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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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18 pages, 4861 KiB  
Article
Shock-Induced Damage Mechanism of Perineuronal Nets
by Khandakar Abu Hasan Al Mahmud, Fuad Hasan, Md Ishak Khan and Ashfaq Adnan
Biomolecules 2022, 12(1), 10; https://doi.org/10.3390/biom12010010 - 22 Dec 2021
Cited by 5 | Viewed by 3380
Abstract
The perineuronal net (PNN) region of the brain’s extracellular matrix (ECM) surrounds the neural networks within the brain tissue. The PNN is a protective net-like structure regulating neuronal activity such as neurotransmission, charge balance, and action potential generation. Shock-induced damage of this essential [...] Read more.
The perineuronal net (PNN) region of the brain’s extracellular matrix (ECM) surrounds the neural networks within the brain tissue. The PNN is a protective net-like structure regulating neuronal activity such as neurotransmission, charge balance, and action potential generation. Shock-induced damage of this essential component may lead to neuronal cell death and neurodegenerations. The shock generated during a vehicle accident, fall, or improvised device explosion may produce sufficient energy to damage the structure of the PNN. The goal is to investigate the mechanics of the PNN in reaction to shock loading and to understand the mechanical properties of different PNN components such as glycan, GAG, and protein. In this study, we evaluated the mechanical strength of PNN molecules and the interfacial strength between the PNN components. Afterward, we assessed the PNN molecules’ damage efficiency under various conditions such as shock speed, preexisting bubble, and boundary conditions. The secondary structure altercation of the protein molecules of the PNN was analyzed to evaluate damage intensity under varying shock speeds. At a higher shock speed, damage intensity is more elevated, and hyaluronan (glycan molecule) is most likely to break at the rigid junction. The primary structure of the protein molecules is least likely to fail. Instead, the molecules’ secondary bonds will be altered. Our study suggests that the number of hydrogen bonds during the shock wave propagation is reduced, which leads to the change in protein conformations and damage within the PNN structure. As such, we found a direct connection between shock wave intensity and PNN damage. Full article
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21 pages, 3971 KiB  
Article
Connexin 43 Gene Ablation Does Not Alter Human Pluripotent Stem Cell Germ Lineage Specification
by Grace A. Christopher, Rebecca J. Noort and Jessica L. Esseltine
Biomolecules 2022, 12(1), 15; https://doi.org/10.3390/biom12010015 - 22 Dec 2021
Cited by 1 | Viewed by 2713
Abstract
During embryonic germ layer development, cells communicate with each other and their environment to ensure proper lineage specification and tissue development. Connexin (Cx) proteins facilitate direct cell–cell communication through gap junction channels. While previous reports suggest that gap junctional intercellular communication may contribute [...] Read more.
During embryonic germ layer development, cells communicate with each other and their environment to ensure proper lineage specification and tissue development. Connexin (Cx) proteins facilitate direct cell–cell communication through gap junction channels. While previous reports suggest that gap junctional intercellular communication may contribute to germ layer formation, there have been limited comprehensive expression analyses or genetic ablation studies on Cxs during human pluripotent stem cell (PSC) germ lineage specification. We screened the mRNA profile and protein expression patterns of select human Cx isoforms in undifferentiated human induced pluripotent stem cells (iPSCs), and after directed differentiation into the three embryonic germ lineages: ectoderm, definitive endoderm, and mesoderm. Transcript analyses by qPCR revealed upregulation of Cx45 and Cx62 in iPSC-derived ectoderm; Cx45 in mesoderm; and Cx30.3, Cx31, Cx32, Cx36, Cx37, and Cx40 in endoderm relative to control human iPSCs. Generated Cx43 (GJA1) CRISPR-Cas9 knockout iPSCs successfully differentiated into cells of all three germ layers, suggesting that Cx43 is dispensable during directed iPSC lineage specification. Furthermore, qPCR screening of select Cx transcripts in our GJA1-/- iPSCs showed no significant Cx upregulation in response to the loss of Cx43 protein. Future studies will reveal possible compensation by additional Cxs, suggesting targets for future CRISPR-Cas9 ablation studies in human iPSC lineage specification. Full article
(This article belongs to the Section Chemical Biology)
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14 pages, 1097 KiB  
Review
Diagnostic and Therapeutic Values of Angiogenic Factors in Endometrial Cancer
by Luka Roškar, Irena Roškar, Tea Lanišnik Rižner and Špela Smrkolj
Biomolecules 2022, 12(1), 7; https://doi.org/10.3390/biom12010007 - 21 Dec 2021
Cited by 10 | Viewed by 4063
Abstract
Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of [...] Read more.
Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of angiogenic factors (AFs) appears early in the process of carcinogenesis. The detection of AFs in plasma and tissue and a better understanding of the angiogenic properties of EC may contribute not only to earlier but also more specific diagnosis and consequently tailored and individual therapeutic approaches. AFs and their receptors also have high potential as binding sites for targeted cancer therapy. In this review, we discuss angiogenesis in EC and the characteristics of the AFs that most contribute to angiogenesis in EC. We also highlight therapeutic strategies that target angiogenesis as potential EC therapy. Full article
(This article belongs to the Special Issue Risk Prediction Tools and Biomarkers in Gynaecological Cancer)
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19 pages, 1064 KiB  
Review
The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies
by Hans Felix Staehle, Heike Luise Pahl and Jonas Samuel Jutzi
Biomolecules 2021, 11(12), 1911; https://doi.org/10.3390/biom11121911 - 20 Dec 2021
Cited by 4 | Viewed by 3304
Abstract
Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone [...] Read more.
Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting. Full article
(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)
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16 pages, 1435 KiB  
Article
Sedimentary Cobalt Protoporphyrin as a Potential Precursor of Prosthetic Heme Group for Bacteria Inhabiting Fossil Organic Matter-Rich Shale Rock
by Robert Stasiuk and Renata Matlakowska
Biomolecules 2021, 11(12), 1913; https://doi.org/10.3390/biom11121913 - 20 Dec 2021
Cited by 1 | Viewed by 2168
Abstract
This study hypothesizes that bacteria inhabiting shale rock affect the content of the sedimentary cobalt protoporphyrin present in it and can use it as a precursor for heme synthesis. To verify this hypothesis, we conducted qualitative and quantitative comparative analyses of cobalt protoporphyrin [...] Read more.
This study hypothesizes that bacteria inhabiting shale rock affect the content of the sedimentary cobalt protoporphyrin present in it and can use it as a precursor for heme synthesis. To verify this hypothesis, we conducted qualitative and quantitative comparative analyses of cobalt protoporphyrin as well as heme, and heme iron in shale rock that were (i) inhabited by bacteria in the field, (ii) treated with bacteria in the laboratory, and with (iii) bacterial culture on synthetic cobalt protoporphyrin. Additionally, we examined the above-mentioned samples for the presence of enzymes involved in the heme biosynthesis and uptake as well as hemoproteins. We found depletion of cobalt protoporphyrin and a much higher heme concentration in the shale rock inhabited by bacteria in the field as well as the shale rock treated with bacteria in the laboratory. Similarly, we observed the accumulation of protoporphyrin in bacterial cells grown on synthetic cobalt protoporphyrin. We detected numerous hemoproteins in metaproteome of bacteria inhabited shale rock in the field and in proteomes of bacteria inhabited shale rock and synthetic cobalt protoporhyrin in the laboratory, but none of them had all the enzymes involved in the heme biosynthesis. However, proteins responsible for heme uptake, ferrochelatase and sirohydrochlorin cobaltochelatase/sirohydrochlorin cobalt-lyase were detected in all studied samples. Full article
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14 pages, 2955 KiB  
Article
Prototype Foamy Virus Integrase Displays Unique Biochemical Activities among Retroviral Integrases
by Anthony J. Rabe, Yow Yong Tan, Ross C. Larue and Kristine E. Yoder
Biomolecules 2021, 11(12), 1910; https://doi.org/10.3390/biom11121910 - 20 Dec 2021
Cited by 2 | Viewed by 2525
Abstract
Integrases of different retroviruses assemble as functional complexes with varying multimers of the protein. Retroviral integrases require a divalent metal cation to perform one-step transesterification catalysis. Tetrameric prototype foamy virus (PFV) intasomes assembled from purified integrase and viral DNA oligonucleotides were characterized for [...] Read more.
Integrases of different retroviruses assemble as functional complexes with varying multimers of the protein. Retroviral integrases require a divalent metal cation to perform one-step transesterification catalysis. Tetrameric prototype foamy virus (PFV) intasomes assembled from purified integrase and viral DNA oligonucleotides were characterized for their activity in the presence of different cations. While most retroviral integrases are inactive in calcium, PFV intasomes appear to be uniquely capable of catalysis in calcium. The PFV intasomes also contrast with other retroviral integrases by displaying an inverse correlation of activity with increasing manganese beginning at relatively low concentrations. The intasomes were found to be significantly more active in the presence of chloride co-ions compared to acetate. While HIV-1 integrase appears to commit to a target DNA within 20 s, PFV intasomes do not commit to target DNA during their reaction lifetime. Together, these data highlight the unique biochemical activities of PFV integrase compared to other retroviral integrases. Full article
(This article belongs to the Section Enzymology)
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14 pages, 1347 KiB  
Article
Dexamethasone for Inner Ear Therapy: Biocompatibility and Bio-Efficacy of Different Dexamethasone Formulations In Vitro
by Ziwen Gao, Jana Schwieger, Farnaz Matin-Mann, Peter Behrens, Thomas Lenarz and Verena Scheper
Biomolecules 2021, 11(12), 1896; https://doi.org/10.3390/biom11121896 - 17 Dec 2021
Cited by 10 | Viewed by 3362
Abstract
Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C22H29FO [...] Read more.
Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C22H29FO5) and dexamethasone dihydrogen phosphate-disodium (DPS, C22H28FNa2O8P) were investigated for biocompatibility and bio-efficacy in vitro. The biocompatibility of each dexamethasone formulation in concentrations from 0.03 to 10,000 µM was evaluated using an MTT assay. The concentrations resulting in the highest cell viability were selected to perform a bio-efficiency test using a TNFα-reduction assay. All dexamethasone formulations up to 900 µM are biocompatible in vitro. DPS-lab becomes toxic at 1000 µM and DPS-med at 2000 µM, while DEX-lab and DEX-med become toxic at 4000 µM. Bio-efficacy was evaluated for DEX-lab and DPS-med at 300 µM, for DEX-med at 60 µM, and DPS-lab at 150 µM, resulting in significantly reduced expression of TNFα, with DPS-lab having the highest effect. Different dexamethasone formulations need to be applied in different concentration ranges to be biocompatible. The concentration to be applied in future studies should carefully be chosen based on the respective dexamethasone form, application route and duration to ensure biocompatibility and bio-efficacy. Full article
(This article belongs to the Special Issue Inner Ear Therapeutics)
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18 pages, 14701 KiB  
Review
Insulin-Responsive Transcription Factors
by Gerald Thiel, Lisbeth A. Guethlein and Oliver G. Rössler
Biomolecules 2021, 11(12), 1886; https://doi.org/10.3390/biom11121886 - 15 Dec 2021
Cited by 13 | Viewed by 4889
Abstract
The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor [...] Read more.
The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor activates intracellular signaling cascades involving the enzymes extracellular signal-regulated protein kinase-1/2 (ERK1/2), phosphatidylinositol 3-kinase, protein kinase B/Akt, and phospholipase Cγ as signal transducers. Insulin receptor stimulation is correlated with multiple physiological and biochemical functions, including glucose transport, glucose homeostasis, food intake, proliferation, glycolysis, and lipogenesis. This review article focuses on the activation of gene transcription as a result of insulin receptor stimulation. Signal transducers such as protein kinases or the GLUT4-induced influx of glucose connect insulin receptor stimulation with transcription. We discuss insulin-responsive transcription factors that respond to insulin receptor activation and generate a transcriptional network executing the metabolic functions of insulin. Importantly, insulin receptor stimulation induces transcription of genes encoding essential enzymes of glycolysis and lipogenesis and inhibits genes encoding essential enzymes of gluconeogenesis. Overall, the activation or inhibition of insulin-responsive transcription factors is an essential aspect of orchestrating a wide range of insulin-induced changes in the biochemistry and physiology of insulin-responsive tissues. Full article
(This article belongs to the Special Issue Obesity, Diabetes, and Cancer: The Role of the Insulin/IGF Axis; Mechanisms and Clinical Implications)
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13 pages, 1829 KiB  
Article
A System-Level Mechanism of Anmyungambi Decoction for Obesity: A Network Pharmacological Approach
by Dongyeop Jang, Hayeong Jeong, Chang-Eop Kim and Jungtae Leem
Biomolecules 2021, 11(12), 1881; https://doi.org/10.3390/biom11121881 - 15 Dec 2021
Cited by 4 | Viewed by 2983
Abstract
Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on [...] Read more.
Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on obesity through network pharmacological approaches. We revealed that targets of AMGB are significantly associated with obesity-related and adipocyte-elevated genes. Evodiamine, berberine, genipin, palmitic acid, genistein, and quercetin were shown to regulate adipocytokine signaling pathway proteins which mainly involved tumor necrosis factor receptor 1, leptin receptor. In terms of the regulatory pathway of lipolysis in adipocytes, norephedrine, pseudoephedrine, quercetin, and limonin were shown to affect adrenergic receptor-beta, protein kinase A, etc. We also found that AMGB has the potentials to enhance the insulin signaling pathway thereby preventing type II diabetes mellitus. Additionally, AMGB was discovered to be able to control not only insulin-related proteins but also inflammatory mediators and apoptotic regulators and caspases, hence reducing hepatocyte injury in nonalcoholic fatty liver disease. Our findings help develop a better understanding of how AMGB controls obesity. Full article
(This article belongs to the Special Issue Phytochemical Constituents of Medicinal Plants for the Treatment of Inflammatory Disease 2021)
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14 pages, 1176 KiB  
Review
Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts
by Ayako Takeuchi and Satoshi Matsuoka
Biomolecules 2021, 11(12), 1876; https://doi.org/10.3390/biom11121876 - 14 Dec 2021
Cited by 12 | Viewed by 2826
Abstract
It has been over 10 years since SLC24A6/SLC8B1, coding the Na+/Ca2+/Li+ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na+-Ca2+ exchange, a major Ca2+ efflux system in cardiac mitochondria. This molecular [...] Read more.
It has been over 10 years since SLC24A6/SLC8B1, coding the Na+/Ca2+/Li+ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na+-Ca2+ exchange, a major Ca2+ efflux system in cardiac mitochondria. This molecular identification enabled us to determine structure–function relationships, as well as physiological/pathophysiological contributions, and our understandings have dramatically increased. In this review, we provide an overview of the recent achievements in relation to NCLX, focusing especially on its heart-specific characteristics, biophysical properties, and spatial distribution in cardiomyocytes, as well as in cardiac mitochondria. In addition, we discuss the roles of NCLX in cardiac functions under physiological and pathophysiological conditions—the generation of rhythmicity, the energy metabolism, the production of reactive oxygen species, and the opening of mitochondrial permeability transition pores. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)
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13 pages, 1295 KiB  
Article
New Variants of the Cytochrome P450 2R1 (CYP2R1) Gene in Individuals with Severe Vitamin D-Activating Enzyme 25(OH)D Deficiency
by Martyna Fronczek, Joanna Katarzyna Strzelczyk, Krzysztof Biernacki, Silvia Salatino, Tadeusz Osadnik and Zofia Ostrowska
Biomolecules 2021, 11(12), 1867; https://doi.org/10.3390/biom11121867 - 12 Dec 2021
Cited by 6 | Viewed by 2751
Abstract
Background: Vitamin D is a fat-soluble cholesterol derivative found in two forms, vitamin D2, and vitamin D3. Cytochrome P450 2R1 (CYP2R1) encoded by the CYP2R1 gene is the major hydroxylase that activates vitamin D by catalyzing the formation of 25-hydroxyvitamin D (25(OH)D). Methods: [...] Read more.
Background: Vitamin D is a fat-soluble cholesterol derivative found in two forms, vitamin D2, and vitamin D3. Cytochrome P450 2R1 (CYP2R1) encoded by the CYP2R1 gene is the major hydroxylase that activates vitamin D by catalyzing the formation of 25-hydroxyvitamin D (25(OH)D). Methods: We collected 89 (100%) subjects, 46 of which (51.69%) had a documented severe deficiency of 25(OH)D (<10 ng/mL) and 43 (48.31%) in the control group with documented optimum levels of 25(OH)D (>30 ng/mL). We performed Sanger sequencing of three selected fragments of the CYP2R1 gene (Ch11: 14878000–14878499; Ch11: 14880058–14880883 and Ch11: 14885321–14886113) that affect the binding of substrates to this enzyme and analyzed the possible involvement of genetic variation in these regions with an increased risk of vitamin D deficiency in healthy Polish individuals. Results: Two substitutions were found within the three fragments. Bioinformatic analysis suggested that one of these (NC_000011.10: g.14878291G>A) may influence the structure and function of CYP2R1. Conclusions: Variant NC_000011.10: g.14878291G>A may have a perturbing effect on heme binding in the active site of CYP2R1 and on the function of 25-hydroxylase and probably affects the concentration of 25(OH)D in vivo. We intend to perform functional verification in a larger patient population to confirm and extend these results. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)
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16 pages, 15180 KiB  
Article
Structural Characterization of Rat Galectin-5, an N-Tailed Monomeric Proto-Type-like Galectin
by Federico M. Ruiz, Francisco J. Medrano, Anna-Kristin Ludwig, Herbert Kaltner, Nadezhda V. Shilova, Nicolai V. Bovin, Hans-Joachim Gabius and Antonio Romero
Biomolecules 2021, 11(12), 1854; https://doi.org/10.3390/biom11121854 - 9 Dec 2021
Cited by 1 | Viewed by 2315
Abstract
Galectins are multi-purpose effectors acting via interactions with distinct counterreceptors based on protein-glycan/protein recognition. These processes are emerging to involve several regions on the protein so that the availability of a detailed structural characterization of a full-length galectin is essential. We report here [...] Read more.
Galectins are multi-purpose effectors acting via interactions with distinct counterreceptors based on protein-glycan/protein recognition. These processes are emerging to involve several regions on the protein so that the availability of a detailed structural characterization of a full-length galectin is essential. We report here the first crystallographic information on the N-terminal extension of the carbohydrate recognition domain of rat galectin-5, which is precisely described as an N-tailed proto-type-like galectin. In the ligand-free protein, the three amino-acid stretch from Ser2 to Ser5 is revealed to form an extra β-strand (F0), and the residues from Thr6 to Asn12 are part of a loop protruding from strands S1 and F0. In the ligand-bound structure, amino acids Ser2–Tyr10 switch position and are aligned to the edge of the β-sandwich. Interestingly, the signal profile in our glycan array screening shows the sugar-binding site to preferentially accommodate the histo-blood-group B (type 2) tetrasaccharide and N-acetyllactosamine-based di- and oligomers. The crystal structures revealed the characteristically preformed structural organization around the central Trp77 of the CRD with involvement of the sequence signature’s amino acids in binding. Ligand binding was also characterized calorimetrically. The presented data shows that the N-terminal extension can adopt an ordered structure and shapes the hypothesis that a ligand-induced shift in the equilibrium between flexible and ordered conformers potentially acts as a molecular switch, enabling new contacts in this region. Full article
(This article belongs to the Special Issue Cell Biology of Galectins)
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23 pages, 5766 KiB  
Article
Cyclic Tetra-Adenylate (cA4) Recognition by Csa3; Implications for an Integrated Class 1 CRISPR-Cas Immune Response in Saccharolobus solfataricus
by Alexander A. Charbonneau, Debra M. Eckert, Colin C. Gauvin, Nathanael G. Lintner and C. Martin Lawrence
Biomolecules 2021, 11(12), 1852; https://doi.org/10.3390/biom11121852 - 9 Dec 2021
Cited by 6 | Viewed by 2882
Abstract
Csa3 family transcription factors are ancillary CRISPR-associated proteins composed of N-terminal CARF domains and C-terminal winged helix-turn-helix domains. The activity of Csa3 transcription factors is thought to be controlled by cyclic oligoadenyate (cOA) second messengers produced by type III CRISPR-Cas surveillance complexes. Here [...] Read more.
Csa3 family transcription factors are ancillary CRISPR-associated proteins composed of N-terminal CARF domains and C-terminal winged helix-turn-helix domains. The activity of Csa3 transcription factors is thought to be controlled by cyclic oligoadenyate (cOA) second messengers produced by type III CRISPR-Cas surveillance complexes. Here we show that Saccharolobus solfataricus Csa3a recognizes cyclic tetra-adenylate (cA4) and that Csa3a lacks self-regulating “ring nuclease” activity present in some other CARF domain proteins. The crystal structure of the Csa3a/cA4 complex was also determined and the structural and thermodynamic basis for cA4 recognition are described, as are conformational changes in Csa3a associated with cA4 binding. We also characterized the effect of cA4 on recognition of putative DNA binding sites. Csa3a binds to putative promoter sequences in a nonspecific, cooperative and cA4-independent manner, suggesting a more complex mode of transcriptional regulation. We conclude the Csa3a/cA4 interaction represents a nexus between the type I and type III CRISPR-Cas systems present in S. solfataricus, and discuss the role of the Csa3/cA4 interaction in coordinating different arms of this integrated class 1 immune system to mount a synergistic, highly orchestrated immune response. Full article
(This article belongs to the Collection Molecular Biology: Feature Papers)
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17 pages, 1386 KiB  
Review
Role of Epithelium-Derived Cytokines in Atopic Dermatitis and Psoriasis: Evidence and Therapeutic Perspectives
by Francesco Borgia, Paolo Custurone, Lucia Peterle, Giovanni Pioggia and Sebastiano Gangemi
Biomolecules 2021, 11(12), 1843; https://doi.org/10.3390/biom11121843 - 7 Dec 2021
Cited by 10 | Viewed by 3326
Abstract
Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A [...] Read more.
Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A new class of products, epithelium-derived cytokines (TSLP, IL-25, IL-33), show an increasing potential for use in target therapy for these patients, and demonstrate a direct link between a generalized inflammatory and oxidative stress status and the human skin. A review was conducted to better understand their role in the aforementioned conditions. Of these three molecules, TSLP led has been most often considered in studies regarding target therapies, and most of the results in the literature are related to this cytokine. These three cytokines share common stimuli and are linked to each other in both acute and chronic phases of these diseases, and have been challenged as target therapies or biomarkers of disease activity. The results lead to the conclusion that epithelium-derived cytokines could represent a therapeutic opportunity for these patients, especially in itch control. Furthermore, they might work better when paired together with currently available therapies or in combination with in-development treatments. Further studies are needed in order to verify the efficacy and safety of the biologic treatments currently under development. Full article
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23 pages, 1422 KiB  
Review
Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence
by Teresa Salvatore, Raffaele Galiero, Alfredo Caturano, Erica Vetrano, Luca Rinaldi, Francesca Coviello, Anna Di Martino, Gaetana Albanese, Raffaele Marfella, Celestino Sardu and Ferdinando Carlo Sasso
Biomolecules 2021, 11(12), 1834; https://doi.org/10.3390/biom11121834 - 4 Dec 2021
Cited by 48 | Viewed by 8518
Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the [...] Read more.
Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved. Full article
(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)
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15 pages, 2992 KiB  
Review
Diet Impact on Obesity beyond Calories and Trefoil Factor Family 2 (TFF2) as an Illustration: Metabolic Implications and Potential Applications
by Abdelaziz Ghanemi, Mayumi Yoshioka and Jonny St-Amand
Biomolecules 2021, 11(12), 1830; https://doi.org/10.3390/biom11121830 - 4 Dec 2021
Cited by 5 | Viewed by 2751
Abstract
Obesity is a health problem with increasing impacts on public health, economy and even social life. In order to reestablish the energy balance, obesity management focuses mainly on two pillars; exercise and diet. Beyond the contribution to the caloric intake, the diet nutrients [...] Read more.
Obesity is a health problem with increasing impacts on public health, economy and even social life. In order to reestablish the energy balance, obesity management focuses mainly on two pillars; exercise and diet. Beyond the contribution to the caloric intake, the diet nutrients and composition govern a variety of properties. This includes the energy balance-independent properties and the indirect metabolic effects. Whereas the energy balance-independent properties are close to “pharmacological” effects and include effects such as antioxidant and anti-inflammatory, the indirect metabolic effects represent the contribution a diet can have on energy metabolism beyond the caloric contribution itself, which include the food intake control and metabolic changes. As an illustration, we also described the metabolic implication and hypothetical pathways of the high-fat diet-induced gene Trefoil Factor Family 2. The properties the diet has can have a variety of applications mainly in pharmacology and nutrition and further explore the “pharmacologically” active food towards potential therapeutic applications. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Eating Disorders and Obesity)
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17 pages, 6521 KiB  
Review
Hyperbaric Oxygen Treatment: Effects on Mitochondrial Function and Oxidative Stress
by Nofar Schottlender, Irit Gottfried and Uri Ashery
Biomolecules 2021, 11(12), 1827; https://doi.org/10.3390/biom11121827 - 3 Dec 2021
Cited by 44 | Viewed by 6979
Abstract
Hyperbaric oxygen treatment (HBOT)—the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA—increases the proportion of dissolved oxygen in the blood five- to twenty-fold. This increase in accessible oxygen places the mitochondrion—the organelle that consumes most of the oxygen that [...] Read more.
Hyperbaric oxygen treatment (HBOT)—the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA—increases the proportion of dissolved oxygen in the blood five- to twenty-fold. This increase in accessible oxygen places the mitochondrion—the organelle that consumes most of the oxygen that we breathe—at the epicenter of HBOT’s effects. As the mitochondrion is also a major site for the production of reactive oxygen species (ROS), it is possible that HBOT will increase also oxidative stress. Depending on the conditions of the HBO treatment (duration, pressure, umber of treatments), short-term treatments have been shown to have deleterious effects on both mitochondrial activity and production of ROS. Long-term treatment, on the other hand, improves mitochondrial activity and leads to a decrease in ROS levels, partially due to the effects of HBOT, which increases antioxidant defense mechanisms. Many diseases and conditions are characterized by mitochondrial dysfunction and imbalance between ROS and antioxidant scavengers, suggesting potential therapeutic intervention for HBOT. In the present review, we will present current views on the effects of HBOT on mitochondrial function and oxidative stress, the interplay between them and the implications for several diseases. Full article
(This article belongs to the Special Issue Oxygen Therapy)
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10 pages, 1571 KiB  
Article
RNR-R2 Upregulation by a Short Non-Coding Viral Transcript
by Karin Broennimann, Inna Ricardo-Lax, Julia Adler, Eleftherios Michailidis, Ype P. de Jong, Nina Reuven and Yosef Shaul
Biomolecules 2021, 11(12), 1822; https://doi.org/10.3390/biom11121822 - 3 Dec 2021
Cited by 1 | Viewed by 2068
Abstract
DNA viruses require dNTPs for replication and have developed different strategies to increase intracellular dNTP pools. Hepatitis B virus (HBV) infects non-dividing cells in which dNTPs are scarce and the question is how viral replication takes place. Previously we reported that the virus [...] Read more.
DNA viruses require dNTPs for replication and have developed different strategies to increase intracellular dNTP pools. Hepatitis B virus (HBV) infects non-dividing cells in which dNTPs are scarce and the question is how viral replication takes place. Previously we reported that the virus induces the DNA damage response (DDR) pathway culminating in RNR-R2 expression and the generation of an active RNR holoenzyme, the key regulator of dNTP levels, leading to an increase in dNTPs. How the virus induces DDR and RNR-R2 upregulation is not completely known. The viral HBx open reading frame (ORF) was believed to trigger this pathway. Unexpectedly, however, we report here that the production of HBx protein is dispensable. We found that a small conserved region of 125 bases within the HBx ORF is sufficient to upregulate RNR-R2 expression in growth-arrested HepG2 cells and primary human hepatocytes. The observed HBV mRNA embedded regulatory element is named ERE. ERE in isolation is sufficient to activate the ATR-Chk1-E2F1-RNR-R2 DDR pathway. These findings demonstrate a non-coding function of HBV transcripts to support its propagation in non-cycling cells. Full article
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16 pages, 1314 KiB  
Review
Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers
by Roberto Maggio, Irene Fasciani, Marco Carli, Francesco Petragnano, Francesco Marampon, Mario Rossi and Marco Scarselli
Biomolecules 2021, 11(12), 1828; https://doi.org/10.3390/biom11121828 - 3 Dec 2021
Cited by 6 | Viewed by 2617
Abstract
Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex [...] Read more.
Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
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15 pages, 1000 KiB  
Review
Mollusc N-glycosylation: Structures, Functions and Perspectives
by Erika Staudacher
Biomolecules 2021, 11(12), 1820; https://doi.org/10.3390/biom11121820 - 3 Dec 2021
Cited by 11 | Viewed by 2288
Abstract
Molluscs display a sophisticated N-glycan pattern on their proteins, which is, in terms of involved structural features, even more diverse than that of vertebrates. This review summarises the current knowledge of mollusc N-glycan structures, with a focus on the functional aspects of the [...] Read more.
Molluscs display a sophisticated N-glycan pattern on their proteins, which is, in terms of involved structural features, even more diverse than that of vertebrates. This review summarises the current knowledge of mollusc N-glycan structures, with a focus on the functional aspects of the corresponding glycoproteins. Furthermore, the potential of mollusc-derived biomolecules for medical applications is addressed, emphasising the importance of mollusc research. Full article
(This article belongs to the Special Issue Glycosylation—The Most Diverse Post-Translational Modification)
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24 pages, 2494 KiB  
Review
Ubiquitin Ligase Redundancy and Nuclear-Cytoplasmic Localization in Yeast Protein Quality Control
by Carolyn Allain Breckel and Mark Hochstrasser
Biomolecules 2021, 11(12), 1821; https://doi.org/10.3390/biom11121821 - 3 Dec 2021
Cited by 18 | Viewed by 4272
Abstract
The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways [...] Read more.
The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways are responsible for the repair or destruction of these abnormal proteins. Most commonly, the ubiquitin-proteasome system (UPS) is employed to recognize and degrade those proteins that cannot be refolded by molecular chaperones. Misfolded substrates are ubiquitylated by a subset of ubiquitin ligases (also called E3s) that operate in different cellular compartments. Recent research in Saccharomyces cerevisiae has shown that the most prominent ligases mediating cytoplasmic and nuclear PQC have overlapping yet distinct substrate specificities. Many substrates have been characterized that can be targeted by more than one ubiquitin ligase depending on their localization, and cytoplasmic PQC substrates can be directed to the nucleus for ubiquitylation and degradation. Here, we review some of the major yeast PQC ubiquitin ligases operating in the nucleus and cytoplasm, as well as current evidence indicating how these ligases can often function redundantly toward substrates in these compartments. Full article
(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)
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10 pages, 1581 KiB  
Review
L-Type Ca2+ Channel Regulation by Calmodulin and CaBP1
by James B. Ames
Biomolecules 2021, 11(12), 1811; https://doi.org/10.3390/biom11121811 - 2 Dec 2021
Cited by 14 | Viewed by 2396
Abstract
L-type voltage-gated Ca2+ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca2+ sensor proteins, calmodulin (CaM) and Ca2+ binding Protein 1 (CaBP1), that oppositely control Ca2+-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif [...] Read more.
L-type voltage-gated Ca2+ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca2+ sensor proteins, calmodulin (CaM) and Ca2+ binding Protein 1 (CaBP1), that oppositely control Ca2+-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif within the C-terminal cytosolic domain of CaV, which promotes increased channel open probability under basal conditions. At elevated cytosolic Ca2+ levels (caused by CaV channel opening), Ca2+-bound CaM binding to CaV is essential for promoting rapid Ca2+-dependent channel inactivation (CDI). By contrast, CaV binding to CaBP1 prevents CDI and promotes Ca2+-induced channel opening (called CDF). In this review, I provide an overview of the known structures of CaM and CaBP1 and their structural interactions with the IQ-motif to help understand how CaM promotes CDI, whereas CaBP1 prevents CDI and instead promotes CDF. Previous electrophysiology studies suggest that Ca2+-free forms of CaM and CaBP1 may pre-associate with CaV under basal conditions. However, previous Ca2+ binding data suggest that CaM and CaBP1 are both calculated to bind to Ca2+ with an apparent dissociation constant of ~100 nM when CaM or CaBP1 is bound to the IQ-motif. Since the neuronal basal cytosolic Ca2+ concentration is ~100 nM, nearly half of the neuronal CaV channels are suggested to be bound to Ca2+-bound forms of either CaM or CaBP1 under basal conditions. The pre-association of CaV with calcified forms of CaM or CaBP1 are predicted here to have functional implications. The Ca2+-bound form of CaBP1 is proposed to bind to CaV under basal conditions to block CaV binding to CaM, which could explain how CaBP1 might prevent CDI. Full article
(This article belongs to the Collection Advances in Metal Binding Proteins)
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17 pages, 2463 KiB  
Article
The Nuts and Bolts of SARS-CoV-2 Spike Receptor-Binding Domain Heterologous Expression
by Mariano Maffei, Linda Celeste Montemiglio, Grazia Vitagliano, Luigi Fedele, Shaila Sellathurai, Federica Bucci, Mirco Compagnone, Valerio Chiarini, Cécile Exertier, Alessia Muzi, Giuseppe Roscilli, Beatrice Vallone and Emanuele Marra
Biomolecules 2021, 11(12), 1812; https://doi.org/10.3390/biom11121812 - 2 Dec 2021
Cited by 19 | Viewed by 3724
Abstract
COVID-19 is a highly infectious disease caused by a newly emerged coronavirus (SARS-CoV-2) that has rapidly progressed into a pandemic. This unprecedent emergency has stressed the significance of developing effective therapeutics to fight the current and future outbreaks. The receptor-binding domain (RBD) of [...] Read more.
COVID-19 is a highly infectious disease caused by a newly emerged coronavirus (SARS-CoV-2) that has rapidly progressed into a pandemic. This unprecedent emergency has stressed the significance of developing effective therapeutics to fight the current and future outbreaks. The receptor-binding domain (RBD) of the SARS-CoV-2 surface Spike protein is the main target for vaccines and represents a helpful “tool” to produce neutralizing antibodies or diagnostic kits. In this work, we provide a detailed characterization of the native RBD produced in three major model systems: Escherichia coli, insect and HEK-293 cells. Circular dichroism, gel filtration chromatography and thermal denaturation experiments indicated that recombinant SARS-CoV-2 RBD proteins are stable and correctly folded. In addition, their functionality and receptor-binding ability were further evaluated through ELISA, flow cytometry assays and bio-layer interferometry. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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16 pages, 1437 KiB  
Review
The Use of Fluorescent Anti-CEA Antibodies to Label, Resect and Treat Cancers: A Review
by Michael A. Turner, Thinzar M. Lwin, Siamak Amirfakhri, Hiroto Nishino, Robert M. Hoffman, Paul J. Yazaki and Michael Bouvet
Biomolecules 2021, 11(12), 1819; https://doi.org/10.3390/biom11121819 - 2 Dec 2021
Cited by 9 | Viewed by 2442
Abstract
A major barrier to the diagnosis and effective treatment of solid-tumor cancers is the difficulty in detection and visualization of tumor margins in primary and metastatic disease. The use of fluorescence can augment the surgeon’s ability to detect cancer and aid in its [...] Read more.
A major barrier to the diagnosis and effective treatment of solid-tumor cancers is the difficulty in detection and visualization of tumor margins in primary and metastatic disease. The use of fluorescence can augment the surgeon’s ability to detect cancer and aid in its resection. Several cancer types express carcinoembryonic antigen (CEA) including colorectal, pancreatic and gastric cancer. Antibodies to CEA have been developed and tagged with near-infrared fluorescent dyes. This review article surveyed the use of CEA antibodies conjugated to fluorescent probes for in vivo studies since 1990. PubMed and Google Scholar databases were queried, and 900 titles and abstracts were screened. Fifty-nine entries were identified as possibly meeting inclusion/exclusion criteria and were reviewed in full. Forty articles were included in the review and their citations were screened for additional entries. A total of 44 articles were included in the final review. The use of fluorescent anti-CEA antibodies has been shown to improve detection and resection of tumors in both murine models and clinically. The cumulative results indicate that fluorescent-conjugated anti-CEA antibodies have important potential to improve cancer diagnosis and surgery. In an emerging technology, anti-CEA fluorescent antibodies have also been successfully used for photoimmunotherapy treatment for cancer. Full article
(This article belongs to the Special Issue Feature Paper from Biomolecules Journal Reviewers)
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35 pages, 1443 KiB  
Review
The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models
by Barbara Kosmowska and Jadwiga Wardas
Biomolecules 2021, 11(12), 1813; https://doi.org/10.3390/biom11121813 - 2 Dec 2021
Cited by 8 | Viewed by 4833
Abstract
Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we [...] Read more.
Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we show that current ET pharmacotherapy often does not sufficiently alleviate disease symptoms and is completely ineffective in more than 30% of patients. At present, deep brain stimulation of the motor thalamus is the most effective ET treatment. However, like any brain surgery, it can cause many undesirable side effects; thus, it is only performed in patients with an advanced disease who are not responsive to drugs. Therefore, it seems extremely important to look for new strategies for treating ET. The purpose of this review is to summarize the current knowledge on the pathomechanism of ET based on studies in animal models of the disease, as well as to present and discuss the results of research available to date on various substances affecting dopamine (mainly D3) or adenosine A1 receptors, which, due to their ability to modulate harmaline-induced tremor, may provide the basis for the development of new potential therapies for ET in the future. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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21 pages, 1857 KiB  
Review
New Insights into the Role of Cysteine Cathepsins in Neuroinflammation
by Anja Pišlar, Lara Bolčina and Janko Kos
Biomolecules 2021, 11(12), 1796; https://doi.org/10.3390/biom11121796 - 30 Nov 2021
Cited by 9 | Viewed by 2892
Abstract
Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that [...] Read more.
Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that aggravate neurodegeneration. To date, most research on neuroinflammation has focused on the role of cysteine cathepsins, the largest cathepsin family. Cysteine cathepsins are primarily responsible for protein degradation in lysosomes; however, they also play a role in regulating a number of other important physiological and pathological processes. This review focuses on the functional roles of cysteine cathepsins in the central nervous system during neuroinflammation, with an emphasis on their roles in the polarization of microglia and neuroinflammation signaling, which in turn causes neuronal death and thus neurodegeneration. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)
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18 pages, 2536 KiB  
Article
Structural and Functional Characterization of Legionella pneumophila Effector MavL
by Kevin Voth, Shivani Pasricha, Ivy Yeuk Wah Chung, Rachelia R. Wibawa, Engku Nuraishah Huda E. Zainudin, Elizabeth L. Hartland and Miroslaw Cygler
Biomolecules 2021, 11(12), 1802; https://doi.org/10.3390/biom11121802 - 30 Nov 2021
Cited by 5 | Viewed by 2373
Abstract
Legionella pneumophila is a Gram-negative intracellular pathogen that causes Legionnaires’ disease in elderly or immunocompromised individuals. This bacterium relies on the Dot/Icm (Defective in organelle trafficking/Intracellular multiplication) Type IV Secretion System (T4SS) and a large (>330) set of effector proteins to colonize the [...] Read more.
Legionella pneumophila is a Gram-negative intracellular pathogen that causes Legionnaires’ disease in elderly or immunocompromised individuals. This bacterium relies on the Dot/Icm (Defective in organelle trafficking/Intracellular multiplication) Type IV Secretion System (T4SS) and a large (>330) set of effector proteins to colonize the host cell. The structural variability of these effectors allows them to disrupt many host processes. Herein, we report the crystal structure of MavL to 2.65 Å resolution. MavL adopts an ADP-ribosyltransferase (ART) fold and contains the distinctive ligand-binding cleft of ART proteins. Indeed, MavL binds ADP-ribose with Kd of 13 µM. Structural overlay of MavL with poly-(ADP-ribose) glycohydrolases (PARGs) revealed a pair of aspartate residues in MavL that align with the catalytic glutamates in PARGs. MavL also aligns with ADP-ribose “reader” proteins (proteins that recognize ADP-ribose). Since no glycohydrolase activity was observed when incubated in the presence of ADP-ribosylated PARP1, MavL may play a role as a signaling protein that binds ADP-ribose. An interaction between MavL and the mammalian ubiquitin-conjugating enzyme UBE2Q1 was revealed by yeast two-hybrid and co-immunoprecipitation experiments. This work provides structural and molecular insights to guide biochemical studies aimed at elucidating the function of MavL. Our findings support the notion that ubiquitination and ADP-ribosylation are global modifications exploited by L. pneumophila. Full article
(This article belongs to the Special Issue Biomolecules of Legionella – Tiny Parts Building the Virulence Machinery)
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28 pages, 6362 KiB  
Article
A Combination of Structural, Genetic, Phenotypic and Enzymatic Analyses Reveals the Importance of a Predicted Fucosyltransferase to Protein O-Glycosylation in the Bacteroidetes
by Markus B. Tomek, Bettina Janesch, Matthias L. Braun, Manfred Taschner, Rudolf Figl, Clemens Grünwald-Gruber, Michael J. Coyne, Markus Blaukopf, Friedrich Altmann, Paul Kosma, Hanspeter Kählig, Laurie E. Comstock and Christina Schäffer
Biomolecules 2021, 11(12), 1795; https://doi.org/10.3390/biom11121795 - 30 Nov 2021
Cited by 6 | Viewed by 2650
Abstract
Diverse members of the Bacteroidetes phylum have general protein O-glycosylation systems that are essential for processes such as host colonization and pathogenesis. Here, we analyzed the function of a putative fucosyltransferase (FucT) family that is widely encoded in Bacteroidetes protein O-glycosylation [...] Read more.
Diverse members of the Bacteroidetes phylum have general protein O-glycosylation systems that are essential for processes such as host colonization and pathogenesis. Here, we analyzed the function of a putative fucosyltransferase (FucT) family that is widely encoded in Bacteroidetes protein O-glycosylation genetic loci. We studied the FucT orthologs of three Bacteroidetes species—Tannerella forsythia, Bacteroides fragilis, and Pedobacter heparinus. To identify the linkage created by the FucT of B. fragilis, we elucidated the full structure of its nine-sugar O-glycan and found that l-fucose is linked β1,4 to glucose. Of the two fucose residues in the T. forsythia O-glycan, the fucose linked to the reducing-end galactose was shown by mutational analysis to be l-fucose. Despite the transfer of l-fucose to distinct hexose sugars in the B. fragilis and T. forsythia O-glycans, the FucT orthologs from B. fragilis, T. forsythia, and P. heparinus each cross-complement the B. fragilis ΔBF4306 and T. forsythia ΔTanf_01305 FucT mutants. In vitro enzymatic analyses showed relaxed acceptor specificity of the three enzymes, transferring l-fucose to various pNP-α-hexoses. Further, glycan structural analysis together with fucosidase assays indicated that the T. forsythia FucT links l-fucose α1,6 to galactose. Given the biological importance of fucosylated carbohydrates, these FucTs are promising candidates for synthetic glycobiology. Full article
(This article belongs to the Special Issue Glycosylation—The Most Diverse Post-Translational Modification)
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13 pages, 3905 KiB  
Article
Hydrogen Bond Arrangement Is Shown to Differ in Coexisting Phases of Aqueous Two-Phase Systems
by Pedro P. Madeira, Amber R. Titus, Luisa A. Ferreira, Alexander I. Belgovskiy, Elizabeth K. Mann, Jay Adin Mann, Jr., William V. Meyer, Anthony E. Smart, Vladimir N. Uversky and Boris Y. Zaslavsky
Biomolecules 2021, 11(12), 1787; https://doi.org/10.3390/biom11121787 - 30 Nov 2021
Cited by 4 | Viewed by 1878
Abstract
Analysis by attenuated total reflection–Fourier transform infrared spectroscopy shows that each coexisting phase in aqueous two-phase systems has a different arrangement of hydrogen bonds. Specific arrangements vary for systems formed by different solutes. The hydrogen bond arrangement is shown to correlate with differences [...] Read more.
Analysis by attenuated total reflection–Fourier transform infrared spectroscopy shows that each coexisting phase in aqueous two-phase systems has a different arrangement of hydrogen bonds. Specific arrangements vary for systems formed by different solutes. The hydrogen bond arrangement is shown to correlate with differences in hydrophobic and electrostatic properties of the different phases of five specific systems, four formed by two polymers and one by a single polymer and salt. The results presented here suggest that the arrangement of hydrogen bonds may be an important factor in phase separation. Full article
(This article belongs to the Special Issue The Physicochemical Basis of Intracellular Phase Separation)
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12 pages, 649 KiB  
Review
Role of Intestinal Alkaline Phosphatase in Innate Immunity
by Sudha B. Singh and Henry C. Lin
Biomolecules 2021, 11(12), 1784; https://doi.org/10.3390/biom11121784 - 29 Nov 2021
Cited by 22 | Viewed by 4216
Abstract
Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel [...] Read more.
Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel disease IBD, necrotizing enterocolitis, and metabolic syndrome and that exogenous IAP supplementation improves the outcomes associated with these disorders. Additionally, studies using transgenic IAP-knock out (IAP-KO) mouse models further support the importance of the defensive role of IAP in the intestine. Supplementation of exogenous IAP and cellular overexpression of IAP have also been used in vitro to dissect out the downstream mechanisms of this protein in mammalian cell lines. Some of the innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of gut barrier integrity, regulation of gut microbial communities and its anti-inflammatory roles. A novel function of IAP recently identified is the induction of autophagy. Due to its critical role in the gut physiology and its excellent safety profile, IAP has been used in phase 2a clinical trials for treating conditions such as sepsis-associated acute kidney injury. Many excellent reviews discuss the role of IAP in physiology and pathophysiology and here we extend these to include recent updates on this important host defense protein and discuss its role in innate immunity via its effects on bacteria as well as on host cells. We will also discuss the relationship between IAP and autophagy and how these two pathways may act in concert to protect the gut. Full article
(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)
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25 pages, 2446 KiB  
Review
Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension
by Bastien Masson, David Montani, Marc Humbert, Véronique Capuano and Fabrice Antigny
Biomolecules 2021, 11(12), 1781; https://doi.org/10.3390/biom11121781 - 27 Nov 2021
Cited by 13 | Viewed by 3154
Abstract
Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies [...] Read more.
Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH. Full article
(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)
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34 pages, 2512 KiB  
Review
The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor
by Alamelu G. Bharadwaj, Emma Kempster and David M. Waisman
Biomolecules 2021, 11(12), 1772; https://doi.org/10.3390/biom11121772 - 26 Nov 2021
Cited by 10 | Viewed by 3269
Abstract
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound [...] Read more.
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term oncogenic plasminogen receptor to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis. Full article
(This article belongs to the Special Issue Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer)
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12 pages, 6838 KiB  
Article
Selective Biological Effects of Selenium-Enriched Polysaccharide (Se-Le-30) Isolated from Lentinula edodes Mycelium on Human Immune Cells
by Beata Kaleta, Aleksander Roszczyk, Michał Zych, Monika Kniotek, Radosław Zagożdżon, Marzenna Klimaszewska, Eliza Malinowska, Michał Pac and Jadwiga Turło
Biomolecules 2021, 11(12), 1777; https://doi.org/10.3390/biom11121777 - 26 Nov 2021
Cited by 10 | Viewed by 2182
Abstract
A common edible mushroom Lentinula edodes, is an important source of numerous biologically active substances, including polysaccharides, with immunomodulatory and antitumor properties. In the present work, the biological activity of the crude, homogenous (Se)-enriched fraction (named Se-Le-30), which has been isolated from L. [...] Read more.
A common edible mushroom Lentinula edodes, is an important source of numerous biologically active substances, including polysaccharides, with immunomodulatory and antitumor properties. In the present work, the biological activity of the crude, homogenous (Se)-enriched fraction (named Se-Le-30), which has been isolated from L. edodes mycelium by a modified Chihara method towards human peripheral blood mononuclear cells (PBMCs) and peripheral granulocytes, was investigated. The Se-Le-30 fraction, an analog of lentinan, significantly inhibited the proliferation of human PBMCs stimulated with anti-CD3 antibodies or allostimulated, and down-regulated the production of tumor necrosis factor (TNF)-α by CD3+ T cells. Moreover, it was found that Se-Le-30 significantly reduced the cytotoxic activity of human natural killer (NK) cells. The results suggested the selective immunosuppressive activity of this fraction, which is non-typical for mushroom derived polysaccharides. Full article
(This article belongs to the Special Issue Biomolecules from Natural Products: Anti-inflammatory and Anti-allergic Activities)
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14 pages, 1977 KiB  
Article
CRISPR/dCas9 Transcriptional Activation of Endogenous Apolipoprotein AI and Paraoxonase 1 in Enterocytes Alleviates Endothelial Cell Dysfunction
by Laura Toma, Teodora Barbălată, Gabriela M. Sanda, Loredan S. Niculescu, Anca V. Sima and Camelia S. Stancu
Biomolecules 2021, 11(12), 1769; https://doi.org/10.3390/biom11121769 - 25 Nov 2021
Cited by 2 | Viewed by 2145
Abstract
Atherosclerosis is the main cause of cardiovascular diseases with high prevalence worldwide. A promising therapeutic strategy to reverse atherosclerotic process is to improve the athero-protective potential of high-density lipoproteins (HDL). Since the small intestine is a source of HDL, we aimed to activate [...] Read more.
Atherosclerosis is the main cause of cardiovascular diseases with high prevalence worldwide. A promising therapeutic strategy to reverse atherosclerotic process is to improve the athero-protective potential of high-density lipoproteins (HDL). Since the small intestine is a source of HDL, we aimed to activate transcription of the endogenous HDL major proteins, apolipoprotein AI (ApoAI) and paraoxonase 1 (PON1), in enterocytes, and to evaluate their potential to correct the pro-inflammatory status of endothelial cells (EC). Caco-2 enterocytes were transfected with CRISPR activation plasmids targeting ApoAI or PON1, and their gene and protein expression were measured in cells and conditioned medium (CM). ATP binding cassette A1 and G8 transporters (ABCA1, ABCG8), scavenger receptor BI (SR-BI), and transcription regulators peroxisome proliferator-activated receptor γ (PPARγ), liver X receptors (LXRs), and sirtuin-1 (SIRT1) were assessed. Anti-inflammatory effects of CM from transfected enterocytes were estimated through its ability to inhibit tumor necrosis factor α (TNFα) activation of EC. Transcriptional activation of ApoAI or PON1 in enterocytes induces: (i) increase of their gene and protein expression, and secretion in CM; (ii) stimulation of ABCA1/G8 and SR-BI; (iii) upregulation of PPARγ, LXRs, and SIRT1. CM from transfected enterocytes attenuated the TNFα-induced inflammatory and oxidative stress in EC, by decreasing TNF receptor 1, monocyte chemoattractant protein-1, and p22phox. In conclusion, transcriptional activation of endogenous ApoAI or PON1 in enterocytes by CRISPR/dCas9 system is a realistic approach to stimulate biogenesis and function of major HDL proteins which can regulate cholesterol efflux transporters and reduce the inflammatory stress in activated EC. Full article
(This article belongs to the Special Issue Lipoproteins: From the Vital Role in Lipid Metabolism to Risk Factors for Atherosclerosis and Future Challenging Therapies)
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10 pages, 3723 KiB  
Article
Planar Boronic Graphene and Nitrogenized Graphene Heterostructure for Protein Stretch and Confinement
by Xuchang Su, Zhi He, Lijun Meng, Hong Liang and Ruhong Zhou
Biomolecules 2021, 11(12), 1756; https://doi.org/10.3390/biom11121756 - 24 Nov 2021
Cited by 1 | Viewed by 1729
Abstract
Single-molecule techniques such as electron tunneling and atomic force microscopy have attracted growing interests in protein sequencing. For these methods, it is critical to refine and stabilize the protein sample to a “suitable mode” before applying a high-fidelity measurement. Here, we show that [...] Read more.
Single-molecule techniques such as electron tunneling and atomic force microscopy have attracted growing interests in protein sequencing. For these methods, it is critical to refine and stabilize the protein sample to a “suitable mode” before applying a high-fidelity measurement. Here, we show that a planar heterostructure comprising boronic graphene (BC3) and nitrogenized graphene (C3N) sandwiched stripe (BC3/C3N/BC3) is capable of the effective stretching and confinement of three types of intrinsically disordered proteins (IDPs), including amyloid-β (1–42), polyglutamine (Q42), and α-Synuclein (61–95). Our molecular dynamics simulations demonstrate that the protein molecules interact more strongly with the C3N stripe than the BC3 one, which leads to their capture, elongation, and confinement along the center C3N stripe of the heterostructure. The conformational fluctuations of IDPs are substantially reduced after being stretched. This design may serve as a platform for single-molecule protein analysis with reduced thermal noise. Full article
(This article belongs to the Special Issue State-of-the-Art Biophysics, Biochemistry and Molecular Biology in China)
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16 pages, 2832 KiB  
Article
MmpA, a Conserved Membrane Protein Required for Efficient Surface Transport of Trehalose Lipids in Corynebacterineae
by Tamaryn J. Cashmore, Stephan Klatt, Rajini Brammananth, Arek K. Rainczuk, Paul K. Crellin, Malcolm J. McConville and Ross L. Coppel
Biomolecules 2021, 11(12), 1760; https://doi.org/10.3390/biom11121760 - 24 Nov 2021
Cited by 2 | Viewed by 2307
Abstract
Cell walls of bacteria of the genera Mycobacterium and Corynebacterium contain high levels of (coryno)mycolic acids. These very long chain fatty acids are synthesized on the cytoplasmic leaflet of the inner membrane (IM) prior to conjugation to the disaccharide, trehalose, and transport to [...] Read more.
Cell walls of bacteria of the genera Mycobacterium and Corynebacterium contain high levels of (coryno)mycolic acids. These very long chain fatty acids are synthesized on the cytoplasmic leaflet of the inner membrane (IM) prior to conjugation to the disaccharide, trehalose, and transport to the periplasm. Recent studies on Corynebacterium glutamicum have shown that acetylation of trehalose monohydroxycorynomycolate (hTMCM) promotes its transport across the inner membrane. Acetylation is mediated by the membrane acetyltransferase, TmaT, and is dependent on the presence of a putative methyltransferase, MtrP. Here, we identify a third protein that is required for the acetylation and membrane transport of hTMCM. Deletion of the C. glutamicum gene NCgl2761 (Rv0226c in Mycobacterium tuberculosis) abolished synthesis of acetylated hTMCM (AcTMCM), resulting in an accumulation of hTMCM in the inner membrane and reduced synthesis of trehalose dihydroxycorynomycolate (h2TDCM), a major outer membrane glycolipid. Complementation with the NCgl2761 gene, designated here as mmpA, restored the hTMCM:h2TDCM ratio. Comprehensive lipidomic analysis of the ΔtmaT, ΔmtrP and ΔmmpA mutants revealed strikingly similar global changes in overall membrane lipid composition. Our findings suggest that the acetylation and membrane transport of hTMCM is regulated by multiple proteins: MmpA, MtrP and TmaT, and that defects in this process lead to global, potentially compensatory changes in the composition of inner and outer membranes. Full article
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19 pages, 5080 KiB  
Article
Vitis OneGenE: A Causality-Based Approach to Generate Gene Networks in Vitis vinifera Sheds Light on the Laccase and Dirigent Gene Families
by Stefania Pilati, Giulia Malacarne, David Navarro-Payá, Gabriele Tomè, Laura Riscica, Valter Cavecchia, José Tomás Matus, Claudio Moser and Enrico Blanzieri
Biomolecules 2021, 11(12), 1744; https://doi.org/10.3390/biom11121744 - 23 Nov 2021
Cited by 13 | Viewed by 3958
Abstract
The abundance of transcriptomic data and the development of causal inference methods have paved the way for gene network analyses in grapevine. Vitis OneGenE is a transcriptomic data mining tool that finds direct correlations between genes, thus producing association networks. As a proof [...] Read more.
The abundance of transcriptomic data and the development of causal inference methods have paved the way for gene network analyses in grapevine. Vitis OneGenE is a transcriptomic data mining tool that finds direct correlations between genes, thus producing association networks. As a proof of concept, the stilbene synthase gene regulatory network obtained with OneGenE has been compared with published co-expression analysis and experimental data, including cistrome data for MYB stilbenoid regulators. As a case study, the two secondary metabolism pathways of stilbenoids and lignin synthesis were explored. Several isoforms of laccase, peroxidase, and dirigent protein genes, putatively involved in the final oxidative oligomerization steps, were identified as specifically belonging to either one of these pathways. Manual curation of the predicted sequences exploiting the last available genome assembly, and the integration of phylogenetic and OneGenE analyses, identified a group of laccases exclusively present in grapevine and related to stilbenoids. Here we show how network analysis by OneGenE can accelerate knowledge discovery by suggesting new candidates for functional characterization and application in breeding programs. Full article
(This article belongs to the Special Issue Gene Regulatory Networks Controlling Secondary Metabolism in Plants: Computational Approaches and Mechanistic Insights)
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18 pages, 2459 KiB  
Article
β-Dystroglycan Restoration and Pathology Progression in the Dystrophic mdx Mouse: Outcome and Implication of a Clinically Oriented Study with a Novel Oral Dasatinib Formulation
by Paola Mantuano, Brigida Boccanegra, Elena Conte, Michela De Bellis, Santa Cirmi, Francesca Sanarica, Ornella Cappellari, Ilaria Arduino, Annalisa Cutrignelli, Angela Assunta Lopedota, Antonietta Mele, Nunzio Denora and Annamaria De Luca
Biomolecules 2021, 11(11), 1742; https://doi.org/10.3390/biom11111742 - 22 Nov 2021
Cited by 13 | Viewed by 2392
Abstract
ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of β-dystroglycan (β-DG), a dystrophin-glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc-TK represents a promising therapeutic target. In mdx mice, a 4-week subcutaneous treatment with dasatinib (DAS), a [...] Read more.
ROS-activated cSrc tyrosine kinase (TK) promotes the degradation of β-dystroglycan (β-DG), a dystrophin-glycoprotein complex component, which may reinforce damaging signals in Duchenne muscular dystrophy (DMD). Therefore, cSrc-TK represents a promising therapeutic target. In mdx mice, a 4-week subcutaneous treatment with dasatinib (DAS), a pan-Src-TKs inhibitor approved as anti-leukemic agent, increased muscle β-DG, with minimal amelioration of morphofunctional indices. To address possible dose/pharmacokinetic (PK) issues, a new oral DAS/hydroxypropyl(HP)-β-cyclodextrin(CD) complex was developed and chronically administered to mdx mice. The aim was to better assess the role of β-DG in pathology progression, meanwhile confirming DAS mechanism of action over the long-term, along with its efficacy and tolerability. The 4-week old mdx mice underwent a 12-week treatment with DAS/HP-β-CD10% dissolved in drinking water, at 10 or 20 mg/kg/day. The outcome was evaluated via in vivo/ex vivo disease-relevant readouts. Oral DAS/HP-β-CD efficiently distributed in mdx mice plasma and tissues in a dose-related fashion. The new DAS formulation confirmed its main upstream mechanism of action, by reducing β-DG phosphorylation and restoring its levels dose-dependently in both diaphragm and gastrocnemius muscle. However, it modestly improved in vivo neuromuscular function, ex vivo muscle force, and histopathology, although the partial recovery of muscle elasticity and the decrease of CK and LDH plasma levels suggest an increased sarcolemmal stability of dystrophic muscles. Our clinically oriented study supports the interest in this new, pediatric-suitable DAS formulation for proper exposure and safety and for enhancing β-DG expression. This latter mechanism is, however, not sufficient by itself to impact on pathology progression. In-depth analyses will be dedicated to elucidating the mechanism limiting DAS effectiveness in dystrophic settings, meanwhile assessing its potential synergy with dystrophin-based molecular therapies. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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20 pages, 3415 KiB  
Article
Emergence and Enhancement of Ultrasensitivity through Posttranslational Modulation of Protein Stability
by Carla M. Kumbale, Eberhard O. Voit and Qiang Zhang
Biomolecules 2021, 11(11), 1741; https://doi.org/10.3390/biom11111741 - 22 Nov 2021
Cited by 2 | Viewed by 1658
Abstract
Signal amplification in biomolecular networks converts a linear input to a steeply sigmoid output and is central to a number of cellular functions including proliferation, differentiation, homeostasis, adaptation, and biological rhythms. One canonical signal amplifying motif is zero-order ultrasensitivity that is mediated through [...] Read more.
Signal amplification in biomolecular networks converts a linear input to a steeply sigmoid output and is central to a number of cellular functions including proliferation, differentiation, homeostasis, adaptation, and biological rhythms. One canonical signal amplifying motif is zero-order ultrasensitivity that is mediated through the posttranslational modification (PTM) cycle of signaling proteins. The functionality of this signaling motif has been examined conventionally by supposing that the total amount of the protein substrates remains constant, as by the classical Koshland–Goldbeter model. However, covalent modification of signaling proteins often results in changes in their stability, which affects the abundance of the protein substrates. Here, we use mathematical models to explore the signal amplification properties in such scenarios and report some novel aspects. Our analyses indicate that PTM-induced protein stabilization brings the enzymes closer to saturation. As a result, ultrasensitivity may emerge or is greatly enhanced, with a steeper sigmoidal response, higher magnitude, and generally longer response time. In cases where PTM destabilizes the protein, ultrasensitivity can be regained through changes in the activities of the involved enzymes or from increased protein synthesis. Importantly, ultrasensitivity is not limited to modified or unmodified protein substrates—when protein turnover is considered, the total free protein substrate can also exhibit ultrasensitivity under several conditions. When full enzymatic reactions are used instead of Michaelis–Menten kinetics for the modeling, the total free protein substrate can even exhibit nonmonotonic dose–response patterns. It is conceivable that cells use inducible protein stabilization as a strategy in the signaling network to boost signal amplification while saving energy by keeping the protein substrate levels low at basal conditions. Full article
(This article belongs to the Special Issue Computational Approaches for the Study of Biomolecular Networks)
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22 pages, 4983 KiB  
Article
Quantitative Morphological Analysis of Filamentous Microorganisms in Cocultures and Monocultures: Aspergillus terreus and Streptomyces rimosus Warfare in Bioreactors
by Anna Ścigaczewska, Tomasz Boruta and Marcin Bizukojć
Biomolecules 2021, 11(11), 1740; https://doi.org/10.3390/biom11111740 - 22 Nov 2021
Cited by 3 | Viewed by 1690
Abstract
The aim of this study was to quantitatively characterize the morphology of the filamentous microorganisms Aspergillus terreus ATCC 20542 and Streptomyces rimosus ATCC 10970, cocultivated in stirred tank bioreactors, and to characterize their mutual influence with the use of quantitative image analysis. Three [...] Read more.
The aim of this study was to quantitatively characterize the morphology of the filamentous microorganisms Aspergillus terreus ATCC 20542 and Streptomyces rimosus ATCC 10970, cocultivated in stirred tank bioreactors, and to characterize their mutual influence with the use of quantitative image analysis. Three distinct coculture initiation strategies were applied: preculture versus preculture, spores versus spores and preculture versus preculture with time delay for one of the species. Bioreactor cocultures were accompanied by parallel monoculture controls. The results recorded for the mono- and cocultures were compared in order to investigate the effect of cocultivation on the morphological evolution of A. terreus and S. rimosus. Morphology-related observations were also confronted with the analysis of secondary metabolism. The morphology of the two studied filamentous species strictly depended on the applied coculture initiation strategy. In the cocultures initiated by the simultaneous inoculation, S. rimosus gained domination or advance over A. terreus. The latter microorganism dominated only in these experiments in which S. rimosus was introduced with a delay. Full article
(This article belongs to the Collection Feature Papers in Synthetic Biology and Bioengineering)
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14 pages, 2047 KiB  
Article
Opposite Effects of Chronic Central Leptin Infusion on Activation of Insulin Signaling Pathways in Adipose Tissue and Liver Are Related to Changes in the Inflammatory Environment
by Vicente Barrios, Ana Campillo-Calatayud, Santiago Guerra-Cantera, Sandra Canelles, Álvaro Martín-Rivada, Laura M. Frago, Julie A. Chowen and Jesús Argente
Biomolecules 2021, 11(11), 1734; https://doi.org/10.3390/biom11111734 - 21 Nov 2021
Cited by 5 | Viewed by 1644
Abstract
Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels [...] Read more.
Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling. Full article
(This article belongs to the Special Issue Novel Insights into the Physiological and Pathological Role of Leptin and Leptin Receptor)
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25 pages, 4177 KiB  
Review
Piezoelectric Signals in Vascularized Bone Regeneration
by Delfo D’Alessandro, Claudio Ricci, Mario Milazzo, Giovanna Strangis, Francesca Forli, Gabriele Buda, Mario Petrini, Stefano Berrettini, Mohammed Jasim Uddin, Serena Danti and Paolo Parchi
Biomolecules 2021, 11(11), 1731; https://doi.org/10.3390/biom11111731 - 20 Nov 2021
Cited by 25 | Viewed by 5291
Abstract
The demand for bone substitutes is increasing in Western countries. Bone graft substitutes aim to provide reconstructive surgeons with off-the-shelf alternatives to the natural bone taken from humans or animal species. Under the tissue engineering paradigm, biomaterial scaffolds can be designed by incorporating [...] Read more.
The demand for bone substitutes is increasing in Western countries. Bone graft substitutes aim to provide reconstructive surgeons with off-the-shelf alternatives to the natural bone taken from humans or animal species. Under the tissue engineering paradigm, biomaterial scaffolds can be designed by incorporating bone stem cells to decrease the disadvantages of traditional tissue grafts. However, the effective clinical application of tissue-engineered bone is limited by insufficient neovascularization. As bone is a highly vascularized tissue, new strategies to promote both osteogenesis and vasculogenesis within the scaffolds need to be considered for a successful regeneration. It has been demonstrated that bone and blood vases are piezoelectric, namely, electric signals are locally produced upon mechanical stimulation of these tissues. The specific effects of electric charge generation on different cells are not fully understood, but a substantial amount of evidence has suggested their functional and physiological roles. This review summarizes the special contribution of piezoelectricity as a stimulatory signal for bone and vascular tissue regeneration, including osteogenesis, angiogenesis, vascular repair, and tissue engineering, by considering different stem cell sources entailed with osteogenic and angiogenic potential, aimed at collecting the key findings that may enable the development of successful vascularized bone replacements useful in orthopedic and otologic surgery. Full article
(This article belongs to the Special Issue New Insights into Stem Cell Regulation)
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15 pages, 2391 KiB  
Article
Assaying Paenibacillus alvei CsaB-Catalysed Ketalpyruvyltransfer to Saccharides by Measurement of Phosphate Release
by Fiona F. Hager-Mair, Cordula Stefanović, Charlie Lim, Katharina Webhofer, Simon Krauter, Markus Blaukopf, Roland Ludwig, Paul Kosma and Christina Schäffer
Biomolecules 2021, 11(11), 1732; https://doi.org/10.3390/biom11111732 - 20 Nov 2021
Cited by 2 | Viewed by 2287
Abstract
Ketalpyruvyltransferases belong to a widespread but little investigated class of enzymes, which utilise phosphoenolpyruvate (PEP) for the pyruvylation of saccharides. Pyruvylated saccharides play pivotal biological roles, ranging from protein binding to virulence. Limiting factors for the characterisation of ketalpyruvyltransferases are the availability of [...] Read more.
Ketalpyruvyltransferases belong to a widespread but little investigated class of enzymes, which utilise phosphoenolpyruvate (PEP) for the pyruvylation of saccharides. Pyruvylated saccharides play pivotal biological roles, ranging from protein binding to virulence. Limiting factors for the characterisation of ketalpyruvyltransferases are the availability of cognate acceptor substrates and a straightforward enzyme assay. We report on a fast ketalpyruvyltransferase assay based on the colorimetric detection of phosphate released during pyruvyltransfer from PEP onto the acceptor via complexation with Malachite Green and molybdate. To optimise the assay for the model 4,6-ketalpyruvyl::ManNAc-transferase CsaB from Paenibacillus alvei, a β-d-ManNAc-α-d-GlcNAc-diphosphoryl-11-phenoxyundecyl acceptor mimicking an intermediate of the bacterium’s cell wall glycopolymer biosynthesis pathway, upon which CsaB is naturally active, was produced chemo-enzymatically and used together with recombinant CsaB. Optimal assay conditions were 5 min reaction time at 37 °C and pH 7.5, followed by colour development for 1 h at 37 °C and measurement of absorbance at 620 nm. The structure of the generated pyruvylated product was confirmed by NMR spectroscopy. Using the established assay, the first kinetic constants of a 4,6-ketalpyuvyl::ManNAc-transferase could be determined; upon variation of the acceptor and PEP concentrations, a KM, PEP of 19.50 ± 3.50 µM and kcat, PEP of 0.21 ± 0.01 s−1 as well as a KM, Acceptor of 258 ± 38 µM and a kcat, Acceptor of 0.15 ± 0.01 s−1 were revealed. P. alvei CsaB was inactive on synthetic pNP-β-d-ManNAc and β-d-ManNAc-β-d-GlcNAc-1-OMe, supporting the necessity of a complex acceptor substrate. Full article
(This article belongs to the Special Issue Glycosylation—The Most Diverse Post-Translational Modification)
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15 pages, 1675 KiB  
Article
Dynamic DNA Methylation Changes in the COMT Gene Promoter Region in Response to Mental Stress and Its Modulation by Transcranial Direct Current Stimulation
by Ariane Wiegand, Arne Blickle, Christof Brückmann, Simone Weller, Vanessa Nieratschker and Christian Plewnia
Biomolecules 2021, 11(11), 1726; https://doi.org/10.3390/biom11111726 - 19 Nov 2021
Cited by 7 | Viewed by 2126
Abstract
Changes in epigenetic modifications present a mechanism how environmental factors, such as the experience of stress, can alter gene regulation. While stress-related disorders have consistently been associated with differential DNA methylation, little is known about the time scale in which these alterations emerge. [...] Read more.
Changes in epigenetic modifications present a mechanism how environmental factors, such as the experience of stress, can alter gene regulation. While stress-related disorders have consistently been associated with differential DNA methylation, little is known about the time scale in which these alterations emerge. We investigated dynamic DNA methylation changes in whole blood of 42 healthy male individuals in response to a stressful cognitive task, its association with concentration changes in cortisol, and its modulation by transcranial direct current stimulation (tDCS). We observed a continuous increase in COMT promotor DNA methylation which correlated with higher saliva cortisol levels and was still detectable one week later. However, this lasting effect was suppressed by concurrent activity-enhancing anodal tDCS to the dorsolateral prefrontal cortex. Our findings support the significance of gene-specific DNA methylation in whole blood as potential biomarkers for stress-related effects. Moreover, they suggest alternative molecular mechanisms possibly involved in lasting behavioral effects of tDCS. Full article
(This article belongs to the Special Issue Key Advances in Brain Stimulation)
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12 pages, 1373 KiB  
Article
Rhamnolipids as a Tool for Eradication of Trichosporon cutaneum Biofilm
by Olga Maťátková, Irena Kolouchová, Kristýna Lokočová, Jana Michailidu, Petr Jaroš, Markéta Kulišová, Tomáš Řezanka and Jan Masák
Biomolecules 2021, 11(11), 1727; https://doi.org/10.3390/biom11111727 - 19 Nov 2021
Cited by 4 | Viewed by 1587
Abstract
Microbial biofilms formed by pathogenic and antibiotic-resistant microorganisms represent a serious threat for public health in medicine and many industrial branches. Biofilms are involved in many persistent and chronic infections, the biofouling of water and food contamination. Therefore, current research is involved in [...] Read more.
Microbial biofilms formed by pathogenic and antibiotic-resistant microorganisms represent a serious threat for public health in medicine and many industrial branches. Biofilms are involved in many persistent and chronic infections, the biofouling of water and food contamination. Therefore, current research is involved in the development of new treatment strategies. Biofilm is a complex system, and thus all aspects of the measurement and monitoring of its growth and eradication in various conditions, including static and dynamic flow, are issues of great importance. The antibiofilm character of rhamnolipid mixtures produced by four Pseudomonas aeruginosa strains was studied under different conditions. For this purpose, the biofilm of opportunistic pathogen Trichosporon cutaneum was used and treated under static conditions (microscope glass coverslip in a Petri dish) and under dynamic conditions (a single-channel flow cell). The results show that the biological activity of rhamnolipids depends both on their properties and on the conditions of the biofilm formation. Therefore, this aspect must be taken into account when planning the experimental or application design. Full article
(This article belongs to the Collection Feature Papers in Biomacromolecules: Lipids)
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18 pages, 958 KiB  
Review
Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era
by Mattia Zaghi, Federica Banfi, Edoardo Bellini and Alessandro Sessa
Biomolecules 2021, 11(11), 1713; https://doi.org/10.3390/biom11111713 - 17 Nov 2021
Cited by 3 | Viewed by 2624
Abstract
The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and [...] Read more.
The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and rare genomic variants and to perform detailed phenotypic characterizations of both physiological organs and experimental models. Recent years have seen the introduction of multiple techniques using NGS to profile transcription, DNA and chromatin modifications, protein binding, etc., that are now allowing us to profile cells in bulk or even at a single-cell level. Although rare and ultra-rare diseases only affect a few people, each of these diseases represent scholarly cases from which a great deal can be learned about the pathological and physiological function of genes, pathways, and mechanisms. Therefore, for rare diseases, state-of-the-art investigations using NGS have double valence: their genomic cause (new variants) and the characterize the underlining the mechanisms associated with them (discovery of gene function) can be found. In a non-exhaustive manner, this review will outline the main usage of NGS-based techniques for the diagnosis and characterization of neurodevelopmental disorders (NDDs), under whose umbrella many rare and ultra-rare diseases fall. Full article
(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)
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13 pages, 1260 KiB  
Article
Late-Stage Functionalisation of Polycyclic (N-Hetero-) Aromatic Hydrocarbons by Detoxifying CYP5035S7 Monooxygenase of the White-Rot Fungus Polyporus arcularius
by Nico D. Fessner, Christopher Grimm, Wolfgang Kroutil and Anton Glieder
Biomolecules 2021, 11(11), 1708; https://doi.org/10.3390/biom11111708 - 17 Nov 2021
Cited by 4 | Viewed by 3194
Abstract
Functionalisation of polycyclic aromatic hydrocarbons (PAHs) and their N-heteroarene analogues (NPAHs) is a tedious synthetic endeavour that requires diverse bottom-up approaches. Cytochrome P450 enzymes of white-rot fungi were shown to participate in the fungal detoxification of xenobiotics and environmental hazards via hydroxylation [...] Read more.
Functionalisation of polycyclic aromatic hydrocarbons (PAHs) and their N-heteroarene analogues (NPAHs) is a tedious synthetic endeavour that requires diverse bottom-up approaches. Cytochrome P450 enzymes of white-rot fungi were shown to participate in the fungal detoxification of xenobiotics and environmental hazards via hydroxylation of PAH compounds. In this paper, the recently discovered activity of the monooxygenase CYP5035S7 towards (N)PAHs was investigated in detail, and products formed from the substrates azulene, acenaphthene, fluorene, anthracene, and phenanthrene by whole-cell biocatalysis were isolated and characterised. The observed regioselectivity of CYP5035S7 could be explained by a combination of the substrate’s electron density and steric factors influencing the substrate orientation giving insight into the active-site geometry of the enzyme. Full article
(This article belongs to the Special Issue Oxygenases: Exploiting Their Catalytic Power)
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16 pages, 2524 KiB  
Article
Characterization of the Biomechanical Properties of Skin Using Vibrational Optical Coherence Tomography: Do Changes in the Biomechanical Properties of Skin Stroma Reflect Structural Changes in the Extracellular Matrix of Cancerous Lesions?
by Frederick H. Silver, Nikita Kelkar, Tanmay Deshmukh, Kelly Ritter, Nicole Ryan and Hari Nadiminti
Biomolecules 2021, 11(11), 1712; https://doi.org/10.3390/biom11111712 - 17 Nov 2021
Cited by 7 | Viewed by 2114
Abstract
Early detection of skin cancer is of critical importance since the five-year survival rate for early detected skin malignancies is 99% but drops to 27% for cancer that has spread to distant lymph nodes and other organs. Over 2.5 million benign skin biopsies [...] Read more.
Early detection of skin cancer is of critical importance since the five-year survival rate for early detected skin malignancies is 99% but drops to 27% for cancer that has spread to distant lymph nodes and other organs. Over 2.5 million benign skin biopsies (55% of the total) are performed each year in the US at an alarming cost of USD ~2.5 B. Therefore there is an unmet need for novel non-invasive diagnostic approaches to better differentiate between cancerous and non-cancerous lesions, especially in cases when there is a legitimate doubt that a biopsy may be required. The purpose of this study is to determine whether the differences in the extracellular matrices among normal skin, actinic keratosis (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) can be assessed non-invasively using vibrational optical coherence tomography (VOCT). VOCT is a new diagnostic technology that uses infrared light and audible sound applied transversely to tissue to measure the resonant frequencies and elastic moduli of cells, dermal collagen, blood vessels and fibrous tissue in skin and lesion stroma without physically touching the skin. Our results indicate that the cellular, vascular and fibrotic resonant frequency peaks are altered in AK, BCC and SCC compared to those peaks observed in normal skin and can serve as physical biomarkers defining the differences between benign and cancerous skin lesions. The resonant frequency is increased from a value of 50 Hz in normal skin to a value of about 80 Hz in pre- and cancerous lesions. A new vascular peak is seen at 130 Hz in cancerous lesions that may reflect the formation of new tumor blood vessels. The peak at 260 Hz is similar to that seen in the skin of a subject with Scleroderma and skin wounds that have healed. The peak at 260 Hz appears to be associated with the deposition of large amounts of stiff fibrous collagen in the stroma surrounding cancerous lesions. Based on the results of this pilot study, VOCT can be used to non-invasively identify physical biomarkers that can help differentiate between benign and cancerous skin lesions. The appearance of new stiff cellular, fragile new vessels, and stiff fibrous material based on resonant frequency peaks and changes in the extracellular matrix can be used as a fingerprint of pre- and cancerous skin lesions. Full article
(This article belongs to the Special Issue Biomolecular Signatures in Reactive Stroma—Inflammation and Wound Healing)
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20 pages, 10229 KiB  
Article
Three-Dimensional Virtual and Printed Prototypes in Complex Congenital and Pediatric Cardiac Surgery—A Multidisciplinary Team-Learning Experience
by Laszlo Kiraly, Nishant C. Shah, Osama Abdullah, Oraib Al-Ketan and Reza Rowshan
Biomolecules 2021, 11(11), 1703; https://doi.org/10.3390/biom11111703 - 16 Nov 2021
Cited by 10 | Viewed by 5198
Abstract
Three-dimensional (3D) virtual modeling and printing advances individualized medicine and surgery. In congenital cardiac surgery, 3D virtual models and printed prototypes offer advantages of better understanding of complex anatomy, hands-on preoperative surgical planning and emulation, and improved communication within the multidisciplinary team and [...] Read more.
Three-dimensional (3D) virtual modeling and printing advances individualized medicine and surgery. In congenital cardiac surgery, 3D virtual models and printed prototypes offer advantages of better understanding of complex anatomy, hands-on preoperative surgical planning and emulation, and improved communication within the multidisciplinary team and to patients. We report our single center team-learning experience about the realization and validation of possible clinical benefits of 3D-printed models in surgical planning of complex congenital cardiac surgery. CT-angiography raw data were segmented into 3D-virtual models of the heart-great vessels. Prototypes were 3D-printed as rigid “blood-volume” and flexible “hollow”. The accuracy of the models was evaluated intraoperatively. Production steps were realized in the framework of a clinical/research partnership. We produced 3D prototypes of the heart-great vessels for 15 case scenarios (nine males, median age: 11 months) undergoing complex intracardiac repairs. Parity between 3D models and intraoperative structures was within 1 mm range. Models refined diagnostics in 13/15, provided new anatomic information in 9/15. As a team-learning experience, all complex staged redo-operations (13/15; Aristotle-score mean: 10.64 ± 1.95) were rehearsed on the 3D models preoperatively. 3D-printed prototypes significantly contributed to an improved/alternative operative plan on the surgical approach, modification of intracardiac repair in 13/15. No operative morbidity/mortality occurred. Our clinical/research partnership provided coverage for the extra time/labor and material/machinery not financed by insurance. 3D-printed models provided a team-learning experience and contributed to the safety of complex congenital cardiac surgeries. A clinical/research partnership may open avenues for bioprinting of patient-specific implants. Full article
(This article belongs to the Special Issue Usefulness and Clinical Applications of 3D Printing in Cardiovascular Diseases)
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Review
Co-Evolution of Breast Milk Lipid Signaling and Thermogenic Adipose Tissue
by Tamás Röszer
Biomolecules 2021, 11(11), 1705; https://doi.org/10.3390/biom11111705 - 16 Nov 2021
Cited by 7 | Viewed by 3046
Abstract
Breastfeeding is a unique and defining behavior of mammals and has a fundamental role in nourishing offspring by supplying a lipid-rich product that is utilized to generate heat and metabolic fuel. Heat generation from lipids is a feature of newborn mammals and is [...] Read more.
Breastfeeding is a unique and defining behavior of mammals and has a fundamental role in nourishing offspring by supplying a lipid-rich product that is utilized to generate heat and metabolic fuel. Heat generation from lipids is a feature of newborn mammals and is mediated by the uncoupling of mitochondrial respiration in specific fat depots. Breastfeeding and thermogenic adipose tissue have a shared evolutionary history: both have evolved in the course of homeothermy evolution; breastfeeding mammals are termed “thermolipials”, meaning “animals with warm fat”. Beyond its heat-producing capacity, thermogenic adipose tissue is also necessary for proper lipid metabolism and determines adiposity in offspring. Recent advances have demonstrated that lipid metabolism in infants is orchestrated by breast milk lipid signals, which establish mother-to-child signaling and control metabolic development in the infant. Breastfeeding rates are declining worldwide, and are paralleled by an alarming increase in childhood obesity, which at least in part may have its roots in the impaired metabolic control by breast milk lipid signals. Full article
(This article belongs to the Special Issue Breast Milk-Derived Biomolecules in Human Health)
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