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Editor’s Choice Articles

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

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12 pages, 1255 KiB  
Review
Regulation of the SUV39H Family Methyltransferases: Insights from Fission Yeast
by Rinko Nakamura and Jun-ichi Nakayama
Biomolecules 2023, 13(4), 593; https://doi.org/10.3390/biom13040593 - 25 Mar 2023
Cited by 1 | Viewed by 1975
Abstract
Histones, which make up nucleosomes, undergo various post-translational modifications, such as acetylation, methylation, phosphorylation, and ubiquitylation. In particular, histone methylation serves different cellular functions depending on the location of the amino acid residue undergoing modification, and is tightly regulated by the antagonistic action [...] Read more.
Histones, which make up nucleosomes, undergo various post-translational modifications, such as acetylation, methylation, phosphorylation, and ubiquitylation. In particular, histone methylation serves different cellular functions depending on the location of the amino acid residue undergoing modification, and is tightly regulated by the antagonistic action of histone methyltransferases and demethylases. The SUV39H family of histone methyltransferases (HMTases) are evolutionarily conserved from fission yeast to humans and play an important role in the formation of higher-order chromatin structures called heterochromatin. The SUV39H family HMTases catalyzes the methylation of histone H3 lysine 9 (H3K9), and this modification serves as a binding site for heterochromatin protein 1 (HP1) to form a higher-order chromatin structure. While the regulatory mechanism of this family of enzymes has been extensively studied in various model organisms, Clr4, a fission yeast homologue, has made an important contribution. In this review, we focus on the regulatory mechanisms of the SUV39H family of proteins, in particular, the molecular mechanisms revealed by the studies of the fission yeast Clr4, and discuss their generality in comparison to other HMTases. Full article
(This article belongs to the Special Issue Yeast Models for Gene Regulation)
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28 pages, 6466 KiB  
Article
Genome and Genetic Engineering of the House Cricket (Acheta domesticus): A Resource for Sustainable Agriculture
by Aaron T. Dossey, Brenda Oppert, Fu-Chyun Chu, Marcé D. Lorenzen, Brian Scheffler, Sheron Simpson, Sergey Koren, J. Spencer Johnston, Kosuke Kataoka and Keigo Ide
Biomolecules 2023, 13(4), 589; https://doi.org/10.3390/biom13040589 - 24 Mar 2023
Cited by 2 | Viewed by 6055
Abstract
Background: The house cricket, Acheta domesticus, is one of the most farmed insects worldwide and the foundation of an emerging industry using insects as a sustainable food source. Edible insects present a promising alternative for protein production amid a plethora of reports [...] Read more.
Background: The house cricket, Acheta domesticus, is one of the most farmed insects worldwide and the foundation of an emerging industry using insects as a sustainable food source. Edible insects present a promising alternative for protein production amid a plethora of reports on climate change and biodiversity loss largely driven by agriculture. As with other crops, genetic resources are needed to improve crickets for food and other applications. Methods: We present the first high quality annotated genome assembly of A. domesticus from long read data and scaffolded to chromosome level, providing information needed for genetic manipulation. Results: Gene groups related to immunity were annotated and will be useful for improving value to insect farmers. Metagenome scaffolds in the A. domesticus assembly, including Invertebrate Iridescent Virus 6 (IIV6), were submitted as host-associated sequences. We demonstrate both CRISPR/Cas9-mediated knock-in and knock-out of A. domesticus and discuss implications for the food, pharmaceutical, and other industries. RNAi was demonstrated to disrupt the function of the vermilion eye-color gene producing a useful white-eye biomarker phenotype. Conclusions: We are utilizing these data to develop technologies for downstream commercial applications, including more nutritious and disease-resistant crickets, as well as lines producing valuable bioproducts, such as vaccines and antibiotics. Full article
(This article belongs to the Special Issue The Genomics Era: From Reference Genomes to Pan-Genomic Graphs)
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20 pages, 2777 KiB  
Review
Bacteriophages of the Order Crassvirales: What Do We Currently Know about This Keystone Component of the Human Gut Virome?
by Linda Smith, Ekaterina Goldobina, Bianca Govi and Andrey N. Shkoporov
Biomolecules 2023, 13(4), 584; https://doi.org/10.3390/biom13040584 - 24 Mar 2023
Cited by 6 | Viewed by 2658
Abstract
The order Crassvirales comprises dsDNA bacteriophages infecting bacteria in the phylum Bacteroidetes that are found in a variety of environments but are especially prevalent in the mammalian gut. This review summarises available information on the genomics, diversity, taxonomy, and ecology of this largely [...] Read more.
The order Crassvirales comprises dsDNA bacteriophages infecting bacteria in the phylum Bacteroidetes that are found in a variety of environments but are especially prevalent in the mammalian gut. This review summarises available information on the genomics, diversity, taxonomy, and ecology of this largely uncultured viral taxon. With experimental data available from a handful of cultured representatives, the review highlights key properties of virion morphology, infection, gene expression and replication processes, and phage-host dynamics. Full article
(This article belongs to the Special Issue Virology 130 Years After Ivanovsky—A Theme Issue Commemorating the Discovery of Viruses by Dmitri Ivanovsky)
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13 pages, 782 KiB  
Review
Mechanical Properties and Functions of Elastin: An Overview
by Hanna Trębacz and Angelika Barzycka
Biomolecules 2023, 13(3), 574; https://doi.org/10.3390/biom13030574 - 22 Mar 2023
Cited by 11 | Viewed by 6076
Abstract
Human tissues must be elastic, much like other materials that work under continuous loads without losing functionality. The elasticity of tissues is provided by elastin, a unique protein of the extracellular matrix (ECM) of mammals. Its function is to endow soft tissues with [...] Read more.
Human tissues must be elastic, much like other materials that work under continuous loads without losing functionality. The elasticity of tissues is provided by elastin, a unique protein of the extracellular matrix (ECM) of mammals. Its function is to endow soft tissues with low stiffness, high and fully reversible extensibility, and efficient elastic–energy storage. Depending on the mechanical functions, the amount and distribution of elastin-rich elastic fibers vary between and within tissues and organs. The article presents a concise overview of the mechanical properties of elastin and its role in the elasticity of soft tissues. Both the occurrence of elastin and the relationship between its spatial arrangement and mechanical functions in a given tissue or organ are overviewed. As elastin in tissues occurs only in the form of elastic fibers, the current state of knowledge about their mechanical characteristics, as well as certain aspects of degradation of these fibers and their mechanical performance, is presented. The overview also outlines the latest understanding of the molecular basis of unique physical characteristics of elastin and, in particular, the origin of the driving force of elastic recoil after stretching. Full article
(This article belongs to the Section Biomacromolecules: Proteins)
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15 pages, 1699 KiB  
Review
Heme Scavenging and Delivery: The Role of Human Serum Albumin
by Giovanna De Simone, Romualdo Varricchio, Tommaso Francesco Ruberto, Alessandra di Masi and Paolo Ascenzi
Biomolecules 2023, 13(3), 575; https://doi.org/10.3390/biom13030575 - 22 Mar 2023
Cited by 5 | Viewed by 3472
Abstract
Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must [...] Read more.
Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must be tightly controlled to maintain cellular homeostasis and to avoid pathological conditions. Therefore, different systems have been developed to scavenge either Hb (i.e., haptoglobin (Hp)) or the free heme (i.e., high-density lipoproteins (HDL), low-density lipoproteins (LDL), hemopexin (Hx), and human serum albumin (HSA)). In the first seconds after heme appearance in the plasma, more than 80% of the heme binds to HDL and LDL, and only the remaining 20% binds to Hx and HSA. Then, HSA slowly removes most of the heme from HDL and LDL, and finally, heme transits to Hx, which releases it into hepatic parenchymal cells. The Hx:heme or HSA:heme complexes are internalized via endocytosis mediated by the CD91 and CD71 receptors, respectively. As heme constitutes a major iron source for pathogens, bacteria have evolved hemophores that can extract and uptake heme from host proteins, including HSA:heme. Here, the molecular mechanisms underlying heme scavenging and delivery from HSA are reviewed. Moreover, the relevance of HSA in disease states associated with increased heme plasma concentrations are discussed. Full article
(This article belongs to the Special Issue Hemoproteins and Proteolytic Enzymes: Variations on the Theme of Functional Modulation: A Themed Issue in Honor of Professor Massimo Coletta)
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14 pages, 1278 KiB  
Review
Alternative mRNA Splicing and Promising Therapies in Cancer
by James D. Fackenthal
Biomolecules 2023, 13(3), 561; https://doi.org/10.3390/biom13030561 - 20 Mar 2023
Cited by 5 | Viewed by 2436
Abstract
Cancer is among the leading causes of mortality worldwide. While considerable attention has been given to genetic and epigenetic sources of cancer-specific cellular activities, the role of alternative mRNA splicing has only recently received attention as a major contributor to cancer initiation and [...] Read more.
Cancer is among the leading causes of mortality worldwide. While considerable attention has been given to genetic and epigenetic sources of cancer-specific cellular activities, the role of alternative mRNA splicing has only recently received attention as a major contributor to cancer initiation and progression. The distribution of alternate mRNA splicing variants in cancer cells is different from their non-cancer counterparts, and cancer cells are more sensitive than non-cancer cells to drugs that target components of the splicing regulatory network. While many of the alternatively spliced mRNAs in cancer cells may represent “noise” from splicing dysregulation, certain recurring splicing variants have been shown to contribute to tumor progression. Some pathogenic splicing disruption events result from mutations in cis-acting splicing regulatory sequences in disease-associated genes, while others may result from shifts in balance among naturally occurring alternate splicing variants among mRNAs that participate in cell cycle progression and the regulation of apoptosis. This review provides examples of cancer-related alternate splicing events resulting from each step of mRNA processing and the promising therapies that may be used to address them. Full article
(This article belongs to the Special Issue The Functions and Mechanisms of Microenvironment in Cancer)
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14 pages, 828 KiB  
Review
The Role of the Transcription Factor Nrf2 in Alzheimer’s Disease: Therapeutic Opportunities
by Laura Maria De Plano, Giovanna Calabrese, Maria Giovanna Rizzo, Salvatore Oddo and Antonella Caccamo
Biomolecules 2023, 13(3), 549; https://doi.org/10.3390/biom13030549 - 17 Mar 2023
Cited by 8 | Viewed by 2506
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of the antioxidant response in cells. Under low ROS levels, Nrf2 is kept in the cytoplasm. However, an increase in ROS production leads to a translocation of Nrf2 into the nucleus, where it activates the transcription of several genes involved in the cells’ antioxidant response. Additionally, Nrf2 activation increases autophagy function. However, in AD, the accumulation of Aβ and tau reduces Nrf2 levels, decreasing the antioxidant response. The reduced Nrf2 levels contribute to the further accumulation of Aβ and tau by impairing their autophagy-mediated turnover. In this review, we discuss the overwhelming evidence indicating that genetic or pharmacological activation of Nrf2 is as a potential approach to mitigate AD pathology. Full article
(This article belongs to the Special Issue Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II)
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15 pages, 1519 KiB  
Article
Comparison of Biomolecular Condensate Localization and Protein Phase Separation Predictors
by Erich R. Kuechler, Alex Huang, Jennifer M. Bui, Thibault Mayor and Jörg Gsponer
Biomolecules 2023, 13(3), 527; https://doi.org/10.3390/biom13030527 - 13 Mar 2023
Cited by 2 | Viewed by 2511
Abstract
Research in the field of biochemistry and cellular biology has entered a new phase due to the discovery of phase separation driving the formation of biomolecular condensates, or membraneless organelles, in cells. The implications of this novel principle of cellular organization are vast [...] Read more.
Research in the field of biochemistry and cellular biology has entered a new phase due to the discovery of phase separation driving the formation of biomolecular condensates, or membraneless organelles, in cells. The implications of this novel principle of cellular organization are vast and can be applied at multiple scales, spawning exciting research questions in numerous directions. Of fundamental importance are the molecular mechanisms that underly biomolecular condensate formation within cells and whether insights gained into these mechanisms provide a gateway for accurate predictions of protein phase behavior. Within the last six years, a significant number of predictors for protein phase separation and condensate localization have emerged. Herein, we compare a collection of state-of-the-art predictors on different tasks related to protein phase behavior. We show that the tested methods achieve high AUCs in the identification of biomolecular condensate drivers and scaffolds, as well as in the identification of proteins able to phase separate in vitro. However, our benchmark tests reveal that their performance is poorer when used to predict protein segments that are involved in phase separation or to classify amino acid substitutions as phase-separation-promoting or -inhibiting mutations. Our results suggest that the phenomenological approach used by most predictors is insufficient to fully grasp the complexity of the phenomenon within biological contexts and make reliable predictions related to protein phase behavior at the residue level. Full article
(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)
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12 pages, 3894 KiB  
Article
Kawain Inhibits Urinary Bladder Carcinogenesis through Epigenetic Inhibition of LSD1 and Upregulation of H3K4 Methylation
by Xia Xu, Xuejiao Tian, Liankun Song, Jun Xie, Joseph C. Liao, Joshua J. Meeks, Xue-Ru Wu, Greg E. Gin, Beverly Wang, Edward Uchio and Xiaolin Zi
Biomolecules 2023, 13(3), 521; https://doi.org/10.3390/biom13030521 - 13 Mar 2023
Cited by 2 | Viewed by 1696
Abstract
Epidemiological evidence suggests that kava (Piper methysticum Forst) drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we [...] Read more.
Epidemiological evidence suggests that kava (Piper methysticum Forst) drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we show that dietary feeding of kawain (a major active component in kava root extracts) to mice either before or after hydroxy butyl(butyl) nitrosamine (OH-BBN) carcinogen exposure slows down urinary bladder carcinogenesis and prolongs the survival of the OH-BBN-exposed mice. OH-BBN-induced bladder tumors exhibit significantly increased expression of lysine-specific demethylase 1 (LSD1), accompanied by decreased levels of H3K4 mono-methylation compared to normal bladder epithelium, whereas dietary kawain reverses the effects of OH-BBN on H3K4 mono-methylation. Human bladder cancer tumor tissues at different pathological grades also show significantly increased expression of LSD1 and decreased levels of H3K4 mono-methylation compared to normal urothelium. In addition, kava root extracts and the kavalactones kawain and methysticin all increase the levels of H3K4 mono- and di-methylation, leading to inhibitory effects on cell migration. Taken together, our results suggest that modification of histone lysine methylation may represent a new approach to bladder cancer prevention and treatment and that kavalactones may be promising agents for bladder cancer interception in both current and former smokers. Full article
(This article belongs to the Special Issue Dietary Phytochemicals - Mediated Cellular Signalling, Epigenetics/Epigenomics and Cancer Chemoprevention)
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23 pages, 1711 KiB  
Review
Actions and Consequences of Insulin in the Striatum
by Jyoti C. Patel, Kenneth D. Carr and Margaret E. Rice
Biomolecules 2023, 13(3), 518; https://doi.org/10.3390/biom13030518 - 11 Mar 2023
Cited by 4 | Viewed by 2267
Abstract
Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which [...] Read more.
Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which shows abundant expression of insulin receptors (InsRs) throughout. These receptors are found on interneurons and striatal projections neurons, as well as on glial cells and dopamine axons. A striking functional consequence of insulin elevation in the striatum is promoting an increase in stimulated dopamine release. This boosting of dopamine release involves InsRs on cholinergic interneurons, and requires activation of nicotinic acetylcholine receptors on dopamine axons. Opposing this dopamine-enhancing effect, insulin also increases dopamine uptake through the action of insulin at InsRs on dopamine axons. Insulin acts on other striatal cells as well, including striatal projection neurons and astrocytes that also influence dopaminergic transmission and striatal function. Linking these cellular findings to behavior, striatal insulin signaling is required for the development of flavor–nutrient learning, implicating insulin as a reward signal in the brain. In this review, we discuss these and other actions of insulin in the striatum, including how they are influenced by diet and other physiological states. Full article
(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)
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14 pages, 1975 KiB  
Article
Dysregulation of AMPA Receptor Trafficking and Intracellular Vesicular Sorting in the Prefrontal Cortex of Dopamine Transporter Knock-Out Rats
by Giorgia Targa, Francesca Mottarlini, Beatrice Rizzi, Damiana Leo, Lucia Caffino and Fabio Fumagalli
Biomolecules 2023, 13(3), 516; https://doi.org/10.3390/biom13030516 - 11 Mar 2023
Cited by 1 | Viewed by 1591
Abstract
Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the [...] Read more.
Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT−/−) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity. Full article
(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))
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23 pages, 2458 KiB  
Article
How Clustered DNA Damage Can Change the Electronic Properties of ds-DNA—Differences between GAG, GAOXOG, and OXOGAOXOG
by Boleslaw Karwowski
Biomolecules 2023, 13(3), 517; https://doi.org/10.3390/biom13030517 - 11 Mar 2023
Cited by 2 | Viewed by 1239
Abstract
Every 24 h, roughly 3 × 1017 incidences of DNA damage are generated in the human body as a result of intra- or extra-cellular factors. The structure of the formed lesions is identical to that formed during radio- or chemotherapy. Increases in [...] Read more.
Every 24 h, roughly 3 × 1017 incidences of DNA damage are generated in the human body as a result of intra- or extra-cellular factors. The structure of the formed lesions is identical to that formed during radio- or chemotherapy. Increases in the clustered DNA damage (CDL) level during anticancer treatment have been observed compared to those found in untreated normal tissues. 7,8-dihydro-8-oxo-2′-deoxyguanosine (OXOG) has been recognized as the most common lesion. In these studies, the influence of OXOG, as an isolated (oligo-OG) or clustered DNA lesion (oligo-OGOG), on charge transfer has been analyzed in comparison to native oligo-G. DNA lesion repair depends on the damage recognition step, probably via charge transfer. Here the electronic properties of short ds-oligonucleotides were calculated and analyzed at the M062x/6-31++G** level of theory in a non-equilibrated and equilibrated solvent state. The rate constant of hole and electron transfer according to Marcus’ theory was also discussed. These studies elucidated that OXOG constitutes the sink for migrated radical cations. However, in the case of oligo-OGOG containing a 5′-OXOGAXOXG-3′ sequence, the 3′-End OXOG becomes predisposed to electron-hole accumulation contrary to the undamaged GAG fragment. Moreover, it was found that the 5′-End OXOG present in an OXOGAOXOG fragment adopts a higher adiabatic ionization potential than the 2′-deoxyguanosine of an undamaged analog if both ds-oligos are present in a cationic form. Because increases in CDL formation have been observed during radio- or chemotherapy, understanding their role in the above processes can be crucial for the efficiency and safety of medical cancer treatment. Full article
(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)
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14 pages, 901 KiB  
Review
Melatonin in Health and Disease: A Perspective for Livestock Production
by Zully E. Contreras-Correa, Riley D. Messman, Rebecca M. Swanson and Caleb O. Lemley
Biomolecules 2023, 13(3), 490; https://doi.org/10.3390/biom13030490 - 07 Mar 2023
Cited by 4 | Viewed by 3500
Abstract
Mounting evidence in the literature indicates an important role of endogenous and exogenous melatonin in driving physiological and molecular adaptations in livestock. Melatonin has been extensively studied in seasonally polyestrous animals whereby supplementation studies have been used to adjust circannual rhythms in herds [...] Read more.
Mounting evidence in the literature indicates an important role of endogenous and exogenous melatonin in driving physiological and molecular adaptations in livestock. Melatonin has been extensively studied in seasonally polyestrous animals whereby supplementation studies have been used to adjust circannual rhythms in herds of animals under abnormal photoperiodic conditions. Livestock undergo multiple metabolic and physiological adaptation processes throughout their production cycle which can result in decreased immune response leading to chronic illness, weight loss, or decreased production efficiency; however, melatonin’s antioxidant capacity and immunostimulatory properties could alleviate these effects. The cardiovascular system responds to melatonin and depending on receptor type and localization, melatonin can vasodilate or vasoconstrict several systemic arteries, thereby controlling whole animal nutrient partitioning via vascular resistance. Increased incidences of non-communicable diseases in populations exposed to circadian disruption have uncovered novel pathways of neurohormones, such as melatonin, influence health, and disease. Perturbations in immune function can negatively impact the growth and development of livestock which has been examined following melatonin supplementation. Specifically, melatonin can influence nutrient uptake, circulating nutrient profiles, and endocrine profiles controlling economically important livestock growth and development. This review focuses on the physiological, cellular, and molecular implications of melatonin on the health and disease of domesticated food animals. Full article
(This article belongs to the Special Issue Melatonin in Health and Disease)
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11 pages, 681 KiB  
Review
Distinct Roles of SELENOF in Different Human Cancers
by Brenna Flowers, Oliwia Bochnacka, Allison Poles, Alan M. Diamond and Irida Kastrati
Biomolecules 2023, 13(3), 486; https://doi.org/10.3390/biom13030486 - 06 Mar 2023
Cited by 3 | Viewed by 1760
Abstract
SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its [...] Read more.
SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its molecular function, and the association of genetic variations in the SELENOF gene to cancer risk or outcome. This review summarizes SELENOF’s discovery, structure, cellular localization, and expression. SELENOF belongs to a new family of thioredoxin-like proteins. Published data summarized here indicate a likely role for SELENOF in redox protein quality control, and in the regulation of lipids, glucose, and energy metabolism. Current evidence indicates that loss of SELENOF contributes to the development of prostate and breast cancer, while its loss may be protective against colon cancer. Additional investigation into SELENOF’s molecular mechanisms and its impact on cancer is warranted. Full article
(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)
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21 pages, 968 KiB  
Review
Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders
by Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis and Konstantinos Palikaras
Biomolecules 2023, 13(3), 478; https://doi.org/10.3390/biom13030478 - 05 Mar 2023
Cited by 6 | Viewed by 5022
Abstract
In recent years, advances in science and technology have improved our quality of life, enabling us to tackle diseases and increase human life expectancy. However, longevity is accompanied by an accretion in the frequency of age-related neurodegenerative diseases, creating a growing burden, with [...] Read more.
In recent years, advances in science and technology have improved our quality of life, enabling us to tackle diseases and increase human life expectancy. However, longevity is accompanied by an accretion in the frequency of age-related neurodegenerative diseases, creating a growing burden, with pervasive social impact for human societies. The cost of managing such chronic disorders and the lack of effective treatments highlight the need to decipher their molecular and genetic underpinnings, in order to discover new therapeutic targets. In this effort, the nematode Caenorhabditis elegans serves as a powerful tool to recapitulate several disease-related phenotypes and provides a highly malleable genetic model that allows the implementation of multidisciplinary approaches, in addition to large-scale genetic and pharmacological screens. Its anatomical transparency allows the use of co-expressed fluorescent proteins to track the progress of neurodegeneration. Moreover, the functional conservation of neuronal processes, along with the high homology between nematode and human genomes, render C. elegans extremely suitable for the study of human neurodegenerative disorders. This review describes nematode models used to study neurodegeneration and underscores their contribution in the effort to dissect the molecular basis of human diseases and identify novel gene targets with therapeutic potential. Full article
(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders II)
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15 pages, 2180 KiB  
Article
Solid-State Preparation and Characterization of 2-Hydroxypropylcyclodextrins-Iodine Complexes as Stable Iodophors
by Sandro Dattilo, Fabiola Spitaleri, Danilo Aleo, Maria Grazia Saita and Angela Patti
Biomolecules 2023, 13(3), 474; https://doi.org/10.3390/biom13030474 - 03 Mar 2023
Cited by 5 | Viewed by 2349
Abstract
The use of iodine as antiseptic poses some issues related to its low water solubility and high volatility. Stable solid iodine-containing formulations are highly advisable and currently limited to the povidone-iodine complex. In this study, complexes of molecular iodine with 2-hydroxypropyl α-, β- [...] Read more.
The use of iodine as antiseptic poses some issues related to its low water solubility and high volatility. Stable solid iodine-containing formulations are highly advisable and currently limited to the povidone-iodine complex. In this study, complexes of molecular iodine with 2-hydroxypropyl α-, β- and γ-cyclodextrins were considered water-soluble iodophors and prepared in a solid state by using three different methods (liquid-assisted grinding, co-evaporation and sealed heating). The obtained solids were evaluated for their iodine content and stability over time in different conditions using a fully validated UV method. The assessment of the actual formation of an inclusion complex in a solid state was carried out by thermal analysis, and the presence of iodine was further confirmed by SEM/EDX and XPS analyses. High levels of iodine content (8.3–10.8%) were obtained with all the tested cyclodextrins, and some influence was exerted by the employed preparation method. Potential use as solid iodophors can be envisaged for these iodine complexes, among which those with 2-hydroxypropyl-α-cyclodextrin were found the most stable, regardless of the preparation technique. The three prepared cyclodextrin–iodine complexes proved effective as bactericides against S. epidermidis. Full article
(This article belongs to the Special Issue Cyclodextrin-Based Drug Release and Drug Delivery Systems)
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18 pages, 3741 KiB  
Review
The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism
by Sayaka Harada, Yoshitaka Taketomi, Toshiki Aiba, Mai Kawaguchi, Tetsuya Hirabayashi, Baasanjav Uranbileg, Makoto Kurano, Yutaka Yatomi and Makoto Murakami
Biomolecules 2023, 13(3), 471; https://doi.org/10.3390/biom13030471 - 03 Mar 2023
Cited by 5 | Viewed by 2360
Abstract
The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, [...] Read more.
The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism. Full article
(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)
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13 pages, 954 KiB  
Article
Insulin Resistance Is Associated with an Unfavorable Serum Lipoprotein Lipid Profile in Women with Newly Diagnosed Gestational Diabetes
by Mikael Huhtala, Tapani Rönnemaa and Kristiina Tertti
Biomolecules 2023, 13(3), 470; https://doi.org/10.3390/biom13030470 - 03 Mar 2023
Cited by 3 | Viewed by 1693
Abstract
Background: Gestational diabetes (GDM) is associated with various degrees of insulin resistance—a feature related to increased risk of adverse perinatal outcomes. We aimed to determine the previously poorly investigated associations between maternal insulin resistance and serum fasting metabolome at the time of GDM [...] Read more.
Background: Gestational diabetes (GDM) is associated with various degrees of insulin resistance—a feature related to increased risk of adverse perinatal outcomes. We aimed to determine the previously poorly investigated associations between maternal insulin resistance and serum fasting metabolome at the time of GDM diagnosis. Methods: Serum lipoprotein and amino acid profile was analyzed in 300 subjects with newly diagnosed GDM using a validated nuclear magnetic resonance spectroscopy protocol. Associations between insulin resistance (homeostasis model assessment of insulin resistance, HOMA2-IR) and serum metabolites were examined with linear regression. Results: We found insulin resistance to be associated with a distinct lipid pattern: increased concentration of VLDL triglycerides and phospholipids and total triglycerides. VLDL size was positively related and LDL and HDL sizes were inversely related to insulin resistance. Of fatty acids, increased total fatty acids, relative increase in saturated and monounsaturated fatty acids, and relative decrease in polyunsaturated and omega fatty acids were related to maternal insulin resistance. Conclusions: In newly diagnosed GDM, the association between maternal insulin resistance and serum lipoprotein profile was largely as described in type 2 diabetes. Lifestyle interventions aiming to decrease insulin resistance from early pregnancy could benefit pregnancy outcomes via more advantageous lipid metabolism. Full article
(This article belongs to the Section Molecular Medicine)
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19 pages, 1044 KiB  
Review
Surface Treatments of PEEK for Osseointegration to Bone
by Jay R. Dondani, Janaki Iyer and Simon D. Tran
Biomolecules 2023, 13(3), 464; https://doi.org/10.3390/biom13030464 - 02 Mar 2023
Cited by 15 | Viewed by 2693
Abstract
Polymers, in general, and Poly (Ether-Ether-Ketone) (PEEK) have emerged as potential alternatives to conventional osseous implant biomaterials. Due to its distinct advantages over metallic implants, PEEK has been gaining increasing attention as a prime candidate for orthopaedic and dental implants. However, PEEK has [...] Read more.
Polymers, in general, and Poly (Ether-Ether-Ketone) (PEEK) have emerged as potential alternatives to conventional osseous implant biomaterials. Due to its distinct advantages over metallic implants, PEEK has been gaining increasing attention as a prime candidate for orthopaedic and dental implants. However, PEEK has a highly hydrophobic and bioinert surface that attenuates the differentiation and proliferation of osteoblasts and leads to implant failure. Several improvements have been made to the osseointegration potential of PEEK, which can be classified into three main categories: (1) surface functionalization with bioactive agents by physical or chemical means; (2) incorporation of bioactive materials either as surface coatings or as composites; and (3) construction of three-dimensionally porous structures on its surfaces. The physical treatments, such as plasma treatments of various elements, accelerated neutron beams, or conventional techniques like sandblasting and laser or ultraviolet radiation, change the micro-geometry of the implant surface. The chemical treatments change the surface composition of PEEK and should be titrated at the time of exposure. The implant surface can be incorporated with a bioactive material that should be selected following the desired use, loading condition, and antimicrobial load around the implant. For optimal results, a combination of the methods above is utilized to compensate for the limitations of individual methods. This review summarizes these methods and their combinations for optimizing the surface of PEEK for utilization as an implanted biomaterial. Full article
(This article belongs to the Special Issue Novel Materials for Biomedical Applications)
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12 pages, 902 KiB  
Review
Compounds Inhibiting Noppera-bo, a Glutathione S-transferase Involved in Insect Ecdysteroid Biosynthesis: Novel Insect Growth Regulators
by Kana Ebihara and Ryusuke Niwa
Biomolecules 2023, 13(3), 461; https://doi.org/10.3390/biom13030461 - 02 Mar 2023
Cited by 4 | Viewed by 2767
Abstract
Glutathione S-transferases (GSTs) are conserved in a wide range of organisms, including insects. In 2014, an epsilon GST, known as Noppera-bo (Nobo), was shown to regulate the biosynthesis of ecdysteroid, the principal steroid hormone in insects. Studies on fruit flies, Drosophila melanogaster [...] Read more.
Glutathione S-transferases (GSTs) are conserved in a wide range of organisms, including insects. In 2014, an epsilon GST, known as Noppera-bo (Nobo), was shown to regulate the biosynthesis of ecdysteroid, the principal steroid hormone in insects. Studies on fruit flies, Drosophila melanogaster, and silkworms, Bombyx mori, demonstrated that loss-of-function mutants of nobo fail to synthesize ecdysteroid and die during development, consistent with the essential function of ecdysteroids in insect molting and metamorphosis. This genetic evidence suggests that chemical compounds that inhibit activity of Nobo could be insect growth regulators (IGRs) that kill insects by disrupting their molting and metamorphosis. In addition, because nobo is conserved only in Diptera and Lepidoptera, a Nobo inhibitor could be used to target IGRs in a narrow spectrum of insect taxa. Dipterans include mosquitoes, some of which are vectors of diseases such as malaria and dengue fever. Given that mosquito control is essential to reduce mosquito-borne diseases, new IGRs that specifically kill mosquito vectors are always in demand. We have addressed this issue by identifying and characterizing several chemical compounds that inhibit Nobo protein in both D. melanogaster and the yellow fever mosquito, Aedes aegypti. In this review, we summarize our findings from the search for Nobo inhibitors. Full article
(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)
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18 pages, 4933 KiB  
Article
Novel scFv against Notch Ligand JAG1 Suitable for Development of Cell Therapies toward JAG1-Positive Tumors
by Gabriela Silva, Ana F. Rodrigues, Susana Ferreira, Carolina Matos, Rute P. Eleutério, Gonçalo Marques, Khrystyna Kucheryava, Ana R. Lemos, Pedro M. F. Sousa, Rute Castro, Ana Barbas, Daniel Simão and Paula M. Alves
Biomolecules 2023, 13(3), 459; https://doi.org/10.3390/biom13030459 - 02 Mar 2023
Cited by 1 | Viewed by 2272
Abstract
The Notch signaling ligand JAG1 is overexpressed in various aggressive tumors and is associated with poor clinical prognosis. Hence, therapies targeting oncogenic JAG1 hold great potential for the treatment of certain tumors. Here, we report the identification of specific anti-JAG1 single-chain variable fragments [...] Read more.
The Notch signaling ligand JAG1 is overexpressed in various aggressive tumors and is associated with poor clinical prognosis. Hence, therapies targeting oncogenic JAG1 hold great potential for the treatment of certain tumors. Here, we report the identification of specific anti-JAG1 single-chain variable fragments (scFvs), one of them endowing chimeric antigen receptor (CAR) T cells with cytotoxicity against JAG1-positive cells. Anti-JAG1 scFvs were identified from human phage display libraries, reformatted into full-length monoclonal antibodies (Abs), and produced in mammalian cells. The characterization of these Abs identified two specific anti-JAG1 Abs (J1.B5 and J1.F1) with nanomolar affinities. Cloning the respective scFv sequences in our second- and third-generation CAR backbones resulted in six anti-JAG1 CAR constructs, which were screened for JAG1-mediated T-cell activation in Jurkat T cells in coculture assays with JAG1-positive cell lines. Studies in primary T cells demonstrated that one CAR harboring the J1.B5 scFv significantly induced effective T-cell activation in the presence of JAG1-positive, but not in JAG1-knockout, cancer cells, and enabled specific killing of JAG1-positive cells. Thus, this new anti-JAG1 scFv represents a promising candidate for the development of cell therapies against JAG1-positive tumors. Full article
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13 pages, 692 KiB  
Review
The Amyloid Cascade Hypothesis in Alzheimer’s Disease: Should We Change Our Thinking?
by Markku Kurkinen, Michał Fułek, Katarzyna Fułek, Jan Aleksander Beszłej, Donata Kurpas and Jerzy Leszek
Biomolecules 2023, 13(3), 453; https://doi.org/10.3390/biom13030453 - 01 Mar 2023
Cited by 15 | Viewed by 5725
Abstract
Old age increases the risk of Alzheimer’s disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 [...] Read more.
Old age increases the risk of Alzheimer’s disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aβ peptides and forming β-amyloid fibrils (Aβ42). However, in clinical trials, reducing Aβ peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin hypothesis, synaptic glutamate signaling, and the role of astrocytes and the glutamate transporter EAAT2 in the development of AD. Full article
(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)
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13 pages, 3375 KiB  
Article
Protein Design Using Physics Informed Neural Networks
by Sara Ibrahim Omar, Chen Keasar, Ariel J. Ben-Sasson and Eldad Haber
Biomolecules 2023, 13(3), 457; https://doi.org/10.3390/biom13030457 - 01 Mar 2023
Cited by 3 | Viewed by 2429
Abstract
The inverse protein folding problem, also known as protein sequence design, seeks to predict an amino acid sequence that folds into a specific structure and performs a specific function. Recent advancements in machine learning techniques have been successful in generating functional sequences, outperforming [...] Read more.
The inverse protein folding problem, also known as protein sequence design, seeks to predict an amino acid sequence that folds into a specific structure and performs a specific function. Recent advancements in machine learning techniques have been successful in generating functional sequences, outperforming previous energy function-based methods. However, these machine learning methods are limited in their interoperability and robustness, especially when designing proteins that must function under non-ambient conditions, such as high temperature, extreme pH, or in various ionic solvents. To address this issue, we propose a new Physics-Informed Neural Networks (PINNs)-based protein sequence design approach. Our approach combines all-atom molecular dynamics simulations, a PINNs MD surrogate model, and a relaxation of binary programming to solve the protein design task while optimizing both energy and the structural stability of proteins. We demonstrate the effectiveness of our design framework in designing proteins that can function under non-ambient conditions. Full article
(This article belongs to the Special Issue Advances in Drug Design and Development for Human Therapeutics Using Artificial Intelligence II)
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39 pages, 3251 KiB  
Review
Actin Bundles Dynamics and Architecture
by Sudeepa Rajan, Dmitri S. Kudryashov and Emil Reisler
Biomolecules 2023, 13(3), 450; https://doi.org/10.3390/biom13030450 - 28 Feb 2023
Cited by 8 | Viewed by 4373
Abstract
Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into [...] Read more.
Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into bundles or regulate their morphology is being identified in cells. With recent advances in high-resolution microscopy and imaging techniques, the complex process of bundles formation and the multiple forms of physiological bundles are beginning to be better understood. Here, we review the physiochemical and biological properties of four families of highly conserved and abundant actin-bundling proteins, namely, α-actinin, fimbrin/plastin, fascin, and espin. We describe the similarities and differences between these proteins, their role in the formation of physiological actin bundles, and their properties—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundles formation, which are known from the available information on the activity of the key actin partners involved in this process. Full article
(This article belongs to the Special Issue Actin and Its Associates: Biophysical Aspects in Functional Roles)
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23 pages, 2023 KiB  
Review
Industrial Production of Proteins with Pichia pastoris—Komagataella phaffii
by Giovanni Davide Barone, Anita Emmerstorfer-Augustin, Antonino Biundo, Isabella Pisano, Paola Coccetti, Valeria Mapelli and Andrea Camattari
Biomolecules 2023, 13(3), 441; https://doi.org/10.3390/biom13030441 - 26 Feb 2023
Cited by 17 | Viewed by 6336
Abstract
Since the mid-1960s, methylotrophic yeast Komagataella phaffii (previously described as Pichia pastoris) has received increasing scientific attention. The interest for the industrial production of proteins for different applications (e.g., feed, food additives, detergent, waste treatment processes, and textile) is a well-consolidated scientific topic, [...] Read more.
Since the mid-1960s, methylotrophic yeast Komagataella phaffii (previously described as Pichia pastoris) has received increasing scientific attention. The interest for the industrial production of proteins for different applications (e.g., feed, food additives, detergent, waste treatment processes, and textile) is a well-consolidated scientific topic, and the importance for this approach is rising in the current era of environmental transition in human societies. This review aims to summarize fundamental and specific information in this scientific field. Additionally, an updated description of the relevant products produced with K. phaffii at industrial levels by a variety of companies—describing how the industry has leveraged its key features, from products for the ingredients of meat-free burgers (e.g., IMPOSSIBLE™ FOODS, USA) to diabetes therapeutics (e.g., Biocon, India)—is provided. Furthermore, active patents and the typical workflow for industrial protein production with this strain are reported. Full article
(This article belongs to the Section Biomacromolecules: Proteins)
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16 pages, 2074 KiB  
Article
LC-MS/MS-Based Proteomics Approach for the Identification of Candidate Serum Biomarkers in Patients with Narcolepsy Type 1
by Akeem Sanni, Mona Goli, Jingfu Zhao, Junyao Wang, Chloe Barsa, Samer El Hayek, Farid Talih, Bartolo Lanuzza, Firas Kobeissy, Giuseppe Plazzi, Monica Moresco, Stefania Mondello, Raffaele Ferri and Yehia Mechref
Biomolecules 2023, 13(3), 420; https://doi.org/10.3390/biom13030420 - 23 Feb 2023
Cited by 4 | Viewed by 3543
Abstract
Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities [...] Read more.
Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities in rapid eye movement. To date, no cure has been established for this life-threatening condition. Misdiagnosis of NT1 is also quite common, although it is not exceedingly rare. Therefore, successfully identifying candidate serum biomarkers for NT1 would be a head start for accurate diagnosis and development of therapeutics for this disorder. This study aims to identify such potential serum biomarkers. A depletion protocol was employed for 27 human serum samples (16 NT1 and 11 healthy controls), followed by applying LC-MS/MS bottom-up proteomics analysis, then LC-PRM-MS for validation. The comparison of the proteome profiles of the low-abundant proteins in the samples was then investigated based on age, sex, sample groups, and the presence of the Human Leukocyte Antigen (HLA) DQB1*0602 allele. The results were tracked to gene expression studies as well as system biology to identify key proteins and understand their relationship in the pathogenesis of NT1. Our results revealed 36 proteins significantly and differentially expressed. Among the impaired pathways and bioprocesses, the complement activation pathway is impaired by six of the differentially expressed proteins (DEPs). They are coded by the genes C2, CFB, C5, C1R, C1S, and MASP1, while 11 DEPs are involved in Acute Phase Response Signaling (APRS), which are coded by the genes FN1, AMBP, APOH, CFB, CP, ITIH2, C5, C2, F2, C1, and ITIH4. The combined AUCs of the downregulated and upregulated DEPs are 0.95 and 0.76, respectively. Overall, this study reveals potential serum-protein biomarkers of NT1 and explains the possible correlation between the biomarkers and pathophysiological effects, as well as important biochemical pathways involved in NT1. Full article
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17 pages, 745 KiB  
Review
Molecular Targets in Campylobacter Infections
by Markus M. Heimesaat, Steffen Backert, Thomas Alter and Stefan Bereswill
Biomolecules 2023, 13(3), 409; https://doi.org/10.3390/biom13030409 - 22 Feb 2023
Cited by 3 | Viewed by 3216
Abstract
Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients [...] Read more.
Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients develop abdominal pain and diarrhea. Post-infectious disorders following acute enteritis may occur and affect the nervous system, the joints or the intestines. Immunocompromising comorbidities in infected patients favor bacteremia, leading to vascular inflammation and septicemia. Prevention of human infection is achieved by hygiene measures focusing on the reduction of pathogenic food contamination. Molecular targets for the treatment and prevention of campylobacteriosis include bacterial pathogenicity and virulence factors involved in motility, adhesion, invasion, oxygen detoxification, acid resistance and biofilm formation. This repertoire of intervention measures has recently been completed by drugs dampening the pro-inflammatory immune responses induced by the Campylobacter endotoxin lipo-oligosaccharide. Novel pharmaceutical strategies will combine anti-pathogenic and anti-inflammatory effects to reduce the risk of both anti-microbial resistance and post-infectious sequelae of acute enteritis. Novel strategies and actual trends in the combat of Campylobacter infections are presented in this review, alongside molecular targets applied for prevention and treatment strategies. Full article
(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)
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20 pages, 1533 KiB  
Review
Cellular Pathogenesis of Hepatic Encephalopathy: An Update
by Kaihui Lu
Biomolecules 2023, 13(2), 396; https://doi.org/10.3390/biom13020396 - 19 Feb 2023
Cited by 7 | Viewed by 6108
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been [...] Read more.
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions. Full article
(This article belongs to the Special Issue The Contribution of Astrocytes to Neuropathology)
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23 pages, 2110 KiB  
Article
Using GPT-3 to Build a Lexicon of Drugs of Abuse Synonyms for Social Media Pharmacovigilance
by Kristy A. Carpenter and Russ B. Altman
Biomolecules 2023, 13(2), 387; https://doi.org/10.3390/biom13020387 - 18 Feb 2023
Cited by 7 | Viewed by 4086
Abstract
Drug abuse is a serious problem in the United States, with over 90,000 drug overdose deaths nationally in 2020. A key step in combating drug abuse is detecting, monitoring, and characterizing its trends over time and location, also known as pharmacovigilance. While federal [...] Read more.
Drug abuse is a serious problem in the United States, with over 90,000 drug overdose deaths nationally in 2020. A key step in combating drug abuse is detecting, monitoring, and characterizing its trends over time and location, also known as pharmacovigilance. While federal reporting systems accomplish this to a degree, they often have high latency and incomplete coverage. Social-media-based pharmacovigilance has zero latency, is easily accessible and unfiltered, and benefits from drug users being willing to share their experiences online pseudo-anonymously. However, unlike highly structured official data sources, social media text is rife with misspellings and slang, making automated analysis difficult. Generative Pretrained Transformer 3 (GPT-3) is a large autoregressive language model specialized for few-shot learning that was trained on text from the entire internet. We demonstrate that GPT-3 can be used to generate slang and common misspellings of terms for drugs of abuse. We repeatedly queried GPT-3 for synonyms of drugs of abuse and filtered the generated terms using automated Google searches and cross-references to known drug names. When generated terms for alprazolam were manually labeled, we found that our method produced 269 synonyms for alprazolam, 221 of which were new discoveries not included in an existing drug lexicon for social media. We repeated this process for 98 drugs of abuse, of which 22 are widely-discussed drugs of abuse, building a lexicon of colloquial drug synonyms that can be used for pharmacovigilance on social media. Full article
(This article belongs to the Special Issue Biomolecular Data Science—in Honor of Professor Philip E. Bourne)
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14 pages, 1452 KiB  
Review
Granzyme B in Autoimmune Skin Disease
by Anna Gleave and David J. Granville
Biomolecules 2023, 13(2), 388; https://doi.org/10.3390/biom13020388 - 18 Feb 2023
Cited by 4 | Viewed by 2792
Abstract
Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. [...] Read more.
Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. Hence, there is an unmet need for novel therapies that block molecular drivers of disease in a local and/or targeted manner. Granzyme B (GzmB) is a serine protease with known cytotoxic activity and emerging extracellular functions, including the cleavage of cell–cell junctions, basement membranes, cell receptors, and other structural proteins. While minimal to absent in healthy skin, GzmB is markedly elevated in alopecia areata, interface dermatitis, pemphigoid disease, psoriasis, systemic sclerosis, and vitiligo. This review will discuss the role of GzmB in immunity, blistering, apoptosis, and barrier dysfunction in the context of autoimmune skin disease. GzmB plays a causal role in the development of pemphigoid disease and carries diagnostic and prognostic significance in cutaneous lupus erythematosus, vitiligo, and alopecia areata. Taken together, these data support GzmB as a promising therapeutic target for autoimmune skin diseases impacted by impaired barrier function, inflammation, and/or blistering. Full article
(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)
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15 pages, 2604 KiB  
Review
Opposing Roles of FACT for Euchromatin and Heterochromatin in Yeast
by Shinya Takahata and Yota Murakami
Biomolecules 2023, 13(2), 377; https://doi.org/10.3390/biom13020377 - 16 Feb 2023
Cited by 1 | Viewed by 2316
Abstract
DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is [...] Read more.
DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is characterized into low-density “euchromatin” and high-density “heterochromatin”, with various factors being involved in its regulation. Here, we focus on chromatin regulation and gene expression by the yeast FACT complex, which functions in both euchromatin and heterochromatin. FACT is known as a histone H2A/H2B chaperone and was initially reported as an elongation factor associated with RNA polymerase II. In budding yeast, FACT activates promoter chromatin by interacting with the transcriptional activators SBF/MBF via the regulation of G1/S cell cycle genes. In fission yeast, FACT plays an important role in the formation of higher-order chromatin structures and transcriptional repression by binding to Swi6, an HP1 family protein, at heterochromatin. This FACT property, which refers to the alternate chromatin-regulation depending on the binding partner, is an interesting phenomenon. Further analysis of nucleosome regulation within heterochromatin is expected in future studies. Full article
(This article belongs to the Special Issue Yeast Models for Gene Regulation)
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22 pages, 1726 KiB  
Review
Mitochondrial Neurodegeneration: Lessons from Drosophila melanogaster Models
by Michele Brischigliaro, Erika Fernandez-Vizarra and Carlo Viscomi
Biomolecules 2023, 13(2), 378; https://doi.org/10.3390/biom13020378 - 16 Feb 2023
Cited by 5 | Viewed by 4890
Abstract
The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely [...] Read more.
The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of D. melanogaster models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of D. melanogaster as a model to study mitochondrial disorders. Full article
(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders II)
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14 pages, 541 KiB  
Review
Complement as a Biomarker for Systemic Lupus Erythematosus
by Masahiro Ayano and Takahiko Horiuchi
Biomolecules 2023, 13(2), 367; https://doi.org/10.3390/biom13020367 - 15 Feb 2023
Cited by 9 | Viewed by 5005
Abstract
Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the [...] Read more.
Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the evaluation of complement status can be useful in the diagnosis of SLE, assessment of disease activity, and prediction of treatment response and prognosis. In addition, novel complement biomarkers, such as split products and cell-bound complement activation products, are considered to be more sensitive than traditional complement markers, such as serum C3 and C4 levels and total complement activity (CH50), which become more widely used. In this review, we report the complement testing in the management of SLE over the last decade and summarize their utility. Full article
(This article belongs to the Special Issue Biomarkers in Systemic Lupus Erythematosus)
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19 pages, 2944 KiB  
Review
Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System
by Hidekazu Sotoyama, Hisaaki Namba, Manavu Tohmi and Hiroyuki Nawa
Biomolecules 2023, 13(2), 372; https://doi.org/10.3390/biom13020372 - 15 Feb 2023
Cited by 3 | Viewed by 2646
Abstract
Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the [...] Read more.
Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune–inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors. Full article
(This article belongs to the Special Issue Neurotrophic Factors and Growth Factors - Historical Perspective and New Directions for Medical Use)
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17 pages, 9451 KiB  
Article
Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABAAR Activation
by Anling Kaplan, Abigail I. Nash, Amanda A. H. Freeman, Lauren G. Lewicki, David B. Rye, Lynn Marie Trotti, Asher L. Brandt and Andrew Jenkins
Biomolecules 2023, 13(2), 365; https://doi.org/10.3390/biom13020365 - 15 Feb 2023
Cited by 1 | Viewed by 2301
Abstract
GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABA [...] Read more.
GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABAARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. We determined modulation with both conventional and microfluidic patch clamp methods. We found that receptor activation was variably modulated by all 11 compounds: Rifampicin (RIF), Metronidazole (MET), Minocycline (MIN), Erythromycin (ERY), Ofloxacin (OFX), Chloroquine (CQ), Hydroxychloroquine sulfate (HCQ), Flumazenil (FLZ), Pentylenetetrazol (PTZ), (-)-Epigallocatechin Gallate (EGCG), and clarithromycin (CLR). The computational modeling of modulator–receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. Our findings suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance. Full article
(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)
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20 pages, 44518 KiB  
Article
Mechanistic Analysis of CCP1 in Generating ΔC2 α-Tubulin in Mammalian Cells and Photoreceptor Neurons
by Takashi Hotta, Alexandra Plemmons, Margo Gebbie, Trevor A. Ziehm, Teresa Lynne Blasius, Craig Johnson, Kristen J. Verhey, Jillian N. Pearring and Ryoma Ohi
Biomolecules 2023, 13(2), 357; https://doi.org/10.3390/biom13020357 - 12 Feb 2023
Cited by 2 | Viewed by 1790
Abstract
An important post-translational modification (PTM) of α-tubulin is the removal of amino acids from its C-terminus. Removal of the C-terminal tyrosine residue yields detyrosinated α-tubulin, and subsequent removal of the penultimate glutamate residue produces ΔC2-α-tubulin. These PTMs alter the ability of the α-tubulin [...] Read more.
An important post-translational modification (PTM) of α-tubulin is the removal of amino acids from its C-terminus. Removal of the C-terminal tyrosine residue yields detyrosinated α-tubulin, and subsequent removal of the penultimate glutamate residue produces ΔC2-α-tubulin. These PTMs alter the ability of the α-tubulin C-terminal tail to interact with effector proteins and are thereby thought to change microtubule dynamics, stability, and organization. The peptidase(s) that produces ΔC2-α-tubulin in a physiological context remains unclear. Here, we take advantage of the observation that ΔC2-α-tubulin accumulates to high levels in cells lacking tubulin tyrosine ligase (TTL) to screen for cytosolic carboxypeptidases (CCPs) that generate ΔC2-α-tubulin. We identify CCP1 as the sole peptidase that produces ΔC2-α-tubulin in TTLΔ HeLa cells. Interestingly, we find that the levels of ΔC2-α-tubulin are only modestly reduced in photoreceptors of ccp1−/− mice, indicating that other peptidases act synergistically with CCP1 to produce ΔC2-α-tubulin in post-mitotic cells. Moreover, the production of ΔC2-α-tubulin appears to be under tight spatial control in the photoreceptor cilium: ΔC2-α-tubulin persists in the connecting cilium of ccp1−/− but is depleted in the distal portion of the photoreceptor. This work establishes the groundwork to pinpoint the function of ΔC2-α-tubulin in proliferating and post-mitotic mammalian cells. Full article
(This article belongs to the Special Issue Molecular Functions of Microtubules)
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21 pages, 2296 KiB  
Article
Targeting of the Interleukin-13 Receptor (IL-13R)α2 Expressing Prostate Cancer by a Novel Hybrid Lytic Peptide
by Riaz Jannoo, Zhidao Xia, Paula E. Row and Venkateswarlu Kanamarlapudi
Biomolecules 2023, 13(2), 356; https://doi.org/10.3390/biom13020356 - 12 Feb 2023
Cited by 2 | Viewed by 1549
Abstract
The IL-13Rα2 cell surface receptor is highly expressed in tumours such as prostate cancer. In this report, we evaluated the hypothesis that prostate cancer cells with enhanced IL-13Rα2 expression are a suitable target for the hybrid lytic peptide (Pep-1-Phor21) peptide, which is generated [...] Read more.
The IL-13Rα2 cell surface receptor is highly expressed in tumours such as prostate cancer. In this report, we evaluated the hypothesis that prostate cancer cells with enhanced IL-13Rα2 expression are a suitable target for the hybrid lytic peptide (Pep-1-Phor21) peptide, which is generated by fusing the IL-13Rα2 specific ligand (Pep-1) and a cell membrane disrupting lytic peptide (Phor21). The expression of IL-13Rα2 mRNA and protein in prostate cancer tissues and cell lines was assessed via real-time PCR (RT-PCR) and immunoblotting. The effect of Pep-1-Phor21 on the viability of prostate cancer cells grown in monolayers (2D) and microtissue spheroids (3D) was assessed via CellTox green cytotoxic assay. IL-13Rα2 expression and Pep-1-Phor21-mediated killing were also determined in the cells treated with epigenetic regulators (Trichostatin A (TSA) and 5-aza-2 deoxycytidine (5-Aza-dC)). The hybrid lytic peptide cytotoxic activity correlated with the expression of IL-13Rα2 in prostate cancer cell lines cultured as monolayers (2D) or 3D spheroids. In addition, TSA or 5-Aza-dC treatment of prostate cancer cells, particularly those with low expression of IL-13Rα2, enhanced the cells’ sensitivity to the lytic peptide by increasing IL-13Rα2 expression. These results demonstrate that the Pep-1-Phor21 hybrid lytic peptide has potent and selective anticancer properties against IL-13Rα2-expressing prostate cancer cells. Full article
(This article belongs to the Special Issue Functional Peptides and Their Interactions: From Molecules to Systems)
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18 pages, 2619 KiB  
Article
Novel Green Fluorescent Polyamines to Analyze ATP13A2 and ATP13A3 Activity in the Mammalian Polyamine Transport System
by Marine Houdou, Nathalie Jacobs, Jonathan Coene, Mujahid Azfar, Roeland Vanhoutte, Chris Van den Haute, Jan Eggermont, Veronique Daniëls, Steven H. L. Verhelst and Peter Vangheluwe
Biomolecules 2023, 13(2), 337; https://doi.org/10.3390/biom13020337 - 09 Feb 2023
Cited by 3 | Viewed by 2562
Abstract
Cells acquire polyamines putrescine (PUT), spermidine (SPD) and spermine (SPM) via the complementary actions of polyamine uptake and synthesis pathways. The endosomal P5B-type ATPases ATP13A2 and ATP13A3 emerge as major determinants of mammalian polyamine uptake. Our biochemical evidence shows that fluorescently [...] Read more.
Cells acquire polyamines putrescine (PUT), spermidine (SPD) and spermine (SPM) via the complementary actions of polyamine uptake and synthesis pathways. The endosomal P5B-type ATPases ATP13A2 and ATP13A3 emerge as major determinants of mammalian polyamine uptake. Our biochemical evidence shows that fluorescently labeled polyamines are genuine substrates of ATP13A2. They can be used to measure polyamine uptake in ATP13A2- and ATP13A3-dependent cell models resembling radiolabeled polyamine uptake. We further report that ATP13A3 enables faster and stronger cellular polyamine uptake than does ATP13A2. We also compared the uptake of new green fluorescent PUT, SPD and SPM analogs using different coupling strategies (amide, triazole or isothiocyanate) and fluorophores (symmetrical BODIPY, BODIPY-FL and FITC). ATP13A2 promotes the uptake of various SPD and SPM analogs, whereas ATP13A3 mainly stimulates the uptake of PUT and SPD conjugates. However, the polyamine linker and coupling position on the fluorophore impacts the transport capacity, whereas replacing the fluorophore affects polyamine selectivity. The highest uptake in ATP13A2 or ATP13A3 cells is observed with BODIPY-FL-amide conjugated to SPD, whereas BODIPY-PUT analogs are specifically taken up via ATP13A3. We found that P5B-type ATPase isoforms transport fluorescently labeled polyamine analogs with a distinct structure–activity relationship (SAR), suggesting that isoform-specific polyamine probes can be designed. Full article
(This article belongs to the Special Issue Polyamine Metabolism and Function)
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15 pages, 4316 KiB  
Article
Time- and Sex-Dependent Effects of Fingolimod Treatment in a Mouse Model of Alzheimer’s Disease
by Pablo Bascuñana, Mirjam Brackhan, Luisa Möhle, Jingyun Wu, Thomas Brüning, Ivan Eiriz, Baiba Jansone and Jens Pahnke
Biomolecules 2023, 13(2), 331; https://doi.org/10.3390/biom13020331 - 09 Feb 2023
Cited by 5 | Viewed by 2037
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition. Full article
(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)
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19 pages, 2650 KiB  
Article
Do Amino Acid Antiporters Have Asymmetric Substrate Specificity?
by Gregory Gauthier-Coles, Stephen J. Fairweather, Angelika Bröer and Stefan Bröer
Biomolecules 2023, 13(2), 301; https://doi.org/10.3390/biom13020301 - 06 Feb 2023
Cited by 4 | Viewed by 1363
Abstract
Amino acid antiporters mediate the 1:1 exchange of groups of amino acids. Whether substrate specificity can be different for the inward and outward facing conformation has not been investigated systematically, although examples of asymmetric transport have been reported. Here we used LC–MS to [...] Read more.
Amino acid antiporters mediate the 1:1 exchange of groups of amino acids. Whether substrate specificity can be different for the inward and outward facing conformation has not been investigated systematically, although examples of asymmetric transport have been reported. Here we used LC–MS to detect the movement of 12C- and 13C-labelled amino acid mixtures across the plasma membrane of Xenopus laevis oocytes expressing a variety of amino acid antiporters. Differences of substrate specificity between transporter paralogs were readily observed using this method. Our results suggest that antiporters are largely symmetric, equalizing the pools of their substrate amino acids. Exceptions are the antiporters y+LAT1 and y+LAT2 where neutral amino acids are co-transported with Na+ ions, favouring their import. For the antiporters ASCT1 and ASCT2 glycine acted as a selective influx substrate, while proline was a selective influx substrate of ASCT1. These data show that antiporters can display non-canonical modes of transport. Full article
(This article belongs to the Special Issue Recent Advances in Amino Acid Transporters)
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17 pages, 3315 KiB  
Review
The Actin Network Interfacing Diverse Integrin-Mediated Adhesions
by Benjamin Geiger, Rajaa Boujemaa-Paterski, Sabina E. Winograd-Katz, Jubina Balan Venghateri, Wen-Lu Chung and Ohad Medalia
Biomolecules 2023, 13(2), 294; https://doi.org/10.3390/biom13020294 - 04 Feb 2023
Cited by 4 | Viewed by 2769
Abstract
The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of [...] Read more.
The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of invading cancer cells display distinct morphologies and apparent functions. Yet, all three share a similar composition and mode of coupling between a protrusive structure (the lamellipodium, the core actin bundle of the podosome, and the invadopodia protrusion, respectively), and a nearby adhesion site. Cytoskeletal or external forces, applied to the adhesion sites, trigger a cascade of unfolding and activation of key adhesome components (e.g., talin, vinculin, integrin), which in turn, trigger the assembly of adhesion sites and generation of adhesion-mediated signals that affect cell behavior and fate. The structural and molecular mechanisms underlying the dynamic crosstalk between the actin cytoskeleton and the adhesome network are discussed. Full article
(This article belongs to the Special Issue Actin and Its Associates: Biophysical Aspects in Functional Roles)
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19 pages, 2829 KiB  
Article
Copper Binding and Redox Activity of α-Synuclein in Membrane-Like Environment
by Chiara Bacchella, Francesca Camponeschi, Paulina Kolkowska, Arian Kola, Isabella Tessari, Maria Camilla Baratto, Marco Bisaglia, Enrico Monzani, Luigi Bubacco, Stefano Mangani, Luigi Casella, Simone Dell’Acqua and Daniela Valensin
Biomolecules 2023, 13(2), 287; https://doi.org/10.3390/biom13020287 - 03 Feb 2023
Cited by 4 | Viewed by 1847
Abstract
α-Synuclein (αSyn) constitutes the main protein component of Lewy bodies, which are the pathologic hallmark in Parkinson’s disease. αSyn is unstructured in solution but the interaction of αSyn with lipid membrane modulates its conformation by inducing an α-helical structure of the N-terminal [...] Read more.
α-Synuclein (αSyn) constitutes the main protein component of Lewy bodies, which are the pathologic hallmark in Parkinson’s disease. αSyn is unstructured in solution but the interaction of αSyn with lipid membrane modulates its conformation by inducing an α-helical structure of the N-terminal region. In addition, the interaction with metal ions can trigger αSyn conformation upon binding and/or through the metal-promoted generation of reactive oxygen species which lead to a cascade of structural alterations. For these reasons, the ternary interaction between αSyn, copper, and membranes needs to be elucidated in detail. Here, we investigated the structural properties of copper-αSyn binding through NMR, EPR, and XAS analyses, with particular emphasis on copper(I) coordination since the reduced state is particularly relevant for oxygen activation chemistry. The analysis was performed in different membrane model systems, such as micellar sodium dodecyl sulfate (SDS) and unilamellar vesicles, comparing the binding of full-length αSyn and N-terminal peptide fragments. The presence of membrane-like environments induced the formation of a copper:αSyn = 1:2 complex where Cu+ was bound to the Met1 and Met5 residues of two helical peptide chains. In this coordination, Cu+ is stabilized and is unreactive in the presence of O2 in catechol substrate oxidation. Full article
(This article belongs to the Special Issue Synuclein Proteins II)
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18 pages, 1505 KiB  
Review
Comparative Research: Regulatory Mechanisms of Ribosomal Gene Transcription in Saccharomyces cerevisiae and Schizosaccharomyces pombe
by Hayato Hirai and Kunihiro Ohta
Biomolecules 2023, 13(2), 288; https://doi.org/10.3390/biom13020288 - 03 Feb 2023
Cited by 4 | Viewed by 2429
Abstract
Restricting ribosome biosynthesis and assembly in response to nutrient starvation is a universal phenomenon that enables cells to survive with limited intracellular resources. When cells experience starvation, nutrient signaling pathways, such as the target of rapamycin (TOR) and protein kinase A (PKA), become [...] Read more.
Restricting ribosome biosynthesis and assembly in response to nutrient starvation is a universal phenomenon that enables cells to survive with limited intracellular resources. When cells experience starvation, nutrient signaling pathways, such as the target of rapamycin (TOR) and protein kinase A (PKA), become quiescent, leading to several transcription factors and histone modification enzymes cooperatively and rapidly repressing ribosomal genes. Fission yeast has factors for heterochromatin formation similar to mammalian cells, such as H3K9 methyltransferase and HP1 protein, which are absent in budding yeast. However, limited studies on heterochromatinization in ribosomal genes have been conducted on fission yeast. Herein, we shed light on and compare the regulatory mechanisms of ribosomal gene transcription in two species with the latest insights. Full article
(This article belongs to the Special Issue Yeast Models for Gene Regulation)
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16 pages, 1862 KiB  
Review
Recent Developments in Biopolymer-Based Hydrogels for Tissue Engineering Applications
by Rikako Hama, Anudari Ulziibayar, James W. Reinhardt, Tatsuya Watanabe, John Kelly and Toshiharu Shinoka
Biomolecules 2023, 13(2), 280; https://doi.org/10.3390/biom13020280 - 02 Feb 2023
Cited by 29 | Viewed by 3254
Abstract
Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the [...] Read more.
Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the molecular structure, especially in the case of polymers. Furthermore, many high-functional hydrogels with drug delivery systems (DDSs), in which drugs or bioactive substances are contained in controlled hydrogels, have been reported. This review focuses on the molecular design and function of biopolymer-based hydrogels and introduces recent developments in functional hydrogels for clinical applications. Full article
(This article belongs to the Special Issue Novel Materials for Biomedical Applications)
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18 pages, 5401 KiB  
Article
Oxaliplatin-Induced Damage to the Gastric Innervation: Role in Nausea and Vomiting
by Ahmed A. Rahman, Philenkosini Masango, Rhian Stavely, Paul Bertrand, Amanda Page and Kulmira Nurgali
Biomolecules 2023, 13(2), 276; https://doi.org/10.3390/biom13020276 - 01 Feb 2023
Cited by 2 | Viewed by 1630
Abstract
Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of [...] Read more.
Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility. Full article
(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)
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17 pages, 5756 KiB  
Article
Oligodendrocytes Prune Axons Containing α-Synuclein Aggregates In Vivo: Lewy Neurites as Precursors of Glial Cytoplasmic Inclusions in Multiple System Atrophy?
by Francesco De Nuccio, Marianna Kashyrina, Francesca Serinelli, Florent Laferrière, Dario Domenico Lofrumento, Francesca De Giorgi and François Ichas
Biomolecules 2023, 13(2), 269; https://doi.org/10.3390/biom13020269 - 01 Feb 2023
Cited by 5 | Viewed by 6605
Abstract
α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson’s disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites [...] Read more.
α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson’s disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites in the neuronal processes. In multiple system atrophy (MSA) α-Syn aggregates are also found within mature oligodendrocytes (OLs) where they form Glial Cytoplasmic Inclusions (GCIs). However, the origin of GCIs remains enigmatic: (i) mature OLs do not express α-Syn, precluding the seeding and the buildup of inclusions and (ii) the artificial overexpression of α-Syn in OLs of transgenic mice results in a burden of soluble phosphorylated α-Syn but fails to form α-Syn fibrils. In contrast, mass spectrometry of α-Syn fibrillar aggregates from MSA patients points to the neuronal origin of the proteins intimately associated with the fibrils within the GCIs. This suggests that GCIs are preassembled in neurons and only secondarily incorporated into OLs. Interestingly, we recently isolated a synthetic human α-Syn fibril strain (1B fibrils) capable of seeding a type of neuronal inclusion observed early and specifically during MSA. Our goal was thus to investigate whether the neuronal α-Syn pathology seeded by 1B fibrils could eventually be transmitted to OLs to form GCIs in vivo. After confirming that mature OLs did not express α-Syn to detectable levels in the adult mouse brain, a series of mice received unilateral intra-striatal injections of 1B fibrils. The resulting α-Syn pathology was visualized using phospho-S129 α-Syn immunoreactivity (pSyn). We found that even though 1B fibrils were injected unilaterally, many pSyn-positive neuronal somas were present in layer V of the contralateral perirhinal cortex after 6 weeks. This suggested a fast retrograde spread of the pathology along the axons of crossing cortico-striatal neurons. We thus scrutinized the posterior limb of the anterior commissure, i.e., the myelinated interhemispheric tract containing the axons of these neurons: we indeed observed numerous pSyn-positive linear Lewy Neurites oriented parallel to the commissural axis, corresponding to axonal segments filled with aggregated α-Syn, with no obvious signs of OL α-Syn pathology at this stage. After 6 months however, the commissural Lewy neurites were no longer parallel but fragmented, curled up, sometimes squeezed in-between two consecutive OLs in interfascicular strands, or even engulfed inside OL perikarya, thus forming GCIs. We conclude that the 1B fibril strain can rapidly induce an α-Syn pathology typical of MSA in mice, in which the appearance of GCIs results from the pruning of diseased axonal segments containing aggregated α-Syn. Full article
(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration 2.0)
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44 pages, 5252 KiB  
Review
Cellular and Molecular Mechanisms of Pathogenesis Underlying Inherited Retinal Dystrophies
by Andrew Manley, Bahar I. Meshkat, Monica M. Jablonski and T.J. Hollingsworth
Biomolecules 2023, 13(2), 271; https://doi.org/10.3390/biom13020271 - 01 Feb 2023
Cited by 5 | Viewed by 3683
Abstract
Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The [...] Read more.
Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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16 pages, 1293 KiB  
Review
The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease
by Kyle S. McCommis and Brian N. Finck
Biomolecules 2023, 13(2), 261; https://doi.org/10.3390/biom13020261 - 31 Jan 2023
Cited by 6 | Viewed by 3533
Abstract
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become [...] Read more.
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
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13 pages, 1037 KiB  
Review
Parietal Epithelial Cell Behavior and Its Modulation by microRNA-193a
by Joyita Bharati, Praveen N. Chander and Pravin C. Singhal
Biomolecules 2023, 13(2), 266; https://doi.org/10.3390/biom13020266 - 31 Jan 2023
Cited by 2 | Viewed by 2308
Abstract
Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, [...] Read more.
Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms’ tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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23 pages, 992 KiB  
Review
Nuclear PTEN’s Functions in Suppressing Tumorigenesis: Implications for Rare Cancers
by Casey G. Langdon
Biomolecules 2023, 13(2), 259; https://doi.org/10.3390/biom13020259 - 30 Jan 2023
Cited by 4 | Viewed by 2933
Abstract
Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect [...] Read more.
Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect pediatric and adult populations. Originally discovered and characterized as a negative regulator of the cytoplasmic, pro-oncogenic phosphoinositide-3-kinase (PI3K) pathway, PTEN is also localized to the nucleus where it can exert tumor-suppressive functions in a PI3K pathway-independent manner. Cancers can usurp the tumor-suppressive functions of PTEN to promote oncogenesis by disrupting homeostatic subcellular PTEN localization. The objective of this review is to describe the changes seen in PTEN subcellular localization during tumorigenesis, how PTEN enters the nucleus, and the spectrum of impacts and consequences arising from disrupted PTEN nuclear localization on tumor promotion. This review will highlight the immediate need in understanding not only the cytoplasmic but also the nuclear functions of PTEN to gain more complete insights into how important PTEN is in preventing human cancers. Full article
(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)
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