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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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35 pages, 1355 KiB  
Review
Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan
by Kimberly L. P. Long, Jocelyn M. Breton, Matthew K. Barraza, Olga S. Perloff and Daniela Kaufer
Biomolecules 2021, 11(2), 283; https://doi.org/10.3390/biom11020283 - 14 Feb 2021
Cited by 20 | Viewed by 7102
Abstract
The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by [...] Read more.
The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research. Full article
(This article belongs to the Special Issue Hormonal Regulation of Neurogenesis in Adults)
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34 pages, 3326 KiB  
Review
Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules
by Chiara Lanzillotta and Fabio Di Domenico
Biomolecules 2021, 11(2), 266; https://doi.org/10.3390/biom11020266 - 11 Feb 2021
Cited by 20 | Viewed by 4119
Abstract
Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development [...] Read more.
Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed. Full article
(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')
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15 pages, 1400 KiB  
Review
The Role of Interferons in the Pathogenesis of Sjögren’s Syndrome and Future Therapeutic Perspectives
by Nicoletta Del Papa, Antonina Minniti, Maurizio Lorini, Vincenzo Carbonelli, Wanda Maglione, Francesca Pignataro, Nicola Montano, Roberto Caporali and Claudio Vitali
Biomolecules 2021, 11(2), 251; https://doi.org/10.3390/biom11020251 - 9 Feb 2021
Cited by 30 | Viewed by 4179
Abstract
There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type [...] Read more.
There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS. Full article
(This article belongs to the Special Issue Emerging Molecular Targets in Sjogren’s Syndrome)
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15 pages, 2371 KiB  
Review
Control of Gene Expression by Exosome-Derived Non-Coding RNAs in Cancer Angiogenesis and Lymphangiogenesis
by Valeria Arcucci, Steven A. Stacker and Marc G. Achen
Biomolecules 2021, 11(2), 249; https://doi.org/10.3390/biom11020249 - 9 Feb 2021
Cited by 20 | Viewed by 3244
Abstract
Tumour angiogenesis and lymphangiogenesis are hallmarks of cancer and have been associated with tumour progression, tumour metastasis and poor patient prognosis. Many factors regulate angiogenesis and lymphangiogenesis in cancer including non-coding RNAs which are a category of RNAs that do not encode proteins [...] Read more.
Tumour angiogenesis and lymphangiogenesis are hallmarks of cancer and have been associated with tumour progression, tumour metastasis and poor patient prognosis. Many factors regulate angiogenesis and lymphangiogenesis in cancer including non-coding RNAs which are a category of RNAs that do not encode proteins and have important regulatory functions at transcriptional and post-transcriptional levels. Non-coding RNAs can be encapsulated in extracellular vesicles called exosomes which are secreted by tumour cells or other cells in the tumour microenvironment and can then be taken up by the endothelial cells of blood vessels and lymphatic vessels. The “delivery” of these non-coding RNAs to endothelial cells in tumours can facilitate tumour angiogenesis and lymphangiogenesis. Here we review recent findings about exosomal non-coding RNAs, specifically microRNAs and long non-coding RNAs, which regulate tumour angiogenesis and lymphangiogenesis in cancer. We then focus on the potential use of these molecules as cancer biomarkers and opportunities for exploiting ncRNAs for the treatment of cancer. Full article
(This article belongs to the Section Molecular Biology)
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14 pages, 808 KiB  
Review
TRPM4 in Cancer—A New Potential Drug Target
by Anna Borgström, Christine Peinelt and Paulina Stokłosa
Biomolecules 2021, 11(2), 229; https://doi.org/10.3390/biom11020229 - 5 Feb 2021
Cited by 29 | Viewed by 6349
Abstract
Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, [...] Read more.
Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target. Full article
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels: Markers and Therapeutic Targets for Cancer?)
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38 pages, 2533 KiB  
Review
The Hulks and the Deadpools of the Cytokinin Universe: A Dual Strategy for Cytokinin Production, Translocation, and Signal Transduction
by Tomáš Hluska, Lucia Hlusková and R. J. Neil Emery
Biomolecules 2021, 11(2), 209; https://doi.org/10.3390/biom11020209 - 3 Feb 2021
Cited by 37 | Viewed by 6797
Abstract
Cytokinins are plant hormones, derivatives of adenine with a side chain at the N6-position. They are involved in many physiological processes. While the metabolism of trans-zeatin and isopentenyladenine, which are considered to be highly active cytokinins, has been extensively studied, [...] Read more.
Cytokinins are plant hormones, derivatives of adenine with a side chain at the N6-position. They are involved in many physiological processes. While the metabolism of trans-zeatin and isopentenyladenine, which are considered to be highly active cytokinins, has been extensively studied, there are others with less obvious functions, such as cis-zeatin, dihydrozeatin, and aromatic cytokinins, which have been comparatively neglected. To help explain this duality, we present a novel hypothesis metaphorically comparing various cytokinin forms, enzymes of CK metabolism, and their signalling and transporter functions to the comics superheroes Hulk and Deadpool. Hulk is a powerful but short-lived creation, whilst Deadpool presents a more subtle and enduring force. With this dual framework in mind, this review compares different cytokinin metabolites, and their biosynthesis, translocation, and sensing to illustrate the different mechanisms behind the two CK strategies. This is put together and applied to a plant developmental scale and, beyond plants, to interactions with organisms of other kingdoms, to highlight where future study can benefit the understanding of plant fitness and productivity. Full article
(This article belongs to the Special Issue Phytohormones 2020)
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17 pages, 2638 KiB  
Article
Anti-Inflammatory Effects of Rosmarinic Acid-Loaded Nanovesicles in Acute Colitis through Modulation of NLRP3 Inflammasome
by Sonia Marinho, Matilde Illanes, Javier Ávila-Román, Virginia Motilva and Elena Talero
Biomolecules 2021, 11(2), 162; https://doi.org/10.3390/biom11020162 - 26 Jan 2021
Cited by 53 | Viewed by 3870
Abstract
Ulcerative colitis (UC), one of the two main types of inflammatory bowel disease, has no effective treatment. Rosmarinic acid (RA) is a polyphenol that, when administered orally, is metabolised in the small intestine, compromising its beneficial effects. We used chitosan/nutriose-coated niosomes loaded with [...] Read more.
Ulcerative colitis (UC), one of the two main types of inflammatory bowel disease, has no effective treatment. Rosmarinic acid (RA) is a polyphenol that, when administered orally, is metabolised in the small intestine, compromising its beneficial effects. We used chitosan/nutriose-coated niosomes loaded with RA to protect RA from gastric degradation and target the colon and evaluated their effect on acute colitis induced by 4% dextran sodium sulphate (DSS) for seven days in mice. RA-loaded nanovesicles (5, 10 and 20 mg/kg) or free RA (20 mg/kg) were orally administered from three days prior to colitis induction and during days 1, 3, 5 and 7 of DSS administration. RA-loaded nanovesicles improved body weight loss and disease activity index as well as increased mucus production and decreased myeloperoxidase activity and TNF-α production. Moreover, RA-loaded nanovesicles downregulated protein expression of inflammasome components such as NLR family pyrin domain-containing 3 (NLRP3), adaptor protein (ASC) and caspase-1, and the consequent reduction of IL-1β levels. Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expression increased after the RA-loaded nanovesicles treatment However, these mechanistic changes were not detected with the RA-free treatment. Our findings suggest that the use of chitosan/nutriose-coated niosomes to increase RA local bioavailability could be a promising nutraceutical strategy for oral colon-targeted UC therapy. Full article
(This article belongs to the Special Issue Therapeutic or Preventive Potential of Dietary Compounds in the Inflammatory Response)
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15 pages, 1700 KiB  
Article
The Middle Part of the Plucked Hair Follicle Outer Root Sheath Is Identified as an Area Rich in Lineage-Specific Stem Cell Markers
by Hanluo Li, Federica Francesca Masieri, Marie Schneider, Alexander Bartella, Sebastian Gaus, Sebastian Hahnel, Rüdiger Zimmerer, Ulrich Sack, Danijela Maksimovic-Ivanic, Sanja Mijatovic, Jan-Christoph Simon, Bernd Lethaus and Vuk Savkovic
Biomolecules 2021, 11(2), 154; https://doi.org/10.3390/biom11020154 - 25 Jan 2021
Cited by 11 | Viewed by 6262
Abstract
Hair follicle outer root sheath (ORS) is a putative source of stem cells with therapeutic capacity. ORS contains several multipotent stem cell populations, primarily in the distal compartment of the bulge region. However, the bulge is routinely obtained using invasive isolation methods, which [...] Read more.
Hair follicle outer root sheath (ORS) is a putative source of stem cells with therapeutic capacity. ORS contains several multipotent stem cell populations, primarily in the distal compartment of the bulge region. However, the bulge is routinely obtained using invasive isolation methods, which require human scalp tissue ex vivo. Non-invasive sampling has been standardized by means of the plucking procedure, enabling to reproducibly obtain the mid-ORS part. The mid-ORS shows potential for giving rise to multiple stem cell populations in vitro. To demonstrate the phenotypic features of distal, middle, and proximal ORS parts, gene and protein expression profiles were studied in physically separated portions. The mid-part of the ORS showed a comparable or higher NGFR, nestin/NES, CD34, CD73, CD44, CD133, CK5, PAX3, MITF, and PMEL expression on both protein and gene levels, when compared to the distal ORS part. Distinct subpopulations of cells exhibiting small and round morphology were characterized with flow cytometry as simultaneously expressing CD73/CD271, CD49f/CD105, nestin, and not CK10. Potentially, these distinct subpopulations can give rise to cultured neuroectodermal and mesenchymal stem cell populations in vitro. In conclusion, the mid part of the ORS holds the potential for yielding multiple stem cells, in particular mesenchymal stem cells. Full article
(This article belongs to the Collection Mesenchymal Stem Cell Fate and Potential Therapy)
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15 pages, 2917 KiB  
Review
Structural Insights into Substrate Recognition and Processing by the 20S Proteasome
by Indrajit Sahu and Michael H. Glickman
Biomolecules 2021, 11(2), 148; https://doi.org/10.3390/biom11020148 - 24 Jan 2021
Cited by 35 | Viewed by 6126
Abstract
Four decades of proteasome research have yielded extensive information on ubiquitin-dependent proteolysis. The archetype of proteasomes is a 20S barrel-shaped complex that does not rely on ubiquitin as a degradation signal but can degrade substrates with a considerable unstructured stretch. Since roughly half [...] Read more.
Four decades of proteasome research have yielded extensive information on ubiquitin-dependent proteolysis. The archetype of proteasomes is a 20S barrel-shaped complex that does not rely on ubiquitin as a degradation signal but can degrade substrates with a considerable unstructured stretch. Since roughly half of all proteasomes in most eukaryotic cells are free 20S complexes, ubiquitin-independent protein degradation may coexist with ubiquitin-dependent degradation by the highly regulated 26S proteasome. This article reviews recent advances in our understanding of the biochemical and structural features that underlie the proteolytic mechanism of 20S proteasomes. The two outer α-rings of 20S proteasomes provide a number of potential docking sites for loosely folded polypeptides. The binding of a substrate can induce asymmetric conformational changes, trigger gate opening, and initiate its own degradation through a protease-driven translocation mechanism. Consequently, the substrate translocates through two additional narrow apertures augmented by the β-catalytic active sites. The overall pulling force through the two annuli results in a protease-like unfolding of the substrate and subsequent proteolysis in the catalytic chamber. Although both proteasomes contain identical β-catalytic active sites, the differential translocation mechanisms yield distinct peptide products. Nonoverlapping substrate repertoires and product outcomes rationalize cohabitation of both proteasome complexes in cells. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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13 pages, 7084 KiB  
Review
Exploring the Intracrine Functions of VEGF-A
by Sophie Wiszniak and Quenten Schwarz
Biomolecules 2021, 11(1), 128; https://doi.org/10.3390/biom11010128 - 19 Jan 2021
Cited by 52 | Viewed by 7631
Abstract
Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and [...] Read more.
Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed “intracrine”, and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics. Full article
(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF): From Basic Mechanisms to Clinical Significance and Drug Development)
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13 pages, 1376 KiB  
Review
Breakdown of Filamentous Myofibrils by the UPS–Step by Step
by Dina Aweida and Shenhav Cohen
Biomolecules 2021, 11(1), 110; https://doi.org/10.3390/biom11010110 - 15 Jan 2021
Cited by 13 | Viewed by 6262
Abstract
Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, [...] Read more.
Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, protein aggregates, and cell surface proteins; and the ubiquitin-proteasome system (UPS), which promotes degradation of mainly soluble proteins. Recent findings indicate that more complex protein structures, such as filamentous assemblies, which are not accessible to the catalytic core of the proteasome in vitro, can be efficiently degraded by this proteolytic machinery in systemic catabolic states in vivo. Mechanisms that loosen the filamentous structure seem to be activated first, hence increasing the accessibility of protein constituents to the UPS. In this review, we will discuss the mechanisms underlying the disassembly and loss of the intricate insoluble filamentous myofibrils, which are responsible for muscle contraction, and whose degradation by the UPS causes weakness and disability in aging and disease. Several lines of evidence indicate that myofibril breakdown occurs in a strictly ordered and controlled manner, and the function of AAA-ATPases is crucial for their disassembly and loss. Full article
(This article belongs to the Special Issue Looking Back and Ahead: Emerging Concepts in Ubiquitin and UBLs)
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39 pages, 11703 KiB  
Review
Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders
by Béla Kiss, István Laszlovszky, Balázs Krámos, András Visegrády, Amrita Bobok, György Lévay, Balázs Lendvai and Viktor Román
Biomolecules 2021, 11(1), 104; https://doi.org/10.3390/biom11010104 - 14 Jan 2021
Cited by 43 | Viewed by 7427
Abstract
Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 [...] Read more.
Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy. Full article
(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)
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22 pages, 3123 KiB  
Review
Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries
by Bobbi Fleiss, Juliette Van Steenwinckel, Cindy Bokobza, Isabelle K. Shearer, Emily Ross-Munro and Pierre Gressens
Biomolecules 2021, 11(1), 99; https://doi.org/10.3390/biom11010099 - 13 Jan 2021
Cited by 43 | Viewed by 5404
Abstract
Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, [...] Read more.
Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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21 pages, 3861 KiB  
Article
Perlecan in the Natural and Cell Therapy Repair of Human Adult Articular Cartilage: Can Modifications in This Proteoglycan Be a Novel Therapeutic Approach?
by John Garcia, Helen S. McCarthy, Jan Herman Kuiper, James Melrose and Sally Roberts
Biomolecules 2021, 11(1), 92; https://doi.org/10.3390/biom11010092 - 13 Jan 2021
Cited by 13 | Viewed by 3152
Abstract
Articular cartilage is considered to have limited regenerative capacity, which has led to the search for therapies to limit or halt the progression of its destruction. Perlecan, a multifunctional heparan sulphate (HS) proteoglycan, promotes embryonic cartilage development and stabilises the mature tissue. We [...] Read more.
Articular cartilage is considered to have limited regenerative capacity, which has led to the search for therapies to limit or halt the progression of its destruction. Perlecan, a multifunctional heparan sulphate (HS) proteoglycan, promotes embryonic cartilage development and stabilises the mature tissue. We investigated the immunolocalisation of perlecan and collagen between donor-matched biopsies of human articular cartilage defects (n = 10 × 2) that were repaired either naturally or using autologous cell therapy, and with age-matched normal cartilage. We explored how the removal of HS from perlecan affects human chondrocytes in vitro. Immunohistochemistry showed both a pericellular and diffuse matrix staining pattern for perlecan in both natural and cell therapy repaired cartilage, which related to whether the morphology of the newly formed tissue was hyaline cartilage or fibrocartilage. Immunostaining for perlecan was significantly greater in both these repair tissues compared to normal age-matched controls. The immunolocalisation of collagens type III and VI was also dependent on tissue morphology. Heparanase treatment of chondrocytes in vitro resulted in significantly increased proliferation, while the expression of key chondrogenic surface and genetic markers was unaffected. Perlecan was more prominent in chondrocyte clusters than in individual cells after heparanase treatment. Heparanase treatment could be a means of increasing chondrocyte responsiveness to cartilage injury and perhaps to improve repair of defects. Full article
(This article belongs to the Special Issue Exploring the Multifaceted Roles of Glycosaminoglycans (GAGs) - New Advances and Further Challenges)
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21 pages, 799 KiB  
Review
Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm
by Alexandra Pum, Maria Ennemoser, Tiziana Adage and Andreas J. Kungl
Biomolecules 2021, 11(1), 91; https://doi.org/10.3390/biom11010091 - 12 Jan 2021
Cited by 69 | Viewed by 6425
Abstract
The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences [...] Read more.
The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences are not completely clear, the presence and involvement of specific chemokines is undoubtedly crucial for the development and progression of COVID-19. Cytokine storm and the often-resulting cytokine release syndrome (CRS) are pathophysiological hallmarks in COVID-19 infections related to its most severe and fatal cases. In this hyperinflammatory event, chemokines and other cytokines are highly upregulated and are therefore not fulfilling their beneficial function in the host response anymore but causing harmful effects. Here, we present the recent views on the involvement of chemokines and selected cytokines in COVID-19 and the therapeutics currently in clinical development targeting or interfering with them, discussing their potentials in the treatment of COVID-19 infections. Full article
(This article belongs to the Special Issue Chemokines in Infectious and Non-infectious Diseases)
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18 pages, 306 KiB  
Review
Efficacy and Safety of Mesenchymal Stem/Stromal Cell Therapy for Inflammatory Bowel Diseases: An Up-to-Date Systematic Review
by Jeffrey Zheng-Hsien Ko, Sheeva Johnson and Maneesh Dave
Biomolecules 2021, 11(1), 82; https://doi.org/10.3390/biom11010082 - 11 Jan 2021
Cited by 38 | Viewed by 4886
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut that can lead to severe gastrointestinal symptoms, malnutrition, and complications such as fistulas and cancer. Mesenchymal stem/stromal cells (MSCs) are being investigated as a novel therapy for IBD and have been [...] Read more.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut that can lead to severe gastrointestinal symptoms, malnutrition, and complications such as fistulas and cancer. Mesenchymal stem/stromal cells (MSCs) are being investigated as a novel therapy for IBD and have been demonstrated to be safe and effective for perianal fistulizing Crohn’s disease (PFCD). This systematic review aims to present the most recent studies on the safety and efficacy of MSC therapy in IBD. A detailed search strategy of clinical trials on MSCs and IBD was performed on PubMed, with 32 studies selected for inclusion in this review. The newest studies on local MSC injection for PFCD continue to support long-term efficacy while maintaining a favorable safety profile. The evidence for systemic MSC infusion in luminal IBD remains mixed due to marked methodological heterogeneity and unclear safety profiles. Although further studies are needed to better establish the role of this novel treatment modality, MSCs are proving to be a very exciting addition to the limited therapies available for IBD. Full article
(This article belongs to the Collection Mesenchymal Stem Cell Fate and Potential Therapy)
23 pages, 1417 KiB  
Review
Glycosaminoglycans in Tissue Engineering: A Review
by Harkanwalpreet Sodhi and Alyssa Panitch
Biomolecules 2021, 11(1), 29; https://doi.org/10.3390/biom11010029 - 29 Dec 2020
Cited by 87 | Viewed by 12677
Abstract
Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key [...] Read more.
Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key in tissue engineering, where the aim is to mimic and regenerate endogenous tissues. Because of this, incorporation of glycosaminoglycans to drive stem cell fate and promote cell proliferation in engineered tissues has gained increasing attention. This review summarizes the role glycosaminoglycans can play in tissue engineering and the recent advances in their use in these constructs. We also evaluate the general trend of research in this niche and provide insight into its future directions. Full article
(This article belongs to the Special Issue Exploring the Multifaceted Roles of Glycosaminoglycans (GAGs) - New Advances and Further Challenges)
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18 pages, 1208 KiB  
Review
Nanobodies Right in the Middle: Intrabodies as Toolbox to Visualize and Modulate Antigens in the Living Cell
by Teresa R. Wagner and Ulrich Rothbauer
Biomolecules 2020, 10(12), 1701; https://doi.org/10.3390/biom10121701 - 21 Dec 2020
Cited by 24 | Viewed by 5707
Abstract
In biomedical research, there is an ongoing demand for new technologies to elucidate disease mechanisms and develop novel therapeutics. This requires comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, post-translational modifications and dynamic interactions of cellular [...] Read more.
In biomedical research, there is an ongoing demand for new technologies to elucidate disease mechanisms and develop novel therapeutics. This requires comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, post-translational modifications and dynamic interactions of cellular components. Traceable intracellular binding molecules provide new opportunities for real-time cellular diagnostics. Most prominently, intrabodies derived from antibody fragments of heavy-chain only antibodies of camelids (nanobodies) have emerged as highly versatile and attractive probes to study and manipulate antigens within the context of living cells. In this review, we provide an overview on the selection, delivery and usage of intrabodies to visualize and monitor cellular antigens in living cells and organisms. Additionally, we summarize recent advances in the development of intrabodies as cellular biosensors and their application to manipulate disease-related cellular processes. Finally, we highlight switchable intrabodies, which open entirely new possibilities for real-time cell-based diagnostics including live-cell imaging, target validation and generation of precisely controllable binding reagents for future therapeutic applications. Full article
(This article belongs to the Special Issue The Therapeutic and Diagnostic Potential of Nanobodies)
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23 pages, 1846 KiB  
Review
Cell-Free DNA-Methylation-Based Methods and Applications in Oncology
by Francesca Galardi, Francesca De Luca, Dario Romagnoli, Chiara Biagioni, Erica Moretti, Laura Biganzoli, Angelo Di Leo, Ilenia Migliaccio, Luca Malorni and Matteo Benelli
Biomolecules 2020, 10(12), 1677; https://doi.org/10.3390/biom10121677 - 15 Dec 2020
Cited by 37 | Viewed by 9117
Abstract
Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm [...] Read more.
Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm being more prevalent, pervasive, and cell- and tumor-type specific than genomics, for which established cfDNA assays already exist. Herein, we report on recent advances on experimental strategies for the analysis of DNAm in cfDNA samples. We describe the main steps of DNAm-based analysis workflows, including pre-analytics of cfDNA samples, DNA treatment, assays for DNAm evaluation, and methods for data analysis. We report on protocols, biomolecular techniques, and computational strategies enabling DNAm evaluation in the context of cfDNA analysis, along with practical considerations on input sample requirements and costs. We provide an overview on existing studies exploiting cell-free DNAm biomarkers for the detection and monitoring of cancer in early and advanced settings, for the evaluation of drug resistance, and for the identification of the cell-of-origin of tumors. Finally, we report on DNAm-based tests approved for clinical use and summarize their performance in the context of liquid biopsy. Full article
(This article belongs to the Special Issue Epigenetics in Cancer)
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25 pages, 2374 KiB  
Review
Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy
by Faheem Shaik, Gary A. Cuthbert, Shervanthi Homer-Vanniasinkam, Stephen P. Muench, Sreenivasan Ponnambalam and Michael A. Harrison
Biomolecules 2020, 10(12), 1673; https://doi.org/10.3390/biom10121673 - 15 Dec 2020
Cited by 54 | Viewed by 7320
Abstract
Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in [...] Read more.
Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in many disease states, including tumour development and progression, there is much interest in understanding the mechanistic basis for how VEGF-A regulates cell and tissue function. VEGF-A binds with high affinity to two VEGF receptor tyrosine kinases (VEGFR1, VEGFR2) and with lower affinity to co-receptors called neuropilin-1 and neuropilin-2 (NRP1, NRP2). Here, we use a structural viewpoint to summarise our current knowledge of VEGF-VEGFR activation and signal transduction. As targeting VEGF-VEGFR activation holds much therapeutic promise, we examine the structural basis for anti-angiogenic therapy using small-molecule compounds such as tyrosine kinase inhibitors that block VEGFR activation and downstream signalling. This review provides a rational basis towards reconciling VEGF and VEGFR structure and function in developing new therapeutics for a diverse range of ailments. Full article
(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF): From Basic Mechanisms to Clinical Significance and Drug Development)
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19 pages, 1742 KiB  
Article
The Application of a Plant Biostimulant Based on Seaweed and Yeast Extract Improved Tomato Fruit Development and Quality
by Giuseppe Mannino, Cristina Campobenedetto, Ivano Vigliante, Valeria Contartese, Carla Gentile and Cinzia M. Bertea
Biomolecules 2020, 10(12), 1662; https://doi.org/10.3390/biom10121662 - 12 Dec 2020
Cited by 61 | Viewed by 6623
Abstract
Plant biostimulants are under investigation as innovative products to improve plant production and fruit quality, without resulting in environmental and food contaminations. Here, the effects of the application of Expando, a biostimulant based on seaweed and yeast extracts, on plant productivity, fruit ripening [...] Read more.
Plant biostimulants are under investigation as innovative products to improve plant production and fruit quality, without resulting in environmental and food contaminations. Here, the effects of the application of Expando, a biostimulant based on seaweed and yeast extracts, on plant productivity, fruit ripening times, and fruit quality of Solanum lycopersicum var. Micro-Tom were evaluated. After biostimulant treatment, a two-week reduction of ripening times and a concomitant enhancement of the production percentage during the earliest ripening times, in terms of both fruit yield (+110%) and size (+85%), were observed. Concerning fruit quality, proximate analysis showed that tomatoes treated with the biostimulant had better nutritional composition compared to untreated samples, since both the quality of unsatured fatty acids (C16:3ω3: +328%; C18:2ω6: −23%) and micronutrients essential for human health (Fe: +14%; Cu: +21%; Zn: +24%) were increased. From a nutraceutical point of view, despite strong changes in bioactive compound profile not being observed, an increase of the antioxidant properties was recorded in fruits harvested by plants treated with the biostimulant (2,2’-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS): +38%; 2,2-diphenyl-1-picrylhydrazyl (DPPH): +11%). In conclusion, the biostimulant application was able to reduce the ripening times and fruit size, while slightly increasing nutritional and nutraceutical values, leading to more marketable tomato fruits. Full article
(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)
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30 pages, 1797 KiB  
Review
An Inside Job: Applications of Intracellular Single Domain Antibodies
by Eline Soetens, Marlies Ballegeer and Xavier Saelens
Biomolecules 2020, 10(12), 1663; https://doi.org/10.3390/biom10121663 - 12 Dec 2020
Cited by 18 | Viewed by 4544
Abstract
Sera of camelid species contain a special kind of antibody that consists only of heavy chains. The variable antigen binding domain of these heavy chain antibodies can be expressed as a separate entity, called a single domain antibody that is characterized by its [...] Read more.
Sera of camelid species contain a special kind of antibody that consists only of heavy chains. The variable antigen binding domain of these heavy chain antibodies can be expressed as a separate entity, called a single domain antibody that is characterized by its small size, high solubility and oftentimes exceptional stability. Because of this, most single domain antibodies fold correctly when expressed in the reducing environment of the cytoplasm, and thereby retain their antigen binding specificity. Single domain antibodies can thus be used to target a broad range of intracellular proteins. Such intracellular single domain antibodies are also known as intrabodies, and have proven to be highly useful tools for basic research by allowing visualization, disruption and even targeted degradation of intracellular proteins. Furthermore, intrabodies can be used to uncover prospective new therapeutic targets and have the potential to be applied in therapeutic settings in the future. In this review we provide a brief overview of recent advances in the field of intracellular single domain antibodies, focusing on their use as research tools and potential therapeutic applications. Special attention is given to the available methods that allow delivery of single domain antibodies into cells. Full article
(This article belongs to the Special Issue The Therapeutic and Diagnostic Potential of Nanobodies)
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26 pages, 1612 KiB  
Review
Cx43 and the Actin Cytoskeleton: Novel Roles and Implications for Cell-Cell Junction-Based Barrier Function Regulation
by Randy E. Strauss and Robert G. Gourdie
Biomolecules 2020, 10(12), 1656; https://doi.org/10.3390/biom10121656 - 10 Dec 2020
Cited by 21 | Viewed by 4588
Abstract
Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this [...] Read more.
Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this review, we focus on the contribution of the gap junction protein, Cx43, to the biophysical and biochemical regulation of barrier function. First, we introduce the structure and canonical channel-dependent functions of Cx43. Second, we define barrier function and examine the key molecular structures fundamental to its regulation. Third, we survey the literature on the channel-dependent roles of connexins in barrier function, with an emphasis on the role of Cx43 and the actin cytoskeleton. Lastly, we discuss findings on the channel-independent roles of Cx43 in its associations with the actin cytoskeleton and focal adhesion structures highlighted by PI3K signaling, in the potential modulation of cellular barriers. Mounting evidence of crosstalk between connexins, the cytoskeleton, focal adhesion complexes, and junctional structures has led to a growing appreciation of how barrier-modulating mechanisms may work together to effect solute and cellular flux across tissue boundaries. This new understanding could translate into improved therapeutic outcomes in the treatment of barrier-associated diseases. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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28 pages, 2942 KiB  
Review
Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease
by Daniel Liedtke, Christine Hofmann, Franz Jakob, Eva Klopocki and Stephanie Graser
Biomolecules 2020, 10(12), 1648; https://doi.org/10.3390/biom10121648 - 8 Dec 2020
Cited by 22 | Viewed by 5440
Abstract
Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and [...] Read more.
Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish. Full article
(This article belongs to the Section Molecular Medicine)
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30 pages, 5094 KiB  
Review
Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells
by Paulina Podkalicka, Jacek Stępniewski, Olga Mucha, Neli Kachamakova-Trojanowska, Józef Dulak and Agnieszka Łoboda
Biomolecules 2020, 10(12), 1614; https://doi.org/10.3390/biom10121614 - 29 Nov 2020
Cited by 29 | Viewed by 5566
Abstract
Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages [...] Read more.
Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages of embryonic development. In culture, hypoxic conditions may facilitate the derivation of embryonic stem cells (ESCs) and the generation of induced pluripotent stem cells (iPSCs), which may serve as a valuable tool for disease modeling. Endothelial cells (ECs), multifunctional components of vascular structures, may be obtained from iPSCs and subsequently used in various (hypoxia-related) disease models to investigate vascular dysfunctions. Although iPSC-ECs demonstrated functionality in vitro and in vivo, ongoing studies are conducted to increase the efficiency of differentiation and to establish the most productive protocols for the application of patient-derived cells in clinics. In this review, we highlight recent discoveries on the role of hypoxia in the derivation of ESCs and the generation of iPSCs. We also summarize the existing protocols of hypoxia-driven differentiation of iPSCs toward ECs and discuss their possible applications in disease modeling and treatment of hypoxia-related disorders. Full article
(This article belongs to the Special Issue Hypoxia and Hypoxia-Inducible Factors in Human Endothelium)
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19 pages, 3119 KiB  
Review
Sequence Features of Mitochondrial Transporter Protein Families
by Gergely Gyimesi and Matthias A. Hediger
Biomolecules 2020, 10(12), 1611; https://doi.org/10.3390/biom10121611 - 28 Nov 2020
Cited by 24 | Viewed by 6276
Abstract
Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical SLC25 (solute carrier family 25) mitochondrial carriers, the past decade has led to the discovery of [...] Read more.
Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical SLC25 (solute carrier family 25) mitochondrial carriers, the past decade has led to the discovery of additional protein families with numerous members that exhibit IMM localization and transporter-like properties. These include mitochondrial pyruvate carriers, sideroflexins, and mitochondrial cation/H+ exchangers. These transport proteins were linked to vital physiological functions and disease. Their structures and transport mechanisms are, however, still largely unknown and understudied. Protein sequence analysis per se can often pinpoint hotspots that are of functional or structural importance. In this review, we summarize current knowledge about the sequence features of mitochondrial transporters with a special focus on the newly included SLC54, SLC55 and SLC56 families of the SLC solute carrier superfamily. Taking a step further, we combine sequence conservation analysis with transmembrane segment and secondary structure prediction methods to extract residue positions and sequence motifs that likely play a role in substrate binding, binding site gating or structural stability. We hope that our review will help guide future experimental efforts by the scientific community to unravel the transport mechanisms and structures of these novel mitochondrial carriers. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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32 pages, 1883 KiB  
Review
The Human Epidermal Basement Membrane: A Shaped and Cell Instructive Platform That Aging Slowly Alters
by Eva Roig-Rosello and Patricia Rousselle
Biomolecules 2020, 10(12), 1607; https://doi.org/10.3390/biom10121607 - 27 Nov 2020
Cited by 68 | Viewed by 17599
Abstract
One of the most important functions of skin is to act as a protective barrier. To fulfill this role, the structural integrity of the skin depends on the dermal-epidermal junction—a complex network of extracellular matrix macromolecules that connect the outer epidermal layer to [...] Read more.
One of the most important functions of skin is to act as a protective barrier. To fulfill this role, the structural integrity of the skin depends on the dermal-epidermal junction—a complex network of extracellular matrix macromolecules that connect the outer epidermal layer to the underlying dermis. This junction provides both a structural support to keratinocytes and a specific niche that mediates signals influencing their behavior. It displays a distinctive microarchitecture characterized by an undulating pattern, strengthening dermal-epidermal connectivity and crosstalk. The optimal stiffness arising from the overall molecular organization, together with characteristic anchoring complexes, keeps the dermis and epidermis layers extremely well connected and capable of proper epidermal renewal and regeneration. Due to intrinsic and extrinsic factors, a large number of structural and biological changes accompany skin aging. These changes progressively weaken the dermal–epidermal junction substructure and affect its functions, contributing to the gradual decline in overall skin physiology. Most changes involve reduced turnover or altered enzymatic or non-enzymatic post-translational modifications, compromising the mechanical properties of matrix components and cells. This review combines recent and older data on organization of the dermal-epidermal junction, its mechanical properties and role in mechanotransduction, its involvement in regeneration, and its fate during the aging process. Full article
(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)
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22 pages, 798 KiB  
Review
Post-Myocardial Infarction Ventricular Remodeling Biomarkers—The Key Link between Pathophysiology and Clinic
by Maria-Madălina Bostan, Cristian Stătescu, Larisa Anghel, Ionela-Lăcrămioara Șerban, Elena Cojocaru and Radu Sascău
Biomolecules 2020, 10(11), 1587; https://doi.org/10.3390/biom10111587 - 23 Nov 2020
Cited by 28 | Viewed by 6903
Abstract
Studies in recent years have shown increased interest in developing new methods of evaluation, but also in limiting post infarction ventricular remodeling, hoping to improve ventricular function and the further evolution of the patient. This is the point where biomarkers have proven effective [...] Read more.
Studies in recent years have shown increased interest in developing new methods of evaluation, but also in limiting post infarction ventricular remodeling, hoping to improve ventricular function and the further evolution of the patient. This is the point where biomarkers have proven effective in early detection of remodeling phenomena. There are six main processes that promote the remodeling and each of them has specific biomarkers that can be used in predicting the evolution (myocardial necrosis, neurohormonal activation, inflammatory reaction, hypertrophy and fibrosis, apoptosis, mixed processes). Some of the biomarkers such as creatine kinase–myocardial band (CK-MB), troponin, and N-terminal-pro type B natriuretic peptide (NT-proBNP) were so convincing that they immediately found their place in the post infarction patient evaluation protocol. Others that are related to more complex processes such as inflammatory biomarkers, atheroma plaque destabilization biomarkers, and microRNA are still being studied, but the results so far are promising. This article aims to review the markers used so far, but also the existing data on new markers that could be considered, taking into consideration the most important studies that have been conducted so far. Full article
(This article belongs to the Special Issue Molecular Biomarkers In Cardiology)
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32 pages, 741 KiB  
Review
Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment
by Laura Walrave, Mathieu Vinken, Luc Leybaert and Ilse Smolders
Biomolecules 2020, 10(11), 1578; https://doi.org/10.3390/biom10111578 - 20 Nov 2020
Cited by 28 | Viewed by 5251
Abstract
In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 [...] Read more.
In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K+ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca2+ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments. Full article
(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)
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34 pages, 8748 KiB  
Review
Clinical Applications of Patient-Specific 3D Printed Models in Cardiovascular Disease: Current Status and Future Directions
by Zhonghua Sun
Biomolecules 2020, 10(11), 1577; https://doi.org/10.3390/biom10111577 - 20 Nov 2020
Cited by 48 | Viewed by 6366
Abstract
Three-dimensional (3D) printing has been increasingly used in medicine with applications in many different fields ranging from orthopaedics and tumours to cardiovascular disease. Realistic 3D models can be printed with different materials to replicate anatomical structures and pathologies with high accuracy. 3D printed [...] Read more.
Three-dimensional (3D) printing has been increasingly used in medicine with applications in many different fields ranging from orthopaedics and tumours to cardiovascular disease. Realistic 3D models can be printed with different materials to replicate anatomical structures and pathologies with high accuracy. 3D printed models generated from medical imaging data acquired with computed tomography, magnetic resonance imaging or ultrasound augment the understanding of complex anatomy and pathology, assist preoperative planning and simulate surgical or interventional procedures to achieve precision medicine for improvement of treatment outcomes, train young or junior doctors to gain their confidence in patient management and provide medical education to medical students or healthcare professionals as an effective training tool. This article provides an overview of patient-specific 3D printed models with a focus on the applications in cardiovascular disease including: 3D printed models in congenital heart disease, coronary artery disease, pulmonary embolism, aortic aneurysm and aortic dissection, and aortic valvular disease. Clinical value of the patient-specific 3D printed models in these areas is presented based on the current literature, while limitations and future research in 3D printing including bioprinting of cardiovascular disease are highlighted. Full article
(This article belongs to the Special Issue Usefulness and Clinical Applications of 3D Printing in Cardiovascular Diseases)
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34 pages, 807 KiB  
Review
Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders
by María S. García-Gutiérrez, Francisco Navarrete, Ani Gasparyan, Amaya Austrich-Olivares, Francisco Sala and Jorge Manzanares
Biomolecules 2020, 10(11), 1575; https://doi.org/10.3390/biom10111575 - 19 Nov 2020
Cited by 149 | Viewed by 55066
Abstract
The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) [...] Read more.
The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders. Full article
(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)
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22 pages, 3543 KiB  
Article
Potential Nutraceutical Properties of Leaves from Several Commonly Cultivated Plants
by Hafsa Amat-ur-Rasool, Fenella Symes, David Tooth, Larissa-Nele Schaffert, Ekramy Elmorsy, Mehboob Ahmed, Shahida Hasnain and Wayne G. Carter
Biomolecules 2020, 10(11), 1556; https://doi.org/10.3390/biom10111556 - 15 Nov 2020
Cited by 27 | Viewed by 5104
Abstract
Chronic dietary ingestion of suitable phytochemicals may assist with limiting or negating neurodegenerative decline. Current therapeutics used to treat Alzheimer disease elicit broad adverse drug reactions, and alternative sources of cholinesterase inhibitors (ChEIs) are required. Herein, we screened methanolic extracts from seven commonly [...] Read more.
Chronic dietary ingestion of suitable phytochemicals may assist with limiting or negating neurodegenerative decline. Current therapeutics used to treat Alzheimer disease elicit broad adverse drug reactions, and alternative sources of cholinesterase inhibitors (ChEIs) are required. Herein, we screened methanolic extracts from seven commonly cultivated plants for their nutraceutical potential; ability to inhibit acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE), and provision of antioxidant activity through their 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical scavenging capabilities. Potential neurotoxicity of plant extracts was examined via application to SHSY-5Y neuroblastoma cells and quantitation of cell viability. Methanolic extracts of Citrus limon (Lemon), Bombax ceiba (Red silk-cotton), Lawsonia inermis (Henna), Eucalyptus globulus (Eucalyptus), Ocimum basilicum (Basil), Citrus reticulata (Mandarin orange), and Mentha spicata (Spearmint) all displayed concentration-dependent inhibition of AChE and BuChE. The majority of extracts inhibited AChE and BuChE to near equipotency, with Henna and Eucalyptus extracts the two most potent ChEIs. All plant extracts were able to scavenge free radicals in a concentration-dependent manner, with Eucalyptus the most potent antioxidant. Toxicity of plant extracts to neuronal cells was concentration dependent, with Eucalyptus also the most toxic extract. Fractionation of plant extracts and analysis by mass spectrometry identified a number of plant polyphenols that might have contributed to the cholinesterase inhibition: 3-caffeoylquinic acid, methyl 4-caffeoylquinate, kaempferol-acetyl-glycoside, quercetin 3-rutinoside, quercetin-acetyl-glycoside, kaempferol 3-O-glucoside, and quercetin 3-O-glucoside. In silico molecular modeling of these polyphenols demonstrated their improved AChE and BuChE binding affinities compared to the current FDA-approved dual ChEI, galantamine. Collectively, all the plant extracts contained nutraceutical agents as antioxidants and ChEIs and, therefore, their chronic consumption may prove beneficial to combat the pathological deficits that accrue in Alzheimer disease. Full article
(This article belongs to the Special Issue Cholinesterase Research)
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14 pages, 1289 KiB  
Review
Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease
by Piergiorgio La Rosa, Sara Petrillo, Maria Teresa Fiorenza, Enrico Silvio Bertini and Fiorella Piemonte
Biomolecules 2020, 10(11), 1551; https://doi.org/10.3390/biom10111551 - 13 Nov 2020
Cited by 25 | Viewed by 4704
Abstract
Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player [...] Read more.
Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress. Full article
(This article belongs to the Special Issue Biomolecules Controlling Transition Metals Derangement and Metal-Based Compounds as Therapeutic Approach for Cancer and Neurodegeneration)
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17 pages, 2491 KiB  
Article
Image Segmentation of the Ventricular Septum in Fetal Cardiac Ultrasound Videos Based on Deep Learning Using Time-Series Information
by Ai Dozen, Masaaki Komatsu, Akira Sakai, Reina Komatsu, Kanto Shozu, Hidenori Machino, Suguru Yasutomi, Tatsuya Arakaki, Ken Asada, Syuzo Kaneko, Ryu Matsuoka, Daisuke Aoki, Akihiko Sekizawa and Ryuji Hamamoto
Biomolecules 2020, 10(11), 1526; https://doi.org/10.3390/biom10111526 - 8 Nov 2020
Cited by 59 | Viewed by 7556
Abstract
Image segmentation is the pixel-by-pixel detection of objects, which is the most challenging but informative in the fundamental tasks of machine learning including image classification and object detection. Pixel-by-pixel segmentation is required to apply machine learning to support fetal cardiac ultrasound screening; we [...] Read more.
Image segmentation is the pixel-by-pixel detection of objects, which is the most challenging but informative in the fundamental tasks of machine learning including image classification and object detection. Pixel-by-pixel segmentation is required to apply machine learning to support fetal cardiac ultrasound screening; we have to detect cardiac substructures precisely which are small and change shapes dynamically with fetal heartbeats, such as the ventricular septum. This task is difficult for general segmentation methods such as DeepLab v3+, and U-net. Hence, here we proposed a novel segmentation method named Cropping-Segmentation-Calibration (CSC) that is specific to the ventricular septum in ultrasound videos in this study. CSC employs the time-series information of videos and specific section information to calibrate the output of U-net. The actual sections of the ventricular septum were annotated in 615 frames from 421 normal fetal cardiac ultrasound videos of 211 pregnant women who were screened. The dataset was assigned a ratio of 2:1, which corresponded to a ratio of the training to test data, and three-fold cross-validation was conducted. The segmentation results of DeepLab v3+, U-net, and CSC were evaluated using the values of the mean intersection over union (mIoU), which were 0.0224, 0.1519, and 0.5543, respectively. The results reveal the superior performance of CSC. Full article
(This article belongs to the Special Issue Application of Artificial Intelligence for Medical Research)
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20 pages, 3216 KiB  
Review
Hyaluronan: Metabolism and Function
by Takashi Kobayashi, Theerawut Chanmee and Naoki Itano
Biomolecules 2020, 10(11), 1525; https://doi.org/10.3390/biom10111525 - 7 Nov 2020
Cited by 163 | Viewed by 13838
Abstract
As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis [...] Read more.
As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis and degradation tightly control the turnover rate, concentration, and molecular size of hyaluronan in tissues. Despite the relatively simple chemical composition of this polysaccharide, its wide range of molecular weights mediate diverse functions that depend on molecular size and tissue concentration. Genetic engineering and pharmacological approaches have demonstrated close associations between hyaluronan metabolism and functions in many physiological and pathological events, including morphogenesis, wound healing, and inflammation. Moreover, emerging evidence has suggested that the accumulation of hyaluronan extracellular matrix and fragments due to the altered expression of hyaluronan synthases and hyaluronidases potentiates cancer development and progression by remodeling the tumor microenvironment. In addition to the well-known functions exerted by extracellular hyaluronan, recent metabolomic approaches have also revealed that its synthesis can regulate cellular functions via the reprogramming of cellular metabolism. This review highlights the current advances in knowledge on the biosynthesis and catabolism of hyaluronan and describes the diverse functions associated with hyaluronan metabolism. Full article
(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)
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24 pages, 1511 KiB  
Review
Structural Conservation and Adaptation of the Bacterial Flagella Motor
by Brittany L. Carroll and Jun Liu
Biomolecules 2020, 10(11), 1492; https://doi.org/10.3390/biom10111492 - 29 Oct 2020
Cited by 26 | Viewed by 9901
Abstract
Many bacteria require flagella for the ability to move, survive, and cause infection. The flagellum is a complex nanomachine that has evolved to increase the fitness of each bacterium to diverse environments. Over several decades, molecular, biochemical, and structural insights into the flagella [...] Read more.
Many bacteria require flagella for the ability to move, survive, and cause infection. The flagellum is a complex nanomachine that has evolved to increase the fitness of each bacterium to diverse environments. Over several decades, molecular, biochemical, and structural insights into the flagella have led to a comprehensive understanding of the structure and function of this fascinating nanomachine. Notably, X-ray crystallography, cryo-electron microscopy (cryo-EM), and cryo-electron tomography (cryo-ET) have elucidated the flagella and their components to unprecedented resolution, gleaning insights into their structural conservation and adaptation. In this review, we focus on recent structural studies that have led to a mechanistic understanding of flagellar assembly, function, and evolution. Full article
(This article belongs to the Special Issue Perspectives on Bacterial Flagellar Motor)
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19 pages, 1107 KiB  
Review
Protective Effects of Epigallocatechin Gallate (EGCG) on Endometrial, Breast, and Ovarian Cancers
by Yun-Ju Huang, Kai-Lee Wang, Hsin-Yuan Chen, Yi-Fen Chiang and Shih-Min Hsia
Biomolecules 2020, 10(11), 1481; https://doi.org/10.3390/biom10111481 - 25 Oct 2020
Cited by 49 | Viewed by 7419
Abstract
Green tea and its major bioactive component, (−)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly antiproliferation, antimetastasis, and apoptosis induction. Many studies have widely investigated the anticancer and synergistic effects of EGCG due to the side effects of conventional cytotoxic agents. This review [...] Read more.
Green tea and its major bioactive component, (−)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly antiproliferation, antimetastasis, and apoptosis induction. Many studies have widely investigated the anticancer and synergistic effects of EGCG due to the side effects of conventional cytotoxic agents. This review summarizes recent knowledge of underlying mechanisms of EGCG on protective roles for endometrial, breast, and ovarian cancers based on both in vitro and in vivo animal studies. EGCG has the ability to regulate many pathways, including the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), inhibition of nuclear factor-κB (NF-κB), and protection against epithelial–mesenchymal transition (EMT). EGCG has also been found to interact with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which affect epigenetic modifications. Finally, the action of EGCG may exert a suppressive effect on gynecological cancers and have beneficial effects on auxiliary therapies for known drugs. Thus, future clinical intervention studies with EGCG will be necessary to more and clear evidence for the benefit to these cancers. Full article
(This article belongs to the Special Issue Biomolecules and Cancer Prevention)
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32 pages, 2420 KiB  
Review
Updating Phospholipase A2 Biology
by Makoto Murakami, Hiroyasu Sato and Yoshitaka Taketomi
Biomolecules 2020, 10(10), 1457; https://doi.org/10.3390/biom10101457 - 19 Oct 2020
Cited by 125 | Viewed by 11713
Abstract
The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids [...] Read more.
The phospholipase A2 (PLA2) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA2 has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA2 reaction. PLA2 enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA2-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA2 superfamily, focusing particularly on the novel roles of PLA2s in vivo. Full article
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
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22 pages, 1142 KiB  
Review
Ubiquitomics: An Overview and Future
by George Vere, Rachel Kealy, Benedikt M. Kessler and Adan Pinto-Fernandez
Biomolecules 2020, 10(10), 1453; https://doi.org/10.3390/biom10101453 - 17 Oct 2020
Cited by 26 | Viewed by 6658
Abstract
Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is a key post-translational modification that determines the fate, function, and turnover of most cellular proteins. Ubiquitin modification exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected [...] Read more.
Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is a key post-translational modification that determines the fate, function, and turnover of most cellular proteins. Ubiquitin modification exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected to lysine, perhaps other amino acid side chains, and N-termini of proteins, often including branching of the ubiquitin chains. Understanding this enormous complexity in protein ubiquitination, the so-called ‘ubiquitin code’, in combination with the ∼1000 enzymes involved in controlling ubiquitin recognition, conjugation, and deconjugation, calls for novel developments in analytical techniques. Here, we review different headways in the field mainly driven by mass spectrometry and chemical biology, referred to as “ubiquitomics”, aiming to understand this system’s biological diversity. Full article
(This article belongs to the Special Issue Looking Back and Ahead: Emerging Concepts in Ubiquitin and UBLs)
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16 pages, 817 KiB  
Review
Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD
by Takefumi Kimura, Sai P. Pydi, Jonathan Pham and Naoki Tanaka
Biomolecules 2020, 10(10), 1445; https://doi.org/10.3390/biom10101445 - 15 Oct 2020
Cited by 27 | Viewed by 9274
Abstract
G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of extracellular ligands. Understanding how GPCRs work at the molecular level has important therapeutic implications, as 30–40% of the drugs currently in clinical use mediate therapeutic effects by acting on GPCRs. [...] Read more.
G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of extracellular ligands. Understanding how GPCRs work at the molecular level has important therapeutic implications, as 30–40% of the drugs currently in clinical use mediate therapeutic effects by acting on GPCRs. Like many other cell types, liver function is regulated by GPCRs. More than 50 different GPCRs are predicted to be expressed in the mouse liver. However, knowledge of how GPCRs regulate liver metabolism is limited. A better understanding of the metabolic role of GPCRs in hepatocytes, the dominant constituent cells of the liver, could lead to the development of novel drugs that are clinically useful for the treatment of various metabolic diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In this review, we describe the functions of multiple GPCRs expressed in hepatocytes and their role in metabolic processes. Full article
(This article belongs to the Special Issue Molecular Pathology and Therapeutics in Non-alcoholic Fatty Liver Disease)
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18 pages, 4222 KiB  
Review
Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression
by Zizhen Ming, Su Yin Lim and Helen Rizos
Biomolecules 2020, 10(10), 1447; https://doi.org/10.3390/biom10101447 - 15 Oct 2020
Cited by 27 | Viewed by 4394
Abstract
Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers. In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of [...] Read more.
Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers. In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of primary melanomas, in over 75% of metastatic melanomas, and in the germline of 40% of families with a predisposition to cutaneous melanoma. The CDKN2A locus encodes two critical tumor suppressor proteins, the cyclin-dependent kinase inhibitor p16INK4a and the p53 regulator p14ARF. The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequence of both p16INK4a and p14ARF. There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14ARF, while not altering the syntenic p16INK4a coding regions. In this review, we describe the frequency and types of somatic alterations affecting the CDKN2A locus in melanoma and germline CDKN2A alterations in familial melanoma, and their functional consequences in melanoma development. We discuss the clinical implications of CDKN2A inactivating alterations and their influence on treatment response and resistance. Full article
(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)
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26 pages, 1456 KiB  
Review
Microglia in Alzheimer’s Disease in the Context of Tau Pathology
by Juan Ramón Perea, Marta Bolós and Jesús Avila
Biomolecules 2020, 10(10), 1439; https://doi.org/10.3390/biom10101439 - 14 Oct 2020
Cited by 67 | Viewed by 12461
Abstract
Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest [...] Read more.
Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation. Full article
(This article belongs to the Special Issue Microglia in Neurodegeneration)
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36 pages, 2126 KiB  
Review
The Dichotomous Role of Inflammation in the CNS: A Mitochondrial Point of View
by Bianca Vezzani, Marianna Carinci, Simone Patergnani, Matteo P. Pasquin, Annunziata Guarino, Nimra Aziz, Paolo Pinton, Michele Simonato and Carlotta Giorgi
Biomolecules 2020, 10(10), 1437; https://doi.org/10.3390/biom10101437 - 13 Oct 2020
Cited by 28 | Viewed by 5110
Abstract
Innate immune response is one of our primary defenses against pathogens infection, although, if dysregulated, it represents the leading cause of chronic tissue inflammation. This dualism is even more present in the central nervous system, where neuroinflammation is both important for the activation [...] Read more.
Innate immune response is one of our primary defenses against pathogens infection, although, if dysregulated, it represents the leading cause of chronic tissue inflammation. This dualism is even more present in the central nervous system, where neuroinflammation is both important for the activation of reparatory mechanisms and, at the same time, leads to the release of detrimental factors that induce neurons loss. Key players in modulating the neuroinflammatory response are mitochondria. Indeed, they are responsible for a variety of cell mechanisms that control tissue homeostasis, such as autophagy, apoptosis, energy production, and also inflammation. Accordingly, it is widely recognized that mitochondria exert a pivotal role in the development of neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s diseases, as well as in acute brain damage, such in ischemic stroke and epileptic seizures. In this review, we will describe the role of mitochondria molecular signaling in regulating neuroinflammation in central nervous system (CNS) diseases, by focusing on pattern recognition receptors (PRRs) signaling, reactive oxygen species (ROS) production, and mitophagy, giving a hint on the possible therapeutic approaches targeting mitochondrial pathways involved in inflammation. Full article
(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders)
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28 pages, 3067 KiB  
Review
Role of Glutathione in Cancer: From Mechanisms to Therapies
by Luke Kennedy, Jagdeep K. Sandhu, Mary-Ellen Harper and Miroslava Cuperlovic-Culf
Biomolecules 2020, 10(10), 1429; https://doi.org/10.3390/biom10101429 - 9 Oct 2020
Cited by 446 | Viewed by 24699
Abstract
Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and [...] Read more.
Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects. Full article
(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)
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17 pages, 2887 KiB  
Article
Modulation of Guanylate Cyclase Activating Protein 1 (GCAP1) Dimeric Assembly by Ca2+ or Mg2+: Hints to Understand Protein Activity
by Francesco Bonì, Valerio Marino, Carlo Bidoia, Eloise Mastrangelo, Alberto Barbiroli, Daniele Dell’Orco and Mario Milani
Biomolecules 2020, 10(10), 1408; https://doi.org/10.3390/biom10101408 - 5 Oct 2020
Cited by 11 | Viewed by 3214
Abstract
The guanylyl cyclase-activating protein 1, GCAP1, activates or inhibits retinal guanylyl cyclase (retGC) depending on cellular Ca2+ concentrations. Several point mutations of GCAP1 have been associated with impaired calcium sensitivity that eventually triggers progressive retinal degeneration. In this work, we demonstrate that [...] Read more.
The guanylyl cyclase-activating protein 1, GCAP1, activates or inhibits retinal guanylyl cyclase (retGC) depending on cellular Ca2+ concentrations. Several point mutations of GCAP1 have been associated with impaired calcium sensitivity that eventually triggers progressive retinal degeneration. In this work, we demonstrate that the recombinant human protein presents a highly dynamic monomer-dimer equilibrium, whose dissociation constant is influenced by salt concentration and, more importantly, by protein binding to Ca2+ or Mg2+. Based on small-angle X-ray scattering data, protein-protein docking, and molecular dynamics simulations we propose two novel three-dimensional models of Ca2+-bound GCAP1 dimer. The different propensity of human GCAP1 to dimerize suggests structural differences induced by cation binding potentially involved in the regulation of retGC activity. Full article
(This article belongs to the Special Issue Metal Binding Proteins 2020)
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15 pages, 2096 KiB  
Article
Direct Effects of D-Chiro-Inositol on Insulin Signaling and Glucagon Secretion of Pancreatic Alpha Cells
by Agnese Filippello, Alessandra Scamporrino, Stefania Di Mauro, Roberta Malaguarnera, Antonino Di Pino, Roberto Scicali, Francesco Purrello and Salvatore Piro
Biomolecules 2020, 10(10), 1404; https://doi.org/10.3390/biom10101404 - 4 Oct 2020
Cited by 11 | Viewed by 3712
Abstract
The insulin resistance state of pancreatic α-cells seems to be related to glucagon hypersecretion in type 2 diabetes. Treatment that can improve the insulin sensitivity of α-cells could control glucagon levels in patients with diabetes mellitus. The aim of this study was to [...] Read more.
The insulin resistance state of pancreatic α-cells seems to be related to glucagon hypersecretion in type 2 diabetes. Treatment that can improve the insulin sensitivity of α-cells could control glucagon levels in patients with diabetes mellitus. The aim of this study was to investigate the preventive role of D-chiro-inositol (DCI), which has insulin receptor-sensitizer effects on insulin signaling pathways and glucagon secretion in pancreatic α-TC1 clone 6 cells. Cells were chronically treated with palmitate to induce insulin resistance in the presence/absence of DCI. DCI treatment improved the insulin signaling pathway and restored insulin-mediated glucagon suppression in α-TC1-6 cells exposed to palmitate. These results indicate that DCI treatment prevents the insulin resistance of α-TC1-6 cells chronically exposed to palmitate. Our data provide evidence that DCI could be useful to improve the insulin sensitivity of pancreatic α-cells in diabetes treatment. Full article
(This article belongs to the Special Issue Pancreatic Islets of Langerhans: Not Only Beta-Cells)
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19 pages, 2458 KiB  
Review
Mitochondrial Potassium Channels as Druggable Targets
by Antoni Wrzosek, Bartłomiej Augustynek, Monika Żochowska and Adam Szewczyk
Biomolecules 2020, 10(8), 1200; https://doi.org/10.3390/biom10081200 - 18 Aug 2020
Cited by 52 | Viewed by 6243
Abstract
Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been [...] Read more.
Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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36 pages, 1810 KiB  
Review
Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases
by Veronika Vozáriková, Nina Kunová, Jacob A. Bauer, Ján Frankovský, Veronika Kotrasová, Katarína Procházková, Vladimíra Džugasová, Eva Kutejová, Vladimír Pevala, Jozef Nosek and Ľubomír Tomáška
Biomolecules 2020, 10(8), 1193; https://doi.org/10.3390/biom10081193 - 16 Aug 2020
Cited by 13 | Viewed by 5136
Abstract
Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression [...] Read more.
Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level. Full article
(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)
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16 pages, 5690 KiB  
Review
Peroxisomal Cofactor Transport
by Anastasija Plett, Lennart Charton and Nicole Linka
Biomolecules 2020, 10(8), 1174; https://doi.org/10.3390/biom10081174 - 12 Aug 2020
Cited by 15 | Viewed by 4643
Abstract
Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum [...] Read more.
Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum (ER), mitochondria, and plastids. Peroxisomes, in common with all other cellular organelles are dependent on a wide range of cofactors, such as adenosine 5′-triphosphate (ATP), Coenzyme A (CoA), and nicotinamide adenine dinucleotide (NAD). The availability of the peroxisomal cofactor pool controls peroxisome function. The levels of these cofactors available for peroxisomal metabolism is determined by the balance between synthesis, import, export, binding, and degradation. Since the final steps of cofactor synthesis are thought to be located in the cytosol, cofactors must be imported into peroxisomes. This review gives an overview about our current knowledge of the permeability of the peroxisomal membrane with the focus on ATP, CoA, and NAD. Several members of the mitochondrial carrier family are located in peroxisomes, catalyzing the transfer of these organic cofactors across the peroxisomal membrane. Most of the functions of these peroxisomal cofactor transporters are known from studies in yeast, humans, and plants. Parallels and differences between the transporters in the different organisms are discussed here. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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15 pages, 1246 KiB  
Article
Targeting Endothelial Dysfunction in Eight Extreme-Critically Ill Patients with COVID-19 Using the Anti-Adrenomedullin Antibody Adrecizumab (HAM8101)
by Mahir Karakas, Dominik Jarczak, Martin Becker, Kevin Roedl, Marylyn M. Addo, Frauke Hein, Andreas Bergmann, Jens Zimmermann, Tim-Philipp Simon, Gernot Marx, Marc Lütgehetmann, Axel Nierhaus and Stefan Kluge
Biomolecules 2020, 10(8), 1171; https://doi.org/10.3390/biom10081171 - 11 Aug 2020
Cited by 23 | Viewed by 6772
Abstract
Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a “treatment on a [...] Read more.
Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a “treatment on a named-patient basis” approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0–16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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