International Journal of Molecular Sciences

15 pages, 1302 KiB

Open AccessArticle

Human Synovia Contains Trefoil Factor Family (TFF) Peptides 1–3 Although Synovial Membrane Only Produces TFF3: Implications in Osteoarthritis and Rheumatoid Arthritis

by Judith Popp, Martin Schicht, Fabian Garreis, Patricia Klinger, Kolja Gelse, Stefan Sesselmann, Michael Tsokos, Saskia Etzold, Dankwart Stiller, Horst Claassen and Friedrich Paulsen

Int. J. Mol. Sci. 2019, 20(23), 6105; https://doi.org/10.3390/ijms20236105 - 3 Dec 2019

Cited by 4 | Viewed by 4319

Abstract

Objective: Trefoil factor family peptide 3 (TFF3) has been shown to support catabolic functions in cases of osteoarthritis (OA). As in joint physiology and diseases such as OA, the synovial membrane (SM) of the joint capsule also plays a central role. We analyze [...] Read more.

Objective: Trefoil factor family peptide 3 (TFF3) has been shown to support catabolic functions in cases of osteoarthritis (OA). As in joint physiology and diseases such as OA, the synovial membrane (SM) of the joint capsule also plays a central role. We analyze the ability of SM to produce TFF compare healthy SM and its secretion product synovial fluid (SF) with SM and SF from patients suffering from OA or rheumatoid arthritis (RA). Methods: Real-time PCR and ELISA were used to measure the expression of TFFs in healthy SM and SM from patients suffering from OA or RA. For tissue localization, we investigated TFF1-3 in differently aged human SM of healthy donors by means of immunohistochemistry, real-time PCR and Western blot. Results: Only TFF3 but not TFF1 and -2 was expressed in SM from healthy donors as well as cases of OA or RA on protein and mRNA level. In contrast, all three TFFs were detected in all samples of SF on the protein level. No significant changes were observed for TFF1 at all. TFF2 was significantly upregulated in RA samples in comparison to OA samples. TFF3 protein was significantly downregulated in OA samples in comparison to healthy samples and cases of RA significantly upregulated compared to OA. In contrast, in SM TFF3 protein was not significantly regulated. Conclusion: The data demonstrate the production of TFF3 in SM. Unexpectedly, SF contains all three known TFF peptides. As neither articular cartilage nor SM produce TFF1 and TFF2, we speculate that these originate with high probability from blood serum. Full article

(This article belongs to the Special Issue TFF Peptides: Lectins in Mucosal Protection and More)

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13 pages, 2068 KiB

Open AccessArticle

Construction of a Robust Cofactor Self-Sufficient Bienzyme Biocatalytic System for Dye Decolorization and its Mathematical Modeling

by Haitao Ding, Wei Luo, Yong Yu and Bo Chen

Int. J. Mol. Sci. 2019, 20(23), 6104; https://doi.org/10.3390/ijms20236104 - 3 Dec 2019

Cited by 8 | Viewed by 2657

Abstract

A triphenylmethane reductase derived from Citrobacter sp. KCTC 18061P was coupled with a glucose 1-dehydrogenase from Bacillus sp. ZJ to construct a cofactor self-sufficient bienzyme biocatalytic system for dye decolorization. Fed-batch experiments showed that the system is robust to maintain its activity after [...] Read more.

A triphenylmethane reductase derived from Citrobacter sp. KCTC 18061P was coupled with a glucose 1-dehydrogenase from Bacillus sp. ZJ to construct a cofactor self-sufficient bienzyme biocatalytic system for dye decolorization. Fed-batch experiments showed that the system is robust to maintain its activity after 15 cycles without the addition of any expensive exogenous NADH. Subsequently, three different machine learning approaches, including multiple linear regression (MLR), random forest (RF), and artificial neural network (ANN), were employed to explore the response of decolorization efficiency to the variables of the bienzyme system. Statistical parameters of these models suggested that a three-layered ANN model with six hidden neurons was capable of predicting the dye decolorization efficiency with the best accuracy, compared with the models constructed by MLR and RF. Weights analysis of the ANN model showed that the ratio between two enzymes appeared to be the most influential factor, with a relative importance of 54.99% during the decolorization process. The modeling results confirmed that the neural networks could effectively reproduce experimental data and predict the behavior of the decolorization process, especially for complex systems containing multienzymes. Full article

(This article belongs to the Special Issue Free and immobilized enzymes for biofuels, biosensing and bioremediation )

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15 pages, 1810 KiB

Open AccessArticle

Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi

by Daniela Hladik, Sonja Buratovic, Christine Von Toerne, Omid Azimzadeh, Prabal Subedi, Jos Philipp, Stefanie Winkler, Annette Feuchtinger, Elenore Samson, Stefanie M. Hauck, Bo Stenerlöw, Per Eriksson, Michael J. Atkinson and Soile Tapio

Int. J. Mol. Sci. 2019, 20(23), 6103; https://doi.org/10.3390/ijms20236103 - 3 Dec 2019

Cited by 8 | Viewed by 3950

Abstract

In children, ketamine sedation is often used during radiological procedures. Combined exposure of ketamine and radiation at doses that alone did not affect learning and memory induced permanent cognitive impairment in mice. The aim of this study was to elucidate the mechanism behind [...] Read more.

In children, ketamine sedation is often used during radiological procedures. Combined exposure of ketamine and radiation at doses that alone did not affect learning and memory induced permanent cognitive impairment in mice. The aim of this study was to elucidate the mechanism behind this adverse outcome. Neonatal male NMRI mice were administered ketamine (7.5 mg kg⁻¹) and irradiated (whole-body, 100 mGy or 200 mGy, ¹³⁷Cs) one hour after ketamine exposure on postnatal day 10. The control mice were injected with saline and sham-irradiated. The hippocampi were analyzed using label-free proteomics, immunoblotting, and Golgi staining of CA1 neurons six months after treatment. Mice co-exposed to ketamine and low-dose radiation showed alterations in hippocampal proteins related to neuronal shaping and synaptic plasticity. The expression of brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein, and postsynaptic density protein 95 were significantly altered only after the combined treatment (100 mGy or 200 mGy combined with ketamine, respectively). Increased numbers of basal dendrites and branching were observed only after the co-exposure, thereby constituting a possible reason for the displayed alterations in behavior. These data suggest that the risk of radiation-induced neurotoxic effects in the pediatric population may be underestimated if based only on the radiation dose. Full article

(This article belongs to the Section Molecular Toxicology)

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16 pages, 2426 KiB

Open AccessReview

Homologous Recombination under the Single-Molecule Fluorescence Microscope

by Dalton R. Gibbs and Soma Dhakal

Int. J. Mol. Sci. 2019, 20(23), 6102; https://doi.org/10.3390/ijms20236102 - 3 Dec 2019

Cited by 9 | Viewed by 4650

Abstract

Homologous recombination (HR) is a complex biological process and is central to meiosis and for repair of DNA double-strand breaks. Although the HR process has been the subject of intensive study for more than three decades, the complex protein–protein and protein–DNA interactions during [...] Read more.

Homologous recombination (HR) is a complex biological process and is central to meiosis and for repair of DNA double-strand breaks. Although the HR process has been the subject of intensive study for more than three decades, the complex protein–protein and protein–DNA interactions during HR present a significant challenge for determining the molecular mechanism(s) of the process. This knowledge gap is largely because of the dynamic interactions between HR proteins and DNA which is difficult to capture by routine biochemical or structural biology methods. In recent years, single-molecule fluorescence microscopy has been a popular method in the field of HR to visualize these complex and dynamic interactions at high spatiotemporal resolution, revealing mechanistic insights of the process. In this review, we describe recent efforts that employ single-molecule fluorescence microscopy to investigate protein–protein and protein–DNA interactions operating on three key DNA-substrates: single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and four-way DNA called Holliday junction (HJ). We also outline the technological advances and several key insights revealed by these studies in terms of protein assembly on these DNA substrates and highlight the foreseeable promise of single-molecule fluorescence microscopy in advancing our understanding of homologous recombination. Full article

(This article belongs to the Special Issue Biological Systems at the Protein Level)

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18 pages, 4352 KiB

Open AccessArticle

MCP-1/MCPIP-1 Signaling Modulates the Effects of IL-1β in Renal Cell Carcinoma through ER Stress-Mediated Apoptosis

by Chia-Huei Lee, Pin-Feng Hung, Shang-Chieh Lu, Hsuan-Lien Chung, Shang-Lun Chiang, Chun-Te Wu, Wei-Chun Chou and Chiao-Yin Sun

Int. J. Mol. Sci. 2019, 20(23), 6101; https://doi.org/10.3390/ijms20236101 - 3 Dec 2019

Cited by 18 | Viewed by 4925

Abstract

In renal cell carcinoma (RCC), interleukin (IL)-1β may be a pro-metastatic cytokine. However, we have not yet noted the clinical association between tumoral expression or serum level of IL-1β and RCC in our patient cohort. Herein, we investigate molecular mechanisms elicited by IL-1β [...] Read more.

In renal cell carcinoma (RCC), interleukin (IL)-1β may be a pro-metastatic cytokine. However, we have not yet noted the clinical association between tumoral expression or serum level of IL-1β and RCC in our patient cohort. Herein, we investigate molecular mechanisms elicited by IL-1β in RCC. We found that IL-1β stimulates substantial monocyte chemoattractant protein (MCP)-1 production in RCC cells by activating NF-kB and AP-1. In our xenograft RCC model, intra-tumoral MCP-1 injection down-regulated Ki67 expression and reduced tumor size. Microarray analysis revealed that MCP-1 treatment altered protein-folding processes in RCC cells. MCP-1-treated RCC cells and xenograft tumors expressed MCP-1-induced protein (MCPIP) and molecules involved in endoplasmic reticulum (ER) stress-mediated apoptosis, namely C/EBP Homologous Protein (CHOP), protein kinase-like ER kinase (PERK), and calnexin (CNX). ER stress-mediated apoptosis in MCP-1-treated RCC cells was confirmed using Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Moreover, ectopic MCPIP expression increased PERK expression in Human embryonic kidney (HEK)293 cells. Our meta-analysis revealed that low MCP-1 levels reduce 1-year post-nephrectomy survival in patients with RCC. Immunohistochemistry indicated that in some RCC biopsy samples, the correlation between MCP-1 or MCPIP expression and tumor stages was inverse. Thus, MCP-1 and MCPIP potentially reduce the IL-1β-mediated oncogenic effect in RCC; our findings suggest that ER stress is a potential RCC treatment target. Full article

(This article belongs to the Special Issue Cancer Metabolism—Metabolites Regulation of Oncogenic Signaling and Epigenetics)

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14 pages, 1695 KiB

Open AccessArticle

A2AR Transmembrane 2 Peptide Administration Disrupts the A2AR-A2AR Homoreceptor but Not the A2AR-D2R Heteroreceptor Complex: Lack of Actions on Rodent Cocaine Self-Administration

by Dasiel O. Borroto-Escuela, Karolina Wydra, Wilber Romero-Fernandez, Zilong Zhou, Malgorzata Frankowska, Malgorzata Filip and Kjell Fuxe

Int. J. Mol. Sci. 2019, 20(23), 6100; https://doi.org/10.3390/ijms20236100 - 3 Dec 2019

Cited by 8 | Viewed by 3227

Abstract

It was previously demonstrated that rat adenosine A2AR transmembrane V peptide administration into the nucleus accumbens enhances cocaine self-administration through disruption of the A2AR-dopamine (D2R) heteroreceptor complex of this region. Unlike human A2AR transmembrane 4 (TM4) and 5 (TM5), A2AR TM2 did not [...] Read more.

It was previously demonstrated that rat adenosine A2AR transmembrane V peptide administration into the nucleus accumbens enhances cocaine self-administration through disruption of the A2AR-dopamine (D2R) heteroreceptor complex of this region. Unlike human A2AR transmembrane 4 (TM4) and 5 (TM5), A2AR TM2 did not interfere with the formation of the A2AR-D2R heteroreceptor complex in cellular models using BRET¹ assay. A2AR TM2 was proposed to be part of the of the receptor interface of the A2AR homomer instead and was therefore tested in the current article for effects on rat cocaine self-administration using rat A2AR synthetic TM2 peptide bilaterally injected into the nucleus accumbens. The injected A2AR TM2 peptide failed to significantly counteract the inhibitory action of the A2AR agonist CGS 21680 (0.1 mg/Kg) on cocaine self-administration. In line with these results, the microinjected A2AR TM2 peptide did not reduce the number of proximity ligation assay blobs identifying A2AR-D2R heteroreceptor complexes in the nucleus accumbens. In contrast, the A2AR TM2 peptide significantly reduced the number of A2AR-A2AR homoreceptor complexes in the nucleus accumbens. As to effects on the receptor–receptor interactions in the A2AR-D2R heteroreceptor complexes, the A2AR TM2 peptide did not alter the significant increase in the D2R Ki, high values produced by the A2AR agonist CGS 21680 ex vivo in the ventral striatum. The results indicate that the accumbal A2AR-A2AR homomeric complexes are not involved in mediating the A2AR agonist-induced inhibition of cocaine self-administration. Full article

(This article belongs to the Special Issue G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond)

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17 pages, 6287 KiB

Open AccessArticle

The Effect of Hydroxamic Siderophores Structure on Acetylation of Histone H3 and Alpha Tubulin in Pinus sylvestris Root Cells

by Joanna Mucha, Tomasz A. Pawłowski, Ewelina A. Klupczyńska, Marzenna Guzicka and Marcin Zadworny

Int. J. Mol. Sci. 2019, 20(23), 6099; https://doi.org/10.3390/ijms20236099 - 3 Dec 2019

Viewed by 2762

Abstract

Protein acetylation affects gene expression, as well as other processes in cells, and it might be dependent on the availability of the metals. However, whether iron chelating compounds (siderophores) can have an effect on the acetylation process in plant roots is largely unknown. [...] Read more.

Protein acetylation affects gene expression, as well as other processes in cells, and it might be dependent on the availability of the metals. However, whether iron chelating compounds (siderophores) can have an effect on the acetylation process in plant roots is largely unknown. In the present study, western blotting and confocal microscopy was used to examine the degree of acetylation of histone H3 and alpha tubulin in Pinus sylvestris root cells in the presence of structurally different siderophores. The effect of metabolites that were produced by pathogenic and mycorrhizal fungi was also assessed. No effect was observed on histone acetylation. By contrast, the metabolites of the pathogenic fungus were able to decrease the level of microtubule acetylation, whereas treatment with iron-free ferrioxamine (DFO) was able to increase it. This latter was not observed when ferrioxamine-iron complexes were used. The pathogen metabolites induced important modifications of cytoskeleton organization. Siderophores also induced changes in the tubulin skeleton and these changes were iron-dependent. The effect of siderophores on the microtubule network was dependent on the presence of iron. More root cells with a depolymerized cytoskeleton were observed when the roots were exposed to iron-free siderophores and the metabolites of pathogenic fungi; whereas, the metabolites from mycorrhizal fungi and iron-enriched forms of siderophores slightly altered the cytoskeleton network of root cells. Collectively, these data indicated that the metabolites of pathogenic fungi mirror siderophore action, and iron limitation can lead to enhanced alternations in cell structure and physiology. Full article

(This article belongs to the Section Molecular Plant Sciences)

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14 pages, 2090 KiB

Open AccessArticle

RankerGUI: A Computational Framework to Compare Differential Gene Expression Profiles Using Rank Based Statistics

by Amarinder Singh Thind, Kumar Parijat Tripathi and Mario Rosario Guarracino

Int. J. Mol. Sci. 2019, 20(23), 6098; https://doi.org/10.3390/ijms20236098 - 3 Dec 2019

Cited by 6 | Viewed by 5933

Abstract

The comparison of high throughput gene expression datasets obtained from different experimental conditions is a challenging task. It provides an opportunity to explore the cellular response to various biological events such as disease, environmental conditions, and drugs. There is a need for tools [...] Read more.

The comparison of high throughput gene expression datasets obtained from different experimental conditions is a challenging task. It provides an opportunity to explore the cellular response to various biological events such as disease, environmental conditions, and drugs. There is a need for tools that allow the integration and analysis of such data. We developed the “RankerGUI pipeline”, a user-friendly web application for the biological community. It allows users to use various rank based statistical approaches for the comparison of full differential gene expression profiles between the same or different biological states obtained from different sources. The pipeline modules are an integration of various open-source packages, a few of which are modified for extended functionality. The main modules include rank rank hypergeometric overlap, enriched rank rank hypergeometric overlap and distance calculations. Additionally, preprocessing steps such as merging differential expression profiles of multiple independent studies can be added before running the main modules. Output plots show the strength, pattern, and trends among complete differential expression profiles. In this paper, we describe the various modules and functionalities of the developed pipeline. We also present a case study that demonstrates how the pipeline can be used for the comparison of differential expression profiles obtained from multiple platforms’ data of the Gene Expression Omnibus. Using these comparisons, we investigate gene expression patterns in kidney and lung cancers. Full article

(This article belongs to the Special Issue Data Analysis and Integration in Cancer Research)

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19 pages, 2254 KiB

Open AccessReview

The Role of Immune Cells and Cytokines in Intestinal Wound Healing

by Xiang Xue and Daniel M. Falcon

Int. J. Mol. Sci. 2019, 20(23), 6097; https://doi.org/10.3390/ijms20236097 - 3 Dec 2019

Cited by 60 | Viewed by 9667

Abstract

Intestinal wound healing is a complicated process that not only involves epithelial cells but also immune cells. In this brief review, we will focus on discussing the contribution and regulation of four major immune cell types (neutrophils, macrophages, regulatory T cells, and innate [...] Read more.

Intestinal wound healing is a complicated process that not only involves epithelial cells but also immune cells. In this brief review, we will focus on discussing the contribution and regulation of four major immune cell types (neutrophils, macrophages, regulatory T cells, and innate lymphoid cells) and four cytokines (interleukin-10, tumor necrosis factor alpha, interleukin-6, and interleukin-22) to the wound repair process in the gut. Better understanding of these immune factors will be important for developing novel targeted therapy. Full article

(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)

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14 pages, 2817 KiB

Open AccessArticle

OsMSR3, a Small Heat Shock Protein, Confers Enhanced Tolerance to Copper Stress in Arabidopsis thaliana

by Yanchun Cui, Manling Wang, Xuming Yin, Guoyun Xu, Shufeng Song, Mingjuan Li, Kai Liu and Xinjie Xia

Int. J. Mol. Sci. 2019, 20(23), 6096; https://doi.org/10.3390/ijms20236096 - 3 Dec 2019

Cited by 31 | Viewed by 4536

Abstract

Copper is a mineral element essential for the normal growth and development of plants; however, excessive levels can severely affect plant growth and development. Oryza sativa L. multiple stress-responsive gene 3 (OsMSR3) is a small, low-molecular-weight heat shock protein (HSP) gene. A previous [...] Read more.

Copper is a mineral element essential for the normal growth and development of plants; however, excessive levels can severely affect plant growth and development. Oryza sativa L. multiple stress-responsive gene 3 (OsMSR3) is a small, low-molecular-weight heat shock protein (HSP) gene. A previous study has shown that OsMSR3 expression improves the tolerance of Arabidopsis to cadmium stress. However, the role of OsMSR3 in the Cu stress response of plants remains unclear, and, thus, this study aimed to elucidate this phenomenon in Arabidopsis thaliana, to further understand the role of small HSPs (sHSPs) in heavy metal resistance in plants. Under Cu stress, transgenic A. thaliana expressing OsMSR3 showed higher tolerance to Cu, longer roots, higher survival rates, biomass, and relative water content, and accumulated more Cu, abscisic acid (ABA), hydrogen peroxide, chlorophyll, carotenoid, superoxide dismutase, and peroxidase than wild-type plants did. Moreover, OsMSR3 expression in A. thaliana increased the expression of antioxidant-related and ABA-responsive genes. Collectively, our findings suggest that OsMSR3 played an important role in regulating Cu tolerance in plants and improved their tolerance to Cu stress through enhanced activation of antioxidative defense mechanisms and positive regulation of ABA-responsive gene expression. Full article

(This article belongs to the Special Issue Heavy Metals Accumulation, Toxicity and Detoxification in Plants)

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15 pages, 4231 KiB

Open AccessArticle

Bioinformatics Analysis of the Lipoxygenase Gene Family in Radish (Raphanus sativus) and Functional Characterization in Response to Abiotic and Biotic Stresses

by Jinglei Wang, Tianhua Hu, Wuhong Wang, Haijiao Hu, Qingzhen Wei, Xiaochun Wei and Chonglai Bao

Int. J. Mol. Sci. 2019, 20(23), 6095; https://doi.org/10.3390/ijms20236095 - 3 Dec 2019

Cited by 19 | Viewed by 4357

Abstract

Lipoxygenases (LOXs) are non-heme iron-containing dioxygenases involved in many developmental and stress-responsive processes in plants. However, little is known about the radish LOX gene family members and their functions in response to biotic and abiotic stresses. In this study, we completed a genome-wide [...] Read more.

Lipoxygenases (LOXs) are non-heme iron-containing dioxygenases involved in many developmental and stress-responsive processes in plants. However, little is known about the radish LOX gene family members and their functions in response to biotic and abiotic stresses. In this study, we completed a genome-wide analysis and expression profiling of RsLOX genes under abiotic and biotic stress conditions. We identified 11 RsLOX genes, which encoded conserved domains, and classified them in 9-LOX and 13-LOX categories according to their phylogenetic relationships. The characteristic structural features of 9-LOX and 13-LOX genes and the encoded protein domains as well as their evolution are presented herein. A qRT-PCR analysis of RsLOX expression levels in the roots under simulated drought, salinity, heat, and cold stresses, as well as in response to a Plasmodiophora brassicae infection, revealed three tandem-clustered RsLOX genes that are involved in responses to various environmental stresses via the jasmonic acid pathway. Our findings provide insights into the evolution and potential biological roles of RsLOXs related to the adaptation of radish to stress conditions. Full article

(This article belongs to the Special Issue Mapping Abiotic Stress-Tolerance Genes in Plants)

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20 pages, 504 KiB

Open AccessReview

microRNAs Tune Oxidative Stress in Cancer Therapeutic Tolerance and Resistance

by Wen Cai Zhang

Int. J. Mol. Sci. 2019, 20(23), 6094; https://doi.org/10.3390/ijms20236094 - 3 Dec 2019

Cited by 19 | Viewed by 4903

Abstract

Relapsed disease following first-line therapy remains one of the central problems in cancer management, including chemotherapy, radiotherapy, growth factor receptor-based targeted therapy, and immune checkpoint-based immunotherapy. Cancer cells develop therapeutic resistance through both intrinsic and extrinsic mechanisms including cellular heterogeneity, drug tolerance, bypassing [...] Read more.

Relapsed disease following first-line therapy remains one of the central problems in cancer management, including chemotherapy, radiotherapy, growth factor receptor-based targeted therapy, and immune checkpoint-based immunotherapy. Cancer cells develop therapeutic resistance through both intrinsic and extrinsic mechanisms including cellular heterogeneity, drug tolerance, bypassing alternative signaling pathways, as well as the acquisition of new genetic mutations. Reactive oxygen species (ROSs) are byproducts originated from cellular oxidative metabolism. Recent discoveries have shown that a disabled antioxidant program leads to therapeutic resistance in several types of cancers. ROSs are finely tuned by dysregulated microRNAs, and vice versa. However, mechanisms of a crosstalk between ROSs and microRNAs in regulating therapeutic resistance are not clear. Here, we summarize how the microRNA–ROS network modulates cancer therapeutic tolerance and resistance and direct new vulnerable targets against drug tolerance and resistance for future applications. Full article

(This article belongs to the Special Issue Crosstalk between MicroRNA and Oxidative Stress in Physiology and Pathology)

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17 pages, 6514 KiB

Open AccessArticle

Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells

by Hui Cao, Qingling Jia, Li Yan, Chuan Chen, Sanli Xing and Dingzhu Shen

Int. J. Mol. Sci. 2019, 20(23), 6093; https://doi.org/10.3390/ijms20236093 - 3 Dec 2019

Cited by 112 | Viewed by 9831

Abstract

Objective: To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. Methods: An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or [...] Read more.

Objective: To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. Methods: An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a CCK-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-β-gal (senescence-associated β-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot. Results: Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects. Conclusion: Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 636 KiB

Open AccessReview

DNA Oxidation and Excision Repair Pathways

by Tae-Hee Lee and Tae-Hong Kang

Int. J. Mol. Sci. 2019, 20(23), 6092; https://doi.org/10.3390/ijms20236092 - 3 Dec 2019

Cited by 62 | Viewed by 18041

Abstract

The physiological impact of the aberrant oxidation products on genomic DNA were demonstrated by embryonic lethality or the cancer susceptibility and/or neurological symptoms of animal impaired in the base excision repair (BER); the major pathway to maintain genomic integrity against non-bulky DNA oxidation. [...] Read more.

The physiological impact of the aberrant oxidation products on genomic DNA were demonstrated by embryonic lethality or the cancer susceptibility and/or neurological symptoms of animal impaired in the base excision repair (BER); the major pathway to maintain genomic integrity against non-bulky DNA oxidation. However, growing evidence suggests that other DNA repair pathways or factors that are not primarily associated with the classical BER pathway are also actively involved in the mitigation of oxidative assaults on the genomic DNA, according to the corresponding types of DNA oxidation. Among others, factors dedicated to lesion recognition in the nucleotide excision repair (NER) pathway have been shown to play eminent roles in the process of lesion recognition and stimulation of the enzyme activity of some sets of BER factors. Besides, substantial bulky DNA oxidation can be preferentially removed by a canonical NER mechanism; therefore, loss of function in the NER pathway shares common features arising from BER defects, including cancer predisposition and neurological disorders, although NER defects generally are nonlethal. Here we discuss recent achievements for delineating newly arising roles of NER lesion recognition factors to facilitate the BER process, and cooperative works of BER and NER pathways in response to the genotoxic oxidative stress. Full article

(This article belongs to the Special Issue DNA Damage, Oxidative Stress and Related Metabolic By-Products in Cancer and Environmental Studies)

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16 pages, 3308 KiB

Open AccessArticle

Multifocal Signal Modulation Therapy by Celecoxib: A Strategy for Managing Castration-Resistant Prostate Cancer

by Roberto Benelli, Paola Barboro, Delfina Costa, Simonetta Astigiano, Ottavia Barbieri, Matteo Capaia, Alessandro Poggi and Nicoletta Ferrari

Int. J. Mol. Sci. 2019, 20(23), 6091; https://doi.org/10.3390/ijms20236091 - 3 Dec 2019

Cited by 11 | Viewed by 3773

Abstract

Background: Prostate cancer (PCa) is a significant health concern throughout the world. Standard therapy for advanced disease consists of anti-androgens, however, almost all prostate tumors become castration resistant (CRPC). Progression from androgen-sensitive PCa to CRPC is promoted by inflammatory signaling through cyclooxygenase-2 (COX-2) [...] Read more.

Background: Prostate cancer (PCa) is a significant health concern throughout the world. Standard therapy for advanced disease consists of anti-androgens, however, almost all prostate tumors become castration resistant (CRPC). Progression from androgen-sensitive PCa to CRPC is promoted by inflammatory signaling through cyclooxygenase-2 (COX-2) expression and ErbB family receptors/AKT activation, compensating androgen receptor inactivity. Methods: Making use of CRPC cell lines, we investigated the effects of the anti-inflammatory drug celecoxib. Biochemical data obtained using immunoblotting, enzyme-linked immunosorbent assay (ELISA), invasion, and xenografts were further integrated by bioinformatic analyses. Results: Celecoxib reduced cell growth and induced apoptosis through AKT blockade, cleavage of poly (ADP-ribose) polymerase-1 (PARP-1), and proteasomal degradation of the anti-apoptotic protein Mcl-1. Epidermal growth factor receptor (EGFR), ErbB2, and ErbB3 degradation, and heterogeneous nuclear ribonucleoprotein K (hnRNP K) downregulation, further amplified the inhibition of androgen signaling. Celecoxib reduced the invasive phenotype of CRPC cells by modulating NF-κB activity and reduced tumor growth in mice xenografts when administered in association with the anti-EGFR receptor antibody cetuximab. Bioinformatic analyses on human prostate cancer datasets support the relevance of these pathways in PCa progression. Conclusions: Signaling nodes at the intersection of pathways implicated in PCa progression are simultaneously modulated by celecoxib treatment. In combination therapies with cetuximab, celecoxib could represent a novel therapeutic strategy to curb signal transduction during CRPC progression. Full article

(This article belongs to the Special Issue Cyclooxygenase and Cancer: Fundamental Molecular Investigations)

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20 pages, 6040 KiB

Open AccessArticle

Disclosure of the Molecular Mechanism of Wheat Leaf Spot Disease Caused by Bipolaris sorokiniana through Comparative Transcriptome and Metabolomics Analysis

by Wei Ye, Taomei Liu, Weimin Zhang, Saini Li, Muzi Zhu, Haohua Li, Yali Kong and Liqiong Xu

Int. J. Mol. Sci. 2019, 20(23), 6090; https://doi.org/10.3390/ijms20236090 - 3 Dec 2019

Cited by 27 | Viewed by 4611

Abstract

Wheat yield is greatly reduced because of the occurrence of leaf spot diseases. Bipolaris sorokiniana is the main pathogenic fungus in leaf spot disease. In this study, B. sorokiniana from wheat leaf (W-B. sorokiniana) showed much stronger pathogenicity toward wheat than [...] Read more.

Wheat yield is greatly reduced because of the occurrence of leaf spot diseases. Bipolaris sorokiniana is the main pathogenic fungus in leaf spot disease. In this study, B. sorokiniana from wheat leaf (W-B. sorokiniana) showed much stronger pathogenicity toward wheat than endophytic B. sorokiniana from Pogostemon cablin (P-B. sorokiniana). The transcriptomes and metabolomics of the two B. sorokiniana strains and transcriptomes of B. sorokiniana-infected wheat leaves were comparatively analyzed. In addition, the expression levels of unigenes related to pathogenicity, toxicity, and cell wall degradation were predicted and validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Results indicated that pathogenicity-related genes, especially the gene encoding loss-of-pathogenicity B (LopB) protein, cell wall-degrading enzymes (particularly glycosyl hydrolase-related genes), and killer and Ptr necrosis toxin-producing related unigenes in the W-B. sorokiniana played important roles in the pathogenicity of W-B. sorokiniana toward wheat. The down-regulation of cell wall protein, photosystem peptide, and rubisco protein suggested impairment of the phytosynthetic system and cell wall of B. sorokiniana-infected wheat. The up-regulation of hydrolase inhibitor, NAC (including NAM, ATAF1 and CUC2) transcriptional factor, and peroxidase in infected wheat tissues suggests their important roles in the defensive response of wheat to W-B. sorokiniana. This is the first report providing a comparison of the transcriptome and metabolome between the pathogenic and endophytic B. sorokiniana strains, thus providing a molecular clue for the pathogenic mechanism of W-B. sorokiniana toward wheat and wheat’s defensive response mechanism to W-B. sorokiniana. Our study could offer molecular clues for controlling the hazard of leaf spot and root rot diseases in wheat, thus improving wheat yield in the future. Full article

(This article belongs to the Special Issue Wheat and Barley: Acclimatization to Abiotic and Biotic Stress)

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22 pages, 1416 KiB

Open AccessReview

Molecular Characterization of XX Maleness

by Romina P. Grinspon and Rodolfo A. Rey

Int. J. Mol. Sci. 2019, 20(23), 6089; https://doi.org/10.3390/ijms20236089 - 3 Dec 2019

Cited by 23 | Viewed by 8385

Abstract

Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies [...] Read more.

Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness. Full article

(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)

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15 pages, 1768 KiB

Open AccessReview

siRNA Conjugated Nanoparticles—A Next Generation Strategy to Treat Lung Cancer

by Rasha Itani and Achraf Al Faraj

Int. J. Mol. Sci. 2019, 20(23), 6088; https://doi.org/10.3390/ijms20236088 - 3 Dec 2019

Cited by 74 | Viewed by 8331

Abstract

Despite major progress in both therapeutic and diagnostic techniques, lung cancer is still considered the leading cause of cancer mortality in the world due to the ineffectiveness of the classical treatments used nowadays. Luckily, the discovery of small interfering RNA (siRNA) planted hope [...] Read more.

Despite major progress in both therapeutic and diagnostic techniques, lung cancer is still considered the leading cause of cancer mortality in the world due to the ineffectiveness of the classical treatments used nowadays. Luckily, the discovery of small interfering RNA (siRNA) planted hope in the hearts of scientists and patients worldwide as a new breakthrough in the world of oncology and a robust tool for finally curing cancer. However, the valuable siRNA must be protected and preserved to ensure the effectiveness of this gene therapy, thus nanoparticles are gaining more attention than previous years as the optimal carriers for this fragile molecule. siRNA-loaded nanoparticles are being extensively investigated to find the appropriate formulation, combination, and delivery route with one objective in mind—successfully overcoming all possible limitations shown in clinical studies and making full use of this novel technique to become the next generation treatment to wipe out many chronic diseases, including cancer. In this review, the benefits of using siRNA and nanoparticles in lung cancer treatment will be globally reviewed before discussing why and how nanoparticles and siRNA can be combined to achieve an efficient treatment of lung cancer for prospective clinical applications. Full article

(This article belongs to the Special Issue Nano-Strategies: The Future Medicine for Fighting Cancer Progression and Drug Resistance)

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15 pages, 1525 KiB

Open AccessArticle

Anti-Inflammatory and Antioxidant Properties of Dehydrated Potato-Derived Bioactive Compounds in Intestinal Cells

by Manuela Giovanna Basilicata, Giacomo Pepe, Shara Francesca Rapa, Fabrizio Merciai, Carmine Ostacolo, Michele Manfra, Veronica Di Sarno, Giuseppina Autore, Daniela De Vita, Stefania Marzocco and Pietro Campiglia

Int. J. Mol. Sci. 2019, 20(23), 6087; https://doi.org/10.3390/ijms20236087 - 3 Dec 2019

Cited by 25 | Viewed by 4830

Abstract

Inflammation and oxidative stress are always more recognized as responsible for chronic disease at the intestinal level. Currently, a growing interest is addressed to the discovery of diet-derived products which have anti-inflammatory and antioxidant properties. This work aims to characterize the pharmacological potential [...] Read more.

Inflammation and oxidative stress are always more recognized as responsible for chronic disease at the intestinal level. Currently, a growing interest is addressed to the discovery of diet-derived products which have anti-inflammatory and antioxidant properties. This work aims to characterize the pharmacological potential of dehydrated potatoes. For this purpose, a simulated gastrointestinal digestion was carried out. The bioaccessible peptides were fractionated on the basis of their molecular weight and tested on intestinal epithelial cells (IEC-6) under oxidative and inflammatory conditions. Our results demonstrate that the tested peptide fractions were able to significantly inhibit tumor necrosis factor-α release and cycloxygenase-2 and inducible nitric oxide synthase expression. The tested peptides also showed significant antioxidant activity, being able to both reduce reactive oxygen species (ROS) release, also from mitochondria, and nitrotyrosine formation, and increase the antioxidant response by heme oxygenase-1 and superoxide dismutase expression. Moreover, the peptide fractions were able to significantly increase the wound repair in IEC-6. The obtained results indicate the anti-inflammatory and antioxidant potential of dehydrated potatoes at the intestinal level. Full article

(This article belongs to the Special Issue Targeted Protection of Bioactive Compounds to Mitochondria)

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15 pages, 2804 KiB

Open AccessArticle

Ginsenosides Rb1 and Rg1 Protect Primary Cultured Astrocytes against Oxygen-Glucose Deprivation/Reoxygenation-Induced Injury via Improving Mitochondrial Function

by Meng Xu, Qing Ma, Chunlan Fan, Xue Chen, Huiming Zhang and Minke Tang

Int. J. Mol. Sci. 2019, 20(23), 6086; https://doi.org/10.3390/ijms20236086 - 3 Dec 2019

Cited by 41 | Viewed by 4112

Abstract

This study aimed to evaluate whether ginsenosides Rb1 (20-S-protopanaxadiol aglycon) and Rg1 (20-S-protopanaxatriol aglycon) have mitochondrial protective effects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in primary mouse astrocytes and to explore the mechanisms involved. The OGD/R model was used to mimic the pathological process [...] Read more.

This study aimed to evaluate whether ginsenosides Rb1 (20-S-protopanaxadiol aglycon) and Rg1 (20-S-protopanaxatriol aglycon) have mitochondrial protective effects against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in primary mouse astrocytes and to explore the mechanisms involved. The OGD/R model was used to mimic the pathological process of cerebral ischemia-reperfusion in vitro. Astrocytes were treated with normal conditions, OGD/R, OGD/R plus Rb1, or OGD/R plus Rg1. Cell viability was measured to evaluate the cytotoxicity of Rb1 and Rg1. Intracellular reactive oxygen species (ROS) and catalase (CAT) were detected to evaluate oxidative stress. The mitochondrial DNA (mtDNA) copy number and mitochondrial membrane potential (MMP) were measured to evaluate mitochondrial function. The activities of the mitochondrial respiratory chain (MRC) complexes I–V and the level of cellular adenosine triphosphate (ATP) were measured to evaluate oxidative phosphorylation (OXPHOS) levels. Cell viability was significantly decreased in the OGD/R group compared to the control group. Rb1 or Rg1 administration significantly increased cell viability. Moreover, OGD/R caused a significant increase in ROS formation and, subsequently, it decreased the activity of CAT and the mtDNA copy number. At the same time, treatment with OGD/R depolarized the MMP in the astrocytes. Rb1 or Rg1 administration reduced ROS production, increased CAT activity, elevated the mtDNA content, and attenuated the MMP depolarization. In addition, Rb1 or Rg1 administration increased the activities of complexes I, II, III, and V and elevated the level of ATP, compared to those in the OGD/R groups. Rb1 and Rg1 have different chemical structures, but exert similar protective effects against astrocyte damage induced by OGD/R. The mechanism may be related to improved efficiency of mitochondrial oxidative phosphorylation and the reduction in ROS production in cultured astrocytes. Full article

(This article belongs to the Section Molecular Pharmacology)

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11 pages, 2282 KiB

Open AccessArticle

Azathioprine Has a Deleterious Effect on the Bone Health of Mice with DSS-Induced Inflammatory Bowel Disease

by Stephanie Morgan, Kirsty M. Hooper, Elspeth M. Milne, Colin Farquharson, Craig Stevens and Katherine A. Staines

Int. J. Mol. Sci. 2019, 20(23), 6085; https://doi.org/10.3390/ijms20236085 - 3 Dec 2019

Cited by 15 | Viewed by 4480

Abstract

Patients with inflammatory bowel disease (IBD) often present poor bone health and are 40% more at risk of bone fracture. Studies have implicated autophagy in IBD pathology and drugs used to treat IBD stimulate autophagy in varying degrees, however, their effect on the [...] Read more.

Patients with inflammatory bowel disease (IBD) often present poor bone health and are 40% more at risk of bone fracture. Studies have implicated autophagy in IBD pathology and drugs used to treat IBD stimulate autophagy in varying degrees, however, their effect on the skeleton is currently unknown. Here, we have utilised the dextran sulphate sodium (DSS) model of colitis in mice to examine the effects of the thiopurine drug azathioprine on the skeleton. Ten-week-old male mice (n = 6/group) received 3.0% DSS in their drinking water for four days, followed by a 14-day recovery period. Mice were treated with 10 mg/kg/day azathioprine or vehicle control. Histopathological analysis of the colon from DSS mice revealed significant increases in scores for inflammation severity, extent, and crypt damage (p < 0.05). Azathioprine provided partial protection to the colon, as reflected by a lack of significant difference in crypt damage and tissue regeneration with DSS treatment. MicroCT of vehicle-treated DSS mice revealed azathioprine treatment had a significant detrimental effect on the trabecular bone microarchitecture, independent of DSS treatment. Specifically, significant decreases were observed in bone volume/tissue volume (p < 0.01), and trabecular number (p < 0.05), with a concurrent significant increase in trabecular pattern factor (p < 0.01). Immunohistochemical labelling for LC3 revealed azathioprine to induce autophagy in the bone marrow. Together these data suggest that azathioprine treatment may have a deleterious effect on IBD patients who may already be at increased risk of osteoporotic bone fractures and thus will inform on future treatment strategies for patient stratification. Full article

(This article belongs to the Special Issue Bone Growth and Osteoporosis)

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16 pages, 2721 KiB

Open AccessArticle

MicroRNA-451 and Genistein Ameliorate Nonalcoholic Steatohepatitis in Mice

by Mailin Gan, Linyuan Shen, Yuan Fan, Ya Tan, Ting Zheng, Guoqing Tang, Lili Niu, Ye Zhao, Lei Chen, Dongmei Jiang, Xuewei Li, Shunhua Zhang and Li Zhu

Int. J. Mol. Sci. 2019, 20(23), 6084; https://doi.org/10.3390/ijms20236084 - 3 Dec 2019

Cited by 14 | Viewed by 3699

Abstract

Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role [...] Read more.

Effective, targeted therapy for chronic liver disease nonalcoholic steatohepatitis (NASH) is imminent. MicroRNAs (miRNAs) are a potential therapeutic target, and natural products that regulate miRNA expression may be a safe and effective treatment strategy for liver disease. Here, we investigated the functional role of miR-451 and the therapeutic effects of genistein in the NASH mouse model. MiR-451 was downregulated in various types of liver inflammation, and subsequent experiments showed that miR-451 regulates liver inflammation via IL1β. Genistein is a phytoestrogen with anti-inflammatory and anti-oxidant effects. Interestingly, we found that the anti-inflammatory effects of genistein were related to miR-451 and was partially antagonized by the miR-451 inhibitor. MiR-451 overexpression or genistein treatment inhibited IL1β expression and inflammation. Taken together, this study shows that miR-451 has a protective effect on hepatic inflammation, and genistein can be used as a natural promoter of miR-451 to ameliorate NASH. Full article

(This article belongs to the Special Issue Innovative Molecular Target and Therapeutic Approaches in Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis (NAFLD/NASH))

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19 pages, 3526 KiB

Open AccessArticle

Dual RNA Sequencing of Vitis vinifera during Lasiodiplodia theobromae Infection Unveils Host–Pathogen Interactions

by Micael F. M. Gonçalves, Rui B. Nunes, Laurentijn Tilleman, Yves Van de Peer, Dieter Deforce, Filip Van Nieuwerburgh, Ana C. Esteves and Artur Alves

Int. J. Mol. Sci. 2019, 20(23), 6083; https://doi.org/10.3390/ijms20236083 - 3 Dec 2019

Cited by 31 | Viewed by 5233

Abstract

Lasiodiplodia theobromae is one of the most aggressive agents of the grapevine trunk disease Botryosphaeria dieback. Through a dual RNA-sequencing approach, this study aimed to give a broader perspective on the infection strategy deployed by L. theobromae, while understanding grapevine response. Approximately [...] Read more.

Lasiodiplodia theobromae is one of the most aggressive agents of the grapevine trunk disease Botryosphaeria dieback. Through a dual RNA-sequencing approach, this study aimed to give a broader perspective on the infection strategy deployed by L. theobromae, while understanding grapevine response. Approximately 0.05% and 90% of the reads were mapped to the genomes of L. theobromae and Vitis vinifera, respectively. Over 2500 genes were significantly differentially expressed in infected plants after 10 dpi, many of which are involved in the inducible defense mechanisms of grapevines. Gene expression analysis showed changes in the fungal metabolism of phenolic compounds, carbohydrate metabolism, transmembrane transport, and toxin synthesis. These functions are related to the pathogenicity mechanisms involved in plant cell wall degradation and fungal defense against antimicrobial substances produced by the host. Genes encoding for the degradation of plant phenylpropanoid precursors were up-regulated, suggesting that the fungus could evade the host defense response using the phenylpropanoid pathway. The up-regulation of many distinct components of the phenylpropanoid pathway in plants supports this hypothesis. Moreover, genes related to phytoalexin biosynthesis, hormone metabolism, cell wall modification enzymes, and pathogenesis-related proteins seem to be involved in the host responses observed. This study provides additional insights into the molecular mechanisms of L. theobromae and V. vinifera interactions. Full article

(This article belongs to the Special Issue Host–Pathogen Interaction)

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19 pages, 3846 KiB

Open AccessArticle

Gel-Based Proteomics of Clinical Samples Identifies Potential Serological Biomarkers for Early Detection of Colorectal Cancer

by Stine F. Thorsen, Irina Gromova, Ib J. Christensen, Simon Fredriksson, Claus L. Andersen, Hans J. Nielsen, Jan Stenvang and José M.A. Moreira

Int. J. Mol. Sci. 2019, 20(23), 6082; https://doi.org/10.3390/ijms20236082 - 2 Dec 2019

Cited by 8 | Viewed by 4085

Abstract

The burden of colorectal cancer (CRC) is considerable—approximately 1.8 million people are diagnosed each year with CRC and of these about half will succumb to the disease. In the case of CRC, there is strong evidence that an early diagnosis leads to a [...] Read more.

The burden of colorectal cancer (CRC) is considerable—approximately 1.8 million people are diagnosed each year with CRC and of these about half will succumb to the disease. In the case of CRC, there is strong evidence that an early diagnosis leads to a better prognosis, with metastatic CRC having a 5-year survival that is only slightly greater than 10% compared with up to 90% for stage I CRC. Clearly, biomarkers for the early detection of CRC would have a major clinical impact. We implemented a coherent gel-based proteomics biomarker discovery platform for the identification of clinically useful biomarkers for the early detection of CRC. Potential protein biomarkers were identified by a 2D gel-based analysis of a cohort composed of 128 CRC and site-matched normal tissue biopsies. Potential biomarkers were prioritized and assays to quantitatively measure plasma expression of the candidate biomarkers were developed. Those biomarkers that fulfilled the preset criteria for technical validity were validated in a case-control set of plasma samples, including 70 patients with CRC, adenomas, or non-cancer diseases and healthy individuals in each group. We identified 63 consistently upregulated polypeptides (factor of four-fold or more) in our proteomics analysis. We selected 10 out of these 63 upregulated polypeptides, and established assays to measure the concentration of each one of the ten biomarkers in plasma samples. Biomarker levels were analyzed in plasma samples from healthy individuals, individuals with adenomas, CRC patients, and patients with non-cancer diseases and we identified one protein, tropomyosin 3 (Tpm3) that could discriminate CRC at a significant level (p = 0.0146). Our results suggest that at least one of the identified proteins, Tpm3, could be used as a biomarker in the early detection of CRC, and further studies should provide unequivocal evidence for the real-life clinical validity and usefulness of Tpm3. Full article

(This article belongs to the Special Issue Proteomics and Nucleotide Profiling as Tools for Biomarker and Drug Target Discovery)

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15 pages, 1995 KiB

Open AccessArticle

Thermoresponsive Catechol Based-Polyelectrolyte Complex Coatings for Controlled Release of Bortezomib

by Berthold Reis, David Vehlow, Tarik Rust, Dirk Kuckling and Martin Müller

Int. J. Mol. Sci. 2019, 20(23), 6081; https://doi.org/10.3390/ijms20236081 - 2 Dec 2019

Cited by 6 | Viewed by 3529

Abstract

To overcome the high relapse rate of multiple myeloma (MM), a drug delivery coating for functionalization of bone substitution materials (BSM) is reported based on adhesive, catechol-containing and stimuli-responsive polyelectrolyte complexes (PECs). This system is designed to deliver the MM drug bortezomib (BZM) [...] Read more.

To overcome the high relapse rate of multiple myeloma (MM), a drug delivery coating for functionalization of bone substitution materials (BSM) is reported based on adhesive, catechol-containing and stimuli-responsive polyelectrolyte complexes (PECs). This system is designed to deliver the MM drug bortezomib (BZM) directly to the anatomical site of action. To establish a gradual BZM release, the naturally occurring caffeic acid (CA) is coupled oxidatively to form poly(caffeic acid) (PCA), which is used as a polyanion for complexation. The catechol functionalities within the PCA are particularly suitable to form esters with the boronic acid group of the BZM, which are then cleaved in the body fluid to administer the drug. To achieve a more thorough control of the release, the thermoresponsive poly(N-isoproplyacrylamide-co-dimethylaminoethylmethacrylate) (P(NIPAM-co-DMAEMA)) was used as a polycation. Using turbidity measurements, it was proven that the lower critical solution temperature (LCST) character of this polymer was transferred to the PECs. Further special temperature dependent attenuated total reflection infrared spectroscopy (ATR-FTIR) showed that coatings formed by PEC immobilization exhibit a similar thermoresponsive performance. By loading the coatings with BZM and studying the release in a model system, via UV/Vis it was observed, that both aims, the retardation and the stimuli control of the release, were achieved. Full article

(This article belongs to the Special Issue Wet Adhesion: New Chemistries, Models and Translation to Materials)

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12 pages, 1212 KiB

Open AccessReview

Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

by Kaye J. Williams and Roben G. Gieling

Int. J. Mol. Sci. 2019, 20(23), 6080; https://doi.org/10.3390/ijms20236080 - 2 Dec 2019

Cited by 28 | Viewed by 4695

Abstract

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal [...] Read more.

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors, II)

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21 pages, 1667 KiB

Open AccessReview

The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids

by Keith A. Kwan Cheung, Hassendrini Peiris, Geoffrey Wallace, Olivia J. Holland and Murray D. Mitchell

Int. J. Mol. Sci. 2019, 20(23), 6079; https://doi.org/10.3390/ijms20236079 - 2 Dec 2019

Cited by 44 | Viewed by 10951

Abstract

Epilepsy is a neurological disorder that affects approximately 50 million people worldwide. There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are [...] Read more.

Epilepsy is a neurological disorder that affects approximately 50 million people worldwide. There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown. Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies. We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment. There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives)

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9 pages, 737 KiB

Open AccessReview

Multipotent Neurotrophic Effects of Hepatocyte Growth Factor in Spinal Cord Injury

by Kentaro Yamane, Haruo Misawa, Tomoyuki Takigawa, Yoshihiro Ito, Toshifumi Ozaki and Akihiro Matsukawa

Int. J. Mol. Sci. 2019, 20(23), 6078; https://doi.org/10.3390/ijms20236078 - 2 Dec 2019

Cited by 13 | Viewed by 5050

Abstract

Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies [...] Read more.

Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies have been conducted in the field of SCI; however, no satisfactory treatment has been established to date. Hepatocyte growth factor (HGF) is one of the neurotrophic growth factors and has been listed as a candidate medicine for SCI treatment. The highlighted effects of HGF on neural regeneration are associated with its anti-inflammatory and anti-fibrotic activities. Moreover, HGF exerts positive effects on transplanted stem cell differentiation into neurons. This paper reviews the mechanisms underlying the therapeutic effects of HGF in SCI recovery, and introduces recent advances in the clinical applications of HGF therapy. Full article

(This article belongs to the Special Issue Hepatocyte Growth Factor (HGF), II)

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15 pages, 3235 KiB

Open AccessArticle

TASK-3 Gene Knockdown Dampens Invasion and Migration and Promotes Apoptosis in KATO III and MKN-45 Human Gastric Adenocarcinoma Cell Lines

by Rocio Cikutović-Molina, Andres A. Herrada, Wendy González, Nelson Brown and Leandro Zúñiga

Int. J. Mol. Sci. 2019, 20(23), 6077; https://doi.org/10.3390/ijms20236077 - 2 Dec 2019

Cited by 20 | Viewed by 4295

Abstract

Incidence and mortality of gastric cancer is increasing worldwide, in part, because of the lack of new therapeutic targets to treat this disease. Different types of ion channels participate in the hallmarks of cancer. In this context, ion channels are known to exert [...] Read more.

Incidence and mortality of gastric cancer is increasing worldwide, in part, because of the lack of new therapeutic targets to treat this disease. Different types of ion channels participate in the hallmarks of cancer. In this context, ion channels are known to exert control over the cell cycle, mechanisms that support survival, angiogenesis, migration, and cell invasion. In particular, TASK-3 (KCNK9), a member of the K2P potassium channel family, has attracted much interest because of its oncogenic properties. However, despite multiple lines of evidence linking TASK-3 to tumorigenesis in various types of cancer, its relationship with gastric cancer has not been fully examined. Therefore, we set out to assess the effect of TASK-3 gene knockdown on KATO III and MKN-45 human gastric adenocarcinoma cell lines by using a short hairpin RNA (shRNA)-mediated knockdown. Our results demonstrate that knocking down TASK-3 reduces cell proliferation and viability because of an increase in apoptosis without an apparent effect on cell cycle checkpoints. In addition, cell migration and invasion are reduced after knocking down TASK-3 in these cell lines. The present study highlights TASK-3 as a key protein involved in migration and cell survival in gastric cancer and corroborates its potential as a therapeutic target for gastric cancer treatment. Full article

(This article belongs to the Section Molecular Oncology)

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12 pages, 3065 KiB

Open AccessArticle

Pisidium coreanum Inhibits Multinucleated Osteoclast Formation and Prevents Estrogen-Deficient Osteoporosis

by Mun Hwan Choi, Kyunghee Lee, Mi Yeong Kim, Hong-In Shin and Daewon Jeong

Int. J. Mol. Sci. 2019, 20(23), 6076; https://doi.org/10.3390/ijms20236076 - 2 Dec 2019

Cited by 6 | Viewed by 3383

Abstract

Mollusks have served as important sources of human food and medicine for a long time. Raw Pisidium coreanum, a freshwater bivalve of the phylum Mollusca, is used in traditional therapies in parts of Asia. However, the therapeutic effects of Pisidium coreanum on [...] Read more.

Mollusks have served as important sources of human food and medicine for a long time. Raw Pisidium coreanum, a freshwater bivalve of the phylum Mollusca, is used in traditional therapies in parts of Asia. However, the therapeutic effects of Pisidium coreanum on bone diseases are not known. We investigated the functional roles of Pisidium coreanum in osteoporotic bone diseases. Pisidium coreanum inhibited the differentiation of bone marrow-derived monocytic cells into mature osteoclasts in vitro. The ovariectomized mice that received oral administration of Pisidium coreanum showed improvements in both trabecular and cortical bones. This preventive activity of Pisidium coreanum against bone loss was due to limited osteoclast maturation with reduced osteoclast surface extent in trabecular bone tissue. The formation of large multinucleated osteoclasts in vitro was significantly decreased in response to Pisidium coreanum, consistent with the reduced expression levels of osteoclast markers and fusion-related genes, such as NFATc1, p65, integrin αvβ3, DC-STAMP, OC-STAMP, Atp6v0d2, FAK, CD44, and MFR. These data suggest that Pisidium coreanum inhibits osteoclast differentiation by negatively regulating the fusion of mononuclear osteoclast precursors. Thus, our data demonstrate the ability of Pisidium coreanum to effectively prevent estrogen-deficient osteoporosis through inhibition of multinucleated osteoclast formation. Full article

(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)

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Int. J. Mol. Sci., Volume 20, Issue 23 (December-1 2019) – 287 articles

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