Previous Issue

E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Table of Contents

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

  • Issues are regarded as officially published after their release is announced to the table of contents alert mailing list.
  • You may sign up for e-mail alerts to receive table of contents of newly released issues.
  • PDF is the official format for papers published in both, html and pdf forms. To view the papers in pdf format, click on the "PDF Full-text" link, and use the free Adobe Readerexternal link to open them.
View options order results:
result details:
Displaying articles 1-270
Export citation of selected articles as:
Open AccessArticle Different Myosin Head Conformations in Bony Fish Muscles Put into Rigor at Different Sarcomere Lengths
Int. J. Mol. Sci. 2018, 19(7), 2091; https://doi.org/10.3390/ijms19072091 (registering DOI)
Received: 30 June 2018 / Revised: 13 July 2018 / Accepted: 14 July 2018 / Published: 18 July 2018
PDF Full-text (1876 KB)
Abstract
At a resting sarcomere length of approximately 2.2 µm bony fish muscles put into rigor in the presence of BDM (2,3-butanedione monoxime) to reduce rigor tension generation show the normal arrangement of myosin head interactions with actin filaments as monitored by low-angle X-ray
[...] Read more.
At a resting sarcomere length of approximately 2.2 µm bony fish muscles put into rigor in the presence of BDM (2,3-butanedione monoxime) to reduce rigor tension generation show the normal arrangement of myosin head interactions with actin filaments as monitored by low-angle X-ray diffraction. However, if the muscles are put into rigor using the same protocol but stretched to 2.5 µm sarcomere length, a markedly different structure is observed. The X-ray diffraction pattern is not just a weaker version of the pattern at full overlap, as might be expected, but it is quite different. It is compatible with the actin-attached myosin heads being in a different conformation on actin, with the average centre of cross-bridge mass at a higher radius than in normal rigor and the myosin lever arms conforming less to the actin filament geometry, probably pointing back to their origins on their parent myosin filaments. The possible nature of this new rigor cross-bridge conformation is discussed in terms of other well-known states such as the weak binding state and the ‘roll and lock’ mechanism; we speculate that we may have trapped most myosin heads in an early attached strong actin-binding state in the cross-bridge cycle on actin. Full article
(This article belongs to the Special Issue The Actin-Myosin Interaction in Muscle)
Open AccessArticle Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton
Int. J. Mol. Sci. 2018, 19(7), 2090; https://doi.org/10.3390/ijms19072090 (registering DOI)
Received: 25 June 2018 / Revised: 13 July 2018 / Accepted: 17 July 2018 / Published: 18 July 2018
PDF Full-text (1685 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for
[...] Read more.
Background: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for clinical use. We anticipated that efficient lead finding and enhancement of activity toward nuclear receptors recognizing endogenous steroidal ligands might be achieved by exhaustive evaluation of a steroid surrogate library coupled with examination of structure-activity relationships (SAR). Method: We evaluated our library of RORs (retinoic acid receptor-related orphan receptors) inverse agonists and/or PR (progesterone receptor) antagonists based on the phenanthridinone skeleton for antagonistic activities toward liver X receptors (LXRs), androgen receptor (AR) and glucocorticoid receptor (GR) and examined their SAR. Results: Potent LXRβ, AR, and GR antagonists were identified. SAR studies led to a potent AR antagonist (IC50: 0.059 μM). Conclusions: Our approach proved effective for efficient lead finding, activity enhancement and preliminary control of selectivity over other receptors. The phenanthridinone skeleton appears to be a promising steroid surrogate. Full article
(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)
Figures

Graphical abstract

Open AccessArticle Using Spectral Representation to Classify Proteins’ Conformational States
Int. J. Mol. Sci. 2018, 19(7), 2089; https://doi.org/10.3390/ijms19072089 (registering DOI)
Received: 7 June 2018 / Revised: 27 June 2018 / Accepted: 28 June 2018 / Published: 18 July 2018
PDF Full-text (1732 KB) | HTML Full-text | XML Full-text
Abstract
Numerous proteins are molecular targets for drug action and hence are important in drug discovery. Structure-based computational drug discovery relies on detailed information regarding protein conformations for subsequent drug screening in silico. There are two key issues in analyzing protein conformations in virtual
[...] Read more.
Numerous proteins are molecular targets for drug action and hence are important in drug discovery. Structure-based computational drug discovery relies on detailed information regarding protein conformations for subsequent drug screening in silico. There are two key issues in analyzing protein conformations in virtual screening. The first considers the protein’s conformational change in response to physical and chemical conditions. The second is the protein’s atomic resolution reconstruction from X-ray crystallography or nuclear magnetic resonance (NMR) data. In this latter problem, information is needed regarding the sample’s position relative to the source of X-rays. Here, we introduce a new measure for classifying protein conformational states using spectral representation and Wigner’s D-functions. Predictions based on the new measure are in good agreement with conformational states of proteins. These results could also be applied to improve conformational alignment of the snapshots given by protein crystallography. Full article
Figures

Graphical abstract

Open AccessArticle Transcriptome Analyses from Mutant Salvia miltiorrhiza Reveals Important Roles for SmGASA4 during Plant Development
Int. J. Mol. Sci. 2018, 19(7), 2088; https://doi.org/10.3390/ijms19072088 (registering DOI)
Received: 22 June 2018 / Revised: 13 July 2018 / Accepted: 13 July 2018 / Published: 18 July 2018
PDF Full-text (2671 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Salvia miltiorrhiza (S. miltiorrhiza) is an important Chinese herb that is derived from the perennial plant of Lamiaceae, which has been used to treat neurasthenic insomnia and cardiovascular disease. We produced a mutant S. miltiorrhiza (MT), from breeding experiments, that possessed
[...] Read more.
Salvia miltiorrhiza (S. miltiorrhiza) is an important Chinese herb that is derived from the perennial plant of Lamiaceae, which has been used to treat neurasthenic insomnia and cardiovascular disease. We produced a mutant S. miltiorrhiza (MT), from breeding experiments, that possessed a large taproot, reduced lateral roots, and defective flowering. We performed transcriptome profiling of wild type (WT) and MT S. miltiorrhiza using second-generation Illumina sequencing to identify differentially expressed genes (DEGs) that could account for these phenotypical differences. Of the DEGs identified, we investigated the role of SmGASA4, the expression of which was down-regulated in MT plants. SmGASA4 was introduced into Arobidopsis and S. militiorrhiza under the control of a CaMV35S promoter to verify its influence on abiotic stress and S. miltiorrhiza secondary metabolism biosynthesis. SmGASA4 was found to promote flower and root development in Arobidopsis. SmGASA4 was also found to be positively regulated by Gibberellin (GA) and significantly enhanced plant resistance to salt, drought, and paclobutrazol (PBZ) stress. SmGASA4 also led to the up-regulation of the genes involved in salvianolic acid biosynthesis, but inhibited the expression of the genes involved in tanshinone biosynthesis. Taken together, our results reveal SmGASA4 as a promising candidate gene to promote S. miltiorrhiza development. Full article
(This article belongs to the Section Molecular Plant Sciences)
Figures

Figure 1

Open AccessReview Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies
Int. J. Mol. Sci. 2018, 19(7), 2087; https://doi.org/10.3390/ijms19072087 (registering DOI)
Received: 8 June 2018 / Revised: 10 July 2018 / Accepted: 14 July 2018 / Published: 18 July 2018
PDF Full-text (1719 KB) | HTML Full-text | XML Full-text
Abstract
Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients′ survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal
[...] Read more.
Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients′ survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author’s own experiences/views. Full article
Figures

Figure 1

Open AccessReview Gene Level Regulation of Na,K-ATPase in the Renal Proximal Tubule Is Controlled by Two Independent but Interacting Regulatory Mechanisms Involving Salt Inducible Kinase 1 and CREB-Regulated Transcriptional Coactivators
Int. J. Mol. Sci. 2018, 19(7), 2086; https://doi.org/10.3390/ijms19072086 (registering DOI)
Received: 30 June 2018 / Revised: 13 July 2018 / Accepted: 16 July 2018 / Published: 18 July 2018
PDF Full-text (2857 KB) | HTML Full-text | XML Full-text
Abstract
For many years, studies concerning the regulation of Na,K-ATPase were restricted to acute regulatory mechanisms, which affected the phosphorylation of Na,K-ATPase, and thus its retention on the plasma membrane. However, in recent years, this focus has changed. Na,K-ATPase has been established as a
[...] Read more.
For many years, studies concerning the regulation of Na,K-ATPase were restricted to acute regulatory mechanisms, which affected the phosphorylation of Na,K-ATPase, and thus its retention on the plasma membrane. However, in recent years, this focus has changed. Na,K-ATPase has been established as a signal transducer, which becomes part of a signaling complex as a consequence of ouabain binding. Na,K-ATPase within this signaling complex is localized in caveolae, where Na,K-ATPase has also been observed to regulate Inositol 1,4,5-Trisphosphate Receptor (IP3R)-mediated calcium release. This latter association has been implicated as playing a role in signaling by G Protein Coupled Receptors (GPCRs). Here, the consequences of signaling by renal effectors that act via such GPCRs are reviewed, including their regulatory effects on Na,K-ATPase gene expression in the renal proximal tubule (RPT). Two major types of gene regulation entail signaling by Salt Inducible Kinase 1 (SIK1). On one hand, SIK1 acts so as to block signaling via cAMP Response Element (CRE) Binding Protein (CREB) Regulated Transcriptional Coactivators (CRTCs) and on the other hand, SIK1 acts so as to stimulate signaling via the Myocyte Enhancer Factor 2 (MEF2)/nuclear factor of activated T cell (NFAT) regulated genes. Ultimate consequences of these pathways include regulatory effects which alter the rate of transcription of the Na,K-ATPase β1 subunit gene atp1b1 by CREB, as well as by MEF2/NFAT. Full article
Figures

Figure 1

Open AccessArticle Constitutive Expression of Aechmea fasciata SPL14 (AfSPL14) Accelerates Flowering and Changes the Plant Architecture in Arabidopsis
Int. J. Mol. Sci. 2018, 19(7), 2085; https://doi.org/10.3390/ijms19072085 (registering DOI)
Received: 21 June 2018 / Revised: 10 July 2018 / Accepted: 14 July 2018 / Published: 18 July 2018
PDF Full-text (5377 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Variations in flowering time and plant architecture have a crucial impact on crop biomass and yield, as well as the aesthetic value of ornamental plants. Aechmea fasciata, a member of the Bromeliaceae family, is a bromeliad variety that is commonly cultivated worldwide.
[...] Read more.
Variations in flowering time and plant architecture have a crucial impact on crop biomass and yield, as well as the aesthetic value of ornamental plants. Aechmea fasciata, a member of the Bromeliaceae family, is a bromeliad variety that is commonly cultivated worldwide. Here, we report the characterization of AfSPL14, a squamosa promoter binding protein-like gene in A. fasciata. AfSPL14 was predominantly expressed in the young vegetative organs of adult plants. The expression of AfSPL14 could be upregulated within 1 h by exogenous ethephon treatment. The constitutive expression of AfSPL14 in Arabidopsis thaliana caused early flowering and variations in plant architecture, including smaller rosette leaves and thicker and increased numbers of main inflorescences. Our findings suggest that AfSPL14 may help facilitate the molecular breeding of A. fasciata, other ornamental and edible bromeliads (e.g., pineapple), and even cereal crops. Full article
(This article belongs to the Special Issue Plant Genetics and Molecular Breeding)
Figures

Figure 1

Open AccessArticle Beneficial Impact and Molecular Mechanism of Bacillus coagulans on Piglets’ Intestine
Int. J. Mol. Sci. 2018, 19(7), 2084; https://doi.org/10.3390/ijms19072084 (registering DOI)
Received: 3 May 2018 / Revised: 27 June 2018 / Accepted: 11 July 2018 / Published: 18 July 2018
PDF Full-text (2397 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this research was to investigate the beneficial impact and molecular mechanism of B. coagulans on piglets’ intestine. Twenty-four 21 days old weaned piglets were allotted to three treatments: Control group (basal diet), B6 group (basal diet + 2 × 10
[...] Read more.
The aim of this research was to investigate the beneficial impact and molecular mechanism of B. coagulans on piglets’ intestine. Twenty-four 21 days old weaned piglets were allotted to three treatments: Control group (basal diet), B6 group (basal diet + 2 × 106 CFU/g B. coagulans), and the B7 group (basal diet + 2 × 107 CFU/g B. coagulans). The results showed that, compared with the control group, the B7 group had a reduced cholesterol content and gamma glutamyl transpeptidase (GGT) in plasma (p < 0.05); the B6 and B7 groups had a significantly decreased diarrhea rate and diamine oxidase (DAO) activity in plasma (p < 0.05), increased villus height in ileum and decreased crypt depth in the jejunum (p < 0.05); increased activities of superoxide dismutase (SOD) and catalase (CAT), and decreased the content of malondialdehyde (MDA) and H2O2 in the intestine (p < 0.05). These data suggested that supplementing B. coagulans had beneficial impacts on promoting nutrients’ metabolism, maintaining intestinal integrity, and alleviating oxidative stress and diarrhea. Further research of molecular mechanisms showed changing expression levels of related proteins and genes, suggesting that these could be involved in the regulation of the impact. The community composition of the gut microbiota was also found to be altered in several operational taxonomic units within the genus, Prevotella (order Bacteroidales), and the order, Clostridiales. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
Figures

Figure 1

Open AccessArticle Protective Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate on Aβ1-42-Induced Cognitive Deficit, Oxidative Stress, Inflammation, and Apoptosis in Mice
Int. J. Mol. Sci. 2018, 19(7), 2083; https://doi.org/10.3390/ijms19072083 (registering DOI)
Received: 8 June 2018 / Revised: 10 July 2018 / Accepted: 16 July 2018 / Published: 18 July 2018
PDF Full-text (2409 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which
[...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia among older people. Although soluble amyloid species are recognized triggers of the disease, no therapeutic approach is able to stop it. 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC) is a major bioactive compound in Wasabia japonica, which is a typical Japanese pungent spice. Recently, in vivo and in vitro studies demonstrated that 6-MSITC has several biological properties. The aim of the present study was to investigate the neuroprotective activity of 6-MSITC in a murine AD model, induced by intracerebroventricular injection of β-amyloid oligomers (Aβ1-42O). The treatment with 6-MSITC started 1 h after the surgery for the next 10 days. Behavioral analysis showed that 6-MSITC ameliorated Aβ1-42O-induced memory impairments. The decrease of glutathione levels and increase of reactive oxygen species in hippocampal tissues following Aβ1-42O injection were reduced by 6-MSITC. Moreover, activation of caspases, increase of inflammatory factors, and phosphorylation of ERK and GSK3 were inhibited by 6-MSITC. These results highlighted an interesting neuroprotective activity of 6-MSITC, which was able to restore a physiological oxidative status, interfere positively with Nrf2-pathway, decrease apoptosis and neuroinflammation and contribute to behavioral recovery. Taken together, these findings demonstrated that 6-MSITC could be a promising complement for AD therapy. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2018)
Figures

Graphical abstract

Open AccessArticle Overexpression of the Rybp Gene Inhibits Differentiation of Bovine Myoblasts into Myotubes
Int. J. Mol. Sci. 2018, 19(7), 2082; https://doi.org/10.3390/ijms19072082 (registering DOI)
Received: 6 June 2018 / Revised: 30 June 2018 / Accepted: 10 July 2018 / Published: 18 July 2018
PDF Full-text (2776 KB) | HTML Full-text | XML Full-text
Abstract
RING1 and YY1 binding protein (Rybp) genes inhibit myogenesis in mice, but there are no reports on the effects of these genes in cattle. The aim of this study is to investigate the roles of the Rybp gene on bovine skeletal
[...] Read more.
RING1 and YY1 binding protein (Rybp) genes inhibit myogenesis in mice, but there are no reports on the effects of these genes in cattle. The aim of this study is to investigate the roles of the Rybp gene on bovine skeletal muscle development and myoblast differentiation. In the present study, the Rybp gene was overexpressed in bovine myoblasts via adenovirus. RNA-seq was performed to screen differentially expressed genes (DEGs). The results showed that overexpressing the Rybp gene inhibits the formation of myotubes. The morphological differences in myoblasts began on the second day and were very significant 6 days after adenovirus induction. A total of 1311 (707 upregulated and 604 downregulated) DEGs were screened using RNA-seq between myoblasts with added negative control adenoviruses (AD-NC) and Rybp adenoviruses (AD-Rybp) after 6 days of induction. Gene ontology (GO) and KEGG analysis revealed that the downregulated DEGs were mainly involved in biological functions related to muscle, and, of the 32 pathways, those associated with muscle development were significantly enriched for the identified DEGs. This study can not only provide a theoretical basis for the regulation of skeletal muscle development in cattle by exploring the roles of the Rybp gene in myoblast differentiation, but it can also lay a theoretical foundation for molecular breeding of beef cattle. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
Figures

Figure 1

Open AccessArticle The Dietary Antioxidant Piceatannol Inhibits Adipogenesis of Human Adipose Mesenchymal Stem Cells and Limits Glucose Transport and Lipogenic Activities in Adipocytes
Int. J. Mol. Sci. 2018, 19(7), 2081; https://doi.org/10.3390/ijms19072081
Received: 5 June 2018 / Revised: 12 July 2018 / Accepted: 13 July 2018 / Published: 17 July 2018
PDF Full-text (2790 KB) | HTML Full-text | XML Full-text
Abstract
Phenolic compounds are among the most investigated herbal remedies, as is especially the case for resveratrol. Many reports have shown its anti-aging properties and the ability to reduce obesity and diabetes induced by high-fat diet in mice. However, such beneficial effects hardly translate
[...] Read more.
Phenolic compounds are among the most investigated herbal remedies, as is especially the case for resveratrol. Many reports have shown its anti-aging properties and the ability to reduce obesity and diabetes induced by high-fat diet in mice. However, such beneficial effects hardly translate from animal models to humans. The scientific community has therefore tested whether other plant phenolic compounds may surpass the effects of resveratrol. In this regard, it has been reported that piceatannol reproduces in rodents the anti-obesity actions of its parent polyphenol. However, the capacity of piceatannol to inhibit adipocyte differentiation in humans has not been characterized so far. Here, we investigated whether piceatannol was antiadipogenic and antilipogenic in human preadipocytes. Human mesenchymal stem cells (hMSC), isolated from adipose tissues of lean and obese individuals, were differentiated into mature adipocytes with or without piceatannol, and their functions were explored. Fifty μM of piceatannol deeply limited synthesis/accumulation of lipids in both murine and hMSC-derived adipocytes. Interestingly, this phenomenon occurred irrespective of being added at the earlier or later stages of adipocyte differentiation. Moreover, piceatannol lowered glucose transport into adipocytes and decreased the expression of key elements of the lipogenic pathway (PPARγ, FAS, and GLUT4). Thus, the confirmation of the antiadipogenic properties of piceatanol in vitro warrants the realization of clinical studies for the application of this compound in the treatment of the metabolic complications associated with obesity. Full article
Figures

Graphical abstract

Open AccessArticle Establishment and Characterization of the Novel High-Grade Serous Ovarian Cancer Cell Line OVPA8
Int. J. Mol. Sci. 2018, 19(7), 2080; https://doi.org/10.3390/ijms19072080
Received: 6 June 2018 / Revised: 10 July 2018 / Accepted: 13 July 2018 / Published: 17 July 2018
PDF Full-text (6670 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most frequent histological type of ovarian cancer and the one with worst prognosis. Unfortunately, the majority of established ovarian cancer cell lines which are used in the research have unclear histological origin and probably do not
[...] Read more.
High-grade serous ovarian carcinoma (HGSOC) is the most frequent histological type of ovarian cancer and the one with worst prognosis. Unfortunately, the majority of established ovarian cancer cell lines which are used in the research have unclear histological origin and probably do not represent HGSOC. Thus, new and reliable models of HGSOC are needed. Ascitic fluid from a patient with recurrent HGSOC was used to establish a stable cancer cell line. Cells were characterized by cytogenetic karyotyping and short tandem repeat (STR) profiling. New generation sequencing was applied to test for hot-spot mutations in 50 cancer-associated genes and fluorescence in situ hybridization (FISH) analysis was used to check for TP53 status. Cells were analyzed for expression of several marker genes/proteins by reverse-transcription polymerase chain reaction (RT-PCR), fluorescence-activated cell sorting (FACS), and immunocytochemistry (ICC). Functional tests were performed to compare OVPA8 cells with five commercially available and frequently used ovarian cancer cell lines: SKOV3, A2780, OVCAR3, ES2, and OAW42. Our newly-established OVPA8 cell line shows morphologic and genetic features consistent with HGSOC, such as epithelial morphology, multiple chromosomal aberrations, TP53 mutation, BRCA1 mutation, and loss of one copy of BRCA2. The OVPA8 line has a stable STR profile. Cells are positive for EpCAM, CK19, and CD44; they have relatively low plating efficiency/ability to form spheroids, a low migration rate, and intermediate invasiveness in matrigel, as compared to other ovarian cancer lines. OVPA8 is sensitive to paclitaxel and resistant to cisplatin. We also tested two FGFR inhibitors; OVPA8 cells were resistant to AZD4547 (AstraZeneca, London, UK), but sensitive to the new inhibitor CPL304-110-01 (Celon Pharma, Łomianki/Kiełpin, Poland). We have established and characterized a novel cell line, OVPA8, which can be a valuable preclinical model for studies on high-grade serous ovarian cancer. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
Figures

Graphical abstract

Open AccessArticle The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors
Int. J. Mol. Sci. 2018, 19(7), 2079; https://doi.org/10.3390/ijms19072079
Received: 30 May 2018 / Revised: 12 July 2018 / Accepted: 13 July 2018 / Published: 17 July 2018
PDF Full-text (3508 KB) | HTML Full-text | XML Full-text
Abstract
Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and
[...] Read more.
Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. Methods: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. Results: From the 46 GCs, 27 tested MSI-high/EBV−, 15 tested MSS/EBV+ and four tested MSS/EBV−. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV− GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV− GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1high/PD-L1low, PD-1high/PDL1high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. Conclusions: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications. Full article
(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)
Figures

Figure 1

Open AccessArticle Generation of Immortalised But Unstable Cells after hTERT Introduction in Telomere-Compromised and p53-Deficient vHMECs
Int. J. Mol. Sci. 2018, 19(7), 2078; https://doi.org/10.3390/ijms19072078
Received: 16 May 2018 / Revised: 11 July 2018 / Accepted: 13 July 2018 / Published: 17 July 2018
PDF Full-text (2401 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse
[...] Read more.
Telomeres, the natural ends of chromosomes, hide the linear telomeric DNA from constitutive exposure to the DNA damage response with a lariat structure or t-loop. Progressive telomere shortening associated with DNA replication in the absence of a compensatory mechanism culminates in t-loop collapse and unmasked telomeres. Dysfunctional telomeres can suppress cancer development by engaging replicative senescence or apoptosis, but they can also promote tumour initiation when cell cycle checkpoints are disabled. In this setting, telomere dysfunction promotes increasing chromosome instability (CIN) through breakage-fusion-bridge cycles. Excessive instability may hamper cell proliferation but might allow for the appearance of some rare advantageous mutations that could be selected and ultimately favour neoplastic progression. With the aim of generating pre-malignant immortalised cells, we ectopically expressed telomerase in telomere-compromised variant human mammary epithelial cells (vHMECs), proficient and deficient for p53, and analysed structural and numerical chromosomal aberrations as well as abnormal nuclear morphologies. Importantly, this study provides evidence that while immortalisation of vHMECs at early stages results in an almost stable karyotype, a transient telomere-dependent CIN period—aggravated by p53 deficiency—and followed by hTERT overexpression serves as a mechanism for the generation of immortal unstable cells which, due to their evolving karyotype, could attain additional promoting properties permissive to malignancy. Full article
(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging)
Figures

Figure 1

Open AccessArticle Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs
Int. J. Mol. Sci. 2018, 19(7), 2077; https://doi.org/10.3390/ijms19072077
Received: 25 June 2018 / Revised: 6 July 2018 / Accepted: 7 July 2018 / Published: 17 July 2018
PDF Full-text (2647 KB) | HTML Full-text | XML Full-text
Abstract
Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS;
[...] Read more.
Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. Methods: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. Results: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down-regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down-regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. Conclusions: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
Figures

Figure 1

Back to Top