International Journal of Molecular Sciences

37 pages, 2397 KiB

Open AccessReview

Effect of Hepatitis Viruses on the Nrf2/Keap1-Signaling Pathway and Its Impact on Viral Replication and Pathogenesis

by Daniela Bender and Eberhard Hildt

Int. J. Mol. Sci. 2019, 20(18), 4659; https://doi.org/10.3390/ijms20184659 - 19 Sep 2019

Cited by 33 | Viewed by 7999

With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). [...] Read more.

With respect to their genome and their structure, the human hepatitis B virus (HBV) and hepatitis C virus (HCV) are complete different viruses. However, both viruses can cause an acute and chronic infection of the liver that is associated with liver inflammation (hepatitis). For both viruses chronic infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Reactive oxygen species (ROS) play a central role in a variety of chronic inflammatory diseases. In light of this, this review summarizes the impact of both viruses on ROS-generating and ROS-inactivating mechanisms. The focus is on the effect of both viruses on the transcription factor Nrf2 (nuclear factor erythroid 2 (NF-E2)-related factor 2). By binding to its target sequence, the antioxidant response element (ARE), Nrf2 triggers the expression of a variety of cytoprotective genes including ROS-detoxifying enzymes. The review summarizes the literature about the pathways for the modulation of Nrf2 that are deregulated by HBV and HCV and describes the impact of Nrf2 deregulation on the viral life cycle of the respective viruses and the virus-associated pathogenesis. Full article

(This article belongs to the Special Issue The Nrf2 Pathway: Regulation, Functions, and Potential Applications)

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15 pages, 3557 KiB

Open AccessArticle

The Cooperative Induction of CCL4 in Human Monocytic Cells by TNF-α and Palmitate Requires MyD88 and Involves MAPK/NF-κB Signaling Pathways

by Sardar Sindhu, Shihab Kochumon, Steve Shenouda, Ajit Wilson, Fahd Al-Mulla and Rasheed Ahmad

Int. J. Mol. Sci. 2019, 20(18), 4658; https://doi.org/10.3390/ijms20184658 - 19 Sep 2019

Cited by 45 | Viewed by 7975

Abstract

Chronic low-grade inflammation, also known as metabolic inflammation, is a hallmark of obesity and parallels with the presence of elevated circulatory levels of free fatty acids and inflammatory cytokines/chemokines. CCL4/MIP-1β chemokine plays a key role in the adipose tissue monocyte recruitment. Increased circulatory [...] Read more.

Chronic low-grade inflammation, also known as metabolic inflammation, is a hallmark of obesity and parallels with the presence of elevated circulatory levels of free fatty acids and inflammatory cytokines/chemokines. CCL4/MIP-1β chemokine plays a key role in the adipose tissue monocyte recruitment. Increased circulatory levels of TNF-α, palmitate and CCL4 are co-expressed in obesity. We asked if the TNF-α/palmitate could interact cooperatively to augment the CCL4 production in human monocytic cells and macrophages. THP-1 cells/primary macrophages were co-treated with TNF-α/palmitate and CCL4 mRNA/protein expression was assessed using qRT-PCR/ELISA. TLR4 siRNA, a TLR4 receptor-blocking antibody, XBlue™-defMyD cells and pathway inhibitors were used to decipher the signaling mechanisms. We found that TNF-α/palmitate co-stimulation augmented the CCL4 expression in monocytic cells and macrophages compared to controls (p < 0.05). TLR4 suppression or neutralization abrogated the CCL4 expression in monocytic cells. Notably, CCL4 cooperative induction in monocytic cells was: (1) Markedly less in MyD88-deficient cells, (2) IRF3 independent, (3) clathrin dependent and (4) associated with the signaling mechanism involving ERK1/2, c-Jun, JNK and NF-κB. In conclusion, TNF-α/palmitate co-stimulation promotes the CCL4 expression in human monocytic cells through the mechanism involving a TLR4-MyD88 axis and MAPK/NF-κB pathways. These findings unravel a novel mechanism of the cooperative induction of CCL4 by TNF-α and palmitate which could be relevant to metabolic inflammation. Full article

(This article belongs to the Special Issue Molecular Research on Metabolic Disorders)

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33 pages, 3453 KiB

Open AccessReview

Impact of RNA Virus Evolution on Quasispecies Formation and Virulence

by Madiiha Bibi Mandary, Malihe Masomian and Chit Laa Poh

Int. J. Mol. Sci. 2019, 20(18), 4657; https://doi.org/10.3390/ijms20184657 - 19 Sep 2019

Cited by 33 | Viewed by 10765

Abstract

RNA viruses are known to replicate by low fidelity polymerases and have high mutation rates whereby the resulting virus population tends to exist as a distribution of mutants. In this review, we aim to explore how genetic events such as spontaneous mutations could [...] Read more.

RNA viruses are known to replicate by low fidelity polymerases and have high mutation rates whereby the resulting virus population tends to exist as a distribution of mutants. In this review, we aim to explore how genetic events such as spontaneous mutations could alter the genomic organization of RNA viruses in such a way that they impact virus replications and plaque morphology. The phenomenon of quasispecies within a viral population is also discussed to reflect virulence and its implications for RNA viruses. An understanding of how such events occur will provide further evidence about whether there are molecular determinants for plaque morphology of RNA viruses or whether different plaque phenotypes arise due to the presence of quasispecies within a population. Ultimately this review gives an insight into whether the intrinsically high error rates due to the low fidelity of RNA polymerases is responsible for the variation in plaque morphology and diversity in virulence. This can be a useful tool in characterizing mechanisms that facilitate virus adaptation and evolution. Full article

(This article belongs to the Special Issue Molecular Research in Emerging Viruses 2019)

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19 pages, 4229 KiB

Open AccessArticle

Modulating Shrimp Tropomyosin-Mediated Allergy: Hypoallergen DNA Vaccines Induce Regulatory T Cells to Reduce Hypersensitivity in Mouse Model

by Christine Y.Y. Wai, Nicki Y.H. Leung, Patrick S.C. Leung and Ka Hou Chu

Int. J. Mol. Sci. 2019, 20(18), 4656; https://doi.org/10.3390/ijms20184656 - 19 Sep 2019

Cited by 15 | Viewed by 4980

Abstract

Shellfish allergy is one of the most common food allergies, with tropomyosin as the major cross-reactive allergen. However, no allergen-specific immunotherapy is clinically available. Recently, we designed two shrimp hypoallergens MEM49 and MED171. This study aimed to examine and compare the efficacy of [...] Read more.

Shellfish allergy is one of the most common food allergies, with tropomyosin as the major cross-reactive allergen. However, no allergen-specific immunotherapy is clinically available. Recently, we designed two shrimp hypoallergens MEM49 and MED171. This study aimed to examine and compare the efficacy of the MEM49- and MED171-based DNA vaccines (pMEM49 and pMED171) in modulating shrimp allergy in a murine model of shrimp tropomyosin sensitivity. Intradermal immunization of BALB/c mice with pMEM49 or pMED171 effectively down-modulated allergic symptoms, tropomyosin-specific IgE levels, intestinal Th2 cytokines expression, and inflammatory cell infiltration. Both pMEM49 and pMED171 increased the frequency of regulatory T cells, but to a greater extent by pMED171 with upregulation of gut-homing molecules integrin-α4β7. The functionality of the pMED171-induced Treg cells was further illustrated by anti-CD25-mediated depletion of Treg cells and the adoptive transfer of CD4⁺CD25⁺Foxp3⁺Treg cells. Collectively, the data demonstrate that intradermal administration of pMED171 leads to the priming, activation, and migration of dermal dendritic cells which subsequently induce Treg cells, both locally and systemically, to downregulate the allergic responses to tropomyosin. This study is the first to demonstrate the potency of hypoallergen-encoding DNA vaccines as a therapeutic strategy for human shellfish allergy via the vigorous induction of functional Treg cells. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis of Food Allergies)

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18 pages, 6915 KiB

Open AccessArticle

Viscoelastic Behavior of Embroidered Scaffolds for ACL Tissue Engineering Made of PLA and P(LA-CL) After In Vitro Degradation

by Judith Hahn, Gundula Schulze-Tanzil, Michaela Schröpfer, Michael Meyer, Clemens Gögele, Mariann Hoyer, Axel Spickenheuer, Gert Heinrich and Annette Breier

Int. J. Mol. Sci. 2019, 20(18), 4655; https://doi.org/10.3390/ijms20184655 - 19 Sep 2019

Cited by 20 | Viewed by 4173

Abstract

A rupture of the anterior cruciate ligament (ACL) is the most common knee ligament injury. Current applied reconstruction methods have limitations in terms of graft availability and mechanical properties. A new approach could be the use of a tissue engineering construct that temporarily [...] Read more.

A rupture of the anterior cruciate ligament (ACL) is the most common knee ligament injury. Current applied reconstruction methods have limitations in terms of graft availability and mechanical properties. A new approach could be the use of a tissue engineering construct that temporarily reflects the mechanical properties of native ligament tissues and acts as a carrier structure for cell seeding. In this study, embroidered scaffolds composed of polylactic acid (PLA) and poly(lactic-co-ε-caprolactone) (P(LA-CL)) threads were tested mechanically for their viscoelastic behavior under in vitro degradation. The relaxation behavior of both scaffold types (moco: mono-component scaffold made of PLA threads, bico: bi-component scaffold made of PLA and P(LA-CL) threads) was comparable to native lapine ACL. Most of the lapine ACL cells survived 32 days of cell culture and grew along the fibers. Cell vitality was comparable for moco and bico scaffolds. Lapine ACL cells were able to adhere to the polymer surfaces and spread along the threads throughout the scaffold. The mechanical behavior of degrading matrices with and without cells showed no significant differences. These results demonstrate the potential of embroidered scaffolds as an ACL tissue engineering approach. Full article

(This article belongs to the Special Issue Tendon/Ligament Reconstruction by Tissue Engineering)

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15 pages, 4192 KiB

Open AccessArticle

Molecular Modeling Studies on the Binding Mode of the PD-1/PD-L1 Complex Inhibitors

by Suliman Almahmoud and Haizhen A. Zhong

Int. J. Mol. Sci. 2019, 20(18), 4654; https://doi.org/10.3390/ijms20184654 - 19 Sep 2019

Cited by 35 | Viewed by 5884

Abstract

The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) is an immune checkpoint (ICP) overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. To determine important residues for ligand binding, we [...] Read more.

The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) is an immune checkpoint (ICP) overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. To determine important residues for ligand binding, we applied molecular docking studies to PD-1/PD-L1 complex inhibitors against the PD-L1 protein. Our data revealed that the residues Tyr56, Asp122, and Lys124 play critical roles in ligand binding to the PD-L1 protein and they could be used to design ligands that are active against the PD-1/PD-L1 complex. The formation of H-bonds with Arg125 of the PD-L1 protein may enhance the potency of the PD-1/PD-L1 binding. Full article

(This article belongs to the Section Molecular Pharmacology)

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28 pages, 1630 KiB

Open AccessReview

Regulatory Effects and Interactions of the Wnt and OPG-RANKL-RANK Signaling at the Bone-Cartilage Interface in Osteoarthritis

by Béla Kovács, Enikő Vajda and Előd Ernő Nagy

Int. J. Mol. Sci. 2019, 20(18), 4653; https://doi.org/10.3390/ijms20184653 - 19 Sep 2019

Cited by 139 | Viewed by 11144

Abstract

Cartilage and the bordering subchondral bone form a functionally active regulatory interface with a prominent role in osteoarthritis pathways. The Wnt and the OPG-RANKL-RANK signaling systems, as key mediators, interact in subchondral bone remodeling. Osteoarthritic osteoblasts polarize into two distinct phenotypes: a low [...] Read more.

Cartilage and the bordering subchondral bone form a functionally active regulatory interface with a prominent role in osteoarthritis pathways. The Wnt and the OPG-RANKL-RANK signaling systems, as key mediators, interact in subchondral bone remodeling. Osteoarthritic osteoblasts polarize into two distinct phenotypes: a low secretory and an activated, pro-inflammatory and anti-resorptive subclass producing high quantities of IL-6, PGE2, and osteoprotegerin, but low levels of RANKL, thus acting as putative effectors of subchondral bone sclerosis. Wnt agonists, Wnt5a, Wisp-1 initiate excessive bone remodeling, while Wnt3a and 5a simultaneously cause loss of proteoglycans and phenotype shift in chondrocytes, with decreased expression of COL2A, aggrecan, and Sox-9. Sclerostin, a Wnt antagonist possesses a protective effect for the cartilage, while DKK-1 inhibits VEGF, suspending neoangiogenesis in the subchondral bone. Experimental conditions mimicking abnormal mechanical load, the pro-inflammatory milieu, but also a decreased OPG/RANKL ratio in the cartilage, trigger chondrocyte apoptosis and loss of the matrix via degradative matrix metalloproteinases, like MMP-13 or MMP-9. Hypoxia, an important cofactor exerts a dual role, promoting matrix synthesis via HIF-1α, a Wnt silencer, but turning on HIF-2α that enhances VEGF and MMP-13, along with aberrant collagen expression and extracellular matrix deterioration in the presence of pro-inflammatory cytokines. Full article

(This article belongs to the Special Issue The Future of Cartilage Repair in Complex Biological Situations)

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19 pages, 3443 KiB

Open AccessArticle

Chromosomal Density of Cancer Up-Regulated Genes, Aberrant Enhancer Activity and Cancer Fitness Genes Are Associated with Transcriptional Cis-Effects of Broad Copy Number Gains in Colorectal Cancer

by Daniele Filippo Condorelli, Anna Provvidenza Privitera and Vincenza Barresi

Int. J. Mol. Sci. 2019, 20(18), 4652; https://doi.org/10.3390/ijms20184652 - 19 Sep 2019

Cited by 15 | Viewed by 3539

Abstract

Broad Copy Number Gains (BCNGs) are copy-number increases of chromosomes or large segments of chromosomal arms. Publicly-available single-nucleotide polymorphism (SNP) array and RNA-Seq data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) consortium allowed us to design better control groups [...] Read more.

Broad Copy Number Gains (BCNGs) are copy-number increases of chromosomes or large segments of chromosomal arms. Publicly-available single-nucleotide polymorphism (SNP) array and RNA-Seq data of colon adenocarcinoma (COAD) samples from The Cancer Genome Atlas (TCGA) consortium allowed us to design better control groups in order to identify changes in expression due to highly recurrent BCNGs (in chromosomes 20, 8, 7, 13). We identified: (1) Overexpressed Transcripts (OverT), transcripts whose expression increases in “COAD groups bearing a specific BCNG” in comparison to “control COAD groups” not bearing it, and (2) up-regulated/down-regulated transcripts, transcripts whose expression increases/decreases in COAD groups in comparison to normal colon tissue. An analysis of gene expression reveals a correlation between the density of up-regulated genes per selected chromosome and the recurrence rate of their BCNGs. We report an enrichment of gained enhancer activity and of cancer fitness genes among OverT genes. These results support the hypothesis that the chromosomal density of overexpressed cancer fitness genes might play a significant role in the selection of gained chromosomes during cancer evolution. Analysis of functional pathways associated with OverT suggest that some multi-subunit protein complexes (eIF2, eIF3, CSTF and CPSF) are candidate targets for silencing transcriptional therapy. Full article

(This article belongs to the Special Issue Transcriptional and Post-Transcriptional Dysregulation and Cancer Driver Pathways)

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1 pages, 181 KiB

Open AccessCorrection

Correction: Concha, G., et al. The Insensitivity of TASK-3 K₂P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure. Int. J. Mol. Sci. 2018, 19, 2437

by Guierdy Concha, Daniel Bustos, Rafael Zúñiga, Marcelo A. Catalán and Leandro Zúñiga

Int. J. Mol. Sci. 2019, 20(18), 4651; https://doi.org/10.3390/ijms20184651 - 19 Sep 2019

Cited by 3 | Viewed by 1950

Abstract

We would like to submit the following correction to our published paper [...] Full article

(This article belongs to the Section Molecular Biophysics)

13 pages, 4681 KiB

Open AccessArticle

Hydroxyapatite Formation on Self-Assembling Peptides with Differing Secondary Structures and Their Selective Adsorption for Proteins

by Suzuka Kojima, Hitomi Nakamura, Sungho Lee, Fukue Nagata and Katsuya Kato

Int. J. Mol. Sci. 2019, 20(18), 4650; https://doi.org/10.3390/ijms20184650 - 19 Sep 2019

Cited by 16 | Viewed by 4023

Abstract

Self-assembling peptides have been employed as biotemplates for biomineralization, as the morphologies and sizes of the inorganic materials can be easily controlled. We synthesized two types of highly ordered self-assembling peptides with different secondary structures and investigated the effects of secondary structures on [...] Read more.

Self-assembling peptides have been employed as biotemplates for biomineralization, as the morphologies and sizes of the inorganic materials can be easily controlled. We synthesized two types of highly ordered self-assembling peptides with different secondary structures and investigated the effects of secondary structures on hydroxyapatite (HAp) biomineralization of peptide templates. All as-synthesized HAp-peptides have a selective protein adsorption capacity for basic protein (e.g., cytochrome c and lysozyme). Moreover, the selectivity was improved as peptide amounts increased. In particular, peptide–HAp templated on β-sheet peptides adsorbed more cytochrome c than peptide–HAp with α-helix structures, due to the greater than 2-times carboxyl group density at their surfaces. It can be expected that self-assembled peptide-templated HAp may be used as carriers for protein immobilization in biosensing and bioseparation applications and as enzyme-stabilizing agents. Full article

(This article belongs to the Special Issue Designer Biopolymers: Self-Assembling Proteins and Nucleic Acids)

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16 pages, 6102 KiB

Open AccessReview

Retinal Ganglion Cell Death as a Late Remodeling Effect of Photoreceptor Degeneration

by Diego García-Ayuso, Johnny Di Pierdomenico, Manuel Vidal-Sanz and María P. Villegas-Pérez

Int. J. Mol. Sci. 2019, 20(18), 4649; https://doi.org/10.3390/ijms20184649 - 19 Sep 2019

Cited by 39 | Viewed by 4983

Abstract

Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially affect rods and cones, situated in the outer retina. For many years it was assumed that these diseases did [...] Read more.

Inherited or acquired photoreceptor degenerations, one of the leading causes of irreversible blindness in the world, are a group of retinal disorders that initially affect rods and cones, situated in the outer retina. For many years it was assumed that these diseases did not spread to the inner retina. However, it is now known that photoreceptor loss leads to an unavoidable chain of events that cause neurovascular changes in the retina including migration of retinal pigment epithelium cells, formation of “subretinal vascular complexes”, vessel displacement, retinal ganglion cell (RGC) axonal strangulation by retinal vessels, axonal transport alteration and, ultimately, RGC death. These events are common to all photoreceptor degenerations regardless of the initial trigger and thus threaten the outcome of photoreceptor substitution as a therapeutic approach, because with a degenerating inner retina, the photoreceptor signal will not reach the brain. In conclusion, therapies should be applied early in the course of photoreceptor degeneration, before the remodeling process reaches the inner retina. Full article

(This article belongs to the Special Issue Retinal Ganglion Cells)

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15 pages, 2192 KiB

Open AccessArticle

A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments

by Nathalie Lagarde, Elodie Goldwaser, Tania Pencheva, Dessislava Jereva, Ilza Pajeva, Julien Rey, Pierre Tuffery, Bruno O. Villoutreix and Maria A. Miteva

Int. J. Mol. Sci. 2019, 20(18), 4648; https://doi.org/10.3390/ijms20184648 - 19 Sep 2019

Cited by 18 | Viewed by 6271

Abstract

Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a [...] Read more.

Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a free web-based protocol dedicated to small-molecule virtual screening that includes three major steps: ADME-Tox filtering (via the web service FAF-Drugs4), docking-based virtual screening (via the web service MTiOpenScreen), and molecular mechanics optimization (via the web service AMMOS2 [Automatic Molecular Mechanics Optimization for in silico Screening]). The online tools FAF-Drugs4, MTiOpenScreen, and AMMOS2 are implemented in the freely accessible RPBS (Ressource Parisienne en Bioinformatique Structurale) platform. The proposed protocol allows users to screen thousands of small molecules and to download the top 1500 docked molecules that can be further processed online. Users can then decide to purchase a small list of compounds for in vitro validation. To demonstrate the potential of this online-based protocol, we performed virtual screening experiments of 4574 approved drugs against three cancer targets. The results were analyzed in the light of published drugs that have already been repositioned on these targets. We show that our protocol is able to identify active drugs within the top-ranked compounds. The web-based protocol is user-friendly and can successfully guide the identification of new promising molecules for chemical biology and drug discovery purposes. Full article

(This article belongs to the Special Issue Recent Advances in Virtual Screening)

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15 pages, 3708 KiB

Open AccessArticle

Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

by Bart Kramer, Luuk de Haan, Marjolein Vermeer, Thomas Olivier, Thomas Hankemeier, Paul Vulto, Jos Joore and Henriëtte L. Lanz

Int. J. Mol. Sci. 2019, 20(18), 4647; https://doi.org/10.3390/ijms20184647 - 19 Sep 2019

Cited by 31 | Viewed by 7065

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers due to a high chemoresistance and poor vascularization, which results in an ineffective systemic therapy. PDAC is characterized by a high intratumoral pressure, which is not captured by current 2D and 3D [...] Read more.

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers due to a high chemoresistance and poor vascularization, which results in an ineffective systemic therapy. PDAC is characterized by a high intratumoral pressure, which is not captured by current 2D and 3D in vitro models. Here, we demonstrated a 3D microfluidic interstitial flow model to mimic the intratumoral pressure in PDAC. We found that subjecting the S2-028 PDAC cell line to interstitial flow inhibits the proliferation, while maintaining a high viability. We observed increased gemcitabine chemoresistance, with an almost nine-fold higher EC50 as compared to a monolayer culture (31 nM versus 277 nM), and an alleviated expression and function of the multidrug resistance protein (MRP) family. In conclusion, we developed a 3D cell culture modality for studying intratissue pressure and flow that exhibits more predictive capabilities than conventional 2D cell culture and is less time-consuming, and more scalable and accessible than animal models. This increase in microphysiological relevance might support improved efficiency in the drug development pipeline. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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22 pages, 1760 KiB

Open AccessReview

Insights into the Functions of LncRNAs in Drosophila

by Keqin Li, Yuanliangzi Tian, Ya Yuan, Xiaolan Fan, Mingyao Yang, Zhi He and Deying Yang

Int. J. Mol. Sci. 2019, 20(18), 4646; https://doi.org/10.3390/ijms20184646 - 19 Sep 2019

Cited by 46 | Viewed by 5932

Abstract

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs longer than 200 nucleotides (nt). LncRNAs have high spatiotemporal specificity, and secondary structures have been preserved throughout evolution. They have been implicated in a range of biological processes and diseases and are emerging [...] Read more.

Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs longer than 200 nucleotides (nt). LncRNAs have high spatiotemporal specificity, and secondary structures have been preserved throughout evolution. They have been implicated in a range of biological processes and diseases and are emerging as key regulators of gene expression at the epigenetic, transcriptional, and post-transcriptional levels. Comparative analyses of lncRNA functions among multiple organisms have suggested that some of their mechanisms seem to be conserved. Transcriptome studies have found that some Drosophila lncRNAs have highly specific expression patterns in embryos, nerves, and gonads. In vivo studies of lncRNAs have revealed that dysregulated expression of lncRNAs in Drosophila may result in impaired embryo development, impaired neurological and gonadal functions, and poor stress resistance. In this review, we summarize the epigenetic, transcriptional, and post-transcriptional mechanisms of lncRNAs and mainly focus on recent insights into the transcriptome studies and biological functions of lncRNAs in Drosophila. Full article

(This article belongs to the Section Molecular Biology)

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18 pages, 3216 KiB

Open AccessArticle

Instrument-Free and Visual Detection of Salmonella Based on Magnetic Nanoparticles and an Antibody Probe Immunosensor

by Liding Zhang, Xuewei Du, Zhixin Chen, Congjie Chen, Nanxin Gong, Yihao Song, Yuzhu Song, Qinqin Han, Xueshan Xia, Haiming Luo and Jinyang Zhang

Int. J. Mol. Sci. 2019, 20(18), 4645; https://doi.org/10.3390/ijms20184645 - 19 Sep 2019

Cited by 15 | Viewed by 4386

Abstract

Salmonella, a common foodborne pathogen, causes many cases of foodborne illness and poses a threat to public health worldwide. Immunological detection systems can be combined with nanoparticles to develop sensitive and portable detection technologies for timely screening of Salmonella infections. Here, we [...] Read more.

Salmonella, a common foodborne pathogen, causes many cases of foodborne illness and poses a threat to public health worldwide. Immunological detection systems can be combined with nanoparticles to develop sensitive and portable detection technologies for timely screening of Salmonella infections. Here, we developed an antibody-probe-based immuno-N-hydroxysuccinimide (NHS) bead (AIB) system to detect Salmonella. After adding the antibody probe, Salmonella accumulated in the samples on the surfaces of the immuno-NHS beads (INBs), forming a sandwich structure (INB–Salmonella–probes). We demonstrated the utility of our AIB diagnostic system for detecting Salmonella in water, milk, and eggs, with a sensitivity of 9 CFU mL⁻¹ in less than 50 min. The AIB diagnostic system exhibits highly specific detection and no cross-reaction with other similar microbial strains. With no specialized equipment or technical requirements, the AIB diagnostic method can be used for visual, rapid, and point-of-care detection of Salmonella. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2019)

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12 pages, 4830 KiB

Open AccessArticle

Numerical Model for Magnetic Fluid Hyperthermia in a Realistic Breast Phantom: Calorimetric Calibration and Treatment Planning

by Arkadiusz Miaskowski and Mahendran Subramanian

Int. J. Mol. Sci. 2019, 20(18), 4644; https://doi.org/10.3390/ijms20184644 - 19 Sep 2019

Cited by 21 | Viewed by 3364

Abstract

This paper aims to apply a proposed, based on calorimetric measurements, a reliable numerical model for magnetic fluid hyperthermia (MFH) treatment planning of breast cancer. Furthermore, we perform a comparative analysis of magnetic nanoparticles (MNPs) and tumour tissue interactions by means of the [...] Read more.

This paper aims to apply a proposed, based on calorimetric measurements, a reliable numerical model for magnetic fluid hyperthermia (MFH) treatment planning of breast cancer. Furthermore, we perform a comparative analysis of magnetic nanoparticles (MNPs) and tumour tissue interactions by means of the magnetic-field-dependent Néel and Brownian relaxation times. The analysis was based on an anatomically correct breast model (developed in-house) and a modified linear response theory, which was applied to investigate the heat dissipation from the magnetic nanoparticles dispersed in the breast tumour. The calculations of the single-domain magnetic power losses were conducted for a case where the magnetic field value and the applied frequency were known, but also for the different concentrations of the MNPs in the tumour. Two scenarios were considered: The MNPs mobilised and immobilised in the tumour. In parallel, the eddy currents effect, together with the related temperature distributions, were considered in order to analyse safety issues. By changing the MNP concentration in the tumour, the corresponding temperature distributions were calculated. The eddy current effect, together with the related temperature distribution, were considered in order to analyse safety issues. Varying the MNP concentration in the tumour, the corresponding temperature distribution was calculated. Moreover, the cumulative equivalent minutes at

43 ℃

were analysed. In the anatomically correct breast phantoms, the tissue location can lead to “hot spots” due to the eddy current effect and subsequently to the high gradients of the temperature. That is why the analysis of safety issues related to the overheating side effect should be taken into consideration during the treatment planning of magnetic fluid hyperthermia. The phenomenon of heat dissipation from MNPs is very sophisticated and depends on their concentration, the distribution and the relaxation mechanism in the tumour, together with magnetic field strength and frequency. Furthermore, we inferred that the phenomenon of heat dissipation from MNPs equally depends on MNP-tissue interactions, and it can lead to 30% differences in the power assessment. Nevertheless, the aforementioned factors should be considered in parallel using anatomical, volume-dependent models to enhance the efficiency of in vivo treatment. Full article

(This article belongs to the Special Issue Magnetic Nanoparticles 2019)

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16 pages, 4186 KiB

Open AccessArticle

Discovery of a Ruthenium Complex for the Theranosis of Glioma through Targeting the Mitochondrial DNA with Bioinformatic Methods

by Le Zhang, Chen Fu, Jin Li, Zizhen Zhao, Yixue Hou, Wei Zhou and Ailing Fu

Int. J. Mol. Sci. 2019, 20(18), 4643; https://doi.org/10.3390/ijms20184643 - 19 Sep 2019

Cited by 14 | Viewed by 3127

Abstract

Glioma is the most aggressive and lethal brain tumor in humans. Mutations of mitochondrial DNA (mtDNA) are commonly found in tumor cells and are closely associated with tumorigenesis and progress. However, glioma-specific inhibitors that reflect the unique feature of tumor cells are rare. [...] Read more.

Glioma is the most aggressive and lethal brain tumor in humans. Mutations of mitochondrial DNA (mtDNA) are commonly found in tumor cells and are closely associated with tumorigenesis and progress. However, glioma-specific inhibitors that reflect the unique feature of tumor cells are rare. Here we uncover RC-7, a ruthenium complex with strong red fluorescence, could bind with glioma mtDNA and then inhibited the growth of human glioma cells but not that of neuronal cells, liver, or endothelial cells. RC-7 significantly reduced energy production and increased the oxidative stress in the glioma cells. Administration of RC-7 into mice not only could be observed in the glioma mass of brain by fluorescence imaging, but also obviously prevented the growth of xenograft glioma and prolonged mouse survival days. The findings suggested the theranostic application of a novel type of complex through targeting the tumor mtDNA. Full article

(This article belongs to the Section Molecular Oncology)

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21 pages, 9897 KiB

Open AccessArticle

Enhanced Senescence Process is the Major Factor Stopping Spike Differentiation of Wheat Mutant ptsd1

by Zhixin Jiao, Junchang Li, Yongjing Ni, Yumei Jiang, Yulong Sun, Junhang An, Huijuan Li, Jing Zhang, Xin Hu, Qiaoyun Li and Jishan Niu

Int. J. Mol. Sci. 2019, 20(18), 4642; https://doi.org/10.3390/ijms20184642 - 19 Sep 2019

Cited by 5 | Viewed by 3630

Abstract

Complete differentiation of the spikes guarantees the final wheat (Triticum aestivum L.) grain yield. A unique wheat mutant that prematurely terminated spike differentiation (ptsd1) was obtained from cultivar Guomai 301 treated with ethyl methane sulfonate (EMS). The molecular mechanism study [...] Read more.

Complete differentiation of the spikes guarantees the final wheat (Triticum aestivum L.) grain yield. A unique wheat mutant that prematurely terminated spike differentiation (ptsd1) was obtained from cultivar Guomai 301 treated with ethyl methane sulfonate (EMS). The molecular mechanism study on ptsd1 showed that the senescence-associated genes (SAGs) were highly expressed, and spike differentiation related homeotic genes were depressed. Cytokinin signal transduction was weakened and ethylene signal transduction was enhanced. The enhanced expression of Ca²⁺ signal transduction related genes and the accumulation of reactive oxygen species (ROS) caused the upper spikelet cell death. Many genes in the WRKY, NAC and ethylene response factor (ERF) transcription factor (TF) families were highly expressed. Senescence related metabolisms, including macromolecule degradation, nutrient recycling, as well as anthocyanin and lignin biosynthesis, were activated. A conserved tae-miR164 and a novel-miR49 and their target genes were extensively involved in the senescence related biological processes in ptsd1. Overall, the abnormal phytohormone homeostasis, enhanced Ca²⁺ signaling and activated senescence related metabolisms led to the spikelet primordia absent their typical meristem characteristics, and ultimately resulted in the phenotype of ptsd1. Full article

(This article belongs to the Special Issue Meristem and Stem Cell Regulation in Plants)

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12 pages, 3553 KiB

Open AccessArticle

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

by Alfonso Gautieri, Marten Beeg, Marco Gobbi, Federica Rigoldi, Laura Colombo and Mario Salmona

Int. J. Mol. Sci. 2019, 20(18), 4641; https://doi.org/10.3390/ijms20184641 - 19 Sep 2019

Cited by 30 | Viewed by 4283

Abstract

The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer’s disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. [...] Read more.

The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer’s disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. However, the molecular mechanisms of the drug’s anti-amyloidogenic property are not understood. In this study, a series of molecular dynamics simulations were performed to explain the molecular mechanism of the destabilization of Aβ42 fibrils by doxycycline and to compare the action of doxycycline with those of iododoxorubicin (a toxic structural homolog of tetracyclines), curcumin (known to have anti-amyloidogenic activity) and gentamicin (an antibiotic with no experimental evidence of anti-amyloidogenic properties). We found that doxycycline tightly binds the exposed hydrophobic amino acids of the Aβ42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to Aβ42 may help devise further strategies for structure-based drug design for Alzheimer’s disease. Full article

(This article belongs to the Section Molecular Biophysics)

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16 pages, 1479 KiB

Open AccessReview

The Link of the Prion Protein with Ca²⁺ Metabolism and ROS Production, and the Possible Implication in Aβ Toxicity

by Agnese De Mario, Caterina Peggion, Maria Lina Massimino, Rosa Pia Norante, Alessandra Zulian, Alessandro Bertoli and Maria Catia Sorgato

Int. J. Mol. Sci. 2019, 20(18), 4640; https://doi.org/10.3390/ijms20184640 - 19 Sep 2019

Cited by 11 | Viewed by 4060

Abstract

The cellular prion protein (PrP^C) is an ubiquitous cell surface protein mostly expressed in neurons, where it localizes to both pre- and post-synaptic membranes. PrP^C aberrant conformers are the major components of mammalian prions, the infectious agents responsible for incurable [...] Read more.

The cellular prion protein (PrP^C) is an ubiquitous cell surface protein mostly expressed in neurons, where it localizes to both pre- and post-synaptic membranes. PrP^C aberrant conformers are the major components of mammalian prions, the infectious agents responsible for incurable neurodegenerative disorders. PrP^C was also proposed to bind aggregated misfolded proteins/peptides, and to mediate their neurotoxic signal. In spite of long-lasting research, a general consensus on the precise pathophysiologic mechanisms of PrP^C has not yet been reached. Here we review our recent data, obtained by comparing primary neurons from PrP-expressing and PrP-knockout mice, indicating a central role of PrP^C in synaptic transmission and Ca²⁺ homeostasis. Indeed, by controlling gene expression and signaling cascades, PrP^C is able to optimize glutamate secretion and regulate Ca²⁺ entry via store-operated channels and ionotropic glutamate receptors, thereby protecting neurons from threatening Ca²⁺ overloads and excitotoxicity. We will also illustrate and discuss past and unpublished results demonstrating that Aβ oligomers perturb Ca²⁺ homeostasis and cause abnormal mitochondrial accumulation of reactive oxygen species by possibly affecting the PrP-dependent downregulation of Fyn kinase activity. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases 2.0)

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18 pages, 2180 KiB

Open AccessArticle

Heightened TLR7/9-Induced IL-10 and CXCL13 Production with Dysregulated NF-ҝB Activation in CD11c^hiCD11b⁺ Dendritic Cells in NZB/W F1 Mice

by Lok Yan Yim, Chak Sing Lau and Vera Sau-Fong Chan

Int. J. Mol. Sci. 2019, 20(18), 4639; https://doi.org/10.3390/ijms20184639 - 19 Sep 2019

Cited by 7 | Viewed by 4443

Abstract

Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease that predominantly affects young females. Dysregulation of different immune cell populations leads to self-tolerance breakdown and subsequent multiple organ damage as the disease develops. Plasmacytoid dendritic cells (pDCs) are potent producers of type [...] Read more.

Systemic lupus erythematosus (SLE) is a chronic, multifactorial autoimmune disease that predominantly affects young females. Dysregulation of different immune cell populations leads to self-tolerance breakdown and subsequent multiple organ damage as the disease develops. Plasmacytoid dendritic cells (pDCs) are potent producers of type I interferon (IFN), while myeloid dendritic cells (mDCs) are more specialized in antigen presentations. We have previously reported that bone-marrow (BM)-derived pDCs from the murine lupus model New Zealand black/white F1 (BWF1) possess abnormalities. Therefore, this study continues to investigate what aberrant properties peripheral pDCs and mDCs possess in BWF1 and how they mediate SLE progression, by comparing their properties in pre-symptomatic and symptomatic mice. Results showed that CD11c^hiCD11b⁺ myeloid DCs expanded during the disease state with down-regulation of co-stimulatory molecules and major histocompatibility complex class II molecules (MHC II), but their capacity to stimulate T cells was not hampered. During the disease state, this subset of mDCs displayed heightened toll-like receptors 7 and 9 (TLR 7/9) responses with increased interleukin 10 (IL-10) and C-X-C motif chemokine ligand 13 (CXCL13) expressions. Moreover, the expressions of myeloid differentiation primary response 88 (Myd88) and nuclear factor kappa B subunit 1 (Nfkb1) were higher in CD11c^hiCD11b⁺ DCs at the disease stage, leading to higher nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 phosphorylation activity. In summary, we reported aberrant phenotypic properties with enhanced TLR7/9 responses of CD11c^hiCD11b⁺ DCs in SLE mediated by aberrant NF-κB signaling pathway. Our findings add additional and novel information to our current understanding of the role of DCs in lupus immunopathogenesis. Lastly, molecular candidates in the NF-κB pathway should be exploited for developing therapeutic targets for SLE. Full article

(This article belongs to the Special Issue Systemic Lupus Erythematosus: Research Updates in Immunopathogenesis, Biomarkers and Therapeutics)

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10 pages, 229 KiB

Open AccessReview

miRNA Profiling for Early Detection and Treatment of Duchenne Muscular Dystrophy

by Heather C. Hrach and Marco Mangone

Int. J. Mol. Sci. 2019, 20(18), 4638; https://doi.org/10.3390/ijms20184638 - 19 Sep 2019

Cited by 27 | Viewed by 5939

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by out of frame mutations in the dystrophin gene. The hallmark symptoms of the condition include progressive degeneration of skeletal muscle, cardiomyopathy, and respiratory dysfunction. The most recent advances in therapeutic strategies [...] Read more.

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by out of frame mutations in the dystrophin gene. The hallmark symptoms of the condition include progressive degeneration of skeletal muscle, cardiomyopathy, and respiratory dysfunction. The most recent advances in therapeutic strategies for the treatment of DMD involve exon skipping or administration of minidystrophin, but these strategies are not yet universally available, nor have they proven to be a definitive cure for all DMD patients. Early diagnosis and tracking of symptom progression of DMD usually relies on creatine kinase tests, evaluation of patient performance in various ambulatory assessments, and detection of dystrophin from muscle biopsies, which are invasive and painful for the patient. While the current research focuses primarily on restoring functional dystrophin, accurate and minimally invasive methods to detect and track both symptom progression and the success of early DMD treatments are not yet available. In recent years, several groups have identified miRNA signature changes in DMD tissue samples, and a number of promising studies consistently detected changes in circulating miRNAs in blood samples of DMD patients. These results could potentially lead to non-invasive detection methods, new molecular approaches to treating DMD symptoms, and new methods to monitor of the efficacy of the therapy. In this review, we focus on the role of circulating miRNAs in DMD and highlight their potential both as a biomarker in the early detection of disease and as a therapeutic target in the prevention and treatment of DMD symptoms. Full article

(This article belongs to the Special Issue New Regulators and Modulators of MicroRNA)

16 pages, 1032 KiB

Open AccessReview

Klotho: A Major Shareholder in Vascular Aging Enterprises

by Kenneth Lim, Arvin Halim, Tzong-shi Lu, Alan Ashworth and Irene Chong

Int. J. Mol. Sci. 2019, 20(18), 4637; https://doi.org/10.3390/ijms20184637 - 19 Sep 2019

Cited by 36 | Viewed by 7042

Abstract

Accelerated vascular aging is a condition that occurs as a complication of several highly prevalent inflammatory conditions such as chronic kidney disease, cancer, HIV infection and diabetes. Age-associated vascular alterations underlie a continuum of expression toward clinically overt cardiovascular disease. This has contributed [...] Read more.

Accelerated vascular aging is a condition that occurs as a complication of several highly prevalent inflammatory conditions such as chronic kidney disease, cancer, HIV infection and diabetes. Age-associated vascular alterations underlie a continuum of expression toward clinically overt cardiovascular disease. This has contributed to the striking epidemiologic transition whereby such noncommunicable diseases have taken center stage as modern-day global epidemics and public health problems. The identification of α-Klotho, a remarkable protein that confers powerful anti-aging properties has stimulated significant interest. In fact, emerging data have provided fundamental rationale for Klotho-based therapeutic intervention for vascular diseases and multiple other potential indications. However, the application of such discoveries in Klotho research remains fragmented due to significant gaps in our molecular understanding of Klotho biology, as well as hurdles in clinical research and experimental barriers that must first be overcome. These advances will be critical to establish the scientific platform from which future Klotho-based interventional trials and therapeutic enterprises can be successfully launched. Full article

(This article belongs to the Special Issue Nutrition and Cardiovascular Health)

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17 pages, 3579 KiB

Open AccessArticle

Identification of Functional and Druggable Sites in Aspergillus fumigatus Essential Phosphatases by Virtual Screening

by Benjamin P. Thornton, Anna Johns, Reem Al-Shidhani, Sandra Álvarez-Carretero, Isabelle S. R. Storer, Michael J. Bromley and Lydia Tabernero

Int. J. Mol. Sci. 2019, 20(18), 4636; https://doi.org/10.3390/ijms20184636 - 19 Sep 2019

Cited by 6 | Viewed by 4398

Abstract

Fungal diseases are a serious health burden worldwide with drug resistance compromising efficacy of the limited arsenal of antifungals available. New drugs with novel mechanisms of action are desperately needed to overcome current challenges. The screening of the Aspergillus fumigatus genome identified 35 [...] Read more.

Fungal diseases are a serious health burden worldwide with drug resistance compromising efficacy of the limited arsenal of antifungals available. New drugs with novel mechanisms of action are desperately needed to overcome current challenges. The screening of the Aspergillus fumigatus genome identified 35 phosphatases, four of which were previously reported as essential for viability. In addition, we validated another three essential phosphatases. Phosphatases control critical events in fungi from cell wall integrity to cell cycle, thus they are attractive targets for drug development. We used VSpipe v1.0, a virtual screening pipeline, to evaluate the druggability of the seven essential phosphatases and identify starting points for drug discovery. Targeted virtual screening and evaluation of the ligand efficiency plots created by VSpipe, enabled us to define the most favourable chemical space for drug development and suggested different modes of inhibition for each phosphatase. Interestingly, the identified ligand binding sites match with functional sites (active site and protein interaction sites) reported for other yeast and human homologues. Thus, the VSpipe virtual screening approach identified both druggable and functional sites in these essential phosphatases for further experimental validation and antifungal drug development. Full article

(This article belongs to the Special Issue Recent Advances in Virtual Screening)

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16 pages, 3417 KiB

Open AccessArticle

MORF9 Functions in Plastid RNA Editing with Tissue Specificity

by Faan Tian, Jinfa Yu, Ya Zhang, Yakun Xie, Binghua Wu and Ying Miao

Int. J. Mol. Sci. 2019, 20(18), 4635; https://doi.org/10.3390/ijms20184635 - 19 Sep 2019

Cited by 15 | Viewed by 3265

Abstract

RNA editing in plant mitochondria and plastids converts specific nucleotides from cytidine (C) to uridine (U). These editing events differ among plant species and are relevant to developmental stages or are impacted by environmental conditions. Proteins of the MORF family are essential components [...] Read more.

RNA editing in plant mitochondria and plastids converts specific nucleotides from cytidine (C) to uridine (U). These editing events differ among plant species and are relevant to developmental stages or are impacted by environmental conditions. Proteins of the MORF family are essential components of plant editosomes. One of the members, MORF9, is considered the core protein of the editing complex and is involved in the editing of most sites in chloroplasts. In this study, the phenotypes of a T-DNA insertion line with loss of MORF9 and of the genetic complementation line of Arabidopsis were analyzed, and the editing efficiencies of plastid RNAs in roots, rosette leaves, and flowers from the morf9 mutant and the wild-type (WT) control were compared by bulk-cDNA sequencing. The results showed that most of the known MORF9-associated plastid RNA editing events in rosette leaves and flowers were similarly reduced by morf9 mutation, with the exception that the editing rate of the sites ndhB-872 and psbF-65 declined in the leaves and that of ndhB-586 decreased only in the flowers. In the roots, however, the loss of MORF9 had a much lower effect on overall plastid RNA editing, with nine sites showing no significant editing efficiency change, including accD-794, ndhD-383, psbZ-50, ndhF-290, ndhD-878, matK-706, clpP1-559, rpoA-200, and ndhD-674, which were reduced in the other tissues. Furthermore, we found that during plant aging, MORF9 mRNA level, but not the protein level, was downregulated in senescent leaves. On the basis of these observations, we suggest that MORF9-mediated RNA editing is tissue-dependent and the resultant organelle proteomes are pertinent to the specific tissue functions. Full article

(This article belongs to the Section Molecular Plant Sciences)

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16 pages, 3527 KiB

Open AccessArticle

FGF23-Mediated Activation of Local RAAS Promotes Cardiac Hypertrophy and Fibrosis

by Ineke Böckmann, Jonas Lischka, Beatrice Richter, Jennifer Deppe, Anja Rahn, Dagmar-Christiane Fischer, Jörg Heineke, Dieter Haffner and Maren Leifheit-Nestler

Int. J. Mol. Sci. 2019, 20(18), 4634; https://doi.org/10.3390/ijms20184634 - 18 Sep 2019

Cited by 77 | Viewed by 6400

Abstract

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed [...] Read more.

Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin–angiotensin–aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of Fgf23 and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced Ngal indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced Tgfb and Ctgf, which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis. Full article

(This article belongs to the Special Issue Fibroblast Growth Factor Signaling in Development and Disease)

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11 pages, 278 KiB

Open AccessArticle

Effects of Tocilizumab, an Anti-Interleukin-6 Receptor Antibody, on Serum Lipid and Adipokine Levels in Patients with Rheumatoid Arthritis

by Elinoar Hoffman, Michal A. Rahat, Joy Feld, Muna Elias, Itzhak Rosner, Lisa Kaly, Idit Lavie, Tal Gazitt and Devy Zisman

Int. J. Mol. Sci. 2019, 20(18), 4633; https://doi.org/10.3390/ijms20184633 - 18 Sep 2019

Cited by 39 | Viewed by 3939

Abstract

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels [...] Read more.

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels in RA patients. Height, weight, disease activity scores, lipid profile and atherogenic indices (AI), leptin, adiponectin, resistin, interleukin-6, and high-sensitivity C-reactive protein (CRP) were measured before and four months after initiation of TCZ in 40 RA patients and 40 healthy controls. Following TCZ treatment, total cholesterol, high density lipoprotein (HDL), and triglycerides were significantly elevated, but no significant changes in weight, body mass index (BMI), low density lipoprotein (LDL), and AI were observed. Compared with controls, significantly higher adiponectin levels were measured in the RA group at baseline. Following TCZ treatment, resistin levels and the leptin-to-adiponectin ratio increased, adiponectin levels decreased, and leptin levels remained unchanged. No correlation was found between the change in adipokine serum levels and changes in the disease activity indices, nor the lipid profile. In conclusion, the changes observed suggest a protective role for TCZ on the metabolic and cardiovascular burden associated with RA, but does not provide a mechanistic explanation for this phenomenon. Full article

(This article belongs to the Special Issue Adipokines 2.0)

16 pages, 7249 KiB

Open AccessArticle

Regenerative Potential of the Product “CardioCell” Derived from the Wharton’s Jelly Mesenchymal Stem Cells for Treating Hindlimb Ischemia

by Aleksandra Musiał-Wysocka, Marta Kot, Maciej Sułkowski and Marcin Majka

Int. J. Mol. Sci. 2019, 20(18), 4632; https://doi.org/10.3390/ijms20184632 - 18 Sep 2019

Cited by 12 | Viewed by 3894

Abstract

In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality in regenerative medicine. They hold great promise for treating civilization-wide diseases, including cardiovascular diseases, such as acute myocardial infarction and critical limb ischemia. MSCs isolated from Wharton’s jelly (WJ-MSCs) [...] Read more.

In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality in regenerative medicine. They hold great promise for treating civilization-wide diseases, including cardiovascular diseases, such as acute myocardial infarction and critical limb ischemia. MSCs isolated from Wharton’s jelly (WJ-MSCs) may be utilized in both cell-based therapy and vascular graft engineering to restore vascular function, thereby providing therapeutic benefits for patients. The efficacy of WJ-MSCs lies in their multipotent differentiation ability toward vascular smooth muscle cells, endothelial cells and other cell types, as well as their capacity to secrete various trophic factors, which are potent in promoting angiogenesis, inhibiting apoptosis and modulating immunoreaction. Ischemic limb disease is caused by insufficient nutrient and oxygen supplies resulting from damaged peripheral arteries. The lack of nutrients and oxygen causes severe tissue damage in the limb, thereby resulting in severe morbidities and mortality. The therapeutic effects of the conventional treatments are still not sufficient. Cell transplantations in small animal model (mice) are vital for deciphering the mechanisms of MSCs’ action in muscle regeneration. The stimulation of angiogenesis is a promising strategy for the treatment of ischemic limbs, restoring blood supply for the ischemic region. In the present study, we focus on the therapeutic properties of the human WJ-MSCs derived product, Cardio. We investigated the role of CardioCell in promoting angiogenesis and relieving hindlimb ischemia. Our results confirm the healing effect of CardioCell and strongly support the use of the WJ-MSCs in regenerative medicine. Full article

(This article belongs to the Special Issue Stem Cell-Based Therapy)

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11 pages, 2182 KiB

Open AccessCommunication

PTEN, A Target of Microrna-374b, Contributes to the Radiosensitivity of Canine Oral Melanoma Cells

by Shunsuke Noguchi, Ryo Ogusu, Yusuke Wada, Satoshi Matsuyama and Takashi Mori

Int. J. Mol. Sci. 2019, 20(18), 4631; https://doi.org/10.3390/ijms20184631 - 18 Sep 2019

Cited by 10 | Viewed by 2941

Abstract

Canine oral malignant melanoma (CoMM) is often treated by radiation therapy in veterinary medicine. However, not all cases are successfully managed by this treatment. For improved efficacy of radiation therapy, biomarkers predicting the radiosensitivity of melanoma cells need to be explored. Here, we, [...] Read more.

Canine oral malignant melanoma (CoMM) is often treated by radiation therapy in veterinary medicine. However, not all cases are successfully managed by this treatment. For improved efficacy of radiation therapy, biomarkers predicting the radiosensitivity of melanoma cells need to be explored. Here, we, first, developed the radioresistant CoMM cell line, KMeC/R. We found that the expression level of phosphatase and tensin homolog (PTEN) of KMeC/R cells was significantly downregulated compared with KMeC cells. Overexpression of PTEN successfully restored the radiosensitivity of KMeC/R cells, and silencing of PTEN significantly increased the radioresistance of the CoMM cells tested. Next, we focused on microRNAs (miRNAs) to explore the mechanisms of downregulation of PTEN in KMeC/R cells. miR-374b was upregulated in KMeC/R cells compared with that in KMeC cells and in the irradiated CoMM cells tested. Furthermore, miR-374b directly targeted PTEN based on the luciferase activity assay. Moreover, the extrinsic miR-374b significantly increased the radioresistance of KMeC cells. In addition, the expression level of PTEN was significantly downregulated and that of miR-374b tended to be upregulated in recurrent CoMM tissues after radiation therapy compared with the pre-treatment tissues. Thus, the current study suggested that the miR-374b/PTEN signaling pathway possibly plays an important role in CoMM radiosensitivity. Full article

(This article belongs to the Section Molecular Oncology)

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14 pages, 3113 KiB

Open AccessArticle

The Evaluation of Glioblastoma Cell Dissociation and Its Influence on Its Behavior

by Veronika Skarkova, Marketa Krupova, Barbora Vitovcova, Adam Skarka, Petra Kasparova, Petr Krupa, Vera Kralova and Emil Rudolf

Int. J. Mol. Sci. 2019, 20(18), 4630; https://doi.org/10.3390/ijms20184630 - 18 Sep 2019

Cited by 8 | Viewed by 3052

Abstract

Purpose: Primary cell lines are a valuable tool for evaluation of tumor behavior or sensitivity to anticancer treatment and appropriate dissociation of cells could preserve genomic profile of the original tissue. The main aim of our study was to compare the influence of [...] Read more.

Purpose: Primary cell lines are a valuable tool for evaluation of tumor behavior or sensitivity to anticancer treatment and appropriate dissociation of cells could preserve genomic profile of the original tissue. The main aim of our study was to compare the influence of two methods of glioblastoma multiforme (GBM) cell derivation (mechanic—MD; enzymatic—ED) on basic biological properties of thus derived cells and correlate them to the ones obtained from stabilized GBM cell line A-172. Methods: Cell proliferation and migration (xCELLigence Real-Time Cell Analysis), expression of microRNAs and protein markers (RT-PCR and Western blotting), morphology (phase contrast and fluorescent microscopy), and accumulation of temozolomide (TMZ) and its metabolite 5-aminoimidazole-4-carboxamide (AIC) inside the cells (LC-MS analysis) were carried out in five different samples of GBM (GBM1, GBM2, GBM32, GBM33, GBM34), with each of them processed by MD and ED types of isolations. The same analyses were done in the A-172 cell line too. Results: Primary GBM cells obtained by ED or MD approaches significantly differ in biological behavior and properties of these cells. Unlike in primary MD GBM cells, higher proliferation, as well as migration, was observed in primary ED GBM cells, which were also associated with the acquired mesenchymal phenotype and higher sensitivity to TMZ. Finally, the same analyses of stabilized GBM cell line A-172 revealed several important differences in measured parameters. Conclusions: GBM cells obtained by MD and ED dissociation show considerable heterogeneity, but based on our results, MD approach should be the preferred method of primary GBM cell isolation Full article

(This article belongs to the Section Molecular Oncology)

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