resolution Chromosome Ideogram Representation of Currently Recognized Genes for Autism Spectrum Disorders
by Merlin G. Butler, Syed K. Rafi and Ann M. Manzardo
Int. J. Mol. Sci. 2015, 16(3), 6464-6495; https://doi.org/10.3390/ijms16036464 - 20 Mar 2015
Cited by 48 | Viewed by 17519
Abstract
Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding [...] Read more.
Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors to access convenient visual images of the location and distribution of ASD genes. Meaningful correlations of the observed phenotype in patients with suspected/confirmed ASD gene(s) at the chromosome region or breakpoint band site can be made to inform diagnosis and gene-based personalized care and provide genetic counselling for families. Full article
(This article belongs to the Special Issue The Identification of the Genetic Components of Autism Spectrum Disorders)
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<p>High-resolution human chromosome ideograms (850 band level) with the ASD gene symbol placed at the chromosomal band location. The centromere area, highlighted in black, separates the upper short “p” arm and lower long “q” arm for each chromosome. The gene symbols are arranged in alphabetical order with the expanded name and chromosome band position listed in <a href="#ijms-16-06464-t001" class="html-table">Table 1</a>.</p> Full article ">Figure 1 Cont.
<p>High-resolution human chromosome ideograms (850 band level) with the ASD gene symbol placed at the chromosomal band location. The centromere area, highlighted in black, separates the upper short “p” arm and lower long “q” arm for each chromosome. The gene symbols are arranged in alphabetical order with the expanded name and chromosome band position listed in <a href="#ijms-16-06464-t001" class="html-table">Table 1</a>.</p> Full article ">
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Article
Cholinergic Transactivation of the EGFR in HaCaT Keratinocytes Stimulates a Flotillin-1 Dependent MAPK-Mediated Transcriptional Response
by Sina Kühne, Wymke Ockenga, Antje Banning and Ritva Tikkanen
Int. J. Mol. Sci. 2015, 16(3), 6447-6463; https://doi.org/10.3390/ijms16036447 - 20 Mar 2015
Cited by 10 | Viewed by 6803
Abstract
Acetylcholine and its receptors regulate numerous cellular processes in keratinocytes and other non-neuronal cells. Muscarinic acetylcholine receptors are capable of transactivating the epidermal growth factor receptor (EGFR) and, downstream thereof, the mitogen-activated protein kinase (MAPK) cascade, which in turn regulates transcription of genes [...] Read more.
Acetylcholine and its receptors regulate numerous cellular processes in keratinocytes and other non-neuronal cells. Muscarinic acetylcholine receptors are capable of transactivating the epidermal growth factor receptor (EGFR) and, downstream thereof, the mitogen-activated protein kinase (MAPK) cascade, which in turn regulates transcription of genes involved in cell proliferation and migration. We here show that cholinergic stimulation of human HaCaT keratinocytes results in increased transcription of matrix metalloproteinase MMP-3 as well as several ligands of the epidermal growth factor family. Since both metalloproteinases and the said ligands are involved in the transactivation of the EGFR, this transcriptional upregulation may provide a positive feed-forward loop for EGFR/MAPK activation. We here also show that the cholinergic EGFR and MAPK activation and the upregulation of MMP-3 and EGF-like ligands are dependent on the expression of flotillin-1 which we have previously shown to be a regulator of MAPK signaling. Full article
(This article belongs to the Collection G Protein-Coupled Receptor Signaling and Regulation)
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<p>Transcriptional upregulation of specific ligands of the EGF family can be suppressed by inhibition of mAChRs, EGFR and MAP kinase signaling. Transcript levels of the EGF family ligands <span class="html-italic">HB-EGF</span> (<b>A</b>–<b>C</b>), <span class="html-italic">TGFα</span> (<b>D</b>–<b>F</b>), <span class="html-italic">AREG</span> (<b>G</b>–<b>I</b>) and <span class="html-italic">EREG</span> (<b>J</b>–<b>L</b>) were measured by qPCR in cells stimulated for 2 h with 100 µM CCh and treated with inhibitors of mAChRs (<b>A</b>,<b>D</b>,<b>G</b>,<b>J</b>: Atropin), EGFR (<b>B</b>,<b>E</b>,<b>H</b>,<b>K</b>: PD 153035) or MEK1/2 (<b>C</b>,<b>F</b>,<b>I</b>,<b>L</b>: U0126). Bars represent the mean ± SD of three independent experiments. Statistical analysis was performed with one-way or two-way ANOVA; <b>*</b><sup>,<b>#</b></sup> <span class="html-italic">p</span> &lt; 0.05, <b>**</b><sup>,<b>##</b></sup> <span class="html-italic">p</span> &lt; 0.01, <b>***</b><sup>,<b>###</b></sup> <span class="html-italic">p</span> &lt; 0.001. <b>*</b> refers to comparison to unstimulated control, <sup>#</sup> to stimulated sample without inhibitor.</p> Full article ">Figure 2
<p><span class="html-italic">MMP-3</span> is upregulated by cholinergic stimuli in a manner dependent on mAChRs, EGFR and MAP kinases. HaCaT cells were stimulated with 100 µM CCh for 2 h and treated or not with inhibitors of the mAChRs, EGFR or MEK1/2. Transcriptional regulation of <span class="html-italic">MMP-3</span> (<b>A</b>–<b>C</b>), MMP-1 (<b>D</b>–<b>F</b>) and <span class="html-italic">ADAM17</span> (<b>G</b>–<b>I</b>) was measured by qPCR. Bars represent the mean ± SD of three independent experiments. Statistical analysis was performed with one-way or two-way ANOVA; <b>*</b> <span class="html-italic">p</span> &lt; 0.05, <b>**</b><sup>,<b>##</b></sup> <span class="html-italic">p</span> &lt; 0.01, <b>***</b><sup>,<b>###</b></sup> <span class="html-italic">p</span> &lt; 0.001. <b>*</b> refers to comparison to unstimulated control, <sup>#</sup> to stimulated sample without inhibitor.</p> Full article ">Figure 3
<p><span class="html-italic">Egr1</span> transcription is stimulated by CCh and repressed by inhibition of mAChRs (<b>A</b>), EGFR (<b>B</b>) and MAP kinases (<b>C</b>). Transcriptional induction of <span class="html-italic">Egr1</span> was measured by qPCR as stated in the legend of <a href="#ijms-16-06447-f002" class="html-fig">Figure 2</a>. Bars represent the mean ± SD of three independent experiments. Statistical analysis was performed with one-way or two-way ANOVA; <b>*</b> <span class="html-italic">p</span> &lt; 0.05, <b>**</b><sup>,<b>##</b></sup> <span class="html-italic">p</span> &lt; 0.01, <b>***</b><sup>,<b>###</b></sup> <span class="html-italic">p</span> &lt; 0.001. <b>*</b> refers to comparison to unstimulated control, <sup>#</sup> to stimulated sample without inhibitor.</p> Full article ">Figure 4
<p>Cholinergic stimulation of HaCaT cells results in increased flotillin expression. HaCaT cells were stimulated with 100 µM CCh as indicated and the mRNA (<b>A</b>) and protein (<b>B</b>) levels of flotillins were determined. Bars in (<b>A</b>) represent the mean of 3 independent experiments. Statistical analysis was performed with one-way ANOVA; <b>*</b> <span class="html-italic">p</span> &lt; 0.05, <b>**</b> <span class="html-italic">p</span> &lt; 0.01; (<b>B</b>) shows a representative Western blot for flotillins upon CCh stimulation.</p> Full article ">Figure 5
<p>Flotillin-1 knockdown impairs cholinergic signaling towards ERK. HaCaT cells were depleted of flotillins by means of specific siRNAs. The cells were starved and stimulated with 100 µM ACh, 1 mM CCh or 100 µM nicotine for 30 min. (<b>A</b>,<b>C</b>): Equal amounts of protein were separated by SDS-PAGE, and the phosphorylation of ERK1/2 was analyzed; (<b>B</b>,<b>D</b>): The amount of pERK1/2 was determined by densitometric quantification and normalized to total ERK1/2. Data are shown relative to the ACh stimulated control cells. Bars represent the mean ± SD of five independent experiments. Statistical analysis was performed with two-way ANOVA; <b>***</b> <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 6
<p>Flotillin-1 is required for CCh-induced transcriptional regulation of EGF family ligands and MMP-3. Stable flotillin-1 and flotillin-2 knockdown and control HaCaT cells were stimulated with 100 µM CCh for 2 h and the transcript levels of EGF family ligands (<b>A</b>–<b>D</b>) and MMP-3 (<b>E</b>) were determined; (<b>F</b>) Knockdown efficiency of flotillin-1 and flotillin-2 as detected by Western blot. Bars represent the mean ± SD of three independent experiments. Statistical analysis was performed with one-way or two-way ANOVA; <b>*</b><sup>,<b>#</b></sup> <span class="html-italic">p</span> &lt; 0.05, <b>**</b><sup>,<b>##</b></sup> <span class="html-italic">p</span> &lt; 0.01, <b>***</b><sup>,<b>###</b></sup> <span class="html-italic">p</span> &lt; 0.001. <b>*</b> refers to comparison to unstimulated control cells, <sup>#</sup> to stimulated sample of the respective cell line.</p> Full article ">
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Review
Primary Biliary Cirrhosis Is a Generalized Autoimmune Epithelitis
by Jun Gao, Liang Qiao and Bingyuan Wang
Int. J. Mol. Sci. 2015, 16(3), 6432-6446; https://doi.org/10.3390/ijms16036432 - 20 Mar 2015
Cited by 9 | Viewed by 9445
Abstract
Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to [...] Read more.
Primary biliary cirrhosis (PBC) is a chronic progressive autoimmune cholestatic liver disease characterized by highly specific antimitochondrial antibodies (AMAs) and the specific immune-mediated injury of small intrahepatic bile ducts. Unique apoptotic feature of biliary epithelial cells (BECs) may contribute to apotope presentation to the immune system, causing unique tissue damage in PBC. Perpetuation of inflammation may result in senescence of BECs, contributing to irreversible loss of bile duct. In addition to the classic liver manifestations, focal inflammation and tissue damage are also seen in salivary glands and urinary tract in a significant proportion of PBC patients. These findings provide potent support to the idea that molecular mimicry may be involved in the breakdown of autoimmune tolerance and mucosal immunity may lead to a systematic epithelitis in PBC patients. Thus, PBC is considered a generalized epithelitis in clinical practice. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)
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<p>Microbial mimic can trigger the self-destructing immunopathogenic process in primary biliary cirrhosis (PBC). PBC-specific mitochondrial autoantigens remains structurally intact and retains its immunogenicity during biliary epithelial cell (BEC) apoptosis leading to the formation of apotope which can be recognized by circulating anti-mitochondrial autoantibody (AMA). The immune complex would stimulate innate and adaptive immunity in s subject with a susceptible genetic background. Progressive BEC damage tilts the balance between cellular injury and proliferative repair, leading to BEC senescence. The senescent BECs can secret a large amount of senescence-associated secretory phenotype (SASP) which may exert cytolytic response on the senescent cells and neighbouring cells. All of these processes can result in the progressive loss of bile ducts and liver fibrosis.</p> Full article ">Figure 2
<p>A pathogenetic view of the relationship between autoimmune epithelitis and PBC. (1) PBC-specific mitochondrial autoantigens remains structurally intact and retains its immunogenicity during BECs apoptosis, leading to selective damage of small bile ducts; (2) Progressive BEC damage may lead to BEC senescence and production of SASPs, resulting in progressive loss of bile ducts and liver fibrosis; (3) Infectious agents, such as <span class="html-italic">E. coli</span>, may drive urethral epithelitis via molecular mimicry, which may be an initial event in PBC immunological breakdown; (4) IgA AMA may be presents in bile, urine and saliva, supporting the idea that IgA AMA is not restricted to biliary tissues but is a more general phenomenon in PBC; and (5) Mucosal immunity in other ductal epithelial tissues such as salivary glands, urinary tract, and gut may induce generalized epithelitis in PBC.</p> Full article ">
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Review
Wilson’s Disease: A Comprehensive Review of the Molecular Mechanisms
by Fei Wu, Jing Wang, Chunwen Pu, Liang Qiao and Chunmeng Jiang
Int. J. Mol. Sci. 2015, 16(3), 6419-6431; https://doi.org/10.3390/ijms16036419 - 20 Mar 2015
Cited by 95 | Viewed by 24221
Abstract
Wilson’s disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, [...] Read more.
Wilson’s disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Human Liver Diseases)
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<p>Diagram of <span class="html-italic">ATP7B</span>. The metal-binding domain contains six copper-binding domains (MBD1-6), all with the conserved sequence motif CXXC. The transmembrane channel consisting of eight discontinuous ion channels may contribute to copper transport (Cylinder1-8). The Cys–Pro–Cys (CPC) sequence motif is the key residue that confers metal ion selectively. ATP binds to the N-domain and the SEHPL motif located in the N-domain. The P-domain is the room for phosphorylation of Asp from the sequence DKTGT. The A-domain is the place where the acyl-phosphate gets dephosphorylated. Mutations may occur at any position of the gene, and then may cause the deposition of copper.</p> Full article ">Figure 2
<p>Copper is delivered by HCTR1 to cytosol where it mainly binds to Atox1. Atox1 transfers copper to TGN and is transported into the lumen with the help of ATP7B. Copper is then incorporated into ceruloplasmin which is then released to vascellum. The excess copper facilitates ATP7B trafficking from the TGN to the lysosome, then copper can be transported to the lysosomal lumen, and the excess copper is excreted to bile via exocytosis. An increasing level of copper also stimulates ATP7B to move to cytosolic vesicles where copper is isolated and then released into the bile duct.</p> Full article ">
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Article
Exploring the Nature of Silicon-Noble Gas Bonds in H3SiNgNSi and HSiNgNSi Compounds (Ng = Xe, Rn)
by Sudip Pan, Ranajit Saha and Pratim K. Chattaraj
Int. J. Mol. Sci. 2015, 16(3), 6402-6418; https://doi.org/10.3390/ijms16036402 - 19 Mar 2015
Cited by 38 | Viewed by 7597
Abstract
Ab initio and density functional theory-based computations are performed to investigate the structure and stability of H3SiNgNSi and HSiNgNSi compounds (Ng = Xe, Rn). They are thermochemically unstable with respect to the dissociation channel producing Ng and H3SiNSi or [...] Read more.
Ab initio and density functional theory-based computations are performed to investigate the structure and stability of H3SiNgNSi and HSiNgNSi compounds (Ng = Xe, Rn). They are thermochemically unstable with respect to the dissociation channel producing Ng and H3SiNSi or HSiNSi. However, they are kinetically stable with respect to this dissociation channel having activation free energy barriers of 19.3 and 23.3 kcal/mol for H3SiXeNSi and H3SiRnNSi, respectively, and 9.2 and 12.8 kcal/mol for HSiXeNSi and HSiRnNSi, respectively. The rest of the possible dissociation channels are endergonic in nature at room temperature for Rn analogues. However, one three-body dissociation channel for H3SiXeNSi and one two-body and one three-body dissociation channels for HSiXeNSi are slightly exergonic in nature at room temperature. They become endergonic at slightly lower temperature. The nature of bonding between Ng and Si/N is analyzed by natural bond order, electron density and energy decomposition analyses. Natural population analysis indicates that they could be best represented as (H3SiNg)+(NSi)− and (HSiNg)+(NSi)−. Energy decomposition analysis further reveals that the contribution from the orbital term (ΔEorb) is dominant (ca. 67%–75%) towards the total attraction energy associated with the Si-Ng bond, whereas the electrostatic term (ΔEelstat) contributes the maximum (ca. 66%–68%) for the same in the Ng–N bond, implying the covalent nature of the former bond and the ionic nature of the latter. Full article
(This article belongs to the Special Issue Chemical Bond and Bonding 2015)
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<p>Pictorial depictions of the energy minimum structures and the transition states (TSs) of H<sub>3</sub>SiNSi, HSiNSi, H<sub>3</sub>SiNgNSi and HSiNgNSi compounds. Point groups along with their electronic states are given in parentheses. <b>TS-1</b> and <b>TS-2</b> are associated with the dissociation of H<sub>3</sub>SiNgNSi and HSiNgNSi, producing Ng and H<sub>3</sub>SiNSi or HSiNSi.</p> Full article ">Figure 2
<p>Contour plots of the Laplacian of the electron density of H<sub>3</sub>SiXeNSi and HSiXeNSi clusters at a particular plane computed at the MP2/def2-QZVPPD/WTBS level (WTBS is used for Xe and Rn; The green-colored region shows the area of ∇<sup>2</sup>ρ(<b>r</b>) &gt; 0, whereas the blue-colored region shows the area of ∇<sup>2</sup>ρ(<b>r</b>) &lt; 0).</p> Full article ">Figure 3
<p>Color-filled maps of the electron localization function of H<sub>3</sub>SiXeNSi and HSiXeNSi clusters at a particular plane computed at the MP2/def2-QZVPPD/WTBS level (WTBS is used for Xe and Rn).</p> Full article ">
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Article
Characterization and Antihyperglycemic Activity of a Polysaccharide from Dioscorea opposita Thunb Roots
by Yijun Fan, Qinyi He, Aoshuang Luo, Miaoyu Wang and Aoxue Luo
Int. J. Mol. Sci. 2015, 16(3), 6391-6401; https://doi.org/10.3390/ijms16036391 - 19 Mar 2015
Cited by 57 | Viewed by 7340
Abstract
A polysaccharide DOTP-80 from Dioscorea opposita Thunb was obtained by using the method of acid water-extraction and ethanol-precipitation. After being purified by chromatography, the structure characteristics of DOTP-80 were established. Based on the calibration curve obtained with standard dextrans, the molecular weight of [...] Read more.
A polysaccharide DOTP-80 from Dioscorea opposita Thunb was obtained by using the method of acid water-extraction and ethanol-precipitation. After being purified by chromatography, the structure characteristics of DOTP-80 were established. Based on the calibration curve obtained with standard dextrans, the molecular weight of the polysaccharide fraction DOTP-80 was calculated to be 123 kDa. The results of Infrared spectrum (FT-IR) indicated that the polysaccharide contained the α-configuration of sugar units. GC-MS analysis revealed that DOTP-80 was mainly composed of mannose and glucose. Alloxan-induced diabetic rats and mice models were developed to evaluate the in vivo hypoglycemic activity of the polysaccharide. The results indicated that a high dose DOTP-80 (400 mg/kg) had strong hypoglycemic activity. Moreover, DOTP-80 could increase the level of antioxidant enzymes (SOD) activity in alloxan-induced diabetic mice and stimulate an increase in glucose disposal in diabetic rats. Therefore, the polysaccharide DOTP-80 should be evaluated as a candidate for future studies on diabetes mellitus. Full article
(This article belongs to the Special Issue Bioactive Carbohydrates and Peptides)
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<p>IR spectrum of the polysaccharide DOTP-80.</p> Full article ">Figure 2
<p>Effect of different doses (mg/kg body weight) of DOTP-80 and Metformin hydrochloride on body weight in alloxan-induced diabetic mice. NC: normal control group; MC: model control.</p> Full article ">Figure 3
<p>SOD activity. Results are presented as means ± standard deviations. * <span class="html-italic">p</span> &lt; 0.05 and ** <span class="html-italic">p</span> &lt; 0.01 (compared with normal control).</p> Full article ">
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Article
SOD2 Activity Is not Impacted by Hyperoxia in Murine Neonatal Pulmonary Artery Smooth Muscle Cells and Mice
by Anita Gupta, Marta Perez, Keng Jin Lee, Joann M. Taylor and Kathryn N. Farrow
Int. J. Mol. Sci. 2015, 16(3), 6373-6390; https://doi.org/10.3390/ijms16036373 - 19 Mar 2015
Cited by 11 | Viewed by 6024
Abstract
Pulmonary hypertension (PH) complicates bronchopulmonary dysplasia (BPD) in 25% of infants. Superoxide dismutase 2 (SOD2) is an endogenous mitochondrial antioxidant, and overexpression protects against acute lung injury in adult mice. Little is known about SOD2 in neonatal lung disease and PH. C57Bl/6 mice [...] Read more.
Pulmonary hypertension (PH) complicates bronchopulmonary dysplasia (BPD) in 25% of infants. Superoxide dismutase 2 (SOD2) is an endogenous mitochondrial antioxidant, and overexpression protects against acute lung injury in adult mice. Little is known about SOD2 in neonatal lung disease and PH. C57Bl/6 mice and isogenic SOD2+/+ and SOD2−/+ mice were placed in room air (control) or 75% O2 (chronic hyperoxia, CH) for 14 days. Right ventricular hypertrophy (RVH) was assessed by Fulton’s index. Medial wall thickness (MWT) and alveolar area were assessed on formalin fixed lung sections. Pulmonary artery smooth muscle cells (PASMC) were placed in 21% or 95% O2 for 24 h. Lung and PASMC protein were analyzed for SOD2 expression and activity. Oxidative stress was measured with a mitochondrially-targeted sensor, mitoRoGFP. CH lungs have increased SOD2 expression, but unchanged activity. SOD2−/+ PASMC have decreased expression and activity at baseline, but increased SOD2 expression in hyperoxia. Hyperoxia increased mitochondrial ROS in SOD2+/+ and SOD2−/+ PASMC. SOD2+/+ and SOD2−/+ CH pups induced SOD2 expression, but not activity, and developed equivalent increases in RVH, MWT, and alveolar area. Since SOD2−/+ mice develop equivalent disease, this suggests other antioxidant systems may compensate for partial SOD2 expression and activity in the neonatal period during hyperoxia-induced oxidative stress. Full article
(This article belongs to the Special Issue Oxidative Stress in Cardiovascular Disease 2015)
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<p>Chronic hyperoxia (CH) exposure increased SOD2 protein expression but not activity in mouse lungs. (<b>A</b>) Expression was measured in lung protein by Western blot in control and CH mice (<span class="html-italic">n</span> = 12 per group, * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> control); (<b>B</b>) Representative Western blot of SOD2 expression is shown with corresponding β-actin; and (<b>C</b>) SOD2 enzymatic activity was measured with a commercially available activity assay in control and CH mice (<span class="html-italic">n</span> = 20 per group). Data are shown as fold mean ± SEM.</p> Full article ">Figure 1 Cont.
<p>Chronic hyperoxia (CH) exposure increased SOD2 protein expression but not activity in mouse lungs. (<b>A</b>) Expression was measured in lung protein by Western blot in control and CH mice (<span class="html-italic">n</span> = 12 per group, * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> control); (<b>B</b>) Representative Western blot of SOD2 expression is shown with corresponding β-actin; and (<b>C</b>) SOD2 enzymatic activity was measured with a commercially available activity assay in control and CH mice (<span class="html-italic">n</span> = 20 per group). Data are shown as fold mean ± SEM.</p> Full article ">Figure 2
<p>Hyperoxia increased SOD2 protein expression but not activity in pulmonary artery smooth muscle cells (PASMC) from SOD2−/+ and SOD2+/+ mice. (<b>A</b>) PASMC were isolated from both SOD2−/+ (HET) and SOD2+/+ (wild-type, WT) mice. PASMC were exposed to hyperoxia (95% O<sub>2</sub>) for 24 h. SOD2 expression was measured by Western blot in lysates from WT and HET PASMC (<span class="html-italic">n</span> = 6 for WT PASMC and <span class="html-italic">n</span> = 10 for HET PASMC) in both room air and hyperoxia (* <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT in 21% O<sub>2</sub>). Data are shown as mean ± SEM; (<b>B</b>) Representative Western blots of SOD2 expression are shown with corresponding β-actin; and (<b>C</b>) PASMC from HET and WT mice were assayed for SOD2 activity using a commercially available activity assay (<span class="html-italic">n</span> = 14 for WT PASMC in 21% O<sub>2</sub> and <span class="html-italic">n</span> = 12 for all other groups; * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT in 21% O<sub>2</sub>). Data are shown as mean ± SEM.</p> Full article ">Figure 2 Cont.
<p>Hyperoxia increased SOD2 protein expression but not activity in pulmonary artery smooth muscle cells (PASMC) from SOD2−/+ and SOD2+/+ mice. (<b>A</b>) PASMC were isolated from both SOD2−/+ (HET) and SOD2+/+ (wild-type, WT) mice. PASMC were exposed to hyperoxia (95% O<sub>2</sub>) for 24 h. SOD2 expression was measured by Western blot in lysates from WT and HET PASMC (<span class="html-italic">n</span> = 6 for WT PASMC and <span class="html-italic">n</span> = 10 for HET PASMC) in both room air and hyperoxia (* <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT in 21% O<sub>2</sub>). Data are shown as mean ± SEM; (<b>B</b>) Representative Western blots of SOD2 expression are shown with corresponding β-actin; and (<b>C</b>) PASMC from HET and WT mice were assayed for SOD2 activity using a commercially available activity assay (<span class="html-italic">n</span> = 14 for WT PASMC in 21% O<sub>2</sub> and <span class="html-italic">n</span> = 12 for all other groups; * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT in 21% O<sub>2</sub>). Data are shown as mean ± SEM.</p> Full article ">Figure 3
<p>Hyperoxia increased ROS in both SOD2+/+ and SOD2−/+ PASMCs. PASMC were isolated from both SOD2−/+ (HET) and SOD2+/+ (WT) mice. PASMC were exposed to hyperoxia (95% O<sub>2</sub>) for 24 h. We utilized a targeted ratiometric redox-sensitive GFP probe (mitoRoGFP) to measure oxidative stress. After obtaining ratiometric measurements of RoGFP using dual laser flow cytometry, the sensor was calibrated by maximally reducing it with dithiothreitol (DTT, 1 mM) and maximally oxidizing it with t-butyl hydroperoxide (TBH, 1 mM). Data are shown as mean fold oxidative stress relative to SOD2+/+ (WT) PASMC in 21% O<sub>2</sub> ± SEM (<span class="html-italic">n</span> = 7 (WT 21% O<sub>2</sub>), 9 (HET 21% O<sub>2</sub>), 8 (WT 95% O<sub>2</sub>), and 10 (HET 95% O<sub>2</sub>); * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT in 21% O<sub>2</sub>, # <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 HET in 21% O<sub>2</sub>).</p> Full article ">Figure 4
<p>SOD2−/+ PASMC have increased phosphodiesterase 5 (PDE5) activity at baseline. PASMC were isolated from both SOD2−/+ (HET) and SOD2+/+ (WT) mice. PASMC were exposed to hyperoxia (95% O<sub>2</sub>) for 24 h. PDE5 activity was measured in PASMC lysates using a commercially available assay, and results are reported as pmol cGMP hydrolyzed/mg/minute (<span class="html-italic">n</span> = 7 (WT 21% O<sub>2</sub>), 5 (HET 21% O<sub>2</sub>), 4 (WT 95% O<sub>2</sub>), 7 (HET 95% O<sub>2</sub>); * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> WT 21% O<sub>2</sub>). Data are shown as mean ± SEM.</p> Full article ">Figure 5
<p>SOD2−/+ mice develop equivalent pulmonary vascular disease in chronic hyperoxia (CH) relative to SOD2+/+ littermates. Neonatal mice (SOD2−/+ (HET) and isogenic SOD2+/+ (WT) littermates) were exposed to chronic hyperoxia (CH) or room air (Control (C)) from birth to 14 days of life. Mice were euthanized on day 14, lungs were inflation fixed, and hearts were dissected. (<b>A</b>) Right ventricular hypertrophy was measured by Fulton’s index (right ventricle (RV) weight/left ventricle plus septum (LV + S) weight) and compared with age-matched control mice (<span class="html-italic">n</span> = 20 per group; * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT Control mice, # <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 HET Control mice). Data are shown as mean ± SEM; (<b>B</b>) Vascular remodeling was measured by medical wall thickness (MWT). Data are shown as mean ± SEM (<span class="html-italic">n</span> = 6–8 vessels per mouse with mice <span class="html-italic">n</span> = 6 (SOD2 WT C), 9 (SOD2 HET C), 4 (SOD2 WT CH), and 11 (SOD2 HET CH); * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT Control mice, # <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 HET Control mice); and (<b>C</b>) Representative HE-stained lung sections (40×) for control (WT and HET) and CH (WT and HET) mice.</p> Full article ">Figure 6
<p>SOD2−/+ mice develop equivalent alveolar simplification in chronic hyperoxia (CH) relative to SOD2+/+ littermates. Neonatal mice (SOD2−/+ (HET) and isogenic SOD2+/+ (WT) littermates) were exposed to chronic hyperoxia (CH) or room air (Control (C)) from birth to 14 days of life. Mice were euthanized on day 14, and lungs were inflation fixed. (<b>A</b>) Mean alveolar area was measured on hemotoxylin-stained lung sections using Scion software. Data are shown as mean ± SEM (<span class="html-italic">n</span> = 8–10 images per mouse with 4 mice per group; * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 WT C mice # <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 HET Control mice); and (<b>B</b>) Representative hematoxylin-stained lung sections (20×) are shown.</p> Full article ">Figure 7
<p>Chronic hyperoxia (CH) exposure increased SOD3 expression in SOD2−/+ mice but does not change SOD1 expression. Neonatal mice (SOD2−/+ (HET) and isogenic SOD2+/+ (WT) littermates) were exposed to chronic hyperoxia (CH) or room air (Control (C)) from birth to 14 days of life. Mice were euthanized on day 14, and lung tissue was harvested. (<b>A</b>) Lung SOD3 protein expression was measured by Western blot from WT and HET mice. Data are shown as fold mean ± SEM (<span class="html-italic">n</span> = 8; * <span class="html-italic">p</span> &lt; 0.05 <span class="html-italic">vs.</span> SOD2 HET C); (<b>B</b>) Representative Western blots of SOD3 expression is shown with corresponding β-actin; (<b>C</b>) Lung SOD1 protein expression was measured by Western blot from WT and HET mice. Data are shown as fold mean ± SEM (<span class="html-italic">n</span> = 6); and (<b>D</b>) Representative Western blot of SOD1 expression is shown with corresponding β-actin.</p> Full article ">
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Review
The Role of Hypoxia-Induced miR-210 in Cancer Progression
by Kyvan Dang and Kenneth A. Myers
Int. J. Mol. Sci. 2015, 16(3), 6353-6372; https://doi.org/10.3390/ijms16036353 - 19 Mar 2015
Cited by 145 | Viewed by 9243
Abstract
Prolonged hypoxia, the event of insufficient oxygen, is known to upregulate tumor development and growth by promoting the formation of a neoplastic environment. The recent discovery that a subset of cellular microRNAs (miRs) are upregulated during hypoxia, where they function to promote tumor [...] Read more.
Prolonged hypoxia, the event of insufficient oxygen, is known to upregulate tumor development and growth by promoting the formation of a neoplastic environment. The recent discovery that a subset of cellular microRNAs (miRs) are upregulated during hypoxia, where they function to promote tumor development, highlights the importance of hypoxia-induced miRs as targets for continued investigation. miRs are short, non-coding transcripts involved in gene expression and regulation. Under hypoxic conditions, miR-210 becomes highly upregulated in response to hypoxia inducing factors (HIFs). HIF-1α drives miR-210’s overexpression and the resultant alteration of cellular processes, including cell cycle regulation, mitochondria function, apoptosis, angiogenesis and metastasis. Here we discuss hypoxia-induced dysregulation of miR-210 and the resultant changes in miR-210 protein targets that regulate cancer progression. Potential methods of targeting miR-210 as a therapeutic tool are also explored. Full article
(This article belongs to the Special Issue Molecular Machinery of Cell Growth Regulation)
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Figure 1

Figure 1
<p>miR-210 binds to the 3' UTR of target mRNAs in order to modulate their transcription. (<b>a</b>) Entire mRNA sequence with seed region highlighted in blue; (<b>b</b>) 3' UTR of some of miR-210’s target mRNAs. Bases that successfully pair to miR-210’s seed region are highlighted in green. Bases that do not successfully pair are highlighted in red.</p> Full article ">Figure 2
<p>Structure, mechanism of function, and advantages of therapeutic strategies used to target miRNAs. For antagomirs, tiny LNAs, and PNAs, molecular structures of the first monomer and linkages are indicated within the black boxes.</p> Full article ">Figure 3
<p>Effects of hypoxia-induced miR-210 on known mRNA targets. Green boxes indicate miR-210 targets that promote oncogenic activity. Red boxes indicate miR-210 targets that promote tumor suppression.</p> Full article ">
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Article
Supramolecular Cationic Assemblies against Multidrug-Resistant Microorganisms: Activity and Mechanism of Action
by Letícia Dias De Melo Carrasco, Jorge Luiz Mello Sampaio and Ana Maria Carmona-Ribeiro
Int. J. Mol. Sci. 2015, 16(3), 6337-6352; https://doi.org/10.3390/ijms16036337 - 19 Mar 2015
Cited by 27 | Viewed by 6843
Abstract
The growing challenge of antimicrobial resistance to antibiotics requires novel synthetic drugs or new formulations for old drugs. Here, cationic nanostructured particles (NPs) self-assembled from cationic bilayer fragments and polyelectrolytes are tested against four multidrug-resistant (MDR) strains of clinical importance. The non-hemolytic poly(diallyldimethylammonium) [...] Read more.
The growing challenge of antimicrobial resistance to antibiotics requires novel synthetic drugs or new formulations for old drugs. Here, cationic nanostructured particles (NPs) self-assembled from cationic bilayer fragments and polyelectrolytes are tested against four multidrug-resistant (MDR) strains of clinical importance. The non-hemolytic poly(diallyldimethylammonium) chloride (PDDA) polymer as the outer NP layer shows a remarkable activity against these organisms. The mechanism of cell death involves bacterial membrane lysis as determined from the leakage of inner phosphorylated compounds and possibly disassembly of the NP with the appearance of multilayered fibers made of the NP components and the biopolymers withdrawn from the cell wall. The NPs display broad-spectrum activity against MDR microorganisms, including Gram-negative and Gram-positive bacteria and yeast. Full article
(This article belongs to the Special Issue Supramolecular Interactions)
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<p>(<b>a</b>–<b>c</b>) Cell viability as a function of DODAB or PDDA concentrations for the <span class="html-italic">P. aeruginosa</span> multidrug-resistant (MDR) strain (5–7 × 10<sup>7</sup> CFU/mL), <span class="html-italic">K. pneumoniae</span> KPC+ (<span class="html-italic">K. pneumoniae</span> carbapenemase (KPC+)) (4–5 × 10<sup>7</sup> CFU/mL) or MRSA (8 × 10<sup>7</sup>–3 × 10<sup>8</sup> CFU/mL); (<b>d</b>–<b>f</b>) leakage of phosphorylated compounds (%) as a function of DODAB or PDDA concentrations for reference (ATCC) or MDR <span class="html-italic">P. aeruginosa</span> (2 × 10<sup>8</sup>–5 × 10<sup>10</sup> CFU/mL), <span class="html-italic">K. pneumoniae</span> (3 × 10<sup>8</sup>–1 × 10<sup>10</sup> CFU/mL) or <span class="html-italic">S. aureus</span> (5 × 10<sup>9</sup>–6 × 10<sup>11</sup> CFU/mL). Interactions took place for 1 h. The minimal microbicidal concentration (MMC) values for PDDA in NPs are indicated by arrows.</p> Full article ">Figure 2
<p>The cell viability of fluconazole-resistant <span class="html-italic">C. albicans</span> at 6–8 × 10<sup>5</sup> CFU/mL as a function of DODAB or PDDA concentrations. Interactions took place for 1 h. The MMC for PDDA in the NPs is indicated by the arrow.</p> Full article ">Figure 3
<p>(<b>a</b>) The logarithm of CFU/mL as a function of DODAB or PDDA concentrations for the <span class="html-italic">C. albicans</span> fluconazole-resistant (R) strain at 5–6 × 10<sup>6</sup> CFU/mL; (<b>b</b>) percentile of the leakage of phosphorylated compounds (%) as a function of DODAB or PDDA concentrations for <span class="html-italic">C. albicans</span> reference (ATCC) and resistant strains at 7 × 10<sup>6</sup>–1 × 10<sup>7</sup> CFU/mL. Interactions took place for 1 h.</p> Full article ">Figure 4
<p>(<b>a</b>) SEM image of NPs; (<b>b</b>) SEM image of NPs and <span class="html-italic">P. aeruginosa</span> MDR cells at 4.4 × 10<sup>3</sup> cells/mL; (<b>c</b>) SEM image of NPs and <span class="html-italic">P. aeruginosa</span> MDR cells at 8.9 × 10<sup>5</sup> cells/mL; (<b>d</b>,<b>e</b>) SEM images of PDDA (1.0 mg/mL) and <span class="html-italic">P. aeruginosa</span> MDR cells at 8.9 × 10<sup>5</sup> cells/mL; (<b>f</b>) <span class="html-italic">P. aeruginosa</span> MDR cells. Final concentrations in the NPs are 0.05 mM DODAB, 0.05 mg/mL CMC and 0.05 mg/mL PDDA.</p> Full article ">
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Review
Mitochondria as Key Targets of Cardioprotection in Cardiac Ischemic Disease: Role of Thyroid Hormone Triiodothyronine
by Francesca Forini, Giuseppina Nicolini and Giorgio Iervasi
Int. J. Mol. Sci. 2015, 16(3), 6312-6336; https://doi.org/10.3390/ijms16036312 - 19 Mar 2015
Cited by 46 | Viewed by 11205
Abstract
Ischemic heart disease is the major cause of mortality and morbidity worldwide. Early reperfusion after acute myocardial ischemia has reduced short-term mortality, but it is also responsible for additional myocardial damage, which in the long run favors adverse cardiac remodeling and heart failure [...] Read more.
Ischemic heart disease is the major cause of mortality and morbidity worldwide. Early reperfusion after acute myocardial ischemia has reduced short-term mortality, but it is also responsible for additional myocardial damage, which in the long run favors adverse cardiac remodeling and heart failure evolution. A growing body of experimental and clinical evidence show that the mitochondrion is an essential end effector of ischemia/ reperfusion injury and a major trigger of cell death in the acute ischemic phase (up to 48–72 h after the insult), the subacute phase (from 72 h to 7–10 days) and chronic stage (from 10–14 days to one month after the insult). As such, in recent years scientific efforts have focused on mitochondria as a target for cardioprotective strategies in ischemic heart disease and cardiomyopathy. The present review discusses recent advances in this field, with special emphasis on the emerging role of the biologically active thyroid hormone triiodothyronine (T3). Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction in Ageing and Diseases)
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<p>Schematic overview of the role of TH in the modulation of the mitochondrial pro-survival (blue connectors) or pro-death (red connectors) signaling networks that control cardiomyocyte fate in the I/R heart. CypD = Cyclophilin D; DRP1 = dynamin-related protein 1; GSK3β = glycogen synthase kinase 3-β; HIF1α = Hypoxia inducible factor 1 α, IRI = ischemia/reperfusion injuries; mitoK-ATP = mitochondrial ATP-dependent potassium channel; mtTFA = mitochondrial transcription factor A; Park = parkin; PTPO = permeability transition pore opening; PGC1-α = peroxisome proliferator-activated receptor-γ coactivator-1α; RISK = reperfusion injury salvage kinase.</p> Full article ">
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Article
Genotyping Test with Clinical Factors: Better Management of Acute Postoperative Pain?
by Aline Hajj, Katell Peoc'h, Jean-Louis Laplanche, Hicham Jabbour, Nicole Naccache, Hicham Abou Zeid, Patricia Yazbeck and Lydia Rabbaa Khabbaz
Int. J. Mol. Sci. 2015, 16(3), 6298-6311; https://doi.org/10.3390/ijms16036298 - 19 Mar 2015
Cited by 13 | Viewed by 6304
Abstract
Individualization of acute postoperative pain treatment on an evidence-based decision process is a major health concern. The aim of this study is to investigate the influence of genetic and non-genetic factors on the variability of response to morphine in acute postoperative pain. A [...] Read more.
Individualization of acute postoperative pain treatment on an evidence-based decision process is a major health concern. The aim of this study is to investigate the influence of genetic and non-genetic factors on the variability of response to morphine in acute postoperative pain. A group of nighty-five patients undergoing major surgery were included prospectively. At 24 h, a logistic regression model was carried out to determine the factors associated with morphine doses given by a Patient Controlled Analgesia device. The dose of morphine was associated with age (p = 0.011), patient weight (p = 0.025) and the duration of operation (p = 0.030). This dose decreased with patient’s age and duration of operation and increased with patient’s weight. OPRM1 and ABCB1 polymorphisms were significantly associated with administered dose of morphine (p = 0.038 and 0.012 respectively). Patients with at least one G allele for c.118A>G OPRM1 polymorphism (AG/GG) needed 4 times the dose of morphine of AA patients. Additionally, patients with ABCB1 CT and CC genotypes for c.3435C>T polymorphism were 5.6 to 7.1 times more prone to receive higher dose of morphine than TT patients. Our preliminary results support the evidence that OPRM1/ABCB1 genotypes along with age, weight and duration of operation have an impact on morphine consumption for acute postoperative pain treatment. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine)
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<p>Doses of morphine at 24 h based on genotype distribution for both <span class="html-italic">OPRM1</span> and <span class="html-italic">ABCB1</span> SNPs. Morphine dose requirements according to the genotypes for the two SNPs <span class="html-italic">OPRM1</span> c.118A&gt;G and <span class="html-italic">ABCB1</span> c.3435C&gt;T. Due to the small number of 118GG patients, the results are grouped by G allele (the patients carrying at least one G allele). o Outliers or doses values that extend more than 1.5 box-lengths from the edge of the box; <b>*</b> Extreme values or doses values that extend 3 box-lengths from the edge of the box.</p> Full article ">
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Review
Role of Pancreatic Transcription Factors in Maintenance of Mature β-Cell Function
by Hideaki Kaneto and Taka-aki Matsuoka
Int. J. Mol. Sci. 2015, 16(3), 6281-6297; https://doi.org/10.3390/ijms16036281 - 18 Mar 2015
Cited by 57 | Viewed by 10530
Abstract
A variety of pancreatic transcription factors including PDX-1 and MafA play crucial roles in the pancreas and function for the maintenance of mature β-cell function. However, when β-cells are chronically exposed to hyperglycemia, expression and/or activities of such transcription factors are reduced, which [...] Read more.
A variety of pancreatic transcription factors including PDX-1 and MafA play crucial roles in the pancreas and function for the maintenance of mature β-cell function. However, when β-cells are chronically exposed to hyperglycemia, expression and/or activities of such transcription factors are reduced, which leads to deterioration of b-cell function. These phenomena are well known as β-cell glucose toxicity in practical medicine as well as in the islet biology research area. Here we describe the possible mechanism for β-cell glucose toxicity found in type 2 diabetes. It is likely that reduced expression levels of PDX-1 and MafA lead to suppression of insulin biosynthesis and secretion. In addition, expression levels of incretin receptors (GLP-1 and GIP receptors) in β-cells are decreased, which likely contributes to the impaired incretin effects found in diabetes. Taken together, down-regulation of insulin gene transcription factors and incretin receptors explains, at least in part, the molecular mechanism for β-cell glucose toxicity. Full article
(This article belongs to the Section Biochemistry)
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<p>Pancreas-related phenotype in knockout mice of each pancreatic transcription factor.</p> Full article ">Figure 2
<p>Pancreatic transcription factor hierarchy during pancreas development. It is well known that many transcription factors are involved in pancreas formation and β-cell differentiation. Among the various transcription factors, PDX-1 plays a crucial role in pancreas formation and β-cell differentiation, and maintenance of mature β-cell function. Ngn3 and NeuroD are also important transcription factors for pancreatic endocrine cell differentiation. MafA expression is induced at the final stage of β-cell differentiation and functions as a potent activator of insulin gene transcription.</p> Full article ">Figure 3
<p>Possible molecular mechanism for suppression of insulin biosynthesis in type 2 diabetes. Under diabetic conditions, hyperglycemia induces oxidative stress and thereby leads to suppression of insulin biosynthesis and secretion, which is accompanied by reduction of nuclear PDX-1 and MafA expression. Therefore, it is likely that induction of oxidative stress and suppression of nuclear PDX-1 and MafA expression are involved in β-cell glucose toxicity found in type 2 diabetes.</p> Full article ">Figure 4
<p>Role of incretin signaling in mature β-cells.</p> Full article ">Figure 5
<p>Down-regulation of incretin receptors in pancreatic β-cells under diabetic conditions. Under diabetic conditions, expression of incretin receptors (GLP-1 and GIP receptors) in β-cells are down-regulated, leading to decrease of insulin secretion, increase of β-cell apoptosis and decrease of β-cell growth. Therefore, it is likely that down-regulation of incretin receptor expression is involved in β-cell glucose toxicity found in type 2 diabetes.</p> Full article ">
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Article
DNA Synthesis during Endomitosis Is Stimulated by Insulin via the PI3K/Akt and TOR Signaling Pathways in the Silk Gland Cells of Bombyx mori
by Yaofeng Li, Xiangyun Chen, Xiaofang Tang, Chundong Zhang, La Wang, Peng Chen, Minhui Pan and Cheng Lu
Int. J. Mol. Sci. 2015, 16(3), 6266-6280; https://doi.org/10.3390/ijms16036266 - 18 Mar 2015
Cited by 14 | Viewed by 7354
Abstract
Silk gland cells undergo multiple endomitotic cell cycles during silkworm larval ontogeny. Our previous study demonstrated that feeding is required for continued endomitosis in the silk gland cells of silkworm larvae. Furthermore, the insulin signaling pathway is closely related to nutritional signals. To [...] Read more.
Silk gland cells undergo multiple endomitotic cell cycles during silkworm larval ontogeny. Our previous study demonstrated that feeding is required for continued endomitosis in the silk gland cells of silkworm larvae. Furthermore, the insulin signaling pathway is closely related to nutritional signals. To investigate whether the insulin signaling pathway is involved in endomitosis in silk gland cells, in this study, we initially analyzed the effects of bovine insulin on DNA synthesis in endomitotic silk gland cells using 5-bromo-2'-deoxyuridine (BrdU) labeling technology, and found that bovine insulin can stimulate DNA synthesis. Insulin signal transduction is mainly mediated via phosphoinositide 3-kinase (PI3K)/Akt, the target of rapamycin (TOR) and the extracellular signal-regulated kinase (ERK) pathways in vertebrates. We ascertained that these three pathways are involved in DNA synthesis in endomitotic silk gland cells using specific inhibitors against each pathway. Moreover, we investigated whether these three pathways are involved in insulin-stimulated DNA synthesis in endomitotic silk gland cells, and found that the PI3K/Akt and TOR pathways, but not the ERK pathway, are involved in this process. These results provide an important theoretical foundation for the further investigations of the mechanism underlying efficient endomitosis in silk gland cells. Full article
(This article belongs to the Section Biochemistry)
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<p>Effects of insulin on DNA synthesis in silk gland cells. (<b>A</b>) Concentration dependent effects <span class="html-italic">in vitro</span>; (<b>B</b>) Time-dependent effects <span class="html-italic">in vitro</span>; (<b>C</b>) Time-dependent effects <span class="html-italic">in vivo</span>; (<b>D</b>) Representative images of BrdU-labeled cells in the silk gland cells at 3 h after the injection of insulin. Scale bar: 100 µm. ASG: anterior silk gland; MSG: middle silk gland; PSG: posterior silk gland. <span class="html-italic">* p &lt;</span> 0.05.</p> Full article ">Figure 2
<p>Effects of the specific pathway inhibitors on DNA synthesis in silk gland cells. (<b>A</b>) Concentration dependent effects <span class="html-italic">in vitro</span>; (<b>B</b>) Time-dependent effects <span class="html-italic">in vitro</span>; (<b>C</b>) Effects of inhibitors <span class="html-italic">in vivo</span>; (<b>D</b>) Representative images of BrdU-labeled silk gland cells 24 h after injection with each specific inhibitor. Scale bar = 100 µm. ASG: anterior silk gland; MSG: middle silk gland; PSG: posterior silk gland. <span class="html-italic">* p &lt;</span> 0.05, ** <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">Figure 2 Cont.
<p>Effects of the specific pathway inhibitors on DNA synthesis in silk gland cells. (<b>A</b>) Concentration dependent effects <span class="html-italic">in vitro</span>; (<b>B</b>) Time-dependent effects <span class="html-italic">in vitro</span>; (<b>C</b>) Effects of inhibitors <span class="html-italic">in vivo</span>; (<b>D</b>) Representative images of BrdU-labeled silk gland cells 24 h after injection with each specific inhibitor. Scale bar = 100 µm. ASG: anterior silk gland; MSG: middle silk gland; PSG: posterior silk gland. <span class="html-italic">* p &lt;</span> 0.05, ** <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">Figure 3
<p>Insulin-activated DNA synthesis of silk gland cells is dependent on PI3K/Akt and TOR signaling, but not ERK signaling. The silk glands of day 1 fourth instar larvae were preincubated with LY294002 (48.8 μM), rapamycin (5.5 μM) or U0126 (21 μM) for 45 min and then incubated with medium containing insulin (1.74 μM) with or without LY294002 (48.8 μM) (<b>A</b>), rapamycin (5.5 μM) (<b>B</b>) or U0126 (21 μM) (<b>C</b>) for 1 h. The silk glands were labeled with BrdU and then analyzed. After preincubation for 45 min, the silk glands were incubated with medium containing 1.74 μM insulin with or without LY294002 (<b>D</b>), rapamycin (<b>E</b>) or U0126 (<b>F</b>) for 15 min. Silk gland lysates were prepared and subjected to an immunoblot analysis with their corresponding antibodies. The results shown are representative of three independent experiments. Con: control; Ins: insulin; LY: LY294002; R: rapamycin; U: U0126. <span class="html-italic">* p &lt;</span> 0.05.</p> Full article ">Figure 4
<p>The relationship of PI3K and TOR signaling in silk gland cells. (<b>A</b>) Effects of insulin-stimulated S6K and 4E-BP phosphorylation by LY294002; and (<b>B</b>) Effects of insulin-stimulated Akt phosphorylation by rapamycin. The results shown are representative of three independent experiments.</p> Full article ">Figure 5
<p>A predicted network that links the growth factor signaling pathways with silk gland cell DNA synthesis in the silkworm. Insulin activated silk gland DNA synthesis via PI3K/AKT/TOR signaling. MAPK/ERK signaling may be activated by other growth factor(s). Solid lines indicate demonstrable or highly likely relations; dashed lines indicate hypothetical interactions.</p> Full article ">
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Article
Prediction of Long-Term Treatment Response to Selective Serotonin Reuptake Inhibitors (SSRIs) Using Scalp and Source Loudness Dependence of Auditory Evoked Potentials (LDAEP) Analysis in Patients with Major Depressive Disorder
by Bun-Hee Lee, Young-Min Park, Seung-Hwan Lee and Miseon Shim
Int. J. Mol. Sci. 2015, 16(3), 6251-6265; https://doi.org/10.3390/ijms16036251 - 18 Mar 2015
Cited by 32 | Viewed by 6835
Abstract
Background: Animal and clinical studies have demonstrated that the loudness dependence of auditory evoked potentials (LDAEP) is inversely related to central serotonergic activity, with a high LDAEP reflecting weak serotonergic neurotransmission and vice versa, though the findings in humans have been less [...] Read more.
Background: Animal and clinical studies have demonstrated that the loudness dependence of auditory evoked potentials (LDAEP) is inversely related to central serotonergic activity, with a high LDAEP reflecting weak serotonergic neurotransmission and vice versa, though the findings in humans have been less consistent. In addition, a high pretreatment LDAEP appears to predict a favorable response to antidepressant treatments that augment the actions of serotonin. The aim of this study was to test whether the baseline LDAEP is correlated with response to long-term maintenance treatment in patients with major depressive disorder (MDD). Methods: Scalp N1, P2 and N1/P2 LDAEP and standardized low resolution brain electromagnetic tomography-localized N1, P2, and N1/P2 LDAEP were evaluated in 41 MDD patients before and after they received antidepressant treatment (escitalopram (n = 32, 10.0 ± 4.0 mg/day), sertraline (n = 7, 78.6 ± 26.7 mg/day), and paroxetine controlled-release formulation (n = 2, 18.8 ± 8.8 mg/day)) for more than 12 weeks. A treatment response was defined as a reduction in the Beck Depression Inventory (BDI) score of >50% between baseline and follow-up. Results: The responders had higher baseline scalp P2 and N1/P2 LDAEP than nonresponders (p = 0.017; p = 0.036). In addition, changes in total BDI score between baseline and follow-up were larger in subjects with a high baseline N1/P2 LDAEP than those with a low baseline N1/P2 LDAEP (p = 0.009). There were significantly more responders in the high-LDAEP group than in the low-LDAEP group (p = 0.041). Conclusions: The findings of this study reveal that a high baseline LDAEP is associated with a clinical response to long-term antidepressant treatment. Full article
(This article belongs to the Section Biochemistry)
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<p>The pretreatment N1/P2 loudness dependence of auditory evoked potentials (LDAEP) of responders and nonresponders (responders were defined as those with a reduction in the Beck Depression Inventory (BDI) score of &gt;50% between baseline and follow-up) among major depressive disorder (MDD) patients (<span class="html-italic">t</span> = −2.176, <span class="html-italic">p</span> = 0.036). The data are presented as mean and standard error values. <b>*</b> Statistically significant difference at <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 2
<p>The pretreatment left P2 standardized low resolution brain electromagnetic tomography (sLORETA)-LDAEP of remitters and nonremitters (remitters were defined as those with &lt;10 points in the post-treatment BDI score) among MDD patients (<span class="html-italic">t</span> = −2.095, <span class="html-italic">p</span> = 0.043). The data are presented as mean and standard error values. <b>*</b> Statistically significant difference at <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 3
<p>Changes in the total BDI score between baseline and follow-up in MDD patients dichotomized according to their pretreatment LDAEP (<span class="html-italic">i.e</span>., low or high). The change in total BDI score differed significantly between the low- and high-LDAEP groups (<span class="html-italic">t</span> = −2.741, <span class="html-italic">p</span> = 0.009). BDI change, change in BDI score from baseline to follow-up. <b>*</b> Statistically significant difference at <span class="html-italic">p</span> &lt; 0.01.</p> Full article ">
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Article
Abortive Infection of Snakehead Fish Vesiculovirus in ZF4 Cells Was Associated with the RLRs Pathway Activation by Viral Replicative Intermediates
by Wenwen Wang, Muhammad Asim, Lizhu Yi, Abeer M. Hegazy, Xianqin Hu, Yang Zhou, Taoshan Ai and Li Lin
Int. J. Mol. Sci. 2015, 16(3), 6235-6250; https://doi.org/10.3390/ijms16036235 - 18 Mar 2015
Cited by 25 | Viewed by 7781
Abstract
Snakehead fish vesiculovirus (SHVV) is a negative strand RNA virus which can cause great economic losses in fish culture. To facilitate the study of SHVV-host interactions, the susceptibility of zebrafish embryonic fibroblast cell line (ZF4) to the SHVV was investigated in this report. [...] Read more.
Snakehead fish vesiculovirus (SHVV) is a negative strand RNA virus which can cause great economic losses in fish culture. To facilitate the study of SHVV-host interactions, the susceptibility of zebrafish embryonic fibroblast cell line (ZF4) to the SHVV was investigated in this report. The results showed that high amount of viral mRNAs and cRNAs were detected at the 3 h post-infection. However, the expressions of the viral mRNAs and cRNA were decreased dramatically after 6 h post-infection. In addition, the expressions of interferon (IFN) and interferon-induced GTP-binding protein Mx were all up regulated significantly at the late stage of the infection. Meanwhile, the expressions of Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated gene 5 (MDA5) were also all up-regulated significantly during the infection. Two isoforms of DrLGP2 from zebrafish were also cloned and analyzed. Interestingly, the expression of DrLGP2a but not DrLGP2b was significantly up-regulated at both mRNA and protein levels, indicating that the two DrLGP2 isoforms might play different roles during the SHVV infection. Transfection experiment showed that viral replicative intermediates were required for the activation of IFN-α expression. Taken together, the abortive infection of SHVV in ZF4 cells was associated with the activation of RLRs pathway, which was activated by viral replicative intermediates. Full article
(This article belongs to the Special Issue Fish Molecular Biology)
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<p>Phylogenetic tree of the laboratory of genetics and physiology 2 (LGP2) from zebrafish and other species. The protein sequences used for phylogenetic analysis were Atlantic salmon LGP2 (<span class="html-italic">Salmo salar</span>, ACI33640.1), channel catfish (<span class="html-italic">Ictalurus punctatus</span>, AFS34610.1), chicken LGP2 (<span class="html-italic">Gallus gallus</span>, AEK21509.1), chimpanzee LGP2 (<span class="html-italic">Pan troglodytes</span>, JAA34322.1), cow LGP2 (<span class="html-italic">Bos taurus</span>, AAI46129.1), <span class="html-italic">crucian</span> LGP2 (Carassius auratus, AEN04474.1), flounder LGP2 (<span class="html-italic">Paralichthys olivaceus</span>, ADM18136.1), goat LGP2 (<span class="html-italic">Capra hircus</span>, XP_005693898.1), grass carp LGP2 (<span class="html-italic">Ctenopharyngodon idella</span>, AFQ93565.1), human LGP2 (<span class="html-italic">Homo sapiens</span>, NM_024119.2), mouse LGP2 (<span class="html-italic">Mus musculus</span>, NM_030150.2), rainbow trout LGP2a (<span class="html-italic">Oncorhynchus mykiss</span> splicevariant 1, CAZ27718.1), rainbow trout LGP2b (<span class="html-italic">Oncorhynchus mykiss</span> splice variant 2, CAZ27720.1), Xenopus LGP2 (<span class="html-italic">Xenopus laevis</span>, NP_001085915.1), zebrafish LGP2a (<span class="html-italic">Danio rerio</span>, KP341002), zebrafish LGP2b (<span class="html-italic">Danio rerio</span>, KP341003).</p> Full article ">Figure 2
<p>(<b>a</b>) Expression of viral N (Nucleoprotein) and G (Glycoprotein) genes mRNA in zebrafish embryonic fibroblast cell line (ZF4) with time after snakehead fish vesiculovirus (SHVV) infection. Expression was determined by qRT-PCR and β-actin was used as an internal control. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3). The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. The asterisk indicated a statistically significant difference (<b>**</b> <span class="html-italic">p</span> &lt; 0.01) compared with 0 h (set as 1); and (<b>b</b>) Expression of viral N and G genes cRNA in ZF4 with time after SHVV infection. Expression was determined by qRT-PCR and β-actin was used as an internal control. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3). The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. The asterisk indicated a statistically significant difference (<b>**</b> <span class="html-italic">p</span> &lt; 0.01) compared with 0 h (set as 1).</p> Full article ">Figure 3
<p>Expression of <span class="html-italic">Mx</span> and interferon (<span class="html-italic">IFN</span>) genes in ZF4 with time after SHVV infection. Expression was determined by qRT-PCR and β-actin was used as an internal control. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3). Fisher’s LSD test was performed. The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. The asterisk indicated a statistically significant difference (<b>**</b> <span class="html-italic">p</span> &lt; 0.01, <b>*</b> <span class="html-italic">p</span> &lt; 0.05) compared with 0 h (set as 1).</p> Full article ">Figure 4
<p>Expression of Retinoic acid-inducible gene I (<span class="html-italic">RIG-I</span>), Melanoma differentiation-associated gene 5 (<span class="html-italic">MDA5</span>), <span class="html-italic">LGP2T</span>, and <span class="html-italic">LGP2a</span> genes in ZF4 with time after SHVV infection. Expression was determined by qRT-PCR and β-actin was used as an internal control. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3). The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. The asterisk indicated a statistically significant difference (<b>**</b> <span class="html-italic">p</span> &lt; 0.01, <b>*</b> <span class="html-italic">p</span> &lt; 0.05) compared with 0 h (set as 1).</p> Full article ">Figure 5
<p>(<b>a</b>) The expression of DrLGP2a, DrLGP2b proteins during the infection with SHVV. The samples were harvested at 0, 3, 6, 12, 24 h post-infection and detected by Western blot. Expression of β-actin was used as the loading control .Molecular weight of DrLGP2a, DrLGP2b and β-actin was 77, 55, and 42 kD, respectively; (<b>b</b>) The relative expression of DrLGP2a <span class="html-italic">versus</span> DrLGP2b proteins infected with SHVV. The samples were harvested at 0, 3, 6, 12, 24 h post-infection and detected by Western blot. Expression of β-actin was used as the internal control. DrLGP2a/DrLGP2b means the amount of DrLGP2a was divided by DrLGP2b. The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3); and (<b>c</b>) The relative expression of DrLGP2a proteins infected with SHVV. The samples were harvested at 0, 3, 6, 12, 24 hpi and detected by Western blot. Expression of β-actin was used as the loading control. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3). The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. The asterisk indicated a statistically significant difference (<b>*</b> <span class="html-italic">p</span> &lt; 0.05) compared with 0 h (set as 1).</p> Full article ">Figure 5 Cont.
<p>(<b>a</b>) The expression of DrLGP2a, DrLGP2b proteins during the infection with SHVV. The samples were harvested at 0, 3, 6, 12, 24 h post-infection and detected by Western blot. Expression of β-actin was used as the loading control .Molecular weight of DrLGP2a, DrLGP2b and β-actin was 77, 55, and 42 kD, respectively; (<b>b</b>) The relative expression of DrLGP2a <span class="html-italic">versus</span> DrLGP2b proteins infected with SHVV. The samples were harvested at 0, 3, 6, 12, 24 h post-infection and detected by Western blot. Expression of β-actin was used as the internal control. DrLGP2a/DrLGP2b means the amount of DrLGP2a was divided by DrLGP2b. The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3); and (<b>c</b>) The relative expression of DrLGP2a proteins infected with SHVV. The samples were harvested at 0, 3, 6, 12, 24 hpi and detected by Western blot. Expression of β-actin was used as the loading control. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3). The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. The asterisk indicated a statistically significant difference (<b>*</b> <span class="html-italic">p</span> &lt; 0.05) compared with 0 h (set as 1).</p> Full article ">Figure 6
<p>Expression of the INF-α in ZF4 transfected with total RNA from ZF4 cultures either 3 or 24 h after SHVV infection. Data were shown as mean ± SE (<span class="html-italic">n</span> = 3). The data were submitted to one-way analysis of variance (one-way ANOVA) followed by Fisher’s LSD test using SPSS. The asterisk indicated a statistically significant difference (<b>**</b> <span class="html-italic">p</span> &lt; 0.01) compared with mock (set as 1).</p> Full article ">
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Article
Molecular Dynamics Simulations of Acylpeptide Hydrolase Bound to Chlorpyrifosmethyl Oxon and Dichlorvos
by Hanyong Jin, Zhenhuan Zhou, Dongmei Wang, Shanshan Guan and Weiwei Han
Int. J. Mol. Sci. 2015, 16(3), 6217-6234; https://doi.org/10.3390/ijms16036217 - 18 Mar 2015
Cited by 21 | Viewed by 6680
Abstract
Acylpeptide hydrolases (APHs) catalyze the removal of N-acylated amino acids from blocked peptides. Like other prolyloligopeptidase (POP) family members, APHs are believed to be important targets for drug design. To date, the binding pose of organophosphorus (OP) compounds of APH, as well [...] Read more.
Acylpeptide hydrolases (APHs) catalyze the removal of N-acylated amino acids from blocked peptides. Like other prolyloligopeptidase (POP) family members, APHs are believed to be important targets for drug design. To date, the binding pose of organophosphorus (OP) compounds of APH, as well as the different OP compounds binding and inducing conformational changes in two domains, namely, α/β hydrolase and β-propeller, remain poorly understood. We report a computational study of APH bound to chlorpyrifosmethyl oxon and dichlorvos. In our docking study, Val471 and Gly368 are important residues for chlorpyrifosmethyl oxon and dichlorvos binding. Molecular dynamics simulations were also performed to explore the conformational changes between the chlorpyrifosmethyl oxon and dichlorvos bound to APH, which indicated that the structural feature of chlorpyrifosmethyl oxon binding in APH permitted partial opening of the β-propeller fold and allowed the chlorpyrifosmethyl oxon to easily enter the catalytic site. These results may facilitate the design of APH-targeting drugs with improved efficacy. Full article
(This article belongs to the Special Issue Proteins and Protein-Ligand Interactions)
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Graphical abstract
Full article ">Figure 1
<p>The active triad of acylpeptide hydrolases (APH): Ser445, His556, and Asp524. Ser445, Gly369 and Tyr446 function as oxyanion hole. PDB Id (1VE7).</p> Full article ">Figure 2
<p>(<b>a</b>) The compartment between the docked ligand (green) and the reference for the crystal structure (red) located in the active site. Calculated by Autodock 4.2; (<b>b</b>) The compartment between the docked ligand (light blue) and the reference for the crystal structure (red) located in the active site. Calculated by Autodock vina; and (<b>c</b>) The compartment between the docked ligand (yellow) and the reference for the crystal structure (red) located in the active site. Calculated by CDOCKER.</p> Full article ">Figure 3
<p>Chemical structure of (<b>a</b>) Chlorpyrifosmethyl oxon; (<b>b</b>) Dichlorvos generated by CLY view v1.0.561 beta; (<b>c</b>) The LUMO orbit of chlorpyrifosmethyl oxon; and (<b>d</b>) The LUMO orbit of dichlorvos generated by Gaussian View 5.0.</p> Full article ">Figure 4
<p>(<b>a</b>) Surface area in each electrostatic potential (ESP) range on the vdW surface of chlorpyrifosmethyl oxon; (<b>b</b>) ESP-mapped molecular vdW surface of chlorpyrifosmethyl oxon; (<b>c</b>) Surface area in each ESP range on the vdW surface of dichlorvos; and (<b>d</b>) ESP-mapped molecular vdW surface of dichlorvos. The unit is in kcal·mol<sup>−1</sup>.</p> Full article ">Figure 5
<p>(<b>a</b>) chlorpyrifosmethyl oxon in the active pocket of APH; and (<b>b</b>) dichlorvos in the active pocket of APH drawn by LIGPLOT.</p> Full article ">Figure 6
<p>(<b>a</b>) Root-mean-square deviation (RMSD) plot of chlorpyrifosmethyl oxon (red) and dichlorvos (black) during 100 ns molecular dynamics (MD); (<b>b</b>) RMSD plot of α<b>/</b>β hydrolase domain (residues 8–23, 325–581) of chlorpyrifosmethyl oxon (black) and dichlorvos (red); and (<b>c</b>) RMSD plot of β-propeller domain (residues 24–324) of chlorpyrifosmethyl oxon (black) and dichlorvos (red).</p> Full article ">Figure 7
<p>(<b>a</b>) RMSF plot during 100 ns MD (residues 24–324 (β–propeller domain)). Color black represent for chlorpyrifosmethyl oxon, and color red represents for dichlorvos; and (<b>b</b>) RMSF plot during 100 ns MD (α<b>/</b>β hydrolase domain (residues 325–581)). Color black represent for chlorpyrifosmethyl oxon, and color red represents for dichlorvos.</p> Full article ">Figure 8
<p>(<b>a</b>) Radius of gyration (Rg) for the chlorpyrifosmethyl oxon (black) and dichlorvos (red) bound to APH; and (<b>b</b>) Solvent accessible surface area for the chlorpyrifosmethyl oxon (black) and dichlorvos (red) bound to APH.</p> Full article ">Figure 9
<p>Cross-correlation matrix of the fluctuations of each of the <span class="html-italic">x</span>, <span class="html-italic">y</span>, and <span class="html-italic">z</span> coordinates of the Cα atoms from their average during 100 ns MD (<b>a</b>) chlorpyrifosmethyl oxon; and (<b>b</b>) dichlorvos. Blue color represents the negative anticorrelation, green represents noncorrelated, random motions, and red represents positive correlation. The two figures were made using Adobe Illustrator CS5.</p> Full article ">Figure 10
<p>The relative Free energy surfaces along the first two principle components (PC-1, PC-2) of (<b>a</b>) chlorpyrifosmethyl oxon-APH; and (<b>b</b>) dichlorvos-APH during 100 ns generated by Sigma plot 12.0 (12.0, Systat software company, San Jose, CA, USA).</p> Full article ">
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Article
Effect of Chemical Treatments on Flax Fibre Reinforced Polypropylene Composites on Tensile and Dome Forming Behaviour
by Wentian Wang, Adrian Lowe and Shankar Kalyanasundaram
Int. J. Mol. Sci. 2015, 16(3), 6202-6216; https://doi.org/10.3390/ijms16036202 - 17 Mar 2015
Cited by 10 | Viewed by 4827
Abstract
Tensile tests were performed on two different natural fibre composites (same constituent material, similar fibre fraction and thickness but different weave structure) to determine changes in mechanical properties caused by various aqueous chemical treatments and whether any permanent changes remain on drying. Scanning [...] Read more.
Tensile tests were performed on two different natural fibre composites (same constituent material, similar fibre fraction and thickness but different weave structure) to determine changes in mechanical properties caused by various aqueous chemical treatments and whether any permanent changes remain on drying. Scanning electronic microscopic examinations suggested that flax fibres and the flax/polypropylene interface were affected by the treatments resulting in tensile property variations. The ductility of natural fibre composites was improved significantly under wet condition and mechanical properties (elongation-to-failure, stiffness and strength) can almost retain back to pre-treated levels when dried from wet condition. Preheating is usually required to improve the formability of material in rapid forming, and the chemical treatments performed in this study were far more effective than preheating. The major breakthrough in improving the formability of natural fibre composites can aid in rapid forming of this class of material system. Full article
(This article belongs to the Special Issue Advances in Anisotropic and Smart Materials)
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<p>The rate of solution uptake (<b>a</b>); and subsequent moisture egress from saturation (<b>b</b>) for the CNFC rectangular samples.</p> Full article ">Figure 2
<p>The rate of solution uptake (<b>a</b>); and subsequent moisture egress from saturation (<b>b</b>) for the NFC rectangular samples.</p> Full article ">Figure 3
<p>Optical micrographs of CNFC composite (<b>a</b>,<b>c</b>) and the NFC composite (<b>b</b>,<b>d</b>). The images (<b>a</b>) and (<b>b</b>) are of the composite surface whilst the images (<b>c</b>) and (<b>d</b>) are of the centre cross-section region.</p> Full article ">Figure 3 Cont.
<p>Optical micrographs of CNFC composite (<b>a</b>,<b>c</b>) and the NFC composite (<b>b</b>,<b>d</b>). The images (<b>a</b>) and (<b>b</b>) are of the composite surface whilst the images (<b>c</b>) and (<b>d</b>) are of the centre cross-section region.</p> Full article ">Figure 4
<p>Tensile property data for CNFC samples under various aqueous treatments showing (<b>a</b>) elongation; (<b>b</b>) stiffness and (<b>c</b>) strength.</p> Full article ">Figure 5
<p>Variations in mechanical properties of the NFC under different chemical treatments obtained through tensile tests, (<b>a</b>) elongation; (<b>b</b>) stiffness and (<b>c</b>) strength.</p> Full article ">Figure 5 Cont.
<p>Variations in mechanical properties of the NFC under different chemical treatments obtained through tensile tests, (<b>a</b>) elongation; (<b>b</b>) stiffness and (<b>c</b>) strength.</p> Full article ">Figure 6
<p>Electron microscope images of CNFC showing (<b>a</b>) untreated; (<b>b</b>) saturated and (<b>c</b>) redried samples that have been fractured under tensile tests.</p> Full article ">Figure 7
<p>Images of the untreated, saturated and dried CNFC (from left to right) after stamp forming experiments from, (<b>a</b>) top view; and (<b>b</b>) front view.</p> Full article ">Figure 8
<p>Images of the untreated, saturated and dried NFC (from left to right) after stamp forming experiments from, (<b>a</b>) top view; and (<b>b</b>) front view.</p> Full article ">Figure 9
<p>A comparison of the forming depth in stamp forming between the CNFC and the NFC.</p> Full article ">
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Review
DNA Damage: A Sensible Mediator of the Differentiation Decision in Hematopoietic Stem Cells and in Leukemia
by Cary N. Weiss and Keisuke Ito
Int. J. Mol. Sci. 2015, 16(3), 6183-6201; https://doi.org/10.3390/ijms16036183 - 17 Mar 2015
Cited by 27 | Viewed by 9780
Abstract
In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to [...] Read more.
In the adult, the source of functionally diverse, mature blood cells are hematopoietic stem cells, a rare population of quiescent cells that reside in the bone marrow niche. Like stem cells in other tissues, hematopoietic stem cells are defined by their ability to self-renew, in order to maintain the stem cell population for the lifetime of the organism, and to differentiate, in order to give rise to the multiple lineages of the hematopoietic system. In recent years, increasing evidence has suggested a role for the accumulation of reactive oxygen species and DNA damage in the decision for hematopoietic stem cells to exit quiescence and to differentiate. In this review, we will examine recent work supporting the idea that detection of cell stressors, such as oxidative and genetic damage, is an important mediator of cell fate decisions in hematopoietic stem cells. We will explore the benefits of such a system in avoiding the development and progression of malignancies, and in avoiding tissue exhaustion and failure. Additionally, we will discuss new work that examines the accumulation of DNA damage and replication stress in aging hematopoietic stem cells and causes us to rethink ideas of genoprotection in the bone marrow niche. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2014)
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<p>The ROS rheostat of hematopoietic stem cell (HSC) maintenance. Accumulation of DNA damage and genotoxic oxidative stress contributes to a common pathway that leads to loss of self-renewal capacity of HSCs and leads HSCs to exit their quiescent state. This contributes to the gradual decline of functional HSCs in the bone marrow. Mixed lineage leukemia 4 (MLL4) activates forkhead box O (FoxO) targets through an unknown mechanism, and MLL4 expression is shown to be protective in the MLL1-AF9 (ALL1-fused gene from chromosome 9, or MLLT3) of AML by reducing the accumulation of ROS and, thus, DNA damage. <span class="html-italic">Mll4</span>-deficiency may also contribute to DNA damage through a ROS-independent mechanism. DNA damage results in the activation of ATM and, subsequently, DDR. Accumulation of γH2AX and co-localization with 53BP1 serve as markers of DDR, as in Flach, <span class="html-italic">et al.</span> Under normal conditions, ATM helps to maintain ROS at low levels. However, in the face of severe DNA damage ATM contributes to the accumulation of ROS and loss of quiescence in HSCs. ATM, ataxia telangiectasia mutated; FoxO, forkhead box O; DDR, DNA damage response; γH2AX, phosphorylated histone H2AX; MLL4, mixed-lineage leukemia 4; mitoBID, mitochondrial BH3 interacting-domain death agonist; MLL4, mixed-lineage leukemia 4; p38 MAPK, p38 mitogen-activated protein kinases; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; SOD2, superoxide dismutase 2; TP53BP1, tumor suppressor p53-binding protein 1. p16INK4A, cyclin dependent kinase inhibitor 2A; AKT, protein kinase 3. Solid arrows represent known mechanisms; dashed arrows labeled with question marks represent unknown mechanisms.</p> Full article ">Figure 2
<p>The alkaline comet assay. The alkaline comet assay allows for the direct microscopic measurement of DNA damage. Isolated cells are mixed with low-temperature gelling agarose and applied to a glass slide. Cells are lysed under alkaline conditions in order to detect single and double strand breaks, though a number of lysis procedures have been described for other purposes. After a brief electrophoresis and staining, DNA damage can be visualized microscopically. High molecular weight DNA, reflecting undamaged DNA, remains in the comet, whereas damaged DNA is susceptible to the electrophoretic field and is found in the tail. A number of methods for quantifying and describing the tail to comet relationship have been described. In Beerman, <span class="html-italic">et al.</span> the authors describe a higher frequency of HSCs with moderate-to-severe DNA damage in aged mice as compared to younger mice [<a href="#B28-ijms-16-06183" class="html-bibr">28</a>]. Damage is also more severe among aged hematopoietic stem cells as compared to aged hematopoietic progenitors.</p> Full article ">
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Review
New Therapies for Dedifferentiated Papillary Thyroid Cancer
by Poupak Fallahi, Valeria Mazzi, Roberto Vita, Silvia Martina Ferrari, Gabriele Materazzi, David Galleri, Salvatore Benvenga, Paolo Miccoli and Alessandro Antonelli
Int. J. Mol. Sci. 2015, 16(3), 6153-6182; https://doi.org/10.3390/ijms16036153 - 17 Mar 2015
Cited by 48 | Viewed by 9905
Abstract
The number of thyroid cancers is increasing. Standard treatment usually includes primary surgery, thyroid-stimulating hormone suppressive therapy, and ablation of the thyroid remnant with radioactive iodine (RAI). Despite the generally good prognosis of thyroid carcinoma, about 5% of patients will develop metastatic disease, [...] Read more.
The number of thyroid cancers is increasing. Standard treatment usually includes primary surgery, thyroid-stimulating hormone suppressive therapy, and ablation of the thyroid remnant with radioactive iodine (RAI). Despite the generally good prognosis of thyroid carcinoma, about 5% of patients will develop metastatic disease, which fails to respond to RAI, exhibiting a more aggressive behavior. The lack of specific, effective and well-tolerated drugs, the scarcity of data about the association of multi-targeting drugs, and the limited role of radioiodine for dedifferentiated thyroid cancer, call for further efforts in the field of new drugs development. Rearranged during transfection (RET)/papillary thyroid carcinoma gene rearrangements, BRAF (B-RAF proto-oncogene, serine/threonine kinase) gene mutations, RAS (rat sarcoma) mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways playing a crucial role in the development of thyroid cancer. Targeted novel compounds have been demonstrated to induce clinical responses and stabilization of disease. Sorafenib has been approved for differentiated thyroid cancer refractory to RAI. Full article
(This article belongs to the Special Issue Advances in Molecular Oncology 2014)
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<p>Molecular targets and tyrosine kinase inhibitors in the signaling pathways involved in dedifferentiated papillary thyroid cancer.</p> Full article ">
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Article
Polyoxygenated Cembrane Diterpenoids from the Soft Coral Sarcophyton ehrenbergi
by Shi-Yie Cheng, Shang-Kwei Wang, Mu-Keng Hsieh and Chang-Yih Duh
Int. J. Mol. Sci. 2015, 16(3), 6140-6152; https://doi.org/10.3390/ijms16036140 - 17 Mar 2015
Cited by 14 | Viewed by 5365
Abstract
Five new polyoxygenated cembranoids, named (+)-1,15-epoxy-2-methoxy-12-methoxycarbonyl-11E-sarcophytoxide (1), (+)-2-epi-12-methoxycarbonyl-11E-sarcophine (2), 3,4-epoxyehrenberoxide A (3), ehrenbergol D (4) and ehrenbergol E (5), were obtained from the soft coral Sarcophyton ehrenbergi [...] Read more.
Five new polyoxygenated cembranoids, named (+)-1,15-epoxy-2-methoxy-12-methoxycarbonyl-11E-sarcophytoxide (1), (+)-2-epi-12-methoxycarbonyl-11E-sarcophine (2), 3,4-epoxyehrenberoxide A (3), ehrenbergol D (4) and ehrenbergol E (5), were obtained from the soft coral Sarcophyton ehrenbergi. The structures of 1–5 were established on the basis of comprehensive NMR and HR-ESI-MS analyses and by comparison with reported data in the literature. Compounds 4 and 5 showed moderate cytotoxicity against P-388 (mouse lymphocytic leukemia) cancer cell line with EC50 values of 2.0 and 3.0 μM, respectively. Compound 2 exhibited slight antiviral activity against HCMV (human cytomegalovirus) with IC50 values of 25.0 μg/mL. Full article
(This article belongs to the Section Biochemistry)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>The structures of (+)-1,15-epoxy-2-methoxy-12-methoxycarbonyl-11<span class="html-italic">E</span>-sarcophytoxide (<b>1</b>), (+)-2-<span class="html-italic">epi</span>-12-methoxycarbonyl-11<span class="html-italic">E</span>-sarcophine (<b>2</b>), 3,4-epoxyehrenberoxide A (<b>3</b>), ehrenbergol D (<b>4</b>) and ehrenbergol E (<b>5</b>).</p> Full article ">Figure 2
<p>Selected <sup>1</sup>H−<sup>1</sup>H COSY (▬) and HMBC (→) correlations of <b>1</b>, <b>3</b> and <b>4</b>.</p> Full article ">Figure 3
<p>Selected NOESY correlations and computer-generated perspective model using MM2 force field calculations for <b>1</b>.</p> Full article ">Figure 4
<p>Selected NOESY correlations and computer-generated perspective model using MM2 force field calculations for <b>3</b>.</p> Full article ">Figure 5
<p>Selected NOESY correlations and computer-generated perspective model using MM2 force field calculations for <b>4</b>.</p> Full article ">
1068 KiB  
Review
Chemopreventive Potential of Green Tea Catechins in Hepatocellular Carcinoma
by Masahito Shimizu, Yohei Shirakami, Hiroyasu Sakai, Masaya Kubota, Takahiro Kochi, Takayasu Ideta, Tsuneyuki Miyazaki and Hisataka Moriwaki
Int. J. Mol. Sci. 2015, 16(3), 6124-6139; https://doi.org/10.3390/ijms16036124 - 17 Mar 2015
Cited by 43 | Viewed by 8943
Abstract
Hepatocellular carcinoma (HCC), which is a common malignancy worldwide, usually develops in a cirrhotic liver due to hepatitis virus infection. Metabolic syndrome, which is frequently complicated by obesity and diabetes mellitus, is also a critical risk factor for liver carcinogenesis. Green tea catechins [...] Read more.
Hepatocellular carcinoma (HCC), which is a common malignancy worldwide, usually develops in a cirrhotic liver due to hepatitis virus infection. Metabolic syndrome, which is frequently complicated by obesity and diabetes mellitus, is also a critical risk factor for liver carcinogenesis. Green tea catechins (GTCs) may possess potent anticancer and chemopreventive properties for a number of different malignancies, including liver cancer. Antioxidant and anti-inflammatory activities are key mechanisms through which GTCs prevent the development of neoplasms, and they also exert cancer chemopreventive effects by modulating several signaling transduction and metabolic pathways. Furthermore, GTCs are considered to be useful for the prevention of obesity- and metabolic syndrome-related carcinogenesis by improving metabolic disorders. Several interventional trials in humans have shown that GTCs may ameliorate metabolic abnormalities and prevent the development of precancerous lesions. The purpose of this article is to review the key mechanisms by which GTCs exert chemopreventive effects in liver carcinogenesis, focusing especially on their ability to inhibit receptor tyrosine kinases and improve metabolic abnormalities. We also review the evidence for GTCs acting to prevent metabolic syndrome-associated liver carcinogenesis. Full article
(This article belongs to the Special Issue Bioactive Phytochemicals in Functional Foods for Cancer Prevention)
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Figure 1
<p>Proposed mechanisms linking metabolic syndrome and liver carcinogenesis. The black arrows at the right corner mean the incidence of hepatocellular carcinoma (HCC) is up-regulated.</p> Full article ">Figure 2
<p>Mechanisms of action of GTCs in the inhibition of metabolic syndrome-related liver carcinogenesis. Metabolic syndrome significantly increases the risk of HCC development. Several pathophysiological mechanisms link metabolic syndrome and liver carcinogenesis, such as insulin resistance, activation of the IGF/IGF-1R axis, chronic inflammation, oxidative stress, and adipokine dysbalance. They appear to be followed by molecular abnormality, including activation of PI3K/Akt and MAPK/ERK signaling, down-regulated phosphorylated-AMPK, and increased pro-inflammatory cytokines. Administration of GTCs significantly reduces the risk of HCC development in obese patients, and this might be associated with decreased insulin resistance and hepatic steatosis, inhibition of the activation of the IGF/IGF-1R axis, and attenuation of oxidative stress and chronic inflammation. Up- and down-pointing solid arrows mean items are up- and down-regulated, respectively.</p> Full article ">
5110 KiB  
Article
In Vitro Corrosion and Cytocompatibility Properties of Nano-Whisker Hydroxyapatite Coating on Magnesium Alloy for Bone Tissue Engineering Applications
by Huawei Yang, Xueyu Yan, Min Ling, Zuquan Xiong, Caiwen Ou and Wei Lu
Int. J. Mol. Sci. 2015, 16(3), 6113-6123; https://doi.org/10.3390/ijms16036113 - 17 Mar 2015
Cited by 24 | Viewed by 6802
Abstract
We report here the successful fabrication of nano-whisker hydroxyapatite (nHA) coatings on Mg alloy by using a simple one-step hydrothermal process in aqueous solution. The nHA coating shows uniform structure and high crystallinity. Results indicate that nHA coating is promising for improving the [...] Read more.
We report here the successful fabrication of nano-whisker hydroxyapatite (nHA) coatings on Mg alloy by using a simple one-step hydrothermal process in aqueous solution. The nHA coating shows uniform structure and high crystallinity. Results indicate that nHA coating is promising for improving the in vitro corrosion and cytocompatibility properties of Mg-based implants and devices for bone tissue engineering. In addition, the simple hydrothermal deposition method used in the current study is also applicable to substrates with complex shapes or surface geometries. Full article
(This article belongs to the Special Issue Biomaterials for Tissue Engineering)
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<p>X-ray diffraction (XRD) patterns of uncoated and nano-whisker hydroxyapatite (nHA) coated ZK60 samples (a.u and deg. are the abbreviation of arbitrary unit and degree, respectively).</p> Full article ">Figure 2
<p>Schematic illustration of the reaction mechanism of calcium phosphate coatings on ZK60 substrate. (1) Anode reaction; (2) Cathode reaction; (3) Transformation of H<sub>2</sub>PO<sub>4</sub><sup>−</sup> to PO<sub>4</sub><sup>3−</sup>; and (4) HA phase producing process.</p> Full article ">Figure 3
<p>SEM images with different magnifications of nHA coatings on ZK60 substrate. (<b>a</b>) Integral morphology of the HA coatings; (<b>b</b>) Middle magnification SEM image; (<b>c</b>) High magnification SEM image; and (<b>d</b>) Bilayer structure of HA.</p> Full article ">Figure 4
<p>Potentiodynamic polarization curves of uncoated and nHA coated ZK60 samples.</p> Full article ">Figure 5
<p>Variation of pH value of immersion solution at different immersion time of uncoated and nHA coated ZK60 samples.</p> Full article ">Figure 6
<p>Surface morphologies of uncoated and nHA coated ZK60 samples after immersion test for 7 days. (<b>a</b>) Uncoated ZK60; and (<b>b</b>) nHA coated sample.</p> Full article ">Figure 7
<p>Cell viability cultured in individual extraction mediums of uncoated and nHA coated ZK60 samples.</p> Full article ">
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