Subjects -> BIOLOGY (Total: 3174 journals)
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BIOLOGY (1491 journals)            First | 1 2 3 4 5 6 7 8 | Last

Showing 201 - 400 of 1720 Journals sorted alphabetically
Biological Research     Open Access   (Followers: 1)
Biological Rhythm Research     Hybrid Journal   (Followers: 1)
Biological Theory     Hybrid Journal   (Followers: 3)
Biological Trace Element Research     Hybrid Journal  
Biologicals     Full-text available via subscription   (Followers: 7)
Biologics: Targets & Therapy     Open Access   (Followers: 1)
Biologie Aujourd'hui     Full-text available via subscription  
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 36)
Biologija     Open Access  
Biology     Open Access   (Followers: 3)
Biology and Philosophy     Hybrid Journal   (Followers: 18)
Biology Bulletin     Hybrid Journal   (Followers: 1)
Biology Bulletin Reviews     Hybrid Journal  
Biology Direct     Open Access   (Followers: 9)
Biology Letters     Full-text available via subscription   (Followers: 44)
Biology Methods and Protocols     Open Access  
Biology of Sex Differences     Open Access   (Followers: 1)
Biology of the Cell     Full-text available via subscription   (Followers: 9)
Biology Open     Open Access  
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 2)
Bioma : Jurnal Ilmiah Biologi     Open Access  
Biomacromolecules     Hybrid Journal   (Followers: 23)
Biomarker Insights     Open Access   (Followers: 2)
Biomarkers     Hybrid Journal   (Followers: 4)
Biomass and Bioenergy     Partially Free   (Followers: 8)
Biomaterials     Hybrid Journal   (Followers: 55)
Biomaterials Advances     Full-text available via subscription   (Followers: 19)
Biomath     Open Access  
Biomatter     Open Access  
Biomechanics and Modeling in Mechanobiology     Hybrid Journal   (Followers: 8)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomedical Engineering     Hybrid Journal   (Followers: 11)
Biomedical Engineering and Computational Biology     Open Access   (Followers: 11)
BioMedical Engineering OnLine     Open Access   (Followers: 4)
Biomedical Engineering: Applications, Basis and Communications     Hybrid Journal   (Followers: 4)
Biomedical Journal     Open Access   (Followers: 5)
Biomedical Science and Engineering     Open Access   (Followers: 5)
Biomedical Signal Processing and Control     Hybrid Journal   (Followers: 9)
BioMetals     Hybrid Journal   (Followers: 1)
Biometrical Letters     Open Access  
Biometrics     Hybrid Journal   (Followers: 51)
Biometrika     Hybrid Journal   (Followers: 21)
Biomimetic Intelligence and Robotics     Open Access  
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
Biomolecules     Open Access   (Followers: 1)
BioNanoScience     Partially Free   (Followers: 3)
Bionature     Open Access   (Followers: 1)
Biopreservation and Biobanking     Hybrid Journal   (Followers: 2)
Bioprocess and Biosystems Engineering     Hybrid Journal   (Followers: 9)
Bioresource Technology     Partially Free   (Followers: 9)
BioRisk     Open Access   (Followers: 2)
Biosaintifika : Journal of Biology & Biology Education     Open Access  
BioScience     Hybrid Journal   (Followers: 27)
Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science     Hybrid Journal   (Followers: 3)
Biosemiotics     Hybrid Journal   (Followers: 1)
Biosensors     Open Access   (Followers: 3)
Biosensors and Bioelectronics     Hybrid Journal   (Followers: 27)
Biosensors and Bioelectronics : X     Open Access   (Followers: 2)
Bioseparation     Hybrid Journal   (Followers: 1)
Biosfer : Jurnal Biologi dan Pendidikan Biologi     Open Access  
Biosfer : Jurnal Tadris Biologi     Open Access  
BioSocieties     Hybrid Journal   (Followers: 3)
Biospecies     Open Access  
BIOspektrum     Hybrid Journal   (Followers: 5)
Biostatistics     Hybrid Journal   (Followers: 18)
Biosystematics and Ecology     Open Access   (Followers: 2)
Biosystems     Hybrid Journal   (Followers: 3)
Biosystems Diversity     Open Access  
Biota Amazônia     Open Access  
Biota Neotropica     Open Access  
Biotechnology Advances     Hybrid Journal   (Followers: 34)
Biotropia : The Southeast Asian Journal of Tropical Biology     Open Access  
Biotropica     Hybrid Journal   (Followers: 19)
Birth Defects Research     Hybrid Journal  
BJHM Open Research     Full-text available via subscription  
BMC Bioinformatics     Open Access   (Followers: 110)
BMC Biology     Open Access   (Followers: 50)
BMC Developmental Biology     Open Access   (Followers: 13)
BMC Evolutionary Biology     Open Access   (Followers: 58)
BMC Genomics     Open Access   (Followers: 69)
BMC Molecular and Cell Biology     Open Access   (Followers: 40)
BMC Proceedings     Full-text available via subscription   (Followers: 2)
BMC Research Notes     Open Access   (Followers: 3)
BMC Structural Biology     Open Access   (Followers: 8)
BMC Systems Biology     Open Access   (Followers: 16)
Boletín Científico : Centro de Museos. Museo de Historia Natural     Open Access  
Boletín del Centro de Investigaciones Biológicas     Open Access  
Boletín Micológico     Open Access  
Bone Reports     Open Access  
Bonorowo Wetlands     Open Access  
Borneo Journal of Resource Science and Technology     Open Access  
Bothalia : African Biodiversity & Conservation     Open Access  
Brain Science Advances     Open Access  
Brazilian Journal of Biological Sciences     Open Access  
Breastfeeding Medicine     Hybrid Journal   (Followers: 20)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 43)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3)
British Poultry Abstracts     Hybrid Journal   (Followers: 3)
Brittonia     Hybrid Journal  
Bulletin de la Société Royale des Sciences de Liège     Open Access  
Bulletin of Experimental Biology and Medicine     Hybrid Journal  
Bulletin of Mathematical Biology     Hybrid Journal   (Followers: 9)
Bulletin of the Ecological Society of America     Open Access   (Followers: 4)
Bulletin of the Lebedev Physics Institute     Hybrid Journal  
Butlletí de la Institució Catalana d'Història Natural     Open Access  
CABI Agriculture and Bioscience     Open Access   (Followers: 1)
Caldasia     Open Access  
Cameroon Journal of Experimental Biology     Open Access  
Canadian Journal of Bioethics     Open Access  
Canadian Journal of Plant Pathology     Hybrid Journal   (Followers: 3)
Çanakkale Onsekiz Mart University Journal of Marine Sciences and Fisheries     Open Access  
Cancer Biology & Therapy     Open Access   (Followers: 11)
Cancer Cell International     Open Access   (Followers: 7)
Carbon Capture Science & Technology     Open Access  
Carbon Management     Hybrid Journal   (Followers: 5)
Carbon Resources Conversion     Open Access   (Followers: 2)
Caryologia : International Journal of Cytology, Cytosystematics and Cytogenetics     Partially Free  
Caucasiana     Open Access  
Cell     Full-text available via subscription   (Followers: 1141)
Cell Adhesion & Migration     Open Access   (Followers: 9)
Cell and Tissue Banking     Hybrid Journal   (Followers: 1)
Cell and Tissue Biology     Hybrid Journal   (Followers: 4)
Cell and Tissue Research     Hybrid Journal   (Followers: 5)
Cell Biochemistry and Function     Hybrid Journal   (Followers: 8)
Cell Biology and Development     Open Access   (Followers: 2)
Cell Biology and Toxicology     Hybrid Journal   (Followers: 10)
Cell Biology Education     Free   (Followers: 4)
Cell Biology International     Hybrid Journal   (Followers: 4)
Cell Biology International Reports     Hybrid Journal   (Followers: 2)
Cell Calcium     Hybrid Journal   (Followers: 2)
Cell Communication & Adhesion     Hybrid Journal   (Followers: 2)
Cell Cycle     Full-text available via subscription   (Followers: 5)
Cell Death and Differentiation     Hybrid Journal   (Followers: 7)
Cell Discovery     Open Access   (Followers: 2)
Cell Division     Open Access   (Followers: 1)
Cell Genomics     Full-text available via subscription   (Followers: 2)
Cell Metabolism     Full-text available via subscription   (Followers: 58)
Cell Proliferation     Open Access  
Cell Reports     Open Access   (Followers: 61)
Cell Reports Medicine     Open Access   (Followers: 3)
Cell Reports Methods     Open Access   (Followers: 1)
Cell Research     Hybrid Journal   (Followers: 11)
Cell Stress and Chaperones     Hybrid Journal   (Followers: 1)
Cell Surface     Open Access  
Cell Systems     Hybrid Journal   (Followers: 7)
Cells     Open Access   (Followers: 2)
Cells & Development     Hybrid Journal   (Followers: 3)
Cells Tissues Organs     Full-text available via subscription   (Followers: 1)
Cellular Immunology     Hybrid Journal   (Followers: 29)
Cellular Logistics     Full-text available via subscription  
Cellular Microbiology     Hybrid Journal   (Followers: 12)
Cellular Oncology     Hybrid Journal   (Followers: 3)
Cellular Reprogramming     Hybrid Journal  
Cellular Signalling     Hybrid Journal   (Followers: 10)
Ceylon Journal of Science     Open Access  
Channels     Open Access   (Followers: 1)
Check List : The Journal of Biodiversity Data     Open Access   (Followers: 2)
Chem     Hybrid Journal  
ChemBioEng Reviews     Full-text available via subscription   (Followers: 3)
Chemosensory Perception     Hybrid Journal  
Chirality     Hybrid Journal  
Chromosoma     Hybrid Journal  
Chromosome Research     Hybrid Journal   (Followers: 2)
Ciencia     Open Access  
Ciencia Amazónica (Iquitos)     Open Access  
Ciência ET Praxis     Open Access  
CienciaUAT     Open Access  
Cladistics     Hybrid Journal   (Followers: 7)
Climate Change Ecology     Open Access   (Followers: 14)
Clinical Dysmorphology     Hybrid Journal  
Clinical Phytoscience     Open Access  
Clinical Proteomics     Open Access   (Followers: 3)
Clinical Spectroscopy     Open Access  
Coevolution     Open Access  
Cogent Biology     Open Access  
Cognitive Neurodynamics     Hybrid Journal   (Followers: 2)
Cold Spring Harbor Perspectives in Biology     Full-text available via subscription   (Followers: 3)
Cold Spring Harbor Protocols     Full-text available via subscription   (Followers: 4)
Communication in Biomathematical Sciences     Open Access   (Followers: 2)
Communications Biology     Open Access  
Communications in Applied Sciences     Open Access  
Communications Materials     Open Access  
Communicative & Integrative Biology     Open Access  
Community Ecology     Full-text available via subscription   (Followers: 27)
Comparative Medicine     Full-text available via subscription   (Followers: 5)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comptes Rendus : Chimie     Open Access  
Comptes Rendus Biologies     Open Access   (Followers: 1)
Computational Biology Journal     Open Access   (Followers: 6)
Computational Mathematics and Mathematical Physics     Hybrid Journal   (Followers: 5)
Computer Methods in Biomechanics and Biomedical Engineering     Hybrid Journal   (Followers: 10)
Computer Methods in Biomechanics and Biomedical Engineering : Imaging & Visualization     Hybrid Journal  
Computers in Biology and Medicine     Hybrid Journal   (Followers: 11)
Connective Tissue Research     Hybrid Journal  
Contact (CTC)     Open Access  
Contributions to Plasma Physics     Hybrid Journal   (Followers: 3)
CRISPR Journal     Hybrid Journal  
Critical Reviews in Clinical Laboratory Sciences     Hybrid Journal   (Followers: 19)
Crustaceana     Hybrid Journal   (Followers: 6)
Cryobiology     Hybrid Journal   (Followers: 3)

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Journal Prestige (SJR): 2.552
Citation Impact (citeScore): 6
Number of Followers: 1  

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ISSN (Online) 2218-273X
Published by MDPI Homepage  [84 journals]
  • Biomolecules, Vol. 12, Pages 615: Essential Oils of Duguetia Species A.
           St. Hill (Annonaceae): Chemical Diversity and Pharmacological Potential

    • Authors: Albert C. dos Santos, Mateus L. Nogueira, Felipe P. de Oliveira, Emmanoel V. Costa, Daniel P. Bezerra
      First page: 615
      Abstract: Duguetia A. St. Hill (Annonaceae) is recognized as one of the major genera with approximately 100 species, 67 of which are found in Brazil (29 of those are endemic). They are arboreal species with edible fruits known as “pindaíba”, “pindaíva” “pinha”, and “envira” in Brazil. Many Duguetia species, in particular, have been used in traditional medicine to treat renal colic, stomachache, rheumatism, cough, toothache, muscle pain, fever, gastrointestinal pain, and breathing difficulties. In this study, we reviewed the chemical constituents and pharmacological properties of essential oils (EOs) from Duguetia species. A total of 12 species were found, along with their EO chemical constituents and bioactivities. Bicyclogermacrene, humulene epoxide II, spathulenol, germacrene D, caryophyllene oxide, viridiflorene, α-pinene, β-caryophyllene, and β-pinene were the main chemical constituents reported. The pharmacological effects of Duguetia species EOs included anti-inflammatory, antinociceptive, antibacterial, antifungal, antioxidant, anti-trypanosoma, cytotoxic and antitumor properties. This information adds to our understanding of the potential of the EOs of Duguetia species.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050615
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 616: Lyso-IP: Uncovering Pathogenic
           Mechanisms of Lysosomal Dysfunction

    • Authors: Chase Chen, Ellen Sidransky, Yu Chen
      First page: 616
      Abstract: Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage diseases but also in a host of others, including common neurodegenerative disorders, such as Alzheimer disease and Parkinson disease. New technological advances have significantly increased our ability to rapidly isolate lysosomes from cells in recent years. The development of the Lyso-IP approach and similar methods now allow for lysosomal purification within ten minutes. Multiple studies using the Lyso-IP approach have revealed novel insights into the pathogenic mechanisms of lysosomal disorders, including Niemann-Pick type C disease, showing the immense potential for this technique. Future applications of rapid lysosomal isolation techniques are likely to greatly enhance our understanding of lysosomal dysfunction in rare and common neurodegeneration causes.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050616
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 617: Structural Insights into the
           Intrinsically Disordered GPCR C-Terminal Region, Major Actor in
           Arrestin-GPCR Interaction

    • Authors: Myriam Guillien, Assia Mouhand, Aurélie Fournet, Amandine Gontier, Aleix Martí Navia, Tiago N. Cordeiro, Frédéric Allemand, Aurélien Thureau, Jean-Louis Banères, Pau Bernadó, Nathalie Sibille
      First page: 617
      Abstract: Arrestin-dependent pathways are a central component of G protein-coupled receptor (GPCRs) signaling. However, the molecular processes regulating arrestin binding are to be further illuminated, in particular with regard to the structural impact of GPCR C-terminal disordered regions. Here, we used an integrated biophysical strategy to describe the basal conformations of the C-terminal domains of three class A GPCRs, the vasopressin V2 receptor (V2R), the growth hormone secretagogue or ghrelin receptor type 1a (GHSR) and the β2-adernergic receptor (β2AR). By doing so, we revealed the presence of transient secondary structures in these regions that are potentially involved in the interaction with arrestin. These secondary structure elements differ from those described in the literature in interaction with arrestin. This suggests a mechanism where the secondary structure conformational preferences in the C-terminal regions of GPCRs could be a central feature for optimizing arrestins recognition.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050617
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 618: The Impact of Pancreatic Exocrine
           Diseases on the β-Cell and Glucose Metabolism—A Review with
           Currently Available Evidence

    • Authors: Marina Ciochina, Daniel Vasile Balaban, George Manucu, Mariana Jinga, Cristian Gheorghe
      First page: 618
      Abstract: Pancreatic exocrine and endocrine dysfunctions often come together in the course of pancreatic diseases as interdependent manifestations of the same organ. However, the mechanisms underlying the bidirectional connection of the exocrine and endocrine pancreas are not fully understood. In this review, we aimed to synthetize the current knowledge regarding the effects of several exocrine pancreatic pathologies on the homeostasis of β-cells, with a special interest in the predisposition toward diabetes mellitus (DM). We focused on the following pancreatic exocrine diseases: chronic pancreatitis, acute pancreatitis, cystic fibrosis, pancreatic cancer, pancreatic resections, and autoimmune pancreatitis. We discuss the pathophysiologic mechanisms behind the impact on β-cell function and evolution into DM, as well as the associated risk factors in progression to DM, and we describe the most relevant and statistically significant findings in the literature. An early and correct diagnosis of DM in the setting of pancreatic exocrine disorders is of paramount importance for anticipating the disease’s course and its therapeutical needs.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050618
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 619: Biology of the Extracellular Proteasome

    • Authors: Gili Ben-Nissan, Naama Katzir, Maria Gabriella Füzesi-Levi, Michal Sharon
      First page: 619
      Abstract: Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and removing damaged proteins. Remarkably, in addition to these well-studied intracellular roles, accumulating data indicate that proteasomes are also present in extracellular body fluids. Not much is known about the origin, biological role, mode(s) of regulation or mechanisms of extracellular transport of these complexes. Nevertheless, emerging evidence indicates that the presence of proteasomes in the extracellular milieu is not a random phenomenon, but rather a regulated, coordinated physiological process. In this review, we provide an overview of the current understanding of extracellular proteasomes. To this end, we examine 143 proteomic datasets, leading us to the realization that 20S proteasome subunits are present in at least 25 different body fluids. Our analysis also indicates that while 19S subunits exist in some of those fluids, the dominant proteasome activator in these compartments is the PA28α/β complex. We also elaborate on the positive correlations that have been identified in plasma and extracellular vesicles, between 20S proteasome and activity levels to disease severity and treatment efficacy, suggesting the involvement of this understudied complex in pathophysiology. In addition, we address the considerations and practical experimental methods that should be taken when investigating extracellular proteasomes. Overall, we hope this review will stimulate new opportunities for investigation and thoughtful discussions on this exciting topic that will contribute to the maturation of the field.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050619
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 620: In Silico Design Strategies for the
           Production of Target Chemical Compounds Using Iterative Single-Level
           Linear Programming Problems

    • Authors: Tomokazu Shirai, Akihiko Kondo
      First page: 620
      Abstract: The optimization of metabolic reaction modifications for the production of target compounds is a complex computational problem whose execution time increases exponentially with the number of metabolic reactions. Therefore, practical technologies are needed to identify reaction deletion combinations to minimize computing times and promote the production of target compounds by modifying intracellular metabolism. In this paper, a practical metabolic design technology named AERITH is proposed for high-throughput target compound production. This method can optimize the production of compounds of interest while maximizing cell growth. With this approach, an appropriate combination of metabolic reaction deletions can be identified by solving a simple linear programming problem. Using a standard CPU, the computation time could be as low as 1 min per compound, and the system can even handle large metabolic models. AERITH was implemented in MATLAB and is freely available for non-profit use.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050620
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 621: Chronic Nicotine Exposure Increases
           Hematoma Expansion following Collagenase-Induced Intracerebral Hemorrhage
           in Rats

    • Authors: Ashish K. Rehni, Sunjoo Cho, Zhexuan Zhang, Weizhao Zhao, Ami P. Raval, Miguel A. Perez-Pinzon, Kunjan R. Dave
      First page: 621
      Abstract: Spontaneous intracerebral hemorrhage (sICH) is a deadly stroke subtype, and tobacco use increases sICH risk. However epidemiological studies show that, there are no confirmatory studies showing the effect of tobacco use on sICH outcome. Therefore, we evaluated the effect of chronic nicotine exposure (as a surrogate for tobacco use) on outcomes following sICH. Young male and female rats were randomly assigned to either nicotine (4.5 mg/kg b.w. per day) or vehicle (saline) treatment (2–3 weeks) groups. sICH was induced by injecting collagenase into the right striatum. Neurological score and hematoma volume were determined 24 h post-sICH. The hematoma volumes in nicotine-treated male and female rats were significantly higher by 42% and 48% when compared to vehicle-treated male and female rats, respectively. Neurological deficits measured in terms of neurological score for the nicotine-treated male and female groups were significantly higher when compared to the respective vehicle-treated male and female groups. Our results show that chronic nicotine exposure increases hematoma volume post-sICH in rats of both sexes. Identifying the mechanism of nicotine-dependent increase in hematoma growth post-sICH will be crucial to understanding the detrimental effect of tobacco use on the severity of bleeding following intracerebral hemorrhage.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050621
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 622: How Similar Are Proteins and

    • Authors: Hay Azulay, Aviv Lutaty, Nir Qvit
      First page: 622
      Abstract: Protein folding and structural biology are highly active disciplines that combine basic research in various fields, including biology, chemistry, physics, and computer science, with practical applications in biomedicine and nanotechnology. However, there are still gaps in the understanding of the detailed mechanisms of protein folding, and protein structure-function relations. In an effort to bridge these gaps, this paper studies the equivalence of proteins and origami. Research on proteins and origami provides strong evidence to support the use of origami folding principles and mechanical models to explain aspects of proteins formation and function. Although not identical, the equivalence of origami and proteins emerges in: (i) the folding processes, (ii) the shape and structure of proteins and origami models, and (iii) the intrinsic mechanical properties of the folded structures/models, which allows them to synchronically fold/unfold and effectively distribute forces to the whole structure. As a result, origami can contribute to the understanding of various key protein-related mechanisms and support the design of de novo proteins and nanomaterials.
      Citation: Biomolecules
      PubDate: 2022-04-21
      DOI: 10.3390/biom12050622
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 623: O-GlcNAcylation and Regulation of
           Galectin-3 in Extraembryonic Endoderm Differentiation

    • Authors: Mohamed I. Gatie, Danielle M. Spice, Amritpal Garha, Adam McTague, Mariam Ahmer, Alexander V. Timoshenko, Gregory M. Kelly
      First page: 623
      Abstract: The regulation of proteins through the addition and removal of O-linked β-N-acetylglucosamine (O-GlcNAc) plays a role in many signaling events, specifically in stem cell pluripotency and the regulation of differentiation. However, these post-translational modifications have not been explored in extraembryonic endoderm (XEN) differentiation. Of the plethora of proteins regulated through O-GlcNAc, we explored galectin-3 as a candidate protein known to have various intracellular and extracellular functions. Based on other studies, we predicted a reduction in global O-GlcNAcylation levels and a distinct galectin expression profile in XEN cells relative to embryonic stem (ES) cells. By conducting dot blot analysis, XEN cells had decreased levels of global O-GlcNAc than ES cells, which reflected a disbalance in the expression of genes encoding O-GlcNAc cycle enzymes. Immunoassays (Western blot and ELISA) revealed that although XEN cells (low O-GlcNAc) had lower concentrations of both intracellular and extracellular galectin-3 than ES cells (high O-GlcNAc), the relative secretion of galectin-3 was significantly increased by XEN cells. Inducing ES cells toward XEN in the presence of an O-GlcNAcase inhibitor was not sufficient to inhibit XEN differentiation. However, global O-GlcNAcylation was found to decrease in differentiated cells and the extracellular localization of galectin-3 accompanies these changes. Inhibiting global O-GlcNAcylation status does not, however, impact pluripotency and the ability of ES cells to differentiate to the XEN lineage.
      Citation: Biomolecules
      PubDate: 2022-04-22
      DOI: 10.3390/biom12050623
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 624: Zinc Metalloprotease ProA from
           Legionella pneumophila Inhibits the Pro-Inflammatory Host Response by
           Degradation of Bacterial Flagellin

    • Authors: Lina Scheithauer, Stefanie Thiem, Can M. Ünal, Ansgar Dellmann, Michael Steinert
      First page: 624
      Abstract: The environmental bacterium Legionella pneumophila is an intracellular pathogen of various protozoan hosts and able to cause Legionnaires’ disease, a severe pneumonia in humans. By encoding a wide selection of virulence factors, the infectious agent possesses several strategies to manipulate its host cells and evade immune detection. In the present study, we demonstrate that the L. pneumophila zinc metalloprotease ProA functions as a modulator of flagellin-mediated TLR5 stimulation and subsequent activation of the pro-inflammatory NF-κB pathway. We found ProA to be capable of directly degrading immunogenic FlaA monomers but not the polymeric form of bacterial flagella. These results indicate a role of the protease in antagonizing immune stimulation, which was further substantiated in HEK-BlueTM hTLR5 Detection assays. Addition of purified proteins, bacterial suspensions of L. pneumophila mutant strains as well as supernatants of human lung tissue explant infection to this reporter cell line demonstrated that ProA specifically decreases the TLR5 response via FlaA degradation. Conclusively, the zinc metalloprotease ProA serves as a powerful regulator of exogenous flagellin and presumably creates an important advantage for L. pneumophila proliferation in mammalian hosts by promoting immune evasion.
      Citation: Biomolecules
      PubDate: 2022-04-22
      DOI: 10.3390/biom12050624
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 625: Nuclear and Cytoplasmatic Players in
           Mitochondria-Related CNS Disorders: Chromatin Modifications and
           Subcellular Trafficking

    • Authors: Matteo Gasparotto, Yi-Shin Lee, Alessandra Palazzi, Marcella Vacca, Francesco Filippini
      First page: 625
      Abstract: Aberrant mitochondrial phenotypes are common to many central nervous system (CNS) disorders, including neurodegenerative and neurodevelopmental diseases. Mitochondrial function and homeostasis depend on proper control of several biological processes such as chromatin remodeling and transcriptional control, post-transcriptional events, vesicle and organelle subcellular trafficking, fusion, and morphogenesis. Mutation or impaired regulation of major players that orchestrate such processes can disrupt cellular and mitochondrial dynamics, contributing to neurological disorders. The first part of this review provides an overview of a functional relationship between chromatin players and mitochondria. Specifically, we relied on specific monogenic CNS disorders which share features with mitochondrial diseases. On the other hand, subcellular trafficking is coordinated directly or indirectly through evolutionarily conserved domains and proteins that regulate the dynamics of membrane compartments and organelles, including mitochondria. Among these “building blocks”, longin domains and small GTPases are involved in autophagy and mitophagy, cell reshaping, and organelle fusion. Impairments in those processes significantly impact CNS as well and are discussed in the second part of the review. Hopefully, in filling the functional gap between the nucleus and cytoplasmic organelles new routes for therapy could be disclosed.
      Citation: Biomolecules
      PubDate: 2022-04-23
      DOI: 10.3390/biom12050625
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 626: Therapeutic Effects of Citrus Flavonoids
           Neohesperidin, Hesperidin and Its Aglycone, Hesperetin, on Bone Health

    • Authors: Adriana de Cássia Ortiz, Simone Ortiz Moura Fideles, Carlos Henrique Bertoni Reis, Márcia Zilioli Bellini, Eliana de Souza Bastos Mazuqueli Pereira, João Paulo Galletti Pilon, Miguel Ângelo de Marchi, Cláudia Rucco Penteado Detregiachi, Uri Adrian Prync Flato, Beatriz Flavia de Moraes Trazzi, Bruna Trazzi Pagani, José Burgos Ponce, Taiane Priscila Gardizani, Fulvia de Souza Veronez, Daniela Vieira Buchaim, Rogerio Leone Buchaim
      First page: 626
      Abstract: Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in seeds, grains, tea, coffee, wine, chocolate, cocoa, vegetables and, mainly, in citrus fruits. Neohesperidin, hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory and antioxidant potential. Neohesperidin, in the form of neohesperidin dihydrochalcone (NHDC), also has dietary properties as a sweetener. In general, these flavanones have been investigated as a strategy to control bone diseases, such as osteoporosis and osteoarthritis. In this literature review, we compiled studies that investigated the effects of neohesperidin, hesperidin and its aglycone, hesperetin, on bone health. In vitro studies showed that these flavanones exerted an antiosteoclastic and anti- inflammatory effects, inhibiting the expression of osteoclastic markers and reducing the levels of reactive oxygen species, proinflammatory cytokines and matrix metalloproteinase levels. Similarly, such studies favored the osteogenic potential of preosteoblastic cells and induced the overexpression of osteogenic markers. In vivo, these flavanones favored the regeneration of bone defects and minimized inflammation in arthritis- and periodontitis-induced models. Additionally, they exerted a significant anticatabolic effect in ovariectomy models, reducing trabecular bone loss and increasing bone mineral density. Although research should advance to the clinical field, these flavanones may have therapeutic potential for controlling the progression of metabolic, autoimmune or inflammatory bone diseases.
      Citation: Biomolecules
      PubDate: 2022-04-23
      DOI: 10.3390/biom12050626
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 627: Plant Extracts Mediated Metal-Based
           Nanoparticles: Synthesis and Biological Applications

    • Authors: Jerry O. Adeyemi, Ayodeji O. Oriola, Damian C. Onwudiwe, Adebola O. Oyedeji
      First page: 627
      Abstract: The vastness of metal-based nanoparticles has continued to arouse much research interest, which has led to the extensive search and discovery of new materials with varying compositions, synthetic methods, and applications. Depending on applications, many synthetic methods have been used to prepare these materials, which have found applications in different areas, including biology. However, the prominent nature of the associated toxicity and environmental concerns involved in most of these conventional methods have limited their continuous usage due to the desire for more clean, reliable, eco-friendly, and biologically appropriate approaches. Plant-mediated synthetic approaches for metal nanoparticles have emerged to circumvent the often-associated disadvantages with the conventional synthetic routes, using bioresources that act as a scaffold by effectively reducing and stabilizing these materials, whilst making them biocompatible for biological cells. This capacity by plants to intrinsically utilize their organic processes to reorganize inorganic metal ions into nanoparticles has thus led to extensive studies into this area of biochemical synthesis and analysis. In this review, we examined the use of several plant extracts as a mediating agent for the synthesis of different metal-based nanoparticles (MNPs). Furthermore, the associated biological properties, which have been suggested to emanate from the influence of the diverse metabolites found in these plants, were also reviewed.
      Citation: Biomolecules
      PubDate: 2022-04-24
      DOI: 10.3390/biom12050627
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 628: Probing Structural Perturbation of
           Biomolecules by Extracting Cryo-EM Data Heterogeneity

    • Authors: Kira DeVore, Po-Lin Chiu
      First page: 628
      Abstract: Single-particle cryogenic electron microscopy (cryo-EM) has become an indispensable tool to probe high-resolution structural detail of biomolecules. It enables direct visualization of the biomolecules and opens a possibility for averaging molecular images to reconstruct a three-dimensional Coulomb potential density map. Newly developed algorithms for data analysis allow for the extraction of structural heterogeneity from a massive and low signal-to-noise-ratio (SNR) cryo-EM dataset, expanding our understanding of multiple conformational states, or further implications in dynamics, of the target biomolecule. This review provides an overview that briefly describes the workflow of single-particle cryo-EM, including imaging and data processing, and new methods developed for analyzing the data heterogeneity to understand the structural variability of biomolecules.
      Citation: Biomolecules
      PubDate: 2022-04-24
      DOI: 10.3390/biom12050628
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 629: COVID-19 and the Brain: The
           Neuropathological Italian Experience on 33 Adult Autopsies

    • Authors: Viscardo P. Fabbri, Mattia Riefolo, Tiziana Lazzarotto, Liliana Gabrielli, Giovanna Cenacchi, Carmine Gallo, Raffaele Aspide, Guido Frascaroli, Rocco Liguori, Raffaele Lodi, Caterina Tonon, Antonietta D’Errico, Maria Pia Foschini
      First page: 629
      Abstract: Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first (February–April 2020) and the second/third (November 2020–April 2021) pandemic waves are described. In all the cases, SARS-CoV-2 RNA was searched. Pathological findings are described and compared with those presently published.
      Citation: Biomolecules
      PubDate: 2022-04-25
      DOI: 10.3390/biom12050629
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 630: Comparative Analysis of the Relative
           Fragmentation Stabilities of Polymorphic Alpha-Synuclein Amyloid Fibrils

    • Authors: Sarina Sanami, Tracey J. Purton, David P. Smith, Mick F. Tuite, Wei-Feng Xue
      First page: 630
      Abstract: The division of amyloid fibril particles through fragmentation is implicated in the progression of human neurodegenerative disorders such as Parkinson’s disease. Fragmentation of amyloid fibrils plays a crucial role in the propagation of the amyloid state encoded in their three-dimensional structures and may have an important role in the spreading of potentially pathological properties and phenotypes in amyloid-associated diseases. However, despite the mechanistic importance of fibril fragmentation, the relative stabilities of different types or different polymorphs of amyloid fibrils toward fragmentation remain to be quantified. We have previously developed an approach to compare the relative stabilities of different types of amyloid fibrils toward fragmentation. In this study, we show that controlled sonication, a widely used method of mechanical perturbation for amyloid seed generation, can be used as a form of mechanical perturbation for rapid comparative assessment of the relative fragmentation stabilities of different amyloid fibril structures. This approach is applied to assess the relative fragmentation stabilities of amyloid formed in vitro from wild type (WT) α-synuclein and two familial mutant variants of α-synuclein (A30P and A53T) that generate morphologically different fibril structures. Our results demonstrate that the fibril fragmentation stabilities of these different α-synuclein fibril polymorphs are all highly length dependent but distinct, with both A30P and A53T α-synuclein fibrils displaying increased resistance towards sonication-induced fibril fragmentation compared with WT α-synuclein fibrils. These conclusions show that fragmentation stabilities of different amyloid fibril polymorph structures can be diverse and suggest that the approach we report here will be useful in comparing the relative stabilities of amyloid fibril types or fibril polymorphs toward fragmentation under different biological conditions.
      Citation: Biomolecules
      PubDate: 2022-04-25
      DOI: 10.3390/biom12050630
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 631: Shell Disorder Models Detect That
           Omicron Has Harder Shells with Attenuation but Is Not a Descendant of the
           Wuhan-Hu-1 SARS-CoV-2

    • Authors: Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky
      First page: 631
      Abstract: Before the SARS-CoV-2 Omicron variant emergence, shell disorder models (SDM) suggested that an attenuated precursor from pangolins may have entered humans in 2017 or earlier. This was based on a shell disorder analysis of SARS-CoV-1/2 and pangolin-Cov-2017. The SDM suggests that Omicron is attenuated with almost identical N (inner shell) disorder as pangolin-CoV-2017 (N-PID (percentage of intrinsic disorder): 44.8% vs. 44.9%—lower than other variants). The outer shell disorder (M-PID) of Omicron is lower than that of other variants and pangolin-CoV-2017 (5.4% vs. 5.9%). COVID-19-related CoVs have the lowest M-PIDs (hardest outer shell) among all CoVs. This is likely to be responsible for the higher contagiousness of SARS-CoV-2 and Omicron, since hard outer shell protects the virion from salivary/mucosal antimicrobial enzymes. Phylogenetic study using M reveals that Omicron branched off from an ancestor of the Wuhan-Hu-1 strain closely related to pangolin-CoVs. M, being evolutionarily conserved in COVID-19, is most ideal for COVID-19 phylogenetic study. Omicron may have been hiding among burrowing animals (e.g., pangolins) that provide optimal evolutionary environments for attenuation and increase shell hardness, which is essential for fecal–oral–respiratory transmission via buried feces. Incoming data support SDM e.g., the presence of fewer infectious particles in the lungs than in the bronchi upon infection.
      Citation: Biomolecules
      PubDate: 2022-04-25
      DOI: 10.3390/biom12050631
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 632: A Novel High-Throughput Assay Reveals
           That the Temperature Induced Increases in Transphosphatidylation of
           Phospholipase D Are Dependent on the Alcohol Acceptor Concentration

    • Authors: Hengzhang Yang, Rüdiger Woscholski
      First page: 632
      Abstract: Phospholipase D reacts with alcohols or water, transphosphatidylating or hydrolysing lipids such as phosphatidylcholine, generating phosphatidylalcohols or phosphatidic acid, respectively. The enzyme has been employed in many applications making use of the transphosphatidylation reaction and the enzyme’s tolerance for organic solvents in order to synthesize natural and artificial phospholipids. Yet, its catalytic properties with respect to the transphosphatidylation reaction are not well understood. Here, we introduce a novel high-throughput assay, making use of 96-well plates, that employs Fluorescamine for the detection of transphosphatidylated amino alcohols. This assay allowed to monitor the KM and VMax at different temperatures, revealing that the former will be elevated by the temperature, while the latter is increased by a combination of both temperature and alcohol acceptor concentration being elevated, suggesting that increase in temperature may open up a new binding site for the alcohol acceptor.
      Citation: Biomolecules
      PubDate: 2022-04-25
      DOI: 10.3390/biom12050632
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 633: The Readthrough Isoform AQP4ex Is
           Constitutively Phosphorylated in the Perivascular Astrocyte Endfeet of
           Human Brain

    • Authors: Roberta Pati, Claudia Palazzo, Onofrio Valente, Pasqua Abbrescia, Raffaella Messina, Nicoletta Concetta Surdo, Konstantinos Lefkimmiatis, Francesco Signorelli, Grazia Paola Nicchia, Antonio Frigeri
      First page: 633
      Abstract: AQP4ex is a recently discovered isoform of AQP4 generated by a translational readthrough mechanism. It is strongly expressed at the astrocyte perivascular endfeet as a component of the supramolecular membrane complex, commonly called orthogonal array of particles (OAP), together with the canonical isoforms M1 and M23 of AQP4. Previous site-directed mutagenesis experiments suggested the potential role of serine331 and serine335, located in the extended peptide of AQP4ex, in water channel activity by phosphorylation. In the present study we evaluated the effective phosphorylation of human AQP4ex. A small scale bioinformatic analysis indicated that only Ser335 is conserved in human, mouse and rat AQP4ex. The phosphorylation site of Ser335 was assessed through generation of phospho-specific antibodies in rabbits. Antibody specificity was first evaluated in binding phosphorylated peptide versus its unphosphorylated analog by ELISA, which was further confirmed by site-directed mutagenesis experiments. Western blot and immunofluorescence experiments revealed strong expression of phosphorylated AQP4ex (p-AQP4ex) in human brain and localization at the perivascular astrocyte endfeet in supramolecular assemblies identified by BN/PAGE experiments. All together, these data reveal, for the first time, the existence of a phosphorylated form of AQP4, at Ser335 in the extended sequence exclusive of AQP4ex. Therefore, we anticipate an important physiological role of p-AQP4ex in human brain water homeostasis.
      Citation: Biomolecules
      PubDate: 2022-04-25
      DOI: 10.3390/biom12050633
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 634: The Mechanism and Regulation of the
           NLRP3 Inflammasome during Fibrosis

    • Authors: Carol M. Artlett
      First page: 634
      Abstract: Fibrosis is often the end result of chronic inflammation. It is characterized by the excessive deposition of extracellular matrix. This leads to structural alterations in the tissue, causing permanent damage and organ dysfunction. Depending on the organ it effects, fibrosis can be a serious threat to human life. The molecular mechanism of fibrosis is still not fully understood, but the NLRP3 (NOD-, LRR- and pyrin–domain–containing protein 3) inflammasome appears to play a significant role in the pathogenesis of fibrotic disease. The NLRP3 inflammasome has been the most extensively studied inflammatory pathway to date. It is a crucial component of the innate immune system, and its activation mediates the secretion of interleukin (IL)-1β and IL-18. NLRP3 activation has been strongly linked with fibrosis and drives the differentiation of fibroblasts into myofibroblasts by the chronic upregulation of IL-1β and IL-18 and subsequent autocrine signaling that maintains an activated inflammasome. Both IL-1β and IL-18 are profibrotic, however IL-1β can have antifibrotic capabilities. NLRP3 responds to a plethora of different signals that have a common but unidentified unifying trigger. Even after 20 years of extensive investigation, regulation of the NLRP3 inflammasome is still not completely understood. However, what is known about NLRP3 is that its regulation and activation is complex and not only driven by various activators but controlled by numerous post-translational modifications. More recently, there has been an intensive attempt to discover NLRP3 inhibitors to treat chronic diseases. This review addresses the role of the NLRP3 inflammasome in fibrotic disorders across many different tissues. It discusses the relationships of various NLRP3 activators to fibrosis and covers different therapeutics that have been developed, or are currently in development, that directly target NLRP3 or its downstream products as treatments for fibrotic disorders.
      Citation: Biomolecules
      PubDate: 2022-04-26
      DOI: 10.3390/biom12050634
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 635: The Synergistic Cooperation between
           TGF-β and Hypoxia in Cancer and Fibrosis

    • Authors: Pramod Mallikarjuna, Yang Zhou, Maréne Landström
      First page: 635
      Abstract: Transforming growth factor β (TGF-β) is a multifunctional cytokine regulating homeostasis and immune responses in adult animals and humans. Aberrant and overactive TGF-β signaling promotes cancer initiation and fibrosis through epithelial–mesenchymal transition (EMT), as well as the invasion and metastatic growth of cancer cells. TGF-β is a key factor that is active during hypoxic conditions in cancer and is thereby capable of contributing to angiogenesis in various types of cancer. Another potent role of TGF-β is suppressing immune responses in cancer patients. The strong tumor-promoting effects of TGF-β and its profibrotic effects make it a focus for the development of novel therapeutic strategies against cancer and fibrosis as well as an attractive drug target in combination with immune regulatory checkpoint inhibitors. TGF-β belongs to a family of cytokines that exert their function through signaling via serine/threonine kinase transmembrane receptors to intracellular Smad proteins via the canonical pathway and in combination with co-regulators such as the adaptor protein and E3 ubiquitin ligases TRAF4 and TRAF6 to promote non-canonical pathways. Finally, the outcome of gene transcription initiated by TGF-β is context-dependent and controlled by signals exerted by other growth factors such as EGF and Wnt. Here, we discuss the synergistic cooperation between TGF-β and hypoxia in development, fibrosis and cancer.
      Citation: Biomolecules
      PubDate: 2022-04-25
      DOI: 10.3390/biom12050635
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 636: Recent Advances in
           Poly(α-L-glutamic acid)-Based Nanomaterials for Drug Delivery

    • Authors: Yu Zhang, Wenliang Song, Yiming Lu, Yixin Xu, Changping Wang, Deng-Guang Yu, Il Kim
      First page: 636
      Abstract: Poly(α-L-glutamic acid) (PGA) is a class of synthetic polypeptides composed of the monomeric unit α-L-glutamic acid. Owing to their biocompatibility, biodegradability, and non-immunogenicity, PGA-based nanomaterials have been elaborately designed for drug delivery systems. Relevant studies including the latest research results on PGA-based nanomaterials for drug delivery have been discussed in this work. The following related topics are summarized as: (1) a brief description of the synthetic strategies of PGAs; (2) an elaborated presentation of the evolving applications of PGA in the areas of drug delivery, including the rational design, precise fabrication, and biological evaluation; (3) a profound discussion on the further development of PGA-based nanomaterials in drug delivery. In summary, the unique structures and superior properties enables PGA-based nanomaterials to represent as an enormous potential in biomaterials-related drug delivery areas.
      Citation: Biomolecules
      PubDate: 2022-04-25
      DOI: 10.3390/biom12050636
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 637: Administration of Hookworm
           Excretory/Secretory Proteins Improves Glucose Tolerance in a Mouse Model
           of Type 2 Diabetes

    • Authors: Zainab Khudhair, Rafid Alhallaf, Ramon M. Eichenberger, Matt Field, Lutz Krause, Javier Sotillo, Alex Loukas
      First page: 637
      Abstract: Diabetes is recognised as the world’s fastest growing chronic condition globally. Helminth infections have been shown to be associated with a lower prevalence of type 2 diabetes (T2D), in part due to their ability to induce a type 2 immune response. Therefore, to understand the molecular mechanisms that underlie the development of T2D-induced insulin resistance, we treated mice fed on normal or diabetes-promoting diets with excretory/secretory products (ES) from the gastrointestinal helminth Nippostrongylus brasiliensis. We demonstrated that treatment with crude ES products from adult worms (AES) or infective third-stage larvae (L3ES) from N. brasiliensis improved glucose tolerance and attenuated body weight gain in mice fed on a high glycaemic index diet. N. brasiliensis ES administration to mice was associated with a type 2 immune response measured by increased eosinophils and IL-5 in peripheral tissues but not IL-4, and with a decrease in the level of IL-6 in adipose tissue and corresponding increase in IL-6 levels in the liver. Moreover, treatment with AES or L3ES was associated with significant changes in the community composition of the gut microbiota at the phylum and order levels. These data highlight a role for N. brasiliensis ES in modulating the immune response associated with T2D, and suggest that N. brasiliensis ES contain molecules with therapeutic potential for treating metabolic syndrome and T2D.
      Citation: Biomolecules
      PubDate: 2022-04-26
      DOI: 10.3390/biom12050637
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 638: Decoding the Role of Melatonin Structure
           on Plasmodium falciparum Human Malaria Parasites Synchronization Using
           2-Sulfenylindoles Derivatives

    • Authors: Lenna Rosanie Cordero Mallaupoma, Bárbara Karina de Menezes Dias, Maneesh Kumar Singh, Rute Isabel Honorio, Myna Nakabashi, Camila de Menezes Kisukuri, Márcio Weber Paixão, Celia R. S. Garcia
      First page: 638
      Abstract: Melatonin acts to synchronize the parasite’s intraerythrocytic cycle by triggering the phospholipase C-inositol 1,4,5-trisphosphate (PLC-IP3) signaling cascade. Compounds with an indole scaffold impair in vitro proliferation of blood-stage malaria parasites, indicating that this class of compounds is potentially emerging antiplasmodial drugs. Therefore, we aimed to study the role of the alkyl and aryl thiol moieties of 14 synthetic indole compounds against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strains of Plasmodium falciparum. Four compounds (3, 26, 18, 21) inhibited the growth of P. falciparum (3D7) by 50% at concentrations below 20 µM. A set of 2-sulfenylindoles also showed activity against Dd2 parasites. Our data suggest that Dd2 parasites are more susceptible to compounds 20 and 28 than 3D7 parasites. These data show that 2-sulfenylindoles are promising antimalarials against chloroquine-resistant parasite strains. We also evaluated the effects of the 14 compounds on the parasitemia of the 3D7 strain and their ability to interfere with the effect of 100 nM melatonin on the parasitemia of the 3D7 strain. Our results showed that compounds 3, 7, 8, 10, 14, 16, 17, and 20 slightly increased the effect of melatonin by increasing parasitemia by 8–20% compared with that of melatonin-only-treated 3D7 parasites. Moreover, we found that melatonin modulates the expression of kinase-related signaling components giving additional evidence to investigate inhibitors that can block melatonin signaling.
      Citation: Biomolecules
      PubDate: 2022-04-26
      DOI: 10.3390/biom12050638
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 639: Fullerenes’ Interactions with
           Plasma Membranes: Insight from the MD Simulations

    • Authors: Nililla Nisoh, Viwan Jarerattanachat, Mikko Karttunen, Jirasak Wong-ekkabut
      First page: 639
      Abstract: Understanding the interactions between carbon nanoparticles (CNPs) and biological membranes is critically important for applications of CNPs in biomedicine and toxicology. Due to the complexity and diversity of the systems, most molecular simulation studies have focused on the interactions of CNPs and single component bilayers. In this work, we performed coarse-grained molecular dynamic (CGMD) simulations to investigate the behaviors of fullerenes in the presence of multiple lipid components in the plasma membranes with varying fullerene concentrations. Our results reveal that fullerenes can spontaneously penetrate the plasma membrane. Interestingly, fullerenes prefer to locate themselves in the region of the highly unsaturated lipids that are enriched in the inner leaflet of the plasma membrane. This causes fullerene aggregation even at low concentrations. When increasing fullerene concentrations, the fullerene clusters grow, and budding may emerge at the inner leaflet of the plasma membrane. Our findings suggest by tuning the lipid composition, fullerenes can be loaded deeply inside the plasma membrane, which can be useful for designing drug carrier liposomes. Moreover, the mechanisms of how fullerenes perturb multicomponent cell membranes and how they directly enter the cell are proposed. These insights can help to determine fullerene toxicity in living cells.
      Citation: Biomolecules
      PubDate: 2022-04-26
      DOI: 10.3390/biom12050639
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 640: TP53 Pathogenic Variants in Early-Onset
           Breast Cancer Patients Fulfilling Hereditary Breast and Ovary Cancer and
           Li-Fraumeni-like Syndromes

    • Authors: Paula Francinete Faustino da Silva, Rebeca Mota Goveia, Thaís Bomfim Teixeira, Bruno Faulin Gamba, Aliny Pereira de Lima, Sílvia Regina Rogatto, Elisângela de Paula Silveira-Lacerda
      First page: 640
      Abstract: TP53 gene mutation is the most common genetic alteration in human malignant tumors and is mainly responsible for Li-Fraumeni syndrome. Among the several cancers related to this syndrome, breast cancer (BC) is the most common. The TP53 p.R337H germline pathogenic variant is highly prevalent in Brazil’s South and Southeast regions, accounting for 0.3% of the general population. We investigated the prevalence of TP53 germline pathogenic variants in a cohort of 83 BC patients from the Midwest Brazilian region. All patients met the clinical criteria for hereditary breast and ovarian cancer syndrome (HBOC) and were negative for BRCA1 and BRCA2 mutations. Moreover, 40 index patients fulfilled HBOC and the Li-Fraumeni-like (LFL) syndromes criteria. The samples were tested using next generation sequencing for TP53. Three patients harbored TP53 missense pathogenic variants (p.Arg248Gln, p.Arg337His, and p.Arg337Cys), confirmed by Sanger sequencing. One (1.2%) patient showed a large TP53 deletion (exons 2–11), which was also confirmed. The p.R337H variant was detected in only one patient. In conclusion, four (4.8%) early-onset breast cancer patients fulfilling the HBOC and LFL syndromes presented TP53 pathogenic variants, confirming the relevance of genetic tests in this group of patients. In contrast to other Brazilian regions, TP53 p.R337H variant appeared with low prevalence.
      Citation: Biomolecules
      PubDate: 2022-04-27
      DOI: 10.3390/biom12050640
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 641: Insights into a Cancer-Target
           Demethylase: Substrate Prediction through Systematic Specificity Analysis
           for KDM3A

    • Authors: Anand Chopra, William G. Willmore, Kyle K. Biggar
      First page: 641
      Abstract: Jumonji C (JmjC) lysine demethylases (KDMs) catalyze the removal of methyl (-CH3) groups from modified lysyl residues. Several JmjC KDMs promote cancerous properties and these findings have primarily been in relation to histone demethylation. However, the biological roles of these enzymes are increasingly being shown to also be attributed to non-histone demethylation. Notably, KDM3A has become relevant to tumour progression due to recent findings of this enzyme’s role in promoting cancerous phenotypes, such as enhanced glucose consumption and upregulated mechanisms of chemoresistance. To aid in uncovering the mechanism(s) by which KDM3A imparts its oncogenic function(s), this study aimed to unravel KDM3A substrate specificity to predict high-confidence substrates. Firstly, substrate specificity was assessed by monitoring activity towards a peptide permutation library of histone H3 di-methylated at lysine-9 (i.e., H3K9me2). From this, the KDM3A recognition motif was established and used to define a set of high-confidence predictions of demethylation sites from within the KDM3A interactome. Notably, this led to the identification of three in vitro substrates (MLL1, p300, and KDM6B), which are relevant to the field of cancer progression. This preliminary data may be exploited in further tissue culture experiments to decipher the avenues by which KDM3A imparts cancerous phenotypes.
      Citation: Biomolecules
      PubDate: 2022-04-27
      DOI: 10.3390/biom12050641
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 642: Are Inflamed Periodontal Tissues
           Endogenous Source of Advanced Glycation End-Products (AGEs) in Individuals
           with and without Diabetes Mellitus' A Systematic Review

    • Authors: Aditi Chopra, Thilini N. Jayasinghe, Joerg Eberhard
      First page: 642
      Abstract: Advanced glycation end-products (AGEs) are heterogeneous compounds formed when excess sugars condense with the amino groups of nucleic acids and proteins. Increased AGEs are associated with insulin resistance and poor glycemic control. Recently, inflamed periodontal tissues and certain oral bacteria were observed to increase the local and systemic AGE levels in both normoglycemic and hyperglycemic individuals. Although hyperglycemia induced AGE and its effect on the periodontal tissues is known, periodontitis as an endogenous source of AGE formation is not well explored. Hence, this systematic review is aimed to explore, for the first time, whether inflamed periodontal tissues and periodontal pathogens have the capacity to modulate AGE levels in individuals with or without T2DM and how this affects the glycemic load. Six electronic databases were searched using the following keywords: (Periodontitis OR Periodontal disease OR Periodontal Inflammation) AND (Diabetes mellitus OR Hyperglycemia OR Insulin resistance) AND Advanced glycation end products. The results yielded 1140 articles, of which 13 articles were included for the review. The results showed that the mean AGE levels in gingival crevicular fluid was higher in individuals with diabetes mellitus and periodontitis (521.9 pg/mL) compared to healthy individuals with periodontitis (234.84 pg/mL). The serum AGE levels in normoglycemic subjects having periodontitis was higher compared to those without periodontitis (15.91 ng/mL vs. 6.60 ng/mL). Tannerella forsythia, a common gram-negative anaerobe periodontal pathogen in the oral biofilm, was observed to produce methylglyoxal (precursor of AGE) in the gingival tissues. Increased AGE deposition and activate of AGE receptors was noted in the presence of periodontitis in both normoglycemic and hyperglycemic individuals. Hence, it can be concluded that periodontitis can modulate the local and systemic levels of AGE levels even in absence of hyperglycemia. This explains the bidirectional relationship between periodontitis and development of prediabetes, incident diabetes, poor glycemic control, and insulin resistance.
      Citation: Biomolecules
      PubDate: 2022-04-27
      DOI: 10.3390/biom12050642
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 643: Hinokiflavone Inhibits MDM2 Activity by
           Targeting the MDM2-MDMX RING Domain

    • Authors: Viktoria K. Ilic, Olga Egorova, Ernest Tsang, Milena Gatto, Yi Wen, Yong Zhao, Yi Sheng
      First page: 643
      Abstract: The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Thus, inhibition of MDM2 activity has been pursued as an attractive direction for the development of anti-cancer therapeutics. Virtual screening was performed using the crystal structure of the MDM2-MDMX RING domain dimer against a natural product library and identified a biflavonoid Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment resulted in the downregulation of MDM2 and MDMX and induction of apoptosis in various cancer cell lines. Hinokiflavone demonstrated p53-dependent and -independent tumor-suppressive activity. This report provides biochemical and cellular evidence demonstrating the anti-cancer effects of Hinokiflavone through targeting the MDM2-MDMX RING domain.
      Citation: Biomolecules
      PubDate: 2022-04-27
      DOI: 10.3390/biom12050643
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 644: Multi-TransDTI: Transformer for
           Drug–Target Interaction Prediction Based on Simple Universal
           Dictionaries with Multi-View Strategy

    • Authors: Gan Wang, Xudong Zhang, Zheng Pan, Alfonso Rodríguez Patón, Shuang Wang, Tao Song, Yuanqiang Gu
      First page: 644
      Abstract: Prediction on drug–target interaction has always been a crucial link for drug discovery and repositioning, which have witnessed tremendous progress in recent years. Despite many efforts made, the existing representation learning or feature generation approaches of both drugs and proteins remain complicated as well as in high dimension. In addition, it is difficult for current methods to extract local important residues from sequence information while remaining focused on global structure. At the same time, massive data is not always easily accessible, which makes model learning from small datasets imminent. As a result, we propose an end-to-end learning model with SUPD and SUDD methods to encode drugs and proteins, which not only leave out the complicated feature extraction process but also greatly reduce the dimension of the embedding matrix. Meanwhile, we use a multi-view strategy with a transformer to extract local important residues of proteins for better representation learning. Finally, we evaluate our model on the BindingDB dataset in comparisons with different state-of-the-art models from comprehensive indicators. In results of 100% BindingDB, our AUC, AUPR, ACC, and F1-score reached 90.9%, 89.8%, 84.2%, and 84.3% respectively, which successively exceed the average values of other models by 2.2%, 2.3%, 2.6%, and 2.6%. Moreover, our model also generally surpasses their performance on 30% and 50% BindingDB datasets.
      Citation: Biomolecules
      PubDate: 2022-04-27
      DOI: 10.3390/biom12050644
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 645: Hepatocellular Carcinoma: The Role of

    • Authors: Sharad Khare, Tripti Khare, Raghu Ramanathan, Jamal A. Ibdah
      First page: 645
      Abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. HCC is diagnosed in its advanced stage when limited treatment options are available. Substantial morphologic, genetic and epigenetic heterogeneity has been reported in HCC, which poses a challenge for the development of a targeted therapy. In this review, we discuss the role and involvement of several microRNAs (miRs) in the heterogeneity and metastasis of hepatocellular carcinoma with a special emphasis on their possible role as a diagnostic and prognostic tool in the risk prediction, early detection, and treatment of hepatocellular carcinoma.
      Citation: Biomolecules
      PubDate: 2022-04-27
      DOI: 10.3390/biom12050645
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 646: Effect of Exogenous Hydrogen Sulfide and
           Polysulfide Donors on Insulin Sensitivity of the Adipose Tissue

    • Authors: Jolanta Kowalczyk-Bołtuć, Krzysztof Wiórkowski, Jerzy Bełtowski
      First page: 646
      Abstract: Hydrogen sulfide (H2S) and inorganic polysulfides are important signaling molecules; however, little is known about their role in adipose tissue. We examined the effect of H2S and polysulfides on insulin sensitivity of the adipose tissue in rats. Plasma glucose, insulin, non-esterified fatty acids, and glycerol were measured after administration of H2S and the polysulfide donors, Na2S and Na2S4, respectively. In addition, the effect of Na2S and Na2S4 on insulin-induced glucose uptake and inhibition of lipolysis was studied in adipose tissue explants ex vivo. Na2S and Na2S4 administered in vivo at a single dose of 100 μmol/kg had no effect on plasma glucose and insulin concentrations. In addition, Na2S and Na2S4 did not modify the effect of insulin on plasma glucose, fatty acids, and glycerol concentrations. Na2S and Na2S4had no effect on the antilipolytic effect of insulin in adipose tissue explants ex vivo. The effect of insulin on 2-deoxyglucose uptake by adipose tissue was impaired in obese rats which was accompanied by lower insulin-induced tyrosine phosphorylation of IRS-1 and Akt. Na2S4, but not Na2S, improved insulin signaling and increased insulin-stimulated 2-deoxyglucose uptake by adipose tissue of obese rats. The results suggest that polysulfides may normalize insulin sensitivity, at least in the adipose tissue, in obesity/metabolic syndrome.
      Citation: Biomolecules
      PubDate: 2022-04-28
      DOI: 10.3390/biom12050646
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 647: GTP-Dependent Regulation of CTP
           Synthase: Evolving Insights into Allosteric Activation and NH3

    • Authors: Stephen L. Bearne, Chen-Jun Guo, Ji-Long Liu
      First page: 647
      Abstract: Cytidine-5′-triphosphate (CTP) synthase (CTPS) is the class I glutamine-dependent amidotransferase (GAT) that catalyzes the last step in the de novo biosynthesis of CTP. Glutamine hydrolysis is catalyzed in the GAT domain and the liberated ammonia is transferred via an intramolecular tunnel to the synthase domain where the ATP-dependent amination of UTP occurs to form CTP. CTPS is unique among the glutamine-dependent amidotransferases, requiring an allosteric effector (GTP) to activate the GAT domain for efficient glutamine hydrolysis. Recently, the first cryo-electron microscopy structure of Drosophila CTPS was solved with bound ATP, UTP, and, notably, GTP, as well as the covalent adduct with 6-diazo-5-oxo-l-norleucine. This structural information, along with the numerous site-directed mutagenesis, kinetics, and structural studies conducted over the past 50 years, provide more detailed insights into the elaborate conformational changes that accompany GTP binding at the GAT domain and their contribution to catalysis. Interactions between GTP and the L2 loop, the L4 loop from an adjacent protomer, the L11 lid, and the L13 loop (or unique flexible “wing” region), induce conformational changes that promote the hydrolysis of glutamine at the GAT domain; however, direct experimental evidence on the specific mechanism by which these conformational changes facilitate catalysis at the GAT domain is still lacking. Significantly, the conformational changes induced by GTP binding also affect the assembly and maintenance of the NH3 tunnel. Hence, in addition to promoting glutamine hydrolysis, the allosteric effector plays an important role in coordinating the reactions catalyzed by the GAT and synthase domains of CTPS.
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050647
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 648: G-Quadruplex-Binding Proteins: Promising
           Targets for Drug Design

    • Authors: Huiling Shu, Rongxin Zhang, Ke Xiao, Jing Yang, Xiao Sun
      First page: 648
      Abstract: G-quadruplexes (G4s) are non-canonical secondary nucleic acid structures. Sequences with the potential to form G4s are abundant in regulatory regions of the genome including telomeres, promoters and 5′ non-coding regions, indicating they fulfill important genome regulatory functions. Generally, G4s perform various biological functions by interacting with proteins. In recent years, an increasing number of G-quadruplex-binding proteins have been identified with biochemical experiments. G4-binding proteins are involved in vital cellular processes such as telomere maintenance, DNA replication, gene transcription, mRNA processing. Therefore, G4-binding proteins are also associated with various human diseases. An intensive study of G4-protein interactions provides an attractive approach for potential therapeutics and these proteins can be considered as drug targets for novel medical treatment. In this review, we present biological functions and structural properties of G4-binding proteins, and discuss how to exploit G4-protein interactions to develop new therapeutic targets.
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050648
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 649: Conversations in Cochlear Implantation:
           The Inner Ear Therapy of Today

    • Authors: Grant Rauterkus, Anne K. Maxwell, Jacob B. Kahane, Jennifer J. Lentz, Moises A. Arriaga
      First page: 649
      Abstract: As biomolecular approaches for hearing restoration in profound sensorineural hearing loss evolve, they will be applied in conjunction with or instead of cochlear implants. An understanding of the current state-of-the-art of this technology, including its advantages, disadvantages, and its potential for delivering and interacting with biomolecular hearing restoration approaches, is helpful for designing modern hearing-restoration strategies. Cochlear implants (CI) have evolved over the last four decades to restore hearing more effectively, in more people, with diverse indications. This evolution has been driven by advances in technology, surgery, and healthcare delivery. Here, we offer a practical treatise on the state of cochlear implantation directed towards developing the next generation of inner ear therapeutics. We aim to capture and distill conversations ongoing in CI research, development, and clinical management. In this review, we discuss successes and physiological constraints of hearing with an implant, common surgical approaches and electrode arrays, new indications and outcome measures for implantation, and barriers to CI utilization. Additionally, we compare cochlear implantation with biomolecular and pharmacological approaches, consider strategies to combine these approaches, and identify unmet medical needs with cochlear implants. The strengths and weaknesses of modern implantation highlighted here can mark opportunities for continued progress or improvement in the design and delivery of the next generation of inner ear therapeutics.
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050649
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 650: Sex Plays a Multifaceted Role in Asthma

    • Authors: Tomomitsu Miyasaka, Kaori Dobashi-Okuyama, Kaori Kawakami, Chiaki Masuda-Suzuki, Motoaki Takayanagi, Isao Ohno
      First page: 650
      Abstract: Sex is considered an important risk factor for asthma onset and exacerbation. The prevalence of asthma is higher in boys than in girls during childhood, which shows a reverse trend after puberty—it becomes higher in adult females than in adult males. In addition, asthma severity, characterized by the rate of hospitalization and relapse after discharge from the emergency department, is higher in female patients. Basic research indicates that female sex hormones enhance type 2 adaptive immune responses, and male sex hormones negatively regulate type 2 innate immune responses. However, whether hormone replacement therapy in postmenopausal women increases the risk of current asthma and asthma onset remains controversial in clinical settings. Recently, sex has also been shown to influence the pathophysiology of asthma in its relationship with genetic or other environmental factors, which modulate asthmatic immune responses in the airway mucosa. In this narrative review, we highlight the role of sex in the continuity of the asthmatic immune response from sensing allergens to Th2 cell activation based on our own data. In addition, we elucidate the interactive role of sex with genetic or environmental factors in asthma exacerbation in women.
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050650
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 651: Hyperthermia Enhances Efficacy of
           Chemotherapeutic Agents in Pancreatic Cancer Cell Lines

    • Authors: Costanza E. Maurici, Robin Colenbier, Britta Wylleman, Luigi Brancato, Eke van Zwol, Johan Van den Bossche, Jean-Pierre Timmermans, Elisa Giovannetti, Marina G. M. C. Mori da Cunha, Johannes Bogers
      First page: 651
      Abstract: Chemotherapy (CT) is the standard care for advanced pancreatic ductal adenocarcinoma (PDAC); however, with limited efficacy. Hyperthermia (HT) treatment has been suggested as a sensitizer to improve outcomes. However, the direct effect of the HT and CT combination is not fully understood. Therefore, we aim to assess the direct cytotoxic effect of HT in PDAC cells as monotherapy or in combination with chemotherapeutics. Different temperatures (37-, 40.5-, 41-, and 41.5 °C) and durations (6-, 12-, and 24 h) were tested in PDAC cell lines (BxPC-3, Capan-1, Capan-2, PANC-1, and MIA-PaCa-2). Different concentrations of gemcitabine, 5-fluorouracil, and cisplatin were also tested in these conditions. The impact on cell metabolic activity was determined by an MTS assay. Enhancement of chemosensitivity was assessed by a reduction in half-maximal inhibitory concentration (IC50). HT and chemotherapeutics interactions were classified as antagonistic, additive, or synergistic using the combination index. HT inhibited cell proliferation in a cell type, temperature, and duration-dependent manner. The induction of apoptosis was seen after 6 h of HT treatment, eventually followed by secondary necrosis. The HT and CT combination led to an IC50 reduction of the tested CT. At 12 h of HT, this effect was between 25 to 90% and reached a 95% reduction at 24 h. The additive or synergistic effect was demonstrated in all cell lines and chemotherapeutics, although, again, this depended on cell type, duration, and temperature. HT is cytotoxic and enhances the therapeutic effectiveness of gemcitabine, 5-fluorouracil, and cisplatin on PDAC cells. This result was further confirmed by the decrease in the expression of RRM2, TS, and ERCC1 in BxPC-3 and Capan-2 cells. These observations warrant further study in specific subsets of PDAC patients to improve their clinical outcomes.
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050651
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 652: Oncogenomic Changes in Pancreatic Cancer
           and Their Detection in Stool

    • Authors: Sammallahti, Sarhadi, Kokkola, Ghanbari, Rezasoltani, Asadzadeh Aghdaei, Puolakkainen, Knuutila
      First page: 652
      Abstract: Pancreatic cancer (PC) is an aggressive malignancy with a dismal prognosis. To improve patient survival, the development of screening methods for early diagnosis is pivotal. Oncogenomic alterations present in tumor tissue are a suitable target for non-invasive screening efforts, as they can be detected in tumor-derived cells, cell-free nucleic acids, and extracellular vesicles, which are present in several body fluids. Since stool is an easily accessible source, which enables convenient and cost-effective sampling, it could be utilized for the screening of these traces. Herein, we explore the various oncogenomic changes that have been detected in PC tissue, such as chromosomal aberrations, mutations in driver genes, epigenetic alterations, and differentially expressed non-coding RNA. In addition, we briefly look into the role of altered gut microbiota in PC and their possible associations with oncogenomic changes. We also review the findings of genomic alterations in stool of PC patients, and the potentials and challenges of their future use for the development of stool screening tools, including the possible combination of genomic and microbiota markers.
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050652
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 653: A Systematic Review and Meta-Analysis of
           Serum Concentrations of Ischaemia-Modified Albumin in Acute Ischaemic
           Stroke, Intracerebral Haemorrhage, and Subarachnoid Haemorrhage

    • Authors: Arduino A. Mangoni, Angelo Zinellu
      First page: 653
      Abstract: The identification of robust circulating biomarkers of stroke may improve outcomes. We conducted a systematic review and meta-analysis of serum concentrations of ischaemia-modified albumin (IMA) in subjects with or without acute ischaemic stroke (AIS), intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH). We searched PubMed, Web of Science, Scopus, and Google Scholar from inception to March 2022. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 17 studies, IMA concentrations were significantly higher in patients with AIS (standard mean difference, SMD = 2.52, 95% CI 1.92 to 3.12; p < 0.001), ICH (SMD = 3.13, 95% CI 1.00 to 5.25; p = 0.004), and SAH (SMD = 4.50, 95% CI 0.91 to 7.01; p = 0.014) vs. controls (very low certainty of evidence). In AIS, the effect size was associated with the male gender, and was relatively larger in studies conducted in Egypt and India and those using enzyme-linked immunosorbent assays. IMA concentrations were progressively higher, by direct comparison, in SAH, ICH, and AIS. In sensitivity analysis, the pooled SMDs were not altered when individual studies were sequentially removed. Our meta-analysis suggests that IMA concentrations might be useful to diagnose stroke and discriminate between AIS, ICH, and SAH (PROSPERO registration number: CRD42021320535).
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050653
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 654: Osteoblast Attachment on Titanium Coated
           with Hydroxyapatite by Atomic Layer Deposition

    • Authors: Kylmäoja, Holopainen, Abushahba, Ritala, Tuukkanen
      First page: 654
      Abstract: Background: The increasing demand for bone implants with improved osseointegration properties has prompted researchers to develop various coating types for metal implants. Atomic layer deposition (ALD) is a method for producing nanoscale coatings conformally on complex three-dimensional surfaces. We have prepared hydroxyapatite (HA) coating on titanium (Ti) substrate with the ALD method and analyzed the biocompatibility of this coating in terms of cell adhesion and viability. Methods: HA coatings were prepared on Ti substrates by depositing CaCO3 films by ALD and converting them to HA by wet treatment in dilute phosphate solution. MC3T3-E1 preosteoblasts were cultured on ALD-HA, glass slides and bovine bone slices. ALD-HA and glass slides were either coated or non-coated with fibronectin. After 48 h culture, cells were imaged with scanning electron microscopy (SEM) and analyzed by vinculin antibody staining for focal adhesion localization. An 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) test was performed to study cell viability. Results: Vinculin staining revealed similar focal adhesion-like structures on ALD-HA as on glass slides and bone, albeit on ALD-HA and bone the structures were thinner compared to glass slides. This might be due to thin and broad focal adhesions on complex three-dimensional surfaces of ALD-HA and bone. The MTT test showed comparable cell viability on ALD-HA, glass slides and bone. Conclusion: ALD-HA coating was shown to be biocompatible in regard to cell adhesion and viability. This leads to new opportunities in developing improved implant coatings for better osseointegration and implant survival.
      Citation: Biomolecules
      PubDate: 2022-04-29
      DOI: 10.3390/biom12050654
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 655: Extracellular Alpha-Synuclein:
           Mechanisms for Glial Cell Internalization and Activation

    • Authors: Cecilia Chavarría, Rodrigo Ivagnes, José M. Souza
      First page: 655
      Abstract: Alpha-synuclein (α-syn) is a small protein composed of 140 amino acids and belongs to the group of intrinsically disordered proteins. It is a soluble protein that is highly expressed in neurons and expressed at low levels in glial cells. The monomeric protein aggregation process induces the formation of oligomeric intermediates and proceeds towards fibrillar species. These α-syn conformational species have been detected in the extracellular space and mediate consequences on surrounding neurons and glial cells. In particular, higher-ordered α-syn aggregates are involved in microglial and oligodendrocyte activation, as well as in the induction of astrogliosis. These phenomena lead to mitochondrial dysfunction, reactive oxygen and nitrogen species formation, and the induction of an inflammatory response, associated with neuronal cell death. Several receptors participate in cell activation and/or in the uptake of α-syn, which can vary depending on the α-syn aggregated state and cell types. The receptors involved in this process are of outstanding relevance because they may constitute potential therapeutic targets for the treatment of PD and related synucleinopathies. This review article focuses on the mechanism associated with extracellular α-syn uptake in glial cells and the consequent glial cell activation that contributes to the neuronal death associated with synucleinopathies.
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050655
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 656: What Is Parvalbumin for'

    • Authors: Eugene A. Permyakov, Vladimir N. Uversky
      First page: 656
      Abstract: Parvalbumin (PA) is a small, acidic, mostly cytosolic Ca2+-binding protein of the EF-hand superfamily. Structural and physical properties of PA are well studied but recently two highly conserved structural motifs consisting of three amino acids each (clusters I and II), which contribute to the hydrophobic core of the EF-hand domains, have been revealed. Despite several decades of studies, physiological functions of PA are still poorly known. Since no target proteins have been revealed for PA so far, it is believed that PA acts as a slow calcium buffer. Numerous experiments on various muscle systems have shown that PA accelerates the relaxation of fast skeletal muscles. It has been found that oxidation of PA by reactive oxygen species (ROS) is conformation-dependent and one more physiological function of PA in fast muscles could be a protection of these cells from ROS. PA is thought to regulate calcium-dependent metabolic and electric processes within the population of gamma-aminobutyric acid (GABA) neurons. Genetic elimination of PA results in changes in GABAergic synaptic transmission. Mammalian oncomodulin (OM), the β isoform of PA, is expressed mostly in cochlear outer hair cells and in vestibular hair cells. OM knockout mice lose their hearing after 3–4 months. It was suggested that, in sensory cells, OM maintains auditory function, most likely affecting outer hair cells’ motility mechanisms.
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050656
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 657: Insect Receptors: Biochemical,
           Physiological and Molecular Studies

    • Authors: Dov Borovsky
      First page: 657
      Abstract: A Biomolecules Special Issue on insect receptors was a great opportunity to invite colleagues from all over the world to contribute original articles and timely reviews on the subject [...]
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050657
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 658: Lung Hyaluronasome: Involvement of Low
           Molecular Weight Ha (Lmw-Ha) in Innate Immunity

    • Authors: Antony Hoarau, Myriam Polette, Christelle Coraux
      First page: 658
      Abstract: Hyaluronic acid (HA) is a major component of the extracellular matrix. It is synthesized by hyaluronan synthases (HAS) into high-molecular-weight chains (HMW-HA) that exhibit anti-inflammatory and immunomodulatory functions. In damaged, infected, and/or inflamed tissues, HMW-HA are degraded by hyaluronidases (HYAL) or reactive oxygen species (ROS) to give rise to low-molecular-weight HAs (LMW-HAs) that are potent pro-inflammatory molecules. Therefore, the size of HA regulates the balance of anti- or pro-inflammatory functions. The activities of HA depend also on its interactions with hyaladherins. HA synthesis, degradation, and activities through HA/receptors interactions define the hyaluronasome. In this review, a short overview of the role of high and low-molecular-weight HA polymers in the lungs is provided. The involvement of LMW-HA in pulmonary innate immunity via the activation of neutrophils, macrophages, dendritic cells, and epithelial cells is described to highlight LMW-HA as a therapeutic target in inflammatory respiratory diseases. Finally, the possibilities to counter LMW-HA’s deleterious effects in the lungs are discussed.
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050658
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 659: Regulation of Δ6Fads2 Gene
           Involved in LC-PUFA Biosynthesis Subjected to Fatty Acid in Large Yellow
           Croaker (Larimichthys Crocea) and Rainbow Trout (Oncorhynchus Mykiss)

    • Authors: Jie Sun, Jingqi Li, Yongnan Li, Jianlong Du, Nannan Zhao, Kangsen Mai, Qinghui Ai
      First page: 659
      Abstract: Δ6 fatty acyl desaturase (Δ6Fads2) is regarded as the first rate-limiting desaturase that catalyzes the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA) from 18-carbon fatty acid in vertebrates, but the underlying regulatory mechanism of fads2 has not been comprehensively understood. This study aimed to investigate the regulation role of fads2 subjected to fatty acid in large yellow croaker and rainbow trout. In vivo, large yellow croaker and rainbow trout were fed a fish oil (FO) diet, a soybean oil (SO) diet or a linseed oil (LO) diet for 10 weeks. The results show that LO and SO can significantly increase fads2 expression (p < 0.05). In vitro experiments were conducted in HEK293T cells or primary hepatocytes to determine the transcriptional regulation of fads2. The results show that CCAAT/enhancer-binding protein α (C/EBPα) can up-regulate fads2 expression. GATA binding protein 3 (GATA3) can up-regulate fads2 expression in rainbow trout but showed opposite effect in large yellow croaker. Furthermore, C/EBPα protein levels were significantly increased by LO and SO (p < 0.05), gata3 expression was increased in rainbow trout by LO but decreased in large yellow croaker by LO and SO. In conclusion, we revealed that FO replaced by LO and SO increased fads2 expression through a C/EBPα and GATA3 dependent mechanism in large yellow croaker and rainbow trout. This study might provide critical insights into the regulatory mechanisms of fads2 expression and LC-PUFA biosynthesis.
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050659
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 660: Silk Fibroin-Based Biomaterials for
           Hemostatic Applications

    • Authors: Md. Tipu Sultan, Heesun Hong, Ok Joo Lee, Olatunji Ajiteru, Young Jin Lee, Ji Seung Lee, Hanna Lee, Soon Hee Kim, Chan Hum Park
      First page: 660
      Abstract: Hemostasis plays an essential role in all surgical procedures. Uncontrolled hemorrhage is the primary cause of death during surgeries, and effective blood loss control can significantly reduce mortality. For modern surgeons to select the right agent at the right time, they must understand the mechanisms of action, the effectiveness, and the possible adverse effects of each agent. Over the past decade, various hemostatic agents have grown intensely. These agents vary from absorbable topical hemostats, including collagen, gelatins, microfibrillar, and regenerated oxidized cellulose, to biologically active topical hemostats such as thrombin, biological adhesives, and other combined agents. Commercially available products have since expanded to include topical hemostats, surgical sealants, and adhesives. Silk is a natural protein consisting of fibroin and sericin. Silk fibroin (SF), derived from silkworm Bombyx mori, is a fibrous protein that has been used mostly in fashion textiles and surgical sutures. Additionally, SF has been widely applied as a potential biomaterial in several biomedical and biotechnological fields. Furthermore, SF has been employed as a hemostatic agent in several studies. In this review, we summarize the several morphologic forms of SF and the latest technological advances on the use of SF-based hemostatic agents.
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050660
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 661: Hyperbaric Oxygen Therapy Improves
           Parkinson’s Disease by Promoting Mitochondrial Biogenesis via the
           SIRT-1/PGC-1α Pathway

    • Authors: Hung-Te Hsu, Ya-Lan Yang, Wan-Hsuan Chang, Wei-Yu Fang, Shu-Hung Huang, Shah-Hwa Chou, Yi-Ching Lo
      First page: 661
      Abstract: Hyperbaric oxygen therapy (HBOT) has been suggested as a potential adjunctive therapy for Parkinson’s disease (PD). PD is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The aim of this study was to investigate the protective mechanisms of HBOT on neurons and motor function in a 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and 1-methyl-4-phenylpyridinium (MPP+)-mediated neurotoxicity in SH-SY5Y cells on the potential protective capability. In vivo: male C57BL/6 mice were randomly divided into three groups: MPTP group, MPTP+HBOT group, and control. The MPTP-treated mice were intraperitoneally administered MPTP (20 mg/kg) four times at 2 h intervals each day. The day after MPTP treatment, MPTP+HBOT mice were exposed to hyperbaric oxygen at 2.5 atmosphere absolute (ATA) with 100% oxygen for 1 h once daily for 7 consecutive days. In vitro: retinoic acid (RA)-differentiated SH-SY5Y cells were treated with MPP+ for 1 h followed by hyperbaric oxygen at 2.5 ATA with 100% oxygen for 1 h. The results showed that MPTP induced a significant loss in tyrosine hydroxylase (TH)-positive neurons in the SNpc of mice. HBOT treatment significantly increased the number of TH-positive neurons, with enhanced neurotrophic factor BDNF, decreased apoptotic signaling and attenuated inflammatory mediators in the midbrain of MPTP-treated mice. In addition, MPTP treatment decreased the locomotor activity and grip strength of mice, and these effects were shown to improve after HBOT treatment. Furthermore, MPTP decreased mitochondrial biogenesis signaling (SIRT-1, PGC-1α and TFAM), as well as mitochondrial marker VDAC expression, while HBOT treatment was shown to upregulate protein expression. In cell experiments, MPP+ reduced neurite length, while HBOT treatment attenuated neurite retraction. Conclusions: the effects of HBOT in MPTP-treated mice might come from promoting mitochondrial biogenesis, decreasing apoptotic signaling and attenuating inflammatory mediators in the midbrain, suggesting its potential benefits in PD treatment.
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050661
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 662: Paradoxical Behavior of Oncogenes
           Undermines the Somatic Mutation Theory

    • Authors: Noemi Monti, Roberto Verna, Aurora Piombarolo, Alessandro Querqui, Mariano Bizzarri, Valeria Fedeli
      First page: 662
      Abstract: The currently accepted theory on the influence of DNA mutations on carcinogenesis (the Somatic Mutation Theory, SMT) is facing an increasing number of controversial results that undermine the explanatory power of mutated genes considered as “causative” factors. Intriguing results have demonstrated that several critical genes may act differently, as oncogenes or tumor suppressors, while phenotypic reversion of cancerous cells/tissues can be achieved by modifying the microenvironment, the mutations they are carrying notwithstanding. Furthermore, a high burden of mutations has been identified in many non-cancerous tissues without any apparent pathological consequence. All things considered, a relevant body of unexplained inconsistencies calls for an in depth rewiring of our theoretical models. Ignoring these paradoxes is no longer sustainable. By avoiding these conundrums, the scientific community will deprive itself of the opportunity to achieve real progress in this important biomedical field. To remedy this situation, we need to embrace new theoretical perspectives, taking the cell–microenvironment interplay as the privileged pathogenetic level of observation, and by assuming new explanatory models based on truly different premises. New theoretical frameworks dawned in the last two decades principally focus on the complex interaction between cells and their microenvironment, which is thought to be the critical level from which carcinogenesis arises. Indeed, both molecular and biophysical components of the stroma can dramatically drive cell fate commitment and cell outcome in opposite directions, even in the presence of the same stimulus. Therefore, such a novel approach can help in solving apparently inextricable paradoxes that are increasingly observed in cancer biology.
      Citation: Biomolecules
      PubDate: 2022-04-30
      DOI: 10.3390/biom12050662
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 663: Exosomes Derived from BM-MSCs Mitigate
           the Development of Chronic Kidney Damage Post-Menopause via Interfering
           with Fibrosis and Apoptosis

    • Authors: Wardah A. Alasmari, Ahmed Abdelfattah-Hassan, Hanaa M. El-Ghazali, Samar A. Abdo, Doaa Ibrahim, Naser A. ElSawy, Eman S. El-Shetry, Ayman A. Saleh, Mohammed A. S. Abourehab, Hala Mahfouz
      First page: 663
      Abstract: The rate of chronic kidney disease (CKD) is increasing globally, and it is caused by continuous damage to kidney tissue. With time the renal damage becomes irreversible, leading to CKD development. In females, post-menopause lack of estrogen supply has been described as a risk factor for CKD development, and studies targeting post-menopause CKD are scarce. In the present study, we used exosomes isolated from bone marrow mesenchymal stem/stromal cells (BM-MSCs) to test their therapeutic potential against the development of CKD. At first, the menopause model was achieved by surgical bilateral ovariectomy in female albino rats. After that, 100 µg of exosomes was given to ovariectomized rats, and the study continued for 2 months. Changes in urine volume, urine protein content, kidney function biochemical parameters (creatinine and BUN), kidney antioxidant parameters (SOD, GPx and CAT), histological changes, immunohistochemical levels of caspase 3, and the gene expression of NGAL (related to kidney damage), TGFβ1 and αSMA (related to fibrosis and EMT), and caspase 3 (related to apoptosis) were studied. After the ovariectomy, the occurrence of CKD was confirmed in the rats by the drastic reduction of serum estrogen and progesterone levels, reduced urine output, increased urinary protein excretion, elevated serum creatinine and BUN, reduced GPx SOD, and CAT in kidney tissue, degenerative and fibrotic lesions in the histopathological examination, higher immunohistochemical expression of caspase 3 and increased expression of all studied genes. After exosomes administration, the entire chronic inflammatory picture in the kidney was corrected, and a near-normal kidney structure and function were attained. This study shows for the first time that BM-MSCs exosomes are potent for reducing apoptosis and fibrosis levels and, thus, can reduce the chronic damage of the kidneys in females that are in their menopause period. Therefore, MSCs-derived exosomes should be considered a valuable therapy for preserving postmenopausal kidney structure and function and, subsequently, could improve the quality of females’ life during menopause.
      Citation: Biomolecules
      PubDate: 2022-05-02
      DOI: 10.3390/biom12050663
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 664: Are There Betel Quid Mixtures Less
           Harmful Than Others' A Scoping Review of the Association between
           Different Betel Quid Ingredients and the Risk of Oral Submucous Fibrosis

    • Authors: Nicola Cirillo, Peter Hung Duong, Wee Teng Er, Casey Thao Nhi Do, Manikkuwadura Eranda Harshan De De Silva, Yining Dong, Sok Ching Cheong, Elizabeth Fitriana Sari, Michael J. McCullough, Pangzhen Zhang, Stephen S. Prime
      First page: 664
      Abstract: Oral submucous fibrosis (OSF) is a potentially malignant condition of the oral cavity characterized by progressive fibrosis of the submucosal tissues. OSF is typically associated with the use of betel quid (BQ), a chewing package made of natural products (e.g., areca nut, betel leaves), with or without smokeless tobacco. BQ ingredients contain pro-carcinogenic bioactive compounds, but also potentially protective biomolecules, and we have shown recently that the chemical properties of different BQ recipes vary, which may explain the unequal prevalence of OSF and oral cancer in BQ users in different geographical regions. Hence, this scoping review was aimed at evaluating the existing literature regarding different BQ compounds and their association with OSF. The repository of the National Library of Medicine (MEDLINE/PubMed), medRxiv databases, Google scholar, Baidu scholar, CNKI, and EBSCO were used to search for publications that investigated the association between BQ chewing and OSF up to November 2021. The search terminology was constructed using the keywords “betel quid” and “oral submucous fibrosis”, and their associated terms, with the use of Boolean operators. The search was conducted under Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, together with clear inclusion and exclusion criteria. The review showed that the risk of developing OSF varied between different BQ recipes, and that chewing BQ mixtures containing betel inflorescence (BI) significantly increased the risk of OSF, as did the addition of tobacco. Conversely, the use of betel leaf in the mixture was likely to be protective, which may be due to the presence of polyphenols. Although further research is needed to determine the effect of individual BQ ingredients in the development of OSF, our pilot results provide the scope and rationale for informing future chemopreventive strategies for OSF and oral cancer in BQ chewers.
      Citation: Biomolecules
      PubDate: 2022-05-02
      DOI: 10.3390/biom12050664
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 665: Multiple Mutations in the Non-Ordered
           Red Ω-Loop Enhance the Membrane-Permeabilizing and Peroxidase-like
           Activity of Cytochrome c

    • Authors: Rita V. Chertkova, Alexander M. Firsov, Nadezda A. Brazhe, Evelina I. Nikelshparg, Zhanna V. Bochkova, Tatyana V. Bryantseva, Marina A. Semenova, Adil A. Baizhumanov, Elena A. Kotova, Mikhail P. Kirpichnikov, Georgy V. Maksimov, Yuriy N. Antonenko, Dmitry A. Dolgikh
      First page: 665
      Abstract: A key event in the cytochrome c-dependent apoptotic pathway is the permeabilization of the outer mitochondrial membrane, resulting in the release of various apoptogenic factors, including cytochrome c, into the cytosol. It is believed that the permeabilization of the outer mitochondrial membrane can be induced by the peroxidase activity of cytochrome c in a complex with cardiolipin. Using a number of mutant variants of cytochrome c, we showed that both substitutions of Lys residues from the universal binding site for oppositely charged Glu residues and mutations leading to a decrease in the conformational mobility of the red Ω-loop in almost all cases did not affect the ability of cytochrome c to bind to cardiolipin. At the same time, the peroxidase activity of all mutant variants in a complex with cardiolipin was three to five times higher than that of the wild type. A pronounced increase in the ability to permeabilize the lipid membrane in the presence of hydrogen peroxide, as measured by calcein leakage from liposomes, was observed only in the case of four substitutions in the red Ω-loop (M4 mutant). According to resonance and surface-enhanced Raman spectroscopy, the mutations caused significant changes in the heme of oxidized cytochrome c molecules resulting in an increased probability of the plane heme conformation and the enhancement of the rigidity of the protein surrounding the heme. The binding of wild-type and mutant forms of oxidized cytochrome c to cardiolipin-containing liposomes caused the disordering of the acyl lipid chains that was more pronounced for the M4 mutant. Our findings indicate that the Ω-loop is important for the pore formation in cardiolipin-containing membranes.
      Citation: Biomolecules
      PubDate: 2022-05-04
      DOI: 10.3390/biom12050665
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 666: Microglia Depletion from Primary Glial
           Cultures Enables to Accurately Address the Immune Response of Astrocytes

    • Authors: Mariana Van Zeller, Ana M. Sebastião, Cláudia A. Valente
      First page: 666
      Abstract: Astrocytes are the most abundant cells in the CNS parenchyma and play an essential role in several brain functions, such as the fine-tuning of synaptic transmission, glutamate uptake and the modulation of immune responses, among others. Much of the knowledge on the biology of astrocytes has come from the study of rodent primary astrocytic cultures. Usually, the culture is a mixed population of astrocytes and a small proportion of microglia. However, it is critical to have a pure culture of astrocytes if one wants to address their inflammatory response. If present, microglia sense the stimulus, rapidly proliferate and react to it, making it unfeasible to assess the individual responsiveness of astrocytes. Microglia have been efficiently eliminated in vivo through PLX-3397, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor. In this work, the effectiveness of PLX-3397 in eradicating microglia from primary mixed glial cultures was evaluated. We tested three concentrations of PLX-3397—0.2 μM, 1 μM and 5 μM—and addressed its impact on the culture yield and viability of astrocytes. PLX-3397 is highly efficient in eliminating microglia without affecting the viability or response of cultured astrocytes. Thus, these highly enriched monolayers of astrocytes allow for the more accurate study of their immune response in disease conditions.
      Citation: Biomolecules
      PubDate: 2022-05-04
      DOI: 10.3390/biom12050666
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 667: Effects of Palmitoylethanolamide on
           Neurodegenerative Diseases: A Review from Rodents to Humans

    • Authors: Eugenia Landolfo, Debora Cutuli, Laura Petrosini, Carlo Caltagirone
      First page: 667
      Abstract: Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different types of neuropathic pain, such as fibromyalgia, osteoarthritis, carpal tunnel syndrome, and many other conditions. The properties of PEA, especially of its micronized or ultra-micronized forms maximizing bioavailability and efficacy, have sparked a series of innovative research to evaluate its possible application as therapeutic agent for neurodegenerative diseases. Neurodegenerative diseases are widespread throughout the world, and although they are numerous and different, they share common patterns of conditions that result from progressive damage to the brain areas involved in mobility, muscle coordination and strength, mood, and cognition. The present review is aimed at illustrating in vitro and in vivo research, as well as human studies, using PEA treatment, alone or in combination with other compounds, in the presence of neurodegeneration. Namely, attention has been paid to the effects of PEA in counteracting neuroinflammatory conditions and in slowing down the progression of diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. Literature research demonstrated the efficacy of PEA in addressing the damage typical of major neurodegenerative diseases.
      Citation: Biomolecules
      PubDate: 2022-05-05
      DOI: 10.3390/biom12050667
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 668: Alanine–Glyoxylate
           Aminotransferase Sustains Cancer Stemness Properties through the
           Upregulation of SOX2 and OCT4 in Hepatocellular Carcinoma Cells

    • Authors: Peng Ye, Xiaoxia Chi, Xiuwen Yan, Fangqin Wu, Zhigang Liang, Wen-Hao Yang
      First page: 668
      Abstract: Liver cancer stem cells (LCSCs) are a small subset of oncogenic cells with a self-renewal ability and drug resistance, and they promote the recurrence and metastasis of hepatocellular carcinoma (HCC). However, the mechanisms regulating LCSCs have not been fully explored. By enriching LCSCs from spheroid cultures and performing transcriptomic analysis, we determined that alanine–glyoxylate aminotransferase (AGXT), which participates in the metabolism of serine and glycine, was significantly upregulated in spheroid cultures, and its function in LCSCs remains unknown. Through the exogenous overexpression or short hairpin RNA knockdown of AGXT in HCC cells, we observed that changes in the AGXT level did not affect the spheroid ability and population of LCSCs. The knockdown of AGXT in LCSCs reduced the number of spheroids and the population of LCSCs; this implies that AGXT is required for the maintenance of cancer stemness rather than as a driver of LCSCs. Mechanistically, AGXT may sustain the self-renewal potential of LCSCs by upregulating the expression of SRY-box transcription factor 2 (SOX2) and octamer-binding transcription factor 4 (OCT4), two well-known master regulators of cancer stemness. Taken together, our study demonstrates the role of AGXT in supporting LCSCs; thus, AGXT merits further exploration.
      Citation: Biomolecules
      PubDate: 2022-05-05
      DOI: 10.3390/biom12050668
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 669: Intracellular and Extracellular

    • Authors: Sreter, Foxall, Varga
      First page: 669
      Abstract: Cell cryopreservation is an essential part of the biotechnology, food, and health care industries. There is a need to develop more effective, less toxic cryoprotective agents (CPAs) and methods, especially for mammalian cells. We investigated the impact of an insect antifreeze protein from Anatolica polita (ApAFP752) on mammalian cell cryopreservation using the human embryonic kidney cell line HEK 293T. An enhanced green fluorescent protein (EGFP)-tagged antifreeze protein, EGFP–ApAFP752, was transfected into the cells and the GFP was used to determine the efficiency of transfection. AFP was assessed for its cryoprotective effects intra- and extracellularly and both simultaneously at different concentrations with and without dimethyl sulfoxide (DMSO) at different concentrations. Comparisons were made to DMSO or medium alone. Cells were cryopreserved at −196 °C for ≥4 weeks. Upon thawing, cellular viability was determined using trypan blue, cellular damage was assessed by lactate dehydrogenase (LDH) assay, and cellular metabolism was measured using a metabolic activity assay (MTS). The use of this AFP significantly improved cryopreserved cell survival when used with DMSO intracellularly. Extracellular AFP also significantly improved cell survival when included in the DMSO freezing medium. Intra- and extracellular AFP used together demonstrated the most significantly increased cryoprotection compared to DMSO alone. These findings present a potential method to improve the viability of cryopreserved mammalian cells.
      Citation: Biomolecules
      PubDate: 2022-05-05
      DOI: 10.3390/biom12050669
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 670: CAST as a Potential Oncogene, Identified
           by Machine Search, in Gastric Cancer Infiltrated with Macrophages and
           Associated with Lgr5

    • Authors: Kuang-Tsu Yang, Chia-Chi Yen, Renin Chang, Jui-Tzu Wang, Jin-Shuen Chen
      First page: 670
      Abstract: Background: Gastric cancer (GC) is one of the leading malignant diseases worldwide, especially in Asia. CAST is a potential oncogene in GC carcinogenesis. The character of macrophage infiltration in the GC microenvironment also remains unaddressed. Methods: We first applied machine searching to evaluate gene candidates for GC. CAST expression and pan-cancer surveyance were analyzed using the Human Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database. The protein–protein interaction (PPI) network was downloaded from STRING. We investigated the impact of CAST on clinical prognosis using a Kaplan–Meier plotter. The correlations between CAST and Lgr5 and macrophage infiltration in GC were determined using TIMER 2.0. Finally, GeneMANIA was also used to evaluate the possible functional linkages between genes. Results: After the machine-assisted search, CAST expression was found to significantly influence the overall survival of GC patients. STRING revealed CAST-related proteomic and transcriptomic associations, mainly concerning the CAPN family. Moreover, CAST significantly impacts the prognosis of GC based on the validation of other datasets. Notably, high CAST expression was correlated with worse overall survival in GC patients (hazard ratio = 1.59; log-rank P = 9.4 × 10−8). CAST and Lgr5 expression were both positively correlated with WNT 2 and WNT 2B. Among the GC patients in several datasets, CAST and macrophage infiltration, evaluated together, showed no obvious association with poor clinical overall survival. Conclusions: CAST plays an important role in the clinical prognosis of GC and is associated with WNT 2/WNT 2B/Lgr5. Our study demonstrates that CAST’s influence on overall survival in GC is regulated by macrophage infiltration.
      Citation: Biomolecules
      PubDate: 2022-05-06
      DOI: 10.3390/biom12050670
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 671: ADP-Induced Conformational Transition of
           Human Adenylate Kinase 1 Is Triggered by Suppressing Internal Motion of
           α3α4 and α7α8 Fragments on the ps-ns Timescale

    • Authors: Chenyun Guo, Haoran Zhang, Weiliang Lin, Hanyu Chen, Ting Chang, Zhihua Wu, Jiaxin Yu, Donghai Lin
      First page: 671
      Abstract: Human adenylate kinase 1 (hAK1) plays a vital role in the energetic and metabolic regulation of cell life, and impaired functions of hAK1 are closely associated with many diseases. In the presence of Mg2+ ions, hAK1 in vivo can catalyze two ADP molecules into one ATP and one AMP molecule, activating the downstream AMP signaling. The ADP-binding also initiates AK1 transition from an open conformation to a closed conformation. However, how substrate binding triggers the conformational transition of hAK1 is still unclear, and the underlying molecular mechanisms remain elusive. Herein, we determined the solution structure of apo-hAK1 and its key residues for catalyzing ADP, and characterized backbone dynamics characteristics of apo-hAK1 and hAK1-Mg2+-ADP complex (holo-hAK1) using NMR relaxation experiments. We found that ADP was primarily bound to a cavity surrounded by the LID, NMP, and CORE domains of hAK1, and identified several critical residues for hAK1 catalyzing ADP including G16, G18, G20, G22, T39, G40, R44, V67, D93, G94, D140, and D141. Furthermore, we found that apo-hAK1 adopts an open conformation with significant ps-ns internal mobility, and Mg2+-ADP binding triggered conformational transition of hAK1 by suppressing the ps-ns internal motions of α3α4 in the NMP domain and α7α8 in the LID domain. Both α3α4 and α7α8 fragments became more rigid so as to fix the substrate, while the catalyzing center of hAK1 experiences promoted µs-ms conformational exchange, potentially facilitating catalysis reaction and conformational transition. Our results provide the structural basis of hAK1 catalyzing ADP into ATP and AMP, and disclose the driving force that triggers the conformational transition of hAK1, which will deepen understanding of the molecular mechanisms of hAK1 functions.
      Citation: Biomolecules
      PubDate: 2022-05-06
      DOI: 10.3390/biom12050671
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 672: Role of TFEB in Autophagy and the
           Pathogenesis of Liver Diseases

    • Authors: Shengmin Yan
      First page: 672
      Abstract: The transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. Mechanistic target of rapamycin (mTOR)-mediated phosphorylation on TFEB is known to regulate TFEB subcellular localization and activity at the lysosomal surface. Recent studies have shown that TFEB also plays a critical role in physiological processes such as lipid metabolism, and dysfunction of TFEB has been observed in the pathogenesis of several diseases. Owing to its ability to improve disease status in murine models, TFEB has attracted attention as a therapeutic target for diseases. In this review, we will present the regulation of TFEB and its role in the pathogenesis of liver diseases, particularly non-alcoholic fatty liver disease (NAFLD).
      Citation: Biomolecules
      PubDate: 2022-05-06
      DOI: 10.3390/biom12050672
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 673: Loricrin at the Boundary between Inside
           and Outside

    • Authors: Yosuke Ishitsuka, Dennis R. Roop
      First page: 673
      Abstract: Cornification is a specialized mode of the cell-death program, exclusively, and is allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name (“lorica” meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes the maturation of the epidermal structure through organizing covalent cross-linkages, endowing the epidermis with the protection against oxidative injuries. By reviewing cornification mechanisms, we seek to classify ichthyosiform dermatoses based on their function, rather than clinical manifestations. We also reviewed recent mechanistic insights into the Kelch-like erythroid cell-derived protein with the cap “n” collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in skin health and diseases, as LOR and NRF2 coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of cross-talking between keratinocytes and epidermal resident leukocytes, dissecting an LOR immunomodulatory function.
      Citation: Biomolecules
      PubDate: 2022-05-06
      DOI: 10.3390/biom12050673
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 674: Th17-Dependent Nasal Hyperresponsiveness
           Is Mitigated by Steroid Treatment

    • Authors: Ueda, Miura, Kawasaki, Ogata, Yamasaki, Miura, Mori, Kaminuma
      First page: 674
      Abstract: Th17 cells are implicated in allergic inflammatory diseases, including allergic rhinitis (AR), though the effect of steroids on Th17 cell-dependent nasal responses is unclear. Herein, we investigated a nasal inflammation model elicited by allergen provocation in mice infused with Th17 cells and its responsiveness against steroid treatment. We transferred BALB/c mice with Th17 cells, which were differentiated in vitro and showed a specific reaction to ovalbumin (OVA). We challenged the transferred mice by intranasal injection of OVA and to some of them, administered dexamethasone (Dex) subcutaneously in advance. Then, we assessed immediate nasal response (INR), nasal hyperresponsiveness (NHR), and inflammatory cell infiltration into the nasal mucosa. The significant nasal inflammatory responses with massive neutrophil accumulation, INR, and NHR were induced upon allergen challenge. Allergen-induced INR and NHR were significantly suppressed by Dex treatment. This study suggested the effectiveness of steroids on Th17 cell-mediated nasal responses in AR.
      Citation: Biomolecules
      PubDate: 2022-05-06
      DOI: 10.3390/biom12050674
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 675: Impacts of Bacteriostatic and
           Bactericidal Antibiotics on the Mitochondria of the Age-Related Macular
           Degeneration Cybrid Cell Lines

    • Authors: Nasim Salimiaghdam, Lata Singh, Mithalesh K. Singh, Marilyn Chwa, Shari R. Atilano, Zahra Mohtashami, Anthony B. Nesburn, Baruch D. Kuppermann, Stephanie Y. Lu, M. Cristina Kenney
      First page: 675
      Abstract: We assessed the potential negative effects of bacteriostatic and bactericidal antibiotics on the AMD cybrid cell lines (K, U and J haplogroups). AMD cybrid cells were created and cultured in 96-well plates and treated with tetracycline (TETRA) and ciprofloxacin (CPFX) for 24 h. Reactive oxygen species (ROS) levels, mitochondrial membrane potential (ΔψM), cellular metabolism and ratio of apoptotic cells were measured using H2DCFDA, JC1, MTT and flow cytometry assays, respectively. Expression of genes of antioxidant enzymes, and pro-inflammatory and pro-apoptotic pathways were evaluated by quantitative real-time PCR (qRT-PCR). Higher ROS levels were found in U haplogroup cybrids when treated with CPFX 60 µg/mL concentrations, lower ΔψM of all haplogroups by CPFX 120 µg/mL, diminished cellular metabolism in all cybrids with CPFX 120 µg/mL, and higher ratio of dead cells in K and J cybrids. CPFX 120 µg/mL induced overexpression of IL-33, CASP-3 and CASP-9 in all cybrids, upregulation of TGF-β1 and SOD2 in U and J cybrids, respectively, along with decreased expression of IL-6 in J cybrids. TETRA 120 µg/mL induced decreased ROS levels in U and J cybrids, increased cellular metabolism of treated U cybrids, higher ratio of dead cells in K and J cybrids and declined ΔψM via all TETRA concentrations in all haplogroups. TETRA 120 µg/mL caused upregulation of IL-6 and CASP-3 genes in all cybrids, higher CASP-7 gene expression in K and U cybrids and downregulation of the SOD3 gene in K and U cybrids. Clinically relevant dosages of ciprofloxacin and tetracycline have potential adverse impacts on AMD cybrids possessing K, J and U mtDNA haplogroups in vitro.
      Citation: Biomolecules
      PubDate: 2022-05-07
      DOI: 10.3390/biom12050675
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 676: Dietary Soy Prevents Alcohol-Mediated
           Neurocognitive Dysfunction and Associated Impairments in Brain Insulin
           Pathway Signaling in an Adolescent Rat Model

    • Authors: Ming Tong, Jason L. Ziplow, Princess Mark, Suzanne M. de la Monte
      First page: 676
      Abstract: Background: Alcohol-related brain degeneration is linked to cognitive-motor deficits and impaired signaling through insulin/insulin-like growth factor type 1 (IGF-1)-Akt pathways that regulate cell survival, plasticity, metabolism, and homeostasis. In addition, ethanol inhibits Aspartyl-asparaginyl-β-hydroxylase (ASPH), a downstream target of insulin/IGF-1-Akt signaling and an activator of Notch networks. Previous studies have suggested that early treatment with insulin sensitizers or dietary soy could reduce or prevent the long-term adverse effects of chronic ethanol feeding. Objective: The goal of this study was to assess the effects of substituting soy isolate for casein to prevent or reduce ethanol’s adverse effects on brain structure and function. Methods: Young adolescent male and female Long Evans were used in a 4-way model as follows: Control + Casein; Ethanol + Casein; Control + Soy; Ethanol + Soy; Control = 0% ethanol; Ethanol = 26% ethanol (caloric). Rats were fed isocaloric diets from 4 to 11 weeks of age. During the final experimental week, the Morris Water maze test was used to assess spatial learning (4 consecutive days), after which the brains were harvested to measure the temporal lobe expression of the total phospho-Akt pathway and downstream target proteins using multiplex bead-based enzyme-linked immunosorbent assays (ELISAs) and duplex ELISAs. Results: Ethanol inhibited spatial learning and reduced brain weight, insulin signaling through Akt, and the expression of ASPH when standard casein was provided as the protein source. The substitution of soy isolate for casein largely abrogated the adverse effects of chronic ethanol feeding. In contrast, Notch signaling protein expression was minimally altered by ethanol or soy isolate. Conclusions: These novel findings suggest that the insulin sensitizer properties of soy isolate may prevent some of the adverse effects that chronic ethanol exposure has on neurobehavioral function and insulin-regulated metabolic pathways in adolescent brains.
      Citation: Biomolecules
      PubDate: 2022-05-08
      DOI: 10.3390/biom12050676
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 677: Inter-Laboratory Concordance of
           Cerebrospinal Fluid and Serum Kappa Free Light Chain Measurements

    • Authors: Patrizia Natali, Roberta Bedin, Gaetano Bernardi, Elena Corsini, Eleonora Cocco, Lucia Schirru, Ilaria Crespi, Marta Lamonaca, Arianna Sala, Cinzia Nicolò, Massimiliano Di Filippo, Alfredo Villa, Viviana Nociti, Teresa De Michele, Paola Cavalla, Paola Caropreso, Francesca Vitetta, Maria Rosaria Cucinelli, Matteo Gastaldi, Tommaso Trenti, Patrizia Sola, Diana Ferraro, on behalf of RIREMS (Rising Researchers in MS) on behalf of RIREMS (Rising Researchers in MS)
      First page: 677
      Abstract: The kappa index (K-Index), calculated by dividing the cerebrospinal fluid (CSF)/serum kappa free light chain (KFLC) ratio by the CSF/serum albumin ratio, is gaining increasing interest as a marker of intrathecal immunoglobulin synthesis. However, data on inter-laboratory agreement of these measures is lacking. The aim was to assess the concordance of CSF and serum KFLC measurements, and of K-index values, across different laboratories. KFLC and albumin of 15 paired CSF and serum samples were analyzed by eight participating laboratories. Four centers used Binding Site instruments and assays (B), three used Siemens instruments and assays (S), and one center used a Siemens instrument with a Binding Site assay (mixed). Absolute individual agreement was calculated using a two-way mixed effects intraclass correlation coefficient (ICC). Cohen’s kappa coefficient (k) was used to measure agreement on positive (≥5.8) K-index values. There was an excellent agreement in CSF KFLC measurements across all laboratories (ICC (95% confidence interval): 0.93 (0.87–0.97)) and of serum KFLC across B and S laboratories (ICC: 0.91 (0.73–0.97)), while ICC decreased (to 0.81 (0.53–0.93)) when including the mixed laboratory in the analysis. Concordance for a positive K-Index was substantial across all laboratories (k = 0.77) and within S laboratories (k = 0.71), and very good (k = 0.89) within B laboratories, meaning that patients rarely get discordant results on K-index positivity notwithstanding the testing in different laboratories and the use of different platforms/assays.
      Citation: Biomolecules
      PubDate: 2022-05-07
      DOI: 10.3390/biom12050677
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 678: The Functional Interplay between
           Ethylene, Hydrogen Sulfide, and Sulfur in Plant Heat Stress Tolerance

    • Authors: Zebus Sehar, Harsha Gautam, Noushina Iqbal, Ameena Fatima Alvi, Badar Jahan, Mehar Fatma, Mohammed Albaqami, Nafees A. Khan
      First page: 678
      Abstract: Plants encounter several abiotic stresses, among which heat stress is gaining paramount attention because of the changing climatic conditions. Severe heat stress conspicuously reduces crop productivity through changes in metabolic processes and in growth and development. Ethylene and hydrogen sulfide (H2S) are signaling molecules involved in defense against heat stress through modulation of biomolecule synthesis, the antioxidant system, and post-translational modifications. Other compounds containing the essential mineral nutrient sulfur (S) also play pivotal roles in these defense mechanisms. As biosynthesis of ethylene and H2S is connected to the S-assimilation pathway, it is logical to consider the existence of a functional interplay between ethylene, H2S, and S in relation to heat stress tolerance. The present review focuses on the crosstalk between ethylene, H2S, and S to highlight their joint involvement in heat stress tolerance.
      Citation: Biomolecules
      PubDate: 2022-05-08
      DOI: 10.3390/biom12050678
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 679: Utilizing the LoxP-Stop-LoxP System to
           Control Transgenic ABC-Transporter Expression In Vitro

    • Authors: Ikechukwu Esobi, Oladosu Olanrewaju, Jing Echesabal-Chen, Alexis Stamatikos
      First page: 679
      Abstract: ABCA1 and ABCG1 are two ABC-transporters well-recognized to promote the efflux of cholesterol to apoAI and HDL, respectively. As these two ABC-transporters are critical to cholesterol metabolism, several studies have assessed the impact of ABCA1 and ABCG1 expression on cellular cholesterol homeostasis through ABC-transporter ablation or overexpressing ABCA1/ABCG1. However, for the latter, there are currently no well-established in vitro models to effectively induce long-term ABC-transporter expression in a variety of cultured cells. Therefore, we performed proof-of-principle in vitro studies to determine whether a LoxP-Stop-LoxP (LSL) system would provide Cre-inducible ABC-transporter expression. In our studies, we transfected HEK293 cells and the HEK293-derived cell line 293-Cre cells with ABCA1-LSL and ABCG1-LSL-based plasmids. Our results showed that while the ABCA1/ABCG1 protein expression was absent in the transfected HEK293 cells, the ABCA1 and ABCG1 protein expression was detected in the 293-Cre cells transfected with ABCA1-LSL and ABCG1-LSL, respectively. When we measured cholesterol efflux in transfected 293-Cre cells, we observed an enhanced apoAI-mediated cholesterol efflux in 293-Cre cells overexpressing ABCA1, and an HDL2-mediated cholesterol efflux in 293-Cre cells constitutively expressing ABCG1. We also observed an appreciable increase in HDL3-mediated cholesterol efflux in ABCA1-overexpressing 293-Cre cells, which suggests that ABCA1 is capable of effluxing cholesterol to small HDL particles. Our proof-of-concept experiments demonstrate that the LSL-system can be used to effectively regulate ABC-transporter expression in vitro, which, in turn, allows ABCA1/ABCG1-overexpression to be extensively studied at the cellular level.
      Citation: Biomolecules
      PubDate: 2022-05-08
      DOI: 10.3390/biom12050679
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 680: Obesogens in Foods

    • Authors: Iva Kladnicka, Monika Bludovska, Iveta Plavinova, Ludek Muller, Dana Mullerova
      First page: 680
      Abstract: Obesogens, as environmental endocrine-disrupting chemicals, are supposed to have had an impact on the prevalence of rising obesity around the world over the last forty years. These chemicals are probably able to contribute not only to the development of obesity and metabolic disturbances in individuals, but also in their progeny, having the capability to epigenetically reprogram genetically inherited set-up points for body weight and body composition control during critical periods of development, such as fetal, early life, and puberty. In individuals, they may act on myriads of neuro-endocrine–immune metabolic regulatory pathways, leading to pathophysiological consequences in adipogenesis, lipogenesis, lipolysis, immunity, the influencing of central appetite and energy expenditure regulations, changes in gut microbiota–intestine functioning, and many other processes. Evidence-based medical data have recently brought much more convincing data about associations of particular chemicals and the probability of the raised risk of developing obesity. Foods are the main source of obesogens. Some obesogens occur naturally in food, but most are environmental chemicals, entering food as a foreign substance, whether in the form of contaminants or additives, and they are used in a large amount in highly processed food. This review article contributes to a better overview of obesogens, their occurrence in foods, and their impact on the human organism.
      Citation: Biomolecules
      PubDate: 2022-05-09
      DOI: 10.3390/biom12050680
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 681: Co-Occurrence of Interleukin-6 Receptor
           Asp358Ala Variant and High Plasma Levels of IL-6: An Evidence of IL-6
           Trans-Signaling Activation in Deep Vein Thrombosis (DVT) Patients

    • Authors: Rossella Salemi, Giuseppe Gattuso, Barbara Tomasello, Alessandro Lavoro, Agostino Gaudio, Massimo Libra, Salvatore Santo Signorelli, Saverio Candido
      First page: 681
      Abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine involved in several mechanisms, and the alteration of IL-6 signaling leads to the overactivation of various processes including immunity, inflammation, and hemostasis. Although IL-6 increase has been documented in venous thromboembolic diseases, the exact involvement of IL-6 signaling in deep vein thrombosis (DVT) has not been fully understood. Consequently, we investigated the involvement of IL-6 trans-signaling in inflammatory events occurring in DVT, focusing on the role of the interleukin-6 receptor (IL6-R) Asp358Ala variant. The circulating levels of IL-6, soluble IL6-R (sIL6-R), and soluble glycoprotein 130, as well as the Asp358Ala genotyping, were assessed in a consecutive cohort of DVT patients and healthy controls. The results indicated that IL-6 was higher in DVT compared to controls. Moreover, sIL6-R levels were strongly correlated to Asp358Ala variant in both groups, showing a high frequency of this mutation across all samples. Interestingly, our results showed a high frequency of both Asp358Ala mutation and raised IL-6 levels in DVT patients (OR = 21.32; p ≤ 0.01), highlighting that this mutation could explain the association between IL-6 overactivation and DVT outcome. Overall, this study represents a proof of concept for the targeting of IL-6 trans-signaling as a new strategy for the DVT adjuvant therapy.
      Citation: Biomolecules
      PubDate: 2022-05-10
      DOI: 10.3390/biom12050681
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 682: Comparative Analysis of rRNA Removal
           Methods for RNA-Seq Differential Expression in Halophilic Archaea

    • Authors: Mar Martinez Pastor, Saaz Sakrikar, Deyra N. Rodriguez, Amy K. Schmid
      First page: 682
      Abstract: Despite intense recent research interest in archaea, the scientific community has experienced a bottleneck in the study of genome-scale gene expression experiments by RNA-seq due to the lack of commercial and specifically designed rRNA depletion kits. The high rRNA:mRNA ratio (80–90%: ~10%) in prokaryotes hampers global transcriptomic analysis. Insufficient ribodepletion results in low sequence coverage of mRNA, and therefore, requires a substantially higher number of replicate samples and/or sequencing reads to achieve statistically reliable conclusions regarding the significance of differential gene expression between case and control samples. Here, we show that after the discontinuation of the previous version of RiboZero (Illumina, San Diego, CA, USA) that was useful in partially or completely depleting rRNA from archaea, archaeal transcriptomics studies have experienced a slowdown. To overcome this limitation, here, we analyze the efficiency for four different hybridization-based kits from three different commercial suppliers, each with two sets of sequence-specific probes to remove rRNA from four different species of halophilic archaea. We conclude that the key for transcriptomic success with the currently available tools is the probe-specificity for the rRNA sequence hybridization. With this paper, we provide insights into the archaeal community for selecting certain reagents and strategies over others depending on the archaeal species of interest. These methods yield improved RNA-seq sensitivity and enhanced detection of low abundance transcripts.
      Citation: Biomolecules
      PubDate: 2022-05-10
      DOI: 10.3390/biom12050682
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 683: The Novel Pimavanserin Derivative
           ST-2300 with Histamine H3 Receptor Affinity Shows Reduced 5-HT2A Binding,
           but Maintains Antidepressant- and Anxiolytic-like Properties in Mice

    • Authors: Venkatachalam, Zhong, Dubiel, Satała, Sadek, Stark
      First page: 683
      Abstract: The therapy of depression is challenging and still unsatisfactory despite the presence of many antidepressant drugs on the market. Consequently, there is a continuous need to search for new, safer, and more effective antidepressant therapeutics. Previous studies have suggested a potential association of brain histaminergic/serotoninergic signaling and antidepressant- and anxiolytic-like effects. Here, we evaluated the in vivo antidepressant- and anxiolytic-like effects of the newly developed multiple-active ligand ST-2300. ST-2300 was developed from 5-HT2A/2C inverse agonist pimavanserin (PIM, ACP-103) and incorporates a histamine H3 receptor (H3R) antagonist pharmacophore. Despite its parent compound, ST-2300 showed only moderate serotonin 5-HT2A antagonist/inverse agonist affinity (Ki value of 1302 nM), but excellent H3R affinity (Ki value of 14 nM). In vivo effects were examined using forced swim test (FST), tail suspension test (TST), and the open field test (OFT) in C57BL/6 mice. Unlike PIM, ST-2300 significantly increased the anxiolytic-like effects in OFT without altering general motor activity. In FST and TST, ST-2300 was able to reduce immobility time similar to fluoxetine (FLX), a recognized antidepressant drug. Importantly, pretreatment with the CNS-penetrant H3R agonist (R)-α-methylhistamine reversed the antidepressant-like effects of ST-2300 in FST and TST, but failed to reverse the ST-2300-provided anxiolytic effects in OFT. Present findings reveal critical structural features that are useful in a rational multiple-pharmacological approach to target H3R/5-HT2A/5-HT2C.
      Citation: Biomolecules
      PubDate: 2022-05-10
      DOI: 10.3390/biom12050683
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 684: Randomizing of Oligopeptide
           Conformations by Nearest Neighbor Interactions between Amino Acid Residues

    • Authors: Reinhard Schweitzer-Stenner, Bridget Milorey, Harald Schwalbe
      First page: 684
      Abstract: Flory’s random coil model assumes that conformational fluctuations of amino acid residues in unfolded poly(oligo)peptides and proteins are uncorrelated (isolated pair hypothesis, IPH). This implies that conformational energies, entropies and solvation free energies are all additive. Nearly 25 years ago, analyses of coil libraries cast some doubt on this notion, in that they revealed that aromatic, but also β-branched side chains, could change the 3J(HNHCα) coupling of their neighbors. Since then, multiple bioinformatical, computational and experimental studies have revealed that conformational propensities of amino acids in unfolded peptides and proteins depend on their nearest neighbors. We used recently reported and newly obtained Ramachandran plots of tetra- and pentapeptides with non-terminal homo- and heterosequences of amino acid residues to quantitatively determine nearest neighbor coupling between them with a Ising type model. Results reveal that, depending on the choice of amino acid residue pairs, nearest neighbor interactions either stabilize or destabilize pairs of polyproline II and β-strand conformations. This leads to a redistribution of population between these conformations and a reduction in conformational entropy. Interactions between residues in polyproline II and turn(helix)-forming conformations seem to be cooperative in most cases, but the respective interaction parameters are subject to large statistical errors.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050684
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 685: Kinases on Double Duty: A Review of
           UniProtKB Annotated Bifunctionality within the Kinome

    • Authors: Aziz M. Rangwala, Victoria R. Mingione, George Georghiou, Markus A. Seeliger
      First page: 685
      Abstract: Phosphorylation facilitates the regulation of all fundamental biological processes, which has triggered extensive research of protein kinases and their roles in human health and disease. In addition to their phosphotransferase activity, certain kinases have evolved to adopt additional catalytic functions, while others have completely lost all catalytic activity. We searched the Universal Protein Resource Knowledgebase (UniProtKB) database for bifunctional protein kinases and focused on kinases that are critical for bacterial and human cellular homeostasis. These kinases engage in diverse functional roles, ranging from environmental sensing and metabolic regulation to immune-host defense and cell cycle control. Herein, we describe their dual catalytic activities and how they contribute to disease pathogenesis.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050685
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 686: miRNA Pattern in Hypoxic
           Microenvironment of Kidney Cancer—Role of PTEN

    • Authors: Aleksandra Majewska, Klaudia Brodaczewska, Aleksandra Filipiak-Duliban, Arkadiusz Kajdasz, Claudine Kieda
      First page: 686
      Abstract: MicroRNAs are post-transcriptional regulators of gene expression, and disturbances of their expression are the basis of many pathological states, including cancers. The miRNA pattern in the context of tumor microenvironment explains mechanisms related to cancer progression and provides a potential target of modern therapies. Here we show the miRNA pattern in renal cancer focusing on hypoxia as a characteristic feature of the tumor microenvironment and dysregulation of PTEN, being a major tumor suppressor. Methods comprised the CRSPR/Cas9 mediated PTEN knockout in the Renca kidney cancer cell line and global miRNA expression analysis in both in vivo and in vitro (in normoxic and hypoxic conditions). The results were validated on human cancer models with distinct PTEN status. The increase in miR-210-3p in hypoxia was universal; however, the hypoxia-induced decrease in PTEN was associated with an increase in miR-221-3p, the loss of PTEN affected the response to hypoxia differently by decreasing miR-10b-5p and increasing miR-206-3p. In turn, the complete loss of PTEN induces miR-155-5p, miR-100-5p. Upregulation of miR-342-3p in knockout PTEN occurred in the context of the whole tumor microenvironment. Thus, effective identification of miRNA patterns in cancers must consider the specificity of the tumor microenvironment together with the mutations of key suppressors.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050686
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 687: Production of New Microbially Conjugated
           Bile Acids by Human Gut Microbiota

    • Authors: Carlos J. Garcia, Vit Kosek, David Beltrán, Francisco A. Tomás-Barberán, Jana Hajslova
      First page: 687
      Abstract: Gut microbes have been recognized to convert human bile acids by deconjugation, dehydroxylation, dehydrogenation, and epimerization of the cholesterol core, but the ability to re-conjugate them with amino acids as an additional conversion has been recently described. These new bile acids are known as microbially conjugated bile acids (MCBAs). The aim of this study was to evaluate the MCBAs diversity produced by the gut microbiota through a metabolomics approach. In this study, fresh fecal samples from healthy donors were evaluated to explore the re-conjugation of chenodeoxycholic and 3-oxo-chenodeoxycholic acids by the human gut microbiota. No significant differences were found between the conversion trend of both BAs incubations. The in vitro results showed a clear trend to first accumulate the epimer isoursochenodeoxycholic acid and the dehydroxylated lithocholic acid derivatives in samples incubated with chenodeoxycholic and 3-oxo-chenodeoxycholic acid. They also showed a strong trend for the production of microbially conjugated dehydroxylated bile acids instead of chenodeoxycholic backbone conjugates. Different molecules and isomers of MCBAs were identified, and the new ones, valolithocholate ester and leucolithocholate ester, were identified and confirmed by MS/MS. These results document the gut microbiota’s capability to produce esters of MCBAs on hydroxyls of the sterol backbone in addition to amides at the C24 acyl site. This study opens a new perspective to study the BAs diversity produced by the human gut microbiota.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050687
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 688: Comparative Transcriptome Analysis of
           Agrobacterium tumefaciens Reveals the Molecular Basis for the Recalcitrant
           Genetic Transformation of Camellia sinensis L.

    • Authors: Ke Jin, Na Tian, Jorge Freire da Silva Ferreira, Devinder Sandhu, Lizheng Xiao, Meiyi Gu, Yiping Luo, Xiangqin Zhang, Guizhi Liu, Zhonghua Liu, Jianan Huang, Shuoqian Liu
      First page: 688
      Abstract: Tea (Camellia sinensis L.), an important economic crop, is recalcitrant to Agrobacterium-mediated transformation (AMT), which has seriously hindered the progress of molecular research on this species. The mechanisms leading to low efficiency of AMT in tea plants, related to the morphology, growth, and gene expression of Agrobacterium tumefaciens during tea-leaf explant infection, were compared to AMT of Nicotiana benthamiana leaves in the present work. Scanning electron microscopy (SEM) images showed that tea leaves induced significant morphological aberrations on bacterial cells and affected pathogen–plant attachment, the initial step of a successful AMT. RNA sequencing and transcriptomic analysis on Agrobacterium at 0, 3 and 4 days after leaf post-inoculation resulted in 762, 1923 and 1656 differentially expressed genes (DEGs) between the tea group and the tobacco group, respectively. The expressions of genes involved in bacterial fundamental metabolic processes, ATP-binding cassette (ABC) transporters, two-component systems (TCSs), secretion systems, and quorum sensing (QS) systems were severely affected in response to the tea-leaf phylloplane. Collectively, these results suggest that compounds in tea leaves, especially gamma-aminobutyrate (GABA) and catechins, interfered with plant–pathogen attachment, essential minerals (iron and potassium) acquisition, and quorum quenching (QQ) induction, which may have been major contributing factors to hinder AMT efficiency of the tea plant.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050688
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 689: Flavonoid Biosynthesis Genes in Triticum
           aestivum L.: Methylation Patterns in Cis-Regulatory Regions of the
           Duplicated CHI and F3H Genes

    • Authors: Ksenia Strygina, Elena Khlestkina
      First page: 689
      Abstract: Flavonoids are a diverse group of secondary plant metabolites that play an important role in the regulation of plant development and protection against stressors. The biosynthesis of flavonoids occurs through the activity of several enzymes, including chalcone isomerase (CHI) and flavanone 3-hydroxylase (F3H). A functional divergence between some copies of the structural TaCHI and TaF3H genes was previously shown in the allohexaploid bread wheat Triticum aestivum L. (BBAADD genome). We hypothesized that the specific nature of TaCHI and TaF3H expression may be induced by the methylation of the promoter. It was found that the predicted position of CpG islands in the promoter regions of the analyzed genes and the actual location of methylation sites did not match. We found for the first time that differences in the methylation status could affect the expression of TaCHI copies, but not the expression of TaF3Hs. At the same time, we revealed significant differences in the structure of the promoters of only the TaF3H genes, while the TaCHI promoters were highly homologous. We assume that the promoter structure in TaF3Hs primarily affects the change in the nature of gene expression. The data obtained are important for understanding the mechanisms that regulate the synthesis of flavonoids in allopolyploid wheat and show that differences in the structure of promoters have a key effect on gene expression.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050689
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 690: Immune-Related Protein Interaction
           Network in Severe COVID-19 Patients toward the Identification of Key
           Proteins and Drug Repurposing

    • Authors: Pakorn Sagulkoo, Apichat Suratanee, Kitiporn Plaimas
      First page: 690
      Abstract: Coronavirus disease 2019 (COVID-19) is still an active global public health issue. Although vaccines and therapeutic options are available, some patients experience severe conditions and need critical care support. Hence, identifying key genes or proteins involved in immune-related severe COVID-19 is necessary to find or develop the targeted therapies. This study proposed a novel construction of an immune-related protein interaction network (IPIN) in severe cases with the use of a network diffusion technique on a human interactome network and transcriptomic data. Enrichment analysis revealed that the IPIN was mainly associated with antiviral, innate immune, apoptosis, cell division, and cell cycle regulation signaling pathways. Twenty-three proteins were identified as key proteins to find associated drugs. Finally, poly (I:C), mitomycin C, decitabine, gemcitabine, hydroxyurea, tamoxifen, and curcumin were the potential drugs interacting with the key proteins to heal severe COVID-19. In conclusion, IPIN can be a good representative network for the immune system that integrates the protein interaction network and transcriptomic data. Thus, the key proteins and target drugs in IPIN help to find a new treatment with the use of existing drugs to treat the disease apart from vaccination and conventional antiviral therapy.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050690
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 691: Biomarker Characterization and
           Prediction of Virulence and Antibiotic Resistance from Helicobacter pylori
           Next Generation Sequencing Data

    • Authors: Joana S. Vital, Luís Tanoeiro, Ricardo Lopes-Oliveira, Filipa F. Vale
      First page: 691
      Abstract: The Gram-negative bacterium Helicobacter pylori colonizes c.a. 50% of human stomachs worldwide and is the major risk factor for gastric adenocarcinoma. Its high genetic variability makes it difficult to identify biomarkers of early stages of infection that can reliably predict its outcome. Moreover, the increasing antibiotic resistance found in H. pylori defies therapy, constituting a major human health problem. Here, we review H. pylori virulence factors and genes involved in antibiotic resistance, as well as the technologies currently used for their detection. Furthermore, we show that next generation sequencing may lead to faster characterization of virulence factors and prediction of the antibiotic resistance profile, thus contributing to personalized treatment and management of H. pylori-associated infections. With this new approach, more and permanent data will be generated at a lower cost, opening the future to new applications for H. pylori biomarker identification and antibiotic resistance prediction.
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050691
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 692: Matrix Metalloproteinases in Health and
           Disease in the Times of COVID-19

    • Authors: Carlos Fernandez-Patron, Eugenio Hardy
      First page: 692
      Abstract: Much has been written about matrix metalloproteinases (MMPs) in health and disease conditions, but their roles in the setting of COVID-19 and associated illnesses remain understudied [...]
      Citation: Biomolecules
      PubDate: 2022-05-11
      DOI: 10.3390/biom12050692
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 693: Correction: Díaz-Talavera et al.
           PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New
           Target for Cancer Therapy. Biomolecules 2022, 12, 248

    • Authors: Alberto Díaz-Talavera, Cristina Montero-Conde, Luis Javier Leandro-García, Mercedes Robledo
      First page: 693
      Abstract: To improve the quality of the original article [...]
      Citation: Biomolecules
      PubDate: 2022-05-12
      DOI: 10.3390/biom12050693
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 694: Natural Products from Plants and Algae
           for Treatment of Alzheimer’s Disease: A Review

    • Authors: Jana Klose, Carola Griehl, Steffen Roßner, Stephan Schilling
      First page: 694
      Abstract: Neurodegenerative disorders including Parkinson’s disease (PD), Huntington’s disease (HD) and the most frequent, Alzheimer’s disease (AD), represent one of the most urgent medical needs worldwide. Despite a significantly developed understanding of disease development and pathology, treatments that stop AD progression are not yet available. The recent approval of sodium oligomannate (GV-971) for AD treatment in China emphasized the potential value of natural products for the treatment of neurodegenerative disorders. Many current clinical studies include the administration of a natural compound as a single and combination treatment. The most prominent mechanisms of action are anti-inflammatory and anti-oxidative activities, thus preserving cellular survival. Here, we review current natural products that are either approved or are in testing for a treatment of neurodegeneration in AD. In addition to the most important compounds of plant origin, we also put special emphasis on compounds from algae, given their neuroprotective activity and their underlying mechanisms of neuroprotection.
      Citation: Biomolecules
      PubDate: 2022-05-12
      DOI: 10.3390/biom12050694
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 695: Clade-Specific Alterations within the
           HIV-1 Capsid Protein with Implications for Nuclear Translocation

    • Authors: Alexej Dick, Megan E. Meuser, Simon Cocklin
      First page: 695
      Abstract: The HIV-1 capsid (CA) protein has emerged as an attractive therapeutic target. However, all inhibitor designs and structural analyses for this essential HIV-1 protein have focused on the clade B HIV-1 (NL4-3) variant. This study creates, overproduces, purifies, and characterizes the CA proteins from clade A1, A2, B, C, and D isolates. These new CA constructs represent novel reagents that can be used in future CA-targeted inhibitor design and to investigate CA proteins’ structural and biochemical properties from genetically diverse HIV-1 subtypes. Moreover, we used surface plasmon resonance (SPR) spectrometry and computational modeling to examine inter-clade differences in CA assembly and binding of PF-74, CPSF-6, and NUP-153. Interestingly, we found that HIV-1 CA from clade A1 does not bind to NUP-153, suggesting that the import of CA core structures through the nuclear pore complex may be altered for viruses from this clade. Overall, we have demonstrated that in silico generated models of the HIV-1 CA protein from clades other than the prototypically used clade B have utility in understanding and predicting biology and antiviral drug design and mechanism of action.
      Citation: Biomolecules
      PubDate: 2022-05-12
      DOI: 10.3390/biom12050695
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 696: Design, Synthesis, and Antisickling
           Investigation of a Nitric Oxide-Releasing Prodrug of 5HMF for the
           Treatment of Sickle Cell Disease

    • Authors: Rana T. Alhashimi, Mohini S. Ghatge, Akua K. Donkor, Tanvi M. Deshpande, Nancy Anabaraonye, Dina Alramadhani, Richmond Danso-Danquah, Boshi Huang, Yan Zhang, Faik N. Musayev, Osheiza Abdulmalik, Martin K. Safo
      First page: 696
      Abstract: 5-hydroxyfurfural (5HMF), an allosteric effector of hemoglobin (Hb) with an ability to increase Hb affinity for oxygen has been studied extensively for its antisickling effect in vitro and in vivo, and in humans for the treatment of sickle cell disease (SCD). One of the downstream pathophysiologies of SCD is nitric oxide (NO) deficiency, therefore increasing NO (bio)availability is known to mitigate the severity of SCD symptoms. We report the synthesis of an NO-releasing prodrug of 5HMF (5HMF-NO), which in vivo, is expected to be bio-transformed into 5HMF and NO, with concomitant therapeutic activities. In vitro studies showed that when incubated with whole blood, 5HMF-NO releases NO, as anticipated. When incubated with sickle blood, 5HMF-NO formed Schiff base adduct with Hb, increased Hb affinity for oxygen, and prevented hypoxia-induced erythrocyte sickling, which at 1 mM concentration were 16%, 10% and 27%, respectively, compared to 21%, 18% and 21% for 5HMF. Crystal structures of 5HMF-NO with Hb showed 5HMF-NO bound to unliganded (deoxygenated) Hb, while the hydrolyzed product, 5HMF bound to liganded (carbonmonoxy-ligated) Hb. Our findings from this proof-of-concept study suggest that the incorporation of NO donor group to 5HMF and analogous molecules could be a novel beneficial strategy to treat SCD and warrants further detailed in vivo studies.
      Citation: Biomolecules
      PubDate: 2022-05-12
      DOI: 10.3390/biom12050696
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 697: Lack of Ecto-5′-Nucleotidase
           Protects Sensitized Mice against Allergen Challenge

    • Authors: Elisabetta Caiazzo, Ida Cerqua, Roberta Turiello, Maria Antonietta Riemma, Giacomo De Palma, Armando Ialenti, Fiorentina Roviezzo, Silvana Morello, Carla Cicala
      First page: 697
      Abstract: Ecto-5′-nucleotidase (CD73), the ectoenzyme that together with CD39 is responsible for extracellular ATP hydrolysis and adenosine accumulation, regulates immune/inflammatory processes by controlling innate and acquired immunity cell functions. We previously demonstrated that CD73 is required for the assessment of a controlled allergic sensitization, in mice. Here, we evaluated the response to aerosolized allergen of female-sensitized mice lacking CD73 in comparison with their wild type counterpart. Results obtained show, in mice lacking CD73, the absence of airway hyperreactivity in response to an allergen challenge, paralleled by reduced airway CD23+B cells and IL4+T cells pulmonary accumulation together with reduced mast cells accumulation and degranulation. Our findings indicate CD73 as a potential therapeutic target for allergic asthma.
      Citation: Biomolecules
      PubDate: 2022-05-13
      DOI: 10.3390/biom12050697
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 698: Extracellular Vesicles from Steatotic
           Hepatocytes Provoke Pro-Fibrotic Responses in Cultured Stellate Cells

    • Authors: Maria Teresa Koenen, Elisa Fabiana Brandt, Dawid Marcin Kaczor, Tim Caspers, Alexandra Catharina Anna Heinzmann, Petra Fischer, Daniel Heinrichs, Theresa Hildegard Wirtz, Christian Trautwein, Rory R Koenen, Marie-Luise Berres
      First page: 698
      Abstract: Hepatic steatosis and chronic hepatocyte damage ultimately lead to liver fibrosis. Key pathophysiological steps are the activation and transdifferentiation of hepatic stellate cells. We assessed the interplay between hepatocytes and hepatic stellate cells under normal and steatotic conditions. We hypothesized that hepatocyte-derived extracellular vesicles (EVs) modify the phenotype of stellate cells. By high speed centrifugation, EVs were isolated from conditioned media of the hepatocellular carcinoma cell line HepG2 under baseline conditions (C-EVs) or after induction of steatosis by linoleic and oleic acids for 24 h (FA-EVs). Migration of the human stellate cell line TWNT4 and of primary human stellate cells towards the respective EVs and sera of MAFLD patients were investigated using Boyden chambers. Phenotype alterations after incubation with EVs were determined by qRT-PCR, Western blotting and immunofluorescence staining. HepG2 cells released more EVs after treatment with fatty acids. Chemotactic migration of TWNT4 and primary hepatic stellate cells was increased, specifically towards FA-EVs. Prolonged incubation of TWNT4 cells with FA-EVs induced expression of proliferation markers and a myofibroblast-like phenotype. Though the expression of the collagen type 1 α1 gene did not change after FA-EV treatment, expression of the myofibroblast markers, e.g., α-smooth-muscle-cell actin and TIMP1, was significantly increased. We conclude that EVs from steatotic hepatocytes can influence the behavior, phenotypes and expression levels of remodeling markers of stellate cells and guides their directed migration. These findings imply EVs as operational, intercellular communicators in the pathophysiology of steatosis-associated liver fibrosis and might represent a novel diagnostic parameter and therapeutic target.
      Citation: Biomolecules
      PubDate: 2022-05-13
      DOI: 10.3390/biom12050698
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 699: Using Vertebrate Stem and Progenitor
           Cells for Cellular Agriculture-State-of-the-Art, Challenges, and Future

    • Authors: Teodora Knežić, Ljiljana Janjušević, Mila Djisalov, Supansa Yodmuang, Ivana Gadjanski
      First page: 699
      Abstract: Global food systems are under significant pressure to provide enough food, particularly protein-rich foods whose demand is on the rise in times of crisis and inflation, as presently existing due to post-COVID-19 pandemic effects and ongoing conflict in Ukraine and resulting in looming food insecurity, according to FAO. Cultivated meat (CM) and cultivated seafood (CS) are protein-rich alternatives for traditional meat and fish that are obtained via cellular agriculture (CA) i.e., tissue engineering for food applications. Stem and progenitor cells are the building blocks and starting point for any CA bioprocess. This review presents CA-relevant vertebrate cell types and procedures needed for their myogenic and adipogenic differentiation since muscle and fat tissue are the primary target tissues for CM/CS production. The review also describes existing challenges, such as a need for immortalized cell lines, or physical and biochemical parameters needed for enhanced meat/fat culture efficiency and ways to address them.
      Citation: Biomolecules
      PubDate: 2022-05-13
      DOI: 10.3390/biom12050699
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 700: Altered Expression of Protamine-like and
           Their DNA Binding Induced by Cr(VI): A Possible Risk to

    • Authors: Claudia Moriello, Martina Costabile, Michele Spinelli, Angela Amoresano, Giancarlo Palumbo, Ferdinando Febbraio, Marina Piscopo
      First page: 700
      Abstract: Chromium (VI) is the most dangerous oxidation state among the stable forms of chromium. In this work, we evaluated the effect of exposing Mytilus galloprovincialis for 24 h to 1, 10, and 100 nM chromium (VI) on the properties of Protamine-like (PLs) and their gene levels in the gonads. Specifically, we analyzed, by AU-PAGE and SDS-PAGE, PLs extracted from unexposed and exposed mussels. In addition, via EMSA, we evaluated the ability of PLs to bind DNA and also verified their potential to protect DNA from oxidative damage. Finally, we assessed possible alterations in gonadal expression of mt10, hsp70, and genes encoding for PLs-II/PL-IV and PL-III. We found that for all experimental approaches the most relevant alterations occurred after exposure to 1 nM Cr(VI). In particular, a comigration of PL-II with PL-III was observed by SDS-PAGE; and a reduced ability of PLs to bind and protect DNA from oxidative damage was recorded. This dose of chromium (VI) exposure was also the one that produced the greatest alterations in the expression of both mt10 and PL-II/PL-IV encoding genes. All of these changes suggest that this dose of chromium (VI) exposure could affect the reproductive health of Mytilus galloprovincialis.
      Citation: Biomolecules
      PubDate: 2022-05-14
      DOI: 10.3390/biom12050700
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 701: Automated–Mechanical Procedure

    • Authors: Mariele Montanari, Sabrina Burattini, Caterina Ciacci, Patrizia Ambrogini, Silvia Carloni, Walter Balduini, Daniele Lopez, Giovanna Panza, Stefano Papa, Barbara Canonico
      First page: 701
      Abstract: The first step to obtain a cellular suspension from tissues is the disaggregation procedure. The cell suspension method has to provide a representative sample of the different cellular subpopulations and to maximize the number of viable functional cells. Here, we analyzed specific cell functions in cell suspensions from several rat tissues obtained by two different methods, automated–mechanical and enzymatic disaggregation. Flow cytometric, confocal, and ultrastructural (TEM) analyses were applied to the spleen, testis, liver and other tissues. Samples were treated by an enzymatic trypsin solution or processed by the Medimachine II (MMII). The automated–mechanical and enzymatic disaggregation procedures have shown to work similarly in some tissues, which displayed comparable amounts of apoptotic/necrotic cells. However, cells obtained by the enzyme-free Medimachine II protocols show a better preservation lysosome and mitochondria labeling, whereas the enzymatic gentle dissociation appears to constantly induce a lower amount of intracellular ROS; nevertheless, lightly increased ROS can be recognized as a complimentary signal to promote cell survival. Therefore, MMII represents a simple, fast, and standardized method for tissue processing, which allows to minimize bias arising from the operator’s ability. Our study points out technical issues to be adopted for specific organs and tissues to obtain functional cells.
      Citation: Biomolecules
      PubDate: 2022-05-14
      DOI: 10.3390/biom12050701
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 702: Targeting of the Peritumoral Adipose
           Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy

    • Authors: Melania Lo Iacono, Chiara Modica, Gaetana Porcelli, Ornella Roberta Brancato, Giampaolo Muratore, Paola Bianca, Miriam Gaggianesi, Alice Turdo, Veronica Veschi, Matilde Todaro, Simone Di Franco, Giorgio Stassi
      First page: 702
      Abstract: The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells (CSCs), drive cancer progression by releasing metabolites and inflammatory adipokines. In this review, we highlight the mechanisms underlying the bidirectional crosstalk among CAAs, CSCs, and stromal cells. Moreover, we focus on the recent advances in the therapeutic targeting of adipocyte-released factors as an innovative strategy to counteract cancer progression.
      Citation: Biomolecules
      PubDate: 2022-05-14
      DOI: 10.3390/biom12050702
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 703: On the Study of Deubiquitinases: Using
           the Right Tools for the Job

    • Authors: Cody Caba, Azam Mohammadzadeh, Yufeng Tong
      First page: 703
      Abstract: Deubiquitinases (DUBs) have been the subject of intense scrutiny in recent years. Many of their diverse enzymatic mechanisms are well characterized in vitro; however, our understanding of these enzymes at the cellular level lags due to the lack of quality tool reagents. DUBs play a role in seemingly every biological process and are central to many human pathologies, thus rendering them very desirable and challenging therapeutic targets. This review aims to provide researchers entering the field of ubiquitination with knowledge of the pharmacological modulators and tool molecules available to study DUBs. A focus is placed on small molecule inhibitors, ubiquitin variants (UbVs), and activity-based probes (ABPs). Leveraging these tools to uncover DUB biology at the cellular level is of particular importance and may lead to significant breakthroughs. Despite significant drug discovery efforts, only approximately 15 chemical probe-quality small molecule inhibitors have been reported, hitting just 6 of about 100 DUB targets. UbV technology is a promising approach to rapidly expand the library of known DUB inhibitors and may be used as a combinatorial platform for structure-guided drug design.
      Citation: Biomolecules
      PubDate: 2022-05-14
      DOI: 10.3390/biom12050703
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 704: CAPTURE of the Human U2 snRNA Genes
           Expands the Repertoire of Associated Factors

    • Authors: Joana Guiro, Mathias Fagbemi, Michael Tellier, Justyna Zaborowska, Stephanie Barker, Marjorie Fournier, Shona Murphy
      First page: 704
      Abstract: In order to identify factors involved in transcription of human snRNA genes and 3′ end processing of the transcripts, we have carried out CRISPR affinity purification in situ of regulatory elements (CAPTURE), which is deadCas9-mediated pull-down, of the tandemly repeated U2 snRNA genes in human cells. CAPTURE enriched many factors expected to be associated with these human snRNA genes including RNA polymerase II (pol II), Cyclin-Dependent Kinase 7 (CDK7), Negative Elongation Factor (NELF), Suppressor of Ty 5 (SPT5), Mediator 23 (MED23) and several subunits of the Integrator Complex. Suppressor of Ty 6 (SPT6); Cyclin K, the partner of Cyclin-Dependent Kinase 12 (CDK12) and Cyclin-Dependent Kinase 13 (CDK13); and SWI/SNF chromatin remodelling complex-associated SWI/SNF-related, Matrix-associated, Regulator of Chromatin (SMRC) factors were also enriched. Several polyadenylation factors, including Cleavage and Polyadenylation Specificity Factor 1 (CPSF1), Cleavage Stimulation Factors 1 and 2 (CSTF1,and CSTF2) were enriched by U2 gene CAPTURE. We have already shown by chromatin immunoprecipitation (ChIP) that CSTF2—and Pcf11 and Ssu72, which are also polyadenylation factors—are associated with the human U1 and U2 genes. ChIP-seq and ChIP-qPCR confirm the association of SPT6, Cyclin K, and CDK12 with the U2 genes. In addition, knockdown of SPT6 causes loss of subunit 3 of the Integrator Complex (INTS3) from the U2 genes, indicating a functional role in snRNA gene expression. CAPTURE has therefore expanded the repertoire of transcription and RNA processing factors associated with these genes and helped to identify a functional role for SPT6.
      Citation: Biomolecules
      PubDate: 2022-05-14
      DOI: 10.3390/biom12050704
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 705: Ferritin-Based Single-Electron Devices

    • Authors: Jacqueline A. Labra-Muñoz, Arie de Reuver, Friso Koeleman, Martina Huber, Herre S. J. van der Zant
      First page: 705
      Abstract: We report on the fabrication of single-electron devices based on horse-spleen ferritin particles. At low temperatures the current vs. voltage characteristics are stable, enabling the acquisition of reproducible data that establishes the Coulomb blockade as the main transport mechanism through them. Excellent agreement between the experimental data and the Coulomb blockade theory is demonstrated. Single-electron charge transport in ferritin, thus, establishes a route for further characterization of their, e.g., magnetic, properties down to the single-particle level, with prospects for electronic and medical applications.
      Citation: Biomolecules
      PubDate: 2022-05-15
      DOI: 10.3390/biom12050705
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 706: Key Molecules of Fatty Acid Metabolism
           in Gastric Cancer

    • Authors: Chunlei Li, Lilong Zhang, Zhendong Qiu, Wenhong Deng, Weixing Wang
      First page: 706
      Abstract: Fatty acid metabolism is closely linked to the progression of gastric cancer (GC), a very aggressive and life-threatening tumor. This study examines linked molecules, such as Sterol Regulatory Element-Binding Protein 1 (SREBP1), ATP Citrate Lyase (ACLY), Acetyl-CoA Synthases (ACSs), Acetyl-CoA Carboxylase (ACC), Fatty Acid Synthase (FASN), Stearoyl-CoA Desaturase 1 (SCD1), CD36, Fatty Acid Binding Proteins (FABPs), and Carnitine palmitoyltransferase 1 (CPT1), as well as their latest studies and findings in gastric cancer to unveil its core mechanism. The major enzymes of fatty acid de novo synthesis are ACLY, ACSs, ACC, FASN, and SCD1, while SREBP1 is the upstream molecule of fatty acid anabolism. Fatty acid absorption is mediated by CD36 and FABPs, and fatty acid catabolism is mediated by CPT1. If at all possible, we will discover novel links between fatty acid metabolism and a prospective gastric cancer target.
      Citation: Biomolecules
      PubDate: 2022-05-15
      DOI: 10.3390/biom12050706
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 707: Gal-2 Increases H3K4me3 and H3K9ac in
           Trophoblasts and Preeclampsia

    • Authors: Laura Hahn, Sarah Meister, Mareike Mannewitz, Susanne Beyer, Stefanie Corradini, Uwe Hasbargen, Sven Mahner, Udo Jeschke, Thomas Kolben, Alexander Burges
      First page: 707
      Abstract: Preeclampsia (PE) is a severe pregnancy disorder with a pathophysiology not yet completely understood and without curative therapy. The histone modifications H3K4me3 and H3K9ac, as well as galectin-2 (Gal-2), are known to be decreased in PE. To gain a better understanding of the development of PE, the influence of Gal-2 on histone modification in trophoblasts and in syncytialisation was investigated. Immunohistochemical stains of 13 PE and 13 control placentas were correlated, followed by cell culture experiments. An analysis of H3K4me3 and H3K9ac was conducted, as well as cell fusion staining with E-cadherin and β-catenin—both after incubation with Gal-2. The expression of H3K4me3 and H3K9ac correlated significantly with the expression of Gal-2. Furthermore, we detected an increase in H3K4me3 and H3K9ac after the addition of Gal-2 to BeWo/HVT cells. Moreover, there was increased fusion of HVT cells after incubation with Gal-2. Gal-2 is associated with the histone modifications H3K4me3 and H3K9ac in trophoblasts. Furthermore, syncytialisation increased after incubation with Gal-2. Therefore, we postulate that Gal-2 stimulates syncytialisation, possibly mediated by H3K4me3 and H3K9ac. Since Gal-2, as well as H3K4me3 and H3K9ac, are decreased in PE, the induction of Gal-2 might be a promising therapeutic target.
      Citation: Biomolecules
      PubDate: 2022-05-15
      DOI: 10.3390/biom12050707
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 708: Artemisia dracunculus L. Ethanolic
           Extract and an Isolated Component, DMC2, Ameliorate Inflammatory Signaling
           in Pancreatic β-Cells via Inhibition of p38 MAPK

    • Authors: Peter Smoak, Susan J. Burke, Thomas M. Martin, Heidi M. Batdorf, Z. Elizabeth Floyd, J. Jason Collier
      First page: 708
      Abstract: Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. Herein, we described the use of 2′,4′-dihydroxy-4-methoxydihydrochalcone (DMC2), a bioactive molecule isolated from an ethanolic extract of Artemisia dracunculus L., as a novel anti-inflammatory agent. The ethanolic extract, termed PMI 5011, reduced IL-1β-mediated NF-κB activity. DMC2 retained this ability, indicating this compound as the likely source of anti-inflammatory activity within the overall PMI 5011 extract. We further examined NF-κB activity using promoter-luciferase reporter constructs, Western blots, mRNA abundance, and protein secretion. Specifically, we found that PMI 5011 and DMC2 each reduced the ability of IL-1β to promote increases in the expression of the Ccl2 and Ccl20 genes. These genes encode proteins that promote immune cell recruitment and are secreted by β-cells in response to IL-1β. Phosphorylation of IκBα and the p65 subunit of NF-κB were not reduced by either PMI 5011 or DMC2; however, phosphorylation of p38 MAPK was blunted in the presence of DMC2. Finally, we observed that while PMI 5011 impaired glucose-stimulated insulin secretion, insulin output was preserved in the presence of DMC2. In conclusion, PMI 5011 and DMC2 reduced inflammation, but only DMC2 did so with the preservation of glucose-stimulated insulin secretion.
      Citation: Biomolecules
      PubDate: 2022-05-15
      DOI: 10.3390/biom12050708
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 709: A High Throughput Lipidomics Method
           Using Scheduled Multiple Reaction Monitoring

    • Authors: Akash Kumar Bhaskar, Salwa Naushin, Arjun Ray, Praveen Singh, Anurag Raj, Shalini Pradhan, Khushboo Adlakha, Towfida Jahan Siddiqua, Dipankar Malakar, Debasis Dash, Shantanu Sengupta
      First page: 709
      Abstract: Lipid compositions of cells, tissues, and bio-fluids are complex, with varying concentrations and structural diversity making their identification challenging. Newer methods for comprehensive analysis of lipids are thus necessary. Herein, we propose a targeted-mass spectrometry based lipidomics screening method using a combination of variable retention time window and relative dwell time weightage. Using this method, we identified more than 1000 lipid species within 24-min. The limit of detection varied from the femtomolar to the nanomolar range. About 883 lipid species were detected with a coefficient of variance <30%. We used this method to identify plasma lipids altered due to vitamin B12 deficiency and found a total of 18 lipid species to be altered. Some of the lipid species with ω-6 fatty acid chains were found to be significantly increased while ω-3 decreased in vitamin B12 deficient samples. This method enables rapid screening of a large number of lipid species in a single experiment and would substantially advance our understanding of the role of lipids in biological processes.
      Citation: Biomolecules
      PubDate: 2022-05-16
      DOI: 10.3390/biom12050709
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 710: Increase in Serum MMP-9 and TIMP-1
           Concentrations during Alcohol Intoxication in Adolescents—A
           Preliminary Study

    • Authors: Katarzyna Zdanowicz, Monika Kowalczuk-Kryston, Witold Olanski, Irena Werpachowska, Wlodzimierz Mielech, Dariusz Marek Lebensztejn
      First page: 710
      Abstract: Background: Alcohol consumption by adolescents is responsible for a number of adverse health and social outcomes. Despite the well-established effect of alcohol use on the development of alcoholic liver disease, the relationship between the pattern of alcohol consumption and liver fibrosis is still unclear. This study is a follow-up to work on liver damage from alcohol intoxication. The aim of our study was to explore the early effects of alcohol intoxication on liver fibrosis in adolescents. Methods: The prospective study included 57 adolescents aged 14–17 years admitted to the emergency department (ED) from February 2017 to June 2018 due to acute alcohol intoxication. Serum levels of amino terminal propeptide of type III procollagen (PIIINP), type IV collagen, matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were determined by enzyme-linked immunosorbent assays. Results: There were significant differences in MMP-9 (p = 0.02) and TIMP-1 (p = 0.007) levels between the study and control groups. Liver parameters and selected markers of fibrosis were similar in groups in terms of blood alcohol concentrations (BAC). MMP-9 was positively correlated with alanine aminotransferase (ALT) (r = 0.38; p = 0.004) and total bilirubin (r = 0.39; p = 0.004). Positive significant correlations were also found between TIMP-1 and ALT (r = 0.47; p < 0.001), AST (r = 0.29; p = 0.03) and total bilirubin (r = 0.32; p = 0.02). In receiver operating characteristic (ROC) analysis, MMP-9 (AUC = 0.67, p = 0.02) and TIMP-1 (AUC = 0.69, p = 0.003) allowed for the differentiation of patients with and without alcohol intoxication. Conclusion: Our results show that even a single episode of alcohol intoxication in adolescents can lead to imbalance in markers of fibrosis.
      Citation: Biomolecules
      PubDate: 2022-05-16
      DOI: 10.3390/biom12050710
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 711: Fluorescent Anti-CEA Nanobody for Rapid
           Tumor-Targeting and Imaging in Mouse Models of Pancreatic Cancer

    • Authors: Thinzar M. Lwin, Michael A. Turner, Hiroto Nishino, Siamak Amirfakhri, Sophie Hernot, Robert M. Hoffman, Michael Bouvet
      First page: 711
      Abstract: Tumor-specific targeting with fluorescent probes can enhance contrast for identification of cancer during surgical resection and visualize otherwise invisible tumor margins. Nanobodies are the smallest naturally-occurring antigen-binding molecules with rapid pharmacokinetics. The present work demonstrates the efficacy of a fluorescent anti-CEA nanobody conjugated to an IR800 dye to target and label patient derived pancreatic cancer xenografts. After intravenous administration, the probe rapidly localized to the pancreatic cancer tumors within an hour and had a tumor-to-background ratio of 2.0 by 3 h. The fluorescence signal was durable over a prolonged period of time. With the rapid kinetics afforded by fluorescent nanobodies, both targeting and imaging can be performed on the same day as surgery.
      Citation: Biomolecules
      PubDate: 2022-05-16
      DOI: 10.3390/biom12050711
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 712: Insulin-Like Growth Factor-Binding
           Protein 7 (IGFBP-7)—New Diagnostic and Prognostic Marker in
           Symptomatic Peripheral Arterial Disease'—Pilot Study

    • Authors: Anna Szyszkowska, Sylwia Barańska, Robert Sawicki, Ewa Tarasiuk, Marlena Dubatówka, Marcin Kondraciuk, Emilia Sawicka-Śmiarowska, Małgorzata Knapp, Jerzy Głowiński, Karol Kamiński, Anna Lisowska
      First page: 712
      Abstract: The aim of our study was to evaluate the importance of insulin-like growth-factor-binding protein 7 (IGFBP-7) as a potential marker of symptomatic peripheral artery disease (PAD) occurrence. The study group consisted of 145 patients with diagnosed PAD, who qualified for the invasive treatment. The control group consisted of 67 individuals representing the local population and an ischemic heart disease (IHD) group of 88 patients after myocardial infarction or percutaneous coronary intervention. Patients with PAD had significantly higher IGFBP-7 concentrations than control group (1.80 ± 1.62 vs. 1.41 ± 0.45 ng/mL, p = 0.04). No significant differences between PAD patients and IHD patients were found (1.80 ± 1.62 vs. 1.76 ± 1.04 ng/mL, p = 0.783). Patients with multilevel PAD presented significantly higher IGFBP-7 concentrations than patients with aortoiliac PAD—median 1.18 (IQR 0.48–2.23) vs. 1.42 ng/mL (0.71–2.63), p = 0.035. In the group of patients who died or had a major adverse cardiovascular event (MACE) during six months of follow-up, a statistically significant higher IGFBP-7 concentration was found (median 2.66 (IQR 1.80–4.93) vs. 1.36 ng/mL (IQR 0.65–2.34), p = 0.004). It seems that IGFBP-7 is elevated in patients with atherosclerotic lesions—regardless of their locations. Further research should be conducted to verify IGFBP-7 usefulness as a predictor of MACE or death.
      Citation: Biomolecules
      PubDate: 2022-05-17
      DOI: 10.3390/biom12050712
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 713: DYT-PRKRA Mutation P222L Enhances
           PACT’s Stimulatory Activity on Type I Interferon Induction

    • Authors: Lauren S. Vaughn, Kenneth Frederick, Samuel B. Burnett, Nutan Sharma, D. Cristopher Bragg, Sarah Camargos, Francisco Cardoso, Rekha C. Patel
      First page: 713
      Abstract: DYT-PRKRA (dystonia 16 or DYT-PRKRA) is caused by mutations in the PRKRA gene that encodes PACT, the protein activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR). PACT participates in several cellular pathways, of which its role as a PKR activator protein during integrated stress response (ISR) is the best characterized. Previously, we have established that the DYT-PRKRA mutations cause enhanced activation of PKR during ISR to sensitize DYT-PRKRA cells to apoptosis. In this study, we evaluate if the most prevalent substitution mutation reported in DYT-PRKRA patients alters PACT’s functional role in induction of type I IFNs via the retinoic acid-inducible gene I (RIG-I) signaling. Our results indicate that the P222L mutation augments PACT’s ability to induce IFN β in response to dsRNA and the basal expression of IFN β and IFN-stimulated genes (ISGs) is higher in DYT-PRKRA patient cells compared to cells from the unaffected controls. Additionally, IFN β and ISGs are also induced at higher levels in DYT-PRKRA cells in response to dsRNA. These results offer a new avenue for investigations directed towards understanding the underlying molecular pathomechanisms in DYT-PRKRA.
      Citation: Biomolecules
      PubDate: 2022-05-17
      DOI: 10.3390/biom12050713
      Issue No: Vol. 12, No. 5 (2022)
  • Biomolecules, Vol. 12, Pages 714: Cerebral Iron Deposition in

    • Authors: Petr Dusek, Tim Hofer, Jan Alexander, Per M. Roos, Jan O. Aaseth
      First page: 714
      Abstract: Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders.
      Citation: Biomolecules
      PubDate: 2022-05-17
      DOI: 10.3390/biom12050714
      Issue No: Vol. 12, No. 5 (2022)
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