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International Journal of Molecular Sciences
Journal Prestige (SJR): 1.26
Citation Impact (citeScore): 4
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  This is an Open Access Journal Open Access journal
ISSN (Print) 1661-6596 - ISSN (Online) 1422-0067
Published by MDPI Homepage  [205 journals]
  • IJMS, Vol. 19, Pages 1573: Bioactivities of Phenolics by Focusing on
           Suppression of Chronic Diseases: A Review

    • Authors: Fereidoon Shahidi, JuDong Yeo
      First page: 1573
      Abstract: Phenolics, which are secondary metabolites of plants, exhibit remarkable bioactivities. In this contribution, we have focused on their protective effect against chronic diseases rather than their antioxidant activities, which have been widely discussed in the literature. A large body of epidemiological studies has proven the bioactivities of phenolics in both standard compounds and natural extracts: namely, anticancer, anti-inflammatory, and antibacterial activities as well as reducing diabetes, cardiovascular disease, and neurodegenerative disease. Phenolics also display anti-analgesic, anti-allergic, and anti-Alzheimer’s properties. Thus, this review provides crucial information for better understanding the bioactivities of phenolics in foods and fills a gap in the existing collective and overall knowledge in the field.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061573
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1574: The Extracts and Major Compounds Derived from
           Astragali Radix Alter Mitochondrial Bioenergetics in Cultured
           Cardiomyocytes: Comparison of Various Polar Solvents and Compounds

    • Authors: Yun Huang, Kenneth Kin Leung Kwan, Ka Wing Leung, Huaiyou Wang, Xiang Peng Kong, Tina Ting Xia Dong, Karl Wah Keung Tsim
      First page: 1574
      Abstract: Astragali Radix (AR) is a widely used “Qi-invigorating” herb in China for its tonic effects in strengthening biological tissues. The extract of AR contains abundant antioxidants, including astragalosides and isoflavonoids. However, very few reports have systematically measured the effects of the major components of AR on cell mitochondrial bioenergetics. Here, a systemic approach employing an extracellular flux analyzer was developed to evaluate mitochondrial respiration in cultured cardiomyocyte cells H9C2. The effects of different polar extractives, as well as of the major compounds of AR, were compared. The contents of astragaloside IV, calycosin, formononetin, and genistein in the AR extracts obtained by using water, 50% ethanol, and 90% ethanol were measured by liquid chromatograph-mass spectrometer (LC–MS). The antioxidant activities of the AR extracts, as well as of their major compounds, were determined by measuring the free radical scavenging activity and protective effects in tert-butyl hydroperoxide (tBHP)-treated H9C2 cells. By monitoring the real-time oxygen consumption rate (OCR) in tBHP-treated cardiomyocytes with a Seahorse extracellular flux analyzer, the tonic effects of the AR extracts and of their main compounds on mitochondrial bioenergetics were evaluated. AR water extracts possessed the strongest antioxidant activity and protective effects in cardiomyocytes exposed to oxidative stress. The protection was proposed to be mediated via increasing the spare respiratory capacity and mitochondrial ATP production in the stressed cells. The major compounds of AR, astragaloside IV and genistein, showed opposite effects in regulating mitochondrial bioenergetics. These results demonstrate that highly polar extracts of AR, especially astragaloside-enriched extracts, possess better tonic effects on mitochondrial bioenergetics of cultured cardiomyocytes than extracts with a lower polarity.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061574
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1575: Regulation of Immune Cell Function by PPARs and
           the Connection with Metabolic and Neurodegenerative Diseases

    • Authors: Gwenaëlle Le Menn, Jaap G. Neels
      First page: 1575
      Abstract: Increasing evidence points towards the existence of a bidirectional interconnection between metabolic disease and neurodegenerative disorders, in which inflammation is linking both together. Activation of members of the peroxisome proliferator-activated receptor (PPAR) family has been shown to have beneficial effects in these interlinked pathologies, and these improvements are often attributed to anti-inflammatory effects of PPAR activation. In this review, we summarize the role of PPARs in immune cell function, with a focus on macrophages and T cells, and how this was shown to contribute to obesity-associated inflammation and insulin resistance, atherosclerosis, and neurodegenerative disorders. We address gender differences as a potential explanation in observed contradictory results, and we highlight PPAR-induced metabolic changes as a potential mechanism of regulation of immune cell function through these nuclear receptors. Together, immune cell-specific activation of PPARs present a promising therapeutic approach to treat both metabolic and neurodegenerative diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061575
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1576: Novel Safranin-Tinted Candida rugosa Lipase
           Nanoconjugates Reagent for Visualizing Latent Fingerprints on Stainless
           Steel Knives Immersed in a Natural Outdoor Pond

    • Authors: Aida Rasyidah Azman, Naji Arafat Mahat, Roswanira Abdul Wahab, Fazira Ilyana Abdul Razak, Hafezul Helmi Hamzah
      First page: 1576
      Abstract: Waterways are popular locations for the disposition of criminal evidence because the recovery of latent fingerprints from such evidence is difficult. Currently, small particle reagent is a method often used to visualize latent fingerprints containing carcinogenic and hazardous compounds. This study proposes an eco-friendly, safranin-tinted Candida rugosa lipase (triacylglycerol ester hydrolysis EC 3.1.1.3) with functionalized carbon nanotubes (CRL-MWCNTS/GA/SAF) as an alternative reagent to the small particle reagent. The CRL-MWCNTS/GA/SAF reagent was compared with the small particle reagent to visualize groomed, full fingerprints deposited on stainless steel knives which were immersed in a natural outdoor pond for 30 days. The quality of visualized fingerprints using the new reagent was similar (modified-Centre for Applied Science and Technology grade: 4; p > 0.05) to small particle reagent, even after 15 days of immersion. Despite the slight decrease in quality of visualized fingerprints using the CRL-MWCNTS/GA/SAF on the last three immersion periods, the fingerprints remained forensically identifiable (modified-Centre for Applied Science and Technology grade: 3). The possible chemical interactions that enabled successful visualization is also discussed. Thus, this novel reagent may provide a relatively greener alternative for the visualization of latent fingerprints on immersed non-porous objects.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061576
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1577: Structural Basis for Mutations of Human
           Aquaporins Associated to Genetic Diseases

    • Authors: Luisa Calvanese, Gabriella D’Auria, Anna Vangone, Lucia Falcigno, Romina Oliva
      First page: 1577
      Abstract: Aquaporins (AQPs) are among the best structural-characterized membrane proteins, fulfilling the role of allowing water flux across cellular membranes. Thus far, 34 single amino acid polymorphisms have been reported in HUMSAVAR for human aquaporins as disease-related. They affect AQP2, AQP5 and AQP8, where they are associated with nephrogenic diabetes insipidus, keratoderma and colorectal cancer, respectively. For half of these mutations, although they are mostly experimentally characterized in their dysfunctional phenotypes, a structural characterization at a molecular level is still missing. In this work, we focus on such mutations and discuss what the structural defects are that they appear to cause. To achieve this aim, we built a 3D molecular model for each mutant and explored the effect of the mutation on all of their structural features. Based on these analyses, we could collect the structural defects of all the pathogenic mutations (here or previously analysed) under few main categories, that we found to nicely correlate with the experimental phenotypes reported for several of the analysed mutants. Some of the structural analyses we present here provide a rationale for previously experimentally observed phenotypes. Furthermore, our comprehensive overview can be used as a reference frame for the interpretation, on a structural basis, of defective phenotypes of other aquaporin pathogenic mutants.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061577
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1578: Natural Products for Drug Discovery in the 21st
           Century: Innovations for Novel Drug Discovery

    • Authors: Nicholas Ekow Thomford, Dimakatso Alice Senthebane, Arielle Rowe, Daniella Munro, Palesa Seele, Alfred Maroyi, Kevin Dzobo
      First page: 1578
      Abstract: The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of “active compound” has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of ‘organ-on chip’ and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review discusses plant-based natural product drug discovery and how innovative technologies play a role in next-generation drug discovery.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061578
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1579: Nanomotors for Nucleic Acid, Proteins,
           Pollutants and Cells Detection

    • Authors: Alejandro Baeza, María Vallet-Regí
      First page: 1579
      Abstract: The development of nanomachines able to operate at the nanoscale, performing complex tasks such as drug delivery, precision surgery, or cell detection, constitutes one of the most important challenges in nanotechnology. The principles that rule the nanoscale are completely different from the ones which govern the macroscopic world and, therefore, the collaboration of scientists with expertise in different fields is required for the effective fabrication of these tiny machines. In this review, the most recent advances carried out in the synthesis and application of nanomachines for diagnosis applications will be presented in order to provide a picture of their potential in the detection of important biomolecules or pathogens in a selective and controlled manner.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061579
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1580: Increased Phenacetin Oxidation upon the L382V
           Substitution in Cytochrome P450 1A2 is Associated with Altered Substrate
           Binding Orientation

    • Authors: Qingbiao Huang, Grazyna D. Szklarz
      First page: 1580
      Abstract: Leucine382 of cytochrome P450 1A2 (CYP1A2) plays an important role in binding and O-dealkylation of phenacetin, with the L382V mutation increasing substrate oxidation (Huang and Szklarz, 2010, Drug Metab. Dispos. 38:1039–1045). This was attributed to altered substrate binding orientation, but no direct experimental evidence had been available. Therefore, in the current studies, we employed nuclear magnetic resonance (NMR) longitudinal (T1) relaxation measurements to investigate phenacetin binding orientations within the active site of CYP1A2 wild type (WT) and mutants. Paramagnetic relaxation time (T1P) for each proton of phenacetin was calculated from the T1 value obtained from the enzymes in ferric and ferrous-CO state in the presence of phenacetin, and used to model the orientation of phenacetin in the active site. All aromatic protons of phenacetin were nearly equidistant from the heme iron (6.34–8.03 Å). In contrast, the distance between the proton of the –OCH2– group, which is abstracted during phenacetin oxidation, and the heme iron, was much shorter in the L382V (5.93 Å) and L382V/N312L (5.96 Å) mutants compared to the N312L mutant (7.84 Å) and the wild type enzyme (6.55 Å), consistent with modeling results. These studies provide direct evidence for the molecular mechanism underlying increased oxidation of phenacetin upon the L382V mutation.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-25
      DOI: 10.3390/ijms19061580
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1581: Stimulatory Effects of Melatonin on Porcine In
           Vitro Maturation Are Mediated by MT2 Receptor

    • Authors: Sanghoon Lee, Jun-Xue Jin, Anukul Taweechaipaisankul, Geon-A Kim, Byeong-Chun Lee
      First page: 1581
      Abstract: Melatonin is a multifunctional molecule with numerous biological activities. The fact that melatonin modulates the functions of porcine granulosa cells via the MT2 receptor suggests the possibility of MT2 receptor-mediation for melatonin to promote cumulus expansion of porcine cumulus-oocyte complexes (COCs). Therefore, we investigated the presence of MT2 in porcine COCs, and the effects of melatonin with or without selective MT2 antagonists (luzindole and 4-P-PDOT) on this process; COCs underwent in vitro maturation culturing with six different conditions (control, melatonin, luzindole, 4-P-PDOT, melatonin + luzindole or melatonin + 4-P-PDOT). Cumulus expansion, oocyte nuclear maturation, and subsequent embryo development after parthenogenetic activation (PA) were evaluated. In experiment 1, MT2 was expressed in both oocytes and cumulus cells. In experiment 2, melatonin significantly increased the proportion of complete cumulus expansion (degree 4), which was inhibited by simultaneous addition of either luzindole or 4-P-PDOT. A similar pattern was observed in the expression of genes related to cumulus expansion, apoptosis, and MT2. In experiment 3, no significant difference was observed in immature, degenerate, and MII oocyte rates among the groups. In experiment 4, melatonin significantly increased blastocyst formation rates and total blastocyst cell numbers after PA, but these effects were abolished when either luzindole or 4-P-PDOT was added concomitantly. In conclusion, our results indicate that the MT2 receptor mediated the stimulatory effects of melatonin on porcine cumulus expansion and subsequent embryo development.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-26
      DOI: 10.3390/ijms19061581
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1582: The Organization of Mitochondrial
           Supercomplexes is Modulated by Oxidative Stress In Vivo in Mouse Models of
           Mitochondrial Encephalopathy

    • Authors: Mir R. Anwar, Amy Saldana-Caboverde, Sofia Garcia, Francisca Diaz
      First page: 1582
      Abstract: We examine the effect of oxidative stress on the stability of mitochondrial respiratory complexes and their association into supercomplexes (SCs) in the neuron-specific Rieske iron sulfur protein (RISP) and COX10 knockout (KO) mice. Previously we reported that these two models display different grades of oxidative stress in distinct brain regions. Using blue native gel electrophoresis, we observed a redistribution of the architecture of SCs in KO mice. Brain regions with moderate levels of oxidative stress (cingulate cortex of both COX10 and RISP KO and hippocampus of the RISP KO) showed a significant increase in the levels of high molecular weight (HMW) SCs. High levels of oxidative stress in the piriform cortex of the RISP KO negatively impacted the stability of CI, CIII and SCs. Treatment of the RISP KO with the mitochondrial targeted antioxidant mitoTEMPO preserved the stability of respiratory complexes and formation of SCs in the piriform cortex and increased the levels of glutathione peroxidase. These results suggest that mild to moderate levels of oxidative stress can modulate SCs into a more favorable architecture of HMW SCs to cope with rising levels of free radicals and cover the energetic needs.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-26
      DOI: 10.3390/ijms19061582
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1583: Genome-Wide Identification and Expression
           Analysis of the UGlcAE Gene Family in Tomato

    • Authors: Xing Ding, Jinhua Li, Yu Pan, Yue Zhang, Lei Ni, Yaling Wang, Xingguo Zhang
      First page: 1583
      Abstract: The UGlcAE has the capability of interconverting UDP-d-galacturonic acid and UDP-d-glucuronic acid, and UDP-d-galacturonic acid is an activated precursor for the synthesis of pectins in plants. In this study, we identified nine UGlcAE protein-encoding genes in tomato. The nine UGlcAE genes that were distributed on eight chromosomes in tomato, and the corresponding proteins contained one or two trans-membrane domains. The phylogenetic analysis showed that SlUGlcAE genes could be divided into seven groups, designated UGlcAE1 to UGlcAE6, of which the UGlcAE2 were classified into two groups. Expression profile analysis revealed that the SlUGlcAE genes display diverse expression patterns in various tomato tissues. Selective pressure analysis indicated that all of the amino acid sites of SlUGlcAE proteins are undergoing purifying selection. Fifteen stress-, hormone-, and development-related elements were identified in the upstream regions (0.5 kb) of these SlUGlcAE genes. Furthermore, we investigated the expression patterns of SlUGlcAE genes in response to three hormones (indole-3-acetic acid (IAA), gibberellin (GA), and salicylic acid (SA)). We detected firmness, pectin contents, and expression levels of UGlcAE family genes during the development of tomato fruit. Here, we systematically summarize the general characteristics of the SlUGlcAE genes in tomato, which could provide a basis for further function studies of tomato UGlcAE genes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-27
      DOI: 10.3390/ijms19061583
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1584: Prioritization of Variants Detected by Next
           Generation Sequencing According to the Mutation Tolerance and Mutational
           Architecture of the Corresponding Genes

    • Authors: Iria Roca, Ana Fernández-Marmiesse, Sofía Gouveia, Marta Segovia, María L. Couce
      First page: 1584
      Abstract: The biggest challenge geneticists face when applying next-generation sequencing technology to the diagnosis of rare diseases is determining which rare variants, from the dozens or hundreds detected, are potentially implicated in the patient’s phenotype. Thus, variant prioritization is an essential step in the process of rare disease diagnosis. In addition to conducting the usual in-silico analyses to predict variant pathogenicity (based on nucleotide/amino-acid conservation and the differences between the physicochemical features of the amino-acid change), three important concepts should be borne in mind. The first is the “mutation tolerance” of the genes in which variants are located. This describes the susceptibility of a given gene to any functional mutation and depends on the strength of purifying selection acting against it. The second is the “mutational architecture” of each gene. This describes the type and location of mutations previously identified in the gene, and their association with different phenotypes or degrees of severity. The third is the mode of inheritance (inherited vs. de novo) of the variants detected. Here, we discuss the importance of each of these concepts for variant prioritization in the diagnosis of rare diseases. Using real data, we show how genes, rather than variants, can be prioritized by calculating a gene-specific mutation tolerance score. We also illustrate the influence of mutational architecture on variant prioritization using five paradigmatic examples. Finally, we discuss the importance of familial variant analysis as final step in variant prioritization.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-27
      DOI: 10.3390/ijms19061584
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1585: Src Cooperates with Oncogenic Ras in
           Tumourigenesis via the JNK and PI3K Pathways in Drosophila epithelial
           Tissue

    • Authors: Carole L.C. Poon, Anthony M. Brumby, Helena E. Richardson
      First page: 1585
      Abstract: The Ras oncogene (Rat Sarcoma oncogene, a small GTPase) is a key driver of human cancer, however alone it is insufficient to produce malignancy, due to the induction of cell cycle arrest or senescence. In a Drosophila melanogaster genetic screen for genes that cooperate with oncogenic Ras (bearing the RasV12 mutation, or RasACT), we identified the Drosophila Src (Sarcoma virus oncogene) family non-receptor tyrosine protein kinase genes, Src42A and Src64B, as promoting increased hyperplasia in a whole epithelial tissue context in the Drosophila eye. Moreover, overexpression of Src cooperated with RasACT in epithelial cell clones to drive neoplastic tumourigenesis. We found that Src overexpression alone activated the Jun N-terminal Kinase (JNK) signalling pathway to promote actin cytoskeletal and cell polarity defects and drive apoptosis, whereas, in cooperation with RasACT, JNK led to a loss of differentiation and an invasive phenotype. Src + RasACT cooperative tumourigenesis was dependent on JNK as well as Phosphoinositide 3-Kinase (PI3K) signalling, suggesting that targeting these pathways might provide novel therapeutic opportunities in cancers dependent on Src and Ras signalling.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-27
      DOI: 10.3390/ijms19061585
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1586: Prognostic Value of RNASEH2A-, CDK1-, and
           CD151-Related Pathway Gene Profiling for Kidney Cancers

    • Authors: Chin-An Yang, Hsi-Yuan Huang, Ju-Chen Yen, Jan-Gowth Chang
      First page: 1586
      Abstract: The nucleotide degrading enzyme gene RNASEH2A (ribonuclease H2 subunit A) has been found to be overexpressed in cancers. Our aim was to understand the role of RNASEH2A in cancer prognostication and to establish a scoring system based on the expressions of genes interacting with RNASEH2A. We screened the nucleotide degrading enzyme gene expression in RNAseq data of 14 cancer types derived from The Cancer Genome Atlas (TCGA) and found that RNASEH2A overexpression was associated with poor patient survival only in renal cell carcinomas (RCCs). Further cluster analyses of samples with poor outcomes revealed that cluster of differentiation 151 (CD151) upregulation correlated with low cyclin dependent kinase 1 (CDK1) and high RNASEH2A expression. The combination of low CD151 expression and high RNASEH2A expression resulted in impaired proliferation in four kidney cancer cell lines, suggesting potential synthetic dosage lethality (SDL) interactions between the two genes. A prognostication scoring system was established based on the expression levels of RNASEH2A-, CDK1-, and CD151-related genes, which could effectively predict the overall survival in a TCGA clear cell RCC cohort (n = 533, 995.3 versus 2242.2 days, p < 0.0001), in another clear cell renal cell carcinoma (ccRCC) cohort E-GEOD-22541 (n = 44, 390.0 versus 1889.2 days, p = 0.0007), and in a TCGA papillary RCC (pRCC) cohort (n = 287, 741.6 versus 1623.7 days, p < 0.0001). Our results provide a clinically applicable prognostication scoring system for renal cancers.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-28
      DOI: 10.3390/ijms19061586
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1587: DNA Damage-Response Pathway Heterogeneity of
           Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to
           8-Chloro-Adenosine

    • Authors: Sheng-Yong Yang, Yi Li, Guo-Shun An, Ju-Hua Ni, Hong-Ti Jia, Shu-Yan Li
      First page: 1587
      Abstract: Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-28
      DOI: 10.3390/ijms19061587
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1588: Palladacyclic Conjugate Group Promotes
           Hybridization of Short Oligonucleotides

    • Authors: Madhuri Hande, Sajal Maity, Tuomas Lönnberg
      First page: 1588
      Abstract: Short oligonucleotides with cyclopalladated benzylamine moieties at their 5′-termini have been prepared to test the possibility of conferring palladacyclic anticancer agents sequence-selectivity by conjugation with a guiding oligonucleotide. Hybridization of these oligonucleotides with natural counterparts was studied by UV and CD (circular dichroism) melting experiments in the absence and presence of a competing ligand (2-mercaptoethanol). Cyclopalladated benzylamine proved to be strongly stabilizing relative to unmetalated benzylamine and modestly stabilizing relative to an extra A•T base pair. The stabilization was largely abolished in the presence of 2-mercaptoethanol, suggesting direct coordination of Pd(II) to a nucleobase of the complementary strand. In all cases, fidelity of Watson-Crick base pairing between the two strands was retained. Hybridization of the cyclopalladated oligonucleotides was characterized by relatively large negative enthalpy and entropy, consistent with stabilizing Pd(II) coordination partially offset by the entropic penalty of imposing conformational constraints on the flexible diethylene glycol linker between the oligonucleotide and the palladacyclic moiety.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-28
      DOI: 10.3390/ijms19061588
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1589: Therapeutics for Inflammatory-Related Diseases
           Based on Plasmon-Activated Water: A Review

    • Authors: Chih-Ping Yang, Yu-Chuan Liu
      First page: 1589
      Abstract: It is recognized that the properties of liquid water can be markedly different from those of bulk one when it is in contact with hydrophobic surfaces or is confined in nano-environments. Because our knowledge regarding water structure on the molecular level of dynamic equilibrium within a picosecond time scale is far from completeness all of water’s conventionally known properties are based on inert “bulk liquid water” with a tetrahedral hydrogen-bonded structure. Actually, the strength of water’s hydrogen bonds (HBs) decides its properties and activities. In this review, an innovative idea on preparation of metastable plasmon-activated water (PAW) with intrinsically reduced HBs, by letting deionized (DI) water flow through gold-supported nanoparticles (AuNPs) under resonant illumination at room temperature, is reported. Compared to DI water, the created stable PAW can scavenge free hydroxyl and 2,2-diphenyl-1-picrylhydrazyl radicals and effectively reduce NO release from lipopolysaccharide-induced inflammatory cells. Moreover, PAW can dramatically induce a major antioxidative Nrf2 gene in human gingival fibroblasts. This further confirms its cellular antioxidative and anti-inflammatory properties. In addition, innovatively therapeutic strategy of daily drinking PAW on inflammatory-related diseases based on animal disease models is demonstrated, examples being chronic kidney disease (CKD), chronic sleep deprivation (CSD), and lung cancer.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-28
      DOI: 10.3390/ijms19061589
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1590: Red to Far-Red Light Ratio Modulates Hormonal
           and Genetic Control of Axillary bud Outgrowth in Chrysanthemum
           (Dendranthema grandiflorum ‘Jinba’)

    • Authors: Cunquan Yuan, Sagheer Ahmad, Tangren Cheng, Jia Wang, Huitang Pan, Liangjun Zhao, Qixiang Zhang
      First page: 1590
      Abstract: Single-flower cut Chrysanthemum (Dendranthema grandiflorum ‘Jinba’) holds a unique status in global floriculture industry. However, the extensive axillary bud outgrowth presents a major drawback. Shade is an environment cue that inhibits shoot branching. Present study was aimed at investigating the effect of ratio of red to far-red light (R:FR) in regulating the lateral bud outgrowth of Chrysanthemum and the detailed mechanism. Results showed that the fate of axillary buds at specific positions in stem exhibited difference in response to R:FR. Decreasing R:FR resulted in elevation of abscisic acid (ABA) accumulation in axillary buds. Expression of ABA, indole-3-acetic acid (IAA) and strigolactones (SL) -related metabolism and signal transduction genes was significantly changed in response to low R:FR. In addition, low R:FR caused the re-distribution of sucrose across the whole plant, driving more sucrose towards bottom buds. Our results indicate that low R:FR not always inhibits bud outgrowth, rather its influence depends on the bud position in the stem. ABA, SL and auxin pathways were involved in the process. Interestingly, sucrose also appears to be involved in the process which is necessary to pay attention in the further studies. The present study also lays the foundation for developing methods to regulate axillary bud outgrowth in Chrysanthemum.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-28
      DOI: 10.3390/ijms19061590
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1591: Structural Biology of STAT3 and Its
           Implications for Anticancer Therapies Development

    • Authors: Jacopo Sgrignani, Maura Garofalo, Milos Matkovic, Jessica Merulla, Carlo V. Catapano, Andrea Cavalli
      First page: 1591
      Abstract: Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and activator of transcription” (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-28
      DOI: 10.3390/ijms19061591
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1592: Recognizing Depression from the
           Microbiota–Gut–Brain Axis

    • Authors: Shan Liang, Xiaoli Wu, Xu Hu, Tao Wang, Feng Jin
      First page: 1592
      Abstract: Major depression is one of the leading causes of disability, morbidity, and mortality worldwide. The brain–gut axis functions are disturbed, revealed by a dysfunction of the brain, immune system, endocrine system, and gut. Traditional depression treatments all target the brain, with different drugs and/or psychotherapy. Unfortunately, most of the patients have never received any treatment. Studies indicate that gut microbiota could be a direct cause for the disorder. Abnormal microbiota and the microbiota–gut–brain dysfunction may cause mental disorders, while correcting these disturbance could alleviate depression. Nowadays, the gut microbiota modulation has become a hot topic in treatment research of mental disorders. Depression is closely related with the health condition of the brain–gut axis, and maintaining/restoring the normal condition of gut microbiota helps in the prevention/therapy of mental disorders.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061592
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1593: Transcriptional Profiles of SmWRKY Family Genes
           and Their Putative Roles in the Biosynthesis of Tanshinone and Phenolic
           Acids in Salvia miltiorrhiza

    • Authors: Haizheng Yu, Wanli Guo, Dongfeng Yang, Zhuoni Hou, Zongsuo Liang
      First page: 1593
      Abstract: Salvia miltiorrhiza Bunge is a Chinese traditional herb for treating cardiovascular and cerebrovascular diseases, and tanshinones and phenolic acids are the dominated medicinal and secondary metabolism constituents of this plant. WRKY transcription factors (TFs) can function as regulators of secondary metabolites biosynthesis in many plants. However, studies on the WRKY that regulate tanshinones and phenolics biosynthesis are limited. In this study, 69 SmWRKYs were identified in the transcriptome database of S. miltiorrhiza, and phylogenetic analysis indicated that some SmWRKYs had closer genetic relationships with other plant WRKYs, which were involved in secondary metabolism. Hairy roots of S. miltiorrhiza were treated by methyl jasmonate (MeJA) to detect the dynamic change trend of SmWRKY, biosynthetic genes, and medicinal ingredients accumulation. Base on those date, a correlation analysis using Pearson’s correlation coefficient was performed to construct gene-to-metabolite network and identify 9 SmWRKYs (SmWRKY1, 7, 19, 29, 45, 52, 56, 58, and 68), which were most likely to be involved in tanshinones and phenolic acids biosynthesis. Taken together, this study has provided a significant resource that could be used for further research on SmWRKY in S. miltiorrhiza and especially could be used as a cue for further investigating SmWRKY functions in secondary metabolite accumulation.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061593
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1594: Candidate Genes for Yellow Leaf Color in Common
           Wheat (Triticum aestivum L.) and Major Related Metabolic Pathways
           according to Transcriptome Profiling

    • Authors: Huiyu Wu, Narong Shi, Xuyao An, Cong Liu, Hongfei Fu, Li Cao, Yi Feng, Daojie Sun, Lingli Zhang
      First page: 1594
      Abstract: The photosynthetic capacity and efficiency of a crop depends on the biosynthesis of photosynthetic pigments and chloroplast development. However, little is known about the molecular mechanisms of chloroplast development and chlorophyll (Chl) biosynthesis in common wheat because of its huge and complex genome. Ygm, a spontaneous yellow-green leaf color mutant of winter wheat, exhibits reduced Chl contents and abnormal chloroplast development. Thus, we searched for candidate genes associated with this phenotype. Comparative transcriptome profiling was performed using leaves from the yellow leaf color type (Y) and normal green color type (G) of the Ygm mutant progeny. We identified 1227 differentially expressed genes (DEGs) in Y compared with G (i.e., 689 upregulated genes and 538 downregulated genes). Gene ontology and pathway enrichment analyses indicated that the DEGs were involved in Chl biosynthesis (i.e., magnesium chelatase subunit H (CHLH) and protochlorophyllide oxidoreductase (POR) genes), carotenoid biosynthesis (i.e., β-carotene hydroxylase (BCH) genes), photosynthesis, and carbon fixation in photosynthetic organisms. We also identified heat shock protein (HSP) genes (sHSP, HSP70, HSP90, and DnaJ) and heat shock transcription factor genes that might have vital roles in chloroplast development. Quantitative RT-PCR analysis of the relevant DEGs confirmed the RNA-Seq results. Moreover, measurements of seven intermediate products involved in Chl biosynthesis and five carotenoid compounds involved in carotenoid-xanthophyll biosynthesis confirmed that CHLH and BCH are vital enzymes for the unusual leaf color phenotype in Y type. These results provide insights into leaf color variation in wheat at the transcriptional level.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061594
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1595: Deciphering RNA-Recognition Patterns of
           Intrinsically Disordered Proteins

    • Authors: Ambuj Srivastava, Shandar Ahmad, M. Michael Gromiha
      First page: 1595
      Abstract: Intrinsically disordered regions (IDRs) and protein (IDPs) are highly flexible owing to their lack of well-defined structures. A subset of such proteins interacts with various substrates; including RNA; frequently adopting regular structures in the final complex. In this work; we have analysed a dataset of protein–RNA complexes undergoing disorder-to-order transition (DOT) upon binding. We found that DOT regions are generally small in size (less than 3 residues) for RNA binding proteins. Like structured proteins; positively charged residues are found to interact with RNA molecules; indicating the dominance of electrostatic and cation-π interactions. However, a comparison of binding frequency shows that interface hydrophobic and aromatic residues have more interactions in only DOT regions than in a protein. Further; DOT regions have significantly higher exposure to water than their structured counterparts. Interactions of DOT regions with RNA increase the sheet formation with minor changes in helix forming residues. We have computed the interaction energy for amino acids–nucleotide pairs; which showed the preference of His–G; Asn–U and Ser–U at for the interface of DOT regions. This study provides insights to understand protein–RNA interactions and the results could also be used for developing a tool for identifying DOT regions in RNA binding proteins.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061595
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1596: Tumor Size-Dependent Anticancer Efficacy of
           Chlorin Derivatives for Photodynamic Therapy

    • Authors: Ji-Eun Chang, Yang Liu, Tae Heon Lee, Woo Kyoung Lee, Il Yoon, Kwhanmien Kim
      First page: 1596
      Abstract: Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 tumor-bearing mice in vivo. Cell viability, microscopy, and fluorescence-activated cell sorting (FACS) analyses were performed for the in vitro studies. MPPa and NMPi showed high phototoxicity in vitro, which was dependent on the concentration of the photosensitizers as well as the light irradiation time. In the animal study, tumor volume change, tumor surface alterations, and hematoxylin & eosin (H&E) and terminal deoxyribonucleotidyl transferse-mediated dUTP nick-end labelling (TUNEL) staining analyses were performed and compared between small (tumor volume of <50 mm3) and large (tumor volume of >50 mm3) size of initial tumors. MPPa and NMPi showed high anticancer efficacy against small-size tumors, indicating that early treatment with PDT is effective. Especially, repeated two times PDT with NMPi allowed almost complete eradication against small-size tumors. However, MPPa and NMPi were not effective against large-size tumors. In conclusion, the two chlorin derivatives, MPPa and NMPi, show good anticancer efficacy as promising photosensitizers for PDT in vitro and in vivo. Moreover, their activity in vivo was significantly dependent on the initial tumor size in mice, which confirms the importance of early cancer treatment.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061596
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1597: Human Fibrinogen: Molecular and Genetic Aspects
           of Congenital Disorders

    • Authors: Giovanni Luca Tiscia, Maurizio Margaglione
      First page: 1597
      Abstract: Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification of molecular causes and of clinical and biochemical phenotypes very challenging. However, the acknowledgement of the type of molecular defect is crucial for a safer therapy, which is going to improve the clinical management of these patients. In this review, some aspects concerning molecular and clinical findings available on congenital fibrinogen disorders will be discussed.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061597
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1598: Genome-Wide Screening and Characterization of
           the Dof Gene Family in Physic Nut (Jatropha curcas L.)

    • Authors: Peipei Wang, Jing Li, Xiaoyang Gao, Di Zhang, Anlin Li, Changning Liu
      First page: 1598
      Abstract: Physic nut (Jatropha curcas L.) is a species of flowering plant with great potential for biofuel production and as an emerging model organism for functional genomic analysis, particularly in the Euphorbiaceae family. DNA binding with one finger (Dof) transcription factors play critical roles in numerous biological processes in plants. Nevertheless, the knowledge about members, and the evolutionary and functional characteristics of the Dof gene family in physic nut is insufficient. Therefore, we performed a genome-wide screening and characterization of the Dof gene family within the physic nut draft genome. In total, 24 JcDof genes (encoding 33 JcDof proteins) were identified. All the JcDof genes were divided into three major groups based on phylogenetic inference, which was further validated by the subsequent gene structure and motif analysis. Genome comparison revealed that segmental duplication may have played crucial roles in the expansion of the JcDof gene family, and gene expansion was mainly subjected to positive selection. The expression profile demonstrated the broad involvement of JcDof genes in response to various abiotic stresses, hormonal treatments and functional divergence. This study provides valuable information for better understanding the evolution of JcDof genes, and lays a foundation for future functional exploration of JcDof genes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061598
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1599: Effects of Periostracum Cicadae on Cytokines
           and Apoptosis Regulatory Proteins in an IgA Nephropathy Rat Model

    • Authors: Lu Yang, Yan Wang, Aobulikasimu Nuerbiye, Ping Cheng, Jin-Hui Wang, Rena Kasimu, Hong Li
      First page: 1599
      Abstract: Periostracum cicadae, the cast-off shell of the cicada Cryptotympana pustulata Fabricius, is used in traditional Chinese medicine for its diaphoretic, anticonvulsive, sedative, antipyretic, and antiallergic effects. However, the exact pathogenesis of immunoglobulin A nephropathy (IgAN) remains unclear, thereby hindering investigations to identify novel therapeutic agents. A rat IgAN model was established by administration of bovine serum albumin, lipopolysaccharide, and carbon tetrachloride, which simultaneously established blood stasis and a heat syndrome model. The animals were sacrificed to detect changes in protein levels in urine and blood. Immunofluorescence was performed to assess IgA deposition in the glomeruli. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematology and eosin, periodic acid-Schiff, TUNEL (TdT-mediated dUTP Nick-End Labeling), and immunohistochemical staining were performed to evaluate histopathological changes in kidney tissues. Additionally, target-related proteins were measured by Western blotting. Periostracum cicadae resulted in a reduction in blood and urine protein levels. Serum TNF-α, IL-1β, and IL-6 levels significantly decreased in the periostracum cicadae-treated groups compared to the IgAN group. Furthermore, a reduction in MCP-1 (Monocyte Chemotactic Protein-1), TLR4 ((Toll-Like Receptor 4)), and IgA expression levels and a dose-dependent increase in caspase 3 expression were observed in response to periostracum cicadae treatment. TGF-β1(Transforming Growth Factor-β) levels decreased, whereas that of Fas increased in the kidney tissues of the periostracum cicadae-treated groups. The findings of the present study indicate that periostracum cicadae induces apoptosis and improves kidney inflammation and fibrosis in IgA nephropathy rat models.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061599
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1600: UDP-Glucose 4-Epimerase and
           β-1,4-Galactosyltransferase from the Oyster Magallana gigas as Valuable
           Biocatalysts for the Production of Galactosylated Products

    • Authors: Hui-Bo Song, Meng He, Zhi-Peng Cai, Kun Huang, Sabine L. Flitsch, Li Liu, Josef Voglmeir
      First page: 1600
      Abstract: Uridine diphosphate galactose (UDP-galactose) is a valuable building block in the enzymatic synthesis of galactose-containing glycoconjugates. UDP-glucose 4-epimerase (UGE) is an enzyme which catalyzes the reversible conversion of abundantly available UDP-glucose to UDP-galactose. Herein, we described the cloning, expression, purification, and biochemical characterization of an unstudied UGE from the oyster Magallana gigas (MgUGE). Activity tests of recombinantly expressed MgUGE, using HPLC (high-performance liquid chromatography), mass spectrometry, and photometric assays, showed an optimal temperature of 16 °C, and reasonable thermal stability up to 37 °C. No metal ions were required for enzymatic activity. The simple nickel-affinity-purification procedure makes MgUGE a valuable biocatalyst for the synthesis of UDP-galactose from UDP-glucose. The biosynthetic potential of MgUGE was further exemplified in a coupled enzymatic reaction with an oyster-derived β-1,4-galactosyltransferase (MgGalT7), allowing the galactosylation of the model substrate para-nitrophenol xylose (pNP-xylose) using UDP-glucose as the starting material.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061600
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1601: In Vitro Antifungal Activity of New and Known
           Geranylated Phenols against Phytophthora cinnamomi Rands

    • Authors: María I. Chavez, Mauricio Soto, Franco A. Cimino, Andrés F. Olea, Luis Espinoza, Katy Díaz, Lautaro Taborga
      First page: 1601
      Abstract: A series of new and known geranylated phenol/methoxyphenol derivatives has been tested in vitro as inhibitor agents of mycelial growth of Phytophthora cinnamomi. The activity of tested compounds is correlated with the nature, number, and position of the substituent group on the aromatic ring. Results indicate that the most active geranylated derivatives are those having two hydroxyl groups (or one –OH and one –OCH3) attached to the aromatic ring. Interestingly, these derivatives are as active as Metalaxil®, a commonly used commercial fungicide. Thus, our results suggest that some of these compounds might be of agricultural interest due to their potential use as fungicides against P. cinnamomi. The effect of structure on fungicide activity is discussed in terms of electronic distribution on both the aromatic ring and side geranyl chain. All tested compounds have been synthesized by direct coupling of geraniol and the respective phenol. Interestingly, new digeranylated derivatives were obtained by increasing the reaction time.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061601
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1602: Immunotherapy for Gastric Cancer: Time for a
           Personalized Approach'

    • Authors: Riccardo Dolcetti, Valli De Re, Vincenzo Canzonieri
      First page: 1602
      Abstract: Over the last decade, our understanding of the mechanisms underlying immune modulation has greatly improved, allowing for the development of multiple therapeutic approaches that are revolutionizing the treatment of cancer. Immunotherapy for gastric cancer (GC) is still in the early phases but is rapidly evolving. Recently, multi-platform molecular analyses of GC have proposed a new classification of this heterogeneous group of tumors, highlighting subset-specific features that may more reliably inform therapeutic choices, including the use of new immunotherapeutic drugs. The clinical benefit and improved survival observed in GC patients treated with immunotherapeutic strategies and their combination with conventional therapies highlighted the importance of the immune environment surrounding the tumor. A thorough investigation of the tumor microenvironment and the complex and dynamic interaction between immune cells and tumor cells is a fundamental requirement for the rational design of novel and more effective immunotherapeutic approaches. This review summarizes the pre-clinical and clinical results obtained so far with immunomodulatory and immunotherapeutic treatments for GC and discusses the novel combination strategies that are being investigated to improve the personalization and efficacy of GC immunotherapy.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-29
      DOI: 10.3390/ijms19061602
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1603: Heterogeneity in Malignant Pleural Mesothelioma

    • Authors: Kathrin Oehl, Bart Vrugt, Isabelle Opitz, Mayura Meerang
      First page: 1603
      Abstract: Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses reveal a high heterogeneity (i) between patients; (ii) within different areas of a given tumor in terms of different clonal compositions; and (iii) during treatment over time. The aim of the present review is to highlight this diversity and its therapeutic implications.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061603
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1604: Targeting the Bacterial Cytoskeleton of the
           Burkholderia cepacia Complex for Antimicrobial Development: A Cautionary
           Tale

    • Authors: Sonya C. Carnell, John D. Perry, Lee Borthwick, Daniela Vollmer, Jacob Biboy, Marcella Facchini, Alessandra Bragonzi, Alba Silipo, Annette C. Vergunst, Waldemar Vollmer, Anjam C. M. Khan, Anthony De Soyza
      First page: 1604
      Abstract: Burkholderia cepacia complex (BCC) bacteria are a group of opportunistic pathogens that cause severe lung infections in cystic fibrosis (CF). Treatment of BCC infections is difficult, due to the inherent and acquired multidrug resistance of BCC. There is a pressing need to find new bacterial targets for antimicrobials. Here, we demonstrate that the novel compound Q22, which is related to the bacterial cytoskeleton destabilising compound A22, can reduce the growth rate and inhibit growth of BCC bacteria. We further analysed the phenotypic effects of Q22 treatment on BCC virulence traits, to assess its feasibility as an antimicrobial. BCC bacteria were grown in the presence of Q22 with a broad phenotypic analysis, including resistance to H2O2-induced oxidative stress, changes in the inflammatory potential of cell surface components, and in-vivo drug toxicity studies. The influence of the Q22 treatment on inflammatory potential was measured by monitoring the cytokine responses of BCC whole cell lysates, purified lipopolysaccharide, and purified peptidoglycan extracted from bacterial cultures grown in the presence or absence of Q22 in differentiated THP-1 cells. BCC bacteria grown in the presence of Q22 displayed varying levels of resistance to H2O2-induced oxidative stress, with some strains showing increased resistance after treatment. There was strain-to-strain variation in the pro-inflammatory ability of bacterial lysates to elicit TNFα and IL-1β from human myeloid cells. Despite minimal toxicity previously shown in vitro with primary CF cell lines, in-vivo studies demonstrated Q22 toxicity in both zebrafish and mouse infection models. In summary, destabilisation of the bacterial cytoskeleton in BCC, using compounds such as Q22, led to increased virulence-related traits in vitro. These changes appear to vary depending on strain and BCC species. Future development of antimicrobials targeting the BCC bacterial cytoskeleton may be hampered if such effects translate into the in-vivo environment of the CF infection.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061604
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1605: Quinolones Modulate Ghrelin Receptor Signaling:
           Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia
           

    • Authors: Cristina Torres-Fuentes, Elena Pastor-Cavada, Rafael Cano, Dalia Kandil, Rachel Shanahan, Rocio Juan, Hamdy Shaban, Gerard P. McGlacken, Harriët Schellekens
      First page: 1605
      Abstract: Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061605
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1606: Preparation of Biodegradable
           Oligo(lactide)s-Grafted Dextran Nanogels for Efficient Drug Delivery by
           Controlling Intracellular Traffic

    • Authors: Yuichi Ohya, Akihiro Takahashi, Akinori Kuzuya
      First page: 1606
      Abstract: Nanogels, nanometer-sized hydrogel particles, have great potential as drug delivery carriers. To achieve effective drug delivery to the active sites in a cell, control of intracellular traffic is important. In this study, we prepared nanogels composed of dextran with oligolactide (OLA) chains attached via disulfide bonds (Dex-g-SS-OLA) that collapse under the reductive conditions of the cytosol to achieve efficient drug delivery. In addition, we introduced galactose (Gal) residues on the nanogels, to enhance cellular uptake by receptor-mediated endocytosis, and secondary oligo-amine (tetraethylenepentamine) groups, to aid in escape from endosomes via proton sponge effects. The obtained Dex-g-SS-OLA with attached Gal residues and tetraethylenepentamine (EI4) groups, EI4/Gal-Dex-g-SS-OLA, formed a nanogel with a hydrodynamic diameter of ca. 203 nm in phosphate-buffered solution. The collapse of the EI4/Gal-Dex-g-SS-OLA nanogels under reductive conditions was confirmed by a decrease in the hydrodynamic diameter in the presence of reductive agents. The specific uptake of the hydrogels into HepG2 cells and their intercellular behavior were investigated by flow cytometry and confocal laser scanning microscopy using fluorescence dye-labeled nanogels. Escape from the endosome and subsequent collapse in the cytosol of the EI4/Gal-Dex-g-SS-OLA were observed. These biodegradable nanogels that collapse under reductive conditions in the cytosol should have great potential as efficient drug carriers in, for example, cancer chemotherapy.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061606
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1607: The Role of Endoplasmic Reticulum
           Stress-Glycogen Synthase Kinase-3 Signaling in Atherogenesis

    • Authors: Aric Huang, Sarvatit Patel, Cameron S. McAlpine, Geoff H. Werstuck
      First page: 1607
      Abstract: Cardiovascular disease (CVD) is the number one cause of global mortality and atherosclerosis is the underlying cause of most CVD. However, the molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are not well understood. The development of new efficient therapies to directly block or slow disease progression will require a better understanding of these mechanisms. Accumulating evidence supports a role for endoplasmic reticulum (ER) stress in all stages of the developing atherosclerotic lesion however, it was not clear how ER stress may contribute to disease progression. Recent findings have shown that ER stress signaling through glycogen synthase kinase (GSK)-3α may significantly contribute to macrophage lipid accumulation, inflammatory cytokine production and M1macrophage polarization. In this review we summarize our knowledge of the potential role of ER stress-GSK3 signaling in the development and progression of atherosclerosis as well as the possible therapeutic implications of this pathway.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061607
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1608: Biochemical Properties of a Decoy
           Oligodeoxynucleotide Inhibitor of STAT3 Transcription Factor

    • Authors: David S. Lee, Rachel A. O’Keefe, Patrick K. Ha, Jennifer R. Grandis, Daniel E. Johnson
      First page: 1608
      Abstract: Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061608
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1609: Ru(II)-Thymine Complex Causes Cell Growth
           Inhibition and Induction of Caspase-Mediated Apoptosis in Human
           Promyelocytic Leukemia HL-60 Cells

    • Authors: Maiara de Souza Oliveira, Ádila Angélica Dantas de Santana, Rodrigo S. Correa, Milena Botelho Pereira Soares, Alzir Azevedo Batista, Daniel Pereira Bezerra
      First page: 1609
      Abstract: Ruthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2′-bipyridine) as a potent cytotoxic agent with the ability to bind to DNA and human and bovine serum albumins. In this study, the underlying cytotoxic mechanism of the [Ru(PPh3)2(Thy)(bipy)]PF6 complex was assessed. This complex displayed potent cytotoxicity in different cancer cell lines; the morphology that is associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation were observed in human promyelocytic leukemia HL-60 cells that were treated with the complex. Moreover, pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through a caspase-mediated pathway. In conclusion, the [Ru(PPh3)2(Thy)(bipy)]PF6 complex displays potent cytotoxicity to different cancer cells and induces caspase-mediated apoptosis in HL-60 cells.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061609
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1610: Circulating Cell-Free DNA as a Prognostic and
           Molecular Marker for Patients with Brain Tumors under Perillyl
           Alcohol-Based Therapy

    • Authors: Giselle Faria, Emanuelle Silva, Clovis Da Fonseca, Thereza Quirico-Santos
      First page: 1610
      Abstract: Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors. The cohort included 130 healthy subjects arranged as control-paired groups and patients at terminal stages with glioblastoma (GBM, n = 122) or brain metastasis (BM, n = 55) from stage IV adenocarcinomas. Serum cfDNA was isolated and quantified by fluorimetry. Compared with the controls (40 ng/mL), patients with brain tumors before ITN-POH treatment had increased (p < 0.0001) cfDNA median levels: GBM (286 ng/mL) and BM (588 ng/mL). ITN-POH treatment was significantly correlated (rho = −0.225; p = 0.024) with survival of >6 months at a concentration of 599 ± 221 ng/mL and of <6 months at 1626 ± 505 ng/mL, but a sharp and abrupt increase of cfDNA and tumor recurrence occurred after ITN-POH discontinuation. Patients under continuous ITN-POH treatment and checked with brain magnetic resonance imaging (MRI) compatible with complete response had cfDNA levels similar to the controls. cfDNA may be used as a noninvasive prognostic and molecular marker for POH-based therapy in brain tumors and as an accurate screening tool for the early detection of tumor progression.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061610
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1611: Dopamine Transporter/α-Synuclein Complexes Are
           Altered in the Post Mortem Caudate Putamen of Parkinson’s Disease: An In
           Situ Proximity Ligation Assay Study

    • Authors: Francesca Longhena, Gaia Faustini, Cristina Missale, Marina Pizzi, Arianna Bellucci
      First page: 1611
      Abstract: Parkinson’s disease (PD) is characterized by the degeneration of the dopaminergic nigrostriatal neurons and the presence of Lewy bodies (LB) and Lewy neurites (LN) mainly composed of α-synuclein. By using the in situ proximity ligation assay (PLA), which allows for the visualization of protein-protein interactions in tissues to detect dopamine transporter (DAT)/α-synuclein complexes, we previously described that these are markedly redistributed in the striatum of human α-synuclein transgenic mice at the phenotypic stage, showing dopamine (DA) release impairment without a DAT drop and motor symptoms. Here, we used the in situ PLA to investigate DAT/α-synuclein complexes in the caudate putamen of PD patients and age-matched controls. They were found to be redistributed and showed an increased size in PD patients, where we observed several neuropil-like and neuritic-like PLA-positive structures. In the PD brains, DAT immunolabeling showed a pattern similar to that of in situ PLA in areas with abundant α-synuclein neuropathology. This notwithstanding, the in situ PLA signal was only partially retracing DAT or α-synuclein immunolabeling, suggesting that a large amount of complexes may have been lost along with the degeneration process. These findings reveal a DAT/α-synuclein neuropathological signature in PD and hint that synaptic alterations involving striatal DAT may derive from α-synuclein aggregation.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061611
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1612: Synthesis and Biological Evaluation of
           Zeise’s Salt Derivatives with Acetylsalicylic Acid Substructure

    • Authors: Alexander Weninger, Daniel Baecker, Victoria Obermoser, Dorothea Egger, Klaus Wurst, Ronald Gust
      First page: 1612
      Abstract: The development of novel biologically active organometallic compounds bearing an acetylsalicylic acid (ASA) substructure led to the synthesis of analogical Zeise-type salts that accordingly inhibit cyclooxygenase (COX) enzymes. In order to determine the influence of the length of the alkyl chain between the platinum(II) center and the ASA moiety, compounds with varying methylene groups (n = 1–4) were synthesized and characterized. For the propene derivative structural elucidation by X-ray crystallography was possible. Prior to evaluation of biological activity, the complexes were investigated regarding their stability in different media, such as water, physiological sodium chloride, and phosphate buffered saline. Therefore, an analytical method based on capillary electrophoresis was established. All of the compounds were tested for their COX inhibitory potential. In general, complexes with longer alkyl chains caused higher inhibition of COX enzymes and the inhibitory potential towards COX enzymes was enhanced when compared to Zeise’s salt. The growth inhibitory effects of the synthesized substances were investigated in vitro against colon carcinoma (HT-29) and breast cancer (MCF-7) cells. The IC50 values of the new derivatives ranged from 30 to 50 µM, whereas neither Zeise’s salt itself nor ASA showed any antiproliferative activity at the used concentrations.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061612
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1613: Effects of PTEN Loss and Activated KRAS
           Overexpression on Mechanical Properties of Breast Epithelial Cells

    • Authors: Will Linthicum, Minh-Tri Ho Thanh, Michele I. Vitolo, Qi Wen
      First page: 1613
      Abstract: It has previously been shown that the simultaneous activation of PI3K (phosphatidylinositol 3-kinase) and Ras/MAPK (mitogen-activated protein kinases) pathways facilitate tumor growth despite only inducing cancer cell dormancy individually. Determining the impacts on cellular mechanics each pathway incites alone and in unison is critical to developing non-toxic cancer therapies for triple-negative breast cancers. PTEN (phosphatase and tensin homolog) knockout and activated KRAS (Kristen rat sarcoma viral oncogene homolog) overexpression in healthy MCF-10A human breast epithelial cells activated the PI3K and Ras/MAPK pathways, respectively. Cell stiffness and fluidity were simultaneously measured using atomic force microscopy. Results suggest that PTEN knockout reduced cell stiffness and increased cell fluidity independent of PI3K activation. Effects of activated KRAS overexpression on cell stiffness depends on rigidity of cell culture substrate. Activated KRAS overexpression also counteracts the effects of PTEN knockout.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061613
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1614: GBS Mapping and Analysis of Genes Conserved
           between Gossypium tomentosum and Gossypium hirsutum Cotton Cultivars that
           Respond to Drought Stress at the Seedling Stage of the BC2F2 Generation

    • Authors: Richard Odongo Magwanga, Pu Lu, Joy Nyangasi Kirungu, Latyr Diouf, Qi Dong, Yangguang Hu, Xiaoyan Cai, Yanchao Xu, Yuqing Hou, Zhongli Zhou, Xingxing Wang, Kunbo Wang, Fang Liu
      First page: 1614
      Abstract: Cotton production is on the decline due to ever-changing environmental conditions. Drought and salinity stress contribute to over 30% of total loss in cotton production, the situation has worsened more due to the narrow genetic base of the cultivated upland cotton. The genetic diversity of upland cotton has been eroded over the years due to intense selection and inbreeding. To break the bottleneck, the wild cotton progenitors offer unique traits which can be introgressed into the cultivated cotton, thereby improving their performance. In this research, we developed a BC2F2 population between wild male parent, G. tomentosum as the donor, known for its high tolerance to drought and the elite female parent, G. hirsutum as the recurrent parent, which is high yielding but sensitive to drought stress. The population was genotyped through the genotyping by sequencing (GBS) method, in which 10,888 single-nucleotide polymorphism (SNP) s were generated and used to construct a genetic map. The map spanned 4191.3 cM, with average marker distance of 0.3849 cM. The map size of the two sub genomes had a narrow range, 2149 cM and 2042.3 cM for At and Dt_sub genomes respectively. A total of 66,434 genes were mined, with 32,032 (48.2%) and 34,402 (51.8%) genes being obtained within the At and Dt_sub genomes respectively. Pkinase (PF00069) was found to be the dominant domain, with 1069 genes. Analysis of the main sub family, serine threonine protein kinases through gene ontology (GO), cis element and miRNA targets analysis revealed that most of the genes were involved in various functions aimed at enhancing abiotic stress tolerance. Further analysis of the RNA sequence data and qRT-PCR validation revealed 16 putative genes, which were highly up regulated under drought stress condition, and were found to be targeted by ghr-miR169a and ghr-miR164, previously associated with NAC(NAM, ATAF1/2 and CUC2) and myeloblastosis (MYB), the top rank drought stress tolerance genes. These genes can be exploited further to aid in development of more drought tolerant cotton genotypes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061614
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1615: Preparation and Characterization of
           Electrostatically Crosslinked Polymer–Liposomes in Anticancer Therapy

    • Authors: Yi-Ting Chiang, Sih-Ying Lyu, Yu-Han Wen, Chun-Liang Lo
      First page: 1615
      Abstract: pH-sensitive polymer–liposomes can rapidly release their payloads. However, it is difficult to simultaneously achieve stability and pH-responsiveness in the polymer–liposomes. In this study, stable and pH-sensitive crosslinked polymer–liposomes were fabricated through electrostatic interactions. The pH-sensitive copolymer methoxy poly(ethylene glycol)-block-poly(methacrylic acid)-cholesterol (mPEG-b-P(MAAc)-chol) and crosslinking reagent poly(ethylene glycol) with end-capped with lysine (PEG-Lys2) were synthesized and characterized. At physiological conditions, the pH-sensitive copolymers were anionic and interacted electrostatically with the cationic crosslinker PEG-Lys2, forming the electrostatically-crosslinked polymer–liposomes and stabilizing the liposomal structure. At pH 5.0, the carboxylic groups in mPEG-b-P(MAAc)-chol were neutralized, and the liposomal structure was destroyed. The particle size of the crosslinked polymer–liposomes was approximately 140 nm and the polymer–liposomes were loaded with the anticancer drug doxorubicin. At pH 7.4, the crosslinked polymer–liposomes exhibited good stability with steady particle size and low drug leakage, even in the presence of fetal bovine serum. At pH 5.0, the architecture of the crosslinked polymer–liposomes was damaged following rapid drug release, as observed by using transmission electron microscopy and their apparent size variation. The crosslinked polymer–liposomes were pH-sensitive within the endosome and in the human breast cancer cells MDA-MB-231, as determined by using confocal laser scanning microscopy. The intracellular drug release profiles indicated cytotoxicity in cancer cells. These results indicated that the highly-stable and pH-sensitive electrostatically-crosslinked polymer–liposomes offered a potent drug-delivery system for use in anticancer therapies.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061615
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1616: Persistent Infiltration and Impaired Response
           of Peripherally-Derived Monocytes after Traumatic Brain Injury in the Aged
           Brain

    • Authors: Austin Chou, Karen Krukowski, Josh M. Morganti, Lara-Kirstie Riparip, Susanna Rosi
      First page: 1616
      Abstract: Traumatic brain injury (TBI) is a leading cause for neurological disabilities world-wide. TBI occurs most frequently among the elderly population, and elderly TBI survivors suffer from reduced recovery and poorer quality of life. The effect of age on the pathophysiology of TBI is still poorly understood. We previously established that peripherally-derived monocytes (CCR2+) infiltrate the injured brain and contribute to chronic TBI-induced cognitive deficits in young animals. Furthermore, age was shown to amplify monocyte infiltration acutely after injury. In the current study, we investigated the impact of age on the subchronic response of peripherally-derived monocytes (CD45hi; CCR2+) and their role in the development of chronic cognitive deficits. In the aged brain, there was a significant increase in the number of peripherally-derived monocytes after injury compared to young, injured animals. The infiltration rate of peripherally-derived monocytes remained elevated subchronically and corresponded with enhanced expression of CCR2 chemotactic ligands. Interestingly, the myeloid cell populations observed in injured aged brains had impaired anti-inflammatory responses compared to those in young animals. Additionally, in the aged animals, there was an expansion of the blood CCR2+ monocyte population after injury that was not present in the young animals. Importantly, knocking out CCR2 to inhibit infiltration of peripherally-derived monocytes prevented chronic TBI-induced spatial memory deficits in the aged mice. Altogether, these results demonstrate the critical effects of age on the peripherally-derived monocyte response during the progression of TBI pathophysiology.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061616
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1617: Ligand Access Channels in Cytochrome P450
           Enzymes: A Review

    • Authors: Philippe Urban, Thomas Lautier, Denis Pompon, Gilles Truan
      First page: 1617
      Abstract: Quantitative structure-activity relationships may bring invaluable information on structural elements of both enzymes and substrates that, together, govern substrate specificity. Buried active sites in cytochrome P450 enzymes are connected to the solvent by a network of channels exiting at the distal surface of the protein. This review presents different in silico tools that were developed to uncover such channels in P450 crystal structures. It also lists some of the experimental evidence that actually suggest that these predicted channels might indeed play a critical role in modulating P450 functions. Amino acid residues at the entrance of the channels may participate to a first global ligand recognition of ligands by P450 enzymes before they reach the buried active site. Moreover, different P450 enzymes show different networks of predicted channels. The plasticity of P450 structures is also important to take into account when looking at how channels might play their role.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061617
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1618: Role of Vitamin D Beyond the Skeletal Function:
           A Review of the Molecular and Clinical Studies

    • Authors: Meenakshi Umar, Konduru S. Sastry, Aouatef I. Chouchane
      First page: 1618
      Abstract: The classical function of Vitamin D, which involves mineral balance and skeletal maintenance, has been known for many years. With the discovery of vitamin D receptors in various tissues, several other biological functions of vitamin D are increasingly recognized and its role in many human diseases like cancer, diabetes, hypertension, cardiovascular, and autoimmune and dermatological diseases is being extensively explored. The non-classical function of vitamin D involves regulation of cellular proliferation, differentiation, apoptosis, and innate and adaptive immunity. In this review, we discuss and summarize the latest findings on the non-classical functions of vitamin D at the cellular/molecular level and its role in complex human diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061618
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1619: The Influence of Selective Laser Melting (SLM)
           Process Parameters on In-Vitro Cell Response

    • Authors: Bartłomiej Wysocki, Joanna Idaszek, Joanna Zdunek, Krzysztof Rożniatowski, Marcin Pisarek, Akiko Yamamoto, Wojciech Święszkowski
      First page: 1619
      Abstract: The use of laser 3D printers is very perspective in the fabrication of solid and porous implants made of various polymers, metals, and its alloys. The Selective Laser Melting (SLM) process, in which consolidated powders are fully melted on each layer, gives the possibility of fabrication personalized implants based on the Computer Aid Design (CAD) model. During SLM fabrication on a 3D printer, depending on the system applied, there is a possibility for setting the amount of energy density (J/mm3) transferred to the consolidated powders, thus controlling its porosity, contact angle and roughness. In this study, we have controlled energy density in a range 8–45 J/mm3 delivered to titanium powder by setting various levels of laser power (25–45 W), exposure time (20–80 µs) and distance between exposure points (20–60 µm). The growing energy density within studied range increased from 63 to 90% and decreased from 31 to 13 µm samples density and Ra parameter, respectively. The surface energy 55–466 mN/m was achieved with contact angles in range 72–128° and 53–105° for water and formamide, respectively. The human mesenchymal stem cells (hMSCs) adhesion after 4 h decreased with increasing energy density delivered during processing within each parameter group. The differences in cells proliferation were clearly seen after a 7-day incubation. We have observed that proliferation was decreasing with increasing density of energy delivered to the samples. This phenomenon was explained by chemical composition of oxide layers affecting surface energy and internal stresses. We have noticed that TiO2, which is the main oxide of raw titanium powder, disintegrated during selective laser melting process and oxygen was transferred into metallic titanium. The typical for 3D printed parts post-processing methods such as chemical polishing in hydrofluoric (HF) or hydrofluoric/nitric (HF/HNO3) acid solutions and thermal treatments were used to restore surface chemistry of raw powders and improve surface.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-30
      DOI: 10.3390/ijms19061619
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1620: Decoding the Divergent Subcellular Location of
           Two Highly Similar Paralogous LEA Proteins

    • Authors: Marie-Hélène Avelange-Macherel, Adrien Candat, Martine Neveu, Dimitri Tolleter, David Macherel
      First page: 1620
      Abstract: Many mitochondrial proteins are synthesized as precursors in the cytosol with an N-terminal mitochondrial targeting sequence (MTS) which is cleaved off upon import. Although much is known about import mechanisms and MTS structural features, the variability of MTS still hampers robust sub-cellular software predictions. Here, we took advantage of two paralogous late embryogenesis abundant proteins (LEA) from Arabidopsis with different subcellular locations to investigate structural determinants of mitochondrial import and gain insight into the evolution of the LEA genes. LEA38 and LEA2 are short proteins of the LEA_3 family, which are very similar along their whole sequence, but LEA38 is targeted to mitochondria while LEA2 is cytosolic. Differences in the N-terminal protein sequences were used to generate a series of mutated LEA2 which were expressed as GFP-fusion proteins in leaf protoplasts. By combining three types of mutation (substitution, charge inversion, and segment replacement), we were able to redirect the mutated LEA2 to mitochondria. Analysis of the effect of the mutations and determination of the LEA38 MTS cleavage site highlighted important structural features within and beyond the MTS. Overall, these results provide an explanation for the likely loss of mitochondrial location after duplication of the ancestral gene.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061620
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1621: Presenilins as Drug Targets for Alzheimer’s
           Disease—Recent Insights from Cell Biology and Electrophysiology as Novel
           Opportunities in Drug Development

    • Authors: R. Scott Duncan, Bob Song, Peter Koulen
      First page: 1621
      Abstract: A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aβ). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aβ. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061621
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1622: Diagnostic and Prognostic Potential of MicroRNA
           Maturation Regulators Drosha, AGO1 and AGO2 in Urothelial Carcinomas of
           the Bladder

    • Authors: Anja Rabien, Nadine Ratert, Anica Högner, Andreas Erbersdobler, Klaus Jung, Thorsten H. Ecke, Ergin Kilic
      First page: 1622
      Abstract: Bladder cancer still requires improvements in diagnosis and prognosis, because many of the cases will recur and/or metastasize with bad outcomes. Despite ongoing research on bladder biomarkers, the clinicopathological impact and diagnostic function of miRNA maturation regulators Drosha and Argonaute proteins AGO1 and AGO2 in urothelial bladder carcinoma remain unclear. Therefore, we conducted immunohistochemical investigations of a tissue microarray composed of 112 urothelial bladder carcinomas from therapy-naïve patients who underwent radical cystectomy or transurethral resection and compared the staining signal with adjacent normal bladder tissue. The correlations of protein expression of Drosha, AGO1 and AGO2 with sex, age, tumor stage, histological grading and overall survival were evaluated in order to identify their diagnostic and prognostic potential in urothelial cancer. Our results show an upregulation of AGO1, AGO2 and Drosha in non-muscle-invasive bladder carcinomas, while there was increased protein expression of only AGO2 in muscle-invasive bladder carcinomas. Moreover, we were able to differentiate between non-muscle-invasive and muscle-invasive bladder carcinoma according to AGO1 and Drosha expression. Finally, despite Drosha being a discriminating factor that can predict the probability of overall survival in the Kaplan–Meier analysis, AGO1 turned out to be independent of all clinicopathological parameters according to Cox regression. In conclusion, we assumed that the miRNA processing factors have clinical relevance as potential diagnostic and prognostic tools for bladder cancer.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061622
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1623: Alteration of Transcripts of Stress-Protective
           Genes and Transcriptional Factors by γ-Aminobutyric Acid (GABA)
           Associated with Improved Heat and Drought Tolerance in Creeping Bentgrass
           (Agrostis stolonifera)

    • Authors: Zhou Li, Yan Peng, Bingru Huang
      First page: 1623
      Abstract: Gamma-aminobutyric acid (GABA) may play a positive role in regulating plant tolerance to drought or heat stress. The objectives of this study were to investigate the physiological effects of GABA on tolerance of creeping bentgrass (Agrostis stolonifera) to heat and drought stress and to determine whether enhanced heat and drought tolerance due to GABA treatment was associated with the up-regulation of selected genes and transcriptional factors involved in stress protection. Creeping bentgrass (cultivar “Penncross”) plants were treated with 0.5 mM GABA or water (untreated control) as a foliar spray and were subsequently exposed to heat stress (35/30 °C, day/night), drought stress by withholding irrigation, or non-stress conditions in controlled-environment growth chambers. Exogenous application of GABA significantly improved plant tolerance to heat and drought stress, as reflected by increased leaf water content, cell membrane stability, and chlorophyll content. The analysis of gene transcript level revealed that exogenous GABA up-regulated the expression of ABF3, POD, APX, HSP90, DHN3, and MT1 during heat stress and the expression of CDPK26, MAPK1, ABF3, WRKY75, MYB13, HSP70, MT1, 14-3-3, and genes (SOD, CAT, POD, APX, MDHAR, DHAR, and GR) encoding antioxidant enzymes during drought stress. The up-regulation of the aforementioned stress-protective genes and transcriptional factors could contribute to improved heat and drought tolerance in creeping bentgrass.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061623
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1624: 3D Bioprinted Artificial Trachea with
           Epithelial Cells and Chondrogenic-Differentiated Bone Marrow-Derived
           Mesenchymal Stem Cells

    • Authors: Sang-Woo Bae, Kang-Woog Lee, Jae-Hyun Park, JunHee Lee, Cho-Rok Jung, JunJie Yu, Hwi-Yool Kim, Dae-Hyun Kim
      First page: 1624
      Abstract: Tracheal resection has limited applicability. Although various tracheal replacement strategies were performed using artificial prosthesis, synthetic stents and tissue transplantation, the best method in tracheal reconstruction remains to be identified. Recent advances in tissue engineering enabled 3D bioprinting using various biocompatible materials including living cells, thereby making the product clinically applicable. Moreover, clinical interest in mesenchymal stem cell has dramatically increased. Here, rabbit bone marrow-derived mesenchymal stem cells (bMSC) and rabbit respiratory epithelial cells were cultured. The chondrogenic differentiation level of bMSC cultured in regular media (MSC) and that in chondrogenic media (d-MSC) were compared. Dual cell-containing artificial trachea were manufactured using a 3D bioprinting method with epithelial cells and undifferentiated bMSC (MSC group, n = 6) or with epithelial cells and chondrogenic-differentiated bMSC (d-MSC group, n = 6). d-MSC showed a relatively higher level of glycosaminoglycan (GAG) accumulation and chondrogenic marker gene expression than MSC in vitro. Neo-epithelialization and neo-vascularization were observed in all groups in vivo but neo-cartilage formation was only noted in d-MSC. The epithelial cells in the 3D bioprinted artificial trachea were effective in respiratory epithelium regeneration. Chondrogenic-differentiated bMSC had more neo-cartilage formation potential in a short period. Nevertheless, the cartilage formation was observed only in a localized area.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061624
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1625: NSC 95397 Suppresses Proliferation and Induces
           Apoptosis in Colon Cancer Cells through MKP-1 and the ERK1/2 Pathway

    • Authors: Navneet Kumar Dubey, Bou-Yue Peng, Chien-Min Lin, Peter D. Wang, Joseph R. Wang, Chun-Hao Chan, Hong-Jian Wei, Win-Ping Deng
      First page: 1625
      Abstract: NSC 95397, a quinone-based small molecule compound, has been identified as an inhibitor for dual-specificity phosphatases, including mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is known to inactivate mitogen-activated protein kinases by dephosphorylating both of their threonine and tyrosine residues. Moreover, owing to their participation in tumorigenesis and drug resistance in colon cancer cells, MKP-1 is an attractive therapeutic target for colon cancer treatment. We therefore investigated the inhibitory activity of NSC 95397 against three colon cancer cell lines including SW480, SW620, and DLD-1, and their underlying mechanisms. The results demonstrated that NSC 95397 reduced cell viability and anchorage-independent growth of all the three colon cancer cell lines through inhibited proliferation and induced apoptosis via regulating cell-cycle-related proteins, including p21, cyclin-dependent kinases, and caspases. Besides, by using mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126, we provided mechanistic evidence that the antineoplastic effects of NSC 95397 were achieved via inhibiting MKP-1 activity followed by ERK1/2 phosphorylation. Conclusively, our results indicated that NSC 95397 might serve as an effective therapeutic intervention for colon cancer through regulating MKP-1 and ERK1/2 pathway.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061625
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1626: Oxaloacetate Ameliorates Chemical Liver Injury
           via Oxidative Stress Reduction and Enhancement of Bioenergetic Fluxes

    • Authors: Ye Kuang, Xiaoyun Han, Mu Xu, Yue Wang, Yuxiang Zhao, Qing Yang
      First page: 1626
      Abstract: Chemical injury is partly due to free radical lipid peroxidation, which can induce oxidative stress and produce a large number of reactive oxygen species (ROS). Oxaloacetic acid is an important intermediary in the tricarboxylic acid cycle (TCA cycle) and participates in metabolism and energy production. In our study, we found that oxaloacetate (OA) effectively alleviated liver injury which was induced by hydrogen peroxide (H2O2) in vitro and carbon tetrachloride (CCl4) in vivo. OA scavenged ROS, prevented oxidative damage and maintained the normal structure of mitochondria. We further confirmed that OA increased adenosine triphosphate (ATP) by promoting the TCA production cycle and oxidative phosphorylation (OXPHOS). Finally, OA inhibited the mitogen-activated protein kinase (MAPK) and apoptotic pathways by suppressing tumor necrosis factor-α (TNF-α). Our findings reveal a mechanism for OA ameliorating chemical liver injury and suggest a possible implementation for preventing the chemical liver injury.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061626
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1627: Nanoparticles for Signaling in Biodiagnosis and
           Treatment of Infectious Diseases

    • Authors: Clara I. Colino, Carmen Gutiérrez Millán, José M. Lanao
      First page: 1627
      Abstract: Advances in nanoparticle-based systems constitute a promising research area with important implications for the treatment of bacterial infections, especially against multidrug resistant strains and bacterial biofilms. Nanosystems may be useful for the diagnosis and treatment of viral and fungal infections. Commercial diagnostic tests based on nanosystems are currently available. Different methodologies based on nanoparticles (NPs) have been developed to detect specific agents or to distinguish between Gram-positive and Gram-negative microorganisms. Also, biosensors based on nanoparticles have been applied in viral detection to improve available analytical techniques. Several point-of-care (POC) assays have been proposed that can offer results faster, easier and at lower cost than conventional techniques and can even be used in remote regions for viral diagnosis. Nanoparticles functionalized with specific molecules may modulate pharmacokinetic targeting recognition and increase anti-infective efficacy. Quorum sensing is a stimuli-response chemical communication process correlated with population density that bacteria use to regulate biofilm formation. Disabling it is an emerging approach for combating its pathogenicity. Natural or synthetic inhibitors may act as antibiofilm agents and be useful for treating multi-drug resistant bacteria. Nanostructured materials that interfere with signal molecules involved in biofilm growth have been developed for the control of infections associated with biofilm-associated infections.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061627
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1628: Fascinating Fasciclins: A Surprisingly
           Widespread Family of Proteins that Mediate Interactions between the Cell
           Exterior and the Cell Surface

    • Authors: Georg J. Seifert
      First page: 1628
      Abstract: The Fasciclin 1 (FAS1) domain is an ancient structural motif in extracellular proteins present in all kingdoms of life and particularly abundant in plants. The FAS1 domain accommodates multiple interaction surfaces, enabling it to bind different ligands. The frequently observed tandem FAS1 arrangement might both positively and negatively regulate ligand binding. Additional protein domains and post-translational modifications are partially conserved between different evolutionary clades. Human FAS1 family members are associated with multiple aspects of health and disease. At the cellular level, mammalian FAS1 proteins are implicated in extracellular matrix structure, cell to extracellular matrix and cell to cell adhesion, paracrine signaling, intracellular trafficking and endocytosis. Mammalian FAS1 proteins bind to the integrin family of receptors and to protein and carbohydrate components of the extracellular matrix. FAS1 protein encoding plant genes exert effects on cellulosic and non-cellulosic cell wall structure and cellular signaling but to establish the modes of action for any plant FAS1 protein still requires biochemical experimentation. In fungi, eubacteria and archaea, the differential presence of FAS1 proteins in closely related organisms and isolated biochemical data suggest functions in pathogenicity and symbiosis. The inter-kingdom comparison of FAS1 proteins suggests that molecular mechanisms mediating interactions between cells and their environment may have evolved at the earliest known stages of evolution.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061628
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1629: Furosine Induced Apoptosis by the Regulation of
           STAT1/STAT2 and UBA7/UBE2L6 Genes in HepG2 Cells

    • Authors: Huiying Li, Lei Xing, Nan Zhao, Jiaqi Wang, Nan Zheng
      First page: 1629
      Abstract: As a typical product in the Miallard reaction, research on the quantitative detection of furosine is abundant, while its bioactivities and toxic effects are still unclear. Our own work recently demonstrated the induction of furosine on apoptosis in HepG2 cells, while the related mechanism remained elusive. In this study, the effects of furosine on cell viability and apoptosis were detected to select the proper dosage, and transcriptomics detection and data analysis were performed to screen out the special genes. Additionally, SiRNA fragments of the selected genes were designed and transfected into HepG2 cells to validate the role of these genes in inducing apoptosis. Results showed that furosine inhibited cell viability and induced cell apoptosis in a dose-dependent manner, as well as activated expressions of the selected genes STAT1 (signal transducer and activator of transcription 1), STAT2 (signal transducer and activator of transcription 2), UBA7 (ubiquitin-like modifier activating enzyme 7), and UBE2L6 (ubiquitin-conjugating enzyme E2L6), which significantly affected downstream apoptosis factors Caspase-3 (cysteinyl aspartate specific proteinase-3), Bcl-2 (B-cell lymphoma gene-2), Bax (BCL2-Associated gene X), and Caspase-9 (cysteinyl aspartate specific proteinase-9). For the first time, we revealed furosine induced apoptosis through two transcriptional regulators (STAT1 and STAT2) and two ubiquitination-related enzymes (UBA7 and UBE2L6).
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061629
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1630: Downregulations of AKT/mTOR Signaling Pathway
           for Salmonella-Mediated Suppression of Matrix Metalloproteinases-9
           Expression in Mouse Tumor Models

    • Authors: Yu-Tzu Tsao, Chun-Yu Kuo, Shun-Ping Cheng, Che-Hsin Lee
      First page: 1630
      Abstract: The roles of Matrix MetalloProteinases (MMPs), such as MMP-9, in tumor metastasis are well studied, and this in turns stimulates the development of MMP inhibitors as antitumor agents. Previously, Salmonella accumulation was observed in the metastatic nodules of the lungs after systemic administration. Salmonella significantly enhanced the survival of the pulmonary metastatic tumor-bearing mice. Based on our previous observation, we hypothesized that Salmonella could affect metastasis-related protein expression. The treatment of Salmonella clearly reduced the expression of MMP-9. Meanwhile, the MMP-9 related signaling pathways, including Phosph-Protein Kinase B (P-AKT) and Phosph-mammalian Targets Of Rapamycin (P-mTOR) were decreased after a Salmonella treatment. The Salmonella inhibited tumor cell migration by wound-healing and Transwell assay. The anti-metastatic effects of Salmonella were evaluated in mice bearing experimental metastasis tumor models. Consequently, Salmonella inhibited the expression of MMP-9 by reducing the AKT/mTOR pathway and metastatic nodules in vivo.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061630
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1631: Mir-34a-5p Mediates Cross-Talk between M2
           Muscarinic Receptors and Notch-1/EGFR Pathways in U87MG Glioblastoma
           Cells: Implication in Cell Proliferation

    • Authors: Maria Di Bari, Valeria Bevilacqua, Antonella De Jaco, Pietro Laneve, Roberta Piovesana, Laura Trobiani, Claudio Talora, Elisa Caffarelli, Ada Maria Tata
      First page: 1631
      Abstract: Glioblastoma (GBM) is the most aggressive human brain tumor. The high growth potential and decreased susceptibility to apoptosis of the glioma cells is mainly dependent on genetic amplifications or mutations of oncogenic or pro-apoptotic genes, respectively. We have previously shown that the activation of the M2 acetylcholine muscarinic receptors inhibited cell proliferation and induced apoptosis in two GBM cell lines and cancer stem cells. The aim of this study was to delve into the molecular mechanisms underlying the M2-mediated cell proliferation arrest. Exploiting U87MG and U251MG cell lines as model systems, we evaluated the ability of M2 receptors to interfere with Notch-1 and EGFR pathways, whose activation promotes GBM proliferation. We demonstrated that the activation of M2 receptors, by agonist treatment, counteracted Notch and EGFR signaling, through different regulatory cascades depending, at least in part, on p53 status. Only in U87MG cells, which mimic p53-wild type GBMs, did M2 activation trigger a molecular circuitry involving p53, Notch-1, and the tumor suppressor mir-34a-5p. This regulatory module negatively controls Notch-1, which affects cell proliferation mainly through the Notch-1/EGFR axis. Our data highlighted, for the first time, a molecular circuitry that is deregulated in the p53 wild type GBM, based on the cross-talk between M2 receptor and the Notch-1/EGFR pathways, mediated by mir-34a-5p.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061631
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1632: Bacterial Toxins and Targeted Brain Therapy:
           New Insights from Cytotoxic Necrotizing Factor 1 (CNF1)

    • Authors: Elena Tantillo, Antonella Colistra, Eleonora Vannini, Chiara Cerri, Laura Pancrazi, Laura Baroncelli, Mario Costa, Matteo Caleo
      First page: 1632
      Abstract: Pathogenic bacteria produce toxins to promote host invasion and, therefore, their survival. The extreme potency and specificity of these toxins confer to this category of proteins an exceptionally strong potential for therapeutic exploitation. In this review, we deal with cytotoxic necrotizing factor (CNF1), a cytotoxin produced by Escherichia coli affecting fundamental cellular processes, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation, cell survival and migration. First, we provide an overview of the mechanisms of action of CNF1 in target cells. Next, we focus on the potential use of CNF1 as a pharmacological treatment in central nervous system’s diseases. CNF1 appears to impact neuronal morphology, physiology, and plasticity and displays an antineoplastic activity on brain tumors. The ability to preserve neural functionality and, at the same time, to trigger senescence and death of proliferating glioma cells, makes CNF1 an encouraging new strategy for the treatment of brain tumors.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061632
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1633: Tuning the Mechanical Properties of a DNA
           Hydrogel in Three Phases Based on ATP Aptamer

    • Authors: Hengyuan Liu, Tianyang Cao, Yun Xu, Yuanchen Dong, Dongsheng Liu
      First page: 1633
      Abstract: By integrating ATP aptamer into the linker DNA, a novel DNA hydrogel was designed, with mechanical properties that could be tuned into three phases. Based on the unique interaction between ATP and its aptamer, the mechanical strength of the hydrogel increased from 204 Pa to 380 Pa after adding ATP. Furthermore, with the addition of the complementary sequence to the ATP aptamer, the mechanical strength could be increased to 570 Pa.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061633
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1634: Revisiting the Role of Plant Transcription
           Factors in the Battle against Abiotic Stress

    • Authors: Sardar-Ali Khan, Meng-Zhan Li, Suo-Min Wang, Hong-Ju Yin
      First page: 1634
      Abstract: Owing to diverse abiotic stresses and global climate deterioration, the agricultural production worldwide is suffering serious losses. Breeding stress-resilient crops with higher quality and yield against multiple environmental stresses via application of transgenic technologies is currently the most promising approach. Deciphering molecular principles and mining stress-associate genes that govern plant responses against abiotic stresses is one of the prerequisites to develop stress-resistant crop varieties. As molecular switches in controlling stress-responsive genes expression, transcription factors (TFs) play crucial roles in regulating various abiotic stress responses. Hence, functional analysis of TFs and their interaction partners during abiotic stresses is crucial to perceive their role in diverse signaling cascades that many researchers have continued to undertake. Here, we review current developments in understanding TFs, with particular emphasis on their functions in orchestrating plant abiotic stress responses. Further, we discuss novel molecular mechanisms of their action under abiotic stress conditions. This will provide valuable information for understanding regulatory mechanisms to engineer stress-tolerant crops.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061634
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1635: Extension of Tissue Plasminogen Activator
           Treatment Window by Granulocyte-Colony Stimulating Factor in a
           Thromboembolic Rat Model of Stroke

    • Authors: Ike C. dela Peña, Samuel Yang, Guofang Shen, Hsiao Fang Liang, Sara Solak, Cesar V. Borlongan
      First page: 1635
      Abstract: When given beyond 4.5 h of stroke onset, tissue plasminogen activator (tPA) induces deleterious side effects in the ischemic brain, notably, hemorrhagic transformation (HT). We examined the efficacy of granulocyte-colony stimulating factor (G-CSF) in reducing delayed tPA-induced HT, cerebral infarction, and neurological deficits in a thromboembolic (TE) stroke model, and whether the effects of G-CSF were sustained for longer periods of recovery. After stroke induction, rats were given intravenous saline (control), tPA (10 mg/kg), or G-CSF (300 μg/kg) + tPA 6 h after stroke. We found that G-CSF reduced delayed tPA-associated HT by 47%, decreased infarct volumes by 33%, and improved motor and neurological deficits by 15% and 25%, respectively. It also prevented delayed tPA treatment-induced mortality by 46%. Immunohistochemistry showed 1.5- and 1.8-fold enrichment of the endothelial progenitor cell (EPC) markers CD34+ and VEGFR2 in the ischemic cortex and striatum, respectively, and 1.7- and 2.8-fold increases in the expression of the vasculogenesis marker von Willebrand factor (vWF) in the ischemic cortex and striatum, respectively, in G-CSF-treated rats compared with tPA-treated animals. Flow cytometry revealed increased mobilization of CD34+ cells in the peripheral blood of rats given G-CSF. These results corroborate the efficacy of G-CSF in enhancing the therapeutic time window of tPA for stroke treatment via EPC mobilization and enhancement of vasculogenesis.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061635
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1636: Fewer Functional Deficits and Reduced Cell
           Death after Ranibizumab Treatment in a Retinal Ischemia Model

    • Authors: Marina Palmhof, Stephanie Lohmann, Dustin Schulte, Gesa Stute, Natalie Wagner, H. Burkhard Dick, Stephanie C. Joachim
      First page: 1636
      Abstract: Retinal ischemia is an important factor in several eye disorders. To investigate the impact of VEGF inhibitors, as a therapeutic option, we studied these in a retinal ischemia animal model. Therefore, animals received bevacizumab or ranibizumab intravitreally one day after ischemia induction. Via electroretinography, a significant decrease in a- and b-wave amplitudes was detected fourteen days after ischemia, but they were reduced to a lesser extent in the ranibizumab group. Ischemic and bevacizumab retinae displayed fewer retinal ganglion cells (RGCs), while no significant cell loss was noted in the ranibizumab group. Apoptosis was reduced after therapy. More autophagocytotic cells were observed in ischemic and bevacizumab eyes, but not in ranibizumab eyes. Additionally, more microglia, as well as active ones, were revealed in all ischemic groups, but the increase was less prominent under ranibizumab treatment. Fewer cone bipolar cells were detected in ischemic eyes, in contrast to bevacizumab and ranibizumab-treated ones. Our results demonstrate a reduced apoptosis and autophagocytosis rate after ranibizumab treatment. Furthermore, a certain protection was seen regarding functionality, RGC, and bipolar cell availability, as well as microglia activation by ranibizumab treatment after ischemic damage. Thus, ranibizumab could be an option for treatment of retinal ischemic injury.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061636
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1637: Use of Curcumin, a Natural Polyphenol for
           Targeting Molecular Pathways in Treating Age-Related Neurodegenerative
           Diseases

    • Authors: Panchanan Maiti, Gary Leo. Dunbar
      First page: 1637
      Abstract: Progressive accumulation of misfolded amyloid proteins in intracellular and extracellular spaces is one of the principal reasons for synaptic damage and impairment of neuronal communication in several neurodegenerative diseases. Effective treatments for these diseases are still lacking but remain the focus of much active investigation. Despite testing several synthesized compounds, small molecules, and drugs over the past few decades, very few of them can inhibit aggregation of amyloid proteins and lessen their neurotoxic effects. Recently, the natural polyphenol curcumin (Cur) has been shown to be a promising anti-amyloid, anti-inflammatory and neuroprotective agent for several neurodegenerative diseases. Because of its pleotropic actions on the central nervous system, including preferential binding to amyloid proteins, Cur is being touted as a promising treatment for age-related brain diseases. Here, we focus on molecular targeting of Cur to reduce amyloid burden, rescue neuronal damage, and restore normal cognitive and sensory motor functions in different animal models of neurodegenerative diseases. We specifically highlight Cur as a potential treatment for Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases. In addition, we discuss the major issues and limitations of using Cur for treating these diseases, along with ways of circumventing those shortcomings. Finally, we provide specific recommendations for optimal dosing with Cur for treating neurological diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061637
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1638: Anti-Apoptosis and Anti-Fibrosis Effects of
           Eriobotrya Japonica in Spontaneously Hypertensive Rat Hearts

    • Authors: Jui-Ting Chiang, Khan Farheen Badrealam, Marthandam Asokan Shibu, Sue-Fei Cheng, Chia-Yao Shen, Chih-Feng Chang, Yueh-Min Lin, Vijaya Padma Viswanadha, Shih-Chieh Liao, Chih-Yang Huang
      First page: 1638
      Abstract: Myocardial apoptosis and fibrosis represent important contributing factors for development of hypertension-induced heart failure. The present study aims to investigate the potential effects of Eriobotrya japonica leaf extract (EJLE) against hypertension-induced cardiac apoptosis and fibrosis in spontaneously hypertensive rats (SHRs). Twelve-week-old male rats were randomly divided into four different groups; control Wistar Kyoto (WKY) rats, hypertensive SHR rats, SHR rats treated with a low dose (100 mg/kg body weight) of EJLE and SHR rats treated with a high dose (300 mg/kg body weight) of EJLE. Animals were acclimatized for 4 weeks and thereafter were gastric fed for 8 weeks with two doses of EJLE per week. The rats were then euthanized following cardiac functional analysis by echocardiography. The cardiac tissue sections were examined by Terminal Deoxynucleotidyl Transferase-Mediated Deoxyuridine Triphosphate (dUTP) Nick End-Labeling (TUNEL) assay, histological staining and Western blotting to assess the cardio-protective effects of EJ in SHR animals. Echocardiographic measurements provided convincing evidence to support the ability of EJ to ameliorate crucial cardiac functional characteristics. Furthermore, our results reveal that supplementation of EJLE effectively attenuated cardiac apoptosis and fibrosis and also enhanced cell survival in hypertensive SHR hearts. Thus, the present study concludes that EJLE potentially provides cardio-protective effects against hypertension-induced cardiac apoptosis and fibrosis in SHR animals.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-05-31
      DOI: 10.3390/ijms19061638
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1639: Metabolic Dysfunction and Peroxisome
           Proliferator-Activated Receptors (PPAR) in Multiple Sclerosis

    • Authors: Véronique Ferret-Sena, Carlos Capela, Armando Sena
      First page: 1639
      Abstract: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) probably caused, in most cases, by the interaction of genetic and environmental factors. This review first summarizes some clinical, epidemiological and pathological characteristics of MS. Then, the involvement of biochemical pathways is discussed in the development and repair of the CNS lesions and the immune dysfunction in the disease. Finally, the potential roles of peroxisome proliferator-activated receptors (PPAR) in MS are discussed. It is suggested that metabolic mechanisms modulated by PPAR provide a window to integrate the systemic and neurological events underlying the pathogenesis of the disease. In conclusion, the reviewed data highlight molecular avenues of understanding MS that may open new targets for improved therapies and preventive strategies for the disease.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061639
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1640: Downregulation of α-Melanocyte-Stimulating
           Hormone-Induced Activation of the Pax3-MITF-Tyrosinase Axis by Sorghum
           Ethanolic Extract in B16F10 Melanoma Cells

    • Authors: Da Hyun Lee, Sung Shin Ahn, Jung-Bong Kim, Yoongho Lim, Young Han Lee, Soon Young Shin
      First page: 1640
      Abstract: Ultraviolet irradiation-induced hyperpigmentation of the skin is associated with excessive melanin production in melanocytes. Tyrosinase (TYR) is a key enzyme catalyzing the rate-limiting step in melanogenesis. TYR expression is controlled by microphthalmia-associated transcription factor (MITF) expression. Sorghum is a cereal crop widely used in a variety of foods worldwide. Sorghum contains many bioactive compounds and is beneficial to human health. However, the effects of sorghum in anti-melanogenesis have not been well characterized. In this study, the biological activity of sorghum ethanolic extract (SEE) on α-melanocyte-stimulating hormone (α-MSH)-induced TYR expression was evaluated in B16F10 melanoma cells. SEE attenuated α-MSH-induced TYR gene promoter activity through the downregulation of the transcription factor MITF. We found that paired box gene 3 (Pax3) contributes to the maximal induction of MITF gene promoter activity. Further analysis demonstrated that SEE inhibited α-MSH-induced Pax3 expression. The collective results indicate that SEE attenuates α-MSH-induced TYR expression through the suppression of Pax3-mediated MITF gene promoter activity. Targeting the Pax3-MITF axis pathway could be considered a potential strategy to increase the efficacy of anti-melanogenesis.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061640
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1641: Biomimetic Layer-by-Layer Self-Assembly of
           Nanofilms, Nanocoatings, and 3D Scaffolds for Tissue Engineering

    • Authors: Shichao Zhang, Malcolm Xing, Bingyun Li
      First page: 1641
      Abstract: Achieving surface design and control of biomaterial scaffolds with nanometer- or micrometer-scaled functional films is critical to mimic the unique features of native extracellular matrices, which has significant technological implications for tissue engineering including cell-seeded scaffolds, microbioreactors, cell assembly, tissue regeneration, etc. Compared with other techniques available for surface design, layer-by-layer (LbL) self-assembly technology has attracted extensive attention because of its integrated features of simplicity, versatility, and nanoscale control. Here we present a brief overview of current state-of-the-art research related to the LbL self-assembly technique and its assembled biomaterials as scaffolds for tissue engineering. An overview of the LbL self-assembly technique, with a focus on issues associated with distinct routes and driving forces of self-assembly, is described briefly. Then, we highlight the controllable fabrication, properties, and applications of LbL self-assembly biomaterials in the forms of multilayer nanofilms, scaffold nanocoatings, and three-dimensional scaffolds to systematically demonstrate advances in LbL self-assembly in the field of tissue engineering. LbL self-assembly not only provides advances for molecular deposition but also opens avenues for the design and development of innovative biomaterials for tissue engineering.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061641
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1642: VEGF Upregulation in Viral Infections and Its
           Possible Therapeutic Implications

    • Authors: Khaled R. Alkharsah
      First page: 1642
      Abstract: Several viruses are recognized as the direct or indirect causative agents of human tumors and other severe human diseases. Vascular endothelial growth factor (VEGF) is identified as a principal proangiogenic factor that enhances the production of new blood vessels from existing vascular network. Therefore, oncogenic viruses such as Kaposi’s sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) and non-oncogenic viruses such as herpes simplex virus (HSV-1) and dengue virus, which lack their own angiogenic factors, rely on the recruitment of cellular genes for angiogenesis in tumor progression or disease pathogenesis. This review summarizes how human viruses exploit the cellular signaling machinery to upregulate the expression of VEGF and benefit from its physiological functions for their own pathogenesis. Understanding the interplay between viruses and VEGF upregulation will pave the way to design targeted and effective therapeutic approaches for viral oncogenesis and severe diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061642
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1643: Treatment with Obestatin—A Ghrelin
           Gene-Encoded Peptide—Reduces the Severity of Experimental Colitis Evoked
           by Trinitrobenzene Sulfonic Acid

    • Authors: Katarzyna Konarska, Jakub Cieszkowski, Zygmunt Warzecha, Piotr Ceranowicz, Anna Chmura, Beata Kuśnierz-Cabala, Krystyna Gałązka, Paweł Kowalczyk, Andrzej Miskiewicz, Thomas Jan Konturek, Michał Pędziwiatr, Artur Dembiński
      First page: 1643
      Abstract: Obestatin is a 23-amino acid peptide derived from proghrelin, a common prohormone for ghrelin and obestatin. Previous studies showed that obestatin exhibited some protective and therapeutic effects in the gut. The aim of our presented study was to examine the effect of treatment with obestatin on trinitrobenzene sulfonic acid (TNBS)-induced colitis. In rats anesthetized with ketamine, colitis was induced through intrarectal administration of 25 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Obestatin was administered intraperitoneally at doses of 4, 8, or 16 nmol/kg, twice per day for four consecutive days. The first dose of obestatin was given one day before the induction of colitis, and the last one was given two days after administration of TNBS. Fourteen days after the induction of colitis, rats were anesthetized again with ketamine, and the severity of colitis was determined. The administration of obestatin had no effect on the parameters tested in rats without the induction of colitis. In rats with colitis, administration of obestatin at doses of 8 or 16 nmol/kg reduced the area of colonic damage, and improved mucosal blood flow in the colon. These effects were accompanied by a reduction in the colitis-evoked increase in the level of blood leukocytes, and mucosal concentration of pro-inflammatory interleukin-1β. Moreover, obestatin administered at doses of 8 or 16 nmol/kg reduced histological signs of colonic damage. The administration of obestatin at a dose of 4 nmol/kg failed to significantly affect the parameters tested. Overall, treatment with obestatin reduced the severity of TNBS-induced colitis in rats. This effect was associated with an improvement in mucosal blood flow in the colon, and a decrease in local and systemic inflammatory processes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061643
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1644: Butterbur Leaves Attenuate Memory Impairment
           and Neuronal Cell Damage in Amyloid Beta-Induced Alzheimer’s Disease
           Models

    • Authors: Namkwon Kim, Jin Gyu Choi, Sangsu Park, Jong Kil Lee, Myung Sook Oh
      First page: 1644
      Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation of amyloid beta (Aβ) as a pathological hallmark. Aβ plays a central role in neuronal degeneration and synaptic dysfunction through the generation of excessive oxidative stress. In the present study, we explored whether leaves of Petasites japonicus (Siebold & Zucc.) Maxim. (PL), called butterbur and traditionally used in folk medicine, show neuroprotective action against Aβ25–35 plaque neurotoxicity in vitro and in vivo. We found that PL protected Aβ25–35 plaque-induced neuronal cell death and intracellular reactive oxygen species generation in HT22 cells by elevating expression levels of phosphorylated cyclic AMP response element-binding protein, heme oxygenase-1, and NAD(P)H quinine dehydrogenase 1. These neuroprotective effects of PL were also observed in Aβ25–35 plaque-injected AD mouse models. Moreover, administration of PL diminished Aβ25–35 plaque-induced synaptic dysfunction and memory impairment in mice. These findings lead us to suggest that PL can protect neurons against Aβ25–35 plaque-induced neurotoxicity and thus may be a potential candidate to regulate the progression of AD.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061644
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1645: Connexins and Pannexins: Important Players in
           Tumorigenesis, Metastasis and Potential Therapeutics

    • Authors: Sheila V. Graham, Jean X. Jiang, Marc Mesnil
      First page: 1645
      Abstract: Since their characterization more than five decades ago, gap junctions and their structural proteins—the connexins—have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. It appeared that if gap junctions or connexins can down regulate cancer cell growth they can be also implied in the migration, invasion and metastatic dissemination of cancer cells. Interestingly, in all these situations, connexins seem to be involved through various mechanisms in which they can act either as gap-junctional intercellular communication mediators, modulators of signalling pathways through their interactome, or as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in cancer progression is even more complicated by the fact that their hemichannel function may overlap with other gap junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061645
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1646: LAT1-Targeting Thermoresponsive Fluorescent
           Polymer Probes for Cancer Cell Imaging

    • Authors: Minami Matsuura, Mariko Ohshima, Yuki Hiruta, Tomohiro Nishimura, Kenichi Nagase, Hideko Kanazawa
      First page: 1646
      Abstract: L-type amino acid transporter 1 (LAT1) is more highly expressed in cancer cells compared with normal cells. LAT1 targeting probes would therefore be a promising tool for cancer cell imaging. In this study, LAT1-targeting thermoresponsive fluorescent polymer probes based on poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(NIPAAm-co-DMAAm)) were synthesized and their affinity for LAT1 was evaluated. The synthesized polymer probes interacted with LAT1 on HeLa cells, and inhibition of l-[3H]-leucine, one of the substrates for LAT1 uptake, was investigated. l-Tyrosine-conjugated P(NIPAAm-co-DMAAm) inhibited the uptake of l-[3H]-leucine, while P(NIPAAm-co-DMAAm) and l-phenylalanine-conjugated P(NIPAAm-co-DMAAm) did not. This result indicated that l-tyrosine-conjugated polymer has a high affinity for LAT1. The fluorescent polymer probes were prepared by modification of a terminal polymer group with fluorescein-5-maleimide (FL). Above the polymer transition temperature, cellular uptake of the polymer probes was observed because the polymers became hydrophobic, which enhanced the interaction with the cell membrane. Furthermore, quantitative analysis of the fluorescent probe using flow cytometry indicated that l-tyrosine-conjugated P(NIPAAm-co-DMAAm)-FL shows higher fluorescence intensity earlier than P(NIPAAm-co-DMAAm)-FL. The result suggested that cellular uptake was promoted by the LAT1 affinity site. The developed LAT1-targeting thermoresponsive fluorescent polymer probes are expected to be useful for cancer cell imaging.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-01
      DOI: 10.3390/ijms19061646
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1647: Current Knowledge on Endocrine Disrupting
           Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to
           Adulthood: Highlights from a National Italian Meeting

    • Authors: Maria Elisabeth Street, Sabrina Angelini, Sergio Bernasconi, Ernesto Burgio, Alessandra Cassio, Cecilia Catellani, Francesca Cirillo, Annalisa Deodati, Enrica Fabbrizi, Vassilios Fanos, Giancarlo Gargano, Enzo Grossi, Lorenzo Iughetti, Pietro Lazzeroni, Alberto Mantovani, Lucia Migliore, Paola Palanza, Giancarlo Panzica, Anna Maria Papini, Stefano Parmigiani, Barbara Predieri, Chiara Sartori, Gabriele Tridenti, Sergio Amarri
      First page: 1647
      Abstract: Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-02
      DOI: 10.3390/ijms19061647
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1648: Signal Transduction in Plant–Nematode
           Interactions

    • Authors: Muhammad Amjad Ali, Muhammad Shahzad Anjam, Muhammad Amjad Nawaz, Hon-Ming Lam, Gyuhwa Chung
      First page: 1648
      Abstract: To successfully invade and infect their host plants, plant parasitic nematodes (PPNs) need to evolve molecular mechanisms to overcome the defense responses from the plants. Nematode-associated molecular patterns (NAMPs), including ascarosides and certain proteins, while instrumental in enabling the infection, can be perceived by the host plants, which then initiate a signaling cascade leading to the induction of basal defense responses. To combat host resistance, some nematodes can inject effectors into the cells of susceptible hosts to reprogram the basal resistance signaling and also modulate the hosts’ gene expression patterns to facilitate the establishment of nematode feeding sites (NFSs). In this review, we summarized all the known signaling pathways involved in plant–nematode interactions. Specifically, we placed particular focus on the effector proteins from PPNs that mimic the signaling of the defense responses in host plants. Furthermore, we gave an updated overview of the regulation by PPNs of different host defense pathways such as salicylic acid (SA)/jasmonic acid (JA), auxin, and cytokinin and reactive oxygen species (ROS) signaling to facilitate their parasitic successes in plants. This review will enhance the understanding of the molecular signaling pathways involved in both compatible and incompatible plant–nematode interactions.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-02
      DOI: 10.3390/ijms19061648
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1649: Effects of Cyclic Mechanical Stretch on the
           Proliferation of L6 Myoblasts and Its Mechanisms: PI3K/Akt and MAPK Signal
           Pathways Regulated by IGF-1 Receptor

    • Authors: Shaoting Fu, Lijun Yin, Xiaojing Lin, Jianqiang Lu, Xiaohui Wang
      First page: 1649
      Abstract: Myoblast proliferation is crucial to skeletal muscle hypertrophy and regeneration. Our previous study indicated that mechanical stretch altered the proliferation of C2C12 myoblasts, associated with insulin growth factor 1 (IGF-1)-mediated phosphoinositide 3-kinase (PI3K)/Akt (also known as protein kinase B) and mitogen-activated protein kinase (MAPK) pathways through IGF-1 receptor (IGF-1R). The purpose of this study was to explore the same stretches on the proliferation of L6 myoblasts and its association with IGF-1-regulated PI3K/Akt and MAPK activations. L6 myoblasts were divided into three groups: control, 15% stretch, and 20% stretch. Stretches were achieved using FlexCell Strain Unit. Cell proliferation and IGF-1 concentration were detected by CCK8 and ELISA, respectively. IGF-1R expression, and expressions and activities of PI3K, Akt, and MAPKs (including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38) were determined by Western blot. We found that 15% stretch promoted, while 20% stretch inhibited L6 myoblast proliferation. A 15% stretch increased IGF-1R level, although had no effect on IGF-1 secretion of L6 myoblasts, and PI3K/Akt and ERK1/2 (not p38) inhibitors attenuated 15% stretch-induced pro-proliferation. Exogenous IGF-1 reversed 20% stretch-induced anti-proliferation, accompanied with increases in IGF-1R level as well as PI3K/Akt and MAPK (ERK1/2 and p38) activations. In conclusion, stretch regulated L6 myoblasts proliferation, which may be mediated by the changes in PI3K/Akt and MAPK activations regulated by IGF-1R, despite no detectable IGF-1 from stretched L6 myoblasts.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-02
      DOI: 10.3390/ijms19061649
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1650: Differential Effects of Statins on Inflammatory
           Interleukin-8 and Antimicrobial Peptide Human Β-Defensin 2 Responses in
           Salmonella-Infected Intestinal Epithelial Cells

    • Authors: Fu-Chen Huang, Shun-Chen Huang
      First page: 1650
      Abstract: Alternative therapies are needed to reduce the use of antibiotics and incidence of drug-resistant Salmonellosis. Previous studies have revealed important roles of statins in regulating innate immunity. Therefore, we investigated the effects of statins on innate immunity in Salmonella-infected intestinal epithelial cells (IECs), which are involved in mucosal innate immunity. SW480 cells and Akt siRNA- or vitamin D receptor (VDR) siRNA-transfected SW480 cells were infected by wild-type S. Typhimurium strain SL1344 in the presence or absence of statins. The mRNA or protein expression was analyzed by real-time quantitative PCR or western blot analysis, respectively. Simvastatin or fluvastatin caused IL-8 (interleukin-8) suppression, but increased hBD-2 mRNA expression in Salmonella-infected SW480 cells. Both statins enhanced phosphorylated Akt and VDR expressions. Akt or VDR knockdown by siRNA counteracted the suppressive effect of simvastatin on IL-8 expression, whereas VDR knockdown diminished the enhanced hBD-2 expression in Salmonella-infected SW480 cells. Therefore, we observed differential regulation of statins on inflammatory IL-8 and anti-microbial hBD-2 expressions in Salmonella-infected IECs via PI3K/Akt signaling and VDR protein expression, respectively. The enhanced activity of antimicrobial peptides by statins in Salmonella-infected IECs could protect the host against infection, and modulation of pro-inflammatory responses could prevent the detrimental effects of overwhelming inflammation in the host.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-02
      DOI: 10.3390/ijms19061650
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1651: Impaired Photic Entrainment of Spontaneous
           Locomotor Activity in Mice Overexpressing Human Mutant α-Synuclein

    • Authors: Martina Pfeffer, Zuzana Zimmermann, Suzana Gispert, Georg Auburger, Horst-Werner Korf, Charlotte von Gall
      First page: 1651
      Abstract: Parkinson’s disease (PD) is characterized by distinct motor and non-motor symptoms. Sleep disorders are the most frequent and challenging non-motor symptoms in PD patients, and there is growing evidence that they are a consequence of disruptions within the circadian system. PD is characterized by a progressive degeneration of the dorsal vagal nucleus and midbrain dopaminergic neurons together with an imbalance of many other neurotransmitters. Mutations in α-synuclein (SNCA), a protein modulating SNARE complex-dependent neurotransmission, trigger dominantly inherited PD variants and sporadic cases of PD. The A53T SNCA missense mutation is associated with an autosomal dominant early-onset familial PD. To test whether this missense mutation affects the circadian system, we analyzed the spontaneous locomotor behavior of non-transgenic wildtype mice and transgenic mice overexpressing mutant human A53T α-synuclein (A53T). The mice were subjected to entrained- and free-running conditions as well as to experimental jet lag. Furthermore, the vesicular glutamate transporter 2 (VGLUT2) in the suprachiasmatic nucleus (SCN) was analyzed by immunohistochemistry. Free-running circadian rhythm and, thus, circadian rhythm generation, were not affected in A53T mice. A53T mice entrained to the light–dark cycle, however, with an advanced phase angle of 2.65 ± 0.5 h before lights off. Moreover, re-entrainment after experimental jet lag was impaired in A53T mice. Finally, VGLUT2 immunoreaction was reduced in the SCN of A53T mice. These data suggest an impaired light entrainment of the circadian system in A53T mice.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-03
      DOI: 10.3390/ijms19061651
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1652: Mechanism of Salt-Induced Self-Compatibility
           Dissected by Comparative Proteomic Analysis in Brassica napus L.

    • Authors: Yong Yang, Zhiquan Liu, Tong Zhang, Guilong Zhou, Zhiqiang Duan, Bing Li, Shengwei Dou, Xiaomei Liang, Jinxing Tu, Jinxiong Shen, Bin Yi, Tingdong Fu, Cheng Dai, Chaozhi Ma
      First page: 1652
      Abstract: Self-incompatibility (SI) in plants genetically prevents self-fertilization to promote outcrossing and genetic diversity. Its hybrids in Brassica have been widely cultivated due to the propagation of SI lines by spraying a salt solution. We demonstrated that suppression of Brassica napus SI from edible salt solution treatment was ascribed to sodium chloride and independent of S haplotypes, but it did not obviously change the expression of SI-related genes. Using the isobaric tags for relative and absolute quantitation (iTRAQ) technique, we identified 885 differentially accumulated proteins (DAPs) in Brassica napus stigmas of un-pollinated (UP), pollinated with compatible pollen (PC), pollinated with incompatible pollen (PI), and pollinated with incompatible pollen after edible salt solution treatment (NA). Of the 307 DAPs in NA/UP, 134 were unique and 94 were shared only with PC/UP. In PC and NA, some salt stress protein species, such as glyoxalase I, were induced, and these protein species were likely to participate in the self-compatibility (SC) pathway. Most of the identified protein species were related to metabolic pathways, biosynthesis of secondary metabolites, ribosome, and so on. A systematic analysis implied that salt treatment-overcoming SI in B. napus was likely conferred by at least five different physiological mechanisms: (i) the use of Ca2+ as signal molecule; (ii) loosening of the cell wall to allow pollen tube penetration; (iii) synthesis of compatibility factor protein species for pollen tube growth; (iv) depolymerization of microtubule networks to facilitate pollen tube movement; and (v) inhibition of protein degradation pathways to restrain the SI response.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-03
      DOI: 10.3390/ijms19061652
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1653: Treadmill Running Ameliorates Destruction of
           Articular Cartilage and Subchondral Bone, Not Only Synovitis, in a
           Rheumatoid Arthritis Rat Model

    • Authors: Seiji Shimomura, Hiroaki Inoue, Yuji Arai, Shuji Nakagawa, Yuta Fujii, Tsunao Kishida, Shohei Ichimaru, Shinji Tsuchida, Toshiharu Shirai, Kazuya Ikoma, Osam Mazda, Toshikazu Kubo
      First page: 1653
      Abstract: We analyzed the influence of treadmill running on rheumatoid arthritis (RA) joints using a collagen-induced arthritis (CIA) rat model. Eight-week-old male Dark Agouti rats were randomly divided into four groups: The control group, treadmill group (30 min/day for 4 weeks from 10-weeks-old), CIA group (induced CIA at 8-weeks-old), and CIA + treadmill group. Destruction of the ankle joint was evaluated by histological analyses. Morphological changes of subchondral bone were analyzed by μ-CT. CIA treatment-induced synovial membrane invasion, articular cartilage destruction, and bone erosion. Treadmill running improved these changes. The synovial membrane in CIA rats produced a large amount of tumor necrosis factor-α and Connexin 43; production was significantly suppressed by treadmill running. On μ-CT of the talus, bone volume fraction (BV/TV) was significantly decreased in the CIA group. Marrow star volume (MSV), an index of bone loss, was significantly increased. These changes were significantly improved by treadmill running. Bone destruction in the talus was significantly increased with CIA and was suppressed by treadmill running. On tartrate-resistant acid phosphate and alkaline phosphatase (TRAP/ALP) staining, the number of osteoclasts around the pannus was decreased by treadmill running. These findings indicate that treadmill running in CIA rats inhibited synovial hyperplasia and joint destruction.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-03
      DOI: 10.3390/ijms19061653
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1654: Upregulation of FLG, LOR, and IVL Expression by
           Rhodiola crenulata Root Extract via Aryl Hydrocarbon Receptor:
           Differential Involvement of OVOL1

    • Authors: Akiko Hashimoto-Hachiya, Gaku Tsuji, Mika Murai, Xianghong Yan, Masutaka Furue
      First page: 1654
      Abstract: Rhodiola species are antioxidative, salubrious plants that are known to inhibit oxidative stress induced by ultraviolet and γ-radiation in epidermal keratinocytes. As certain phytochemicals activate aryl hydrocarbon receptors (AHR) or OVO-like 1 (OVOL1) to upregulate the expression of epidermal barrier proteins such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL), we investigated such regulation by Rhodiola crenulata root extract (RCE). We demonstrated that RCE induced FLG and LOR upregulation in an AHR-OVOL1-dependent fashion. However, RCE-mediated IVL upregulation was AHR-dependent but OVOL1-independent. Coordinated upregulation of skin barrier proteins by RCE via AHR may be beneficial in the management of barrier-disrupted inflammatory skin diseases such as atopic dermatitis.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061654
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1655: Biological Basis of Tumor Angiogenesis and
           Therapeutic Intervention: Past, Present, and Future

    • Authors: Girolamo Ranieri
      First page: 1655
      Abstract: n/a
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061655
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1656: A New Perspective: Mitochondrial Stat3 as a
           Regulator for Lymphocyte Function

    • Authors: Mercedes Rincon, Felipe Valença Pereira
      First page: 1656
      Abstract: Stat3 as a transcription factor regulating gene expression in lymphocytes during the immune response is well known. However, since the pioneering studies discovering the presence of Stat3 in mitochondria and its role in regulating mitochondrial metabolism, only a few studies have investigated this non-conventional function of Stat3 in lymphocytes. From this perspective, we review what is known about Stat3 as a transcription factor and what is known and unknown about mitochondrial Stat3 (mitoStat3) in lymphocytes. We also provide a framework to consider how some of the functions previously assigned to Stat3 as regulator of gene transcription could be mediated by mitoStat3 in lymphocytes. The goal of this review is to stimulate interest for future studies investigating mitoStat3 in the immune response that could lead to the generation of alternative pharmacological inhibitors of mitoStat3 for the treatment of chronic inflammatory diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061656
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1657: Some Biological Consequences of the Inhibition
           of Na,K-ATPase by Translationally Controlled Tumor Protein (TCTP)

    • Authors: Jiwon Jung, Seonhyung Ryu, In A Ki, Hyun Ae Woo, Kyunglim Lee
      First page: 1657
      Abstract: Na,K-ATPase is an ionic pump that regulates the osmotic equilibrium and membrane potential of cells and also functions as a signal transducer. The interaction of Na,K-ATPase with translationally controlled tumor protein (TCTP) results, among others, in the inhibition of the former’s pump activity and in the initiation of manifold biological and pathological phenomena. These phenomena include hypertension and cataract development in TCTP-overexpressing transgenic mice, as well as the induction of tumorigenesis signaling pathways and the activation of Src that ultimately leads to cell proliferation and migration. This review attempts to collate the biological effects of Na,K-ATPase and TCTP interaction and suggests that this interaction has the potential to serve as a possible therapeutic target for selected diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061657
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1658: The Pattern of Signatures in Gastric Cancer
           Prognosis

    • Authors: Julita Machlowska, Ryszard Maciejewski, Robert Sitarz
      First page: 1658
      Abstract: Gastric cancer is one of the most common malignancies worldwide and it is a fourth leading cause of cancer-related death. Carcinogenesis is a multistage disease process specified by the gradual procurement of mutations and epigenetic alterations in the expression of different genes, which finally lead to the occurrence of a malignancy. These genes have diversified roles regarding cancer development. Intracellular pathways are assigned to the expression of different genes, signal transduction, cell-cycle supervision, genomic stability, DNA repair, and cell-fate destination, like apoptosis, senescence. Extracellular pathways embrace tumour invasion, metastasis, angiogenesis. Altered expression patterns, leading the different clinical responses. This review highlights the list of molecular biomarkers that can be used for prognostic purposes and provide information on the likely outcome of the cancer disease in an untreated individual.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061658
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1659: Cx43 Channel Gating and Permeation: Multiple
           Phosphorylation-Dependent Roles of the Carboxyl Terminus

    • Authors: José F. Ek-Vitorín, Tasha K. Pontifex, Janis M. Burt
      First page: 1659
      Abstract: Connexin 43 (Cx43), a gap junction protein seemingly fit to support cardiac impulse propagation and synchronic contraction, is phosphorylated in normoxia by casein kinase 1 (CK1). However, during cardiac ischemia or pressure overload hypertrophy, this phosphorylation fades, Cx43 abundance decreases at intercalated disks and increases at myocytes’ lateral borders, and the risk of arrhythmia rises. Studies in wild-type and transgenic mice indicate that enhanced CK1-phosphorylation of Cx43 protects from arrhythmia, while dephosphorylation precedes arrhythmia vulnerability. The mechanistic bases of these Cx43 (de)phosphoform-linked cardiac phenotypes are unknown. We used patch-clamp and dye injection techniques to study the channel function (gating, permeability) of Cx43 mutants wherein CK1-targeted serines were replaced by aspartate (Cx43-CK1-D) or alanine (Cx43-CK1-A) to emulate phosphorylation and dephosphorylation, respectively. Cx43-CK1-D, but not Cx43-CK1-A, displayed high Voltage-sensitivity and variable permselectivity. Both mutants showed multiple channel open states with overall increased conductivity, resistance to acidification-induced junctional uncoupling, and hemichannel openings in normal external calcium. Modest differences in the mutant channels’ function and regulation imply the involvement of dissimilar structural conformations of the interacting domains of Cx43 in electrical and chemical gating that may contribute to the divergent phenotypes of CK1-(de)phospho-mimicking Cx43 transgenic mice and that may bear significance in arrhythmogenesis.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061659
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1660: Interaction of Nevirapine with the Peptide
           Binding Groove of HLA-DRB1*01:01 and Its Effect on the Conformation of
           HLA-Peptide Complex

    • Authors: Makoto Hirasawa, Katsunobu Hagihara, Koji Abe, Osamu Ando, Noriaki Hirayama
      First page: 1660
      Abstract: Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 and its possible effect on the position and orientation of the ligand peptide derived from hemagglutinin (HA). In silico analyses suggested that nevirapine interacts with HLA-DRB1*01:01 around the P4 pocket within the peptide binding groove and the HA peptide stably binds on top of nevirapine at the groove. The analyses also showed that binding of nevirapine at the groove will significantly change the inter-helical distances of the groove. An in vitro competitive assay showed that nevirapine (1000 μM) increases the binding of the HA peptide to HLA-DRB1*01:01 in an allele-specific manner. These results indicate that nevirapine might interact directly with the P4 pocket and modifies its structure, which could change the orientation of loaded peptides and the conformation of HLA-DRB1*01:01; these changes could be distinctively recognized by T-cell receptors. Through this molecular mechanism, nevirapine might stimulate the immune system, resulting in hepatic hypersensitivity reactions.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061660
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1661: TRAIL/NF-κB/CX3CL1 Mediated Onco-Immuno
           Crosstalk Leading to TRAIL Resistance of Pancreatic Cancer Cell Lines

    • Authors: Claudia Geismann, Wiebke Erhart, Frauke Grohmann, Stefan Schreiber, Günter Schneider, Heiner Schäfer, Alexander Arlt
      First page: 1661
      Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a challenging problem in the clinical field. One characteristic of PDAC is a distinct desmoplasia consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, contributing to therapy resistance. It is well established that the NF-κB signaling pathway controls inflammation, cancer progression and apoptosis resistance in PDAC. This study attempts to identify NF-κB target genes mediating therapy resistance of humane PDAC cell lines towards death ligand induced apoptosis. By using a genome wide unbiased approach the chemokine CX3CL1 was established as a central NF-κB target gene mediating therapy resistance. While no direct impact of CX3CL1 expression on cancer cell apoptosis was identified in co-culture assays it became apparent that CX3CL1 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells giving rise to therapy resistance.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061661
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1662: Regulation and Evolution of NLR Genes: A Close
           Interconnection for Plant Immunity

    • Authors: Grazia M. Borrelli, Elisabetta Mazzucotelli, Daniela Marone, Cristina Crosatti, Vania Michelotti, Giampiero Valè, Anna M. Mastrangelo
      First page: 1662
      Abstract: NLR (NOD-like receptor) genes belong to one of the largest gene families in plants. Their role in plants’ resistance to pathogens has been clearly described for many members of this gene family, and dysregulation or overexpression of some of these genes has been shown to induce an autoimmunity state that strongly affects plant growth and yield. For this reason, these genes have to be tightly regulated in their expression and activity, and several regulatory mechanisms are described here that tune their gene expression and protein levels. This gene family is subjected to rapid evolution, and to maintain diversity at NLRs, a plethora of genetic mechanisms have been identified as sources of variation. Interestingly, regulation of gene expression and evolution of this gene family are two strictly interconnected aspects. Indeed, some examples have been reported in which mechanisms of gene expression regulation have roles in promotion of the evolution of this gene family. Moreover, co-evolution of the NLR gene family and other gene families devoted to their control has been recently demonstrated, as in the case of miRNAs.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-04
      DOI: 10.3390/ijms19061662
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1663: Connexins and Pannexins in Vascular Function
           and Disease

    • Authors: Filippo Molica, Xavier F. Figueroa, Brenda R. Kwak, Brant E. Isakson, Jonathan M. Gibbins
      First page: 1663
      Abstract: Connexins (Cxs) and pannexins (Panxs) are ubiquitous membrane channel forming proteins that are critically involved in many aspects of vascular physiology and pathology. The permeation of ions and small metabolites through Panx channels, Cx hemichannels and gap junction channels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. This review provides an overview of current knowledge with respect to the pathophysiological role of these channels in large arteries, the microcirculation, veins, the lymphatic system and platelet function. The essential nature of these membrane proteins in vascular homeostasis is further emphasized by the pathologies that are linked to mutations and polymorphisms in Cx and Panx genes.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061663
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1664: Luteoloside Inhibits Proliferation and Promotes
           Intrinsic and Extrinsic Pathway-Mediated Apoptosis Involving MAPK and mTOR
           Signaling Pathways in Human Cervical Cancer Cells

    • Authors: Junli Shao, Chaoxi Wang, Linqiu Li, Hairong Liang, Juanxiu Dai, Xiaoxuan Ling, Huanwen Tang
      First page: 1664
      Abstract: Cervical cancer is a common gynecological malignancy with high incidence and mortality. Drugs commonly used in chemotherapy are often accompanied by strong side-effects. To find an anti-cervical cancer drug with high effects and low toxicity, luteoloside was used to treat the cervical cancer cell line Hela to investigate its effects on cell morphology, proliferation, apoptosis, and related proteins. The study demonstrated that luteoloside could inhibit proliferation remarkably; promote apoptosis and cytochrome C release; decrease the mitochondrial membrane potential and reactive oxygen species level; upregulate the expression of Fas, Bax, p53, phospho-p38, phospho-JNK, and cleaved PARP; downregulate the expression of Bcl-2 and phospho-mTOR; activate caspase-3 and caspase-8; change the nuclear morphology, and fragmentate DNA in Hela cells. These results strongly suggest that luteoloside can significantly inhibit the proliferation and trigger apoptosis in Hela cells. In contrast, luteoloside had less proliferation inhibiting effects on the normal cell lines HUVEC12 and LO2, and minor apoptosis promoting effects on HUVEC12 cells. Furthermore, the luteoloside-induced apoptosis in Hela cells is mediated by both intrinsic and extrinsic pathways and the effects of luteoloside may be regulated by the mitogen-activated protein kinases and mTOR signaling pathways via p53.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061664
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1665: Interleukin-34 Regulates Th1 and Th17 Cytokine
           Production by Activating Multiple Signaling Pathways through CSF-1R in
           Chicken Cell Lines

    • Authors: Anh Duc Truong, Yeojin Hong, Janggeun Lee, Kyungbaek Lee, Dong Yong Kil, Hyun S. Lillehoj, Yeong Ho Hong
      First page: 1665
      Abstract: Interleukin-34 (IL-34) is a newly recognized cytokine with functions similar to macrophage colony-stimulating factor 1. It is expressed in macrophages and fibroblasts, where it induces cytokine production; however, the mechanism of chicken IL-34 (chIL-34) signaling has not been identified to date. The aim of this study was to analyze the signal transduction pathways and specific biological functions associated with chIL-34 in chicken macrophage (HD11) and fibroblast (OU2) cell lines. We found that IL-34 is a functional ligand for the colony-stimulating factor receptor (CSF-1R) in chicken cell lines. Treatment with chIL-34 increased the expression of Th1 and Th17 cytokines through phosphorylation of tyrosine and serine residues in Janus kinase (JAK) 2, tyrosine kinase 2 (TYK2), signal transducer and activator of transcription (STAT) 1, STAT3, and Src homology 2-containing tyrosine phosphatase 2 (SHP-2), which also led to phosphorylation of NF-κB1, p-mitogen-activated protein kinase kinase kinase 7 (TAK1), MyD88, suppressor of cytokine signaling 1 (SOCS1), and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Taken together, these results suggest that chIL-34 functions by binding to CSF-1R and activating the JAK/STAT, nuclear factor κ B (NF-κB), and mitogen-activated protein kinase signaling pathways; these signaling events regulate cytokine expression and suggest roles for chIL-34 in innate and adaptive immunity.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061665
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1666: Wheat Gene TaATG8j Contributes to Stripe Rust
           Resistance

    • Authors: Md. Abdullah-Al Mamun, Chunlei Tang, Yingchao Sun, Md. Nazrul Islam, Peng Liu, Xiaojie Wang, Zhensheng Kang
      First page: 1666
      Abstract: Autophagy-related 8 (ATG8) protein has been reported to be involved in plant’s innate immune response, but it is not clear whether such genes play a similar role in cereal crops against obligate biotrophic fungal pathogens. Here, we reported an ATG8 gene from wheat (Triticum aestivum), designated TaATG8j. This gene has three copies located in chromosomes 2AS, 2BS, and 2DS. The transcriptions of all three copies were upregulated in plants of the wheat cultivar Suwon 11, inoculated with an avirulent race (CYR23) of Puccinia striiformis f. sp. tritici (Pst), the causal fungal pathogen of stripe rust. The transient expression of TaATG8j in Nicotiana benthamiana showed that TaATG8j proteins were distributed throughout the cytoplasm, but mainly in the nucleus and plasma membrane. The overexpression of TaATG8j in N. benthamiana slightly delayed the cell death caused by the mouse apoptotic protein BAX (BCL2-associated X protein). However, the expression of TaATG8j in yeast (Schizosaccharomyces pombe) induced cell death. The virus-induced gene silencing of all TaATG8j copies rendered Suwon 11 susceptible to the avirulent Pst race CYR23, accompanied by an increased fungal biomass and a decreased necrotic area per infection site. These results indicate that TaATG8j contributes to wheat resistance against stripe rust fungus by regulating cell death, providing information for the understanding of the mechanisms of wheat resistance to the stripe rust pathogen.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061666
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1667: Design of a Seed-Specific Chimeric Promoter
           with a Modified Expression Profile to Improve Seed Oil Content

    • Authors: Toshihiro Aoyagi, Masaya Kobayashi, Akiko Kozaki
      First page: 1667
      Abstract: Increasing the yield of plant oil is an important objective to meet the demand for sustainable resources and energy. Some attempts to enhance the expression of genes involved in oil synthesis in seeds have succeeded in increasing oil content. In many cases, the promoters of seed-storage protein genes have been used as seed-specific promoters. However, conventional promoters are developmentally regulated and their expression periods are limited. We constructed a chimeric promoter that starts to express in the early stage of seed development, and high-level expression is retained until the later stage by connecting the promoters of the biotin carboxyl carrier protein 2 (BCCP2) gene encoding the BCCP2 subunit of acetyl-CoA carboxylase and the fatty acid elongase 1 (FAE1) gene from Arabidopsis. The constructed promoter was ligated upstream of the TAG1 gene encoding diacylglycerol acyltransferase 1 and introduced into Arabidopsis. Seeds from transgenic plants carrying AtTAG1 under the control of the chimeric promoter showed increased oil content (up by 18–73%) compared with wild-type seeds. The novel expression profile of the chimeric promoter showed that this could be a promising strategy to manipulate the content of seed-storage oils and other compounds.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061667
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1668: Pyrrolizidine Alkaloids: Chemistry,
           Pharmacology, Toxicology and Food Safety

    • Authors: Rute Moreira, David M. Pereira, Patrícia Valentão, Paula B. Andrade
      First page: 1668
      Abstract: Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which can be exploited in drug discovery programs. In this work we review the current body of knowledge regarding the chemistry, toxicology, pharmacology and food safety of PA.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061668
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1669: Pathophysiological Mechanisms of Chronic Venous
           Disease and Implications for Venoactive Drug Therapy

    • Authors: Armando Mansilha, Joel Sousa
      First page: 1669
      Abstract: Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles of inflammation and endothelial dysfunction been properly assessed. Although still incompletely understood, current knowledge of the pathophysiological mechanisms of CVD reveals several potential targets and strategies for therapeutic intervention, some of which are addressable by currently available venoactive drugs. The roles of these drugs in the clinical improvement of venous tone and contractility, reduction of edema and inflammation, as well as in improved microcirculation and venous ulcer healing have been studied extensively, with favorable results reported in the literature. Here, we aim to review these pathophysiological mechanisms and their implications regarding currently available venoactive drug therapies.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061669
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1670: Methyl 3,4-Dihydroxybenzoate Enhances
           Resistance to Oxidative Stressors and Lifespan in C. elegans Partially via
           daf-2/daf-16

    • Authors: Xiang-Nan Mi, Li-Fang Wang, Yang Hu, Jun-Ping Pan, Yi-Rong Xin, Jia-Hui Wang, Hai-Ju Geng, Song-Hui Hu, Qin Gao, Huan-Min Luo
      First page: 1670
      Abstract: Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of C. elegans and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of eat-2 (ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span–extending activity of MDHB is completely abolished in daf-2 (e1370) mutations, which suggests that daf-2 is crucial for a MDHB-induced pro-longevity effect in C. elegans. Moreover, MDHB enhances the nuclear localization of daf-16/FoxO, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in C. elegans. Therefore, our results indicate that MDHB at least partially acts as a modulator of the daf-2/daf-16 pathway to extend the lifespan of C. elegans, and MDHB might be a promising therapeutic agent for age-related diseases.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061670
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1672: Vitamin D Receptor Is Necessary for
           Mitochondrial Function and Cell Health

    • Authors: Chiara Ricca, Alessia Aillon, Loredana Bergandi, Daniela Alotto, Carlotta Castagnoli, Francesca Silvagno
      First page: 1672
      Abstract: Vitamin D receptor (VDR) mediates many genomic and non-genomic effects of vitamin D. Recently, the mitochondrial effects of vitamin D have been characterized in many cell types. In this article, we investigated the importance of VDR not only in mitochondrial activity and integrity but also in cell health. The silencing of the receptor in different healthy, non-transformed, and cancer cells initially decreased cell growth and modulated the cell cycle. We demonstrated that, in silenced cells, the increased respiratory activity was associated with elevated reactive oxygen species (ROS) production. In the long run, the absence of the receptor caused impairment of mitochondrial integrity and, finally, cell death. Our data reveal that VDR plays a central role in protecting cells from excessive respiration and production of ROS that leads to cell damage. Because we confirmed our observations in different models of both normal and cancer cells, we conclude that VDR is essential for the health of human tissues.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061672
      Issue No: Vol. 19, No. 6 (2018)
       
  • IJMS, Vol. 19, Pages 1673: Rv0613c/MSMEG_1285 Interacts with HBHA and
           Mediates Its Proper Cell-Surface Exposure in Mycobacteria

    • Authors: Romain Veyron-Churlet, Vincent Dupres, Jean-Michel Saliou, Frank Lafont, Dominique Raze, Camille Locht
      First page: 1673
      Abstract: Heparin-binding haemagglutinin (HBHA) is a surface-exposed virulence factor of Mycobacterium tuberculosis and is involved in the binding of mycobacteria to non-phagocytic cells, allowing for extra-pulmonary dissemination of the bacilli. Despite its surface exposure, HBHA is not produced as a pre-protein containing a typical cleavable N-terminal signal peptide and is thus likely secreted by a Sec-independent, as of yet unknown mechanism. Here, we used the bacterial adenylate cyclase two-hybrid system to identify the proteins encoded by rv0613c and mmpL14 as being able to interact with HBHA. Our study was focused on Rv0613c, as it showed more consistent interactions with HBHA than MmpL14. Deletion of its orthologous gene MSMEG_1285 in recombinant Mycobacterium smegmatis producing HBHA from M. tuberculosis resulted in the loss of proper surface exposure of HBHA, as evidenced by atomic force microscopy. Furthermore, the lack of MSMEG_1285 also abolished the clumping phenotype and rough colony morphology of the recombinant M. smegmatis and reduced its adherence to A549 epithelial cells. These phenotypes have previously been associated with surface-exposed HBHA. Thus, MSMEG_1285 is directly involved in the proper cell-surface exposure of HBHA. These observations identify MSMEG_1285/Rv0613c as the first accessory protein involved in the cell surface exposure of HBHA.
      Citation: International Journal of Molecular Sciences
      PubDate: 2018-06-05
      DOI: 10.3390/ijms19061673
      Issue No: Vol. 19, No. 6 (2018)
       
 
 
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