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Int. J. Mol. Sci., Volume 20, Issue 14 (July-2 2019)

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Open AccessCorrection
Correction: An, F., et al. A Conjugate of Pentamethine Cyanine and 18F as a Positron Emission Tomography/Near-Infrared Fluorescence Probe for Multimodality Tumor Imaging. Int. J. Mol. Sci. 2017, 18, 1214
Int. J. Mol. Sci. 2019, 20(14), 3584; https://doi.org/10.3390/ijms20143584 (registering DOI)
Received: 16 July 2019 / Accepted: 16 July 2019 / Published: 22 July 2019
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Abstract
The authors wish to make the following corrections to this paper [...] Full article
Open AccessArticle
Ureaplasma Species Modulate Cytokine and Chemokine Responses in Human Brain Microvascular Endothelial Cells
Int. J. Mol. Sci. 2019, 20(14), 3583; https://doi.org/10.3390/ijms20143583 (registering DOI)
Received: 28 May 2019 / Revised: 11 July 2019 / Accepted: 18 July 2019 / Published: 22 July 2019
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Abstract
Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. [...] Read more.
Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation. Full article
(This article belongs to the Special Issue Small Vessel Disease: A Whole Brain Disease)
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Open AccessArticle
In Silico Analysis of Gene Expression Change Associated with Copy Number of Enhancers in Pancreatic Adenocarcinoma
Int. J. Mol. Sci. 2019, 20(14), 3582; https://doi.org/10.3390/ijms20143582 (registering DOI)
Received: 5 May 2019 / Revised: 6 June 2019 / Accepted: 11 July 2019 / Published: 22 July 2019
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Abstract
Understanding the gene regulatory network governing cancer initiation and progression is necessary, although it remains largely unexplored. Enhancer elements represent the center of this regulatory circuit. The study aims to identify the gene expression change driven by copy number variation in enhancer elements [...] Read more.
Understanding the gene regulatory network governing cancer initiation and progression is necessary, although it remains largely unexplored. Enhancer elements represent the center of this regulatory circuit. The study aims to identify the gene expression change driven by copy number variation in enhancer elements of pancreatic adenocarcinoma (PAAD). The pancreatic tissue specific enhancer and target gene data were taken from EnhancerAtlas. The gene expression and copy number data were taken from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) and copy number variations (CNVs) were identified between matched tumor-normal samples of PAAD. Significant CNVs were matched onto enhancer coordinates by using genomic intersection functionality from BEDTools. By combining the gene expression and CNV data, we identified 169 genes whose expression shows a positive correlation with the CNV of enhancers. We further identified 16 genes which are regulated by a super enhancer and 15 genes which have high prognostic potential (Z-score > 1.96). Cox proportional hazard analysis of these genes indicates that these are better predictors of survival. Taken together, our integrative analytical approach identifies enhancer CNV-driven gene expression change in PAAD, which could lead to better understanding of PAAD pathogenesis and to the design of enhancer-based cancer treatment strategies. Full article
(This article belongs to the Section Molecular Informatics)
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Open AccessReview
BNP as a Major Player in the Heart-Kidney Connection
Int. J. Mol. Sci. 2019, 20(14), 3581; https://doi.org/10.3390/ijms20143581 (registering DOI)
Received: 22 June 2019 / Revised: 15 July 2019 / Accepted: 17 July 2019 / Published: 22 July 2019
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Abstract
Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we [...] Read more.
Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we review the functions and the roles of BNP in the heart-kidney interaction. In addition, we discuss the relevant molecular mechanisms that suggest BNP is protective against chronic kidney diseases and heart failure, especially in terms of the counterparts of the renin-angiotensin-aldosterone system (RAAS). The renal medulla has been reported to express depressor substances. The extract of the papillary tips from kidneys may induce the expression and secretion of BNP from cardiomyocytes. A better understanding of these processes will help accelerate pharmacological treatments for heart-kidney disease. Full article
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Open AccessReview
The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders
Int. J. Mol. Sci. 2019, 20(14), 3580; https://doi.org/10.3390/ijms20143580 (registering DOI)
Received: 9 June 2019 / Revised: 17 July 2019 / Accepted: 19 July 2019 / Published: 22 July 2019
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Abstract
Leukotrienes (LTs) are lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases. They exert their biological effects by binding to specific G-protein-coupled receptors. Each LT receptor subtype exhibits unique functions and expression patterns. LTs play roles in various [...] Read more.
Leukotrienes (LTs) are lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases. They exert their biological effects by binding to specific G-protein-coupled receptors. Each LT receptor subtype exhibits unique functions and expression patterns. LTs play roles in various allergic diseases, including asthma (neutrophilic asthma and aspirin-sensitive asthma), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and anaphylaxis. This review summarizes the biology of LTs and their receptors, recent developments in the area of anti-LT strategies (in settings such as ongoing clinical studies), and prospects for future therapeutic applications. Full article
(This article belongs to the Special Issue Lipid Mediators in Allergic Diseases)
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Open AccessArticle
Behavior of Embedded Cation-Exchange Particles in a DC Electric Field
Int. J. Mol. Sci. 2019, 20(14), 3579; https://doi.org/10.3390/ijms20143579 (registering DOI)
Received: 26 June 2019 / Revised: 17 July 2019 / Accepted: 21 July 2019 / Published: 22 July 2019
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Abstract
Electrodialysis and electrodeionization are separation processes whose performance depends on the quality and properties of ion-exchange membranes. One of the features that largely affects these properties is heterogeneity of the membranes both on the macroscopic and microscopic level. Macroscopic heterogeneity is an intrinsic [...] Read more.
Electrodialysis and electrodeionization are separation processes whose performance depends on the quality and properties of ion-exchange membranes. One of the features that largely affects these properties is heterogeneity of the membranes both on the macroscopic and microscopic level. Macroscopic heterogeneity is an intrinsic property of heterogeneous ion-exchange membranes. In these membranes, the functional ion-exchange component is dispersed in a non-conductive binder. The functional component is finely ground ion-exchange resin particles. The understanding of the effect of structure on the heterogeneous membrane properties and behavior is thus of utmost importance since it does not only affect the actual performance but also the cost and therefore competitiveness of the aforementioned separation processes. Here we study the electrokinetic behavior of cation-exchange resin particle systems with well-defined geometrical structure. This approach can be understood as a bottom up approach regarding the membrane preparation. We prepare a structured cation-exchange membrane by using its fundamental component, which is the ion exchange resin. We then perform an experimental study with four different experimental systems in which the number of used cation-exchange particles changes from 1 to 4. These systems are studied by means of basic electrochemical characterization measurements, such as measurement of current–voltage curves and direct optical observation of phenomena that occur at the interface between the ion-exchange system and the adjacent electrolyte. Our work aims at better understanding of the relation between the structure and the membrane properties and of how structure affects electrokinetic behavior of these systems. Full article
(This article belongs to the Special Issue Ion and Molecule Transport in Membrane Systems)
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Open AccessReview
The Cytoskeleton of the Retinal Pigment Epithelium: from Normal Aging to Age-Related Macular Degeneration
Int. J. Mol. Sci. 2019, 20(14), 3578; https://doi.org/10.3390/ijms20143578 (registering DOI)
Received: 3 June 2019 / Revised: 15 July 2019 / Accepted: 18 July 2019 / Published: 22 July 2019
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Abstract
The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, [...] Read more.
The retinal pigment epithelium (RPE) is a unique epithelium, with major roles which are essential in the visual cycle and homeostasis of the outer retina. The RPE is a monolayer of polygonal and pigmented cells strategically placed between the neuroretina and Bruch membrane, adjacent to the fenestrated capillaries of the choriocapillaris. It shows strong apical (towards photoreceptors) to basal/basolateral (towards Bruch membrane) polarization. Multiple functions are bound to a complex structure of highly organized and polarized intracellular components: the cytoskeleton. A strong connection between the intracellular cytoskeleton and extracellular matrix is indispensable to maintaining the function of the RPE and thus, the photoreceptors. Impairments of these intracellular structures and the regular architecture they maintain often result in a disrupted cytoskeleton, which can be found in many retinal diseases, including age-related macular degeneration (AMD). This review article will give an overview of current knowledge on the molecules and proteins involved in cytoskeleton formation in cells, including RPE and how the cytoskeleton is affected under stress conditions—especially in AMD. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))
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Open AccessReview
Biological Functions and Molecular Mechanisms of Antibiotic Tigecycline in the Treatment of Cancers
Int. J. Mol. Sci. 2019, 20(14), 3577; https://doi.org/10.3390/ijms20143577 (registering DOI)
Received: 14 June 2019 / Revised: 17 July 2019 / Accepted: 19 July 2019 / Published: 22 July 2019
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Abstract
As an FDA-approved drug, glycylcycline tigecycline has been used to treat complicated microbial infections. However, recent studies in multiple hematologic and malignant solid tumors reveal that tigecycline treatment induces cell cycle arrest, apoptosis, autophagy and oxidative stress. In addition, tigecycline also inhibits mitochondrial [...] Read more.
As an FDA-approved drug, glycylcycline tigecycline has been used to treat complicated microbial infections. However, recent studies in multiple hematologic and malignant solid tumors reveal that tigecycline treatment induces cell cycle arrest, apoptosis, autophagy and oxidative stress. In addition, tigecycline also inhibits mitochondrial oxidative phosphorylation, cell proliferation, migration, invasion and angiogenesis. Importantly, combinations of tigecycline with chemotherapeutic or targeted drugs such as venetoclax, doxorubicin, vincristine, paclitaxel, cisplatin, and imatinib, have shown to be promising strategies for cancer treatment. Mechanism of action studies reveal that tigecycline leads to the inhibition of mitochondrial translation possibly through interacting with mitochondrial ribosome. Meanwhile, this drug also interferes with several other cell pathways/targets including MYC, HIFs, PI3K/AKT or AMPK-mediated mTOR, cytoplasmic p21 CIP1/Waf1, and Wnt/β-catenin signaling. These evidences indicate that antibiotic tigecycline is a promising drug for cancer treatment alone or in combination with other anticancer drugs. This review summarizes the biological function of tigecycline in the treatment of tumors and comprehensively discusses its mode of action. Full article
(This article belongs to the Section Molecular Pharmacology)
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Open AccessReview
Reactive Oxygen Species in Osteoclast Differentiation and Possible Pharmaceutical Targets of ROS-Mediated Osteoclast Diseases
Int. J. Mol. Sci. 2019, 20(14), 3576; https://doi.org/10.3390/ijms20143576 (registering DOI)
Received: 30 June 2019 / Revised: 19 July 2019 / Accepted: 21 July 2019 / Published: 22 July 2019
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Abstract
Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction–oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to [...] Read more.
Reactive oxygen species (ROS) and free radicals are essential for transmission of cell signals and other physiological functions. However, excessive amounts of ROS can cause cellular imbalance in reduction–oxidation reactions and disrupt normal biological functions, leading to oxidative stress, a condition known to be responsible for the development of several diseases. The biphasic role of ROS in cellular functions has been a target of pharmacological research. Osteoclasts are derived from hematopoietic progenitors in the bone and are essential for skeletal growth and remodeling, for the maintenance of bone architecture throughout lifespan, and for calcium metabolism during bone homeostasis. ROS, including superoxide ion (O2) and hydrogen peroxide (H2O2), are important components that regulate the differentiation of osteoclasts. Under normal physiological conditions, ROS produced by osteoclasts stimulate and facilitate resorption of bone tissue. Thus, elucidating the effects of ROS during osteoclast differentiation is important when studying diseases associated with bone resorption such as osteoporosis. This review examines the effect of ROS on osteoclast differentiation and the efficacy of novel chemical compounds with therapeutic potential for osteoclast related diseases. Full article
(This article belongs to the Special Issue Tumor Bone Microenvironment, Bone Turnover and Stem Cell)
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Open AccessArticle
Smooth Muscle Phenotype in Idiopathic Pulmonary Hypertension: Hyper-Proliferative but not Cancerous
Int. J. Mol. Sci. 2019, 20(14), 3575; https://doi.org/10.3390/ijms20143575 (registering DOI)
Received: 3 June 2019 / Revised: 12 July 2019 / Accepted: 18 July 2019 / Published: 22 July 2019
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Abstract
Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from [...] Read more.
Idiopathic pulmonary arterial hypertension (IPAH) is a complex disease associated with vascular remodeling and a proliferative disorder in pulmonary artery smooth muscle cells (PASMCs) that has been variably described as having neoplastic features. To decode the phenotype of PASMCs in IPAH, PASMCs from explanted lungs of patients with IPAH (IPAH-PASMCs) and from controls (C-PASMCs) were cultured. The IPAH-PASMCs grew faster than the controls; however, both growth curves plateaued, suggesting contact inhibition in IPAH cells. No proliferation was seen without stimulation with exogenous growth factors, suggesting that IPAH cells are incapable of self-sufficient growth. IPAH-PASMCs were more resistant to apoptosis than C-PASMCs, consistent with the increase in the Bcl2/Bax ratio. As cell replication is governed by telomere length, these parameters were assessed jointly. Compared to C-PASMCs, IPAH-PASMCs had longer telomeres, but a limited replicative capacity. Additionally, it was noted that IPAH-PASMCs had a shift in energy production from mitochondrial oxidative phosphorylation to aerobic glycolysis. As DNA damage and genomic instability are strongly implicated in IPAH development a comparative genomic hybridization was performed on genomic DNA from PASMCs which showed multiple break-points unaffected by IPAH severity. Activation of DNA damage/repair factors (γH2AX, p53, and GADD45) in response to cisplatin was measured. All proteins showed lower phosphorylation in IPAH samples than in controls, suggesting that the cells were resistant to DNA damage. Despite the cancer-like processes that are associated with end-stage IPAH-PASMCs, we identified no evidence of self-sufficient proliferation in these cells—the defining feature of neoplasia. Full article
(This article belongs to the Section Molecular Biology)
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Open AccessArticle
Bakuchiol Suppresses Inflammatory Responses Via the Downregulation of the p38 MAPK/ERK Signaling Pathway
Int. J. Mol. Sci. 2019, 20(14), 3574; https://doi.org/10.3390/ijms20143574 (registering DOI)
Received: 14 June 2019 / Revised: 18 July 2019 / Accepted: 19 July 2019 / Published: 22 July 2019
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Abstract
The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin [...] Read more.
The purpose of the present study was to evaluate the effects of bakuchiol on the inflammatory response and to identify the molecular mechanism of the inflammatory effects in a lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial cell line and mice model. The production of prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay. The mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, and IL-6 was measured using reverse transcription–polymerase chain reaction analysis. Mitogen-activated protein kinase (MAPK) phosphorylation was determined by western blot analysis. In vitro experiments, bakuchiol significantly suppressed the production of PGE2 and IL-6 in LPS-stimulated BV-2 cells, without causing cytotoxicity. In parallel, bakuchiol significantly inhibited the LPS-stimulated expression of iNOS, COX-2, and IL-6 in BV-2 cells. However, bakuchiol had no effect on the LPS-stimulated production and mRNA expression of TNF-α or on LPS-stimulated c-Jun NH2-terminal kinase phosphorylation. In contrast, p38 MAPK and extracellular signal-regulated kinase (ERK) phosphorylation were inhibited by bakuchiol. In vivo experiments, Bakuchiol reduced microglial activation in the hippocampus and cortex tissue of LPS-injected mice. Bakuchiol significantly suppressed LPS-injected production of TNF-α and IL-6 in serum. These results indicate that the anti-neuroinflammatory effects of bakuchiol in activated microglia are mainly regulated by the inhibition of the p38 MAPK and ERK pathways. We suggest that bakuchiol may be beneficial for various neuroinflammatory diseases. Full article
(This article belongs to the Section Molecular Pharmacology)
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Open AccessArticle
The Maize Clade A PP2C Phosphatases Play Critical Roles in Multiple Abiotic Stress Responses
Int. J. Mol. Sci. 2019, 20(14), 3573; https://doi.org/10.3390/ijms20143573 (registering DOI)
Received: 2 July 2019 / Revised: 17 July 2019 / Accepted: 18 July 2019 / Published: 22 July 2019
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Abstract
As the core components of abscisic acid (ABA) signal pathway, Clade A PP2C (PP2C-A) phosphatases in ABA-dependent stress responses have been well studied in Arabidopsis. However, the roles and natural variations of maize PP2C-A in stress responses remain largely unknown. In this [...] Read more.
As the core components of abscisic acid (ABA) signal pathway, Clade A PP2C (PP2C-A) phosphatases in ABA-dependent stress responses have been well studied in Arabidopsis. However, the roles and natural variations of maize PP2C-A in stress responses remain largely unknown. In this study, we investigated the expression patterns of ZmPP2C-As treated with multiple stresses and generated transgenic Arabidopsis plants overexpressing most of the ZmPP2C-A genes. The results showed that the expression of most ZmPP2C-As were dramatically induced by multiple stresses (drought, salt, and ABA), indicating that these genes may have important roles in response to these stresses. Compared with wild-type plants, ZmPP2C-A1, ZmPP2C-A2, and ZmPP2C-A6 overexpression plants had higher germination rates after ABA and NaCl treatments. ZmPP2C-A2 and ZmPP2C-A6 negatively regulated drought responses as the plants overexpressing these genes had lower survival rates, higher leaf water loss rates, and lower proline accumulation compared to wild type plants. The natural variations of ZmPP2C-As associated with drought tolerance were also analyzed and favorable alleles were detected. We widely studied the roles of ZmPP2C-A genes in stress responses and the natural variations detected in these genes have the potential to be used as molecular markers in genetic improvement of maize drought tolerance. Full article
(This article belongs to the Special Issue Mechanisms of Drought Stress Tolerance in Plants)
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Open AccessArticle
Targeting HIV/HCV Coinfection Using a Machine Learning-Based Multiple Quantitative Structure-Activity Relationships (Multiple QSAR) Method
Int. J. Mol. Sci. 2019, 20(14), 3572; https://doi.org/10.3390/ijms20143572 (registering DOI)
Received: 2 July 2019 / Revised: 13 July 2019 / Accepted: 21 July 2019 / Published: 22 July 2019
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Abstract
Human immunodeficiency virus type-1 and hepatitis C virus (HIV/HCV) coinfection occurs when a patient is simultaneously infected with both human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV), which is common today in certain populations. However, the treatment of coinfection is a [...] Read more.
Human immunodeficiency virus type-1 and hepatitis C virus (HIV/HCV) coinfection occurs when a patient is simultaneously infected with both human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV), which is common today in certain populations. However, the treatment of coinfection is a challenge because of the special considerations needed to ensure hepatic safety and avoid drug–drug interactions. Multitarget inhibitors with less toxicity may provide a promising therapeutic strategy for HIV/HCV coinfection. However, the identification of one molecule that acts on multiple targets simultaneously by experimental evaluation is costly and time-consuming. In silico target prediction tools provide more opportunities for the development of multitarget inhibitors. In this study, by combining Naïve Bayes (NB) and support vector machine (SVM) algorithms with two types of molecular fingerprints, MACCS and extended connectivity fingerprints 6 (ECFP6), 60 classification models were constructed to predict compounds that were active against 11 HIV-1 targets and four HCV targets based on a multiple quantitative structure–activity relationships (multiple QSAR) method. Five-fold cross-validation and test set validation were performed to measure the performance of the 60 classification models. Our results show that the 60 multiple QSAR models appeared to have high classification accuracy in terms of the area under the ROC curve (AUC) values, which ranged from 0.83 to 1 with a mean value of 0.97 for the HIV-1 models and from 0.84 to 1 with a mean value of 0.96 for the HCV models. Furthermore, the 60 models were used to comprehensively predict the potential targets of an additional 46 compounds, including 27 approved HIV-1 drugs, 10 approved HCV drugs and nine selected compounds known to be active against one or more targets of HIV-1 or HCV. Finally, 20 hits, including seven approved HIV-1 drugs, four approved HCV drugs, and nine other compounds, were predicted to be HIV/HCV coinfection multitarget inhibitors. The reported bioactivity data confirmed that seven out of nine compounds actually interacted with HIV-1 and HCV targets simultaneously with diverse binding affinities. The remaining predicted hits and chemical-protein interaction pairs with the potential ability to suppress HIV/HCV coinfection are worthy of further experimental investigation. This investigation shows that the multiple QSAR method is useful in predicting chemical-protein interactions for the discovery of multitarget inhibitors and provides a unique strategy for the treatment of HIV/HCV coinfection. Full article
(This article belongs to the Special Issue Artificial Intelligence and Computer Aided Drug Design)
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Open AccessArticle
Deciphering the Origin and Evolution of the X1X2Y System in Two Closely-Related Oplegnathus Species (Oplegnathidae and Centrarchiformes)
Int. J. Mol. Sci. 2019, 20(14), 3571; https://doi.org/10.3390/ijms20143571
Received: 12 June 2019 / Revised: 5 July 2019 / Accepted: 13 July 2019 / Published: 22 July 2019
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Abstract
Oplegnathus fasciatus and O. punctatus (Teleostei: Centrarchiformes: Oplegnathidae), are commercially important rocky reef fishes, endemic to East Asia. Both species present an X1X2Y sex chromosome system. Here, we investigated the evolutionary forces behind the origin and differentiation of [...] Read more.
Oplegnathus fasciatus and O. punctatus (Teleostei: Centrarchiformes: Oplegnathidae), are commercially important rocky reef fishes, endemic to East Asia. Both species present an X1X2Y sex chromosome system. Here, we investigated the evolutionary forces behind the origin and differentiation of these sex chromosomes, with the aim to elucidate whether they had a single or convergent origin. To achieve this, conventional and molecular cytogenetic protocols, involving the mapping of repetitive DNA markers, comparative genomic hybridization (CGH), and whole chromosome painting (WCP) were applied. Both species presented similar 2n, karyotype structure and hybridization patterns of repetitive DNA classes. 5S rDNA loci, besides being placed on the autosomal pair 22, resided in the terminal region of the long arms of both X1 chromosomes in females, and on the X1 and Y chromosomes in males. Furthermore, WCP experiments with a probe derived from the Y chromosome of O. fasciatus (OFAS-Y) entirely painted the X1 and X2 chromosomes in females and the X1, X2, and Y chromosomes in males of both species. CGH failed to reveal any sign of sequence differentiation on the Y chromosome in both species, thereby suggesting the shared early stage of neo-Y chromosome differentiation. Altogether, the present findings confirmed the origin of the X1X2Y sex chromosomes via Y-autosome centric fusion and strongly suggested their common origin. Full article
(This article belongs to the Special Issue Chromosome and Karyotype Variation)
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Open AccessArticle
High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction
Int. J. Mol. Sci. 2019, 20(14), 3570; https://doi.org/10.3390/ijms20143570
Received: 7 June 2019 / Revised: 12 July 2019 / Accepted: 15 July 2019 / Published: 22 July 2019
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Abstract
The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs’ progression are still unclear. In this regard, high-mobility group box protein 1 (HMGB1), an inflammatory mediator, has [...] Read more.
The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is implicated in the pathogenesis of cardiovascular diseases (CVDs). The molecular mechanisms of how TMAO induces atherosclerosis and CVDs’ progression are still unclear. In this regard, high-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to disrupt cell–cell junctions, resulting in vascular endothelial hyper permeability leading to endothelial dysfunction. The present study tested whether TMAO associated endothelial dysfunction results via HMGB1 activation. Biochemical and RT-PCR analysis showed that TMAO increased the HMGB1 expression in a dose-dependent manner in endothelial cells. However, prior treatment with glycyrrhizin, an HMGB1 binder, abolished the TMAO-induced HMGB1 production in endothelial cells. Furthermore, Western blot and immunofluorescent analysis showed significant decrease in the expression of cell–cell junction proteins ZO-2, Occludin, and VE-cadherin in TMAO treated endothelial cells compared with control cells. However, prior treatment with glycyrrhizin attenuated the TMAO-induced cell–cell junction proteins’ disruption. TMAO increased toll-like receptor 4 (TLR4) expression in endothelial cells. Inhibition of TLR4 expression by TLR4 siRNA protected the endothelial cells from TMAO associated tight junction protein disruption via HMGB1. In conclusion, our results demonstrate that HMGB1 is one of the important mediators of TMAO-induced endothelial dysfunction. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
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Open AccessCommunication
Identification of Jasmonic Acid Biosynthetic Genes in Sweet Cherry and Expression Analysis in Four Ancient Varieties from Tuscany
Int. J. Mol. Sci. 2019, 20(14), 3569; https://doi.org/10.3390/ijms20143569
Received: 26 June 2019 / Revised: 15 July 2019 / Accepted: 18 July 2019 / Published: 22 July 2019
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Abstract
Sweet cherries are non-climacteric fruits whose early development is characterized by high levels of the phytohormone jasmonic acid (JA). Important parameters, such as firmness and susceptibility to cracking, can be affected by pre- and postharvest treatments of sweet cherries with JA. Despite the [...] Read more.
Sweet cherries are non-climacteric fruits whose early development is characterized by high levels of the phytohormone jasmonic acid (JA). Important parameters, such as firmness and susceptibility to cracking, can be affected by pre- and postharvest treatments of sweet cherries with JA. Despite the impact of JA on sweet cherry development and fruit characteristics, there are no studies (to the best of our knowledge) identifying the genes involved in the JA biosynthetic pathway in this species. We herein identify the sweet cherry members of the lipoxygenase family (13-LOX); allene oxide synthase, allene oxide cyclase and 12-oxo-phytodienoic acid reductase 3, as well as genes encoding the transcriptional master regulator MYC2. We analyze their expression pattern in four non-commercial Tuscan varieties (‘Carlotta’, ‘Maggiola’, ‘Morellona’, ‘Crognola’) having different levels of bioactives (namely phenolics). The highest differences are found in two genes encoding 13-LOX in the variety ‘Maggiola’ and one MYC2 isoform in ‘Morellona’. No statistically-significant variations are instead present in the allene oxide synthase, allene oxide cyclase and 12-oxo-phytodienoic acid reductase 3. Our data pave the way to follow-up studies on the JA signaling pathway in these ancient varieties, for example in relation to development and post-harvest storage. Full article
(This article belongs to the Special Issue Jasmonic Acid Pathway in Plants)
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Open AccessArticle
Cell Type-Specific TGF-β Mediated EMT in 3D and 2D Models and Its Reversal by TGF-β Receptor Kinase Inhibitor in Ovarian Cancer Cell Lines
Int. J. Mol. Sci. 2019, 20(14), 3568; https://doi.org/10.3390/ijms20143568
Received: 1 July 2019 / Revised: 18 July 2019 / Accepted: 19 July 2019 / Published: 22 July 2019
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Abstract
Transcriptome profiling of 3D models compared to 2D models in various cancer cell lines shows differential expression of TGF-β-mediated and cell adhesion pathways. Presence of TGF-β in these cell lines shows an increased invasion potential which is specific to cell type. In the [...] Read more.
Transcriptome profiling of 3D models compared to 2D models in various cancer cell lines shows differential expression of TGF-β-mediated and cell adhesion pathways. Presence of TGF-β in these cell lines shows an increased invasion potential which is specific to cell type. In the present study, we identified exogenous addition of TGF-β can induce Epithelial to Mesenchymal Transition (EMT) in a few cancer cell lines. RNA sequencing and real time PCR were carried out in different ovarian cancer cell lines to identify molecular profiling and metabolic profiling. Since EMT induction by TGF-β is cell-type specific, we decided to select two promising ovarian cancer cell lines as model systems to study EMT. TGF-β modulation in EMT and cancer invasion were successfully depicted in both 2D and 3D models of SKOV3 and CAOV3 cell lines. Functional evaluation in 3D and 2D models demonstrates that the addition of the exogenous TGF-β can induce EMT and invasion in cancer cells by turning them into aggressive phenotypes. TGF-β receptor kinase I inhibitor (LY364947) can revert the TGF-β effect in these cells. In a nutshell, TGF-β can induce EMT and migration, increase aggressiveness, increase cell survival, alter cell characteristics, remodel the Extracellular Matrix (ECM) and increase cell metabolism favorable for tumor invasion and metastasis. We concluded that transcriptomic and phenotypic effect of TGF-β and its inhibitor is cell-type specific and not cancer specific. Full article
(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)
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Open AccessReview
The Key Role of Epithelial to Mesenchymal Transition (EMT) in Hypertensive Kidney Disease
Int. J. Mol. Sci. 2019, 20(14), 3567; https://doi.org/10.3390/ijms20143567
Received: 20 May 2019 / Revised: 12 July 2019 / Accepted: 18 July 2019 / Published: 21 July 2019
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Abstract
Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of [...] Read more.
Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT), originally described as a key process for organ development and metastasis budding in cancer, plays a key role in the development of renal fibrosis in several diseases, including hypertensive nephroangiosclerosis. We herein reviewed the concept of EMT and its role in renal diseases, with particular focus on hypertensive kidney disease, the second leading cause of end-stage renal disease after diabetes mellitus. After discussing the pathophysiology of hypertensive nephropathy, the ‘classic’ view of hypertensive nephrosclerosis entailing hyalinization, and sclerosis of interlobular and afferent arterioles, we examined the changes occurring in the glomerulus and tubulo-interstitium and the studies that investigated the role of EMT and its molecular mechanisms in hypertensive kidney disease. Finally, we examined the reasons why some studies failed to provide solid evidence for renal EMT in hypertension. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT))
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Open AccessArticle
Highly Efficient and Stable Removal of Arsenic by Live Cell Fabricated Magnetic Nanoparticles
Int. J. Mol. Sci. 2019, 20(14), 3566; https://doi.org/10.3390/ijms20143566
Received: 5 June 2019 / Revised: 16 July 2019 / Accepted: 19 July 2019 / Published: 21 July 2019
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Abstract
As concerns about public health and environmental problems regarding contamination by toxic substances increase worldwide, the development of a highly effective and specific treatment method is imperative. Although physicochemical arsenic treatment methods have been developed, microbial in vivo remediation processes using live cell [...] Read more.
As concerns about public health and environmental problems regarding contamination by toxic substances increase worldwide, the development of a highly effective and specific treatment method is imperative. Although physicochemical arsenic treatment methods have been developed, microbial in vivo remediation processes using live cell fabricated nanoparticles have not yet been reported. Herein, we report the development of magnetic iron nanoparticles immobilized an extremophilic microorganism, Deinococcus radiodurans R1, capable of removing toxic arsenic species. First, in vivo synthesis of magnetic iron nanoparticles was successfully achieved with the D. radiodurans R1 strain and characterized by scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX), dynamic light scattering (DLS), zeta-potential, Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) analysis. Second, the maximum removal capacity of the magnetic iron nanoparticle-immobilized D. radiodurans R1 strain (DR-FeNPs) for arsenic [As(V)] was evaluated under the optimized conditions. Finally, the removal capacity of DR-FeNPs in the presence of various competitive anions was also investigated to simulate the practical application. More than 98% of As(V) was efficiently removed by DR-FeNPs within 1 h, and the removal efficiency was stably maintained for up to 32 h (98.97%). Furthermore, the possibility of recovery of DR-FeNPs after use was also suggested using magnets as a proof-of-concept. Full article
(This article belongs to the Special Issue Magnetic Nanoparticles 2019)
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Open AccessArticle
Non-Cytotoxic Agarose/Hydroxyapatite Composite Scaffolds for Drug Release
Int. J. Mol. Sci. 2019, 20(14), 3565; https://doi.org/10.3390/ijms20143565
Received: 6 July 2019 / Revised: 18 July 2019 / Accepted: 18 July 2019 / Published: 21 July 2019
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Abstract
Healing of large bone defects requires implants or scaffolds that provide structural guidance for cell growth, differentiation, and vascularization. In the present work, an agarose-hydroxyapatite composite scaffold was developed that acts not only as a 3D matrix, but also as a release system. [...] Read more.
Healing of large bone defects requires implants or scaffolds that provide structural guidance for cell growth, differentiation, and vascularization. In the present work, an agarose-hydroxyapatite composite scaffold was developed that acts not only as a 3D matrix, but also as a release system. Hydroxyapatite (HA) was incorporated into the agarose gels in situ in various ratios by a simple procedure consisting of precipitation, cooling, washing, and drying. The resulting gels were characterized regarding composition, porosity, mechanical properties, and biocompatibility. A pure phase of carbonated HA was identified in the scaffolds, which had pore sizes of up to several hundred micrometers. Mechanical testing revealed elastic moduli of up to 2.8 MPa for lyophilized composites. MTT testing on Lw35human mesenchymal stem cells (hMSCs) and osteosarcoma MG-63 cells proved the biocompatibility of the scaffolds. Furthermore, scaffolds were loaded with model drug compounds for guided hMSC differentiation. Different release kinetic models were evaluated for adenosine 5′-triphosphate (ATP) and suramin, and data showed a sustained release behavior over four days. Full article
(This article belongs to the Special Issue Polysaccharides in Drug Delivery)
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Open AccessReview
Alteration of Sphingolipids in Biofluids: Implications for Neurodegenerative Diseases
Int. J. Mol. Sci. 2019, 20(14), 3564; https://doi.org/10.3390/ijms20143564
Received: 15 June 2019 / Revised: 12 July 2019 / Accepted: 13 July 2019 / Published: 21 July 2019
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Abstract
Sphingolipids (SL) modulate several cellular processes including cell death, proliferation and autophagy. The conversion of sphingomyelin (SM) to ceramide and the balance between ceramide and sphingosine-1-phosphate (S1P), also known as the SL rheostat, have been associated with oxidative stress and neurodegeneration. Research in [...] Read more.
Sphingolipids (SL) modulate several cellular processes including cell death, proliferation and autophagy. The conversion of sphingomyelin (SM) to ceramide and the balance between ceramide and sphingosine-1-phosphate (S1P), also known as the SL rheostat, have been associated with oxidative stress and neurodegeneration. Research in the last decade has focused on the possibility of targeting the SL metabolism as a therapeutic option; and SL levels in biofluids, including serum, plasma, and cerebrospinal fluid (CSF), have been measured in several neurodegenerative diseases with the aim of finding a diagnostic or prognostic marker. Previous reviews focused on results from diseases such as Alzheimer’s Disease (AD), evaluated total SL or species levels in human biofluids, post-mortem tissues and/or animal models. However, a comprehensive review of SL alterations comparing results from several neurodegenerative diseases is lacking. The present work compiles data from circulating sphingolipidomic studies and attempts to elucidate a possible connection between certain SL species and neurodegeneration processes. Furthermore, the effects of ceramide species according to their acyl-chain length in cellular pathways such as apoptosis and proliferation are discussed in order to understand the impact of the level alteration in specific species. Finally, enzymatic regulations and the possible influence of insulin resistance in the level alteration of SL are evaluated. Full article
(This article belongs to the Special Issue Lipidomics and Neurodegenerative Diseases)
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Open AccessOpinion
Neuroprotective Potential of GDF11: Myth or Reality?
Int. J. Mol. Sci. 2019, 20(14), 3563; https://doi.org/10.3390/ijms20143563
Received: 22 April 2019 / Revised: 4 June 2019 / Accepted: 5 June 2019 / Published: 21 July 2019
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Abstract
In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been [...] Read more.
In the brain, aging is accompanied by cellular and functional deficiencies that promote vulnerability to neurodegenerative disorders. In blood plasma from young and old animals, various factors such as growth differentiation factor 11 (GDF11), whose levels are elevated in young animals, have been identified. The blood concentrations of these factors appear to be inversely correlated with the age-related decline of neurogenesis. The identification of GDF11 as a “rejuvenating factor” opens up perspectives for the treatment of neurodegenerative diseases. As a pro-neurogenic and pro-angiogenic agent, GDF11 may constitute a basis for novel therapeutic strategies. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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Open AccessArticle
Vitamin D Alleviates Rotavirus Infection through a Microrna-155-5p Mediated Regulation of the TBK1/IRF3 Signaling Pathway In Vivo and In Vitro
Int. J. Mol. Sci. 2019, 20(14), 3562; https://doi.org/10.3390/ijms20143562
Received: 10 June 2019 / Revised: 9 July 2019 / Accepted: 16 July 2019 / Published: 21 July 2019
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Abstract
(1) Background: Vitamin D (VD) plays a vital role in anti-viral innate immunity. However, the role of VD in anti-rotavirus and its mechanism is still unclear. The present study was performed to investigate whether VD alleviates rotavirus (RV) infection through a microRNA-155-5p (miR-155-5p)-mediated [...] Read more.
(1) Background: Vitamin D (VD) plays a vital role in anti-viral innate immunity. However, the role of VD in anti-rotavirus and its mechanism is still unclear. The present study was performed to investigate whether VD alleviates rotavirus (RV) infection through a microRNA-155-5p (miR-155-5p)-mediated regulation of TANK-binding kinase 1 (TBK1)/interferon regulatory factors 3 (IRF3) signaling pathway in vivo and in vitro. (2) Methods: The efficacy of VD treatment was evaluated in DLY pig and IPEC-J2. Dual-luciferase reporter activity assay was performed to verify the role of miR-155-5p in 1α,25-dihydroxy-VD3 (1,25D3) mediating the regulation of the TBK1/IRF3 signaling pathway. (3) Results: A 5000 IU·kg–1 dietary VD3 supplementation attenuated RV-induced the decrease of the villus height and crypt depth (p < 0.05), and up-regulated TBK1, IRF3, and IFN-β mRNA expressions in the jejunum (p < 0.05). Incubation with 1,25D3 significantly decreased the RV mRNA expression and the RV antigen concentration, and increased the TBK1 mRNA and protein levels, and the phosphoprotein IRF3 (p-IRF3) level (p < 0.05). The expression of miR-155-5p was up-regulated in response to an RV infection in vivo and in vitro (p < 0.05). 1,25D3 significantly repressed the up-regulation of miR-155-5p in vivo and in vitro (p < 0.05). Overexpression of miR-155-5p remarkably suppressed the mRNA and protein levels of TBK1 and p-IRF3 (p < 0.01), while the inhibition of miR-155-5p had an opposite effect. Luciferase activity assays confirmed that miR-155-5p regulated RV replication by directly targeting TBK1, and miR-155-5p suppressed the TBK1 protein level (p < 0.01). (4) Conclusions: These results indicate that miR-155-5p is involved in 1,25D3 mediating the regulation of the TBK1/IRF3 signaling pathway by directly targeting TBK1. Full article
(This article belongs to the Section Molecular Immunology)
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Open AccessReview
The Atherogenic Role of Circulating Modified Lipids in Atherosclerosis
Int. J. Mol. Sci. 2019, 20(14), 3561; https://doi.org/10.3390/ijms20143561
Received: 5 June 2019 / Revised: 21 June 2019 / Accepted: 19 July 2019 / Published: 20 July 2019
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Abstract
Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the [...] Read more.
Lipid accumulation in the arterial wall is a crucial event in the development of atherosclerotic lesions. Circulating low-density lipoprotein (LDL) is the major source of lipids that accumulate in the atherosclerotic plaques. It was discovered that not all LDL is atherogenic. In the blood plasma of atherosclerotic patients, LDL particles are the subject of multiple enzymatic and non-enzymatic modifications that determine their atherogenicity. Desialylation is the primary and the most important atherogenic LDL modification followed by a cascade of other modifications that also increase blood atherogenicity. The enzyme trans-sialidase is responsible for the desialylation of LDL, therefore, its activity plays an important role in atherosclerosis development. Moreover, circulating modified LDL is associated with immune complexes that also have a strong atherogenic potential. Moreover, it was shown that antibodies to modified LDL are also atherogenic. The properties of modified LDL were described, and the strong evidence indicating that it is capable of inducing intracellular accumulation of lipids was presented. The accumulated evidence indicated that the molecular properties of modified LDL, including LDL-containing immune complexes can serve as the prognostic/diagnostic biomarkers and molecular targets for the development of anti-atherosclerotic drugs. Full article
(This article belongs to the Special Issue Lipoprotein Nanoparticles for Diagnosis and Therapy)
Open AccessArticle
Unique Phase Transition of Exogenous Fusion Elastin-like Polypeptides in the Solution Containing Polyethylene Glycol
Int. J. Mol. Sci. 2019, 20(14), 3560; https://doi.org/10.3390/ijms20143560
Received: 24 June 2019 / Revised: 12 July 2019 / Accepted: 15 July 2019 / Published: 20 July 2019
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Abstract
Elastin-Like polypeptides (ELPs), as well-known temperature-controlled bio-macromolecules, are widely used. However, little is known about the interactions between ELPs and macromolecules, which is an important yet neglected problem. Here, the phase transition characteristics of an ELPs-SpyCatcher fusion protein (E-C) in the presence of [...] Read more.
Elastin-Like polypeptides (ELPs), as well-known temperature-controlled bio-macromolecules, are widely used. However, little is known about the interactions between ELPs and macromolecules, which is an important yet neglected problem. Here, the phase transition characteristics of an ELPs-SpyCatcher fusion protein (E-C) in the presence of polyethylene glycol (PEG) in single salts (Na2CO3, Na2SO4, NaCl) solutions were investigated using a UV spectrophotometer, DLC, and fluorescence spectroscopy, and we got some interesting results. The phases transition of E-C occurred at a concentration lower than 0.5 mol/L Na2CO3/PEG2000, while in single Na2CO3 (<0.5 mol/L), the phase transition of E-C did not occur. In the Na2CO3/PEG solution, we observed a unique two-step phase transition of E-C when the Na2CO3 concentration was 0.5 mol/L and PEG2000 concentration was less than 0.15 g/mL, respectively. In the Na2CO3/PEG2000 solution, the phase-transition temperature of E-C decreased with the increase of PEG concentration, but increased in the Na2SO4/PEG2000 solution, while it remained unchanged in the NaCl/PEG2000 solution. However, the phase-transition temperature of the linear ELPs40 decreased under the same salts/PEG2000 solutions. We also addressed the possible molecular mechanism of the interesting results. In contrast to the current well-understood salts-ELPs interactions, this work provides some new insights into the interaction between the PEG-salts-ELPs in solution. Full article
(This article belongs to the Section Macromolecules)
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Open AccessReview
Autophagy: New Insights into Mechanisms of Action and Resistance of Treatment in Acute Promyelocytic leukemia
Int. J. Mol. Sci. 2019, 20(14), 3559; https://doi.org/10.3390/ijms20143559
Received: 28 June 2019 / Revised: 15 July 2019 / Accepted: 18 July 2019 / Published: 20 July 2019
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Abstract
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the [...] Read more.
Autophagy is one of the main cellular catabolic pathways controlling a variety of physiological processes, including those involved in self-renewal, differentiation and death. While acute promyelocytic leukemia (APL) cells manifest low levels of expression of autophagy genes associated with reduced autophagy activity, the introduction of all-trans retinoid acid (ATRA)—a differentiating agent currently used in clinical settings—restores autophagy in these cells. ATRA-induced autophagy is involved in granulocytes differentiation through a mechanism that involves among others the degradation of the PML-RARα oncoprotein. Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemia retinoic acid receptor alpha gene (PML-RARα) in APL cells. Hence, enhancing autophagy may have therapeutic benefits in maturation-resistant APL cells. However, the role of autophagy in response to APL therapy is not so simple, because some autophagy proteins have been shown to play a pro-survival role upon ATRA and ATO treatment, and both agents can activate ETosis, a type of cell death mediated by the release of neutrophil extracellular traps (ETs). This review highlights recent findings on the impact of autophagy on the mechanisms of action of ATRA and ATO in APL cells. We also discuss the potential role of autophagy in the development of resistance to treatment, and of differentiation syndrome in APL. Full article
(This article belongs to the Special Issue Drug Resistance in Hematologic Malignancies)
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Open AccessArticle
Can We Still Trust Docking Results? An Extension of the Applicability of DockBench on PDBbind Database
Int. J. Mol. Sci. 2019, 20(14), 3558; https://doi.org/10.3390/ijms20143558
Received: 17 June 2019 / Revised: 12 July 2019 / Accepted: 18 July 2019 / Published: 20 July 2019
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Abstract
The number of entries in the Protein Data Bank (PDB) has doubled in the last decade, and it has increased tenfold in the last twenty years. The availability of an ever-growing number of structures is having a huge impact on the Structure-Based Drug [...] Read more.
The number of entries in the Protein Data Bank (PDB) has doubled in the last decade, and it has increased tenfold in the last twenty years. The availability of an ever-growing number of structures is having a huge impact on the Structure-Based Drug Discovery (SBDD), allowing investigation of new targets and giving the possibility to have multiple structures of the same macromolecule in a complex with different ligands. Such a large resource often implies the choice of the most suitable complex for molecular docking calculation, and this task is complicated by the plethora of possible posing and scoring function algorithms available, which may influence the quality of the outcomes. Here, we report a large benchmark performed on the PDBbind database containing more than four thousand entries and seventeen popular docking protocols. We found that, even in protein families wherein docking protocols generally showed acceptable results, certain ligand-protein complexes are poorly reproduced in the self-docking procedure. Such a trend in certain protein families is more pronounced, and this underlines the importance in identification of a suitable protein–ligand conformation coupled to a well-performing docking protocol. Full article
(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design)
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Open AccessArticle
RcAP1, a Homolog of APETALA1, is Associated with Flower Bud Differentiation and Floral Organ Morphogenesis in Rosa chinensis
Int. J. Mol. Sci. 2019, 20(14), 3557; https://doi.org/10.3390/ijms20143557
Received: 3 June 2019 / Revised: 17 July 2019 / Accepted: 18 July 2019 / Published: 20 July 2019
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Abstract
Rosa chinensis is one of the most popular flower plants worldwide. The recurrent flowering trait greatly enhances the ornamental value of roses, and is the result of the constant formation of new flower buds. Flower bud differentiation has always been a major topic [...] Read more.
Rosa chinensis is one of the most popular flower plants worldwide. The recurrent flowering trait greatly enhances the ornamental value of roses, and is the result of the constant formation of new flower buds. Flower bud differentiation has always been a major topic of interest among researchers. The APETALA1 (AP1) MADS-box (Mcm1, Agamous, Deficiens and SRF) transcription factor-encoding gene is important for the formation of the floral meristem and floral organs. However, research on the rose AP1 gene has been limited. Thus, we isolated AP1 from Rosa chinensis ‘Old Blush’. An expression analysis revealed that RcAP1 was not expressed before the floral primordia formation stage in flower buds. The overexpression of RcAP1 in Arabidopsis thaliana resulted in an early-flowering phenotype. Additionally, the virus-induced down-regulation of RcAP1 expression delayed flowering in ‘Old Blush’. Moreover, RcAP1 was specifically expressed in the sepals of floral organs, while its expression was down-regulated in abnormal sepals and leaf-like organs. These observations suggest that RcAP1 may contribute to rose bud differentiation as well as floral organ morphogenesis, especially the sepals. These results may help for further characterization of the regulatory mechanisms of the recurrent flowering trait in rose. Full article
(This article belongs to the Special Issue Plant Cell and Organism Development)
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Open AccessArticle
Elucidation of the Molecular Mechanism Underlying Lippia citriodora(Lim.)-Induced Relaxation and Anti-Depression
Int. J. Mol. Sci. 2019, 20(14), 3556; https://doi.org/10.3390/ijms20143556
Received: 24 June 2019 / Revised: 16 July 2019 / Accepted: 18 July 2019 / Published: 20 July 2019
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Abstract
Lippia citriodora ethanolic extract (VEE) and verbascoside (Vs), a phenypropanoid glycoside, have been demonstrated to exert relaxant and anxiolytic properties. However, the molecular mechanisms behind their effects are still unclear. In this work, we studied the effects and action mechanisms of VEE and [...] Read more.
Lippia citriodora ethanolic extract (VEE) and verbascoside (Vs), a phenypropanoid glycoside, have been demonstrated to exert relaxant and anxiolytic properties. However, the molecular mechanisms behind their effects are still unclear. In this work, we studied the effects and action mechanisms of VEE and Vs in vivo and in vitro, on human neurotypic SH-SY5Y cells.TST was conducted on mice treated orally with VEE (25, 50 and 100 mg/Kg), Vs (2.5 and 5 mg/Kg), Bupropion (20 mg/Kg) and Milli-Q water. Higher dose of VEE-treated mice showed an increase of immobility time compared to control groups, indicating an induction of relaxation. This effect was found to be induced by regulation of genes playing key roles in calcium homeostasis (calcium channels), cyclic AMP (cAMP) production and energy metabolism. On the other hand, low doses of VEE and Vs showed an antidepressant-like effect and was confirmed by serotonin, noradrenalin, dopamine and BDNF expressions. Finally, VEE and Vsenhancedcell viability, mitochondrial activity and calcium uptake in vitro confirming in vivo findings. Our results showed induction of relaxation and antidepressant-like effects depending on the administered dose of VEE and Vs, through modulation of cAMP and calcium. Full article
(This article belongs to the Special Issue Natural Products and Neuroprotection)
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Open AccessReview
Role of Tricellular Tight Junction Protein Lipolysis-Stimulated Lipoprotein Receptor (LSR) in Cancer Cells
Int. J. Mol. Sci. 2019, 20(14), 3555; https://doi.org/10.3390/ijms20143555
Received: 19 June 2019 / Revised: 17 July 2019 / Accepted: 19 July 2019 / Published: 20 July 2019
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Abstract
Maintaining a robust epithelial barrier requires the accumulation of tight junction proteins, LSR/angulin-1 and tricellulin, at the tricellular contacts. Alterations in the localization of these proteins temporarily cause epithelial barrier dysfunction, which is closely associated with not only physiological differentiation but also cancer [...] Read more.
Maintaining a robust epithelial barrier requires the accumulation of tight junction proteins, LSR/angulin-1 and tricellulin, at the tricellular contacts. Alterations in the localization of these proteins temporarily cause epithelial barrier dysfunction, which is closely associated with not only physiological differentiation but also cancer progression and metastasis. In normal human endometrial tissues, the endometrial cells undergo repeated proliferation and differentiation under physiological conditions. Recent observations have revealed that the localization and expression of LSR/angulin-1 and tricellulin are altered in a menstrual cycle-dependent manner. Moreover, it has been shown that endometrial cancer progression affects these alterations. This review highlights the differences in the localization and expression of tight junction proteins in normal endometrial cells and endometrial cancers and how they cause functional changes in cells. Full article
(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)
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