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Volume 20
Issue 11
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Int. J. Mol. Sci., Volume 20, Issue 11 (June-1 2019) – 244 articles

Cover Story (view full-size image): The cynaroside luteolin-7-O-β-d-glucoside (LUT-7G) is able to induce keratinocyte differentiation and inhibit the proliferative effects of the IL-22/IL6 pathway in vivo in a psoriatic mouse model. Now we know that LUT-7G blocks the cell energy metabolism, depressing the glycolytic and Krebs pathways by the direct inhibition of hexokinase 2 (HEK2) activity. LUT-7G is proposed as a potential candidate for the treatment of inflammatory and proliferative diseases, and its role in HEK2 inhibition opens new perspectives in nutrition and in cancer therapy for the potential inhibition of the Warburg effect. View this paper.
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15 pages, 1630 KiB  
Review
Lysophosphatidic Acid Signaling in Diabetic Nephropathy
by Jong Han Lee, Donghee Kim, Yoon Sin Oh and Hee-Sook Jun
Int. J. Mol. Sci. 2019, 20(11), 2850; https://doi.org/10.3390/ijms20112850 - 11 Jun 2019
Cited by 47 | Viewed by 7377
Abstract
Lysophosphatidic acid (LPA) is a bioactive phospholipid present in most tissues and body fluids. LPA acts through specific LPA receptors (LPAR1 to LPAR6) coupled with G protein. LPA binds to receptors and activates multiple cellular signaling pathways, subsequently exerting various biological functions, such [...] Read more.
Lysophosphatidic acid (LPA) is a bioactive phospholipid present in most tissues and body fluids. LPA acts through specific LPA receptors (LPAR1 to LPAR6) coupled with G protein. LPA binds to receptors and activates multiple cellular signaling pathways, subsequently exerting various biological functions, such as cell proliferation, migration, and apoptosis. LPA also induces cell damage through complex overlapping pathways, including the generation of reactive oxygen species, inflammatory cytokines, and fibrosis. Several reports indicate that the LPA–LPAR axis plays an important role in various diseases, including kidney disease, lung fibrosis, and cancer. Diabetic nephropathy (DN) is one of the most common diabetic complications and the main risk factor for chronic kidney diseases, which mostly progress to end-stage renal disease. There is also growing evidence indicating that the LPA–LPAR axis also plays an important role in inducing pathological alterations of cell structure and function in the kidneys. In this review, we will discuss key mediators or signaling pathways activated by LPA and summarize recent research findings associated with DN. Full article
(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)
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19 pages, 7731 KiB  
Article
The Novel Cerato-Platanin-Like Protein FocCP1 from Fusarium oxysporum Triggers an Immune Response in Plants
by Songwei Li, Yijie Dong, Lin Li, Yi Zhang, Xiufen Yang, Hongmei Zeng, Mingwang Shi, Xinwu Pei, Dewen Qiu and Qianhua Yuan
Int. J. Mol. Sci. 2019, 20(11), 2849; https://doi.org/10.3390/ijms20112849 - 11 Jun 2019
Cited by 27 | Viewed by 4471
Abstract
Panama disease, or Fusarium wilt, the most serious disease in banana cultivation, is caused by Fusarium oxysporum f. sp. cubense (FOC) and has led to great economic losses worldwide. One effective way to combat this disease is by enhancing host plant resistance. The [...] Read more.
Panama disease, or Fusarium wilt, the most serious disease in banana cultivation, is caused by Fusarium oxysporum f. sp. cubense (FOC) and has led to great economic losses worldwide. One effective way to combat this disease is by enhancing host plant resistance. The cerato-platanin protein (CPP) family is a group of small secreted cysteine-rich proteins in filamentous fungi. CPPs as elicitors can trigger the immune system resulting in defense responses in plants. In this study, we characterized a novel cerato-platanin-like protein in the secretome of Fusarium oxysporum f. sp. cubense race 4 (FOC4), named FocCP1. In tobacco, the purified recombinant FocCP1 protein caused accumulation of reactive oxygen species (ROS), formation of necrotic reaction, deposition of callose, expression of defense-related genes, and accumulation of salicylic acid (SA) and jasmonic acid (JA) in tobacco. These results indicated that FocCP1 triggered a hypersensitive response (HR) and systemic acquired resistance (SAR) in tobacco. Furthermore, FocCP1 enhanced resistance tobacco mosaic virus (TMV) disease and Pseudomonas syringae pv. tabaci 6605 (Pst. 6605) infection in tobacco and improved banana seedling resistance to FOC4. All results provide the possibility of further research on immune mechanisms of plant and pathogen interactions, and lay a foundation for a new biological strategy of banana wilt control in the future. Full article
(This article belongs to the Section Molecular Plant Sciences)
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13 pages, 1104 KiB  
Article
Detecting Brachypodium distachyon Chromosomes Bd4 and Bd5 in MH- and X-Ray-Induced Micronuclei Using mcFISH
by Arita Kus, Joanna Szymanowska-Pułka, Jolanta Kwasniewska and Robert Hasterok
Int. J. Mol. Sci. 2019, 20(11), 2848; https://doi.org/10.3390/ijms20112848 - 11 Jun 2019
Cited by 6 | Viewed by 3497
Abstract
Micronuclei are biomarkers of genotoxic effects and chromosomal instability. They are formed when chromosome fragments or whole chromosomes fail to disjoin into daughter nuclei. We present qualitative and quantitative analyses of the involvement of specific chromosome regions of chromosomes Bd4 and Bd5 in [...] Read more.
Micronuclei are biomarkers of genotoxic effects and chromosomal instability. They are formed when chromosome fragments or whole chromosomes fail to disjoin into daughter nuclei. We present qualitative and quantitative analyses of the involvement of specific chromosome regions of chromosomes Bd4 and Bd5 in the formation of micronuclei of Brachypodium distachyon root tip cells following maleic hydrazide (MH) treatment and X-radiation. This is visualised by cytomolecular approaches using bacterial artificial chromosome (BAC)-based multicolour fluorescence in situ hybridisation (mcFISH) in combination with 5S and 25S rDNA probes. The results showed that the long arm of submetacentric chromosome Bd4 forms micronuclei at twice the frequency of its short arm, suggesting that the former is more prone to double-strand breaks (DSBs). In contrast, no difference was observed in the frequency of micronuclei derived from the long and short arms of submetacentric chromosome Bd5. Interestingly, the proximal region of the short arm of Bd5 is more prone to DSBs than its distal part. This demonstrates that 5S rDNA and 35S rDNA loci are not “hot spots” for DNA breaks after the application of these mutagens. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Plants)
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19 pages, 3492 KiB  
Article
Stabilization of Intrinsically Disordered DKK2 Protein by Fusion to RNA-Binding Domain
by Hye Min Lee, Soon Bin Kwon, Ahyun Son, Doo Hyun Kim, Kyun-Hwan Kim, Jonghyo Lim, Young-Guen Kwon, Jin Sun Kang, Byung Kyu Lee, Young Ho Byun and Baik L. Seong
Int. J. Mol. Sci. 2019, 20(11), 2847; https://doi.org/10.3390/ijms20112847 - 11 Jun 2019
Cited by 4 | Viewed by 4284
Abstract
Intrinsic disorders are a common feature of hub proteins in eukaryotic interactomes controlling the signaling pathways. The intrinsically disordered proteins (IDPs) are prone to misfolding, and maintaining their functional stability remains a major challenge in validating their therapeutic potentials. Considering that IDPs are [...] Read more.
Intrinsic disorders are a common feature of hub proteins in eukaryotic interactomes controlling the signaling pathways. The intrinsically disordered proteins (IDPs) are prone to misfolding, and maintaining their functional stability remains a major challenge in validating their therapeutic potentials. Considering that IDPs are highly enriched in RNA-binding proteins (RBPs), here we reasoned and confirmed that IDPs could be stabilized by fusion to RBPs. Dickkopf2 (DKK2), Wnt antagonist and a prototype IDP, was fused with lysyl-tRNA synthetase (LysRS), with or without the fragment crystallizable (Fc) domain of an immunoglobulin and expressed predominantly as a soluble form from a bacterial host. The functional competence was confirmed by in vitro Wnt signaling reporter and tube formation in human umbilical vein endothelial cells (HUVECs) and in vivo Matrigel plug assay. The removal of LysRS by site-specific protease cleavage prompted the insoluble aggregation, confirming that the linkage to RBP chaperones the functional competence of IDPs. While addressing to DKK2 as a key modulator for cancer and ischemic vascular diseases, our results suggest the use of RBPs as stabilizers of disordered proteinaceous materials for acquiring and maintaining the structural stability and functional competence, which would impact the druggability of a variety of IDPs from human proteome. Full article
(This article belongs to the Special Issue Protein Folding)
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14 pages, 4153 KiB  
Article
Investigation by DFT Methods of the Damage of Human Serum Albumin Including Amino Acid Derivative Schiff Base Zn(II) Complexes by IR-FEL Irradiation
by Yuika Onami, Ryousuke Koya, Takayasu Kawasaki, Hiroki Aizawa, Ryo Nakagame, Yoshito Miyagawa, Tomoyuki Haraguchi, Takashiro Akitsu, Koichi Tsukiyama and Mauricio A. Palafox
Int. J. Mol. Sci. 2019, 20(11), 2846; https://doi.org/10.3390/ijms20112846 - 11 Jun 2019
Cited by 11 | Viewed by 4454
Abstract
An infrared free electron laser (IR-FEL) can decompose aggregated proteins by excitation of vibrational bands. In this study, we prepared hybrid materials of protein (human serum albumin; HSA) including several new Schiff base Zn(II) complexes incorporating amino acid (alanine and valine) or dipeptide [...] Read more.
An infrared free electron laser (IR-FEL) can decompose aggregated proteins by excitation of vibrational bands. In this study, we prepared hybrid materials of protein (human serum albumin; HSA) including several new Schiff base Zn(II) complexes incorporating amino acid (alanine and valine) or dipeptide (gly-gly) derivative moieties, which were synthesized and characterized with UV-vis, circular dichroism (CD), and IR spectra. Density functional theory (DFT) and time dependent DFT (TD-DFT) calculations were also performed to investigate vibrational modes of the Zn(II) complexes. An IR-FEL was used to irradiate HSA as well as hybrid materials of HSA-Zn(II) complexes at wavelengths corresponding to imine C=N, amide I, and amide II bands. Analysis of secondary structures suggested that including a Zn(II) complex into HSA led to the structural change of HSA, resulting in a more fragile structure than the original HSA. The result was one of the characteristic features of vibrational excitation of IR-FEL in contrast to electronic excitation by UV or visible light. Full article
(This article belongs to the Special Issue DFT Applications to Biomolecules and Complex Reactions)
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12 pages, 10206 KiB  
Article
Prediction of Enzyme Function Based on Three Parallel Deep CNN and Amino Acid Mutation
by Ruibo Gao, Mengmeng Wang, Jiaoyan Zhou, Yuhang Fu, Meng Liang, Dongliang Guo and Junlan Nie
Int. J. Mol. Sci. 2019, 20(11), 2845; https://doi.org/10.3390/ijms20112845 - 11 Jun 2019
Cited by 20 | Viewed by 3633
Abstract
During the past decade, due to the number of proteins in PDB database being increased gradually, traditional methods cannot better understand the function of newly discovered enzymes in chemical reactions. Computational models and protein feature representation for predicting enzymatic function are more important. [...] Read more.
During the past decade, due to the number of proteins in PDB database being increased gradually, traditional methods cannot better understand the function of newly discovered enzymes in chemical reactions. Computational models and protein feature representation for predicting enzymatic function are more important. Most of existing methods for predicting enzymatic function have used protein geometric structure or protein sequence alone. In this paper, the functions of enzymes are predicted from many-sided biological information including sequence information and structure information. Firstly, we extract the mutation information from amino acids sequence by the position scoring matrix and express structure information with amino acids distance and angle. Then, we use histogram to show the extracted sequence and structural features respectively. Meanwhile, we establish a network model of three parallel Deep Convolutional Neural Networks (DCNN) to learn three features of enzyme for function prediction simultaneously, and the outputs are fused through two different architectures. Finally, The proposed model was investigated on a large dataset of 43,843 enzymes from the PDB and achieved 92.34% correct classification when sequence information is considered, demonstrating an improvement compared with the previous result. Full article
(This article belongs to the Section Molecular Informatics)
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15 pages, 1305 KiB  
Review
Multiple Modes of Vitamin K Actions in Aging-Related Musculoskeletal Disorders
by Kotaro Azuma and Satoshi Inoue
Int. J. Mol. Sci. 2019, 20(11), 2844; https://doi.org/10.3390/ijms20112844 - 11 Jun 2019
Cited by 44 | Viewed by 7288
Abstract
Vitamin K is a fat-soluble vitamin that was originally found as an essential factor for blood coagulation. With the discovery of its role as a co-factor for γ-glutamyl carboxylase (GGCX), its function for blood coagulation was understood as the activation of several blood [...] Read more.
Vitamin K is a fat-soluble vitamin that was originally found as an essential factor for blood coagulation. With the discovery of its role as a co-factor for γ-glutamyl carboxylase (GGCX), its function for blood coagulation was understood as the activation of several blood coagulation factors by their γ-carboxylation. Over the last two decades, other modes of vitamin K actions have been discovered, such as the regulation of transcription by activating the steroid and xenobiotic receptor (SXR), physical association to 17β-Hydroxysteroid dehydrogenase type 4 (17β-HSD4), covalent modification of Bcl-2 antagonist killer 1 (Bak), and the modulation of protein kinase A (PKA) activity. In addition, several epidemiological studies have revealed that vitamin K status is associated with some aging-related diseases including osteoporosis, osteoarthritis, and sarcopenia. Clinical studies on single nucleotide polymorphisms of GGCX suggested an association between higher GGCX activity and bone protective effect, while recent findings using conditional knockout mice implied that a contribution in protective effect for bone loss by GGCX in osteoblastic lineage was unclear. GGCX in other cell lineages or in other tissues might play a protective role for osteoporosis. Meanwhile, animal experiments by our groups among others revealed that SXR, a putative receptor for vitamin K, could be important in the bone metabolism. In terms of the cartilage protective effect of vitamin K, both GGCX- and SXR-dependent mechanisms have been suggested. In clinical studies on osteoarthritis, the γ-carboxylation of matrix Gla protein (MGP) and gla-rich protein (GRP) may have a protective role for the disease. It is also suggested that SXR signaling has protective role for cartilage by inducing family with sequence similarity 20a (Fam20a) expression in chondrocytes. In the case of sarcopenia, a high vitamin K status in plasma was associated with muscle strength, large muscle mass, and high physical performance in some observational studies. However, the basic studies explaining the effects of vitamin K on muscular tissue are limited. Further research on vitamin K will clarify new biological mechanisms which contribute to human longevity and health through the prevention and treatment of aging-related musculoskeletal disorders. Full article
(This article belongs to the Special Issue Molecular Aspects of the Action of Vitamin K and its Related Compounds)
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16 pages, 2596 KiB  
Article
Inhibition of Karyopherin-α2 Augments Radiation-Induced Cell Death by Perturbing BRCA1-Mediated DNA Repair
by Kyung-Hee Song, Seung-Youn Jung, Jeong-In Park, Jiyeon Ahn, Jong Kuk Park, Hong-Duck Um, In-Chul Park, Sang-Gu Hwang, Hunjoo Ha and Jie-Young Song
Int. J. Mol. Sci. 2019, 20(11), 2843; https://doi.org/10.3390/ijms20112843 - 11 Jun 2019
Cited by 9 | Viewed by 3590
Abstract
Ionizing radiation (IR) has been widely used in the treatment of cancer. Radiation-induced DNA damage triggers the DNA damage response (DDR), which can confer radioresistance and early local recurrence by activating DNA repair pathways. Since karyopherin-α2 (KPNA2), playing an important role in nucleocytoplasmic [...] Read more.
Ionizing radiation (IR) has been widely used in the treatment of cancer. Radiation-induced DNA damage triggers the DNA damage response (DDR), which can confer radioresistance and early local recurrence by activating DNA repair pathways. Since karyopherin-α2 (KPNA2), playing an important role in nucleocytoplasmic transport, was significantly increased by IR in our previous study, we aimed to determine the function of KPNA2 with regard to DDR. Exposure to radiation upregulated KPNA2 expression in human colorectal cancer HT29 and HCT116 cells and breast carcinoma MDA-MB-231 cells together with the increased expression of DNA repair protein BRCA1. The knockdown of KPNA2 effectively increased apoptotic cell death via inhibition of BRCA1 nuclear import following IR. Therefore, we propose that KPNA2 is a potential target for overcoming radioresistance via interruption to DDR. Full article
(This article belongs to the Section Biochemistry)
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18 pages, 1120 KiB  
Review
Frailty, Cognitive Decline, Neurodegenerative Diseases and Nutrition Interventions
by María Elena Gómez-Gómez and Sara C. Zapico
Int. J. Mol. Sci. 2019, 20(11), 2842; https://doi.org/10.3390/ijms20112842 - 11 Jun 2019
Cited by 87 | Viewed by 11598
Abstract
Currently the human population is aging faster. This leads to higher dependency rates and the transformation of health and social care to adapt to this aged population. Among the changes developed by this population is frailty. It is defined as a clinically detectable [...] Read more.
Currently the human population is aging faster. This leads to higher dependency rates and the transformation of health and social care to adapt to this aged population. Among the changes developed by this population is frailty. It is defined as a clinically detectable syndrome, related to the aging of multiple physiological systems, which prompts a situation of vulnerability. The etiology of frailty seems to be multifactorial and its pathophysiology is influenced by the interaction of numerous factors. Morley et al. propose four main mechanisms triggering the frailty: atherosclerosis, sarcopenia, cognitive deterioration and malnutrition, with their respective metabolic alterations. Malnutrition is associated with cognitive impairment or functional loss, but it is also known that an inadequate nutritional status predisposes to cognitive frailty. Additionally, nutritional factors that may influence vascular risk factors will potentially have an effect on dementia decline among patients with cognitive frailty. This review aims to describe the nutritional factors that have been researched so far which may lead to the development of frailty, and especially cognitive decline. Full article
(This article belongs to the Special Issue Nutrition and Aging)
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34 pages, 570 KiB  
Review
NAFLD in Some Common Endocrine Diseases: Prevalence, Pathophysiology, and Principles of Diagnosis and Management
by Amedeo Lonardo, Alessandro Mantovani, Simonetta Lugari and Giovanni Targher
Int. J. Mol. Sci. 2019, 20(11), 2841; https://doi.org/10.3390/ijms20112841 - 11 Jun 2019
Cited by 71 | Viewed by 7055
Abstract
Secondary nonalcoholic fatty liver disease (NAFLD) defines those complex pathophysiological and clinical consequences that ensue when the liver becomes an ectopic site of lipid storage owing to reasons other than its mutual association with the metabolic syndrome. Disorders affecting gonadal hormones, thyroid hormones, [...] Read more.
Secondary nonalcoholic fatty liver disease (NAFLD) defines those complex pathophysiological and clinical consequences that ensue when the liver becomes an ectopic site of lipid storage owing to reasons other than its mutual association with the metabolic syndrome. Disorders affecting gonadal hormones, thyroid hormones, or growth hormones (GH) may cause secondary forms of NAFLD, which exhibit specific pathophysiologic features and, in theory, the possibility to receive an effective treatment. Here, we critically discuss epidemiological and pathophysiological features, as well as principles of diagnosis and management of some common endocrine diseases, such as polycystic ovary syndrome (PCOS), hypothyroidism, hypogonadism, and GH deficiency. Collectively, these forms of NAFLD secondary to specific endocrine derangements may be envisaged as a naturally occurring disease model of NAFLD in humans. Improved understanding of such endocrine secondary forms of NAFLD promises to disclose novel clinical associations and innovative therapeutic approaches, which may potentially be applied also to selected cases of primary NAFLD. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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32 pages, 810 KiB  
Review
Biology and Role of Extracellular Vesicles (EVs) in the Pathogenesis of Thrombosis
by Marta Zarà, Gianni Francesco Guidetti, Marina Camera, Ilaria Canobbio, Patrizia Amadio, Mauro Torti, Elena Tremoli and Silvia Stella Barbieri
Int. J. Mol. Sci. 2019, 20(11), 2840; https://doi.org/10.3390/ijms20112840 - 11 Jun 2019
Cited by 118 | Viewed by 7562
Abstract
Extracellular vesicles (EVs) are well-established mediators of cell-to-cell communication. EVs can be released by every cell type and they can be classified into three major groups according to their biogenesis, dimension, density, and predominant protein markers: exosomes, microvesicles, and apoptotic bodies. During their [...] Read more.
Extracellular vesicles (EVs) are well-established mediators of cell-to-cell communication. EVs can be released by every cell type and they can be classified into three major groups according to their biogenesis, dimension, density, and predominant protein markers: exosomes, microvesicles, and apoptotic bodies. During their formation, EVs associate with specific cargo from their parental cell that can include RNAs, free fatty acids, surface receptors, and proteins. The biological function of EVs is to maintain cellular and tissue homeostasis by transferring critical biological cargos to distal or neighboring recipient cells. On the other hand, their role in intercellular communication may also contribute to the pathogenesis of several diseases, including thrombosis. More recently, their physiological and biochemical properties have suggested their use as a therapeutic tool in tissue regeneration as well as a novel option for drug delivery. In this review, we will summarize the impact of EVs released from blood and vascular cells in arterial and venous thrombosis, describing the mechanisms by which EVs affect thrombosis and their potential clinical applications. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)
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23 pages, 1059 KiB  
Review
CAR-Based Strategies beyond T Lymphocytes: Integrative Opportunities for Cancer Adoptive Immunotherapy
by Ramona Rotolo, Valeria Leuci, Chiara Donini, Anna Cykowska, Loretta Gammaitoni, Giovanni Medico, Giorgio Valabrega, Massimo Aglietta and Dario Sangiolo
Int. J. Mol. Sci. 2019, 20(11), 2839; https://doi.org/10.3390/ijms20112839 - 11 Jun 2019
Cited by 32 | Viewed by 6585
Abstract
Chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR Ts) produced impressive clinical results against selected hematological malignancies, but the extension of CAR T cell therapy to the challenging field of solid tumors has not, so far, replicated similar clinical outcomes. Many efforts are currently [...] Read more.
Chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR Ts) produced impressive clinical results against selected hematological malignancies, but the extension of CAR T cell therapy to the challenging field of solid tumors has not, so far, replicated similar clinical outcomes. Many efforts are currently dedicated to improve the efficacy and safety of CAR-based adoptive immunotherapies, including application against solid tumors. A promising approach is CAR engineering of immune effectors different from αβT lymphocytes. Herein we reviewed biological features, therapeutic potential, and safety of alternative effectors to conventional CAR T cells: γδT, natural killer (NK), NKT, or cytokine-induced killer (CIK) cells. The intrinsic CAR-independent antitumor activities, safety profile, and ex vivo expansibility of these alternative immune effectors may favorably contribute to the clinical development of CAR strategies. The proper biological features of innate immune response effectors may represent an added value in tumor settings with heterogeneous CAR target expression, limiting the risk of tumor clonal escape. All these properties bring out CAR engineering of alternative immune effectors as a promising integrative option to be explored in future clinical studies. Full article
(This article belongs to the Special Issue CAR-T Cell Therapy)
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24 pages, 1229 KiB  
Review
Thrombosis Risk Associated with Head and Neck Cancer: A Review
by Pierre Haen, Diane Mege, Lydie Crescence, Françoise Dignat-George, Christophe Dubois and Laurence Panicot-Dubois
Int. J. Mol. Sci. 2019, 20(11), 2838; https://doi.org/10.3390/ijms20112838 - 11 Jun 2019
Cited by 25 | Viewed by 5142
Abstract
Venous thromboembolism (VTE) is a common complication for cancer patients. VTE-associated risk varies according to the type of tumor disease. Head and neck cancer is a common cancer worldwide, and most tumors are squamous cell carcinomas due to tobacco and alcohol abuse. The [...] Read more.
Venous thromboembolism (VTE) is a common complication for cancer patients. VTE-associated risk varies according to the type of tumor disease. Head and neck cancer is a common cancer worldwide, and most tumors are squamous cell carcinomas due to tobacco and alcohol abuse. The risk of VTE associated with head and neck (H&N) cancer is considered empirically low, but despite the high incidence of H&N cancer, few data are available on this cancer; thus, it is difficult to state the risk of VTE. Our review aims to clarify this situation and tries to assess the real VTE risk associated with H&N cancer. We report that most clinical studies have concluded that there is a very low thrombosis risk associated with H&N cancer. Even with the biases that often exist, this clinical review seems to confirm that the risk of VTE was empirically hypothesized. Furthermore, we highlight that H&N cancer has all the biological features of a cancer associated with a high thrombosis risk, including a strong expression of procoagulant proteins, modified thrombosis/fibrinolysis mechanisms, and secretions of procoagulant microparticles and procoagulant cytokines. Thus, this is a paradoxical situation, and some undiscovered mechanisms that could explain this clinical biological ambivalence might exist. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis of Thrombotic Diseases)
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45 pages, 3071 KiB  
Review
The Role of Epigenetics in Placental Development and the Etiology of Preeclampsia
by Clara Apicella, Camino S. M. Ruano, Céline Méhats, Francisco Miralles and Daniel Vaiman
Int. J. Mol. Sci. 2019, 20(11), 2837; https://doi.org/10.3390/ijms20112837 - 11 Jun 2019
Cited by 103 | Viewed by 12265
Abstract
In this review, we comprehensively present the function of epigenetic regulations in normal placental development as well as in a prominent disease of placental origin, preeclampsia (PE). We describe current progress concerning the impact of DNA methylation, non-coding RNA (with a special emphasis [...] Read more.
In this review, we comprehensively present the function of epigenetic regulations in normal placental development as well as in a prominent disease of placental origin, preeclampsia (PE). We describe current progress concerning the impact of DNA methylation, non-coding RNA (with a special emphasis on long non-coding RNA (lncRNA) and microRNA (miRNA)) and more marginally histone post-translational modifications, in the processes leading to normal and abnormal placental function. We also explore the potential use of epigenetic marks circulating in the maternal blood flow as putative biomarkers able to prognosticate the onset of PE, as well as classifying it according to its severity. The correlation between epigenetic marks and impacts on gene expression is systematically evaluated for the different epigenetic marks analyzed. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Preeclampsia)
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13 pages, 974 KiB  
Review
Programmed Cell Death-1 Receptor (PD-1)-Mediated Regulation of Innate Lymphoid Cells
by Grace Mallett, Arian Laurence and Shoba Amarnath
Int. J. Mol. Sci. 2019, 20(11), 2836; https://doi.org/10.3390/ijms20112836 - 11 Jun 2019
Cited by 22 | Viewed by 6783
Abstract
Programmed cell death-1 (PD-1) is a cell surface receptor that dampens adaptive immune responses. PD-1 is activated by the engagement of its ligands PDL-1 or PDL-2. This results in the inhibition of T cell proliferation, differentiation, cytokine secretion, and cytolytic function. Although a [...] Read more.
Programmed cell death-1 (PD-1) is a cell surface receptor that dampens adaptive immune responses. PD-1 is activated by the engagement of its ligands PDL-1 or PDL-2. This results in the inhibition of T cell proliferation, differentiation, cytokine secretion, and cytolytic function. Although a great deal is known about PD-1 mediated regulation of CD4+ and CD8+ T cells, its expression and function in innate lymphoid cells (ILCs) are yet to be fully deciphered. This review summarizes the role of PD-1 in (1) modulating ILC development, (2) ILC function, and (3) PD-1 signaling in ILC. Finally, we explore how PD-1 based immunotherapies may be beneficial in boosting ILC responses in cancer, infections, and other immune-related disorders. Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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15 pages, 1240 KiB  
Article
Regulation of Serum Sphingolipids in Andean Children Born and Living at High Altitude (3775 m)
by Pietro Barbacini, Josefina Casas, Enrica Torretta, Daniele Capitanio, Gustavo Maccallini, Valeria Hirschler and Cecilia Gelfi
Int. J. Mol. Sci. 2019, 20(11), 2835; https://doi.org/10.3390/ijms20112835 - 11 Jun 2019
Cited by 16 | Viewed by 4122
Abstract
Recent studies on Andean children indicate a prevalence of dyslipidemia and hypertension compared to dwellers at lower altitudes, suggesting that despite similar food intake and daily activities, they undergo different metabolic adaptations. In the present study, the sphingolipid pattern was investigated in serum [...] Read more.
Recent studies on Andean children indicate a prevalence of dyslipidemia and hypertension compared to dwellers at lower altitudes, suggesting that despite similar food intake and daily activities, they undergo different metabolic adaptations. In the present study, the sphingolipid pattern was investigated in serum of 7 underweight (UW), 30 normal weight (NW), 13 overweight (OW), and 9 obese (O) Andean children by liquid chromatography-mass spectrometry (LC-MS). Results indicate that levels of Ceramides (Cers) and sphingomyelins (SMs) correlate positively with biochemical parameters (except for Cers and Vitamin D, which correlate negatively), whereas sphingosine-1-phosphate (S1P) correlates negatively. Correlation results and LC-MS data identify the axis high density lipoprotein-cholesterol (HDL-C), Cers, and S1P as related to hypoxia adaptation. Specifically UW children are characterized by increased levels of S1P compared to O and lower levels of Cers compared to NW children. Furthermore, O children show lower levels of S1P and similar levels of Cers and SMs as NW. In conclusion, our results indicate that S1P is the primary target of hypoxia adaptation in Andean children, and its levels are associated with hypoxia tolerance. Furthermore, S1P can act as marker of increased risk of metabolic syndrome and cardiac dysfunction in young Andeans living at altitude. Full article
(This article belongs to the Special Issue Adaptation to Hypoxia: A Chimera?)
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12 pages, 2505 KiB  
Article
IRTKS Promotes Insulin Signaling Transduction through Inhibiting SHIP2 Phosphatase Activity
by Chongchao Wu, Xiaofang Cui, Liyu Huang, Xueying Shang, Binghao Wu, Na Wang, Kunyan He and Zeguang Han
Int. J. Mol. Sci. 2019, 20(11), 2834; https://doi.org/10.3390/ijms20112834 - 11 Jun 2019
Cited by 12 | Viewed by 3497
Abstract
Insulin signaling is mediated by a highly integrated network that controls glucose metabolism, protein synthesis, cell growth, and differentiation. Our previous work indicates that the insulin receptor tyrosine kinase substrate (IRTKS), also known as BAI1-associated protein 2-like 1 (BAIAP2L1), is a novel regulator [...] Read more.
Insulin signaling is mediated by a highly integrated network that controls glucose metabolism, protein synthesis, cell growth, and differentiation. Our previous work indicates that the insulin receptor tyrosine kinase substrate (IRTKS), also known as BAI1-associated protein 2-like 1 (BAIAP2L1), is a novel regulator of insulin network, but the mechanism has not been fully studied. In this work we reveal that IRTKS co-localizes with Src homology (SH2) containing inositol polyphosphate 5-phosphatase-2 (SHIP2), and the SH3 domain of IRTKS directly binds to SHIP2’s catalytic domain INPP5c. IRTKS suppresses SHIP2 phosphatase to convert phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3, PIP3) to phosphatidylinositol (3,4) bisphosphate (PI(3,4)P2). IRTKS-knockout significantly increases PI(3,4)P2 level and decreases cellular PI(3,4,5)P3 content. Interestingly, the interaction between IRTKS and SHIP2 is dynamically regulated by insulin, which feeds back and affects the tyrosine phosphorylation of IRTKS. Furthermore, IRTKS overexpression elevates PIP3, activates the AKT–mTOR signaling pathway, and increases cell proliferation. Thereby, IRTKS not only associates with insulin receptors to activate PI3K but also interacts with SHIP2 to suppress its activity, leading to PIP3 accumulation and the activation of the AKT–mTOR signaling pathway to modulate cell proliferation. Full article
(This article belongs to the Section Molecular Biology)
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16 pages, 1352 KiB  
Review
Contribution of Impaired Insulin Signaling to the Pathogenesis of Diabetic Cardiomyopathy
by Mònica Zamora and Josep A. Villena
Int. J. Mol. Sci. 2019, 20(11), 2833; https://doi.org/10.3390/ijms20112833 - 11 Jun 2019
Cited by 46 | Viewed by 7124
Abstract
Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the [...] Read more.
Diabetic cardiomyopathy (DCM) has emerged as a relevant cause of heart failure among the diabetic population. Defined as a cardiac dysfunction that develops in diabetic patients independently of other major cardiovascular risks factors, such as high blood pressure and coronary artery disease, the underlying cause of DCMremains to be unveiled. Several pathogenic factors, including glucose and lipid toxicity, mitochondrial dysfunction, increased oxidative stress, sustained activation of the renin-angiotensin system (RAS) or altered calcium homeostasis, have been shown to contribute to the structural and functional alterations that characterize diabetic hearts. However, all these pathogenic mechanisms appear to stem from the metabolic inflexibility imposed by insulin resistance or lack of insulin signaling. This results in absolute reliance on fatty acids for the synthesis of ATP and impairment of glucose oxidation. Glucose is then rerouted to other metabolic pathways, with harmful effects on cardiomyocyte function. Here, we discuss the role that impaired cardiac insulin signaling in diabetic or insulin-resistant individuals plays in the onset and progression of DCM. Full article
(This article belongs to the Special Issue Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities)
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16 pages, 599 KiB  
Review
Minimal Residual Disease Monitoring with Next-Generation Sequencing Methodologies in Hematological Malignancies
by Ricardo Sánchez, Rosa Ayala and Joaquín Martínez-López
Int. J. Mol. Sci. 2019, 20(11), 2832; https://doi.org/10.3390/ijms20112832 - 10 Jun 2019
Cited by 38 | Viewed by 6320
Abstract
Ultra-deep next-generation sequencing has emerged in recent years as an important diagnostic tool for the detection and follow-up of tumor burden in most of the known hematopoietic malignancies. Meticulous and high-throughput methods for the lowest possible quantified disease are needed to address the [...] Read more.
Ultra-deep next-generation sequencing has emerged in recent years as an important diagnostic tool for the detection and follow-up of tumor burden in most of the known hematopoietic malignancies. Meticulous and high-throughput methods for the lowest possible quantified disease are needed to address the deficiencies of more classical techniques. Precision-based approaches will allow us to correctly stratify each patient based on the minimal residual disease (MRD) after a treatment cycle. In this review, we consider the most prominent ways to approach next-generation sequencing methodologies to follow-up MRD in hematological neoplasms. Full article
(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias)
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11 pages, 2659 KiB  
Article
A Soft Matrix Enhances the Cancer Stem Cell Phenotype of HCC Cells
by Boren Tian, Qing Luo, Yang Ju and Guanbin Song
Int. J. Mol. Sci. 2019, 20(11), 2831; https://doi.org/10.3390/ijms20112831 - 10 Jun 2019
Cited by 40 | Viewed by 4152
Abstract
Cancer stem cells (CSCs) comprise a small portion of cancer cells, have greater self-renewal ability and metastatic potential than non-CSCs and are resistant to drugs and radiotherapy. CSCs and non-CSCs, which can reversibly change their stemness states, typically play roles in plasticity and [...] Read more.
Cancer stem cells (CSCs) comprise a small portion of cancer cells, have greater self-renewal ability and metastatic potential than non-CSCs and are resistant to drugs and radiotherapy. CSCs and non-CSCs, which can reversibly change their stemness states, typically play roles in plasticity and cancer cell heterogeneity. Furthermore, the component that plays a key role in affecting CSC plasticity remains unknown. In this study, we utilized mechanically tunable polyacrylamide (PA) hydrogels to simulate different stiffnesses of the liver tissue matrix in various stages. Our results showed that hepatocellular carcinoma (HCC) cells were small and round in a soft matrix. The soft matrix increased the expression levels of liver cancer cells with stemness properties (LCSC) surface markers in HCC cells and the number of side population (SP) cells. Moreover, the soft matrix elicited early cell cycle arrest in the G1 phase and increased the cell sphere-forming ability. In addition, cells grown on the soft matrix showed enhanced chemoresistance and tumorigenicity potential. In summary, our study demonstrated that a soft matrix increases the stemness of HCC cells. Full article
(This article belongs to the Special Issue Cancer Cell Reprogramming)
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11 pages, 2770 KiB  
Article
Enhanced Ganoderic Acids Accumulation and Transcriptional Responses of Biosynthetic Genes in Ganoderma lucidum Fruiting Bodies by Elicitation Supplementation
by Li Meng, Xiaoran Bai, Shaoyan Zhang, Mengfei Zhang, Sen Zhou, Irum Mukhtar, Li Wang, Zhuang Li and Wei Wang
Int. J. Mol. Sci. 2019, 20(11), 2830; https://doi.org/10.3390/ijms20112830 - 10 Jun 2019
Cited by 15 | Viewed by 3793
Abstract
Ganoderic acids (GAs) are a type of highly oxygenated lanostane-type triterpenoids that are responsible for the pharmacological activities of Ganoderma lucidum. They have been investigated for their biological activities, including antibacterial, antiviral, antitumor, anti-HIV-1, antioxidation, and cholesterol reduction functions. Inducer supplementation is [...] Read more.
Ganoderic acids (GAs) are a type of highly oxygenated lanostane-type triterpenoids that are responsible for the pharmacological activities of Ganoderma lucidum. They have been investigated for their biological activities, including antibacterial, antiviral, antitumor, anti-HIV-1, antioxidation, and cholesterol reduction functions. Inducer supplementation is viewed as a promising technology for the production of GAs. This study found that supplementation with sodium acetate (4 mM) significantly increased the GAs content of fruiting bodies by 28.63% compared to the control. In order to explore the mechanism of ganoderic acid accumulation, the transcriptional responses of key GAs biosynthetic genes, including the acetyl coenzyme A synthase gene, and the expression levels of genes involved in calcineurin signaling and acetyl-CoA content have been analyzed. The results showed that the expression of three key GAs biosynthetic genes (hmgs, fps, and sqs) were significantly up-regulated. Analysis indicated that the acetate ion increased the expression of genes related to acetic acid assimilation and increased GAs biosynthesis, thereby resulting in the accumulation of GAs. Further investigation of the expression levels of genes involved in calcineurin signaling revealed that Na+ supplementation and the consequent exchange of Na+/Ca2+ induced GAs biosynthesis. Overall, this study indicates a feasible new approach of utilizing sodium acetate elicitation for the enhanced production of valuable GAs content in G. lucidum, and also provided the primary mechanism of GAs accumulation. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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18 pages, 1599 KiB  
Review
Insect ATP-Binding Cassette (ABC) Transporters: Roles in Xenobiotic Detoxification and Bt Insecticidal Activity
by Chao Wu, Swapan Chakrabarty, Minghui Jin, Kaiyu Liu and Yutao Xiao
Int. J. Mol. Sci. 2019, 20(11), 2829; https://doi.org/10.3390/ijms20112829 - 10 Jun 2019
Cited by 92 | Viewed by 12066
Abstract
ATP-binding cassette (ABC) transporters, a large class of transmembrane proteins, are widely found in organisms and play an important role in the transport of xenobiotics. Insect ABC transporters are involved in insecticide detoxification and Bacillus thuringiensis (Bt) toxin perforation. The complete ABC transporter [...] Read more.
ATP-binding cassette (ABC) transporters, a large class of transmembrane proteins, are widely found in organisms and play an important role in the transport of xenobiotics. Insect ABC transporters are involved in insecticide detoxification and Bacillus thuringiensis (Bt) toxin perforation. The complete ABC transporter is composed of two hydrophobic transmembrane domains (TMDs) and two nucleotide binding domains (NBDs). Conformational changes that are needed for their action are mediated by ATP hydrolysis. According to the similarity among their sequences and organization of conserved ATP-binding cassette domains, insect ABC transporters have been divided into eight subfamilies (ABCA–ABCH). This review describes the functions and mechanisms of ABC transporters in insecticide detoxification, plant toxic secondary metabolites transport and insecticidal activity of Bt toxin. With improved understanding of the role and mechanisms of ABC transporter in resistance to insecticides and Bt toxins, we can identify valuable target sites for developing new strategies to control pests and manage resistance and achieve green pest control. Full article
(This article belongs to the Special Issue Molecular Ecology, Physiology and Biochemistry of Insects)
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18 pages, 4993 KiB  
Article
Assessment of the Antiangiogenic and Anti-Inflammatory Properties of a Maslinic Acid Derivative and its Potentiation using Zinc Chloride
by Ioana Zinuca Pavel, Rene Csuk, Corina Danciu, Stefana Avram, Flavia Baderca, Andreea Cioca, Elena-Alina Moacă, Ciprian-Valentin Mihali, Iulia Pinzaru, Danina Mirela Muntean and Cristina Adriana Dehelean
Int. J. Mol. Sci. 2019, 20(11), 2828; https://doi.org/10.3390/ijms20112828 - 10 Jun 2019
Cited by 19 | Viewed by 4006
Abstract
Maslinic acid is a pentacyclic triterpene with a plethora of biological activities, including anti-inflammatory, antioxidant, antimicrobial, cardioprotective, and antitumor effects. New derivatives with improved properties and broad-spectrum activity can be obtained following structural changes of the compound. The present study was aimed to [...] Read more.
Maslinic acid is a pentacyclic triterpene with a plethora of biological activities, including anti-inflammatory, antioxidant, antimicrobial, cardioprotective, and antitumor effects. New derivatives with improved properties and broad-spectrum activity can be obtained following structural changes of the compound. The present study was aimed to characterize a benzylamide derivative of maslinic acid—benzyl (2α, 3β) 2,3-diacetoxy-olean−12-en-28-amide (EM2)—with respect to the anti-angiogenic and anti-inflammatory effects in two in vivo experimental models. Consequently, the compound showed good tolerability and lack of irritation in the chorioallantoic membrane assay with no impairment of the normal angiogenic process during the tested stages of development. In the acute ear inflammation murine model, application of EM2 induced a mild anti-inflammatory effect that was potentiated by the association with zinc chloride (ZnCl2). A decrease in dermal thickness of mice ears was observed when EM2 and ZnCl2 were applied separately or in combination. Moreover, hyalinization of the dermis appeared only when EM2 was associated with ZnCl2, strongly suggesting the role of their combination in wound healing. Full article
(This article belongs to the Special Issue Bioactive Nutrients, Immunity and Inflammation)
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15 pages, 2367 KiB  
Article
Conservation of Small Regulatory RNAs in Vibrio parahaemolyticus: Possible role of RNA-OUT Encoded by the Pathogenicity Island (VPaI-7) of Pandemic Strains
by Nicolás Plaza, Diliana Pérez-Reytor, Sebastián Ramírez-Araya, Alequis Pavón, Gino Corsini, David E. Loyola, Víctor Jaña, Leonardo Pavéz, Paola Navarrete, Roberto Bastías, Daniel Castillo and Katherine García
Int. J. Mol. Sci. 2019, 20(11), 2827; https://doi.org/10.3390/ijms20112827 - 10 Jun 2019
Cited by 4 | Viewed by 3067
Abstract
Small regulatory RNAs (sRNAs) are molecules that play an important role in the regulation of gene expression. sRNAs in bacteria can affect important processes, such as metabolism and virulence. Previous studies showed a significant role of sRNAs in the Vibrio species, but knowledge [...] Read more.
Small regulatory RNAs (sRNAs) are molecules that play an important role in the regulation of gene expression. sRNAs in bacteria can affect important processes, such as metabolism and virulence. Previous studies showed a significant role of sRNAs in the Vibrio species, but knowledge about Vibrio parahaemolyticus is limited. Here, we examined the conservation of sRNAs between V. parahaemolyticus and other human Vibrio species, in addition to investigating the conservation between V. parahaemolyticus strains differing in pandemic origin. Our results showed that only 7% of sRNAs were conserved between V. parahaemolyticus and other species, but 88% of sRNAs were highly conserved within species. Nonetheless, two sRNAs coding to RNA-OUT, a component of the Tn10/IS10 system, were exclusively present in pandemic strains. Subsequent analysis showed that both RNA-OUT were located in pathogenicity island-7 and would interact with transposase VPA1379, according to the model of pairing of IS10-encoded antisense RNAs. According to the location of RNA-OUT/VPA1379, we also investigated if they were expressed during infection. We observed that the transcriptional level of VPA1379 was significantly increased, while RNA-OUT was decreased at three hours post-infection. We suggest that IS10 transcription increases in pandemic strains during infection, probably to favor IS10 transposition and improve their fitness when they are facing adverse conditions. Full article
(This article belongs to the Special Issue Host–Pathogen Interaction)
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19 pages, 4944 KiB  
Article
RTA 408 Inhibits Interleukin-1β-Induced MMP-9 Expression via Suppressing Protein Kinase-Dependent NF-κB and AP-1 Activation in Rat Brain Astrocytes
by Chien-Chung Yang, Chih-Chung Lin, Mei-Jie Jou, Li-Der Hsiao and Chuen-Mao Yang
Int. J. Mol. Sci. 2019, 20(11), 2826; https://doi.org/10.3390/ijms20112826 - 10 Jun 2019
Cited by 21 | Viewed by 4366
Abstract
Neuroinflammation is characterized by the elevated expression of various inflammatory proteins, including matrix metalloproteinases (MMPs), induced by various pro-inflammatory mediators, which play a critical role in neurodegenerative disorders. Interleukin-1β (IL-1β) has been shown to induce the upregulation of MMP-9 through nicotinamide adenine dinucleotide [...] Read more.
Neuroinflammation is characterized by the elevated expression of various inflammatory proteins, including matrix metalloproteinases (MMPs), induced by various pro-inflammatory mediators, which play a critical role in neurodegenerative disorders. Interleukin-1β (IL-1β) has been shown to induce the upregulation of MMP-9 through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-reactive oxygen species (ROS)-dependent signaling pathways. N-(2-cyano-3,12-dioxo-28-noroleana-1,9(11)-dien-17-yl)-2-2-difluoropropanamide (RTA 408), a novel synthetic triterpenoid, has been shown to possess anti-oxidant and anti-inflammatory properties in various types of cells. Here, we evaluated the effects of RTA 408 on IL-1β-induced inflammatory responses by suppressing MMP-9 expression in a rat brain astrocyte (RBA-1) line. IL-1β-induced MMP-9 protein and mRNA expression, and promoter activity were attenuated by RTA 408. The increased level of ROS generation in RBA-1 cells exposed to IL-1β was attenuated by RTA 408, as determined by using 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) and CellROX. In addition, the inhibitory effects of RTA 408 on MMP-9 expression resulted from the suppression of the IL-1β-stimulated activation of Pyk2 (proline-rich tyrosine kinase), platelet-derived growth factor receptor β (PDGFRβ), Akt, ROS, and mitogen-activated protein kinases (MAPKs). Pretreatment with RTA 408 attenuated the IL-1β-induced c-Jun phosphorylation, mRNA expression, and promoter activity. IL-1β-stimulated nuclear factor-κB (NF-κB) p65 phosphorylation, translocation, and promoter activity were also attenuated by RTA 408. Furthermore, IL-1β-induced glial fibrillary acidic protein (GFAP) protein and mRNA expression, and cell migration were attenuated by pretreatment with RTA 408. These results provide new insights into the mechanisms by which RTA 408 attenuates IL-1β-mediated inflammatory responses and exerts beneficial effects for the management of brain diseases. Full article
(This article belongs to the Special Issue Neuroprotective Strategies 2019)
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14 pages, 550 KiB  
Article
Deficiency of GD3 Synthase in Mice Resulting in the Attenuation of Bone Loss with Aging
by Shoyoku Yo, Kazunori Hamamura, Yoshitaka Mishima, Kosuke Hamajima, Hironori Mori, Koichi Furukawa, Hisataka Kondo, Kenjiro Tanaka, Takuma Sato, Ken Miyazawa, Shigemi Goto and Akifumi Togari
Int. J. Mol. Sci. 2019, 20(11), 2825; https://doi.org/10.3390/ijms20112825 - 10 Jun 2019
Cited by 9 | Viewed by 3373
Abstract
Gangliosides are widely expressed in almost all tissues and cells and are also considered to be essential in the development and maintenance of various organs and tissues. However, little is known about their roles in bone metabolism. In this study, we investigated the [...] Read more.
Gangliosides are widely expressed in almost all tissues and cells and are also considered to be essential in the development and maintenance of various organs and tissues. However, little is known about their roles in bone metabolism. In this study, we investigated the effects of genetic deletion of ganglioside D3 (GD3) synthase, which is responsible for the generation of all b-series gangliosides, on bone metabolism. Although b-series gangliosides were not expressed in osteoblasts, these gangliosides were expressed in pre-osteoclasts. However, the expression of these gangliosides was decreased after induction of osteoclastogenesis by receptor activator of nuclear factor kappa-B ligand (RANKL). Three-dimensional micro-computed tomography (3D-μCT) analysis revealed that femoral cancellous bone mass in GD3 synthase-knockout (GD3S KO) mice was higher than that in wild type (WT) mice at the age of 40 weeks, although there were no differences in that between GD3S KO and WT mice at 15 weeks old. Whereas bone formation parameters (osteoblast numbers/bone surface and osteoblast surface/bone surface) in GD3S KO mice did not differ from WT mice, bone resorption parameters (osteoclast numbers/bone surface and osteoclast surface/bone surface) in GD3S KO mice became significantly lower than those in WT mice at 40 weeks of age. Collectively, this study demonstrates that deletion of GD3 synthase attenuates bone loss that emerges with aging. Full article
(This article belongs to the Special Issue Gangliosides: Modes of Action and Cell Fates)
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17 pages, 1295 KiB  
Review
Clinical Applications of Natriuretic Peptides in Heart Failure and Atrial Fibrillation
by Masako Baba, Kentaro Yoshida and Masaki Ieda
Int. J. Mol. Sci. 2019, 20(11), 2824; https://doi.org/10.3390/ijms20112824 - 10 Jun 2019
Cited by 30 | Viewed by 4707
Abstract
Natriuretic peptides (NPs) have become important diagnostic and prognostic biomarkers in cardiovascular diseases, particularly in heart failure (HF). Diagnosis and management of coronary artery disease and atrial fibrillation (AF) can also be guided by NP levels. When interpreting NP levels, however, the caveat [...] Read more.
Natriuretic peptides (NPs) have become important diagnostic and prognostic biomarkers in cardiovascular diseases, particularly in heart failure (HF). Diagnosis and management of coronary artery disease and atrial fibrillation (AF) can also be guided by NP levels. When interpreting NP levels, however, the caveat is that age, sex, body mass index, renal dysfunction, and race affect the clearance of NPs, resulting in different cut-off values in clinical practice. In AF, NP levels have been associated with incident AF in the general population, recurrences after catheter ablation, prediction of clinical prognosis, and the risk of stroke. In this article, we first review and summarize the current evidence and the roles of B-type NP and atrial NP in HF and coronary artery disease and then focus on the increasing utility of NPs in the diagnosis and management of and the research into AF. Full article
(This article belongs to the Special Issue Molecular Basis of Cardiovascular Diseases: Implications of Natriuretic Peptides)
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16 pages, 1152 KiB  
Article
High PD-L1 Expression Predicts for Worse Outcome of Leukemia Patients with Concomitant NPM1 and FLT3 Mutations
by Barbora Brodská, Petra Otevřelová, Cyril Šálek, Ota Fuchs, Zdenka Gašová and Kateřina Kuželová
Int. J. Mol. Sci. 2019, 20(11), 2823; https://doi.org/10.3390/ijms20112823 - 10 Jun 2019
Cited by 41 | Viewed by 3853
Abstract
Compared to solid tumors, the role of PD-L1 in hematological malignancies is less explored, and the knowledge in this area is mostly limited to lymphomas. However, several studies indicated that PD-L1 is also overexpressed in myeloid malignancies. Successful treatment of the acute myeloid [...] Read more.
Compared to solid tumors, the role of PD-L1 in hematological malignancies is less explored, and the knowledge in this area is mostly limited to lymphomas. However, several studies indicated that PD-L1 is also overexpressed in myeloid malignancies. Successful treatment of the acute myeloid leukemia (AML) is likely associated with elimination of the residual disease by the immune system, and possible involvement of PD-L1 in this process remains to be elucidated. We analyzed PD-L1 expression on AML primary cells by flow cytometry and, in parallel, transcript levels were determined for the transcription variants v1 and v2. The ratio of v1/v2 cDNA correlated with the surface protein amount, and high v1/v2 levels were associated with worse overall survival (p = 0.0045). The prognostic impact of PD-L1 was limited to AML with mutated nucleophosmin and concomitant internal tandem duplications in the FLT3 gene (p less than 0.0001 for this particular AML subgroup). Full article
(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)
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25 pages, 2144 KiB  
Review
Lymphocyte Subsets and Inflammatory Cytokines of Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma
by Alessandro Allegra, Vanessa Innao, Andrea Gaetano Allegra, Marta Pugliese, Eleonora Di Salvo, Elvira Ventura-Spagnolo, Caterina Musolino and Sebastiano Gangemi
Int. J. Mol. Sci. 2019, 20(11), 2822; https://doi.org/10.3390/ijms20112822 - 10 Jun 2019
Cited by 21 | Viewed by 5486
Abstract
Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to [...] Read more.
Almost all multiple myeloma (MM) cases have been demonstrated to be linked to earlier monoclonal gammopathy of undetermined significance (MGUS). Nevertheless, there are no identified characteristics in the diagnosis of MGUS that have been helpful in differentiating subjects whose cancer may progress to a malignant situation. Regarding malignancy, the role of lymphocyte subsets and cytokines at the beginning of neoplastic diseases is now incontestable. In this review, we have concentrated our attention on the equilibrium between the diverse lymphocyte subsets and the cytokine system and summarized the current state of knowledge, providing an overview of the condition of the entire system in MGUS and MM. In an age where the therapy of neoplastic monoclonal gammopathies largely relies on drugs capable of acting on the immune system (immunomodulants, immunological checkpoint inhibitors, CAR-T), detailed knowledge of the the differences existing in benign and neoplastic forms of gammopathy is the main foundation for the adequate and optimal use of new drugs. Full article
(This article belongs to the Section Molecular Immunology)
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17 pages, 5244 KiB  
Article
A Vector-Based Method to Analyze the Topography of Glial Networks
by Sara Eitelmann, Jan J. Hirtz and Jonathan Stephan
Int. J. Mol. Sci. 2019, 20(11), 2821; https://doi.org/10.3390/ijms20112821 - 10 Jun 2019
Cited by 4 | Viewed by 2634
Abstract
Anisotropy of tracer-coupled networks is a hallmark in many brain regions. In the past, the topography of these networks was analyzed using various approaches, which focused on different aspects, e.g., position, tracer signal, or direction of coupled cells. Here, we developed a vector-based [...] Read more.
Anisotropy of tracer-coupled networks is a hallmark in many brain regions. In the past, the topography of these networks was analyzed using various approaches, which focused on different aspects, e.g., position, tracer signal, or direction of coupled cells. Here, we developed a vector-based method to analyze the extent and preferential direction of tracer spreading. As a model region, we chose the lateral superior olive—a nucleus that exhibits specialized network topography. In acute slices, sulforhodamine 101-positive astrocytes were patch-clamped and dialyzed with the GJ-permeable tracer neurobiotin, which was subsequently labeled with avidin alexa fluor 488. A predetermined threshold was used to differentiate between tracer-coupled and tracer-uncoupled cells. Tracer extent was calculated from the vector means of tracer-coupled cells in four 90° sectors. We then computed the preferential direction using a rotating coordinate system and post hoc fitting of these results with a sinusoidal function. The new method allows for an objective analysis of tracer spreading that provides information about shape and orientation of GJ networks. We expect this approach to become a vital tool for the analysis of coupling anisotropy in many brain regions. Full article
(This article belongs to the Section Molecular Neurobiology)
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