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

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Open AccessReview Structure and Mechanism of the Divalent Anion/Na+ Symporter
Int. J. Mol. Sci. 2019, 20(2), 440; https://doi.org/10.3390/ijms20020440 (registering DOI)
Received: 21 December 2018 / Revised: 14 January 2019 / Accepted: 18 January 2019 / Published: 21 January 2019
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Abstract
Integral membrane proteins of the divalent anion/Na+ symporter (DASS) family are conserved from bacteria to humans. DASS proteins typically mediate the coupled uptake of Na+ ions and dicarboxylate, tricarboxylate, or sulfate. Since the substrates for DASS include key intermediates and regulators
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Integral membrane proteins of the divalent anion/Na+ symporter (DASS) family are conserved from bacteria to humans. DASS proteins typically mediate the coupled uptake of Na+ ions and dicarboxylate, tricarboxylate, or sulfate. Since the substrates for DASS include key intermediates and regulators of energy metabolism, alterations of DASS function profoundly affect fat storage, energy expenditure and life span. Furthermore, loss-of-function mutations in a human DASS have been associated with neonatal epileptic encephalopathy. More recently, human DASS has also been implicated in the development of liver cancers. Therefore, human DASS proteins are potentially promising pharmacological targets for battling obesity, diabetes, kidney stone, fatty liver, as well as other metabolic and neurological disorders. Despite its clinical relevance, the mechanism by which DASS proteins recognize and transport anionic substrates remains unclear. Recently, the crystal structures of a bacterial DASS and its humanized variant have been published. This article reviews the mechanistic implications of these structures and suggests future work to better understand how the function of DASS can be modulated for potential therapeutic benefit. Full article
(This article belongs to the Section Molecular Biology)
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Open AccessArticle Gut Microbiota and Predicted Metabolic Pathways in a Sample of Mexican Women Affected by Obesity and Obesity Plus Metabolic Syndrome
Int. J. Mol. Sci. 2019, 20(2), 438; https://doi.org/10.3390/ijms20020438 (registering DOI)
Received: 21 December 2018 / Revised: 17 January 2019 / Accepted: 17 January 2019 / Published: 21 January 2019
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Abstract
Obesity is an excessive fat accumulation that could lead to complications like metabolic syndrome. There are reports on gut microbiota and metabolic syndrome in relation to dietary, host genetics, and other environmental factors; however, it is necessary to explore the role of the
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Obesity is an excessive fat accumulation that could lead to complications like metabolic syndrome. There are reports on gut microbiota and metabolic syndrome in relation to dietary, host genetics, and other environmental factors; however, it is necessary to explore the role of the gut microbiota metabolic pathways in populations like Mexicans, where the prevalence of obesity and metabolic syndrome is high. This study identify alterations of the gut microbiota in a sample of healthy Mexican women (CO), women with obesity (OB), and women with obesity plus metabolic syndrome (OMS). We studied 67 women, characterizing their anthropometric and biochemical parameters along with their gut bacterial diversity by high-throughput DNA sequencing. Our results indicate that in OB or OMS women, Firmicutes was the most abundant bacterial phylum. We observed significant changes in abundances of bacteria belonging to the Ruminococcaceae, Lachnospiraceae, and Erysipelotrichaceae families and significant enrichment of gut bacteria from 16 different taxa that might explain the observed metabolic alterations between the groups. Finally, the predicted functional metagenome of the gut microbiota found in each category shows differences in metabolic pathways related to lipid metabolism. We demonstrate that Mexican women have a particular bacterial gut microbiota characteristic of each phenotype. There are bacteria that potentially explain the observed metabolic differences between the groups, and gut bacteria in OMS and OB conditions carry more genes of metabolic pathways implicated in lipid metabolism. Full article
(This article belongs to the Special Issue Bioactives and Nutraceuticals in Metabolic Syndrome)
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Open AccessArticle Lectin Sequence Distribution in QTLs from Rice (Oryza sativa) Suggest A Role in Morphological Traits and Stress Responses
Int. J. Mol. Sci. 2019, 20(2), 437; https://doi.org/10.3390/ijms20020437 (registering DOI)
Received: 9 December 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 20 January 2019
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Abstract
Rice (Oryza sativa) is one of the main staple crops worldwide but suffers from important yield losses due to different abiotic and biotic stresses. Analysis of quantitative trait loci (QTL) is a classical genetic method which enables the creation of more
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Rice (Oryza sativa) is one of the main staple crops worldwide but suffers from important yield losses due to different abiotic and biotic stresses. Analysis of quantitative trait loci (QTL) is a classical genetic method which enables the creation of more resistant cultivars but does not yield information on the genes directly involved or responsible for the desired traits. Lectins are known as proteins with diverse functions in plants. Some of them are abundant proteins in seeds and are considered as storage/defense proteins while other lectins are known as stress-inducible proteins, implicated in stress perception and signal transduction as part of plant innate immunity. We investigated the distribution of lectin sequences in different QTL related to stress tolerance/resistance, morphology, and physiology through mapping of the lectin sequences and QTL regions on the chromosomes and subsequent statistical analysis. Furthermore, the domain structure and evolutionary relationships of the lectins in O. sativa spp. indica and japonica were investigated. Our results revealed that lectin sequences are statistically overrepresented in QTLs for (a)biotic resistance/tolerance as well as in QTLs related to economically important traits such as eating quality and sterility. These findings contribute to the characterization of the QTL sequences and can provide valuable information to the breeders. Full article
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Open AccessArticle Expression of Hypoxia-Inducible Factor 1α (HIF-1α) and Genes of Related Pathways in Altered Gravity
Int. J. Mol. Sci. 2019, 20(2), 436; https://doi.org/10.3390/ijms20020436 (registering DOI)
Received: 15 November 2018 / Revised: 15 January 2019 / Accepted: 17 January 2019 / Published: 20 January 2019
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Abstract
Immune system deterioration in space represents a major risk, which has to be mitigated for exploration-class missions into the solar system. Altered gravitational forces have been shown to regulate adaptation processes in cells of the immune system, which are important for appropriate risk
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Immune system deterioration in space represents a major risk, which has to be mitigated for exploration-class missions into the solar system. Altered gravitational forces have been shown to regulate adaptation processes in cells of the immune system, which are important for appropriate risk management, monitoring and development of countermeasures. T lymphocytes and cells of the monocyte-macrophage system are highly migratory cell types that frequently encounter a wide range of oxygen tensions in human tissues and in hypoxic areas, even under homeostatic conditions. Hypoxia-inducible factor 1 and 2 (HIF’s) might have an important role in activation of T cells and cells of the monocyte-macrophages system. Thus, we investigated the regulation of HIF-dependent and, therefore, hypoxia-signaling systems in both cell types in altered gravity and performed transcript and protein analysis from parabolic flight and suborbital ballistic rocket experiments. We found that HIF-1α and HIF-1-dependent transcripts were differently regulated in altered gravity, whereas HIF-1α-dependent gene expression adapted after 5 min microgravity. Inter-platform comparisons identified PDK1 as highly responsive to gravitational changes in human U937 myelomonocytic cells and in Jurkat T cells. We suggest HIF-1 as a potential pharmacological target for counteracting immune system deterioration during space flight. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessReview Current Trends in Fabrication of Biomaterials for Bone and Cartilage Regeneration: Materials Modifications and Biophysical Stimulations
Int. J. Mol. Sci. 2019, 20(2), 435; https://doi.org/10.3390/ijms20020435 (registering DOI)
Received: 21 December 2018 / Revised: 15 January 2019 / Accepted: 18 January 2019 / Published: 20 January 2019
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Abstract
The aim of engineering of biomaterials is to fabricate implantable biocompatible scaffold that would accelerate regeneration of the tissue and ideally protect the wound against biodevice-related infections, which may cause prolonged inflammation and biomaterial failure. To obtain antimicrobial and highly biocompatible scaffolds promoting
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The aim of engineering of biomaterials is to fabricate implantable biocompatible scaffold that would accelerate regeneration of the tissue and ideally protect the wound against biodevice-related infections, which may cause prolonged inflammation and biomaterial failure. To obtain antimicrobial and highly biocompatible scaffolds promoting cell adhesion and growth, materials scientists are still searching for novel modifications of biomaterials. This review presents current trends in the field of engineering of biomaterials concerning application of various modifications and biophysical stimulation of scaffolds to obtain implants allowing for fast regeneration process of bone and cartilage as well as providing long-lasting antimicrobial protection at the site of injury. The article describes metal ion and plasma modifications of biomaterials as well as post-surgery external stimulations of implants with ultrasound and magnetic field, providing accelerated regeneration process. Finally, the review summarizes recent findings concerning the use of piezoelectric biomaterials in regenerative medicine. Full article
(This article belongs to the Special Issue Biomaterials for Musculoskeletal System)
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Open AccessReview Extracellular Vesicle-Mediated Cell–Cell Communication in the Nervous System: Focus on Neurological Diseases
Int. J. Mol. Sci. 2019, 20(2), 434; https://doi.org/10.3390/ijms20020434 (registering DOI)
Received: 10 December 2018 / Revised: 12 January 2019 / Accepted: 17 January 2019 / Published: 20 January 2019
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Abstract
Extracellular vesicles (EVs), including exosomes, are membranous particles released by cells into the extracellular space. They are involved in cell differentiation, tissue homeostasis, and organ remodelling in virtually all tissues, including the central nervous system (CNS). They are secreted by a range of
[...] Read more.
Extracellular vesicles (EVs), including exosomes, are membranous particles released by cells into the extracellular space. They are involved in cell differentiation, tissue homeostasis, and organ remodelling in virtually all tissues, including the central nervous system (CNS). They are secreted by a range of cell types and via blood reaching other cells whose functioning they can modify because they transport and deliver active molecules, such as proteins of various types and functions, lipids, DNA, and miRNAs. Since they are relatively easy to isolate, exosomes can be characterized, and their composition elucidated and manipulated by bioengineering techniques. Consequently, exosomes appear as promising theranostics elements, applicable to accurately diagnosing pathological conditions, and assessing prognosis and response to treatment in a variety of disorders. Likewise, the characteristics and manageability of exosomes make them potential candidates for delivering selected molecules, e.g., therapeutic drugs, to specific target tissues. All these possible applications are pertinent to research in neurophysiology, as well as to the study of neurological disorders, including CNS tumors, and autoimmune and neurodegenerative diseases. In this brief review, we discuss what is known about the role and potential future applications of exosomes in the nervous system and its diseases, focusing on cell–cell communication in physiology and pathology. Full article
(This article belongs to the Special Issue Focus on Exosome-Based Cell-Cell Communication in Health and Disease)
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Open AccessArticle The Effect of Psyllium Husk on Intestinal Microbiota in Constipated Patients and Healthy Controls
Int. J. Mol. Sci. 2019, 20(2), 433; https://doi.org/10.3390/ijms20020433 (registering DOI)
Received: 17 December 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 20 January 2019
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Abstract
Psyllium is a widely used treatment for constipation. It traps water in the intestine increasing stool water, easing defaecation and altering the colonic environment. We aimed to assess the impact of psyllium on faecal microbiota, whose key role in gut physiology is being
[...] Read more.
Psyllium is a widely used treatment for constipation. It traps water in the intestine increasing stool water, easing defaecation and altering the colonic environment. We aimed to assess the impact of psyllium on faecal microbiota, whose key role in gut physiology is being increasingly recognised. We performed two randomised, placebo-controlled, double-blinded trials comparing 7 days of psyllium with a placebo (maltodextrin) in 8 healthy volunteers and 16 constipated patients respectively. We measured the patients’ gastrointestnal (GI) transit, faecal water content, short-chain fatty acid (SCFA) and the stool microbiota composition. While psyllium supplement had a small but significant effect on the microbial composition of healthy adults (increasing Veillonella and decreasing Subdoligranulum), in constipated subjects there were greater effects on the microbial composition (increased Lachnospira, Faecalibacterium, Phascolarctobacterium, Veillonella and Sutterella and decreased uncultured Coriobacteria and Christensenella) and alterations in the levels of acetate and propionate. We found several taxa to be associated with altered GI transit, SCFAs and faecal water content in these patients. Significant increases in three genera known to produce butyrate, Lachnospira, Roseburia and Faecalibacterium, correlated with increased faecal water. In summary, psyllium supplementation increased stool water and this was associated with significant changes in microbiota, most marked in constipated patients. Full article
(This article belongs to the Special Issue Microbiota, Food and Health)
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Open AccessReview Resistance to Cereal Cyst Nematodes in Wheat and Barley: An Emphasis on Classical and Modern Approaches
Int. J. Mol. Sci. 2019, 20(2), 432; https://doi.org/10.3390/ijms20020432 (registering DOI)
Received: 7 December 2018 / Revised: 8 January 2019 / Accepted: 15 January 2019 / Published: 19 January 2019
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Abstract
Cereal cyst nematodes (CCNs) are among the most important nematode pests that limit production of small grain cereals like wheat and barley. These nematodes alone are estimated to reduce production of crops by 10% globally. This necessitates a huge enhancement of nematode resistance
[...] Read more.
Cereal cyst nematodes (CCNs) are among the most important nematode pests that limit production of small grain cereals like wheat and barley. These nematodes alone are estimated to reduce production of crops by 10% globally. This necessitates a huge enhancement of nematode resistance in cereal crops against CCNs. Nematode resistance in wheat and barley in combination with higher grain yields has been a preferential research area for cereal nematologists. This usually involved the targeted genetic exploitations through natural means of classical selection breeding of resistant genotypes and finding quantitative trait luci (QTLs) associated with resistance genes. These improvements were based on available genetic diversity among the crop plants. Recently, genome-wide association studies have widely been exploited to associate nematode resistance or susceptibility with particular regions of the genome. Use of biotechnological tools through the application of various transgenic strategies for enhancement of nematode resistance in various crop plants including wheat and barley had also been an important area of research. These modern approaches primarily include the use of gene silencing, exploitation of nematode effector genes, proteinase inhibitors, chemodisruptive peptides and a combination of one or more of these approaches. Furthermore, the perspective genome editing technologies including CRISPR-Cas9 could also be helpful for improving CCN resistance in wheat and barley. The information provided in this review will be helpful to enhance resistance against CCNs and will attract the attention of the scientific community towards this neglected area. Full article
(This article belongs to the Special Issue Molecular Advances in Wheat and Barley)
Open AccessArticle Non-Targeted Metabolomics Reveals Sorghum Rhizosphere-Associated Exudates are Influenced by the Belowground Interaction of Substrate and Sorghum Genotype
Int. J. Mol. Sci. 2019, 20(2), 431; https://doi.org/10.3390/ijms20020431 (registering DOI)
Received: 29 December 2018 / Revised: 12 January 2019 / Accepted: 14 January 2019 / Published: 19 January 2019
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Abstract
Root exudation is an important plant process by which roots release small molecules into the rhizosphere that serve in overall plant functioning. Yet, there is a major gap in our knowledge in translating plant root exudation in artificial systems (i.e., hydroponics, sterile media)
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Root exudation is an important plant process by which roots release small molecules into the rhizosphere that serve in overall plant functioning. Yet, there is a major gap in our knowledge in translating plant root exudation in artificial systems (i.e., hydroponics, sterile media) to crops, specifically for soils expected in field conditions. Sorghum (Sorghum bicolor L. Moench) root exudation was determined using both ultra-performance liquid chromatography and gas chromatography mass spectrometry-based non-targeted metabolomics to evaluate variation in exudate composition of two sorghum genotypes among three substrates (sand, clay, and soil). Above and belowground plant traits were measured to determine the interaction between sorghum genotype and belowground substrate. Plant growth and quantitative exudate composition were found to vary largely by substrate. Two types of changes to rhizosphere metabolites were observed: rhizosphere-enhanced metabolites (REMs) and rhizosphere-abated metabolites (RAMs). More REMs and RAMs were detected in sand and clay substrates compared to the soil substrate. This study demonstrates that belowground substrate influences the root exudate profile in sorghum, and that two sorghum genotypes exuded metabolites at different magnitudes. However, metabolite identification remains a major bottleneck in non-targeted metabolite profiling of the rhizosphere. Full article
(This article belongs to the Special Issue Plant Metabolism in Crops: A Systems Biology Perspective)
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Open AccessArticle Effect of Polymer Phase Transition Behavior on Temperature-Responsive Polymer-Modified Liposomes for siRNA Transfection
Int. J. Mol. Sci. 2019, 20(2), 430; https://doi.org/10.3390/ijms20020430 (registering DOI)
Received: 10 January 2019 / Revised: 15 January 2019 / Accepted: 15 January 2019 / Published: 19 January 2019
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Abstract
Small interfering RNAs (siRNAs) have been attracting significant attention owing to their gene silencing properties, which can be utilized to treat intractable diseases. In this study, two temperature-responsive liposomal siRNA carriers were prepared by modifying liposomes with different polymers—poly(N-isopropylacrylamide-co-
[...] Read more.
Small interfering RNAs (siRNAs) have been attracting significant attention owing to their gene silencing properties, which can be utilized to treat intractable diseases. In this study, two temperature-responsive liposomal siRNA carriers were prepared by modifying liposomes with different polymers—poly(N-isopropylacrylamide-co-N,N-dimethylaminopropyl acrylamide) (P(NIPAAm-co-DMAPAAm)) and poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) P(NIPAAm-co-DMAAm). The phase transition of P(NIPAAm-co-DMAPAAm) was sharper than that of P(NIPAAm-co-DMAAm), which is attributed to the lower co-monomer content. The temperature dependent fixed aqueous layer thickness (FALT) of the prepared liposomes indicated that modifying liposomes with P(NIPAAm-co-DMAPAAm) led to a significant change in the thickness of the fixed aqueous monolayer between 37 °C and 42 °C; while P(NIPAAm-co-DMAAm) modification led to FALT changes over a broader temperature range. The temperature-responsive liposomes exhibited cellular uptake at 42 °C, but were not taken up by cells at 37 °C. This is likely because the thermoresponsive hydrophilic/hydrophobic changes at the liposome surface induced temperature-responsive cellular uptake. Additionally, siRNA transfection of cells for the prevention of luciferase and vascular endothelial growth factor (VEGF) expression was modulated by external temperature changes. P(NIPAAm-co-DMAPAAm) modified liposomes in particular exhibited effective siRNA transfection properties with low cytotoxicity compared with P(NIPAAm-co-DMAAm) modified analogues. These results indicated that the prepared temperature-responsive liposomes could be used as effective siRNA carriers whose transfection properties can be modulated by temperature. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction 2019)
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Open AccessArticle BAP1 Status Determines the Sensitivity of Malignant Mesothelioma Cells to Gemcitabine Treatment
Int. J. Mol. Sci. 2019, 20(2), 429; https://doi.org/10.3390/ijms20020429 (registering DOI)
Received: 24 October 2018 / Revised: 11 January 2019 / Accepted: 12 January 2019 / Published: 19 January 2019
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Abstract
Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the BRCA1 associated protein 1 gene (BAP1) in the development of MMe. In this study, the chemosensitivity of human mesothelioma
[...] Read more.
Malignant mesothelioma (MMe) is a cancer with poor prognosis and resistance to standard treatments. Recent reports have highlighted the role of the BRCA1 associated protein 1 gene (BAP1) in the development of MMe. In this study, the chemosensitivity of human mesothelioma cell lines carrying BAP1 wild-type (WT), mutant and silenced was analysed. The BAP1 mutant cells were significantly less sensitive than BAP1 WT cell lines to the clinically relevant drug gemcitabine. Silencing of BAP1 significantly increased resistance of MMe cells to gemcitabine. Cell cycle analysis suggested that gemcitabine induced Sub-G1 phase accumulation of the BAP1 WT cells and increased in the S-phase in both BAP1 WT and mutant cells. Analysis of the role of BAP1 in apoptosis suggested that gemcitabine induced early apoptosis in both BAP1 WT and BAP1 mutant cells but with a much higher degree in the WT cells. Effects on the population of cells in late apoptosis, which can mark necrosis and necroptosis, could not be seen in the mutant cells, highlighting the possibility that BAP1 plays a role in several types of cell death. Significantly decreased DNA damage in the form of double-strand breaks was observed in gemcitabine-treated BAP1 mutant cells, compared to BAP1 WT cells under the same conditions. After BAP1 silencing, a significant decrease in DNA damage in the form of double-strand breaks was observed compared to cells transfected with scramble siRNA. Taken together, the results presented in this manuscript shed light on the role of BAP1 in the response of MMe cells to gemcitabine treatment and in particular in the control of the DNA damage response, therefore providing a potential route for more efficient MMe therapy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessArticle Decidual Interleukin-22-Producing CD4+ T Cells (Th17/Th0/IL-22+ and Th17/Th2/IL-22+, Th2/IL-22+, Th0/IL-22+), Which Also Produce IL-4, Are Involved in the Success of Pregnancy
Int. J. Mol. Sci. 2019, 20(2), 428; https://doi.org/10.3390/ijms20020428 (registering DOI)
Received: 18 December 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 19 January 2019
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Abstract
Trophoblast expressing paternal HLA-C resembles a semiallograft, and could be rejected by maternal T cells. IL-22 seems to be involved in allograft rejection and thus could be responsible for miscarriages. We examined the role of decidual IL-22-producing CD4+ T on human pregnancy. In
[...] Read more.
Trophoblast expressing paternal HLA-C resembles a semiallograft, and could be rejected by maternal T cells. IL-22 seems to be involved in allograft rejection and thus could be responsible for miscarriages. We examined the role of decidual IL-22-producing CD4+ T on human pregnancy. In those experiencing successful pregnancy and those experiencing unexplained recurrent abortion (URA), the levels of IL-22 produced by decidual CD4+ T cells are higher than those of peripheral blood T cells. We found a correlation of IL-22 and IL-4 produced by decidual CD4+ T cells in those experiencing successful pregnancy, not in those experiencing URA. The correlation of IL-22 and IL-4 was also found in the serum of successful pregnancy. A prevalence of CD4+ T cells producing IL-22 and IL-4 (Th17/Th2/IL-22+, Th17/Th0/IL-22+, Th17/Th2/IL-22+, and Th0/IL-22+ cells) was observed in decidua of those experiencing successful pregnancy, whereas Th17/Th1/IL-22+ cells, which do not produce IL-4, are prevalent in those experiencing URA. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells are exclusively present at the embryo implantation site where IL-4, GATA-3, IL-17A, ROR-C, IL-22, and AHR mRNA are expressed. T-bet and IFN-γ mRNA are found away from the implantation site. There is no pathogenic role of IL-22 when IL-4 is also produced by decidual CD4+ cells. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells seem to be crucial for embryo implantation. Full article
(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)
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Open AccessArticle Imaging of Metastatic Cancer Cells in Sentinel Lymph Nodes using Affibody Probes and Possibility of a Theranostic Approach
Int. J. Mol. Sci. 2019, 20(2), 427; https://doi.org/10.3390/ijms20020427 (registering DOI)
Received: 4 December 2018 / Revised: 12 January 2019 / Accepted: 15 January 2019 / Published: 19 January 2019
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Abstract
The accurate detection of lymph node metastases is essential for treatment success in early-stage malignant cancer. Sentinel lymph node (SLN) biopsy is the most effective procedure for detecting small or micrometastases that are undetectable by conventional imaging modalities. To demonstrate a new approach
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The accurate detection of lymph node metastases is essential for treatment success in early-stage malignant cancer. Sentinel lymph node (SLN) biopsy is the most effective procedure for detecting small or micrometastases that are undetectable by conventional imaging modalities. To demonstrate a new approach for developing a more efficient SLN biopsy procedure, we reported a two-stage imaging method combining lymphoscintigraphy and near-infrared (NIR) fluorescence imaging to depict metastatic cancer cells in SLNs in vivo. Furthermore, the theranostic potential of the combined procedure was examined by cell culture and xenograft mouse model. Anti-HER2 and anti-epidermal growth factor receptor (EGFR) affibody probes were used for NIR fluorescence imaging. Strong NIR fluorescence signal intensity of the anti-EGFR affibody probe was observed in SAS cells (EGFR positive). Radioactivity in the SLNs was clearly observed in the in vivo studies. High anti-EGFR affibody NIR fluorescence intensity was observed in the metastatic lymph nodes in mice. The addition of the IR700-conjugated anti-EGFR affibody to the culture medium decreased the proliferation of SAS cells. Decreased proliferation was shown in Ki-67 immunohistochemistry in xenograft tumors. Our data suggest that a two-stage combined imaging method using lymphoscintigraphy and affibody probes may offer the direct visualization of metastatic lymph nodes as an easily applied technique in SLN biopsy. Although further animal studies are required to assess the effect of treating lymphatic metastasis in this approach, our study results provide a foundation for the further development of this promising imaging and treatment strategy for earlier lymph node metastasis detection and treatment. Full article
(This article belongs to the collection Bioactive Nanoparticles)
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Open AccessReview Exploiting the Therapeutic Potential of Endogenous Immunomodulatory Systems in Multiple Sclerosis—Special Focus on the Peroxisome Proliferator-Activated Receptors (PPARs) and the Kynurenines
Int. J. Mol. Sci. 2019, 20(2), 426; https://doi.org/10.3390/ijms20020426 (registering DOI)
Received: 5 December 2018 / Revised: 13 January 2019 / Accepted: 15 January 2019 / Published: 19 January 2019
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Abstract
Multiple sclerosis (MS) is a progressive neurodegenerative disease, characterized by autoimmune central nervous system (CNS) demyelination attributable to a disturbed balance between encephalitic T helper 1 (Th1) and T helper 17 (Th17) and immunomodulatory regulatory T cell (Treg) and T helper 2 (Th2)
[...] Read more.
Multiple sclerosis (MS) is a progressive neurodegenerative disease, characterized by autoimmune central nervous system (CNS) demyelination attributable to a disturbed balance between encephalitic T helper 1 (Th1) and T helper 17 (Th17) and immunomodulatory regulatory T cell (Treg) and T helper 2 (Th2) cells, and an alternatively activated macrophage (M2) excess. Endogenous molecular systems regulating these inflammatory processes have recently been investigated to identify molecules that can potentially influence the course of the disease. These include the peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1alpha (PGC-1α), and kynurenine pathway metabolites. Although all PPARs ameliorate experimental autoimmune encephalomyelitis (EAE), recent evidence suggests that PPARα, PPARβ/δ agonists have less pronounced immunomodulatory effects and, along with PGC-1α, are not biomarkers of neuroinflammation in contrast to PPARγ. Small clinical trials with PPARγ agonists have been published with positive results. Proposed as immunomodulatory and neuroprotective, the therapeutic use of PGC-1α activation needs to be assessed in EAE/MS. The activation of indolamine 2,3-dioxygenase (IDO), the rate-limiting step of the kynurenine pathway of tryptophan (Trp) metabolism, plays crucial immunomodulatory roles. Indeed, Trp metabolites have therapeutic relevance in EAE and drugs with structural analogy to kynurenines, such as teriflunomide, are already approved for MS. Further studies are required to gain deeper knowledge of such endogenous immunomodulatory pathways with potential therapeutic implications in MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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Open AccessArticle A Proteome Approach Reveals Differences between Fertile Women and Patients with Repeated Implantation Failure on Endometrial Level–Does hCG Render the Endometrium of RIF Patients?
Int. J. Mol. Sci. 2019, 20(2), 425; https://doi.org/10.3390/ijms20020425 (registering DOI)
Received: 27 December 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 19 January 2019
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Abstract
Background: The molecular signature of endometrial receptivity still remains barely understood, especially when focused on the possible benefit of therapeutical interventions and implantation-related pathologies. Therefore, the protein composition of tissue and isolated primary cells (endometrial stromal cells, ESCs) from endometrial scratchings of ART
[...] Read more.
Background: The molecular signature of endometrial receptivity still remains barely understood, especially when focused on the possible benefit of therapeutical interventions and implantation-related pathologies. Therefore, the protein composition of tissue and isolated primary cells (endometrial stromal cells, ESCs) from endometrial scratchings of ART (Assisted Reproductive Techniques) patients with repeated implantation failure (RIF) was compared to volunteers with proven fertility during the time of embryo implantation (LH + 7). Furthermore, an analysis of the endometrial tissue of fertile women infused with human chorionic gonadotropin (hCG) was conducted. Methods: Endometrial samples (n = 6 RIF, n = 10 fertile controls) were split into 3 pieces: 1/3 each was frozen in liquid nitrogen, 1/3 fixed in PFA and 1/3 cultured. Protein lysates prepared from fresh frozen tissue were processed for mass spectrometric analysis. Results: Three proteins (EPPK1, BCLAF1 and PTMA) showed a statistically altered abundance in the endometrial tissue of RIF patients. Furthermore, pathways like metabolism, immune system, ferroptosis and the endoplasmic reticulum were altered in RIF patients. Remarkably, endometrial tissues of RIF patients showed a significantly higher (p-value = 9 × 10−8) protein intensity correlation (Pearson’s correlation coefficient = 0.95) compared to fertile women (Pearson’s correlation coefficient = 0.88). The in vivo infusion of hCG stimulated proteins of endocytosis, HIF1 signalling and chemokine production. Notably, patients suffering from RIF had a clinical pregnancy rate of 19% after the intrauterine infusion of hCG before embryo transfer (ET) compared to their failed previous cycles. Conclusion: Our study showed for the first time that the endometrial proteome composition of RIF patients differs from fertile controls during the window of implantation. The intrauterine infusion of hCG prior to an embryo transfer might improve the chemokine triggered embryo-endometrial dialogue and intensify the angiogenesis and immune response. From a clinical point of view, the hCG infusion prior to an embryo transfer might increase the pregnancy rate of RIF patients. Full article
(This article belongs to the Special Issue Reproductive Immunology: Cellular and Molecular Biology)
Open AccessArticle Multifaceted Role of PheDof12-1 in the Regulation of Flowering Time and Abiotic Stress Responses in Moso Bamboo (Phyllostachys edulis)
Int. J. Mol. Sci. 2019, 20(2), 424; https://doi.org/10.3390/ijms20020424 (registering DOI)
Received: 23 December 2018 / Revised: 7 January 2019 / Accepted: 17 January 2019 / Published: 19 January 2019
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Abstract
DNA binding with one finger (Dof) proteins, forming an important transcriptional factor family, are involved in gene transcriptional regulation, development, stress responses, and flowering responses in annual plants. However, knowledge of Dofs in perennial and erratically flowering moso bamboo is limited. In view
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DNA binding with one finger (Dof) proteins, forming an important transcriptional factor family, are involved in gene transcriptional regulation, development, stress responses, and flowering responses in annual plants. However, knowledge of Dofs in perennial and erratically flowering moso bamboo is limited. In view of this, a Dof gene, PheDof12-1, was isolated from moso bamboo. PheDof12-1 is located in the nucleus and has the highest expression in palea and the lowest in bract. Moreover, PheDof12-1 expression is high in flowering leaves, then declines during flower development. The transcription level of PheDof12-1 is highly induced by cold, drought, salt, and gibberellin A3 (GA3) stresses. The functional characteristics of PheDof are researched for the first time in Arabidopsis, and the results show that transgenic Arabidopsis overexpressing PheDof12-1 shows early flowering under long-day (LD) conditions but there is no effect on flowering time under short-day (SD) conditions; the transcription levels of FT, SOC1, and AGL24 are upregulated; and FLC and SVP are downregulated. PheDof12-1 exhibits a strong diurnal rhythm, inhibited by light treatment and induced in dark. Yeast one-hybrid (Y1H) assay shows that PheDof12-1 can bind to the promoter sequence of PheCOL4. Taken together, these results indicate that PheDof12-1 might be involved in abiotic stress and flowering time, which makes it an important candidate gene for studying the molecular regulation mechanisms of moso bamboo flowering. Full article
(This article belongs to the Section Molecular Microbiology)
Open AccessReview Antifouling (Bio)materials for Electrochemical (Bio)sensing
Int. J. Mol. Sci. 2019, 20(2), 423; https://doi.org/10.3390/ijms20020423 (registering DOI)
Received: 18 December 2018 / Revised: 13 January 2019 / Accepted: 16 January 2019 / Published: 19 January 2019
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Abstract
(Bio)fouling processes arising from nonspecific adsorption of biological materials (mainly proteins but also cells and oligonucleotides), reaction products of neurotransmitters oxidation, and precipitation/polymerization of phenolic compounds, have detrimental effects on reliable electrochemical (bio)sensing of relevant analytes and markers either directly or after prolonged
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(Bio)fouling processes arising from nonspecific adsorption of biological materials (mainly proteins but also cells and oligonucleotides), reaction products of neurotransmitters oxidation, and precipitation/polymerization of phenolic compounds, have detrimental effects on reliable electrochemical (bio)sensing of relevant analytes and markers either directly or after prolonged incubation in rich-proteins samples or at extreme pH values. Therefore, the design of antifouling (bio)sensing interfaces capable to minimize these undesired processes is a substantial outstanding challenge in electrochemical biosensing. For this purpose, efficient antifouling strategies involving the use of carbon materials, metallic nanoparticles, catalytic redox couples, nanoporous electrodes, electrochemical activation, and (bio)materials have been proposed so far. In this article, biomaterial-based strategies involving polymers, hydrogels, peptides, and thiolated self-assembled monolayers are reviewed and critically discussed. The reported strategies have been shown to be successful to overcome (bio)fouling in a diverse range of relevant practical applications. We highlight recent examples for the reliable sensing of particularly fouling analytes and direct/continuous operation in complex biofluids or harsh environments. Opportunities, unmet challenges, and future prospects in this field are also pointed out. Full article
(This article belongs to the Special Issue Biomaterial Application in Sensors)
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Open AccessArticle Towards Unraveling the Histone Code by Fragment Blind Docking
Int. J. Mol. Sci. 2019, 20(2), 422; https://doi.org/10.3390/ijms20020422 (registering DOI)
Received: 19 December 2018 / Revised: 11 January 2019 / Accepted: 16 January 2019 / Published: 19 January 2019
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Abstract
Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the
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Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the N-terminal peptide tails of histones. Determination of structures of histone-reader complexes would be a key to unravel the histone code and the design of new drugs. However, the large number of possible histone complex variations imposes a true challenge for experimental structure determination techniques. Calculation of such complexes is difficult due to considerable size and flexibility of peptides and the shallow binding surfaces of the readers. Moreover, location of the binding sites is often unknown, which requires a blind docking search over the entire surface of the target protein. To accelerate the work in this field, a new approach is presented for prediction of the structure of histone H3 peptide tails docked to their targets. Using a fragmenting protocol and a systematic blind docking method, a collection of well-positioned fragments of the H3 peptide is produced. After linking the fragments, reconstitution of anchoring regions of the target-bound H3 peptide conformations was possible. As a first attempt of combination of blind and fragment docking approaches, our new method is named fragment blind docking (FBD). Full article
(This article belongs to the Section Molecular Biophysics)
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Open AccessReview Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases
Int. J. Mol. Sci. 2019, 20(2), 421; https://doi.org/10.3390/ijms20020421 (registering DOI)
Received: 29 December 2018 / Revised: 14 January 2019 / Accepted: 15 January 2019 / Published: 19 January 2019
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Abstract
MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as
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MicroRNAs (miRs) are endogenous non-coding RNA molecules that play important roles in human health and disease by regulating gene expression and cellular processes. In recent years, with the increasing scientific knowledge and new discovery of miRs and their gene targets, as well as the plentiful experimental evidence that shows dysregulation of miRs in a wide variety of human diseases, the computational modeling approach has emerged as an effective tool to help researchers identify novel functional associations between differential miR expression and diseases, dissect the phenotypic expression patterns of miRs in gene regulatory networks, and elucidate the critical roles of miRs in the modulation of disease pathways from mechanistic and quantitative perspectives. Here we will review the recent systems biology studies that employed different kinetic modeling techniques to provide mechanistic insights relating to the regulatory function and therapeutic potential of miRs in human diseases. Some of the key computational aspects to be discussed in detail in this review include (i) models of miR-mediated network motifs in the regulation of gene expression, (ii) models of miR biogenesis and miR–target interactions, and (iii) the incorporation of such models into complex disease pathways in order to generate mechanistic, molecular- and systems-level understanding of pathophysiology. Other related bioinformatics tools such as computational platforms that predict miR-disease associations will also be discussed, and we will provide perspectives on the challenges and opportunities in the future development and translational application of data-driven systems biology models that involve miRs and their regulatory pathways in human diseases. Full article
(This article belongs to the Special Issue Computational Models in Non-Coding RNA and Human Disease)
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Open AccessReview Calcium: A Critical Factor in Pollen Germination and Tube Elongation
Int. J. Mol. Sci. 2019, 20(2), 420; https://doi.org/10.3390/ijms20020420 (registering DOI)
Received: 10 December 2018 / Revised: 20 December 2018 / Accepted: 25 December 2018 / Published: 19 January 2019
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Abstract
Pollen is the male gametophyte of higher plants. Its major function is to deliver sperm cells to the ovule to ensure successful fertilization. During this process, many interactions occur among pollen tubes and pistil cells and tissues, and calcium ion (Ca2+)
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Pollen is the male gametophyte of higher plants. Its major function is to deliver sperm cells to the ovule to ensure successful fertilization. During this process, many interactions occur among pollen tubes and pistil cells and tissues, and calcium ion (Ca2+) dynamics mediate these interactions among cells to ensure that pollen reaches the embryo sac. Although the precise functions of Ca2+ dynamics in the cells are unknown, we can speculate about its roles on the basis of its spatial and temporal characteristics during these interactions. The results of many studies indicate that calcium is a critical element that is strongly related to pollen germination and pollen tube growth. Full article
(This article belongs to the Special Issue Calcium Signals in Plant Cells)
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Open AccessArticle Expressing Double-Stranded RNAs of Insect Hormone-Related Genes Enhances Baculovirus Insecticidal Activity
Int. J. Mol. Sci. 2019, 20(2), 419; https://doi.org/10.3390/ijms20020419 (registering DOI)
Received: 17 December 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 18 January 2019
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Abstract
Baculoviruses have already been used for insect pest control, but the slow killing speed limits their further promotion and application. Here we provide a strategy for improving baculovirus insecticidal activity using Helicoverpa armigera nucleopolyhedrovirus (HearNPV) to express double-stranded RNAs (dsRNAs) targeting cotton bollworm
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Baculoviruses have already been used for insect pest control, but the slow killing speed limits their further promotion and application. Here we provide a strategy for improving baculovirus insecticidal activity using Helicoverpa armigera nucleopolyhedrovirus (HearNPV) to express double-stranded RNAs (dsRNAs) targeting cotton bollworm (Helicoverpa armigera) juvenile hormone (JH)-related genes. Droplet-feeding bioassays show that the 50% lethal concentration (LC50) values of recombinant baculoviruses expressing the dsRNA of JH acid methyl transferase gene (HaJHAMT) and the JH acid binding protein gene (HaJHBP) were 1.24 × 104 polyhedral inclusion bodies (PIB)/mL and 2.26 × 104 PIB/mL, respectively. Both were much lower than the control value (8.12 × 104 PIB/mL). Meanwhile, the LT50 of recombinant baculovirus expressing dsRNA of HaJHBP was only 54.2% of the control value, which means that larval death was accelerated. Furthermore, the mRNA level of target genes was reduced in recombinant baculovirus-treated cotton bollworm larvae. Transcription of several key genes involved in hormone signaling pathways—for example, ecdysone receptor gene (HaEcR)—was also altered. This study establishes a new strategy for pest management by interfering with insect hormone-related gene expression via baculoviruses, and the engineered baculoviruses have great potential application in cotton production. Full article
(This article belongs to the Special Issue Plant-Insect Interactions 2018)
Open AccessArticle Prognostic relevance of RIP140 and ERβ expression in unifocal versus multifocal breast cancers: a preliminary report
Int. J. Mol. Sci. 2019, 20(2), 418; https://doi.org/10.3390/ijms20020418 (registering DOI)
Received: 9 November 2018 / Revised: 21 December 2018 / Accepted: 16 January 2019 / Published: 18 January 2019
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Abstract
The aim of this study was to investigate the expression of two nuclear receptor transcriptional coregulators, namely RIP140 (receptor-interacting protein of 140 kDa) and LCoR (ligand-dependent corepressor) in unifocal versus multifocal breast cancers. The expression of these two proteins was analyzed by immunohistochemistry
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The aim of this study was to investigate the expression of two nuclear receptor transcriptional coregulators, namely RIP140 (receptor-interacting protein of 140 kDa) and LCoR (ligand-dependent corepressor) in unifocal versus multifocal breast cancers. The expression of these two proteins was analyzed by immunohistochemistry in a matched-pair cohort of 21 unifocal and 21 multifocal breast tumors. The expression of the two estrogen receptors (ERα and ERβ) was studied in parallel. RIP140 and LCoR levels appeared lower in unifocal tumors compared to multifocal samples (decreased of immune-reactive scores and reduced number of high expressing cells). In both tumor types, RIP140 and LCoR expression was correlated with each other and with expression of ERβ. Very interestingly, the expression of RIP140, LCoR, and ERβ was inversely correlated with overall survival only for the unifocal group. The negative correlation with overall and recurrence free survival was more pronounced in patients whose unifocal tumors expressed high levels of both RIP140 and ERβ. Altogether, this preliminary report indicates that the ERβ/RIP140 signaling is altered in unifocal breast cancers and correlated with patient outcome. Further investigation is needed to decipher the molecular mechanisms and the biological relevance of this deregulation. Full article
(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)
Open AccessCommunication Efficient Selection of Antibodies Reactive to Homologous Epitopes on Human and Mouse Hepatocyte Growth Factors by Next-Generation Sequencing-Based Analysis of the B Cell Repertoire
Int. J. Mol. Sci. 2019, 20(2), 417; https://doi.org/10.3390/ijms20020417 (registering DOI)
Received: 19 December 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 18 January 2019
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Abstract
: YYB-101 is a humanized rabbit anti-human hepatocyte growth factor (HGF)-neutralizing antibody currently in clinical trial. To test the effect of HGF neutralization with antibody on anti-cancer T cell immunity, we generated surrogate antibodies that are reactive to the mouse homologue of the
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: YYB-101 is a humanized rabbit anti-human hepatocyte growth factor (HGF)-neutralizing antibody currently in clinical trial. To test the effect of HGF neutralization with antibody on anti-cancer T cell immunity, we generated surrogate antibodies that are reactive to the mouse homologue of the epitope targeted by YYB-101. First, we immunized a chicken with human HGF and monitored changes in the B cell repertoire by next-generation sequencing (NGS). We then extracted the VH gene repertoire from the NGS data, clustered it into components by sequence homology, and classified the components by the change in the number of unique VH sequences and the frequencies of the VH sequences within each component following immunization. Those changes should accompany the preferential proliferation and somatic hypermutation or gene conversion of B cells encoding HGF-reactive antibodies. One component showed significant increases in the number and frequencies of unique VH sequences and harbored genes encoding antibodies that were reactive to human HGF and competitive with YYB-101 for HGF binding. Some of the antibodies also reacted to mouse HGF. The selected VH sequences shared 98.3% identity and 98.9% amino acid similarity. It is therefore likely that the antibodies encoded by them all react to the epitope targeted by YYB-101. Full article
(This article belongs to the Special Issue Hepatocyte Growth Factor (HGF))
Open AccessArticle A New Approach for Improving the Antibacterial and Tumor Cytotoxic Activities of Pipemidic Acid by Including It in Trimethyl-β-cyclodextrin
Int. J. Mol. Sci. 2019, 20(2), 416; https://doi.org/10.3390/ijms20020416 (registering DOI)
Received: 28 November 2018 / Revised: 10 January 2019 / Accepted: 16 January 2019 / Published: 18 January 2019
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Abstract
Pipemidic acid (HPPA) is a quinolone antibacterial agent used mostly to treat gram-negative infections of the urinary tract, but its therapeutic use is limited because of its low solubility. Thus, to improve drug solubility, natural cyclodextrins (CDs) are used for their ability of
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Pipemidic acid (HPPA) is a quinolone antibacterial agent used mostly to treat gram-negative infections of the urinary tract, but its therapeutic use is limited because of its low solubility. Thus, to improve drug solubility, natural cyclodextrins (CDs) are used for their ability of including guest molecules within their cavities. The aim of this work was to evaluate the antibacterial activity and the preliminary anticancer activity of HPPA included into Heptakis (2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB) as a possible approach for a new innovative formulation. The inclusion complex of HPPA with TRIMEB was prepared in solid state by the kneading method and confirmed by FT-IR and powered X-ray diffraction. The association in aqueous solutions of pipemidic acid with TRIMEB was investigated by UV-Vis spectroscopy. Job’s plots have been drawn by UV-visible spectroscopy to confirm the 1:1 stoichiometry of the host–guest assembly. The antibacterial activity of HPPA, TRIMEB and of their complex was tested on Escherichia coli, Pseudomonas aeruginosa, and Staphilococcus aureus. The complex was able to increase 47.36% of the median antibacterial activity of the free HPPA against E. coli (IC50 = 249 µM vs. 473 µM). Furthermore, these samples were tested on HepG-2 and MCF-7. After 72 h, the median tumoral cytotoxicity exerted by the complex was increased by 78.08% and 94.27% for HepG-2 and MCF-7 respectively, showing a stronger bioactivity of the complex than the single HAPPA. Full article
(This article belongs to the Section Biochemistry)
Open AccessArticle Understanding Changes in Tomato Cell Walls in Roots and Fruits: The Contribution of Arbuscular Mycorrhizal Colonization
Int. J. Mol. Sci. 2019, 20(2), 415; https://doi.org/10.3390/ijms20020415 (registering DOI)
Received: 12 November 2018 / Revised: 3 January 2019 / Accepted: 16 January 2019 / Published: 18 January 2019
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Abstract
Modifications in cell wall composition, which can be accompanied by changes in its structure, were already reported during plant interactions with other organisms, such as the mycorrhizal fungi. Arbuscular mycorrhizal (AM) fungi are among the most widespread soil organisms that colonize the roots
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Modifications in cell wall composition, which can be accompanied by changes in its structure, were already reported during plant interactions with other organisms, such as the mycorrhizal fungi. Arbuscular mycorrhizal (AM) fungi are among the most widespread soil organisms that colonize the roots of land plants, where they facilitate mineral nutrient uptake from the soil in exchange for plant-assimilated carbon. In AM symbiosis, the host plasma membrane invaginates and proliferates around all the developing intracellular fungal structures, and cell wall material is laid down between this membrane and the fungal cell surface. In addition, to improve host nutrition and tolerance/resistance to environmental stresses, AM symbiosis was shown to modulate fruit features. In this study, Comprehensive Microarray Polymer Profiling (CoMMP) technique was used to verify the impact of the AM symbiosis on the tomato cell wall composition both at local (root) and systemic level (fruit). Multivariate data analyses were performed on the obtained datasets looking for the effects of fertilization, inoculation with AM fungi, and the fruit ripening stage. Results allowed for the discernment of cell wall component modifications that were correlated with mycorrhizal colonization, showing a different tomato response to AM colonization and high fertilization, both at the root and the systemic level. Full article
(This article belongs to the Section Molecular Plant Sciences)
Open AccessArticle WRKYs, the Jack-of-various-Trades, Modulate Dehydration Stress in Populus davidiana—A Transcriptomic Approach
Int. J. Mol. Sci. 2019, 20(2), 414; https://doi.org/10.3390/ijms20020414 (registering DOI)
Received: 27 December 2018 / Revised: 14 January 2019 / Accepted: 15 January 2019 / Published: 18 January 2019
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Abstract
Populus davidiana, native to Korea and central Asian countries, is a major contributor to the Korean forest cover. In the current study, using high-throughput RNA-seq mediated transcriptome analysis, we identified about 87 P. davidiana WRKY transcription factors (PopdaWRKY TFs) that showed differential
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Populus davidiana, native to Korea and central Asian countries, is a major contributor to the Korean forest cover. In the current study, using high-throughput RNA-seq mediated transcriptome analysis, we identified about 87 P. davidiana WRKY transcription factors (PopdaWRKY TFs) that showed differential expression to dehydration stress in both sensitive and tolerant cultivars. Our results suggested that, on average, most of the WRKY genes were upregulated in tolerant cultivars but downregulated in sensitive cultivars. Based on protein sequence alignment, P. davidiana WRKYs were classified into three major groups, I, II, III, and further subgroups. Phylogenetic analysis showed that WRKY TFs and their orthologs in Arabidopsis and rice were clustered together in the same subgroups, suggesting similar functions across species. Significant correlation was found among qRT-PCR and RNA-seq analysis. In vivo analysis using model plant Arabidopsis showed that atwrky62 (orthologous to Potri.016G137900) knockout mutants were significantly sensitive to dehydration possibly due to an inability to close their stomata under dehydration conditions. In addition, a concomitant decrease in expression of ABA biosynthetic genes was observed. The AtHK1 that regulates stomatal movement was also downregulated in atwrky62 compared to the wild type. Taken together, our findings suggest a regulatory role of PopdaWRKYs under dehydration stress. Full article
(This article belongs to the Special Issue Mechanisms of Drought Stress Tolerance in Plants)
Open AccessArticle Arabidopsis CNGC Family Members Contribute to Heavy Metal Ion Uptake in Plants
Int. J. Mol. Sci. 2019, 20(2), 413; https://doi.org/10.3390/ijms20020413 (registering DOI)
Received: 30 November 2018 / Revised: 10 January 2019 / Accepted: 16 January 2019 / Published: 18 January 2019
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Abstract
Heavy metal ions, including toxic concentrations of essential ions, negatively affect diverse metabolic and cellular processes. Heavy metal ions are known to enter cells in a non-selective manner; however, few studies have examined the regulation of heavy metal ion transport. Plant cyclic nucleotide-gated
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Heavy metal ions, including toxic concentrations of essential ions, negatively affect diverse metabolic and cellular processes. Heavy metal ions are known to enter cells in a non-selective manner; however, few studies have examined the regulation of heavy metal ion transport. Plant cyclic nucleotide-gated channels (CNGCs), a type of Ca2+-permeable-channel, have been suggested to be involved in the uptake of both essential and toxic cations. To determine the candidates responsible for heavy metal ion transport, a series of Arabidopsis CNGC mutants were examined for their response to Pb2+ and Cd2+ ions. The primary focus was on root growth and the analysis of the concentration of heavy metals in plants. Results, based on the analysis of primary root length, indicated that AtCNGC1, AtCNGC10, AtCNGC13 and AtCNGC19 play roles in Pb2+ toxicity, while AtCNGC11, AtCNGC13, AtCNGC16 and AtCNGC20 function in Cd2+ toxicity in Arabidopsis. Ion content analysis verified that the mutations of AtCNGC1 and AtCNGC13 resulted in reduced Pb2+ accumulation, while the mutations of AtCNGC11, AtCNGC15 and AtCNGC19 resulted in less Pb2+ and Cd2+ accumulation in plants. These findings provide functional evidence which support the roles of these AtCNGCs in the uptake and transport of Pb2+ or Cd2+ ion in plants. Full article
(This article belongs to the Special Issue Ion Transporters and Abiotic Stress Tolerance in Plants)
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Open AccessReview Targeting PI3K Signaling in Acute Lymphoblastic Leukemia
Int. J. Mol. Sci. 2019, 20(2), 412; https://doi.org/10.3390/ijms20020412 (registering DOI)
Received: 14 December 2018 / Revised: 13 January 2019 / Accepted: 14 January 2019 / Published: 18 January 2019
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Abstract
Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stroma cells triggers intracellular signals regulating cell-adhesion-mediated drug resistance (CAM-DR). Stromal cell protection of ALL cells has been shown to require active AKT. In chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT
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Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stroma cells triggers intracellular signals regulating cell-adhesion-mediated drug resistance (CAM-DR). Stromal cell protection of ALL cells has been shown to require active AKT. In chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT pathway is reported. A novel FDA-approved PI3Kδ inhibitor, CAL-101/idelalisib, leads to downregulation of p-AKT and increased apoptosis of CLL cells. Recently, two additional PI3K inhibitors have received FDA approval. As the PI3K/AKT pathway is also implicated in adhesion-mediated survival of ALL cells, PI3K inhibitors have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K in normal hematopoietic cells, and in ALL. We focus on summarizing targeting strategies of PI3K in ALL. Full article
(This article belongs to the Special Issue Signaling Promiscuity of PI3K)
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Open AccessReview Ceramide and Regulation of Vascular Tone
Int. J. Mol. Sci. 2019, 20(2), 411; https://doi.org/10.3390/ijms20020411 (registering DOI)
Received: 20 November 2018 / Revised: 2 January 2019 / Accepted: 16 January 2019 / Published: 18 January 2019
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Abstract
In addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of physiological functions. This review aims to provide updated information on the role of ceramide in the
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In addition to playing a role as a structural component of cellular membranes, ceramide is now clearly recognized as a bioactive lipid implicated in a variety of physiological functions. This review aims to provide updated information on the role of ceramide in the regulation of vascular tone. Ceramide may induce vasodilator or vasoconstrictor effects by interacting with several signaling pathways in endothelial and smooth muscle cells. There is a clear, albeit complex, interaction between ceramide and redox signaling. In fact, reactive oxygen species (ROS) activate different ceramide generating pathways and, conversely, ceramide is known to increase ROS production. In recent years, ceramide has emerged as a novel key player in oxygen sensing in vascular cells and mediating vascular responses of crucial physiological relevance such as hypoxic pulmonary vasoconstriction (HPV) or normoxic ductus arteriosus constriction. Likewise, a growing body of evidence over the last years suggests that exaggerated production of vascular ceramide may have detrimental effects in a number of pathological processes including cardiovascular and lung diseases. Full article
(This article belongs to the Special Issue Ceramide)
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Open AccessArticle HADC8 Inhibitor WK2-16 Therapeutically Targets Lipopolysaccharide-Induced Mouse Model of Neuroinflammation and Microglial Activation
Int. J. Mol. Sci. 2019, 20(2), 410; https://doi.org/10.3390/ijms20020410 (registering DOI)
Received: 12 December 2018 / Revised: 14 January 2019 / Accepted: 15 January 2019 / Published: 18 January 2019
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Abstract
Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has
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Glial activation and neuroinflammatory processes play important roles in the pathogenesis of brain abscess and neurodegenerative diseases. Activated glial cells can secrete various proinflammatory cytokines and neurotoxic mediators, which contribute to the exacerbation of neuronal cell death. The inhibition of glial activation has been shown to alleviate neurodegenerative conditions. The present study was to investigate the specific HDAC8 inhibitor WK2-16, especially its effects on the neuroinflammatory responses through glial inactivation. WK2-16 significantly reduced the gelatinolytic activity of MMP-9, and expression of COX-2/iNOS proteins in striatal lipopolysaccharide (LPS)-induced neuroinflammation in C57BL/6 mice. The treatment of WK2-16 markedly improved neurobehavioral deficits. Immunofluorescent staining revealed that WK2-16 reduced LPS-stimulated astrogliosis and microglial activation in situ. Consistently, cellular studies revealed that WK2-16 significantly suppressed LPS-induced mouse microglia BV-2 cell proliferation. WK2-16 was proven to concentration-dependently induce the levels of acetylated SMC3 in microglial BV-2 cells. It also reduced the expression of COX-2/iNOS proteins and TNF-α production in LPS-activated microglial BV-2 cells. The signaling studies demonstrated that WK2-16 markedly inhibited LPS-activated STAT-1/-3 and Akt activation, but not NF-κB or MAPK signaling. In summary, the HADC8 inhibitor WK2-16 exhibited neuroprotective effects through its anti-neuroinflammation and glial inactivation properties, especially in microglia in vitro and in vivo. Full article
(This article belongs to the Special Issue Histone Deacetylase Inhibitors in Health and Disease)
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