International Journal of Molecular Sciences

10 pages, 10345 KiB

Open AccessArticle

Pyridazino-1,3a,6a-Triazapentalenes as Versatile Fluorescent Probes: Impact of Their Post-Functionalization and Application for Cellular Imaging

by Doina Sirbu, Nicolas Chopin, Ivana Martinić, Moussa Ndiaye, Svetlana V. Eliseeva, Marie-Aude Hiebel, Stéphane Petoud and Franck Suzenet

Int. J. Mol. Sci. 2021, 22(12), 6645; https://doi.org/10.3390/ijms22126645 - 21 Jun 2021

Cited by 7 | Viewed by 2582

Abstract

Pyridazino-1,3a,6a-triazapentalenes (PyTAP) are compact fused 6/5/5 tricyclic scaffolds which exhibit promising fluorescent properties. Chemically stable, they can be post-functionalized using standard Pd-catalyzed cross-coupling chemistry. Several original PyTAP bearing additional unsaturated substituents in positions 2 and 8 were synthetized and their spectroscopic properties analyzed. [...] Read more.

Pyridazino-1,3a,6a-triazapentalenes (PyTAP) are compact fused 6/5/5 tricyclic scaffolds which exhibit promising fluorescent properties. Chemically stable, they can be post-functionalized using standard Pd-catalyzed cross-coupling chemistry. Several original PyTAP bearing additional unsaturated substituents in positions 2 and 8 were synthetized and their spectroscopic properties analyzed. They have been successfully tested as fluorescent probes for cellular imaging. Full article

(This article belongs to the Special Issue Advanced Fluorescent Probes for Structural and Functional Imaging of Biological Systems 2.0)

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17 pages, 4291 KiB

Open AccessArticle

Integrated Insight into the Molecular Mechanisms of Spontaneous Abortion during Early Pregnancy in Pigs

by Xupeng Zang, Ting Gu, Wenjing Wang, Chen Zhou, Yue Ding, Shengchen Gu, Zhiqian Xu, Yanshe Xie, Zicong Li, Gengyuan Cai, Bin Hu, Linjun Hong and Zhenfang Wu

Int. J. Mol. Sci. 2021, 22(12), 6644; https://doi.org/10.3390/ijms22126644 - 21 Jun 2021

Cited by 9 | Viewed by 3128

Abstract

Due to the high rate of spontaneous abortion (SAB) in porcine pregnancy, there is a major interest and concern on commercial pig farming worldwide. Whereas the perturbed immune response at the maternal–fetal interface is an important mechanism associated with the spontaneous embryo loss [...] Read more.

Due to the high rate of spontaneous abortion (SAB) in porcine pregnancy, there is a major interest and concern on commercial pig farming worldwide. Whereas the perturbed immune response at the maternal–fetal interface is an important mechanism associated with the spontaneous embryo loss in the early stages of implantation in porcine, data on the specific regulatory mechanism of the SAB at the end stage of the implantation remains scant. Therefore, we used high-throughput sequencing and bioinformatics tools to analyze the healthy and arresting endometrium on day 28 of pregnancy. We identified 639 differentially expressed lncRNAs (DELs) and 2357 differentially expressed genes (DEGs) at the end stage of implantation, and qRT-PCR was used to verify the sequencing data. Gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immunohistochemistry analysis demonstrated weaker immune response activities in the arresting endometrium compared to the healthy one. Using the lasso regression analysis, we screened the DELs and constructed an immunological competitive endogenous RNA (ceRNA) network related to SAB, including 4 lncRNAs, 11 miRNAs, and 13 genes. In addition, Blast analysis showed the applicability of the constructed ceRNA network in different species, and subsequently determined HOXA-AS2 in pigs. Our study, for the first time, demonstrated that the SAB events at the end stages of implantation is associated with the regulation of immunobiological processes, and a specific molecular regulatory network was obtained. These novel findings may provide new insight into the possibility of increasing the litter size of sows, making pig breeding better and thus improving the efficiency of animal husbandry production. Full article

(This article belongs to the Special Issue Reproductive Immunology and Pregnancy 2.0)

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20 pages, 4162 KiB

Open AccessArticle

Putative Cooperative ATP–DnaA Binding to Double-Stranded DnaA Box and Single-Stranded DnaA-Trio Motif upon Helicobacter pylori Replication Initiation Complex Assembly

by Pawel Jaworski, Dorota Zyla-Uklejewicz, Malgorzata Nowaczyk-Cieszewska, Rafal Donczew, Thorsten Mielke, Christoph Weigel and Anna Zawilak-Pawlik

Int. J. Mol. Sci. 2021, 22(12), 6643; https://doi.org/10.3390/ijms22126643 - 21 Jun 2021

Cited by 6 | Viewed by 2898

Abstract

oriC is a region of the bacterial chromosome at which the initiator protein DnaA interacts with specific sequences, leading to DNA unwinding and the initiation of chromosome replication. The general architecture of oriCs is universal; however, the structure of oriC and the [...] Read more.

oriC is a region of the bacterial chromosome at which the initiator protein DnaA interacts with specific sequences, leading to DNA unwinding and the initiation of chromosome replication. The general architecture of oriCs is universal; however, the structure of oriC and the mode of orisome assembly differ in distantly related bacteria. In this work, we characterized oriC of Helicobacter pylori, which consists of two DnaA box clusters and a DNA unwinding element (DUE); the latter can be subdivided into a GC-rich region, a DnaA-trio and an AT-rich region. We show that the DnaA-trio submodule is crucial for DNA unwinding, possibly because it enables proper DnaA oligomerization on ssDNA. However, we also observed the reverse effect: DNA unwinding, enabling subsequent DnaA–ssDNA oligomer formation—stabilized DnaA binding to box ts1. This suggests the interplay between DnaA binding to ssDNA and dsDNA upon DNA unwinding. Further investigation of the ts1 DnaA box revealed that this box, together with the newly identified c-ATP DnaA box in oriC1, constitute a new class of ATP–DnaA boxes. Indeed, in vitro ATP–DnaA unwinds H. pylori oriC more efficiently than ADP–DnaA. Our results expand the understanding of H. pylori orisome formation, indicating another regulatory pathway of H. pylori orisome assembly. Full article

(This article belongs to the Section Molecular Biology)

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18 pages, 1540 KiB

Open AccessReview

Targeting Mitochondria in Diabetes

by Nina Krako Jakovljevic, Kasja Pavlovic, Aleksandra Jotic, Katarina Lalic, Milica Stoiljkovic, Ljiljana Lukic, Tanja Milicic, Marija Macesic, Jelena Stanarcic Gajovic and Nebojsa M. Lalic

Int. J. Mol. Sci. 2021, 22(12), 6642; https://doi.org/10.3390/ijms22126642 - 21 Jun 2021

Cited by 59 | Viewed by 8614

Abstract

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy [...] Read more.

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes. Full article

(This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases)

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15 pages, 3882 KiB

Open AccessArticle

Mitochondrial Function Are Disturbed in the Presence of the Anticancer Drug, 3-Bromopyruvate

by Magdalena Cal, Irwin Matyjaszczyk, Karolina Filik, Rafał Ogórek, Young Ko and Stanisław Ułaszewski

Int. J. Mol. Sci. 2021, 22(12), 6640; https://doi.org/10.3390/ijms22126640 - 21 Jun 2021

Cited by 3 | Viewed by 3296

Abstract

3-bromopuryvate (3-BP) is a compound with unique antitumor activity. It has a selective action against tumor cells that exhibit the Warburg effect. It has been proven that the action of 3-BP is pleiotropic: it acts on proteins, glycolytic enzymes, reduces the amount of [...] Read more.

3-bromopuryvate (3-BP) is a compound with unique antitumor activity. It has a selective action against tumor cells that exhibit the Warburg effect. It has been proven that the action of 3-BP is pleiotropic: it acts on proteins, glycolytic enzymes, reduces the amount of ATP, induces the formation of ROS (reactive oxygen species), and induces nuclear DNA damage. Mitochondria are important organelles for the proper functioning of the cell. The production of cellular energy (ATP), the proper functioning of the respiratory chain, or participation in the production of amino acids are one of the many functions of mitochondria. Here, for the first time, we show on the yeast model that 3-BP acts in the eukaryotic cell also by influence on mitochondria and that agents inhibiting mitochondrial function can potentially be used in cancer therapy with 3-BP. We show that cells with functional mitochondria are more resistant to 3-BP than rho⁰ cells. Using an MTT assay (a colorimetric assay for assessing cell metabolic activity), we demonstrated that 3-BP decreased mitochondrial activity in yeast in a dose-dependent manner. 3-BP induces mitochondrial-dependent ROS generation which results in ∆sod2, ∆por1, or ∆gpx1 mutant sensitivity to 3-BP. Probably due to ROS mtDNA lesions rise during 3-BP treatment. Our findings may have a significant impact on the therapy with 3-BP. Full article

(This article belongs to the Special Issue Advances in Molecular Activity of Potential Drugs)

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11 pages, 2496 KiB

Open AccessArticle

Virtual Evolution of HVEM Segment for Checkpoint Inhibitor Discovery

by Mingjia Yu, Huimin Zhao, Yuhui Miao, Shi-Zhong Luo and Song Xue

Int. J. Mol. Sci. 2021, 22(12), 6638; https://doi.org/10.3390/ijms22126638 - 21 Jun 2021

Cited by 7 | Viewed by 3056

Abstract

Immune therapy has emerged as an effective treatment against cancers. Inspired by the PD-1/PD-L1 antibodies, which have achieved great success in clinical, other immune checkpoint proteins have drawn increasing attention in cancer research. B and T lymphocyte attenuator (BTLA) and herpes virus entry [...] Read more.

Immune therapy has emerged as an effective treatment against cancers. Inspired by the PD-1/PD-L1 antibodies, which have achieved great success in clinical, other immune checkpoint proteins have drawn increasing attention in cancer research. B and T lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) are potential targets for drug development. The co-crystal structure of BTLA/HVEM have revealed that HVEM (26–38) fragment is the core sequence which directly involved on the interface. Herein, we conducted virtual evolution with this sequence by using saturation mutagenesis in silico and mutants with lower binding energy were selected. Wet-lab experiments confirmed that several of them possessed higher affinity with BTLA. Based on the best mutant of the core sequence, extended peptides with better efficacy were obtained. Furthermore, the mechanism of the effects of mutations was revealed by computational analysis. The mutated peptide discovered here can be a potent inhibitor to block BTLA/HVEM interaction and its mechanism may extend people’s view on inhibitor discovery for the checkpoint pair. Full article

(This article belongs to the Special Issue Structure, Function and Evolution of Protein Domains)

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18 pages, 1084 KiB

Open AccessReview

Novel Applications of NSAIDs: Insight and Future Perspectives in Cardiovascular, Neurodegenerative, Diabetes and Cancer Disease Therapy

by Edmundas Kaduševičius

Int. J. Mol. Sci. 2021, 22(12), 6637; https://doi.org/10.3390/ijms22126637 - 21 Jun 2021

Cited by 25 | Viewed by 6999

Abstract

Once it became clear that inflammation takes place in the modulation of different degenerative disease including neurodegenerative, cardiovascular, diabetes and cancer the researchers has started intensive programs evaluating potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention or therapy of these diseases. [...] Read more.

Once it became clear that inflammation takes place in the modulation of different degenerative disease including neurodegenerative, cardiovascular, diabetes and cancer the researchers has started intensive programs evaluating potential role of non-steroidal anti-inflammatory drugs (NSAIDs) in the prevention or therapy of these diseases. This review discusses the novel mechanism of action of NSAIDs and its potential use in the pharmacotherapy of neurodegenerative, cardiovascular, diabetes and cancer diseases. Many different molecular and cellular factors which are not yet fully understood play an important role in the pathogenesis of inflammation, axonal damage, demyelination, atherosclerosis, carcinogenesis thus further NSAID studies for a new potential indications based on precise pharmacotherapy model are warranted since NSAIDs are a heterogeneous group of medicines with relative different pharmacokinetics and pharmacodynamics profiles. Hopefully the new data from studies will fill in the gap between experimental and clinical results and translate our knowledge into successful disease therapy. Full article

(This article belongs to the Special Issue Molecular Mechanism(s) of Non-steroidal Anti-inflammatory Drugs in the Prevention of Metabolic Diseases)

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17 pages, 2316 KiB

Open AccessReview

Natural Phytochemicals Derived from Gymnosperms in the Prevention and Treatment of Cancers

by Tayyebeh Ghaffari, Joo-Hyun Hong, Solmaz Asnaashari, Safar Farajnia, Abbas Delazar, Hamed Hamishehkar and Ki Hyun Kim

Int. J. Mol. Sci. 2021, 22(12), 6636; https://doi.org/10.3390/ijms22126636 - 21 Jun 2021

Cited by 13 | Viewed by 5220

Abstract

The incidence of various types of cancer is increasing globally. To reduce the critical side effects of cancer chemotherapy, naturally derived compounds have been considered for cancer treatment. Gymnosperms are a group of plants found worldwide that have traditionally been used for therapeutic [...] Read more.

The incidence of various types of cancer is increasing globally. To reduce the critical side effects of cancer chemotherapy, naturally derived compounds have been considered for cancer treatment. Gymnosperms are a group of plants found worldwide that have traditionally been used for therapeutic applications. Paclitaxel is a commercially available anticancer drug derived from gymnosperms. Other natural compounds with anticancer activities, such as pinostrobin and pinocembrin, are extracted from pine heartwood, and pycnogenol and enzogenol from pine bark. Gymnosperms have great potential for further study for the discovery of new anticancer compounds. This review aims to provide a rational understanding and the latest developments in potential anticancer compounds derived from gymnosperms. Full article

(This article belongs to the Special Issue Phytochemicals from Aromatic and Medicinal Plants: From Identification to Biomedical Applications)

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11 pages, 525 KiB

Open AccessReview

Contribution of K2P Potassium Channels to Cardiac Physiology and Pathophysiology

by Salvador Herrera-Pérez, Ana Campos-Ríos, Lola Rueda-Ruzafa and José Antonio Lamas

Int. J. Mol. Sci. 2021, 22(12), 6635; https://doi.org/10.3390/ijms22126635 - 21 Jun 2021

Cited by 9 | Viewed by 4151

Abstract

Years before the first two-pore domain potassium channel (K2P) was cloned, certain ion channels had already been demonstrated to be present in the heart with characteristics and properties usually attributed to the TREK channels (a subfamily of K2P channels). K2P channels were later [...] Read more.

Years before the first two-pore domain potassium channel (K2P) was cloned, certain ion channels had already been demonstrated to be present in the heart with characteristics and properties usually attributed to the TREK channels (a subfamily of K2P channels). K2P channels were later detected in cardiac tissue by RT-PCR, although the distribution of the different K2P subfamilies in the heart seems to depend on the species analyzed. In order to collect relevant information in this regard, we focus here on the TWIK, TASK and TREK cardiac channels, their putative roles in cardiac physiology and their implication in coronary pathologies. Most of the RNA expression data and electrophysiological recordings available to date support the presence of these different K2P subfamilies in distinct cardiac cells. Likewise, we show how these channels may be involved in certain pathologies, such as atrial fibrillation, long QT syndrome and Brugada syndrome. Full article

(This article belongs to the Special Issue Membrane Channels in Health and Diseases)

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13 pages, 691 KiB

Open AccessReview

Mitochondrial DNA Copy Number and Developmental Origins of Health and Disease (DOHaD)

by Hisanori Fukunaga

Int. J. Mol. Sci. 2021, 22(12), 6634; https://doi.org/10.3390/ijms22126634 - 21 Jun 2021

Cited by 19 | Viewed by 6013

Abstract

Mitochondrial dysfunction is known to contribute to mitochondrial diseases, as well as to a variety of aging-based pathologies. Mitochondria have their own genomes (mitochondrial DNA (mtDNA)) and the abnormalities, such as point mutations, deletions, and copy number variations, are involved in mitochondrial dysfunction. [...] Read more.

Mitochondrial dysfunction is known to contribute to mitochondrial diseases, as well as to a variety of aging-based pathologies. Mitochondria have their own genomes (mitochondrial DNA (mtDNA)) and the abnormalities, such as point mutations, deletions, and copy number variations, are involved in mitochondrial dysfunction. In recent years, several epidemiological studies and animal experiments have supported the Developmental Origin of Health and Disease (DOHaD) theory, which states that the environment during fetal life influences the predisposition to disease and the risk of morbidity in adulthood. Mitochondria play a central role in energy production, as well as in various cellular functions, such as apoptosis, lipid metabolism, and calcium metabolism. In terms of the DOHaD theory, mtDNA copy number may be a mediator of health and disease. This paper summarizes the results of recent epidemiological studies on the relationship between environmental factors and mtDNA copy number during pregnancy from the perspective of DOHaD theory. The results of these studies suggest a hypothesis that mtDNA copy number may reflect environmental influences during fetal life and possibly serve as a surrogate marker of health risks in adulthood. Full article

(This article belongs to the Special Issue Mitochondrial DNA and RNA)

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12 pages, 1866 KiB

Open AccessArticle

Preconceptional Immunization Can Modulate Offspring Intrathymic IL-17-Producing γδT Cells with Epigenetic Implications Mediated by microRNAs

by Thamires Rodrigues de-Sousa, Rodrigo Pessôa, Andrezza Nascimento, Beatriz Oliveira Fagundes, Fábio da Ressureição Sgnotto, Alberto José da Silva Duarte, Sabri Saeed Sanabani and Jefferson Russo Victor

Int. J. Mol. Sci. 2021, 22(12), 6633; https://doi.org/10.3390/ijms22126633 - 21 Jun 2021

Cited by 1 | Viewed by 2557

Abstract

The mechanisms through which maternal immunization can modulate offspring thymic maturation of lymphocytes are not fully understood. Here, we aimed to evaluate whether maternal OVA-immunization can inhibit the maturation of IL-17-producing γδT cells in offspring thymus, and if this mechanism has epigenetic implications [...] Read more.

The mechanisms through which maternal immunization can modulate offspring thymic maturation of lymphocytes are not fully understood. Here, we aimed to evaluate whether maternal OVA-immunization can inhibit the maturation of IL-17-producing γδT cells in offspring thymus, and if this mechanism has epigenetic implications mediated by microRNAs (miRNAs) expression. Wild-type (WT) C57BL/6 females were immunized with OVA in Alum or Alum alone and were mated with normal WT males. Evaluating their offspring thymus at 3 or 20 days old (d.o.), we observed that maternal OVA immunization could inhibit the thymic frequency of offspring CD27- and IL-17⁺ γδT cells at the neonatal and until 20 days old. Furthermore, we evaluated the expression of function-related γ and δ variable γδTCR chains (Vγ1, Vγ2, Vγ3, Vδ4, and Vδ6.3), observing that maternal OVA-immunization inhibits Vγ2 chains expression. The small RNAs (sRNAs), particularly miRNAs, and messenger RNAs (mRNA) expression profiles by pools of thymus tissue samples (from 9 to 11 mice) from offspring OVA-immunized or Alum-immunized mothers were analyzed via Illumina sequencing platform and bioinformatics approaches. Using a fold change >4, our results showed that seven miRNAs (mmu-miR-126a-3p, 101a-3p, 744-3p,142-5p, 15a-5p, 532-5p, and 98-5p) were differentially expressed between both groups. Ten target genes were predicted to interact with the seven selected miRNAs. There were no enriched categories of gene ontology functional annotation and pathway enrichment analysis for the target genes. Interestingly, four of the identified miRNAs (mmu-miR-15a, mmu-miR-101 mmu-miR-126, and mmu-miR-142) are related to IL-17 production. Our data is of significance because we demonstrate that maternal immunization can modulate offspring thymic maturation of IL-17-producing γδT cells possibly by an epigenetic mechanism mediated by miRNAs. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 970 KiB

Open AccessReview

The Role of Neuropeptide B and Its Receptors in Controlling Appetite, Metabolism, and Energy Homeostasis

by Tatiana Wojciechowicz, Maria Billert, Mariami Jasaszwili, Mathias Z. Strowski, Krzysztof W. Nowak and Marek Skrzypski

Int. J. Mol. Sci. 2021, 22(12), 6632; https://doi.org/10.3390/ijms22126632 - 21 Jun 2021

Cited by 6 | Viewed by 3129

Abstract

Neuropeptide B (NPB) is a peptide hormone that was initially described in 2002. In humans, the biological effects of NPB depend on the activation of two G protein-coupled receptors, NPBWR1 (GPR7) and NPBWR2 (GPR8), and, in rodents, NPBWR1. NPB and its receptors are [...] Read more.

Neuropeptide B (NPB) is a peptide hormone that was initially described in 2002. In humans, the biological effects of NPB depend on the activation of two G protein-coupled receptors, NPBWR1 (GPR7) and NPBWR2 (GPR8), and, in rodents, NPBWR1. NPB and its receptors are expressed in the central nervous system (CNS) and in peripheral tissues. NPB is also present in the circulation. In the CNS, NPB modulates appetite, reproduction, pain, anxiety, and emotions. In the peripheral tissues, NPB controls secretion of adrenal hormones, pancreatic beta cells, and various functions of adipose tissue. Experimental downregulation of either NPB or NPBWR1 leads to adiposity. Here, we review the literature with regard to NPB-dependent control of metabolism and energy homeostasis. Full article

(This article belongs to the Special Issue Neuropeptides in Food Intake Regulation)

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15 pages, 2280 KiB

Open AccessArticle

D-Amino Acid-Containing Lipopeptides Derived from the Lead Peptide BP100 with Activity against Plant Pathogens

by Àngel Oliveras, Luís Moll, Gerard Riesco-Llach, Arnau Tolosa-Canudas, Sergio Gil-Caballero, Esther Badosa, Anna Bonaterra, Emilio Montesinos, Marta Planas and Lidia Feliu

Int. J. Mol. Sci. 2021, 22(12), 6631; https://doi.org/10.3390/ijms22126631 - 21 Jun 2021

Cited by 11 | Viewed by 2979

Abstract

From a previous collection of lipopeptides derived from BP100, we selected 18 sequences in order to improve their biological profile. In particular, analogues containing a D-amino acid at position 4 were designed, prepared, and tested against plant pathogenic bacteria and fungi. The [...] Read more.

From a previous collection of lipopeptides derived from BP100, we selected 18 sequences in order to improve their biological profile. In particular, analogues containing a D-amino acid at position 4 were designed, prepared, and tested against plant pathogenic bacteria and fungi. The biological activity of these sequences was compared with that of the corresponding parent lipopeptides with all L-amino acids. In addition, the influence of the length of the hydrophobic chain on the biological activity was evaluated. Interestingly, the incorporation of a D-amino acid into lipopeptides bearing a butanoyl or a hexanoyl chain led to less hemolytic sequences and, in general, that were as active or more active than the corresponding all L-lipopeptides. The best lipopeptides were BP475 and BP485, both incorporating a D-Phe at position 4 and a butanoyl group, with MIC values between 0.8 and 6.2 µM, low hemolysis (0 and 24% at 250 µM, respectively), and low phytotoxicity. Characterization by NMR of the secondary structure of BP475 revealed that the D-Phe at position 4 disrupts the α-helix and that residues 6 to 10 are able to fold in an α-helix. This secondary structure would be responsible for the high antimicrobial activity and low hemolysis of this lipopeptide. Full article

(This article belongs to the Special Issue Design and Synthesis of Peptides: Impact on Current Biomedicine, Biotechnology, and Chemical Biology)

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28 pages, 2848 KiB

Open AccessStudy Protocol

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

by Vilbert Sikorski, Pasi Karjalainen, Daria Blokhina, Kati Oksaharju, Jahangir Khan, Shintaro Katayama, Helena Rajala, Satu Suihko, Suvi Tuohinen, Kari Teittinen, Annu Nummi, Antti Nykänen, Arda Eskin, Christoffer Stark, Fausto Biancari, Jan Kiss, Jarmo Simpanen, Jussi Ropponen, Karl Lemström, Kimmo Savinainen, Maciej Lalowski, Markku Kaarne, Mikko Jormalainen, Outi Elomaa, Pertti Koivisto, Peter Raivio, Pia Bäckström, Sebastian Dahlbacka, Simo Syrjälä, Tiina Vainikka, Tommi Vähäsilta, Nurcan Tuncbag, Mati Karelson, Eero Mervaala, Tatu Juvonen, Mika Laine, Jari Laurikka, Antti Vento and Esko Kankuri Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(12), 6630; https://doi.org/10.3390/ijms22126630 - 21 Jun 2021

Cited by 9 | Viewed by 7209

Abstract

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and [...] Read more.

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m⁶A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m⁶A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m⁶A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets. Full article

(This article belongs to the Special Issue Coronary Syndromes – Advances in Diagnostics and Therapy)

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14 pages, 1168 KiB

Open AccessReview

Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic

by Umberto Tarantino, Ida Cariati, Chiara Greggi, Elena Gasbarra, Alberto Belluati, Luigi Ciolli, Giulio Maccauro, Alberto Momoli, Simone Ripanti, Francesco Falez and Maria Luisa Brandi

Int. J. Mol. Sci. 2021, 22(12), 6629; https://doi.org/10.3390/ijms22126629 - 21 Jun 2021

Cited by 22 | Viewed by 6892

Abstract

Cigarette smoking has a negative impact on the skeletal system, as it reduces bone mass and increases fracture risk through its direct or indirect effects on bone remodeling. Recent evidence demonstrates that smoking causes an imbalance in bone turnover, making bone vulnerable to [...] Read more.

Cigarette smoking has a negative impact on the skeletal system, as it reduces bone mass and increases fracture risk through its direct or indirect effects on bone remodeling. Recent evidence demonstrates that smoking causes an imbalance in bone turnover, making bone vulnerable to osteoporosis and fragility fractures. Moreover, cigarette smoking is known to have deleterious effects on fracture healing, as a positive correlation between the daily number of cigarettes smoked and years of exposure has been shown, even though the underlying mechanisms are not fully understood. It is also well known that smoking causes several medical/surgical complications responsible for longer hospital stays and a consequent increase in the consumption of resources. Smoking cessation is, therefore, highly advisable to prevent the onset of bone metabolic disease. However, even with cessation, some of the consequences appear to continue for decades afterwards. Based on this evidence, the aim of our review was to evaluate the impact of smoking on the skeletal system, especially on bone fractures, and to identify the pathophysiological mechanisms responsible for the impairment of fracture healing. Since smoking is a major public health concern, understanding the association between cigarette smoking and the occurrence of bone disease is necessary in order to identify potential new targets for intervention. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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9 pages, 4916 KiB

Open AccessArticle

The Unusual Role of Pro in Cu(II) Binding by His₂-Cyclopentapeptide

by Aleksandra Pieniężna, Aleksandra Kotynia and Justyna Brasuń

Int. J. Mol. Sci. 2021, 22(12), 6628; https://doi.org/10.3390/ijms22126628 - 21 Jun 2021

Viewed by 1880

Abstract

In this paper, we present findings from studying the interaction of copper(II) ions with the His₂-cyclopentapeptide and the role of proline used for the purpose of potentiometric titration and UV-Vis, CD and EPR spectroscopic measurements. Experiments of two homodetic peptides differing [...] Read more.

In this paper, we present findings from studying the interaction of copper(II) ions with the His₂-cyclopentapeptide and the role of proline used for the purpose of potentiometric titration and UV-Vis, CD and EPR spectroscopic measurements. Experiments of two homodetic peptides differing by one amino acid residue were conducted for a ligand to metal ratio of 1:1 in the pH range 2.5–11.0. The presented studies reveal that peptides form only mononuclear complexes, and the CuH₂L complex appears in the system first (for both L1 and L2). Study results show that the presence of Pro influences the structure of formed complexes and their stabilities and has a strong impact on the efficiency of copper(II) coordination. Full article

(This article belongs to the Section Biochemistry)

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12 pages, 550 KiB

Open AccessReview

The Evolving Role of Fetuin-A in Nonalcoholic Fatty Liver Disease: An Overview from Liver to the Heart

by Teoman Dogru, Ali Kirik, Hasan Gurel, Ali A. Rizvi, Manfredi Rizzo and Alper Sonmez

Int. J. Mol. Sci. 2021, 22(12), 6627; https://doi.org/10.3390/ijms22126627 - 21 Jun 2021

Cited by 19 | Viewed by 4292

Abstract

Nonalcoholic fatty liver disease (NAFLD) is strongly associated to the features of metabolic syndrome which can progress to cirrhosis, liver failure and hepatocellular carcinoma. However, the most common cause of mortality in people with NAFLD is not liver-related but stems from atherosclerotic cardiovascular [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated to the features of metabolic syndrome which can progress to cirrhosis, liver failure and hepatocellular carcinoma. However, the most common cause of mortality in people with NAFLD is not liver-related but stems from atherosclerotic cardiovascular disease (CVD). The prevalence of NAFLD is on the rise, mainly as a consequence of its close association with two major worldwide epidemics, obesity and type 2 diabetes (T2D). The exact pathogenesis of NAFLD and especially the mechanisms leading to disease progression and CVD have not been completely elucidated. Human fetuin-A (alpha-2-Heremans Schmid glycoprotein), a glycoprotein produced by the liver and abundantly secreted into the circulation appears to play a role in insulin resistance, metabolic syndrome and inflammation. This review discusses the links between NAFLD and CVD by specifically focusing on fetuin-A’s function in the pathogenesis of NAFLD and atherosclerotic CVD. Full article

(This article belongs to the Special Issue Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies)

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32 pages, 979 KiB

Open AccessReview

Functions of Matricellular Proteins in Dental Tissues and Their Emerging Roles in Orofacial Tissue Development, Maintenance, and Disease

by Georgia Nikoloudaki

Int. J. Mol. Sci. 2021, 22(12), 6626; https://doi.org/10.3390/ijms22126626 - 21 Jun 2021

Cited by 14 | Viewed by 4125

Abstract

Matricellular proteins (MCPs) are defined as extracellular matrix (ECM) associated proteins that are important regulators and integrators of microenvironmental signals, contributing to the dynamic nature of ECM signalling. There is a growing understanding of the role of matricellular proteins in cellular processes governing [...] Read more.

Matricellular proteins (MCPs) are defined as extracellular matrix (ECM) associated proteins that are important regulators and integrators of microenvironmental signals, contributing to the dynamic nature of ECM signalling. There is a growing understanding of the role of matricellular proteins in cellular processes governing tissue development as well as in disease pathogenesis. In this review, the expression and functions of different MP family members (periostin, CCNs, TSPs, SIBLINGs and others) are presented, specifically in relation to craniofacial development and the maintenance of orofacial tissues, including bone, gingiva, oral mucosa, palate and the dental pulp. As will be discussed, each MP family member has been shown to have non-redundant roles in development, tissue homeostasis, wound healing, pathology and tumorigenesis of orofacial and dental tissues. Full article

(This article belongs to the Special Issue Matricellular Proteins: Modifiers of Cell Behavior in Development, Disease & Tissue Remodeling)

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14 pages, 1269 KiB

Open AccessArticle

Placental Glucose Transporters and Response to Bisphenol A in Pregnancies from of Normal and Overweight Mothers

by Leonardo Ermini, Anna Maria Nuzzo, Francesca Ietta, Roberta Romagnoli, Laura Moretti, Bianca Masturzo, Luana Paulesu and Alessandro Rolfo

Int. J. Mol. Sci. 2021, 22(12), 6625; https://doi.org/10.3390/ijms22126625 - 21 Jun 2021

Cited by 7 | Viewed by 2937

Abstract

Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacture of polycarbonate plastics and epoxy resins and a component of liquid and food storages. Among health disorders potentially attributed to BPA, the effects on metabolism have been especially studied. BPA represents [...] Read more.

Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacture of polycarbonate plastics and epoxy resins and a component of liquid and food storages. Among health disorders potentially attributed to BPA, the effects on metabolism have been especially studied. BPA represents a hazard in prenatal life because of its presence in tissues and fluids during pregnancy. Our recent study in rats fed with BPA showed a placental increase in glucose type 1 transporter (GLUT-1), suggesting a higher uptake of glucose. However, the role of BPA on GLUT transporters in pregnant women with metabolic dysfunction has not yet been investigated. In this study, placental tissue from 26 overweight (OW) women and 32 age-matched normal weight (NW) pregnant women were examined for expression of GLUT1 and GLUT4. Placental explants from OW and NW mothers were exposed to BPA 1 nM and 1 μM and tested for GLUTs expression. The data showed a different response of placental explants to BPA in GLUT1 expression with an increase in NW mothers and a decrease in OW ones. GLUT4 expression was lower in the explants from OW than NW mothers, while no difference was showed between OW and NW in placental biopsies for any of the transporters. Full article

(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)

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12 pages, 1889 KiB

Open AccessArticle

Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation

by Annamaria Szenasi, Krisztina Amrein, Endre Czeiter, Nikolett Szarka, Peter Toth and Akos Koller

Int. J. Mol. Sci. 2021, 22(12), 6624; https://doi.org/10.3390/ijms22126624 - 21 Jun 2021

Cited by 5 | Viewed by 3379

Abstract

(1) Background: Traumatic brain injury (TBI) frequently occurs worldwide, resulting in high morbidity and mortality. Here, we hypothesized that TBI impairs an autoregulatory mechanism, namely the flow-induced constriction of isolated rat middle cerebral arteries (MCAs). (2) Methods: TBI was induced in anaesthetized rats [...] Read more.

(1) Background: Traumatic brain injury (TBI) frequently occurs worldwide, resulting in high morbidity and mortality. Here, we hypothesized that TBI impairs an autoregulatory mechanism, namely the flow-induced constriction of isolated rat middle cerebral arteries (MCAs). (2) Methods: TBI was induced in anaesthetized rats by weight drop model, and then MCAs were isolated and transferred into a pressure-flow chamber. The internal diameter was measured by a video-microscopy. (3) Results: In MCAs from intact rats, increases in flow and pressure + flow elicited constrictions (−26 ± 1.9 µm and −52 ± 2.8 µm, p < 0.05), which were significantly reduced after TBI or in the presence of thromboxane-prostanoid (TP receptor) antagonist SQ 29,548. Flow-induced constrictions were significantly reduced by HET0016, inhibitor of cytochrome P450 4A (CYP450 4A). Arachidonic acid, (AA, 10⁻⁷ M), and CYP-450 4A metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) elicited constrictions of intact MCA (−26 ± 2.3% and −31 ± 3.6%), which were significantly reduced after TBI (to 11 ± 1.3% and −16 ±2.5%). The TP receptor agonist U46619 (10⁻⁷ M) elicited substantial constrictions of MCA from intact rats (−21 ± 3.3%), which were also significantly reduced, after TBI (to −16 ± 2.4%). (4) Conclusions: Flow-induced constrictor response of MCA is impaired by traumatic brain injury, likely due to the reduced ability of cytochrome P450 4A to convert arachidonic acid to constrictor prostaglandins and the mitigated sensitivity of thromboxane-prostanoid receptors. Full article

(This article belongs to the Special Issue Molecular Vascular Physiology)

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15 pages, 697 KiB

Open AccessReview

Improvement of Glucose Tolerance by Food Factors Having Glucagon-Like Peptide-1 Releasing Activity

by Tohru Hira, Aphichat Trakooncharoenvit, Hayate Taguchi and Hiroshi Hara

Int. J. Mol. Sci. 2021, 22(12), 6623; https://doi.org/10.3390/ijms22126623 - 21 Jun 2021

Cited by 17 | Viewed by 10086

Abstract

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated [...] Read more.

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone released from enteroendocrine L cells in response to meal ingestion. GLP-1 receptor agonists and GLP-1 enhancers have been clinically employed to treat diabetes owing to their glucose-dependent insulin-releasing activity. The release of GLP-1 is primarily stimulated by macronutrients such as glucose and fatty acids, which are nutritionally indispensable; however, excessive intake of sugar and fat is responsible for the development of obesity and diabetes. Therefore, GLP-1 releasing food factors, such as dietary peptides and non-nutrients, are deemed desirable for improving glucose tolerance. Human and animal studies have revealed that dietary proteins/peptides have a potent effect on stimulating GLP-1 secretion. Studies in enteroendocrine cell models have shown that dietary peptides, amino acids, and phytochemicals, such as quercetin, can directly stimulate GLP-1 secretion. In our animal experiments, these food factors improved glucose metabolism and increased GLP-1 secretion. Furthermore, some dietary peptides not only stimulated GLP-1 secretion but also reduced plasma peptidase activity, which is responsible for GLP-1 inactivation. Herein, we review the relationship between GLP-1 and food factors, especially dietary peptides and flavonoids. Accordingly, utilization of food factors with GLP-1-releasing/enhancing activity is a promising strategy for preventing and treating obesity and diabetes. Full article

(This article belongs to the Special Issue The Effect of Phytochemicals and Food Bioactive Compounds on Diabetes)

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15 pages, 2309 KiB

Open AccessArticle

Telomere Length in Chromosomally Normal and Abnormal Miscarriages and Ongoing Pregnancies and Its Association with 5-hydroxymethylcytosine Patterns

by Mikhail I. Krapivin, Andrei V. Tikhonov, Olga A. Efimova, Anna A. Pendina, Anna A. Smirnova, Olga G. Chiryaeva, Olga E. Talantova, Lubov’ I. Petrova, Vera S. Dudkina and Vladislav S. Baranov

Int. J. Mol. Sci. 2021, 22(12), 6622; https://doi.org/10.3390/ijms22126622 - 21 Jun 2021

Cited by 4 | Viewed by 2276

Abstract

The present study investigates telomere length (TL) in dividing chorionic cytotrophoblast cells from karyotypically normal and abnormal first trimester miscarriages and ongoing pregnancies. Using Q-FISH, we measured relative TLs in the metaphase chromosomes of 61 chorionic villous samples. Relative TLs did not differ [...] Read more.

The present study investigates telomere length (TL) in dividing chorionic cytotrophoblast cells from karyotypically normal and abnormal first trimester miscarriages and ongoing pregnancies. Using Q-FISH, we measured relative TLs in the metaphase chromosomes of 61 chorionic villous samples. Relative TLs did not differ between karyotypically normal samples from miscarriages and those from ongoing pregnancies (p = 0.3739). However, among the karyotypically abnormal samples, relative TLs were significantly higher in ongoing pregnancies than in miscarriages (p < 0.0001). Relative TLs were also significantly higher in chorion samples from karyotypically abnormal ongoing pregnancies than in those from karyotypically normal ones (p = 0.0018) in contrast to miscarriages, where relative TL values were higher in the karyotypically normal samples (p = 0.002). In the karyotypically abnormal chorionic cytotrophoblast, the TL variance was significantly lower than in any other group (p < 0.05). Assessed by TL ratios between sister chromatids, interchromatid TL asymmetry demonstrated similar patterns across all of the chorion samples (p = 0.22) but significantly exceeded that in PHA-stimulated lymphocytes (p < 0.0001, p = 0.0003). The longer telomere was predominantly present in the hydroxymethylated sister chromatid in chromosomes featuring hemihydroxymethylation (containing 5-hydroxymethylcytosine in only one sister chromatid)—a typical sign of chorionic cytotrophoblast cells. Our results suggest that the phenomena of interchromatid TL asymmetry and its association to 5hmC patterns in chorionic cytotrophoblast, which are potentially linked to telomere lengthening through recombination, are inherent to the development programme. The TL differences in chorionic cytotrophoblast that are associated with karyotype and embryo viability seem to be determined by heredity rather than telomere elongation mechanisms. The inheritance of long telomeres by a karyotypically abnormal embryo promotes his development, whereas TL in karyotypically normal first-trimester embryos does not seem to have a considerable impact on developmental capacity. Full article

(This article belongs to the Special Issue Structural Variations of the Genome)

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18 pages, 5975 KiB

Open AccessArticle

Electrophysiology of hiPSC-Cardiomyocytes Co-Cultured with HEK Cells Expressing the Inward Rectifier Channel

by Ana Da Silva Costa, Peter Mortensen, Maria P. Hortigon-Vinagre, Marcel A. G. van der Heyden, Francis L. Burton, Hao Gao, Radostin D. Simitev and Godfrey L. Smith

Int. J. Mol. Sci. 2021, 22(12), 6621; https://doi.org/10.3390/ijms22126621 - 21 Jun 2021

Cited by 4 | Viewed by 3417

Abstract

The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) complicates their use for therapeutic and pharmacological purposes. An insufficient inward rectifying current (I_K1) and the presence of a funny current (if) cause spontaneous electrical activity. This study tests the hypothesis [...] Read more.

The immature electrophysiology of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) complicates their use for therapeutic and pharmacological purposes. An insufficient inward rectifying current (I_K1) and the presence of a funny current (if) cause spontaneous electrical activity. This study tests the hypothesis that the co-culturing of hiCMs with a human embryonic kidney (HEK) cell-line expressing the Kir2.1 channel (HEK-I_K1) can generate an electrical syncytium with an adult-like cardiac electrophysiology. The mechanical activity of co-cultures using different HEK-I_K1:hiCM ratios was compared with co-cultures using wildtype (HEK–WT:hiCM) or hiCM alone on days 3–8 after plating. Only ratios of 1:3 and 1:1 showed a significant reduction in spontaneous rate at days 4 and 6, suggesting that I_K1 was influencing the electrophysiology. Detailed analysis at day 4 revealed an increased incidence of quiescent wells or sub-areas. Electrical activity showed a decreased action potential duration (APD) at 20% and 50%, but not at 90%, alongside a reduced amplitude of the aggregate AP signal. A computational model of the 1:1 co-culture replicates the electrophysiological effects of HEK–WT. The addition of the I_K1 conductance reduced the spontaneous rate and APD20, 50 and 90, and minor variation in the intercellular conductance caused quiescence. In conclusion, a 1:1 co-culture HEK-I_K1:hiCM caused changes in electrophysiology and spontaneous activity consistent with the integration of I_K1 into the electrical syncytium. However, the additional electrical effects of the HEK cell at 1:1 increased the possibility of electrical quiescence before sufficient I_K1 was integrated into the syncytium. Full article

(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)

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4 pages, 184 KiB

Open AccessEditorial

Understanding Amyloid Structures and Disease: A Continuing Challenge in Health Research

by Grazia Chiellini

Int. J. Mol. Sci. 2021, 22(12), 6620; https://doi.org/10.3390/ijms22126620 - 21 Jun 2021

Cited by 3 | Viewed by 1788

Abstract

Neurodegenerative disorders (NDDs), including Alzheimer’s, Parkinson’s, and Huntington’s diseases, are a highly prevalent class of disorders that share the presence of aberrant aggregates called amyloids in the nervous system [...] Full article

(This article belongs to the Special Issue Understanding Amyloid Structures and Disease: A Continuing Challenge in Health Research)

30 pages, 1194 KiB

Open AccessReview

Objective and Measurable Biomarkers in Chronic Subjective Tinnitus

by Dae-Woong Kang, Sung-Soo Kim, Dong-Choon Park, Sang-Hoon Kim and Seung-Geun Yeo

Int. J. Mol. Sci. 2021, 22(12), 6619; https://doi.org/10.3390/ijms22126619 - 21 Jun 2021

Cited by 17 | Viewed by 5350

Abstract

Tinnitus is associated with increased social costs and reduced quality of life through sleep disorders or psychological distress. The pathophysiology of chronic subjective tinnitus, which accounts for most tinnitus, has not been clearly elucidated. This is because chronic subjective tinnitus is difficult to [...] Read more.

Tinnitus is associated with increased social costs and reduced quality of life through sleep disorders or psychological distress. The pathophysiology of chronic subjective tinnitus, which accounts for most tinnitus, has not been clearly elucidated. This is because chronic subjective tinnitus is difficult to evaluate objectively, and there are no objective markers that represent the diagnosis or therapeutic effect of tinnitus. Based on the results of studies on patients with chronic subjective tinnitus, objective and measurable biomarkers that help to identify the pathophysiology of tinnitus have been summarized. A total of 271 studies in PubMed, 303 in EMBASE, and 45 in Cochrane Library were found on biomarkers related to chronic subjective tinnitus published until April 2021. Duplicate articles, articles not written in English, review articles, case reports, and articles that did not match our topic were excluded. A total of 49 studies were included. Three specimens, including blood, saliva, and urine, and a total of 58 biomarkers were used as indicators for diagnosis, evaluation, prognosis, and therapeutic effectiveness of tinnitus. Biomarkers were classified into eight categories comprising metabolic, hemostatic, inflammatory, endocrine, immunological, neurologic, and oxidative parameters. Biomarkers can help in the diagnosis, measure the severity, predict prognosis, and treatment outcome of tinnitus. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

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23 pages, 3081 KiB

Open AccessArticle

Functionalization of Photosensitized Silica Nanoparticles for Advanced Photodynamic Therapy of Cancer

by Ruth Prieto-Montero, Alejandro Prieto-Castañeda, Alberto Katsumiti, Miren P. Cajaraville, Antonia R. Agarrabeitia, María J. Ortiz and Virginia Martínez-Martínez

Int. J. Mol. Sci. 2021, 22(12), 6618; https://doi.org/10.3390/ijms22126618 - 21 Jun 2021

Cited by 12 | Viewed by 4587

Abstract

BODIPY dyes have recently attracted attention as potential photosensitizers. In this work, commercial and novel photosensitizers (PSs) based on BODIPY chromophores (haloBODIPYs and orthogonal dimers strategically designed with intense bands in the blue, green or red region of the visible spectra and high [...] Read more.

BODIPY dyes have recently attracted attention as potential photosensitizers. In this work, commercial and novel photosensitizers (PSs) based on BODIPY chromophores (haloBODIPYs and orthogonal dimers strategically designed with intense bands in the blue, green or red region of the visible spectra and high singlet oxygen production) were covalently linked to mesoporous silica nanoparticles (MSNs) further functionalized with PEG and folic acid (FA). MSNs approximately 50 nm in size with different functional groups were synthesized to allow multiple alternatives of PS-PEG-FA decoration of their external surface. Different combinations varying the type of PS (commercial Rose Bengal, Thionine and Chlorine e6 or custom-made BODIPY-based), the linkage design, and the length of PEG are detailed. All the nanosystems were physicochemically characterized (morphology, diameter, size distribution and PS loaded amount) and photophysically studied (absorption capacity, fluorescence efficiency, and singlet oxygen production) in suspension. For the most promising PS-PEG-FA silica nanoplatforms, the biocompatibility in dark conditions and the phototoxicity under suitable irradiation wavelengths (blue, green, or red) at regulated light doses (10–15 J/cm²) were compared with PSs free in solution in HeLa cells in vitro. Full article

(This article belongs to the Special Issue Nanomaterials in Cancer Diagnosis and Therapy)

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14 pages, 1739 KiB

Open AccessReview

From Genetic Mutations to Molecular Basis of Heart Failure Treatment: An Overview of the Mechanism and Implication of the Novel Modulators for Cardiac Myosin

by Yu-Jen Chen, Chian-Shiu Chien, Chern-En Chiang, Chen-Huan Chen and Hao-Min Cheng

Int. J. Mol. Sci. 2021, 22(12), 6617; https://doi.org/10.3390/ijms22126617 - 21 Jun 2021

Cited by 10 | Viewed by 6451

Abstract

Heart failure (HF) is a syndrome encompassing several important etiologies that lead to the imbalance between oxygen demand and supply. Despite the usage of guideline-directed medical therapy for HF has shown better outcomes, novel therapeutic strategies are desirable, especially for patients with preserved [...] Read more.

Heart failure (HF) is a syndrome encompassing several important etiologies that lead to the imbalance between oxygen demand and supply. Despite the usage of guideline-directed medical therapy for HF has shown better outcomes, novel therapeutic strategies are desirable, especially for patients with preserved or mildly reduced left ventricular ejection fraction. In this regard, understanding the molecular basis for cardiomyopathies is expected to fill in the knowledge gap and generate new therapies to improve prognosis for HF. This review discusses an evolutionary mechanism designed to regulate cardiac contraction and relaxation through the most often genetically determined cardiomyopathies associated with HF. In addition, both the myosin inhibitor and myosin activator are promising new treatments for cardiomyopathies. A comprehensive review from genetic mutations to the molecular basis of direct sarcomere modulators will help shed light on future studies for a better characterization of HF etiologies and potential therapeutic targets. Full article

(This article belongs to the Special Issue Heart Failure: From Molecular Basis to Therapy 2.0)

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27 pages, 2905 KiB

Open AccessReview

On the Use of Surface Plasmon Resonance Biosensing to Understand IgG-FcγR Interactions

by Catherine Forest-Nault, Jimmy Gaudreault, Olivier Henry, Yves Durocher and Gregory De Crescenzo

Int. J. Mol. Sci. 2021, 22(12), 6616; https://doi.org/10.3390/ijms22126616 - 21 Jun 2021

Cited by 24 | Viewed by 4522

Abstract

Surface plasmon resonance (SPR)-based optical biosensors offer real-time and label-free analysis of protein interactions, which has extensively contributed to the discovery and development of therapeutic monoclonal antibodies (mAbs). As the biopharmaceutical market for these biologics and their biosimilars is rapidly growing, the role [...] Read more.

Surface plasmon resonance (SPR)-based optical biosensors offer real-time and label-free analysis of protein interactions, which has extensively contributed to the discovery and development of therapeutic monoclonal antibodies (mAbs). As the biopharmaceutical market for these biologics and their biosimilars is rapidly growing, the role of SPR biosensors in drug discovery and quality assessment is becoming increasingly prominent. One of the critical quality attributes of mAbs is the N-glycosylation of their Fc region. Other than providing stability to the antibody, the Fc N-glycosylation influences immunoglobulin G (IgG) interactions with the Fcγ receptors (FcγRs), modulating the immune response. Over the past two decades, several studies have relied on SPR-based assays to characterize the influence of N-glycosylation upon the IgG-FcγR interactions. While these studies have unveiled key information, many conclusions are still debated in the literature. These discrepancies can be, in part, attributed to the design of the reported SPR-based assays as well as the methodology applied to SPR data analysis. In fact, the SPR biosensor best practices have evolved over the years, and several biases have been pointed out in the development of experimental SPR protocols. In parallel, newly developed algorithms and data analysis methods now allow taking into consideration complex biomolecular kinetics. In this review, we detail the use of different SPR biosensing approaches for characterizing the IgG-FcγR interactions, highlighting their merit and inherent experimental complexity. Furthermore, we review the latest SPR-derived conclusions on the influence of the N-glycosylation upon the IgG-FcγR interactions and underline the differences and similarities across the literature. Finally, we explore new avenues taking advantage of novel computational analysis of SPR results as well as the latest strategies to control the glycoprofile of mAbs during production, which could lead to a better understanding and modelling of the IgG-FcγRs interactions. Full article

(This article belongs to the Special Issue Fc Receptors)

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22 pages, 4803 KiB

Open AccessArticle

Recent Developments on gMicroMC: Transport Simulations of Proton and Heavy Ions and Concurrent Transport of Radicals and DNA

by Youfang Lai, Xun Jia and Yujie Chi

Int. J. Mol. Sci. 2021, 22(12), 6615; https://doi.org/10.3390/ijms22126615 - 21 Jun 2021

Cited by 6 | Viewed by 2653

Abstract

Mechanistic Monte Carlo (MC) simulation of radiation interaction with water and DNA is important for the understanding of biological responses induced by ionizing radiation. In our previous work, we employed the Graphical Processing Unit (GPU)-based parallel computing technique to develop a novel, highly [...] Read more.

Mechanistic Monte Carlo (MC) simulation of radiation interaction with water and DNA is important for the understanding of biological responses induced by ionizing radiation. In our previous work, we employed the Graphical Processing Unit (GPU)-based parallel computing technique to develop a novel, highly efficient, and open-source MC simulation tool, gMicroMC, for simulating electron-induced DNA damages. In this work, we reported two new developments in gMicroMC: the transport simulation of protons and heavy ions and the concurrent transport of radicals in the presence of DNA. We modeled these transports based on electromagnetic interactions between charged particles and water molecules and the chemical reactions between radicals and DNA molecules. Various physical properties, such as Linear Energy Transfer (LET) and particle range, from our simulation agreed with data published by NIST or simulation results from other CPU-based MC packages. The simulation results of DNA damage under the concurrent transport of radicals and DNA agreed with those from nBio-Topas simulation in a comprehensive testing case. GPU parallel computing enabled high computational efficiency. It took 41 s to simultaneously transport 100 protons with an initial kinetic energy of 10 MeV in water and 470 s to transport 10

^{5}

radicals up to 1 µs in the presence of DNA. Full article

(This article belongs to the Special Issue Advances in Molecular Simulation)

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18 pages, 1004 KiB

Open AccessReview

THE MAIN CYTOTOXIC EFFECTS OF METHYLSELENINIC ACID ON VARIOUS CANCER CELLS

by Elena G. Varlamova and Egor A. Turovsky

Int. J. Mol. Sci. 2021, 22(12), 6614; https://doi.org/10.3390/ijms22126614 - 21 Jun 2021

Cited by 36 | Viewed by 3149

Abstract

Studies of recent decades have repeatedly demonstrated the cytotoxic effect of selenium-containing compounds on cancer cells of various origins. Particular attention in these studies is paid to methylseleninic acid, a widespread selenium-containing compound of organic nature, for several reasons: it has a selective [...] Read more.

Studies of recent decades have repeatedly demonstrated the cytotoxic effect of selenium-containing compounds on cancer cells of various origins. Particular attention in these studies is paid to methylseleninic acid, a widespread selenium-containing compound of organic nature, for several reasons: it has a selective cytotoxic effect on cancer cells, it is cytotoxic in small doses, it is able to generate methylselenol, excluding the action of the enzyme β-lyase. All these qualities make methylseleninic acid an attractive substrate for the production of anticancer drugs on its basis with a well-pronounced selective effect. However, the studies available to date indicate that there is no strictly specific molecular mechanism of its cytotoxic effect in relation to different cancer cell lines and cancer models. This review contains generalized information on the dose- and time-dependent regulation of the toxic effect of methylseleninic acid on the proliferative properties of a number of cancer cell lines. In addition, special attention in this review is paid to the influence of this selenium-containing compound on the regulation of endoplasmic reticulum stress and on the expression of seven selenoproteins, which are localized in the endoplasmic reticulum. Full article

(This article belongs to the Special Issue Epigenetics in Molecular Toxicology)

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