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Volume 21
Issue 7
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Int. J. Mol. Sci., Volume 21, Issue 7 (April-1 2020) – 400 articles

Cover Story (view full-size image): Many integral membrane proteins, including ion channels, are modulated structurally and functionally by the surrounding lipids, but the molecular mechanisms behind it remain largely unknown. Here, we have reviewed the multiple alterations lipids cause on the prokaryotic KcsA, possibly the best studied ion channel undergoing lipid modulation. Interestingly, most such effects have in common the initial binding of anionic lipids to two key arginine residues located at non-annular lipid binding sites on the channel protein. Thus, processes as different as the inactivation of channel K+ currents or the assembly of clusters from individual KcsA channels depend on such lipid binding. View this paper.
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10 pages, 2401 KiB  
Article
Therapeutic Effects of Human Amniotic Epithelial Stem Cells in a Transgenic Mouse Model of Alzheimer’s Disease
by Ka Young Kim, Yoo-Hun Suh and Keun-A Chang
Int. J. Mol. Sci. 2020, 21(7), 2658; https://doi.org/10.3390/ijms21072658 - 10 Apr 2020
Cited by 20 | Viewed by 4378
Abstract
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized clinically by cognitive decline and pathologically by the development of amyloid plaques. AD is the most common cause of dementia among older people. However, there is currently no cure for AD. In this study, [...] Read more.
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized clinically by cognitive decline and pathologically by the development of amyloid plaques. AD is the most common cause of dementia among older people. However, there is currently no cure for AD. In this study, we aimed to elucidate the therapeutic effects of human amniotic epithelial stem cells (hAESCs) in a transgenic mouse model of AD. Tg2576 transgenic (Tg) mice underwent behavioral tests, namely the Morris water maze and Y-maze tests, to assess their cognitive function. In the Morris water maze test, hAESC-treated Tg mice exhibited significantly shorter escape latencies than vehicle-treated Tg mice. In the Y-maze test, hAESC-treated Tg mice exhibited significantly higher rate of spontaneous alteration than vehicle-treated Tg mice, while the total number of arm entries did not differ between the groups. Furthermore, Congo red staining revealed that hAESCs injection reduced the number of amyloid plaques present in the brains of Tg mice. Finally, beta-secretase (BACE) activity was significantly decreased in Tg mice at 60 min after hAESCs injection. In this study, we found that intracerebral injection of hAESCs alleviated cognitive impairment in a Tg2576 mouse model of AD. Our results indicate that hAESCs injection reduced amyloid plaques caused by reduced BACE activity. These results indicate that hAESCs may be a useful therapeutic agent for the treatment of AD-related memory impairment. Full article
(This article belongs to the Special Issue Applications of Mesenchymal Stem Cells in Neuroscience)
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19 pages, 1768 KiB  
Review
A Review of SARS-CoV-2 and the Ongoing Clinical Trials
by Yung-Fang Tu, Chian-Shiu Chien, Aliaksandr A. Yarmishyn, Yi-Ying Lin, Yung-Hung Luo, Yi-Tsung Lin, Wei-Yi Lai, De-Ming Yang, Shih-Jie Chou, Yi-Ping Yang, Mong-Lien Wang and Shih-Hwa Chiou
Int. J. Mol. Sci. 2020, 21(7), 2657; https://doi.org/10.3390/ijms21072657 - 10 Apr 2020
Cited by 520 | Viewed by 50234
Abstract
The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) in Wuhan, China, which rapidly grew into a global pandemic, marked the third introduction of a virulent coronavirus into the human society, affecting not only the healthcare system, but also the global [...] Read more.
The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) in Wuhan, China, which rapidly grew into a global pandemic, marked the third introduction of a virulent coronavirus into the human society, affecting not only the healthcare system, but also the global economy. Although our understanding of coronaviruses has undergone a huge leap after two precedents, the effective approaches to treatment and epidemiological control are still lacking. In this article, we present a succinct overview of the epidemiology, clinical features, and molecular characteristics of SARS-CoV-2. We summarize the current epidemiological and clinical data from the initial Wuhan studies, and emphasize several features of SARS-CoV-2, which differentiate it from SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), such as high variability of disease presentation. We systematize the current clinical trials that have been rapidly initiated after the outbreak of COVID-19 pandemic. Whereas the trials on SARS-CoV-2 genome-based specific vaccines and therapeutic antibodies are currently being tested, this solution is more long-term, as they require thorough testing of their safety. On the other hand, the repurposing of the existing therapeutic agents previously designed for other virus infections and pathologies happens to be the only practical approach as a rapid response measure to the emergent pandemic, as most of these agents have already been tested for their safety. These agents can be divided into two broad categories, those that can directly target the virus replication cycle, and those based on immunotherapy approaches either aimed to boost innate antiviral immune responses or alleviate damage induced by dysregulated inflammatory responses. The initial clinical studies revealed the promising therapeutic potential of several of such drugs, including favipiravir, a broad-spectrum antiviral drug that interferes with the viral replication, and hydroxychloroquine, the repurposed antimalarial drug that interferes with the virus endosomal entry pathway. We speculate that the current pandemic emergency will be a trigger for more systematic drug repurposing design approaches based on big data analysis. Full article
(This article belongs to the Section Molecular Microbiology)
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18 pages, 3603 KiB  
Article
A Novel Ruthenium Based Coordination Compound Against Pathogenic Bacteria
by Vishma Pratap Sur, Aninda Mazumdar, Pavel Kopel, Soumajit Mukherjee, Petr Vítek, Hana Michalkova, Markéta Vaculovičová and Amitava Moulick
Int. J. Mol. Sci. 2020, 21(7), 2656; https://doi.org/10.3390/ijms21072656 - 10 Apr 2020
Cited by 14 | Viewed by 4908
Abstract
The current epidemic of antibiotic-resistant infections urges to develop alternatives to less-effective antibiotics. To assess anti-bacterial potential, a novel coordinate compound (RU-S4) was synthesized using ruthenium-Schiff base-benzimidazole ligand, where ruthenium chloride was used as the central atom. RU-S4 was characterized by scanning electron [...] Read more.
The current epidemic of antibiotic-resistant infections urges to develop alternatives to less-effective antibiotics. To assess anti-bacterial potential, a novel coordinate compound (RU-S4) was synthesized using ruthenium-Schiff base-benzimidazole ligand, where ruthenium chloride was used as the central atom. RU-S4 was characterized by scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDS), and Raman spectroscopy. Antibacterial effect of RU-S4 was studied against Staphylococcus aureus (NCTC 8511), vancomycin-resistant Staphylococcus aureus (VRSA) (CCM 1767), methicillin-resistant Staphylococcus aureus (MRSA) (ST239: SCCmecIIIA), and hospital isolate Staphylococcus epidermidis. The antibacterial activity of RU-S4 was checked by growth curve analysis and the outcome was supported by optical microscopy imaging and fluorescence LIVE/DEAD cell imaging. In vivo (balb/c mice) infection model prepared with VRSA (CCM 1767) and treated with RU-S4. In our experimental conditions, all infected mice were cured. The interaction of coordination compound with bacterial cells were further confirmed by cryo-scanning electron microscope (Cryo-SEM). RU-S4 was completely non-toxic against mammalian cells and in mice and subsequently treated with synthesized RU-S4. Full article
(This article belongs to the Special Issue Staphylococcus aureus Infection: Pathogenesis, Antimicrobial Resistance and Diagnostics)
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6 pages, 227 KiB  
Editorial
Salicylic Acid Signalling in Plants
by Tibor Janda, Gabriella Szalai and Magda Pál
Int. J. Mol. Sci. 2020, 21(7), 2655; https://doi.org/10.3390/ijms21072655 - 10 Apr 2020
Cited by 64 | Viewed by 6600
Abstract
Ten articles published in the “Special Issue: Salicylic Acid Signalling in Plants” are summarized, in order to get a global picture about the mode of action of salicylic acid in plants, and about its interaction with other stress-signalling routes. Its ecological aspects and [...] Read more.
Ten articles published in the “Special Issue: Salicylic Acid Signalling in Plants” are summarized, in order to get a global picture about the mode of action of salicylic acid in plants, and about its interaction with other stress-signalling routes. Its ecological aspects and possible practical use are also discussed. Full article
(This article belongs to the Special Issue Salicylic Acid Signalling in Plants)
17 pages, 5636 KiB  
Article
The Interactions between the Antimicrobial Peptide P-113 and Living Candida albicans Cells Shed Light on Mechanisms of Antifungal Activity and Resistance
by Kuang-Ting Cheng, Chih-Lung Wu, Bak-Sau Yip, Ya-Han Chih, Kuang-Li Peng, Su-Ya Hsu, Hui-Yuan Yu and Jya-Wei Cheng
Int. J. Mol. Sci. 2020, 21(7), 2654; https://doi.org/10.3390/ijms21072654 - 10 Apr 2020
Cited by 23 | Viewed by 4236
Abstract
In the absence of proper immunity, such as in the case of acquired immune deficiency syndrome (AIDS) patients, Candida albicans, the most common human fungal pathogen, may cause mucosal and even life-threatening systemic infections. P-113 (AKRHHGYKRKFH), an antimicrobial peptide (AMP) derived from [...] Read more.
In the absence of proper immunity, such as in the case of acquired immune deficiency syndrome (AIDS) patients, Candida albicans, the most common human fungal pathogen, may cause mucosal and even life-threatening systemic infections. P-113 (AKRHHGYKRKFH), an antimicrobial peptide (AMP) derived from the human salivary protein histatin 5, shows good safety and efficacy profiles in gingivitis and human immunodeficiency virus (HIV) patients with oral candidiasis. However, little is known about how P-113 interacts with Candida albicans or its degradation by Candida-secreted proteases that contribute to the fungi’s resistance. Here, we use solution nuclear magnetic resonance (NMR) methods to elucidate the molecular mechanism of interactions between P-113 and living Candida albicans cells. Furthermore, we found that proteolytic cleavage of the C-terminus prevents the entry of P-113 into cells and that increasing the hydrophobicity of the peptide can significantly increase its antifungal activity. These results could help in the design of novel antimicrobial peptides that have enhanced stability in vivo and that can have potential therapeutic applications. Full article
(This article belongs to the Special Issue Selected Papers from the 8th Asia-Pacific NMR Symposium (APNMR): Recent Advances in NMR Spectroscopy)
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14 pages, 1852 KiB  
Review
Circulating Tumor Cell Clusters: United We Stand Divided We Fall
by Samuel Amintas, Aurélie Bedel, François Moreau-Gaudry, Julian Boutin, Louis Buscail, Jean-Philippe Merlio, Véronique Vendrely, Sandrine Dabernat and Etienne Buscail
Int. J. Mol. Sci. 2020, 21(7), 2653; https://doi.org/10.3390/ijms21072653 - 10 Apr 2020
Cited by 81 | Viewed by 6508
Abstract
The presence of circulating tumor cells (CTCs) and CTC clusters, also known as tumor microemboli, in biological fluids has long been described. Intensive research on single CTCs has made a significant contribution in understanding tumor invasion, metastasis tropism, and intra-tumor heterogeneity. Moreover, their [...] Read more.
The presence of circulating tumor cells (CTCs) and CTC clusters, also known as tumor microemboli, in biological fluids has long been described. Intensive research on single CTCs has made a significant contribution in understanding tumor invasion, metastasis tropism, and intra-tumor heterogeneity. Moreover, their being minimally invasive biomarkers has positioned them for diagnosis, prognosis, and recurrence monitoring tools. Initially, CTC clusters were out of focus, but major recent advances in the knowledge of their biogenesis and dissemination reposition them as critical actors in the pathophysiology of cancer, especially metastasis. Increasing evidence suggests that “united” CTCs, organized in clusters, resist better and carry stronger metastatic capacities than “divided” single CTCs. This review gathers recent insight on CTC cluster origin and dissemination. We will focus on their distinct molecular package necessary to resist multiple cell deaths that all circulating cells normally face. We will describe the molecular basis of their increased metastatic potential as compared to single CTCs. We will consider their clinical relevance as prognostic biomarkers. Finally, we will propose future directions for research and clinical applications in this promising topic in cancer. Full article
(This article belongs to the Special Issue Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics)
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21 pages, 4622 KiB  
Article
Functional Analysis of IRF1 Reveals its Role in the Activation of the Type I IFN Pathway in Golden Pompano, Trachinotus ovatus (Linnaeus 1758)
by Ke-Cheng Zhu, Nan Zhang, Bao-Suo Liu, Liang Guo, Hua-Yang Guo, Shi-Gui Jiang and Dian-Chang Zhang
Int. J. Mol. Sci. 2020, 21(7), 2652; https://doi.org/10.3390/ijms21072652 - 10 Apr 2020
Cited by 13 | Viewed by 3406
Abstract
Interferon (IFN) regulatory factor 1 (IRF1), a transcription factor with a novel helix–turn–helix DNA-binding domain, plays a crucial role in innate immunity by regulating the type I IFN signaling pathway. However, the regulatory mechanism through which IRF1 regulates type I IFN in fish [...] Read more.
Interferon (IFN) regulatory factor 1 (IRF1), a transcription factor with a novel helix–turn–helix DNA-binding domain, plays a crucial role in innate immunity by regulating the type I IFN signaling pathway. However, the regulatory mechanism through which IRF1 regulates type I IFN in fish is not yet elucidated. In the present study, IRF1 was characterized from golden pompano, Trachinotus ovatus (designated ToIRF1), and its immune function was identified to elucidate the transcriptional regulatory mechanism of ToIFNa3. The full-length complementary DNA (cDNA) of IRF1 is 1763 bp, including a 900-bp open reading frame (ORF) encoding a 299-amino-acid polypeptide. The putative protein sequence has 42.7–71.7% identity to fish IRF1 and possesses a representative conserved domain (a DNA-binding domain (DBD) at the N-terminus). The genomic DNA sequence of ToIRF1 consists of eight exons and seven introns. Moreover, ToIRF1 is constitutively expressed in all examined tissues, with higher levels being observed in immune-relevant tissues (whole blood, gill, and skin). Additionally, Cryptocaryon irritans challenge in vivo increases ToIRF1 expression in the skin as determined by Western blotting (WB); however, protein levels of ToIRF1 in the gill did not change significantly. The subcellular localization indicates that ToIRF1 is localized in the nucleus and cytoplasm with or without polyinosinic/polycytidylic acid (poly (I:C)) induction. Furthermore, overexpression of ToIRF1 or ToIFNa3 shows that ToIRF1 can notably activate ToIFNa3 and interferon signaling molecule expression. Promoter sequence analysis finds that several interferon stimulating response element (ISRE) binding sites are present in the promoter of ToIFNa3. Additionally, truncation, point mutation, and electrophoretic mobile shift (EMSA) assays confirmed that ToIRF1 M5 ISRE binding sites are functionally important for ToIFNa3 transcription. These results may help to illuminate the roles of teleost IRF1 in the transcriptional mechanisms of type I IFN in the immune process. Full article
(This article belongs to the Section Molecular Biology)
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14 pages, 10401 KiB  
Article
The Role of Taste Receptor mTAS1R3 in Chemical Communication of Gametes
by Michaela Frolikova, Tereza Otcenaskova, Eliska Valasková, Pavla Postlerova, Romana Stopkova, Pavel Stopka and Katerina Komrskova
Int. J. Mol. Sci. 2020, 21(7), 2651; https://doi.org/10.3390/ijms21072651 - 10 Apr 2020
Cited by 9 | Viewed by 3229
Abstract
Fertilization is a multiple step process leading to the fusion of female and male gametes and the formation of a zygote. Besides direct gamete membrane interaction via binding receptors localized on both oocyte and sperm surface, fertilization also involves gamete communication via chemical [...] Read more.
Fertilization is a multiple step process leading to the fusion of female and male gametes and the formation of a zygote. Besides direct gamete membrane interaction via binding receptors localized on both oocyte and sperm surface, fertilization also involves gamete communication via chemical molecules triggering various signaling pathways. This work focuses on a mouse taste receptor, mTAS1R3, encoded by the Tas1r3 gene, as a potential receptor mediating chemical communication between gametes using the C57BL/6J lab mouse strain. In order to specify the role of mTAS1R3, we aimed to characterize its precise localization in testis and sperm using super resolution microscopy. The testis cryo-section, acrosome-intact sperm released from cauda epididymis and sperm which underwent the acrosome reaction (AR) were evaluated. The mTAS1R3 receptor was detected in late spermatids where the acrosome was being formed and in the acrosomal cap of acrosome intact sperm. AR is triggered in mice during sperm maturation in the female reproductive tract and by passing through the egg surroundings such as cumulus oophorus cells. This AR onset is independent of the extracellular matrix of the oocyte called zona pellucida. After AR, the relocation of mTAS1R3 to the equatorial segment was observed and the receptor remained exposed to the outer surroundings of the female reproductive tract, where its physiological ligand, the amino acid L-glutamate, naturally occurs. Therefore, we targeted the possible interaction in vitro between the mTAS1R3 and L-glutamate as a part of chemical communication between sperm and egg and used an anti-mTAS1R3-specific antibody to block it. We detected that the acrosome reacted spermatozoa showed a chemotactic response in the presence of L-glutamate during and after the AR, and it is likely that mTAS1R3 acted as its mediator. Full article
(This article belongs to the Special Issue Advances in Molecular Regulation of Spermatozoa Function)
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13 pages, 1954 KiB  
Article
Karyopherin α-2 Mediates MDC1 Nuclear Import through a Functional Nuclear Localization Signal in the tBRCT Domain of MDC1
by Kamalakannan Radhakrishnan, Seon-Joo Park, Seok Won Kim, Gurusamy Hariharasudhan, Seo-Yeon Jeong, In Youb Chang and Jung-Hee Lee
Int. J. Mol. Sci. 2020, 21(7), 2650; https://doi.org/10.3390/ijms21072650 - 10 Apr 2020
Cited by 4 | Viewed by 3608
Abstract
Mediator of DNA damage checkpoint protein 1 (MDC1) plays a vital role in DNA damage response (DDR) by coordinating the repair of double strand breaks (DSBs). Here, we identified a novel interaction between MDC1 and karyopherin α-2 (KPNA2), a nucleocytoplasmic transport adaptor, and [...] Read more.
Mediator of DNA damage checkpoint protein 1 (MDC1) plays a vital role in DNA damage response (DDR) by coordinating the repair of double strand breaks (DSBs). Here, we identified a novel interaction between MDC1 and karyopherin α-2 (KPNA2), a nucleocytoplasmic transport adaptor, and showed that KPNA2 is necessary for MDC1 nuclear import. Thereafter, we identified a functional nuclear localization signal (NLS) between amino acid residues 1989–1994 of the two Breast Cancer 1 (BRCA1) carboxyl-terminal (tBRCT) domain of MDC1 and demonstrated disruption of this NLS impaired interaction between MDC1 and KPNA2 and reduced nuclear localization of MDC1. In KPNA2-depleted cells, the recruitment of MDC1, along with the downstream signaling p roteins Ring Finger Protein 8 (RNF8), 53BP1-binding protein 1 (53BP1), BRCA1, and Ring Finger Protein 168 (RNF168), to DNA damage sites was abolished. Additionally, KPNA2-depleted cells had a decreased rate of homologous recombination (HR) repair. Our data suggest that KPNA2-mediated MDC1 nuclear import is important for DDR signaling and DSB repair. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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13 pages, 3183 KiB  
Article
Combination of Arsenic Trioxide and Valproic Acid Efficiently Inhibits Growth of Lung Cancer Cells via G2/M-Phase Arrest and Apoptotic Cell Death
by Hyun Kyung Park, Bo Ram Han and Woo Hyun Park
Int. J. Mol. Sci. 2020, 21(7), 2649; https://doi.org/10.3390/ijms21072649 - 10 Apr 2020
Cited by 27 | Viewed by 3967
Abstract
Arsenic trioxide (ATO; As2O3) has anti-cancer effects in various solid tumors as well as hematological malignancy. Valproic acid (VPA), which is known to be a histone deacetylase inhibitor, has also anti-cancer properties in several cancer cells including lung cancer [...] Read more.
Arsenic trioxide (ATO; As2O3) has anti-cancer effects in various solid tumors as well as hematological malignancy. Valproic acid (VPA), which is known to be a histone deacetylase inhibitor, has also anti-cancer properties in several cancer cells including lung cancer cells. Combined treatment of ATO and VPA (ATO/VPA) could synergistically enhance anti-cancer effects and reduce ATO toxicity ATO. In this study, the combined anti-cancer effects of ATO and VPA (ATO/VPA) was investigated in NCI-H460 and NCI-H1299 lung cancer cells in vitro and in vivo. A combination of 3 μM ATO and 3 mM VPA (ATO/VPA) strongly inhibited the growths of both lung cancer cell types. DNA flow cytometry indicated that ATO/VPA significantly induced G2/M-phase arrest in both cell lines. In addition, ATO/VPA strongly increased the percentages of sub-G1 cells and annexin V-FITC positive cells in both cells. However, lactate dehydrogenase (LDH) release from cells was not increased in ATO/VPA-treated cells. In addition, ATO/VPA increased apoptosis in both cell types, accompanied by loss of mitochondrial membrane potential (MMP, ∆Ψm), activation of caspases, and cleavage of anti-poly ADP ribose polymerase-1. Moreover, a pan-caspase inhibitor, Z-VAD, significantly reduced apoptotic cell death induced by ATO/VPA. In the xenograft model, ATO/VPA synergistically inhibited growth of NCI-H460-derived xenograft tumors. In conclusion, the combination of ATO/VPA effectively inhibited the growth of lung cancer cells through G2/M-phase arrest and apoptotic cell death, and had a synergistic antitumor effect in vivo. Full article
(This article belongs to the Section Molecular Oncology)
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46 pages, 2352 KiB  
Review
Multifaceted Role of PRDM Proteins in Human Cancer
by Amelia Casamassimi, Monica Rienzo, Erika Di Zazzo, Anna Sorrentino, Donatella Fiore, Maria Chiara Proto, Bruno Moncharmont, Patrizia Gazzerro, Maurizio Bifulco and Ciro Abbondanza
Int. J. Mol. Sci. 2020, 21(7), 2648; https://doi.org/10.3390/ijms21072648 - 10 Apr 2020
Cited by 44 | Viewed by 8205
Abstract
The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [...] Read more.
The PR/SET domain family (PRDM) comprise a family of genes whose protein products share a conserved N-terminal PR [PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ1 (retinoblastoma protein-interacting zinc finger gene 1)] homologous domain structurally and functionally similar to the catalytic SET [Su(var)3-9, enhancer-of-zeste and trithorax] domain of histone methyltransferases (HMTs). These genes are involved in epigenetic regulation of gene expression through their intrinsic HMTase activity or via interactions with other chromatin modifying enzymes. In this way they control a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, and maintenance of immune cell homeostasis. In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications. A common characteristic of most PRDM genes is to encode for two main molecular variants with or without the PR domain. They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed. In this scenario, PRDM proteins are involved in cancer onset, invasion, and metastasis and their altered expression is related to poor prognosis and clinical outcome. These functions strongly suggest their potential use in cancer management as diagnostic or prognostic tools and as new targets of therapeutic intervention. Full article
(This article belongs to the Special Issue Zinc-Finger Proteins in Health and Disease: Focus on PRDMs)
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3 pages, 184 KiB  
Reply
Reply to Comments: Using the Cardio-Ankle Vascular Index (CAVI) or the Mathematical Correction Form (CAVI0) in Clinical Practice
by Bart Spronck, Alexander Jurko, Michal Mestanik, Alberto P. Avolio and Ingrid Tonhajzerova
Int. J. Mol. Sci. 2020, 21(7), 2647; https://doi.org/10.3390/ijms21072647 - 10 Apr 2020
Cited by 3 | Viewed by 2443
Abstract
We read with great interest Alizargar et al [...] Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Pathophysiology and Molecular Mechanisms)
12 pages, 2987 KiB  
Article
CD44 Can Compensate for IgSF11 Deficiency by Associating with the Scaffold Protein PSD-95 during Osteoclast Differentiation
by Hyunsoo Kim, Noriko Takegahara, Matthew C. Walsh and Yongwon Choi
Int. J. Mol. Sci. 2020, 21(7), 2646; https://doi.org/10.3390/ijms21072646 - 10 Apr 2020
Cited by 6 | Viewed by 3201
Abstract
Differentiation of osteoclasts, which are specialized multinucleated macrophages capable of bone resorption, is driven primarily by receptor activator of NF-κB ligand (RANKL). Additional signaling from cell surface receptors, such as cell adhesion molecules (CAMs), is also required for osteoclast maturation. Previously, we have [...] Read more.
Differentiation of osteoclasts, which are specialized multinucleated macrophages capable of bone resorption, is driven primarily by receptor activator of NF-κB ligand (RANKL). Additional signaling from cell surface receptors, such as cell adhesion molecules (CAMs), is also required for osteoclast maturation. Previously, we have demonstrated that immunoglobulin superfamily 11 (IgSF11), a member of the immunoglobulin-CAM (IgCAM) family, plays an important role in osteoclast differentiation through association with the scaffold protein postsynaptic density protein 95 (PSD-95). Here, we demonstrate that the osteoclast-expressed CAM CD44 can compensate for IgSF11 deficiency when cell–cell interaction conditions are suboptimal by associating with PSD-95. Impaired osteoclast differentiation in IgSF11-deficient (IgSF11−/−) cultures was rescued by antibody-mediated stimulation of CD44 or by treatment with low-molecular-weight hyaluronan (LMW-HA), a CD44 ligand. Biochemical analysis revealed that PSD-95, which is required for osteoclast differentiation, associates with CD44 in osteoclasts regardless of the presence or absence of IgSF11. RNAi-mediated knockdown of PSD-95 abrogated the effects of either CD44 stimulation or LMW-HA treatment on osteoclast differentiation, suggesting that CD44, similar to IgSF11, is functionally associated with PSD-95 during osteoclast differentiation. Taken together, these results reveal that CD44 can compensate for IgSF11 deficiency in osteoclasts through association with PSD-95. Full article
(This article belongs to the Special Issue Osteoclast Multinucleation Mechanisms)
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22 pages, 406 KiB  
Review
Promising Perspectives for Detection, Identification, and Quantification of Plant Pathogenic Fungi and Oomycetes through Targeting Mitochondrial DNA
by Tomasz Kulik, Katarzyna Bilska and Maciej Żelechowski
Int. J. Mol. Sci. 2020, 21(7), 2645; https://doi.org/10.3390/ijms21072645 - 10 Apr 2020
Cited by 29 | Viewed by 4394
Abstract
Fungi and oomycetes encompass many pathogens affecting crops worldwide. Their effective control requires screening pathogens across the local and international trade networks along with the monitoring of pathogen inocula in the field. Fundamentals to all of these concerns are their efficient detection, identification, [...] Read more.
Fungi and oomycetes encompass many pathogens affecting crops worldwide. Their effective control requires screening pathogens across the local and international trade networks along with the monitoring of pathogen inocula in the field. Fundamentals to all of these concerns are their efficient detection, identification, and quantification. The use of molecular markers showed the best promise in the field of plant pathogen diagnostics. However, despite the unquestionable benefits of DNA-based methods, two significant limitations are associated with their use. The first limitation concerns the insufficient level of sensitivity due to the very low and uneven distribution of pathogens in plant material. The second limitation pertains to the inability of widely used diagnostic assays to detect cryptic species. Targeting mtDNA appears to provide a solution to these challenges. Its high copy number in microbial cells makes mtDNA an attractive target for developing highly sensitive assays. In addition, previous studies on different pathogen taxa indicated that mitogenome sequence variation could improve cryptic species delimitation accuracy. This review sheds light on the potential application of mtDNA for pathogen diagnostics. This paper covers a brief description of qPCR and DNA barcoding as two major strategies enabling the diagnostics of plant pathogenic fungi and oomycetes. Both strategies are discussed along with the potential use of mtDNA, including their strengths and weaknesses. Full article
(This article belongs to the Section Molecular Microbiology)
23 pages, 1628 KiB  
Article
Novel Urethane-Dimethacrylate Monomers and Compositions for Use as Matrices in Dental Restorative Materials
by Izabela M. Barszczewska-Rybarek, Marta W. Chrószcz and Grzegorz Chladek
Int. J. Mol. Sci. 2020, 21(7), 2644; https://doi.org/10.3390/ijms21072644 - 10 Apr 2020
Cited by 42 | Viewed by 4422
Abstract
In this study, novel urethane-dimethacrylate monomers were synthesized from 1,3-bis(1-isocyanato-1-methylethyl)benzene (MEBDI) and oligoethylene glycols monomethacrylates, containing one to three oxyethylene groups. They can potentially be utilized as matrices in dental restorative materials. The obtained monomers were used to prepare four new formulations. Two [...] Read more.
In this study, novel urethane-dimethacrylate monomers were synthesized from 1,3-bis(1-isocyanato-1-methylethyl)benzene (MEBDI) and oligoethylene glycols monomethacrylates, containing one to three oxyethylene groups. They can potentially be utilized as matrices in dental restorative materials. The obtained monomers were used to prepare four new formulations. Two of them were solely composed of the MEBDI-based monomers. In a second pair, a monomer based on triethylene glycol monomethacrylate, used in 20 wt.%, was replaced with triethylene glycol dimethacrylate (TEGDMA), a reactive diluent typically used in dental materials. For comparison purposes, two formulations, using typical dental dimethacrylates (bisphenol A glycerolate dimethacrylate (Bis-GMA), urethane-dimethacrylate (UDMA) and TEGDMA) were prepared. The monomers and mixtures were tested for the viscosity and density. The homopolymers and copolymers, obtained via photopolymerization, were tested for the degree of conversion, polymerization shrinkage, water sorption and solubility, hardness, flexural strength and modulus. The newly developed formulations achieved promising physico-chemical and mechanical characteristics so as to be suitable for applications as dental composite matrices. A combination of the MEBDI-based urethane-dimethacrylates with TEGDMA resulted in copolymers with a high degree of conversion, low polymerization shrinkage, low water sorption and water solubility, and good mechanical properties. These parameters showed an improvement in relation to currently used dental formulations. Full article
(This article belongs to the Special Issue Recent Advances in Dental Materials and Biomaterials)
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15 pages, 2212 KiB  
Article
Patches and Blebs: A Comparative Study of the Composition and Biophysical Properties of Two Plasma Membrane Preparations from CHO Cells
by Bingen G. Monasterio, Noemi Jiménez-Rojo, Aritz B. García-Arribas, Howard Riezman, Félix M. Goñi and Alicia Alonso
Int. J. Mol. Sci. 2020, 21(7), 2643; https://doi.org/10.3390/ijms21072643 - 10 Apr 2020
Cited by 7 | Viewed by 4160
Abstract
This study was aimed at preparing and characterizing plasma membranes (PM) from Chinese Hamster Ovary (CHO) cells. Two methods of PM preparation were applied, one based on adhering cells to a poly-lysine-coated surface, followed by hypotonic lysis and removal of intracellular components, so [...] Read more.
This study was aimed at preparing and characterizing plasma membranes (PM) from Chinese Hamster Ovary (CHO) cells. Two methods of PM preparation were applied, one based on adhering cells to a poly-lysine-coated surface, followed by hypotonic lysis and removal of intracellular components, so that PM patches remain adhered to each other, and a second one consisting of bleb induction in cells, followed by separation of giant plasma membrane vesicles (GPMV). Both methods gave rise to PM in sufficient amounts to allow biophysical and biochemical characterization. Laurdan generalized polarization was used to measure molecular order in membranes, PM preparations were clearly more ordered than the average cell membranes (GP ≈0.450 vs. ≈0.20 respectively). Atomic force microscopy was used in the force spectroscopy mode to measure breakthrough forces of PM, both PM preparations provided values in the 4–6 nN range, while the corresponding value for whole cell lipid extracts was ≈2 nN. Lipidomic analysis of the PM preparations revealed that, as compared to the average cell membranes, PM were enriched in phospholipids containing 30–32 C atoms in their acyl chains but were relatively poor in those containing 34–40 C atoms. PM contained more saturated and less polyunsaturated fatty acids than the average cell membranes. Blebs (GPMV) and patches were very similar in their lipid composition, except that blebs contained four-fold the amount of cholesterol of patches (≈23 vs. ≈6 mol% total membrane lipids) while the average cell lipids contained 3 mol%. The differences in lipid composition are in agreement with the observed variations in physical properties between PM and whole cell membranes. Full article
(This article belongs to the Special Issue Lipid-Protein and Protein-Protein Interactions in Membranes)
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15 pages, 4771 KiB  
Article
Moss-Derived Human Recombinant GAA Provides an Optimized Enzyme Uptake in Differentiated Human Muscle Cells of Pompe Disease
by Stefan Hintze, Sarah Limmer, Paulina Dabrowska-Schlepp, Birgit Berg, Nicola Krieghoff, Andreas Busch, Andreas Schaaf, Peter Meinke and Benedikt Schoser
Int. J. Mol. Sci. 2020, 21(7), 2642; https://doi.org/10.3390/ijms21072642 - 10 Apr 2020
Cited by 13 | Viewed by 4779
Abstract
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The result of the GAA deficiency is a ubiquitous lysosomal and non-lysosomal accumulation of glycogen. The most affected tissues are heart, skeletal muscle, liver, and [...] Read more.
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The result of the GAA deficiency is a ubiquitous lysosomal and non-lysosomal accumulation of glycogen. The most affected tissues are heart, skeletal muscle, liver, and the nervous system. Replacement therapy with the currently approved enzyme relies on M6P-mediated endocytosis. However, therapeutic outcomes still leave room for improvement, especially with regard to skeletal muscles. We tested the uptake, activity, and effect on glucose metabolism of a non-phosphorylated recombinant human GAA produced in moss (moss-GAA). Three variants of moss-GAA differing in glycosylation pattern have been analyzed: two with terminal mannose residues in a paucimannosidic (Man3) or high-mannose (Man 5) configuration and one with terminal N-acetylglucosamine residues (GnGn). Compared to alglucosidase alfa the moss-GAA GnGn variant showed increased uptake in differentiated myotubes. Moreover, incubation of immortalized muscle cells of Gaa−/− mice with moss-GAA GnGn led to similarly efficient clearance of accumulated glycogen as with alglucosidase alfa. These initial data suggest that M6P-residues might not always be necessary for the cellular uptake in enzyme replacement therapy (ERT) and indicate the potential of moss-GAA GnGn as novel alternative drug for targeting skeletal muscle in Pompe patients. Full article
(This article belongs to the Special Issue Pathophysiology, Molecular Mechanism and Therapeutic Strategies of Lysosomal Storage Disorders (LSD))
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23 pages, 1285 KiB  
Review
Myocardium Metabolism in Physiological and Pathophysiological States: Implications of Epicardial Adipose Tissue and Potential Therapeutic Targets
by Nerea Gandoy-Fieiras, Jose Ramon Gonzalez-Juanatey and Sonia Eiras
Int. J. Mol. Sci. 2020, 21(7), 2641; https://doi.org/10.3390/ijms21072641 - 10 Apr 2020
Cited by 26 | Viewed by 5337
Abstract
The main energy substrate of adult cardiomyocytes for their contractility are the fatty acids. Its metabolism generates high ATP levels at the expense of high oxygen consumption in the mitochondria. Under low oxygen supply, they can get energy from other substrates, mainly glucose, [...] Read more.
The main energy substrate of adult cardiomyocytes for their contractility are the fatty acids. Its metabolism generates high ATP levels at the expense of high oxygen consumption in the mitochondria. Under low oxygen supply, they can get energy from other substrates, mainly glucose, lactate, ketone bodies, etc., but the mitochondrial dysfunction, in pathological conditions, reduces the oxidative metabolism. In consequence, fatty acids are stored into epicardial fat and its accumulation provokes inflammation, insulin resistance, and oxidative stress, which enhance the myocardium dysfunction. Some therapies focused on improvement the fatty acids entry into mitochondria have failed to demonstrate benefits on cardiovascular disorders. Oppositely, those therapies with effects on epicardial fat volume and inflammation might improve the oxidative metabolism of myocardium and might reduce the cardiovascular disease progression. This review aims at explain (a) the energy substrate adaptation of myocardium in physiological conditions, (b) the reduction of oxidative metabolism in pathological conditions and consequences on epicardial fat accumulation and insulin resistance, and (c) the reduction of cardiovascular outcomes after regulation by some therapies. Full article
(This article belongs to the Special Issue Adipogenesis and Adipose Tissue Metabolism)
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17 pages, 2892 KiB  
Article
Histone Deacetylase TaHDT701 Functions in TaHDA6-TaHOS15 Complex to Regulate Wheat Defense Responses to Blumeria graminis f.sp. tritici
by Pengfei Zhi, Lingyao Kong, Jiao Liu, Xiaona Zhang, Xiaoyu Wang, Haoyu Li, Maokai Sun, Yan Li and Cheng Chang
Int. J. Mol. Sci. 2020, 21(7), 2640; https://doi.org/10.3390/ijms21072640 - 10 Apr 2020
Cited by 31 | Viewed by 3628
Abstract
Powdery mildew disease caused by Blumeria graminis f.sp. tritici (Bgt) leads to severe economic losses in bread wheat (Triticum aestivum L.). To date, only a few epigenetic modulators have been revealed to regulate wheat powdery mildew resistance. In this study, [...] Read more.
Powdery mildew disease caused by Blumeria graminis f.sp. tritici (Bgt) leads to severe economic losses in bread wheat (Triticum aestivum L.). To date, only a few epigenetic modulators have been revealed to regulate wheat powdery mildew resistance. In this study, the histone deacetylase 2 (HD2) type histone deacetylase TaHDT701 was identified as a negative regulator of wheat defense responses to Bgt. Using multiple approaches, we demonstrated that TaHDT701 associates with the RPD3 type histone deacetylase TaHDA6 and the WD40-repeat protein TaHOS15 to constitute a histone deacetylase complex, in which TaHDT701 could stabilize the TaHDA6-TaHOS15 association. Furthermore, knockdown of TaHDT701, TaHDA6, and TaHOS15 resulted in enhanced wheat powdery mildew resistance, suggesting that the TaHDT701-TaHDA6-TaHOS15 histone deacetylase complex negatively regulates wheat defense responses to Bgt. Moreover, chromatin immunoprecipitation assays revealed that TaHDT701 could function in concert with TaHOS15 to recruit TaHDA6 to the promoters of defense-related genes such as TaPR1, TaPR2, TaPR5, and TaWRKY45. In addition, silencing of TaHDT701, TaHDA6, and TaHOS15 resulted in the up-regulation of TaPR1, TaPR2, TaPR5, and TaWRKY45 accompanied with increased histone acetylation and methylation, as well as reduced nucleosome occupancy, at their promoters, suggesting that the TaHDT701-TaHDA6-TaHOS15 histone deacetylase complex suppresses wheat powdery mildew resistance by modulating chromatin state at defense-related genes. Full article
(This article belongs to the Special Issue Wheat and Barley: Acclimatization to Abiotic and Biotic Stress)
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2 pages, 177 KiB  
Correction
Correction:Chlamydia psittaci PmpD-N Modulated Chicken Macrophage Function by Triggering Th2 Polarization and the TLR2/MyD88/NF-κB Signaling Pathway
by Jun Chu, Xiaohui Li, Guanggang Qu, Yihui Wang, Qiang Li, Yongxia Guo, Lei Hou, Jue Liu, Francis O. Eko and Cheng He
Int. J. Mol. Sci. 2020, 21(7), 2639; https://doi.org/10.3390/ijms21072639 - 10 Apr 2020
Cited by 2 | Viewed by 2093
Abstract
The authors would like to make the following corrections to their paper, published in the International Journal of Molecular Sciences [...] Full article
(This article belongs to the Special Issue Intracellular Organelle Rearrangement Induced by Pathogenic Infections)
3 pages, 820 KiB  
Correction
Correction: Wang, Y.T., et al. Selenium Nanoparticle Synthesized by Proteus mirabilis YC801: An Efficacious Pathway for Selenite Biotransformation and Detoxification. Int. J. Mol. Sci. 2018, 19, 3809
by Yuting Wang, Xian Shu, Jinyan Hou, Weili Lu, Weiwei Zhao, Shengwei Huang and Lifang Wu
Int. J. Mol. Sci. 2020, 21(7), 2638; https://doi.org/10.3390/ijms21072638 - 10 Apr 2020
Cited by 3 | Viewed by 2043
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Section Biochemistry)
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19 pages, 5045 KiB  
Article
Electrophoretic Deposition of Copper(II)–Chitosan Complexes for Antibacterial Coatings
by Muhammad Asim Akhtar, Kanwal Ilyas, Ivo Dlouhý, Filip Siska and Aldo R. Boccaccini
Int. J. Mol. Sci. 2020, 21(7), 2637; https://doi.org/10.3390/ijms21072637 - 10 Apr 2020
Cited by 43 | Viewed by 5657
Abstract
Bacterial infection associated with medical implants is a major threat to healthcare. This work reports the fabrication of Copper(II)–Chitosan (Cu(II)–CS) complex coatings deposited by electrophoretic deposition (EPD) as potential antibacterial candidate to combat microorganisms to reduce implant related infections. The successful deposition of [...] Read more.
Bacterial infection associated with medical implants is a major threat to healthcare. This work reports the fabrication of Copper(II)–Chitosan (Cu(II)–CS) complex coatings deposited by electrophoretic deposition (EPD) as potential antibacterial candidate to combat microorganisms to reduce implant related infections. The successful deposition of Cu(II)–CS complex coatings on stainless steel was confirmed by physicochemical characterizations. Morphological and elemental analyses by scanning electron microscopy (SEM) and energy-dispersive X-ray (EDX) spectroscopy verified the uniform distribution of copper in the Chitosan (CS) matrix. Moreover, homogeneous coatings without precipitation of metallic copper were confirmed by X-ray diffraction (XRD) spectroscopy and SEM micrographs. Controlled swelling behavior depicted the chelation of copper with polysaccharide chains that is key to the stability of Cu(II)–CS coatings. All investigated systems exhibited stable degradation rate in phosphate buffered saline (PBS)–lysozyme solution within seven days of incubation. The coatings presented higher mechanical properties with the increase in Cu(II) concentration. The crack-free coatings showed mildly hydrophobic behavior. Antibacterial assays were performed using both Gram-positive and Gram-negative bacteria. Outstanding antibacterial properties of the coatings were confirmed. After 24 h of incubation, cell studies of coatings confirms that up to a certain threshold concentration of Cu(II) were not cytotoxic to human osteoblast-like cells. Overall, our results show that uniform and homogeneous Cu(II)–CS coatings with good antibacterial and enhanced mechanical stability could be successfully deposited by EPD. Such antibiotic-free antibacterial coatings are potential candidates for biomedical implants. Full article
(This article belongs to the Special Issue Chitosan Functionalizations, Formulations and Composites)
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14 pages, 3589 KiB  
Article
Underlying Ossification Phenotype in a Murine Model of Metastatic Synovial Sarcoma
by Matthew Kirkham, Austen Kalivas, Kaniz Fatema, Sarah Luelling, Brooke H. Dubansky, Benjamin Dubansky, Kevin B. Jones and Jared J. Barrott
Int. J. Mol. Sci. 2020, 21(7), 2636; https://doi.org/10.3390/ijms21072636 - 10 Apr 2020
Cited by 3 | Viewed by 3930
Abstract
Synovial sarcoma, an uncommon cancer, typically affects young adults. Survival rates range from 36% to 76%, decreasing significantly when metastases are present. Synovial sarcomas form in soft tissues, often near bones, with about 10% demonstrating ossification in the tumor. The literature is inconclusive [...] Read more.
Synovial sarcoma, an uncommon cancer, typically affects young adults. Survival rates range from 36% to 76%, decreasing significantly when metastases are present. Synovial sarcomas form in soft tissues, often near bones, with about 10% demonstrating ossification in the tumor. The literature is inconclusive on whether the presence of ossification portends a worse prognosis. To this end, we analyzed our genetic mouse models of synovial sarcoma to determine the extent of ossification in the tumors and its relationship with morbidity. We noted higher ossification within our metastatic mouse model of synovial sarcoma. Not only did we observe ossification within the tumors at a frequency of 7%, but an even higher frequency, 72%, of bone reactivity was detected by radiography. An enrichment of bone development genes was associated with primary tumors, even in the absence of an ossification phenotype. In spite of the ossification being intricately linked with the metastatic model, the presence of ossification was not associated with a faster or worse morbidity in the mice. Our conclusion is that both metastasis and ossification are dependent on time, but that they are independent of one another. Full article
(This article belongs to the Special Issue Cancer Cell Reprogramming)
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18 pages, 5095 KiB  
Article
Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies
by Ana Nikolic, Takako I Jones, Monica Govi, Fabiano Mele, Louise Maranda, Francesco Sera, Giulia Ricci, Lucia Ruggiero, Liliana Vercelli, Simona Portaro, Luisa Villa, Chiara Fiorillo, Lorenzo Maggi, Lucio Santoro, Giovanni Antonini, Massimiliano Filosto, Maurizio Moggio, Corrado Angelini, Elena Pegoraro, Angela Berardinelli, Maria Antonetta Maioli, Grazia D’Angelo, Antonino Di Muzio, Gabriele Siciliano, Giuliano Tomelleri, Maurizio D’Esposito, Floriana Della Ragione, Arianna Brancaccio, Rachele Piras, Carmelo Rodolico, Tiziana Mongini, Frederique Magdinier, Valentina Salsi, Peter L. Jones and Rossella Tupleradd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2020, 21(7), 2635; https://doi.org/10.3390/ijms21072635 - 10 Apr 2020
Cited by 16 | Viewed by 3803
Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the [...] Read more.
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis. We exploited the Italian Registry for FSHD, in which FSHD families are classified using the Clinical Comprehensive Evaluation Form (CCEF). A total of 122 index cases showing a classical FSHD phenotype (CCEF, category A) and 110 relatives were selected to test with the receiver operating characteristic (ROC) curve, the diagnostic and predictive value of D4Z4 methylation. Moreover, we performed DNA methylation analysis in selected large families with reduced penetrance characterized by the co-presence of subjects carriers of one D4Z4 reduced allele with no signs of disease or presenting the classic FSHD clinical phenotype. We observed a wide variability in the D4Z4 methylation levels among index cases revealing no association with clinical manifestation or disease severity. By extending the analysis to family members, we revealed the low predictive value of D4Z4 methylation in detecting the affected condition. In view of the variability in D4Z4 methylation profiles observed in our large cohort, we conclude that D4Z4 methylation does not mirror the clinical expression of FSHD. We recommend that measurement of this epigenetic mark must be interpreted with caution in clinical practice. Full article
(This article belongs to the Special Issue Epigenetic Alterations in Neuromuscular Disorders)
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17 pages, 1799 KiB  
Article
Identification and Characterization of the Lactating Mouse Mammary Gland Citrullinome
by Guangyuan Li, Coleman H. Young, Bryce Snow, Amanda O. Christensen, M. Kristen Demoruelle, Venkatesh V. Nemmara, Paul R. Thompson, Heather M. Rothfuss and Brian D. Cherrington
Int. J. Mol. Sci. 2020, 21(7), 2634; https://doi.org/10.3390/ijms21072634 - 10 Apr 2020
Cited by 6 | Viewed by 3630
Abstract
Citrullination is a post-translational modification (PTM) in which positively charged peptidyl-arginine is converted into neutral peptidyl-citrulline by peptidylarginine deiminase (PAD or PADI) enzymes. The full protein citrullinome in many tissues is unknown. Herein, we used mass spectrometry and identified 107 citrullinated proteins in [...] Read more.
Citrullination is a post-translational modification (PTM) in which positively charged peptidyl-arginine is converted into neutral peptidyl-citrulline by peptidylarginine deiminase (PAD or PADI) enzymes. The full protein citrullinome in many tissues is unknown. Herein, we used mass spectrometry and identified 107 citrullinated proteins in the lactation day 9 (L9) mouse mammary gland including histone H2A, α-tubulin, and β-casein. Given the importance of prolactin to lactation, we next tested if it stimulates PAD-catalyzed citrullination using mouse mammary epithelial CID-9 cells. Stimulation of CID-9 cells with 5 µg/mL prolactin for 10 min induced a 2-fold increase in histone H2A citrullination and a 4.5-fold increase in α-tubulin citrullination. We next investigated if prolactin-induced citrullination regulates the expression of lactation genes β-casein (Csn2) and butyrophilin (Btn1a1). Prolactin treatment for 12 h increased β-casein and butyrophilin mRNA expression; however, this increase was significantly inhibited by the pan-PAD inhibitor, BB-Cl-amidine (BB-ClA). We also examined the effect of tubulin citrullination on the overall polymerization rate of microtubules. Our results show that citrullinated tubulin had a higher maximum overall polymerization rate. Our work suggests that protein citrullination is an important PTM that regulates gene expression and microtubule dynamics in mammary epithelial cells. Full article
(This article belongs to the Special Issue Peptidylarginine Deiminases and Protein Deimination in Health and Disease)
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13 pages, 429 KiB  
Review
Genes and Diet in the Prevention of Chronic Diseases in Future Generations
by Marica Franzago, Daniele Santurbano, Ester Vitacolonna and Liborio Stuppia
Int. J. Mol. Sci. 2020, 21(7), 2633; https://doi.org/10.3390/ijms21072633 - 10 Apr 2020
Cited by 73 | Viewed by 17240
Abstract
Nutrition is a modifiable key factor that is able to interact with both the genome and epigenome to influence human health and fertility. In particular, specific genetic variants can influence the response to dietary components and nutrient requirements, and conversely, the diet itself [...] Read more.
Nutrition is a modifiable key factor that is able to interact with both the genome and epigenome to influence human health and fertility. In particular, specific genetic variants can influence the response to dietary components and nutrient requirements, and conversely, the diet itself is able to modulate gene expression. In this context and the era of precision medicine, nutrigenetic and nutrigenomic studies offer significant opportunities to improve the prevention of metabolic disturbances, such as Type 2 diabetes, gestational diabetes, hypertension, and cardiovascular diseases, even with transgenerational effects. The present review takes into account the interactions between diet, genes and human health, and provides an overview of the role of nutrigenetics, nutrigenomics and epigenetics in the prevention of non-communicable diseases. Moreover, we focus our attention on the mechanism of intergenerational or transgenerational transmission of the susceptibility to metabolic disturbances, and underline that the reversibility of epigenetic modifications through dietary intervention could counteract perturbations induced by lifestyle and environmental factors. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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30 pages, 2485 KiB  
Review
Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities
by Lucas Opazo-Ríos, Sebastián Mas, Gema Marín-Royo, Sergio Mezzano, Carmen Gómez-Guerrero, Juan Antonio Moreno and Jesús Egido
Int. J. Mol. Sci. 2020, 21(7), 2632; https://doi.org/10.3390/ijms21072632 - 10 Apr 2020
Cited by 201 | Viewed by 15643
Abstract
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal [...] Read more.
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity. Full article
(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)
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21 pages, 1207 KiB  
Review
Inducible Polarized Secretion of Exosomes in T and B Lymphocytes
by Victor Calvo and Manuel Izquierdo
Int. J. Mol. Sci. 2020, 21(7), 2631; https://doi.org/10.3390/ijms21072631 - 10 Apr 2020
Cited by 41 | Viewed by 6189
Abstract
Exosomes are extracellular vesicles (EV) of endosomal origin (multivesicular bodies, MVB) constitutively released by many different eukaryotic cells by fusion of MVB to the plasma membrane. However, inducible exosome secretion controlled by cell surface receptors is restricted to very few cell types and [...] Read more.
Exosomes are extracellular vesicles (EV) of endosomal origin (multivesicular bodies, MVB) constitutively released by many different eukaryotic cells by fusion of MVB to the plasma membrane. However, inducible exosome secretion controlled by cell surface receptors is restricted to very few cell types and a limited number of cell surface receptors. Among these, exosome secretion is induced in T lymphocytes and B lymphocytes when stimulated at the immune synapse (IS) via T-cell receptors (TCR) and B-cell receptors (BCR), respectively. IS formation by T and B lymphocytes constitutes a crucial event involved in antigen-specific, cellular, and humoral immune responses. Upon IS formation by T and B lymphocytes with antigen-presenting cells (APC), the convergence of MVB towards the microtubule organization center (MTOC), and MTOC polarization to the IS, are involved in polarized exosome secretion at the synaptic cleft. This specialized mechanism provides the immune system with a finely-tuned strategy to increase the specificity and efficiency of crucial secretory effector functions of B and T lymphocytes. As inducible exosome secretion by antigen-receptors is a critical and unique feature of the immune system this review considers the study of the traffic events leading to polarized exosome secretion at the IS and some of their biological consequences. Full article
(This article belongs to the Special Issue Signaling and Organelle Polarization at the Immunological Synapse)
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18 pages, 1762 KiB  
Article
The Effect of Nanosystems on ATP-Binding Cassette Transporters: Understanding the Influence of Nanosystems on Multidrug Resistance Protein-1 and P-glycoprotein
by Francisco V.C. Mello, Gabriela N. de Moraes, Raquel C. Maia, Jennifer Kyeremateng, Surtaj Hussain Iram and Ralph Santos-Oliveira
Int. J. Mol. Sci. 2020, 21(7), 2630; https://doi.org/10.3390/ijms21072630 - 10 Apr 2020
Cited by 9 | Viewed by 3543
Abstract
The cancer multidrug resistance is involved in the failure of several treatments during cancer treatment. It is a phenomenon that has been receiving great attention in the last years due to the sheer amount of mechanisms discovered and involved in the process of [...] Read more.
The cancer multidrug resistance is involved in the failure of several treatments during cancer treatment. It is a phenomenon that has been receiving great attention in the last years due to the sheer amount of mechanisms discovered and involved in the process of resistance which hinders the effectiveness of many anti-cancer drugs. Among the mechanisms involved in the multidrug resistance, the participation of ATP-binding cassette (ABC) transporters is the main one. The ABC transporters are a group of plasma membrane and intracellular organelle proteins involved in the process of externalization of substrates from cells, which are expressed in cancer. They are involved in the clearance of intracellular metabolites as ions, hormones, lipids and other small molecules from the cell, affecting directly and indirectly drug absorption, distribution, metabolism and excretion. Other mechanisms responsible for resistance are the signaling pathways and the anti- and pro-apoptotic proteins involved in cell death by apoptosis. In this study we evaluated the influence of three nanosystem (Graphene Quantum Dots (GQDs), mesoporous silica (MSN) and poly-lactic nanoparticles (PLA)) in the main mechanism related to the cancer multidrug resistance such as the Multidrug Resistance Protein-1 and P-glycoprotein. We also evaluated this influence in a group of proteins involved in the apoptosis-related resistance including cIAP-1, XIAP, Bcl-2, BAK and Survivin proteins. Last, colonogenic and MTT (3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assays have also been performed. The results showed, regardless of the concentration used, GQDs, MSN and PLA were not cytotoxic to MDA-MB-231 cells and showed no impairment in the colony formation capacity. In addition, it has been observed that P-gp membrane expression was not significantly altered by any of the three nanomaterials. The results suggest that GQDs nanoparticles would be suitable for the delivery of other multidrug resistance protein 1 (MRP1) substrate drugs that bind to the transporter at the same binding pocket, while MSN can strongly inhibit doxorubicin efflux by MRP1. On the other hand, PLA showed moderate inhibition of doxorubicin efflux by MRP1 suggesting that this nanomaterial can also be useful to treat MDR (Multidrug resistance) due to MRP1 overexpression. Full article
(This article belongs to the Special Issue Nanomedicine, Nanopharmacy and Nanobiomaterials)
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2 pages, 161 KiB  
Correction
Correction: Shoombuatong, W., et al. iQSP: A Sequence-Based Tool for the Prediction and Analysis of Quorum Sensing Peptides via Chou’s 5-Steps Rule and Informative Physicochemical Properties. Int. J. Mol. Sci. 2020, 21, 75
by Phasit Charoenkwan, Nalini Schaduangrat, Chanin Nantasenamat, Theeraphon Piacham and Watshara Shoombuatong
Int. J. Mol. Sci. 2020, 21(7), 2629; https://doi.org/10.3390/ijms21072629 - 10 Apr 2020
Cited by 4 | Viewed by 2188
Abstract
The authors wish to make the following corrections to this paper: [...] Full article
(This article belongs to the Section Molecular Informatics)
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