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Int. J. Mol. Sci., Volume 20, Issue 21 (November-1 2019) – 276 articles

Cover Story (view full-size image): MeCP2 is an epigenetic factor mutated in Rett syndrome, a neurodevelopmental disorder. MeCP2 and ATRX accumulate at chromocenters, which form repressive nuclear compartments. We show that MeCP2 and ATRX are reciprocally dependent on their expression and targeting of chromocenters in neurons. ATRX contributes to chromocenter clustering, the accumulation of HP1 at chromocenters and, as MeCP2, modulates their expression. Moreover, ATRX and HP1 targeting of chromocenters depend on an RNA moiety. We dissected the functional interplay between MeCP2 and ATRX in heterochromatin organization in neurons. View this paper.
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16 pages, 1500 KiB  
Article
First Insights on the Presence of the Unfolded Protein Response in Human Spermatozoa
by Joana Santiago, Joana Vieira Silva and Margarida Fardilha
Int. J. Mol. Sci. 2019, 20(21), 5518; https://doi.org/10.3390/ijms20215518 - 05 Nov 2019
Cited by 17 | Viewed by 3846
Abstract
The unfolded protein response (UPR) is involved in protein quality control and is activated in response to several stressors. Although in testis the UPR mechanisms are well described, their presence in spermatozoa is contentious. We aimed to investigate the presence of UPR-related proteins [...] Read more.
The unfolded protein response (UPR) is involved in protein quality control and is activated in response to several stressors. Although in testis the UPR mechanisms are well described, their presence in spermatozoa is contentious. We aimed to investigate the presence of UPR-related proteins in human sperm and the impact of oxidative stress induction in UPR activation. To identify UPR-related proteins in human sperm, a bioinformatic approach was adopted. To explore the activation of UPR, sperm were exposed to hydrogen peroxide (H2O2) and motility, vitality, and the levels of UPR-related proteins were assessed. We identified 97 UPR-related proteins in human sperm and showed, for the first time, the presence of HSF1, GADD34, and phosphorylated eIF2α. Additionally, the exposure of human sperm to H2O2 resulted in a significant decrease in sperm viability and motility and an increase in the levels of HSF1, HSP90, HSP60, HSP27, and eIF2α; all proteins involved in sensing and response to unfolded proteins. This study gave us a first insight into the presence of UPR mechanisms in the male gamete. However, the belief that sperm are devoid of transcription and translation highlight the need to clarify if these pathways are activated in sperm in the same way as in somatic cells. Full article
(This article belongs to the Special Issue Advances in Molecular Regulation of Spermatozoa Function)
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15 pages, 3147 KiB  
Article
Proteomic Analysis of Urinary Extracellular Vesicles Reveals a Role for the Complement System in Medullary Sponge Kidney Disease
by Maurizio Bruschi, Simona Granata, Giovanni Candiano, Antonia Fabris, Andrea Petretto, Gian Marco Ghiggeri, Giovanni Gambaro and Gianluigi Zaza
Int. J. Mol. Sci. 2019, 20(21), 5517; https://doi.org/10.3390/ijms20215517 - 05 Nov 2019
Cited by 15 | Viewed by 3543
Abstract
Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The [...] Read more.
Medullary sponge kidney (MSK) disease is a rare and neglected kidney condition often associated with nephrocalcinosis/nephrolithiasis and cystic anomalies in the precalyceal ducts. Little is known about the pathogenesis of this disease, so we addressed the knowledge gap using a proteomics approach. The protein content of microvesicles/exosomes isolated from urine of 15 MSK and 15 idiopathic calcium nephrolithiasis (ICN) patients was investigated by mass spectrometry, followed by weighted gene co-expression network analysis, support vector machine (SVM) learning, and partial least squares discriminant analysis (PLS-DA) to select the most discriminative proteins. Proteomic data were verified by ELISA. We identified 2998 proteins in total, 1764 (58.9%) of which were present in both vesicle types in both diseases. Among the MSK samples, only 65 (2.2%) and 137 (4.6%) proteins were exclusively found in the microvesicles and exosomes, respectively. Similarly, among the ICN samples, only 75 (2.5%) and 94 (3.1%) proteins were exclusively found in the microvesicles and exosomes, respectively. SVM learning and PLS-DA revealed a core panel of 20 proteins that distinguished extracellular vesicles representing each clinical condition with an accuracy of 100%. Among them, three exosome proteins involved in the lectin complement pathway maximized the discrimination between MSK and ICN: Ficolin 1, Mannan-binding lectin serine protease 2, and Complement component 4-binding protein β. ELISA confirmed the proteomic results. Our data show that the complement pathway is involved in the MSK, revealing a new range of potential therapeutic targets and early diagnostic biomarkers. Full article
(This article belongs to the Special Issue Rare Kidney Diseases: New Translational Research Approach to Improve Diagnosis and Therapy)
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16 pages, 6371 KiB  
Article
Numerical Study of Bubble Breakup in Fractal Tree-Shaped Microchannels
by Chengbin Zhang, Xuan Zhang, Qianwen Li and Liangyu Wu
Int. J. Mol. Sci. 2019, 20(21), 5516; https://doi.org/10.3390/ijms20215516 - 05 Nov 2019
Cited by 4 | Viewed by 2711
Abstract
Hydrodynamic behaviors of bubble stream flow in fractal tree-shaped microchannels is investigated numerically based on a two-dimensional volume of fluid (VOF) method. Bubble breakup is examined in each level of bifurcation and the transition of breakup regimes is discussed in particular. The pressure [...] Read more.
Hydrodynamic behaviors of bubble stream flow in fractal tree-shaped microchannels is investigated numerically based on a two-dimensional volume of fluid (VOF) method. Bubble breakup is examined in each level of bifurcation and the transition of breakup regimes is discussed in particular. The pressure variations at the center of different levels of bifurcations are analyzed in an effort to gain further insight into the underlying mechanism of bubble breakup affected by multi-levels of bifurcations in tree-shaped microchannel. The results indicate that due to the structure of the fractal tree-shaped microchannel, both lengths of bubbles and local capillary numbers decrease along the microchannel under a constant inlet capillary number. Hence the transition from the obstructed breakup and obstructed-tunnel combined breakup to coalescence breakup is observed when the bubbles are flowing into a higher level of bifurcations. Compared with the breakup of the bubbles in the higher level of bifurcations, the behaviors of bubbles show stronger periodicity in the lower level of bifurcations. Perturbations grow and magnify along the flow direction and the flow field becomes more chaotic at higher level of bifurcations. Besides, the feedback from the unequal downstream pressure to the upstream lower level of bifurcations affects the bubble breakup and enhances the upstream asymmetrical behaviors. Full article
(This article belongs to the Special Issue Drug Delivery and Scaffolding in the Era of 3D-Printing and Microfluidic Techniques: Challenges and Opportunities)
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17 pages, 3807 KiB  
Article
Comparative Transcriptome Analysis Reveals the Cause for Accumulation of Reactive Oxygen Species During Pollen Abortion in Cytoplasmic Male-Sterile Kenaf Line 722HA
by Bujin Zhou, Yiding Liu, Zhengxia Chen, Dongmei Liu, Yining Wang, Jie Zheng, Xiaofang Liao and and Ruiyang Zhou
Int. J. Mol. Sci. 2019, 20(21), 5515; https://doi.org/10.3390/ijms20215515 - 05 Nov 2019
Cited by 13 | Viewed by 2753
Abstract
Cytoplasmic male sterility (CMS) is a maternally inherited trait used for hybrid production in plants, a novel kenaf CMS line 722HA was derived from the thermo-sensitive male-sterile mutant ‘HMS’ by recurrent backcrossing with 722HB. The line 722HA has great potential for hybrid breeding [...] Read more.
Cytoplasmic male sterility (CMS) is a maternally inherited trait used for hybrid production in plants, a novel kenaf CMS line 722HA was derived from the thermo-sensitive male-sterile mutant ‘HMS’ by recurrent backcrossing with 722HB. The line 722HA has great potential for hybrid breeding in kenaf. However, the underlying molecular mechanism that controls pollen abortion in 722HA remains unclear, thus limiting the full utilization of this line. To understand the possible mechanism governing pollen abortion in 722HA, cytological, transcriptomic, and biochemical analyses were carried out to compare the CMS line 722HA and its maintainer line 722HB. Cytological observations of the microspore development revealed premature degradation of the tapetum at the mononuclear stage, which resulted in pollen dysfunction. The k-means clustering analysis of differentially expressed genes (DEGs) revealed that these genes are related to processes associated with the accumulation of reactive oxygen species (ROS), including electron transport chain, F1F0-ATPase proton transport, positive regulation of superoxide dismutase (SOD), hydrogen peroxide catabolic, and oxidation-reduction. Biochemical analysis indicated that ROS-scavenging capability was lower in 722HA than in 722HB, resulting in an accumulation of excess ROS, which is consistent with the transcriptome results. Taken together, these results demonstrate that excessive ROS accumulation may affect the normal development of microspores. Our study provides new insight into the molecular mechanism of pollen abortion in 722HA and will promote further studies of kenaf hybrids. Full article
(This article belongs to the Special Issue Plant Fertility and Sexual Reproduction)
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10 pages, 2031 KiB  
Article
Clinical Response to Personalized Exercise Therapy in Heart Failure Patients with Reduced Ejection Fraction Is Accompanied by Skeletal Muscle Histological Alterations
by Tatiana A. Lelyavina, Victoria L. Galenko, Oksana A. Ivanova, Margarita Y. Komarova, Elena V. Ignatieva, Maria A. Bortsova, Galina Y. Yukina, Natalia V. Khromova, Maria Yu. Sitnikova, Anna A. Kostareva, Alexey Sergushichev and Renata I. Dmitrieva
Int. J. Mol. Sci. 2019, 20(21), 5514; https://doi.org/10.3390/ijms20215514 - 05 Nov 2019
Cited by 3 | Viewed by 3681
Abstract
Heart failure (HF) is associated with skeletal muscle wasting and exercise intolerance. This study aimed to evaluate the exercise-induced clinical response and histological alterations. One hundred and forty-four HF patients were enrolled. The individual training program was determined as a workload at or [...] Read more.
Heart failure (HF) is associated with skeletal muscle wasting and exercise intolerance. This study aimed to evaluate the exercise-induced clinical response and histological alterations. One hundred and forty-four HF patients were enrolled. The individual training program was determined as a workload at or close to the lactate threshold (LT1); clinical data were collected before and after 12 weeks/6 months of training. The muscle biopsies from eight patients were taken before and after 12 weeks of training: histology analysis was used to evaluate muscle morphology. Most of the patients demonstrated a positive response after 12 weeks of the physical rehabilitation program in one or several parameters tested, and 30% of those showed improvement in all four of the following parameters: oxygen uptake (VO2) peak, left ventricular ejection fraction (LVEF), exercise tolerance (ET), and quality of life (QOL); the walking speed at LT1 after six months of training showed a significant rise. Along with clinical response, the histological analysis detected a small but significant decrease in both fiber and endomysium thickness after the exercise training course indicating the stabilization of muscle mechanotransduction system. Together, our data show that the beneficial effect of personalized exercise therapy in HF patients depends, at least in part, on the improvement in skeletal muscle physiological and biochemical performance. Full article
(This article belongs to the Special Issue Signalling Pathways in Skeletal Muscle Differentiation, Histogenesis and Repair)
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17 pages, 7008 KiB  
Article
ZmRAD51C Is Essential for Double-Strand Break Repair and Homologous Recombination in Maize Meiosis
by Juli Jing, Ting Zhang, Yazhong Wang, Zhenhai Cui and Yan He
Int. J. Mol. Sci. 2019, 20(21), 5513; https://doi.org/10.3390/ijms20215513 - 05 Nov 2019
Cited by 16 | Viewed by 4187
Abstract
Radiation sensitive 51 (RAD51) recombinases play crucial roles in meiotic double-strand break (DSB) repair mediated by homologous recombination (HR) to ensure the correct segregation of homologous chromosomes. In this study, we identified the meiotic functions of ZmRAD51C, the maize homolog of Arabidopsis [...] Read more.
Radiation sensitive 51 (RAD51) recombinases play crucial roles in meiotic double-strand break (DSB) repair mediated by homologous recombination (HR) to ensure the correct segregation of homologous chromosomes. In this study, we identified the meiotic functions of ZmRAD51C, the maize homolog of Arabidopsis and rice RAD51C. The Zmrad51c mutants exhibited regular vegetative growth but complete sterility for both male and female inflorescence. However, the mutants showed hypersensitivity to DNA damage by mitomycin C. Cytological analysis indicated that homologous chromosome pairing and synapsis were rigorously inhibited, and meiotic chromosomes were often entangled from diplotene to metaphase I, leading to chromosome fragmentation at anaphase I. Immunofluorescence analysis showed that although the signals of the axial element absence of first division (AFD1) and asynaptic1 (ASY1) were normal, the assembly of the central element zipper1 (ZYP1) was severely disrupted. The DSB formation was normal in Zmrad51c meiocytes, symbolized by the regular occurrence of γH2AX signals. However, RAD51 and disrupted meiotic cDNA 1 (DMC1) signals were never detected at the early stage of prophase I in the mutant. Taken together, our results indicate that ZmRAD51C functions crucially for both meiotic DSB repair and homologous recombination in maize. Full article
(This article belongs to the Special Issue DNA Damage and Repair in Plants)
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8 pages, 1784 KiB  
Article
Time-Resolved Spectroscopic Study of N,N–Di(4–bromo)nitrenium Ions in Acidic Aqueous Solution
by Lili Du, Zhiping Yan, Xueqin Bai, Runhui Liang and David Lee Phillips
Int. J. Mol. Sci. 2019, 20(21), 5512; https://doi.org/10.3390/ijms20215512 - 05 Nov 2019
Cited by 4 | Viewed by 2945
Abstract
Nitrenium ions are common reactive intermediates with high activities towards some biological nucleophiles. In this paper, we employed femtosecond transient absorption (fs-TA) and nanosecond transient absorption (ns-TA) as well as nanosecond time-resolved resonance Raman (ns-TR3) spectroscopy and density function theory (DFT) [...] Read more.
Nitrenium ions are common reactive intermediates with high activities towards some biological nucleophiles. In this paper, we employed femtosecond transient absorption (fs-TA) and nanosecond transient absorption (ns-TA) as well as nanosecond time-resolved resonance Raman (ns-TR3) spectroscopy and density function theory (DFT) calculations to study the spectroscopic properties of the N(4,4′–dibromodiphenylamino)–2,4,6–trimethylpyridinium BF4− salt (1) in an acidic aqueous solution. Efficient cleavage of the N–N bond (4 ps) to form the N,N–di(4–bromophenyl)nitrenium ion (DN) was also observed in the acidic aqueous solution. As a result, the dication intermediate 4 appears more likely to be produced after abstracting a proton for the nitrenium ion DN in the acid solution first, followed by an electron abstraction to form the radical cation intermediate 3. These new and more extensive time-resolved spectroscopic data will be useful to help to develop an improved understanding of the identity, nature, and properties of nitrenium ions involved in reactions under acidic aqueous conditions. Full article
(This article belongs to the Section Physical Chemistry and Chemical Physics)
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21 pages, 817 KiB  
Review
Therapeutic Properties of Mesenchymal Stem Cell on Organ Ischemia-Reperfusion Injury
by Joan Oliva
Int. J. Mol. Sci. 2019, 20(21), 5511; https://doi.org/10.3390/ijms20215511 - 05 Nov 2019
Cited by 29 | Viewed by 7736
Abstract
The shortage of donor organs is a major global concern. Organ failure requires the transplantation of functional organs. Donor’s organs are preserved for variable periods of warm and cold ischemia time, which requires placing them into a preservation device. Ischemia and reperfusion damage [...] Read more.
The shortage of donor organs is a major global concern. Organ failure requires the transplantation of functional organs. Donor’s organs are preserved for variable periods of warm and cold ischemia time, which requires placing them into a preservation device. Ischemia and reperfusion damage the organs, due to the lack of oxygen during the ischemia step, as well as the oxidative stress during the reperfusion step. Different methodologies are developed to prevent or to diminish the level of injuries. Preservation solutions were first developed to maximize cold static preservation, which includes the addition of several chemical compounds. The next chapter of organ preservation comes with the perfusion machine, where mechanical devices provide continuous flow and oxygenation ex vivo to the organs being preserved. In the addition of inhibitors of mitogen-activated protein kinase and inhibitors of the proteasome, mesenchymal stem cells began being used 13 years ago to prevent or diminish the organ’s injuries. Mesenchymal stem cells (e.g., bone marrow stem cells, adipose derived stem cells and umbilical cord stem cells) have proven to be powerful tools in repairing damaged organs. This review will focus upon the use of some bone marrow stem cells, adipose-derived stem cells and umbilical cord stem cells on preventing or decreasing the injuries due to ischemia-reperfusion. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Ischemia-Reperfusion Injury 2.0)
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17 pages, 3834 KiB  
Article
Targeting Cancer Resistance via Multifunctional Gold Nanoparticles
by Pedro Pedrosa, M. Luísa Corvo, Margarida Ferreira-Silva, Pedro Martins, Manuela Colla Carvalheiro, Pedro M. Costa, Carla Martins, L. M. D. R. S. Martins, Pedro V. Baptista and Alexandra R. Fernandes
Int. J. Mol. Sci. 2019, 20(21), 5510; https://doi.org/10.3390/ijms20215510 - 05 Nov 2019
Cited by 23 | Viewed by 3923
Abstract
Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new [...] Read more.
Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new generations of compounds, nanotechnology-based delivery strategies can significantly improve the in vivo drug stability and target specificity for overcoming drug resistance. In this study, multifunctional gold nanoparticles (AuNP) have been used as a nanoplatform for the targeted delivery of an original anticancer agent, a Zn(II) coordination compound [Zn(DION)2]Cl2 (ZnD), toward better efficacy against DOX-resistant colorectal carcinoma cells (HCT116 DR). Selective delivery of the ZnD nanosystem to cancer cells was achieved by active targeting via cetuximab, NanoZnD, which significantly inhibited cell proliferation and triggered the death of resistant tumor cells, thus improving efficacy. In vivo studies in a colorectal DOX-resistant model corroborated the capability of NanoZnD for the selective targeting of cancer cells, leading to a reduction of tumor growth without systemic toxicity. This approach highlights the potential of gold nanoformulations for the targeting of drug-resistant cancer cells. Full article
(This article belongs to the Special Issue Translating Gold Nanoparticles to Diagnostics and Therapeutics 2.0)
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21 pages, 5283 KiB  
Review
Imaging Metabolically Active Fat: A Literature Review and Mechanistic Insights
by Joseph Frankl, Amber Sherwood, Deborah J. Clegg, Philipp E. Scherer and Orhan K. Öz
Int. J. Mol. Sci. 2019, 20(21), 5509; https://doi.org/10.3390/ijms20215509 - 05 Nov 2019
Cited by 11 | Viewed by 5724
Abstract
Currently, obesity is one of the leading causes death in the world. Shortly before 2000, researchers began describing metabolically active adipose tissue on cancer-surveillance 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in adult humans. This tissue generates heat through mitochondrial uncoupling and [...] Read more.
Currently, obesity is one of the leading causes death in the world. Shortly before 2000, researchers began describing metabolically active adipose tissue on cancer-surveillance 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in adult humans. This tissue generates heat through mitochondrial uncoupling and functions similar to classical brown and beige adipose tissue in mice. Despite extensive research, human brown/beige fat’s role in resistance to obesity in humans has not yet been fully delineated. FDG uptake is the de facto gold standard imaging technique when studying brown adipose tissue, although it has not been rigorously compared to other techniques. We, therefore, present a concise review of established and emerging methods to image brown adipose tissue activity in humans. Reviewed modalities include anatomic imaging with CT and magnetic resonance imaging (MRI); molecular imaging with FDG, fatty acids, and acetate; and emerging techniques. FDG-PET/CT is the most commonly used modality because of its widespread use in cancer imaging, but there are mechanistic reasons to believe other radiotracers may be more sensitive and accurate at detecting brown adipose tissue activity. Radiation-free modalities may help the longitudinal study of brown adipose tissue activity in the future. Full article
(This article belongs to the Special Issue Molecular Imaging in Diabetes, Obesity and Infections)
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11 pages, 749 KiB  
Article
Independent and Combined Effects of Telomere Shortening and mtDNA4977 Deletion on Long-term Outcomes of Patients with Coronary Artery Disease
by Cecilia Vecoli, Andrea Borghini, Silvia Pulignani, Antonella Mercuri, Stefano Turchi, Eugenio Picano and Maria Grazia Andreassi
Int. J. Mol. Sci. 2019, 20(21), 5508; https://doi.org/10.3390/ijms20215508 - 05 Nov 2019
Cited by 14 | Viewed by 2608
Abstract
Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA4977 [...] Read more.
Aging is one of the main risk factors for cardiovascular disease, resulting in a progressive organ and cell decline. This study evaluated a possible joint impact of two emerging hallmarks of aging, leucocyte telomere length (LTL) and common mitochondrial DNA deletion (mtDNA4977), on major adverse cardiovascular events (MACEs) and all-cause mortality in patients with coronary artery disease (CAD). We studied 770 patients (673 males, 64.8 ± 8.3 years) with known or suspected stable CAD. LTL and mtDNA4977 deletion were assessed in peripheral blood using qRT-PCR. During a median follow-up of 5.4 ± 1.2 years, MACEs were 140 while 86 deaths were recorded. After adjustments for confounding risk factors, short LTLs and high mtDNA4977 deletion levels acted independently as predictors of MACEs (HR: 2.2, 95% CI: 1.2–3.9, p = 0.01 and HR: 1.7, 95% CI: 1.1–2.9, p = 0.04; respectively) and all-cause mortality events (HR: 2.1, 95% CI: 1.1–4.6, p = 0.04 and HR: 2.3, 95% CI: 1.1–4.9, p = 0.02; respectively). Patients with both short LTLs and high mtDNA4977 deletion levels had an increased risk for MACEs (HR: 4.3; 95% CI: 1.9–9.6; p = 0.0006) and all-cause mortality (HR: 6.0; 95% CI: 2.0–18.4; p = 0.001). The addition of mtDNA4977 deletion to a clinical reference model was associated with a significant net reclassification improvement (NRI = 0.18, p = 0.01). Short LTL and high mtDNA4977 deletion showed independent and joint predictive value on adverse cardiovascular outcomes and all-cause mortality in patients with CAD. These findings strongly support the importance of evaluating biomarkers of physiological/biological age, which can predict disease risk and mortality more accurately than chronological age. Full article
(This article belongs to the Special Issue Targeting Mitochondria in Aging and Disease)
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17 pages, 1899 KiB  
Review
The Alanine World Model for the Development of the Amino Acid Repertoire in Protein Biosynthesis
by Vladimir Kubyshkin and Nediljko Budisa
Int. J. Mol. Sci. 2019, 20(21), 5507; https://doi.org/10.3390/ijms20215507 - 05 Nov 2019
Cited by 21 | Viewed by 6781
Abstract
A central question in the evolution of the modern translation machinery is the origin and chemical ethology of the amino acids prescribed by the genetic code. The RNA World hypothesis postulates that templated protein synthesis has emerged in the transition from RNA to [...] Read more.
A central question in the evolution of the modern translation machinery is the origin and chemical ethology of the amino acids prescribed by the genetic code. The RNA World hypothesis postulates that templated protein synthesis has emerged in the transition from RNA to the Protein World. The sequence of these events and principles behind the acquisition of amino acids to this process remain elusive. Here we describe a model for this process by following the scheme previously proposed by Hartman and Smith, which suggests gradual expansion of the coding space as GC–GCA–GCAU genetic code. We point out a correlation of this scheme with the hierarchy of the protein folding. The model follows the sequence of steps in the process of the amino acid recruitment and fits well with the co-evolution and coenzyme handle theories. While the starting set (GC-phase) was responsible for the nucleotide biosynthesis processes, in the second phase alanine-based amino acids (GCA-phase) were recruited from the core metabolism, thereby providing a standard secondary structure, the α-helix. In the final phase (GCAU-phase), the amino acids were appended to the already existing architecture, enabling tertiary fold and membrane interactions. The whole scheme indicates strongly that the choice for the alanine core was done at the GCA-phase, while glycine and proline remained rudiments from the GC-phase. We suggest that the Protein World should rather be considered the Alanine World, as it predominantly relies on the alanine as the core chemical scaffold. Full article
(This article belongs to the Special Issue Origins of Protein Translation)
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16 pages, 5158 KiB  
Article
Analysis of the Differential Exosomal miRNAs of DC2.4 Dendritic Cells Induced by Toxoplasma gondii Infection
by Dong-Liang Li, Wei-Hao Zou, Sheng-Qun Deng and Hong-Juan Peng
Int. J. Mol. Sci. 2019, 20(21), 5506; https://doi.org/10.3390/ijms20215506 - 05 Nov 2019
Cited by 11 | Viewed by 3599
Abstract
Toxoplasma gondii is an intracellular parasite that infects humans and other warm-blooded animals. Exosomes are endocytic-derived vesicles released by cells, representing an important mode of intercellular communication. In exosomes, specific molecules of proteins, lipids, and mRNAs or miRNAs have been detected, some of [...] Read more.
Toxoplasma gondii is an intracellular parasite that infects humans and other warm-blooded animals. Exosomes are endocytic-derived vesicles released by cells, representing an important mode of intercellular communication. In exosomes, specific molecules of proteins, lipids, and mRNAs or miRNAs have been detected, some of which are capable of transferring biologically active molecules to recipient cells. Dendritic cells (DCs) are the only antigen-presenting cells (APCs) that activate the initial immune response. In this study, high-throughput sequencing was used to analyze the exosomal miRNA profile of DC2.4 cells infected with Toxoplasma gondii for 28 h, compared with those of uninfected DC2.4 cells. Differential exosomal miRNAs (DEmiRs) from these two cell groups were analyzed. Through high-throughput sequencing, 3434 DEmiRs were obtained, and 12 stably enriched DEmiRNAs were verified by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) and selected for further analysis. The target genes of these 12 miRNAs were predicted with online analysis software and subjected to bioinformatics analyses including protein–protein interaction (PPI) network analysis, key driver analysis (KDA), gene ontology (GO) enrichment, and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. These DEmiRs were found to be associated with a variety of biological processes and signaling pathways involved in host ubiquitin system, innate immunity, biosynthesis, and transferase activity and could be potential biomarkers for T. gondii infection. Full article
(This article belongs to the Section Molecular Biology)
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12 pages, 3007 KiB  
Article
Biological Features Implies Potential Use of Autologous Adipose-Derived Stem/Progenitor Cells in Wound Repair and Regenerations for the Patients with Lipodystrophy
by Keiji Suzuki, Sadanori Akita, Hiroshi Yoshimoto, Akira Ohtsuru, Akiyoshi Hirano and Shunichi Yamashita
Int. J. Mol. Sci. 2019, 20(21), 5505; https://doi.org/10.3390/ijms20215505 - 05 Nov 2019
Cited by 8 | Viewed by 2749
Abstract
A paradigm shift in plastic and reconstructive surgery is brought about the usage of cell-based therapies for wound healing and regeneration. Considering the imitations in the reconstructive surgeries in restoring tissue loss and deficiency, stem cell-based therapy, in particular, has been expected to [...] Read more.
A paradigm shift in plastic and reconstructive surgery is brought about the usage of cell-based therapies for wound healing and regeneration. Considering the imitations in the reconstructive surgeries in restoring tissue loss and deficiency, stem cell-based therapy, in particular, has been expected to pave the way for a new solution to the regenerative approaches. Limitations in the reconstructive surgeries in restoring tissue loss and deficiency have paved the way for new regenerative approaches. Among them, adipose-derived stem/progenitor cells (ADSCs)-based therapy could be the most promising clue, since ADSCs have pluripotent differentiation capabilities not only in adipocytes but also in a variety of cell types. Accumulating evidences have indicated that the unfavorable development of adipose-tissue damage, namely, lipodystrophy, is a systemic complication, which is closely related to metabolic abnormality. Considering ADSC-based regenerative medicine should be applied for the treatment of lipodystrophy, it is inevitable to ascertain whether the ADSCs obtained from the patients with lipodystrophy are capable of being used. It will be very promising and realistic if this concept is applied to lipoatrophy; one form of lipodystrophies that deteriorates the patients’ quality of life because of excessive loss of soft tissue in the exposed areas such as face and extremities. Since lipodystrophy is frequently observed in the human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART), the present study aims to examine the biological potentials of ADSCs isolated from the HIV-infected patients with lipodystrophy associated with the HAART treatment. Growth properties, adipogenic differentiation, and mitochondrial reactive oxygen species (ROS) production were examined in ADSCs from HIV-infected and HIV-uninfected patients. Our results clearly demonstrated that ADSCs from both patients showed indistinguishable growth properties and potentials for adipocyte differentiation in vitro. Thus, although the number of cases were limited, ADSCs isolated from the patients with lipodystrophy retain sufficient physiological and biological activity for the reconstitution of adipose-tissue, suggesting that ADSCs from the patients with lipodystrophy could be used for autologous ADSC-based regenerative therapy. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration: Mechanisms, Signaling)
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20 pages, 2510 KiB  
Review
Mouse Models of Human Claudin-Associated Disorders: Benefits and Limitations
by Murat Seker, Cármen Fernández-Rodríguez, Luis Alfonso Martínez-Cruz and Dominik Müller
Int. J. Mol. Sci. 2019, 20(21), 5504; https://doi.org/10.3390/ijms20215504 - 05 Nov 2019
Cited by 10 | Viewed by 3657
Abstract
In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial [...] Read more.
In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial regulation of its major protein family called claudins. Besides the fact that the expression of claudins has been identified in different forms of human diseases like cancer, clearly defined mutations in the corresponding claudin genes have been shown to cause distinct human disorders. Such disorders comprise the skin and its adjacent structures, liver, kidney, the inner ear, and the eye. From the phenotype analysis, it has also become clear that different claudins can cause a complex phenotype when expressed in different organs. To gain deeper insights into the physiology and pathophysiology of claudin-associated disorders, several mouse models have been generated. In order to model human disorders in detail, they have been designed either as full knockouts, knock-downs or knock-ins by a variety of techniques. Here, we review human disorders caused by CLDN mutations and their corresponding mouse models that have been generated thus far and assess their usefulness as a model for the corresponding human disorder. Full article
(This article belongs to the Special Issue The Tight Junction and Its Proteins: More Than Just a Barrier)
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19 pages, 582 KiB  
Review
Immune and Inflammatory Cells of the Tumor Microenvironment Represent Novel Therapeutic Targets in Classical Hodgkin Lymphoma
by Eleonora Calabretta, Francesco d’Amore and Carmelo Carlo-Stella
Int. J. Mol. Sci. 2019, 20(21), 5503; https://doi.org/10.3390/ijms20215503 - 05 Nov 2019
Cited by 25 | Viewed by 5429
Abstract
Classical Hodgkin Lymphoma (cHL) is a B-cell malignancy that, typically, responds well to standard therapies. However, patients who relapse after standard regimens or are refractory to induction therapy have a dismal outcome. The implementation of novel therapies such as the anti-CD30 monoclonal antibody [...] Read more.
Classical Hodgkin Lymphoma (cHL) is a B-cell malignancy that, typically, responds well to standard therapies. However, patients who relapse after standard regimens or are refractory to induction therapy have a dismal outcome. The implementation of novel therapies such as the anti-CD30 monoclonal antibody Brentuximab Vedotin and immune checkpoint inhibitors has provided curative options for many of these patients. Nonetheless, responses are rarely durable, emphasizing the need for new agents. cHL is characterized by a unique microenvironment in which cellular and humoral components interact to promote tumor survival and dissemination. Knowledge of the complex composition of cHL microenvironment is constantly evolving; in particular, there is growing interest in certain cell subsets such as tumor-associated macrophages, myeloid-derived suppressor cells and neutrophils, all of which have a relevant role in the pathogenesis of the disease. The unique biology of the cHL microenvironment has provided opportunities to develop new drugs, many of which are currently being tested in preclinical and clinical settings. In this review, we will summarize novel insights in the crosstalk between tumor cells and non-malignant inflammatory cells. In addition, we will discuss the relevance of tumor-microenvironment interactions as potential therapeutic targets. Full article
(This article belongs to the Special Issue The Importance of Tumor-Host Interactions in Adult B-Cell Leukemias and Lymphomas)
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23 pages, 2480 KiB  
Article
Lysozyme-Induced Transcriptional Regulation of TNF-α Pathway Genes in Cells of the Monocyte Lineage
by Alberta Bergamo, Marco Gerdol, Alberto Pallavicini, Samuele Greco, Isabelle Schepens, Romain Hamelin, Florence Armand, Paul J. Dyson and Gianni Sava
Int. J. Mol. Sci. 2019, 20(21), 5502; https://doi.org/10.3390/ijms20215502 - 05 Nov 2019
Cited by 18 | Viewed by 3533
Abstract
Lysozyme is one of the most important anti-bacterial effectors in the innate immune system of animals. Besides its direct antibacterial enzymatic activity, lysozyme displays other biological properties, pointing toward a significant anti-inflammatory effect, many aspects of which are still elusive. Here we investigate [...] Read more.
Lysozyme is one of the most important anti-bacterial effectors in the innate immune system of animals. Besides its direct antibacterial enzymatic activity, lysozyme displays other biological properties, pointing toward a significant anti-inflammatory effect, many aspects of which are still elusive. Here we investigate the perturbation of gene expression profiles induced by lysozyme in a monocyte cell line in vitro considering a perspective as broad as the whole transcriptome profiling. The results of the RNA-seq experiment show that lysozyme induces transcriptional modulation of the TNF-α/IL-1β pathway genes in U937 monocytes. The analysis of transcriptomic profiles with IPA® identified a simple but robust molecular network of genes, in which the regulation trends are fully consistent with the anti-inflammatory activity of lysozyme. This study provides the first evidence in support of the anti-inflammatory action of lysozyme on the basis of transcriptomic regulation data resulting from the broad perspective of a whole-transcriptome profiling. Such important effects can be achieved with the supplementation of relatively low concentrations of lysozyme, for a short time of exposure. These new insights allow the potential of lysozyme in pharmacological applications to be better exploited. Full article
(This article belongs to the Special Issue Natural Anti-inflammatory Agents 2019)
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14 pages, 1192 KiB  
Review
The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins
by Izzy Owen and Frank Shewmaker
Int. J. Mol. Sci. 2019, 20(21), 5501; https://doi.org/10.3390/ijms20215501 - 05 Nov 2019
Cited by 124 | Viewed by 9013
Abstract
Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions. Here, we discuss how [...] Read more.
Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions. Here, we discuss how post-translational modifications of intrinsically disordered protein segments can regulate the molecular condensation of macromolecules into functional phase-separated complexes. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins 2019)
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28 pages, 662 KiB  
Review
Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells
by George Anderson, Moses Rodriguez and Russel J. Reiter
Int. J. Mol. Sci. 2019, 20(21), 5500; https://doi.org/10.3390/ijms20215500 - 05 Nov 2019
Cited by 60 | Viewed by 9886
Abstract
Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: [...] Read more.
Recent data highlight the important roles of the gut microbiome, gut permeability, and alterations in mitochondria functioning in the pathophysiology of multiple sclerosis (MS). This article reviews such data, indicating two important aspects of alterations in the gut in the modulation of mitochondria: (1) Gut permeability increases toll-like receptor (TLR) activators, viz circulating lipopolysaccharide (LPS), and exosomal high-mobility group box (HMGB)1. LPS and HMGB1 increase inducible nitric oxide synthase and superoxide, leading to peroxynitrite-driven acidic sphingomyelinase and ceramide. Ceramide is a major driver of MS pathophysiology via its impacts on glia mitochondria functioning; (2) Gut dysbiosis lowers production of the short-chain fatty acid, butyrate. Butyrate is a significant positive regulator of mitochondrial function, as well as suppressing the levels and effects of ceramide. Ceramide acts to suppress the circadian optimizers of mitochondria functioning, viz daytime orexin and night-time melatonin. Orexin, melatonin, and butyrate increase mitochondria oxidative phosphorylation partly via the disinhibition of the pyruvate dehydrogenase complex, leading to an increase in acetyl-coenzyme A (CoA). Acetyl-CoA is a necessary co-substrate for activation of the mitochondria melatonergic pathway, allowing melatonin to optimize mitochondrial function. Data would indicate that gut-driven alterations in ceramide and mitochondrial function, particularly in glia and immune cells, underpin MS pathophysiology. Aryl hydrocarbon receptor (AhR) activators, such as stress-induced kynurenine and air pollutants, may interact with the mitochondrial melatonergic pathway via AhR-induced cytochrome P450 (CYP)1b1, which backward converts melatonin to N-acetylserotonin (NAS). The loss of mitochnodria melatonin coupled with increased NAS has implications for altered mitochondrial function in many cell types that are relevant to MS pathophysiology. NAS is increased in secondary progressive MS, indicating a role for changes in the mitochondria melatonergic pathway in the progression of MS symptomatology. This provides a framework for the integration of diverse bodies of data on MS pathophysiology, with a number of readily applicable treatment interventions, including the utilization of sodium butyrate. Full article
(This article belongs to the Special Issue Multiple Actions of Melatonin on Improving Female and Male Reproductive Health)
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12 pages, 2447 KiB  
Article
Let-7f: A New Potential Circulating Biomarker Identified by miRNA Profiling of Cells Isolated from Human Abdominal Aortic Aneurysm
by Rafaelle Spear, Ludovic Boytard, Renaud Blervaque, Maggy Chwastyniak, David Hot, Jonathan Vanhoutte, Nicolas Lamblin, Philippe Amouyel and Florence Pinet
Int. J. Mol. Sci. 2019, 20(21), 5499; https://doi.org/10.3390/ijms20215499 - 05 Nov 2019
Cited by 10 | Viewed by 2633
Abstract
Abdominal aortic aneurysm (AAA) is a progressive vascular disease responsible for 1–4% of the deaths in elderly men. This study aimed to characterize specific microRNA (miRNA) expression in aneurysmal smooth muscle cells (SMCs) and macrophages in order to identify circulating miRNAs associated with [...] Read more.
Abdominal aortic aneurysm (AAA) is a progressive vascular disease responsible for 1–4% of the deaths in elderly men. This study aimed to characterize specific microRNA (miRNA) expression in aneurysmal smooth muscle cells (SMCs) and macrophages in order to identify circulating miRNAs associated with AAA. We screened 850 miRNAs in aneurysmal SMCs, M1 and M2 macrophages, and in control SMCs isolated by micro-dissection from aortic biopsies using microarray analysis. In all, 92 miRNAs were detected and 10 miRNAs were selected for validation by qRT-PCR in isolated cells (n = 5), whole control and aneurysmal aorta biopsies (n = 13), and plasma from patients (n = 24) undergoing AAA (over 50 mm) repair matched to patients (n = 18) with peripheral arterial disease (PAD) with atherosclerosis but not AAA. Seven miRNAs were modulated similarly in all aneurysmal cells. The Let-7f was downregulated in aneurysmal cells compared to control SMCs with a significant lower expression in M1 compared to M2 macrophages (0.1 fold, p = 0.03), correlated with a significant downregulation in whole aneurysmal aorta compared to control aorta (0.2 fold, p = 0.03). Significant levels of circulating let-7f (p = 0.048) were found in AAA patients compared to PAD patients with no significant correlation with aortic diameter (R2 = 0.03). Our study underlines the utility of profiling isolated aneurysmal cells to identify other miRNAs for which the modulation of expression might be masked when the whole aorta is used. The results highlight let-7f as a new potential biomarker for AAA. Full article
(This article belongs to the Special Issue RNAs in Cardiovascular Diseases-CardioRNA EU COST Action)
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22 pages, 634 KiB  
Review
Circulating-Free DNA Analysis in Hepatocellular Carcinoma: A Promising Strategy to Improve Patients’ Management and Therapy Outcomes
by Silvia Mezzalira, Elena De Mattia, Michela Guardascione, Chiara Dalle Fratte, Erika Cecchin and Giuseppe Toffoli
Int. J. Mol. Sci. 2019, 20(21), 5498; https://doi.org/10.3390/ijms20215498 - 05 Nov 2019
Cited by 23 | Viewed by 5589
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic [...] Read more.
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic mutations found in a HCC tumor may represent targets for innovative drugs as well as prognostic/predictive markers. Nonetheless, surgical or bioptic tissue is hardly accessible in HCC and a single tumor sample is poorly representative of the tumor genetic heterogeneity. In this context, analyzing the circulating cell-free DNA (ccfDNA) and its tumor-derived fraction (ctDNA) could represent a promising strategy of liquid biopsy. Recent data suggested that the fluctuation of the ccfDNA quantity in the plasma of HCC patients could anticipate the detection of tumor progression. The presence of somatic mutations in p53 signaling, Wnt/β-catenin, chromatin remodeling, response to oxidative stress and telomerase maintenance pathways can also be studied in ccfDNA bypassing the need to perform a tumor biopsy. The profiling of ccfDNA fragmentation and the methylation pattern could further improve the clinical management of HCC patients. Performing a dynamic monitoring in the course of systemic treatment with sorafenib or regorafenib is a possible way to provide insights into the resistance mechanism, and to identify predictive and prognostic genetic alterations, helping the clinicians in terms of treatment decision making. This review will discuss the most recent literature data about the use of ccfDNA to monitor and improve the treatment of HCC. Full article
(This article belongs to the Special Issue Pharmacogenetics and Personalized Medicine 2.0)
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15 pages, 4301 KiB  
Article
In Situ Formation of Ag Nanoparticles in Mesoporous TiO2 Films Decorated on Bamboo via Self-Sacrificing Reduction to Synthesize Nanocomposites with Efficient Antifungal Activity
by Jingpeng Li, Minglei Su, Anke Wang, Zaixing Wu, Yuhe Chen, Daochun Qin and Zehui Jiang
Int. J. Mol. Sci. 2019, 20(21), 5497; https://doi.org/10.3390/ijms20215497 - 05 Nov 2019
Cited by 22 | Viewed by 3233
Abstract
We developed a novel green approach for the in situ fabrication of Ag NPs in mesoporous TiO2 films via the bamboo self-sacrificing reduction of Ag(NH3)2+ ions, which can inhibit fungal growth on the bamboo surface. Mesoporous anatase TiO [...] Read more.
We developed a novel green approach for the in situ fabrication of Ag NPs in mesoporous TiO2 films via the bamboo self-sacrificing reduction of Ag(NH3)2+ ions, which can inhibit fungal growth on the bamboo surface. Mesoporous anatase TiO2 (MT) films were first synthesized on bamboo via a hydrothermal method. Then, Ag NPs with a 5.3 nm mean diameter were incorporated into the pore channels of optimal MT/bamboo (MTB) samples at room temperature without the addition of reducing agents, such that the Ag NPs were almost entirely embedded into the MT films. Our analysis indicated that the solubilized lignin from bamboo, which is rich in oxygen-containing functional groups, serves as a green reductant for reducing the Ag(NH3)2+ ions to Ag NPs. Antifungal experiments with Trichoderma viride under dark conditions highlighted that the antifungal activity of the Ag/MT/bamboo samples were greater than those of naked bamboo, MTB, and Ag/bamboo, suggesting that these hybrid nanomaterials produce a synergistic antifungal effect that is unrelated to photoactivity. The inhibition of Penicillium citrinum effectively followed a similar trend. This newly developed bamboo protection method may provide a sustainable, eco-friendly, and efficient method for enhancing the antifungal characteristics of traditional bamboo, having the potential to prolong the service life of bamboo materials, particularly under dark conditions. Full article
(This article belongs to the Special Issue Silver Nano/Microparticles: Modification and Applications 2.0)
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16 pages, 570 KiB  
Review
Dimorphism of HLA-E and Its Disease Association
by Leonid Kanevskiy, Sofya Erokhina, Polina Kobyzeva, Maria Streltsova, Alexander Sapozhnikov and Elena Kovalenko
Int. J. Mol. Sci. 2019, 20(21), 5496; https://doi.org/10.3390/ijms20215496 - 04 Nov 2019
Cited by 31 | Viewed by 4097
Abstract
HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic [...] Read more.
HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER, HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders. Full article
(This article belongs to the Section Molecular Immunology)
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20 pages, 1070 KiB  
Review
Pluripotent Cell Models for Gonadal Research
by Daniel Rodríguez Gutiérrez and Anna Biason-Lauber
Int. J. Mol. Sci. 2019, 20(21), 5495; https://doi.org/10.3390/ijms20215495 - 04 Nov 2019
Cited by 6 | Viewed by 4059
Abstract
Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous conditions not as rare as previously thought. Part of the obstacles in proper management of these patients [...] Read more.
Sex development is a complex process involving many genes and hormones. Defects in this process lead to Differences of Sex Development (DSD), a group of heterogeneous conditions not as rare as previously thought. Part of the obstacles in proper management of these patients is due to an incomplete understanding of the genetics programs and molecular pathways involved in sex development and DSD. Several challenges delay progress and the lack of a proper model system for the single patient severely hinders advances in understanding these diseases. The revolutionary techniques of cellular reprogramming and guided in vitro differentiation allow us now to exploit the versatility of induced pluripotent stem cells to create alternatives models for DSD, ideally on a patient-specific personalized basis. Full article
(This article belongs to the Special Issue Molecular Aspects of Sex Development in Mammals: New Insight)
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28 pages, 5506 KiB  
Article
Non-Typical Fluorescence Effects and Biological Activity in Selected 1,3,4-thiadiazole Derivatives: Spectroscopic and Theoretical Studies on Substituent, Molecular Aggregation, and pH Effects
by Iwona Budziak, Dariusz Karcz, Marcin Makowski, Kamila Rachwał, Karolina Starzak, Alicja Matwijczuk, Beata Myśliwa-Kurdziel, Anna Oniszczuk, Maciej Combrzyński, Anna Podleśna and Arkadiusz Matwijczuk
Int. J. Mol. Sci. 2019, 20(21), 5494; https://doi.org/10.3390/ijms20215494 - 04 Nov 2019
Cited by 14 | Viewed by 3544
Abstract
The below article presents the results of spectroscopic research, theoretical (time-dependent density functional theory (TD-DFT)), microbiological, and antioxidative calculations for three compounds from the group of 1,3,4-thiadiazoles: 2-amino-5-phenyl-1,3,4-thiadiazole (TB), 2-amino-5-(2-hydroxyphenyl)-1,3,4-thiadiazole (TS), 2-amino-5-(2-hydroxy-5-sulfobenzoyl)-1,3,4-thiadiazole (TSF). In the fluorescence emission spectra (TS) of solutions with varying [...] Read more.
The below article presents the results of spectroscopic research, theoretical (time-dependent density functional theory (TD-DFT)), microbiological, and antioxidative calculations for three compounds from the group of 1,3,4-thiadiazoles: 2-amino-5-phenyl-1,3,4-thiadiazole (TB), 2-amino-5-(2-hydroxyphenyl)-1,3,4-thiadiazole (TS), 2-amino-5-(2-hydroxy-5-sulfobenzoyl)-1,3,4-thiadiazole (TSF). In the fluorescence emission spectra (TS) of solutions with varying concentrations of hydrogen ions, a particularly interesting effect of dual fluorescence was observed. The aforementioned effect was observed even more clearly in the environment of butan-1-ol, relative to the compound’s concentration. Depending on the modification of the resorcylic substituent (TS and TSF), we observed the emergence of two separate, partially overlapping, fluorescence emission spectra or a single emission spectrum. Interpretation of the obtained spectra using stationary and time-resolved spectroscopy allowed the correlation of the effect’s emergence with the phenomenon of molecular aggregation (of a particular type) as well as, above all, the structure of the substituent system. The overlap of said effects most likely induces the processes related to the phenomenon of charge transfer (in TS) and is responsible for the observed fluorescence effects. Also, the position of the –OH group (in the resorcylic ring) is significant and can facilitate the charge transfer (CT). The determinations of the changes in the dipole moment and TD-DFT calculations further corroborate the above assumption. The following paper presents the analysis (the first for this particular group of analogues) of the fluorescence effects relative to the changes in the structure of the resorcylic group combined with pH effects. The results of biological studies also indicate the highest pharmacological potential of the analogue in the case where the effects of dual fluorescence emission are observed, which predisposes this particular group of fluorophores as effective fluorescence probes or potential pharmaceuticals with antimycotic properties. Full article
(This article belongs to the Section Molecular Biophysics)
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17 pages, 5032 KiB  
Article
Maintenance of Type 2 Response by CXCR6-Deficient ILC2 in Papain-Induced Lung Inflammation
by Sylvain Meunier, Sylvestre Chea, Damien Garrido, Thibaut Perchet, Maxime Petit, Ana Cumano and Rachel Golub
Int. J. Mol. Sci. 2019, 20(21), 5493; https://doi.org/10.3390/ijms20215493 - 04 Nov 2019
Cited by 8 | Viewed by 3644
Abstract
Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still [...] Read more.
Innate lymphoid cells (ILC) are important players of early immune defenses in situations like lymphoid organogenesis or in case of immune response to inflammation, infection and cancer. Th1 and Th2 antagonism is crucial for the regulation of immune responses, however mechanisms are still unclear for ILC functions. ILC2 and NK cells were reported to be both involved in allergic airway diseases and were shown to be able to interplay in the regulation of the immune response. CXCR6 is a common chemokine receptor expressed by all ILC, and its deficiency affects ILC2 and ILC1/NK cell numbers and functions in lungs in both steady-state and inflammatory conditions. We determined that the absence of a specific ILC2 KLRG1+ST2− subset in CXCR6-deficient mice is probably dependent on CXCR6 for its recruitment to the lung under inflammation. We show that despite their decreased numbers, lung CXCR6-deficient ILC2 are even more activated cells producing large amount of type 2 cytokines that could drive eosinophilia. This is strongly associated to the decrease of the lung Th1 response in CXCR6-deficient mice. Full article
(This article belongs to the Special Issue Targeting Group 2 Innate Lymphoid Cells (ILC2) in Disease: Central Regulators in Immunity, Tissue Homeostasis, and Physiology)
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12 pages, 2270 KiB  
Article
Oxidative Stress Markers to Investigate the Effects of Hyperoxia in Anesthesia
by Sara Ottolenghi, Federico Maria Rubino, Giovanni Sabbatini, Silvia Coppola, Alice Veronese, Davide Chiumello and Rita Paroni
Int. J. Mol. Sci. 2019, 20(21), 5492; https://doi.org/10.3390/ijms20215492 - 04 Nov 2019
Cited by 28 | Viewed by 3944
Abstract
Oxygen (O2) is commonly used in clinical practice to prevent or treat hypoxia, but if used in excess (hyperoxia), it may act as toxic. O2 toxicity arises from the enhanced formation of Reactive Oxygen Species (ROS) that exceed the antioxidant [...] Read more.
Oxygen (O2) is commonly used in clinical practice to prevent or treat hypoxia, but if used in excess (hyperoxia), it may act as toxic. O2 toxicity arises from the enhanced formation of Reactive Oxygen Species (ROS) that exceed the antioxidant defenses and generate oxidative stress. In this study, we aimed at assessing whether an elevated fraction of inspired oxygen (FiO2) during and after general anesthesia may contribute to the unbalancing of the pro-oxidant/antioxidant equilibrium. We measured five oxidative stress biomarkers in blood samples from patients undergoing elective abdominal surgery, randomly assigned to FiO2 = 0.40 vs. 0.80: hydroperoxides, antioxidants, nitrates and nitrites (NOx), malondialdehyde (MDA), and glutathionyl hemoglobin (HbSSG). The MDA concentration was significantly higher 24 h after surgery, and the body antioxidant defense lower, in the FiO2 = 0.80 group with respect to both the FiO2 = 0.40 group and the baseline values (p ≤ 0.05, Student’s t-test). HbSSG in red blood cells was also higher in the FiO2 = 0.80 group at the end of the surgery. NOx was higher in the FiO2 = 0.80 group than the FiO2 = 0.40 group at t = 2 h after surgery. MDA, the main end product of the peroxidation of polyunsaturated fatty acids directly influenced by FiO2, may represent the best marker to assess the pro-oxidant/antioxidant equilibrium after surgery. Full article
(This article belongs to the Special Issue Adaptation to Hypoxia: A Chimera?)
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23 pages, 2435 KiB  
Review
The Development of Functional Non-Viral Vectors for Gene Delivery
by Suryaji Patil, Yong-Guang Gao, Xiao Lin, Yu Li, Kai Dang, Ye Tian, Wen-Juan Zhang, Shan-Feng Jiang, Abdul Qadir and Ai-Rong Qian
Int. J. Mol. Sci. 2019, 20(21), 5491; https://doi.org/10.3390/ijms20215491 - 04 Nov 2019
Cited by 175 | Viewed by 10892
Abstract
Gene therapy is manipulation in/of gene expression in specific cells/tissue to treat diseases. This manipulation is carried out by introducing exogenous nucleic acids, such as DNA or RNA, into the cell. Because of their negative charge and considerable larger size, the delivery of [...] Read more.
Gene therapy is manipulation in/of gene expression in specific cells/tissue to treat diseases. This manipulation is carried out by introducing exogenous nucleic acids, such as DNA or RNA, into the cell. Because of their negative charge and considerable larger size, the delivery of these molecules, in general, should be mediated by gene vectors. Non-viral vectors, as promising delivery systems, have received considerable attention due to their low cytotoxicity and non-immunogenicity. As research continued, more and more functional non-viral vectors have emerged. They not only have the ability to deliver a gene into the cells but also have other functions, such as the performance of fluorescence imaging, which aids in monitoring their progress, targeted delivery, and biodegradation. Recently, many reviews related to non-viral vectors, such as polymers and cationic lipids, have been reported. However, there are few reviews regarding functional non-viral vectors. This review summarizes the common functional non-viral vectors developed in the last ten years and their potential applications in the future. The transfection efficiency and the transport mechanism of these materials were also discussed in detail. We hope that this review can help researchers design more new high-efficiency and low-toxicity multifunctional non-viral vectors, and further accelerate the progress of gene therapy. Full article
(This article belongs to the Section Molecular Biology)
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30 pages, 9709 KiB  
Article
Composition of the Reconstituted Cell Wall in Protoplast-Derived Cells of Daucus Is Affected by Phytosulfokine (PSK)
by Kamila Godel-Jędrychowska, Katarzyna Maćkowska, Ewa Kurczyńska and Ewa Grzebelus
Int. J. Mol. Sci. 2019, 20(21), 5490; https://doi.org/10.3390/ijms20215490 - 04 Nov 2019
Cited by 10 | Viewed by 4969
Abstract
Phytosulfokine-α (PSK), a peptidyl plant growth factor, has been recognized as a promising intercellular signaling molecule involved in cellular proliferation and dedifferentiation. It was shown that PSK stimulated and enhanced cell divisions in protoplast cultures of several species leading to callus and proembryogenic [...] Read more.
Phytosulfokine-α (PSK), a peptidyl plant growth factor, has been recognized as a promising intercellular signaling molecule involved in cellular proliferation and dedifferentiation. It was shown that PSK stimulated and enhanced cell divisions in protoplast cultures of several species leading to callus and proembryogenic mass formation. Since PSK had been shown to cause an increase in efficiency of somatic embryogenesis, it was reasonable to check the distribution of selected chemical components of the cell walls during the protoplast regeneration process. So far, especially for the carrot, a model species for in vitro cultures, it has not been specified what pectic, arabinogalactan protein (AGP) and extensin epitopes are involved in the reconstruction of the wall in protoplast-derived cells. Even less is known about the correlation between wall regeneration and the presence of PSK during the protoplast culture. Three Daucus taxa, including the cultivated carrot, were analyzed during protoplast regeneration. Several antibodies directed against wall components (anti-pectin: LM19, LM20, anti-AGP: JIM4, JIM8, JIM13 and anti-extensin: JIM12) were used. The obtained results indicate a diverse response of the used Daucus taxa to PSK in terms of protoplast-derived cell development, and diversity in the chemical composition of the cell walls in the control and the PSK-treated cultures. Full article
(This article belongs to the Special Issue Plant Cell and Organism Development)
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14 pages, 4945 KiB  
Article
RON Receptor Tyrosine Kinase Regulates Epithelial Mesenchymal Transition and the Expression of Pro-Fibrotic Markers via Src/Smad Signaling in HK-2 and NRK49F Cells
by Jung Sun Park, Hoon-In Choi, Dong-Hyun Kim, Chang Seong Kim, Eun Hui Bae, Seong Kwon Ma and Soo Wan Kim
Int. J. Mol. Sci. 2019, 20(21), 5489; https://doi.org/10.3390/ijms20215489 - 04 Nov 2019
Cited by 14 | Viewed by 3771
Abstract
Receptor tyrosine kinases (RTKs) play important roles in the pathogenic processes of kidney fibrosis. However, the pathophysiological roles of recepteur d’origine nantais (RON), one of the receptor tyrosine kinases, have not yet been defined. We investigated whether the activation or sequence-specific small interfering [...] Read more.
Receptor tyrosine kinases (RTKs) play important roles in the pathogenic processes of kidney fibrosis. However, the pathophysiological roles of recepteur d’origine nantais (RON), one of the receptor tyrosine kinases, have not yet been defined. We investigated whether the activation or sequence-specific small interfering RNA (siRNA) suppression of RON could regulate epithelial mesenchymal transition (EMT) and the expression of pro-fibrotic markers, and its underlying molecular mechanisms. Stable cell lines and transient transfection for RON and the transfected cells of siRNA for RON were developed to investigate the molecular mechanisms in human kidney proximal tubular epithelial (HK-2) and interstitial fibroblasts (NRK49F) cells. RON overexpression induced EMT and increased expression of fibrosis-related proteins such as N-cadherin, vimentin, transforming growth factor-β (TGFβ), αSMA, and fibronectin in HK-2 and NRK49F cells. RON overexpression increased various RTKs and the phosphorylation of Src (Y416) and Smad, while inhibition of RON by siRNA attenuated the expression of EMT- and fibrosis-related proteins and decreased RTKs such as insulin-like growth factor receptor (IGFR), fibroblast growth factor receptor 1 (FGFR1), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), as well as the phosphorylation of Src and Smad pathways. siRNA silencing of Src also attenuated the expression of IGFR, FGFR1, VEGFR, and PDGFR. Inhibition of RON can exert an anti-fibrotic effect by the inhibition of EMT and other RTKs through control of Src and Smad pathways in HK-2 and NRK49F cells. Full article
(This article belongs to the Special Issue Kinase Signal Transduction 2.0)
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