Biomolecules

14 pages, 1564 KiB

Open AccessEditor’s ChoiceReview

Aquaporin-4 in Neuromyelitis Optica Spectrum Disorders: A Target of Autoimmunity in the Central Nervous System

by Yoichiro Abe and Masato Yasui

Biomolecules 2022, 12(4), 591; https://doi.org/10.3390/biom12040591 - 17 Apr 2022

Cited by 16 | Viewed by 3875

Since the discovery of a specific autoantibody in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2004, the water channel aquaporin-4 (AQP4) has attracted attention as a target of autoimmune diseases of the central nervous system. In NMOSD, the autoantibody (NMO-IgG) binds to [...] Read more.

Since the discovery of a specific autoantibody in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2004, the water channel aquaporin-4 (AQP4) has attracted attention as a target of autoimmune diseases of the central nervous system. In NMOSD, the autoantibody (NMO-IgG) binds to the extracellular loops of AQP4 as expressed in perivascular astrocytic end-feet and disrupts astrocytes in a complement-dependent manner. NMO-IgG is an excellent marker for distinguishing the disease from other inflammatory demyelinating diseases, such as multiple sclerosis. The unique higher-order structure of AQP4—called orthogonal arrays of particles (OAPs)—as well as its subcellular localization may play a crucial role in the pathogenesis of the disease. Recent studies have also demonstrated complement-independent cytotoxic effects of NMO-IgG. Antibody-induced endocytosis of AQP4 has been suggested to be involved in this mechanism. This review focuses on the binding properties of antibodies that recognize the extracellular region of AQP4 and the characteristics of AQP4 that are implicated in the pathogenesis of NMOSD. Full article

(This article belongs to the Special Issue Aquaporins in the CNS–in Honor of the 30th Anniversary of the Discovery of Aquaporins)

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19 pages, 940 KiB

Open AccessEditor’s ChoiceReview

Potential Effects of Natural H₂S-Donors in Hypertension Management

by Eugenia Piragine, Valentina Citi, Kim Lawson, Vincenzo Calderone and Alma Martelli

Biomolecules 2022, 12(4), 581; https://doi.org/10.3390/biom12040581 - 14 Apr 2022

Cited by 17 | Viewed by 3179

Abstract

After the discovery of hydrogen sulfide (H₂S) in the central nervous system by Abe and Kimura in 1996, the physiopathological role of H₂S has been widely investigated in several systems such as the cardiovascular. In particular, H₂S [...] Read more.

After the discovery of hydrogen sulfide (H₂S) in the central nervous system by Abe and Kimura in 1996, the physiopathological role of H₂S has been widely investigated in several systems such as the cardiovascular. In particular, H₂S plays a pivotal role in the control of vascular tone, exhibiting mechanisms of action able to induce vasodilation: for instance, activation of potassium channels (KATP and Kv7) and inhibition of 5-phosphodiesterase (5-PDE). These findings paved the way for the research of natural and synthetic exogenous H₂S-donors (i.e., molecules able to release H₂S) in order to have new tools for the management of hypertension. In this scenario, some natural molecules derived from Alliaceae (i.e., garlic) and Brassicaceae (i.e., rocket or broccoli) botanical families show the profile of slow H₂S-donors able to mimic the endogenous production of this gasotransmitter and therefore can be viewed as interesting potential tools for management of hypertension or pre-hypertension. In this article, the preclinical and clinical impacts of these natural H₂S-donors on hypertension and vascular integrity have been reviewed in order to give a complete panorama of their potential use for the management of hypertension and related vascular diseases. Full article

(This article belongs to the Special Issue Hydrogen Sulfide and Polysulfides, Endogenous Mammalian Transmitters——Honorary Special Issue Commemorating the Work of Prof. Hideo Kimura)

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15 pages, 4081 KiB

Open AccessEditor’s ChoiceReview

The Interplay of Microtubules with Mitochondria–ER Contact Sites (MERCs) in Glioblastoma

by Francesca Grespi, Caterina Vianello, Stefano Cagnin, Marta Giacomello and Agnese De Mario

Biomolecules 2022, 12(4), 567; https://doi.org/10.3390/biom12040567 - 12 Apr 2022

Cited by 5 | Viewed by 3772

Abstract

Gliomas are heterogeneous neoplasms, classified into grade I to IV according to their malignancy and the presence of specific histological/molecular hallmarks. The higher grade of glioma is known as glioblastoma (GB). Although progress has been made in surgical and radiation treatments, its clinical [...] Read more.

Gliomas are heterogeneous neoplasms, classified into grade I to IV according to their malignancy and the presence of specific histological/molecular hallmarks. The higher grade of glioma is known as glioblastoma (GB). Although progress has been made in surgical and radiation treatments, its clinical outcome is still unfavorable. The invasive properties of GB cells and glioma aggressiveness are linked to the reshaping of the cytoskeleton. Recent works suggest that the different susceptibility of GB cells to antitumor immune response is also associated with the extent and function of mitochondria–ER contact sites (MERCs). The presence of MERCs alterations could also explain the mitochondrial defects observed in GB models, including abnormalities of energy metabolism and disruption of apoptotic and calcium signaling. Based on this evidence, the question arises as to whether a MERCs–cytoskeleton crosstalk exists, and whether GB progression is linked to an altered cytoskeleton–MERCs interaction. To address this possibility, in this review we performed a meta-analysis to compare grade I and grade IV GB patients. From this preliminary analysis, we found that GB samples (grade IV) are characterized by altered expression of cytoskeletal and MERCs related genes. Among them, the cytoskeleton-associated protein 4 (CKAP4 or CLIMP-63) appears particularly interesting as it encodes a MERCs protein controlling the ER anchoring to microtubules (MTs). Although further in-depth analyses remain necessary, this perspective review may provide new hints to better understand GB molecular etiopathogenesis, by suggesting that cytoskeletal and MERCs alterations cooperate to exacerbate the cellular phenotype of high-grade GB and that MERCs players can be exploited as novel biomarkers/targets to enhance the current therapy for GB. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders)

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18 pages, 4950 KiB

Open AccessEditor’s ChoiceArticle

Toxic Effects of Endocrine Disruptor Exposure on Collagen-Induced Arthritis

by Ramona D’Amico, Enrico Gugliandolo, Marika Cordaro, Roberta Fusco, Tiziana Genovese, Alessio Filippo Peritore, Rosalia Crupi, Livia Interdonato, Davide Di Paola, Salvatore Cuzzocrea, Daniela Impellizzeri, Rosalba Siracusa and Rosanna Di Paola

Biomolecules 2022, 12(4), 564; https://doi.org/10.3390/biom12040564 - 10 Apr 2022

Cited by 18 | Viewed by 2465

Abstract

Endocrine disruptors (EDs) are chemical substances capable of affecting endocrine system functioning and interfering with organ morphogenesis and physiological functions. The development and regeneration of bone tissues have a complex hormonal regulation, and therefore, bone tissue cells can be considered potential targets for [...] Read more.

Endocrine disruptors (EDs) are chemical substances capable of affecting endocrine system functioning and interfering with organ morphogenesis and physiological functions. The development and regeneration of bone tissues have a complex hormonal regulation, and therefore, bone tissue cells can be considered potential targets for endocrine disruptors. In that regard, the aim of this research was to investigate the impact of ED exposure on the inflammatory response and oxidative stress in an experimental model of collagen-induced arthritis (CIA). Arthritis was induced by an emulsion of type II collagen (CII) and complete Freund’s adjuvant, which was administered intradermally on days 0 and 21. Mice from day 21 to day 35 received the following EDs by oral gavage: cypermethrin (CP), diethyl phthalate (DEP), vinclozolin (VCZ), 17α-ethinylestradiol (EE), perfluorooctanesulfonic acid (PFOS) and atrazine (ATR). ED exposure caused worsening of clinical signs (erythema and edema in the hind paws), histological and radiographic changes, as well as behavioral deficits, induced by CII injections. Furthermore, ED exposure significantly increased the degree of inflammation and oxidative damage induced by arthritis; this upregulation was more evident after exposure to ATR than to other EDs. The results from our study suggest that exposure to EDs may play a deleterious role in the progression of RA; therefore, exposure to EDs should be limited. Full article

(This article belongs to the Special Issue Molecular Effects of Environmental Pollutants on Health of Human, Animals and Plants)

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15 pages, 2438 KiB

Open AccessEditor’s ChoiceArticle

Distribution of Charged Residues Affects the Average Size and Shape of Intrinsically Disordered Proteins

by Greta Bianchi, Marco Mangiagalli, Alberto Barbiroli, Sonia Longhi, Rita Grandori, Carlo Santambrogio and Stefania Brocca

Biomolecules 2022, 12(4), 561; https://doi.org/10.3390/biom12040561 - 9 Apr 2022

Cited by 11 | Viewed by 3128

Abstract

Intrinsically disordered proteins (IDPs) are ensembles of interconverting conformers whose conformational properties are governed by several physico-chemical factors, including their amino acid composition and the arrangement of oppositely charged residues within the primary structure. In this work, we investigate the effects of charge [...] Read more.

Intrinsically disordered proteins (IDPs) are ensembles of interconverting conformers whose conformational properties are governed by several physico-chemical factors, including their amino acid composition and the arrangement of oppositely charged residues within the primary structure. In this work, we investigate the effects of charge patterning on the average compactness and shape of three model IDPs with different proline content. We model IDP ensemble conformations as ellipsoids, whose size and shape are calculated by combining data from size-exclusion chromatography and native mass spectrometry. For each model IDP, we analyzed the wild-type protein and two synthetic variants with permuted positions of charged residues, where positive and negative amino acids are either evenly distributed or segregated. We found that charge clustering induces remodeling of the conformational ensemble, promoting compaction and/or increasing spherical shape. Our data illustrate that the average shape and volume of the ensembles depend on the charge distribution. The potential effect of other factors, such as chain length, number of proline residues, and secondary structure content, is also discussed. This methodological approach is a straightforward way to model IDP average conformation and decipher the salient sequence attributes influencing IDP structural properties. Full article

(This article belongs to the Special Issue Physics of Protein Folding, Misfolding, and Intrinsic Disorder: A Themed Issue in Honour of Professor Vladimir Uversky on the Occasion of His 60th Birthday)

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15 pages, 4421 KiB

Open AccessEditor’s ChoiceArticle

Cell Culture Media, Unlike the Presence of Insulin, Affect α-Synuclein Aggregation in Dopaminergic Neurons

by Irena Hlushchuk, Justyna Barut, Mikko Airavaara, Kelvin Luk, Andrii Domanskyi and Piotr Chmielarz

Biomolecules 2022, 12(4), 563; https://doi.org/10.3390/biom12040563 - 9 Apr 2022

Cited by 4 | Viewed by 3705

Abstract

There are several links between insulin resistance and neurodegenerative disorders such as Parkinson’s disease. However, the direct influence of insulin signaling on abnormal α-synuclein accumulation—a hallmark of Parkinson’s disease—remains poorly explored. To our best knowledge, this work is the first attempt to investigate [...] Read more.

There are several links between insulin resistance and neurodegenerative disorders such as Parkinson’s disease. However, the direct influence of insulin signaling on abnormal α-synuclein accumulation—a hallmark of Parkinson’s disease—remains poorly explored. To our best knowledge, this work is the first attempt to investigate the direct effects of insulin signaling on pathological α-synuclein accumulation induced by the addition of α-synuclein preformed fibrils in primary dopaminergic neurons. We found that modifying insulin signaling through (1) insulin receptor inhibitor GSK1904529A, (2) SHIP2 inhibitor AS1949490 or (3) PTEN inhibitor VO-OHpic failed to significantly affect α-synuclein aggregation in dopaminergic neurons, in contrast to the aggregation-reducing effects observed after the addition of glial cell line-derived neurotrophic factor. Subsequently, we tested different media formulations, with and without insulin. Again, removal of insulin from cell culturing media showed no effect on α-synuclein accumulation. We observed, however, a reduced α-synuclein aggregation in neurons cultured in neurobasal medium with a B27 supplement, regardless of the presence of insulin, in contrast to DMEM/F12 medium with an N2 supplement. The effects of culture conditions were present only in dopaminergic but not in primary cortical or hippocampal cells, indicating the unique sensitivity of the former. Altogether, our data contravene the direct involvement of insulin signaling in the modulation of α-synuclein aggregation in dopamine neurons. Moreover, we show that the choice of culturing media can significantly affect preformed fibril-induced α-synuclein phosphorylation in a primary dopaminergic cell culture. Full article

(This article belongs to the Special Issue Signaling Biomolecules in the Central Nervous System (CNS)—At the Nexus of Neuropsychiatric and Neurodegenerative Disorders)

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21 pages, 2081 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Parkin as a Molecular Bridge Linking Alzheimer’s and Parkinson’s Diseases?

by Frédéric Checler and Cristine Alves da Costa

Biomolecules 2022, 12(4), 559; https://doi.org/10.3390/biom12040559 - 9 Apr 2022

Cited by 4 | Viewed by 3171

Abstract

Alzheimer’s (AD) and Parkinson’s (PD) diseases are two distinct age-related pathologies that are characterized by various common dysfunctions. They are referred to as proteinopathies characterized by ubiquitinated protein accumulation and aggregation. This accumulation is mainly due to altered lysosomal and proteasomal clearing processes [...] Read more.

Alzheimer’s (AD) and Parkinson’s (PD) diseases are two distinct age-related pathologies that are characterized by various common dysfunctions. They are referred to as proteinopathies characterized by ubiquitinated protein accumulation and aggregation. This accumulation is mainly due to altered lysosomal and proteasomal clearing processes and is generally accompanied by ER stress disturbance, autophagic and mitophagic defects, mitochondrial structure and function alterations and enhanced neuronal cell death. Genetic approaches aimed at identifying molecular triggers responsible for familial forms of AD or PD have helped to understand the etiology of their sporadic counterparts. It appears that several proteins thought to contribute to one of these pathologies are also likely to contribute to the other. One such protein is parkin (PK). Here, we will briefly describe anatomical lesions and genetic advances linked to AD and PD as well as the main cellular processes commonly affected in these pathologies. Further, we will focus on current studies suggesting that PK could well participate in AD and thereby act as a molecular bridge between these two pathologies. In particular, we will focus on the transcription factor function of PK and its newly described transcriptional targets that are directly related to AD- and PD-linked cellular defects. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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12 pages, 2442 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Differentiating Inhibitors of Closely Related Protein Kinases with Single- or Multi-Target Activity via Explainable Machine Learning and Feature Analysis

by Christian Feldmann and Jürgen Bajorath

Biomolecules 2022, 12(4), 557; https://doi.org/10.3390/biom12040557 - 8 Apr 2022

Cited by 6 | Viewed by 2334

Abstract

Protein kinases are major drug targets. Most kinase inhibitors are directed against the adenosine triphosphate (ATP) cofactor binding site, which is largely conserved across the human kinome. Hence, such kinase inhibitors are often thought to be promiscuous. However, experimental evidence and activity data [...] Read more.

Protein kinases are major drug targets. Most kinase inhibitors are directed against the adenosine triphosphate (ATP) cofactor binding site, which is largely conserved across the human kinome. Hence, such kinase inhibitors are often thought to be promiscuous. However, experimental evidence and activity data for publicly available kinase inhibitors indicate that this is not generally the case. We have investigated whether inhibitors of closely related human kinases with single- or multi-kinase activity can be differentiated on the basis of chemical structure. Therefore, a test system consisting of two distinct kinase triplets has been devised for which inhibitors with reported triple-kinase activities and corresponding single-kinase activities were assembled. Machine learning models derived on the basis of chemical structure distinguished between these multi- and single-kinase inhibitors with high accuracy. A model-independent explanatory approach was applied to identify structural features determining accurate predictions. For both kinase triplets, the analysis revealed decisive features contained in multi-kinase inhibitors. These features were found to be absent in corresponding single-kinase inhibitors, thus providing a rationale for successful machine learning. Mapping of features determining accurate predictions revealed that they formed coherent and chemically meaningful substructures that were characteristic of multi-kinase inhibitors compared with single-kinase inhibitors. Full article

(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)

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18 pages, 2963 KiB

Open AccessEditor’s ChoiceArticle

Cytokine Profile and Anti-Inflammatory Activity of a Standardized Conditioned Medium Obtained by Coculture of Monocytes and Mesenchymal Stromal Cells (PRS CK STORM)

by Juan Pedro Lapuente, Alejandro Blázquez-Martínez, Joaquín Marco-Brualla, Gonzalo Gómez, Paula Desportes, Jara Sanz, Pablo Fernández, Mario García-Gil, Fernando Bermejo, Juan V. San Martín, Alicia Algaba, Juan Carlos De Gregorio, Daniel Lapuente, Almudena De Gregorio, Belén Lapuente, María de la Viñas Andrés and Alberto Anel

Biomolecules 2022, 12(4), 534; https://doi.org/10.3390/biom12040534 - 31 Mar 2022

Cited by 4 | Viewed by 4020

Abstract

Intercellular communication between monocytes/macrophages and cells involved in tissue regeneration, such as mesenchymal stromal cells (MSCs) and primary tissue cells, is essential for tissue regeneration and recovery of homeostasis. Typically, in the final phase of the inflammation-resolving process, this intercellular communication drives an [...] Read more.

Intercellular communication between monocytes/macrophages and cells involved in tissue regeneration, such as mesenchymal stromal cells (MSCs) and primary tissue cells, is essential for tissue regeneration and recovery of homeostasis. Typically, in the final phase of the inflammation-resolving process, this intercellular communication drives an anti-inflammatory immunomodulatory response. To obtain a safe and effective treatment to counteract the cytokine storm associated with a disproportionate immune response to severe infections, including that associated with COVID-19, by means of naturally balanced immunomodulation, our group has standardized the production under GMP-like conditions of a secretome by coculture of macrophages and MSCs. To characterize this proteome, we determined the expression of molecules related to cellular immune response and tissue regeneration, as well as its possible toxicity and anti-inflammatory potency. The results show a specific molecular pattern of interaction between the two cell types studied, with an anti-inflammatory and regenerative profile. In addition, the secretome is not toxic by itself on human PBMC or on THP-1 monocytes and prevents lipopolysaccharide (LPS)-induced growth effects on those cell types. Finally, PRS CK STORM prevents LPS-induced TNF-A and IL-1Β secretion from PBMC and from THP-1 cells at the same level as hydrocortisone, demonstrating its anti-inflammatory potency. Full article

(This article belongs to the Special Issue New Insights into the Regulation of Inflammation: Mechanisms, Mediators and Therapeutic Targeting)

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18 pages, 4471 KiB

Open AccessEditor’s ChoiceReview

Cellular Distribution of Brain Aquaporins and Their Contribution to Cerebrospinal Fluid Homeostasis and Hydrocephalus

by José Luis Trillo-Contreras, Reposo Ramírez-Lorca, Javier Villadiego and Miriam Echevarría

Biomolecules 2022, 12(4), 530; https://doi.org/10.3390/biom12040530 - 31 Mar 2022

Cited by 11 | Viewed by 2894

Abstract

Brain aquaporins facilitate the movement of water between the four water compartments: blood, cerebrospinal fluid, interstitial fluid, and intracellular fluid. This work analyzes the expression of the four most abundant aquaporins (AQPs) (AQP1, AQP4, AQP9, and AQP11) in the brains of mice and [...] Read more.

Brain aquaporins facilitate the movement of water between the four water compartments: blood, cerebrospinal fluid, interstitial fluid, and intracellular fluid. This work analyzes the expression of the four most abundant aquaporins (AQPs) (AQP1, AQP4, AQP9, and AQP11) in the brains of mice and discuss their contribution to hydrocephalus. We analyzed available data from single-cell RNA sequencing of the central nervous system of mice to describe the expression of aquaporins and compare their distribution with that based on qPCR, western blot, and immunohistochemistry assays. Expression of AQP1 in the apical cell membrane of choroid plexus epithelial cells and of AQP4 in ependymal cells, glia limitans, and astrocyte processes in the pericapillary end foot is consistent with the involvement of both proteins in cerebrospinal fluid homeostasis. The expression of both aquaporins compensates for experimentally induced hydrocephalus in the animals. Recent data demonstrate that hypoxia in aged animals alters AQP4 expression in the choroidal plexus and cortex, increasing the ventricle size and intraventricular pressure. Cerebral distensibility is reduced in parallel with a reduction in cerebrospinal fluid drainage and cognitive deterioration. We propose that aged mice chronically exposed to hypoxia represent an excellent experimental model for studying the pathophysiological characteristics of idiopathic normal pressure hydrocephalus and roles for AQPs in such disease. Full article

(This article belongs to the Special Issue Aquaporins in the CNS–in Honor of the 30th Anniversary of the Discovery of Aquaporins)

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17 pages, 4398 KiB

Open AccessEditor’s ChoiceArticle

Membrane Activity of LL-37 Derived Antimicrobial Peptides against Enterococcus hirae: Superiority of SAAP-148 over OP-145

by Paulina Piller, Heimo Wolinski, Robert A. Cordfunke, Jan Wouter Drijfhout, Sandro Keller, Karl Lohner and Nermina Malanovic

Biomolecules 2022, 12(4), 523; https://doi.org/10.3390/biom12040523 - 30 Mar 2022

Cited by 13 | Viewed by 2436

Abstract

The development of antimicrobial agents against multidrug-resistant bacteria is an important medical challenge. Antimicrobial peptides (AMPs), human cathelicidin LL-37 and its derivative OP-145, possess a potent antimicrobial activity and were under consideration for clinical trials. In order to overcome some of the challenges [...] Read more.

The development of antimicrobial agents against multidrug-resistant bacteria is an important medical challenge. Antimicrobial peptides (AMPs), human cathelicidin LL-37 and its derivative OP-145, possess a potent antimicrobial activity and were under consideration for clinical trials. In order to overcome some of the challenges to their therapeutic potential, a very promising AMP, SAAP-148 was designed. Here, we studied the mode of action of highly cationic SAAP-148 in comparison with OP-145 on membranes of Enterococcus hirae at both cellular and molecular levels using model membranes composed of major constituents of enterococcal membranes, that is, anionic phosphatidylglycerol (PG) and cardiolipin (CL). In all assays used, SAAP-148 was consistently more efficient than OP-145, but both peptides displayed pronounced time and concentration dependences in killing bacteria and performing at the membrane. At cellular level, Nile Red-staining of enterococcal membranes showed abnormalities and cell shrinkage, which is also reflected in depolarization and permeabilization of E. hirae membranes. At the molecular level, both peptides abolished the thermotropic phase transition and induced disruption of PG/CL. Interestingly, the membrane was disrupted before the peptides neutralized the negative surface charge of PG/CL. Our results demonstrate that SAAP-148, which kills bacteria at a significantly lower concentration than OP-145, shows stronger effects on membranes at the cellular and molecular levels. Full article

(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)

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14 pages, 3464 KiB

Open AccessFeature PaperEditor’s ChoiceReview

A Structural Perspective on Calprotectin as a Ligand of Receptors Mediating Inflammation and Potential Drug Target

by Velia Garcia, Yasiru Randika Perera and Walter Jacob Chazin

Biomolecules 2022, 12(4), 519; https://doi.org/10.3390/biom12040519 - 30 Mar 2022

Cited by 10 | Viewed by 4738

Abstract

Calprotectin, a heterodimer of S100A8 and S100A9 EF-hand calcium-binding proteins, is an integral part of the innate immune response. Calprotectin (CP) serves as a ligand for several pattern recognition cell surface receptors including the receptor for advanced glycation end products (RAGE), toll-like receptor [...] Read more.

Calprotectin, a heterodimer of S100A8 and S100A9 EF-hand calcium-binding proteins, is an integral part of the innate immune response. Calprotectin (CP) serves as a ligand for several pattern recognition cell surface receptors including the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and cluster of differentiation 33 (CD33). The receptors initiate kinase signaling cascades that activate inflammation through the NF-kB pathway. Receptor activation by CP leads to upregulation of both receptor and ligand, a positive feedback loop associated with specific chronic inflammatory syndromes. Hence, CP and its two constituent homodimers have been viewed as potential targets to suppress certain chronic inflammation pathologies. A variety of inhibitors of CP and other S100 proteins have been investigated for more than 30 years, but no candidates have advanced significantly into clinical trials. Here, current knowledge of the interactions of CP with its receptors is reviewed along with recent progress towards the development of CP-directed chemotherapeutics. Full article

(This article belongs to the Special Issue S100 Proteins—Intracellular and Extracellular Function in Norm and Pathology)

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16 pages, 8033 KiB

Open AccessEditor’s ChoiceArticle

Mass Spectrometry-Based Proteome Profiling of Extracellular Vesicles Derived from the Cerebrospinal Fluid of Adult Rhesus Monkeys Exposed to Cocaine throughout Gestation

by Hilal A. Rather, Shalini Mishra, Yixin Su, Ashish Kumar, Sangeeta Singh, Biswapriya B. Misra, Jingyun Lee, Cristina M. Furdui, Lindsey R. Hamilton, Robert W. Gould, Susan H. Nader, Michael A. Nader and Gagan Deep

Biomolecules 2022, 12(4), 510; https://doi.org/10.3390/biom12040510 - 28 Mar 2022

Cited by 4 | Viewed by 2643

Abstract

Cocaine use disorder has been reported to cause transgenerational effects. However, due to the lack of standardized biomarkers, the effects of cocaine use during pregnancy on postnatal development and long-term neurobiological and behavioral outcomes have not been investigated thoroughly. Therefore, in this study, [...] Read more.

Cocaine use disorder has been reported to cause transgenerational effects. However, due to the lack of standardized biomarkers, the effects of cocaine use during pregnancy on postnatal development and long-term neurobiological and behavioral outcomes have not been investigated thoroughly. Therefore, in this study, we examined extracellular vesicles (EVs) in adult (~12 years old) female and male rhesus monkeys prenatally exposed to cocaine (n = 11) and controls (n = 9). EVs were isolated from the cerebrospinal fluid (CSF) and characterized for the surface expression of specific tetraspanins, concentration (particles/mL), size distribution, and cargo proteins by mass spectrometry (MS). Transmission electron microscopy following immunogold labeling for tetraspanins (CD63, CD9, and CD81) confirmed the successful isolation of EVs. Nanoparticle tracking analyses showed that the majority of the particles were <200 nm in size, suggesting an enrichment for small EVs (sEV). Interestingly, the prenatally cocaine-exposed group showed ~54% less EV concentration in CSF compared to the control group. For each group, MS analyses identified a number of proteins loaded in CSF-EVs, many of which are commonly listed in the ExoCarta database. Ingenuity pathway analysis (IPA) demonstrated the association of cargo EV proteins with canonical pathways, diseases and disorders, upstream regulators, and top enriched network. Lastly, significantly altered proteins between groups were similarly characterized by IPA, suggesting that prenatal cocaine exposure could be potentially associated with long-term neuroinflammation and risk for neurodegenerative diseases. Overall, these results indicate that CSF-EVs could potentially serve as biomarkers to assess the transgenerational adverse effects due to prenatal cocaine exposure. Full article

(This article belongs to the Special Issue Translational Biomarkers in Addictive Disorders)

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11 pages, 1158 KiB

Open AccessEditor’s ChoiceReview

Cannabis Biomolecule Effects on Cancer Cells and Cancer Stem Cells: Cytotoxic, Anti-Proliferative, and Anti-Migratory Activities

by Hadar Peeri and Hinanit Koltai

Biomolecules 2022, 12(4), 491; https://doi.org/10.3390/biom12040491 - 24 Mar 2022

Cited by 15 | Viewed by 6196

Abstract

Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM [...] Read more.

Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa. Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. Yet, due to scarcity of clinical trials, there remains no solid basis for the anti-cancer therapeutic potential of cannabis compounds. Full article

(This article belongs to the Special Issue Chemistry, Biosynthesis and Biological Activity of Natural Substances: A Themed Issue Dedicated to Professor Evidente)

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27 pages, 3494 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Sarcoplasmic Reticulum of Skeletal Muscle Cells: A Labyrinth of Membrane Contact Sites

by Daniela Rossi, Enrico Pierantozzi, David Osamwonuyi Amadsun, Sara Buonocore, Egidio Maria Rubino and Vincenzo Sorrentino

Biomolecules 2022, 12(4), 488; https://doi.org/10.3390/biom12040488 - 23 Mar 2022

Cited by 8 | Viewed by 9972

Abstract

The sarcoplasmic reticulum of skeletal muscle cells is a highly ordered structure consisting of an intricate network of tubules and cisternae specialized for regulating Ca²⁺ homeostasis in the context of muscle contraction. The sarcoplasmic reticulum contains several proteins, some of which support [...] Read more.

The sarcoplasmic reticulum of skeletal muscle cells is a highly ordered structure consisting of an intricate network of tubules and cisternae specialized for regulating Ca²⁺ homeostasis in the context of muscle contraction. The sarcoplasmic reticulum contains several proteins, some of which support Ca²⁺ storage and release, while others regulate the formation and maintenance of this highly convoluted organelle and mediate the interaction with other components of the muscle fiber. In this review, some of the main issues concerning the biology of the sarcoplasmic reticulum will be described and discussed; particular attention will be addressed to the structure and function of the two domains of the sarcoplasmic reticulum supporting the excitation–contraction coupling and Ca²⁺-uptake mechanisms. Full article

(This article belongs to the Special Issue State-of-the-Art of Myology in Italy 2020–2021)

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30 pages, 2036 KiB

Open AccessEditor’s ChoiceReview

Role of Ion Channel Remodeling in Endothelial Dysfunction Induced by Pulmonary Arterial Hypertension

by Joana Santos-Gomes, Hélène Le Ribeuz, Carmen Brás-Silva, Fabrice Antigny and Rui Adão

Biomolecules 2022, 12(4), 484; https://doi.org/10.3390/biom12040484 - 22 Mar 2022

Cited by 12 | Viewed by 3879

Abstract

Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase [...] Read more.

Endothelial dysfunction is a key player in advancing vascular pathology in pulmonary arterial hypertension (PAH), a disease essentially characterized by intense remodeling of the pulmonary vasculature, vasoconstriction, endothelial dysfunction, inflammation, oxidative stress, and thrombosis in situ. These vascular features culminate in an increase in pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past years, there has been a great development in our understanding of pulmonary endothelial biology related to the genetic and molecular mechanisms that modulate the endothelial response to direct or indirect injury and how their dysregulation can promote PAH pathogenesis. Ion channels are key regulators of vasoconstriction and proliferative/apoptotic phenotypes; however, they are poorly studied at the endothelial level. The current review will describe and categorize different expression, functions, regulation, and remodeling of endothelial ion channels (K⁺, Ca²⁺, Na⁺, and Cl⁻ channels) in PAH. We will focus on the potential pathogenic role of ion channel deregulation in the onset and progression of endothelial dysfunction during the development of PAH and its potential therapeutic role. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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16 pages, 2492 KiB

Open AccessEditor’s ChoiceArticle

Targeted Degradation of 53BP1 Using Ubiquitin Variant Induced Proximity

by Bayonle Aminu, Julia Fux, Evan Mallette, Nathaniel Petersen and Wei Zhang

Biomolecules 2022, 12(4), 479; https://doi.org/10.3390/biom12040479 - 22 Mar 2022

Cited by 5 | Viewed by 3446

Abstract

In recent years, researchers have leveraged the ubiquitin-proteasome system (UPS) to induce selective degradation of proteins by E3 ubiquitin ligases, which has great potential as novel therapeutics for human diseases, including cancer and neurodegenerative disorders. However, despite extensive efforts, only a handful of [...] Read more.

In recent years, researchers have leveraged the ubiquitin-proteasome system (UPS) to induce selective degradation of proteins by E3 ubiquitin ligases, which has great potential as novel therapeutics for human diseases, including cancer and neurodegenerative disorders. However, despite extensive efforts, only a handful of ~600 human E3 ligases were utilized, and numerous protein–protein interaction surfaces on E3 ligases were not explored. To tackle these problems, we leveraged a structure-based protein engineering technology to develop a multi-domain fusion protein bringing functional E3 ligases to the proximity of a target protein to trigger its proteasomal degradation, which we termed Ubiquitin Variant Induced Proximity (UbVIP). We first generated non-inhibitory synthetic UbV binders for a selected group of human E3 ligases. With these UbVs employed as E3 ligase engagers, we designed a library of UbVIPs targeting a DNA damage response protein 53BP1. We observed that two UbVIPs recruiting RFWD3 and NEDD4L could effectively induce proteasome degradation of 53BP1 in human cell lines. This provides a proof-of-principle that UbVs can act as a means of targeted degradation for nucleus-localized proteins. Our work demonstrated that UbV technology is suitable to develop protein-based molecules for targeted degradation and can help identify novel E3 ligases for future therapeutic development. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

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12 pages, 1759 KiB

Open AccessEditor’s ChoiceArticle

Identification of Regions Involved in the Physical Interaction between Melanocortin Receptor Accessory Protein 2 and Prokineticin Receptor 2

by Maria Rosaria Fullone, Daniela Maftei, Martina Vincenzi, Roberta Lattanzi and Rossella Miele

Biomolecules 2022, 12(3), 474; https://doi.org/10.3390/biom12030474 - 20 Mar 2022

Cited by 10 | Viewed by 2042

Abstract

Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an [...] Read more.

Melanocortin Receptor Accessory Protein 2 (MRAP2) modulates the trafficking and signal transduction of several G-protein-coupled receptors (GPCRs) involved in the control of energy homeostasis, such as Prokineticin receptors (PKRs). They bind the endogenous ligand prokineticin 2 (PK2), a novel adipokine that has an anorexic effect and modulates thermoregulation and energy homeostasis. In the present work, we used biochemical techniques to analyze the mechanism of interaction of MRAP2 with PKR2 and we identified the specific amino acid regions involved in the complex formation. Our results indicate that MRAP2 likely binds to the N-terminal region of PKR2, preventing glycosylation and consequently the correct receptor localization. We also identified a C-terminal region of MRAP2 that is critical for the interaction with PKR2. Consequently, we analyzed the role of the prokineticin transduction system in the regulation of MRAP2 expression in tissues involved in the control of food intake: at the central level, in hypothalamic explants, and at the peripheral level, in adipocytes. We demonstrated the modulation of MRAP2 expression by the prokineticin transduction system. Full article

(This article belongs to the Collection Feature Papers in Section Molecular Medicine)

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25 pages, 7004 KiB

Open AccessEditor’s ChoiceReview

Glucose Oxidase, an Enzyme “Ferrari”: Its Structure, Function, Production and Properties in the Light of Various Industrial and Biotechnological Applications

by Jacob A. Bauer, Monika Zámocká, Juraj Majtán and Vladena Bauerová-Hlinková

Biomolecules 2022, 12(3), 472; https://doi.org/10.3390/biom12030472 - 19 Mar 2022

Cited by 70 | Viewed by 14126

Abstract

Glucose oxidase (GOx) is an important oxidoreductase enzyme with many important roles in biological processes. It is considered an “ideal enzyme” and is often called an oxidase “Ferrari” because of its fast mechanism of action, high stability and specificity. Glucose oxidase catalyzes the [...] Read more.

Glucose oxidase (GOx) is an important oxidoreductase enzyme with many important roles in biological processes. It is considered an “ideal enzyme” and is often called an oxidase “Ferrari” because of its fast mechanism of action, high stability and specificity. Glucose oxidase catalyzes the oxidation of

β

-d-glucose to d-glucono-

δ

-lactone and hydrogen peroxide in the presence of molecular oxygen. d-glucono-

δ

-lactone is sequentially hydrolyzed by lactonase to d-gluconic acid, and the resulting hydrogen peroxide is hydrolyzed by catalase to oxygen and water. GOx is presently known to be produced only by fungi and insects. The current main industrial producers of glucose oxidase are Aspergillus and Penicillium. An important property of GOx is its antimicrobial effect against various pathogens and its use in many industrial and medical areas. The aim of this review is to summarize the structure, function, production strains and biophysical and biochemical properties of GOx in light of its various industrial, biotechnological and medical applications. Full article

(This article belongs to the Special Issue Recombinant Enzymes/Proteins in Biotechnology)

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15 pages, 2483 KiB

Open AccessEditor’s ChoiceArticle

Impact of Molecule Concentration, Diffusion Rates and Surface Passivation on Single-Molecule Fluorescence Studies in Solution

by Olessya Yukhnovets, Henning Höfig, Nuno Bustorff, Alexandros Katranidis and Jörg Fitter

Biomolecules 2022, 12(3), 468; https://doi.org/10.3390/biom12030468 - 18 Mar 2022

Cited by 2 | Viewed by 2404

Abstract

For single-molecule studies in solution, very small concentrations of dye-labelled molecules are employed in order to achieve single-molecule sensitivity. In typical studies with confocal microscopes, often concentrations in the pico-molar regime are required. For various applications that make use of single-molecule Förster resonance [...] Read more.

For single-molecule studies in solution, very small concentrations of dye-labelled molecules are employed in order to achieve single-molecule sensitivity. In typical studies with confocal microscopes, often concentrations in the pico-molar regime are required. For various applications that make use of single-molecule Förster resonance energy transfer (smFRET) or two-color coincidence detection (TCCD), the molecule concentration must be set explicitly to targeted values and furthermore needs to be stable over a period of several hours. As a consequence, specific demands must be imposed on the surface passivation of the cover slides during the measurements. The aim of having only one molecule in the detection volume at the time is not only affected by the absolute molecule concentration, but also by the rate of diffusion. Therefore, we discuss approaches to control and to measure absolute molecule concentrations. Furthermore, we introduce an approach to calculate the probability of chance coincidence events and demonstrate that measurements with challenging smFRET samples require a strict limit of maximal sample concentrations in order to produce meaningful results. Full article

(This article belongs to the Special Issue Single-Molecule Protein Dynamics)

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14 pages, 1810 KiB

Open AccessEditor’s ChoiceArticle

Alpha-Synuclein-Specific Naturally Occurring Antibodies Inhibit Aggregation In Vitro and In Vivo

by Anne K. Braczynski, Marc Sevenich, Ian Gering, Tatsiana Kupreichyk, Emil D. Agerschou, Yannick Kronimus, Pardes Habib, Matthias Stoldt, Dieter Willbold, Jörg B. Schulz, Jan-Philipp Bach, Björn H. Falkenburger and Wolfgang Hoyer

Biomolecules 2022, 12(3), 469; https://doi.org/10.3390/biom12030469 - 18 Mar 2022

Cited by 9 | Viewed by 2900

Abstract

Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against [...] Read more.

Parkinson’s disease (PD) is associated with motor and non-motor symptoms and characterized by aggregates of alpha-synuclein (αSyn). Naturally occurring antibodies (nAbs) are part of the innate immune system, produced without prior contact to their specific antigen, and polyreactive. The abundance of nAbs against αSyn is altered in patients with PD. In this work, we biophysically characterized nAbs against αSyn (nAbs-αSyn) and determined their biological effects. nAbs-αSyn were isolated from commercial intravenous immunoglobulins using column affinity purification. Biophysical properties were characterized using a battery of established in vitro assays. Biological effects were characterized in HEK293T cells transiently transfected with fluorescently tagged αSyn. Specific binding of nAbs-αSyn to monomeric αSyn was demonstrated by Dot blot, ELISA, and Surface Plasmon Resonance. nAbs-αSyn did not affect viability of HEK293T cells as reported by Cell Titer Blue and LDH Assays. nAbs-αSyn inhibited fibrillation of αSyn reported by the Thioflavin T aggregation assay. Altered fibril formation was confirmed with atomic force microscopy. In cells transfected with EGFP-tagged αSyn we observed reduced formation of aggresomes, perinuclear accumulations of αSyn aggregates. The results demonstrate that serum of healthy individuals contains nAbs that specifically bind αSyn and inhibit aggregation of αSyn in vitro. The addition of nAbs-αSyn to cultured cells affects intracellular αSyn aggregates. These findings help understanding the role of the innate immune systems for the pathogenesis of PD and suggest that systemic αSyn binding agents could potentially affect neuronal αSyn pathology. Full article

(This article belongs to the Special Issue Synuclein Proteins)

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24 pages, 2520 KiB

Open AccessEditor’s ChoiceReview

Acetylation, Phosphorylation, Ubiquitination (Oh My!): Following Post-Translational Modifications on the Ubiquitin Road

by Rachel E. Lacoursiere, Dania Hadi and Gary S. Shaw

Biomolecules 2022, 12(3), 467; https://doi.org/10.3390/biom12030467 - 18 Mar 2022

Cited by 16 | Viewed by 5336

Abstract

Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is [...] Read more.

Ubiquitination is controlled by a series of E1, E2, and E3 enzymes that can ligate ubiquitin to cellular proteins and dictate the turnover of a substrate and the outcome of signalling events such as DNA damage repair and cell cycle. This process is complex due to the combinatorial power of ~35 E2 and ~1000 E3 enzymes involved and the multiple lysine residues on ubiquitin that can be used to assemble polyubiquitin chains. Recently, mass spectrometric methods have identified that most enzymes in the ubiquitination cascade can be further modified through acetylation or phosphorylation under particular cellular conditions and altered modifications have been noted in different cancers and neurodegenerative diseases. This review provides a cohesive summary of ubiquitination, acetylation, and phosphorylation sites in ubiquitin, the human E1 enzyme UBA1, all E2 enzymes, and some representative E3 enzymes. The potential impacts these post-translational modifications might have on each protein function are highlighted, as well as the observations from human disease. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

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25 pages, 6038 KiB

Open AccessEditor’s ChoiceArticle

Calystegines Improve the Metabolic Activity of Human Adipose Derived Stromal Stem Cells (ASCs) under Hyperglycaemic Condition through the Reduction of Oxidative/ER Stress, Inflammation, and the Promotion of the AKT/PI3K/mTOR Pathway

by Anna Kowalczuk, Nabila Bourebaba, Juliia Panchuk, Krzysztof Marycz and Lynda Bourebaba

Biomolecules 2022, 12(3), 460; https://doi.org/10.3390/biom12030460 - 16 Mar 2022

Cited by 7 | Viewed by 2503

Abstract

Hyperglycaemia and its resulting glucotoxicity are among the most prominent hallmarks of diabetes mellitus (DM) development. Persistent hyperglycaemia further leads to oxidative stress via mitochondrial dysfunction and subsequent ER stress onset, while associated hyperlipidaemia triggers the adipose tissue to secrete pro-inflammatory cytokines. In [...] Read more.

Hyperglycaemia and its resulting glucotoxicity are among the most prominent hallmarks of diabetes mellitus (DM) development. Persistent hyperglycaemia further leads to oxidative stress via mitochondrial dysfunction and subsequent ER stress onset, while associated hyperlipidaemia triggers the adipose tissue to secrete pro-inflammatory cytokines. In this study, the effect of calystegines has been investigated in an experimental model of hyperglycaemia induced on human ASCs cells. Different cellular pathways including apoptosis, oxidative and ER stress, inflammation as well as Pi3K/AKT/mTOR metabolic-associated axis have been evaluated by means on RT-qPCR, western blot, and flow cytometry techniques. Treatment of HuASCs cells with calystegines strongly promoted the hyperglycaemic cells survival and significantly diminished oxidative stress, mitochondrial dynamics failure and ER stress, while improving the endogenous cellular antioxidant defenses. Interestingly, nortropane alkaloids efficiently prevented the hyperglycaemia-mediated inflammatory response, as evidenced by the regulation of the pro- and anti-inflammatory response in HuASCs cells. Finally, we evidenced that calystegines may exert their protective effect on HuASCs cells metabolic functions through the restoration of the defective PI3K/AKT/mTOR pathway. Overall, the present investigation demonstrated that calystegines possess important abilities to protect HuASCs against hyperglycaemia-induced cellular dysfunction, and it evidenced that the observed effects are associated to the promotion of PI3K/AKT/mTOR pathway. Full article

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13 pages, 287 KiB

Open AccessEditor’s ChoiceReview

Applications of Single-Cell Sequencing Technology to the Enteric Nervous System

by Richard A. Guyer, Jessica L. Mueller and Allan M. Goldstein

Biomolecules 2022, 12(3), 452; https://doi.org/10.3390/biom12030452 - 15 Mar 2022

Cited by 4 | Viewed by 3425

Abstract

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, [...] Read more.

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, thus revealing cellular diversity within organs and permitting lineage reconstruction in developing tissues. Application of these methods to the enteric nervous system has yielded a wealth of data and biological insights. We review recent papers applying single-cell sequencing tools to the nascent neural crest and to the developing and mature enteric nervous system. These studies have shown significant diversity of enteric neurons and glia, suggested paradigms for neuronal specification, and revealed signaling pathways active during development. As technology evolves and multiome techniques combining two or more of transcriptomic, genomic, epigenetic, and proteomic data become prominent, we anticipate these modalities will become commonplace in ENS research and may find a role in diagnostic testing and personalized therapeutics. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

27 pages, 4788 KiB

Open AccessEditor’s ChoiceArticle

Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress

by Lidia Ciccone, Giovanni Petrarolo, Francesca Barsuglia, Carole Fruchart-Gaillard, Evelyne Cassar Lajeunesse, Adeniyi T. Adewumi, Mahmoud E. S. Soliman, Concettina La Motta, Elisabetta Orlandini and Susanna Nencetti

Biomolecules 2022, 12(3), 448; https://doi.org/10.3390/biom12030448 - 14 Mar 2022

Cited by 12 | Viewed by 2882

Abstract

Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is [...] Read more.

Aldose reductase (ALR2) is the enzyme in charge of developing cellular toxicity caused by diabetic hyperglycemia, which in turn leads to the generation of reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant anti-oxidant activity through dual-acting agents is now recognized as the gold standard treatment for preventing or at least delaying the progression of diabetic complications. Herein we describe a novel series of (E)-benzaldehyde O-benzyl oximes 6a–e, 7a–e, 8a–e, and 9–11 as ALR2 inhibitors endowed with anti-oxidant properties. Inspired by the natural products, the synthesized derivatives are characterized by a different polyhydroxy substitution pattern on their benzaldehyde fragment, which proved crucial for both the enzyme inhibitory activity and the anti-oxidant capacity. Derivatives (E)-2,3,4-trihydroxybenzaldehyde O-(3-methoxybenzyl) oxime (7b) and (E)-2,3,4-trihydroxybenzaldehyde O-(4-methoxybenzyl) oxime (8b) turned out to be the most effective dual-acting products, proving to combine the best ALR2 inhibitory properties with significant anti-oxidant efficacy. Full article

(This article belongs to the Special Issue Aldose Reductase: Functions, Inhibitors and Molecular Mechanisms)

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25 pages, 3696 KiB

Open AccessEditor’s ChoiceReview

Endogenous Human Proteins Interfering with Amyloid Formation

by Anna L. Gharibyan, Sanduni Wasana Jayaweera, Manuela Lehmann, Intissar Anan and Anders Olofsson

Biomolecules 2022, 12(3), 446; https://doi.org/10.3390/biom12030446 - 14 Mar 2022

Cited by 7 | Viewed by 3380

Abstract

Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents [...] Read more.

Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions. Full article

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23 pages, 1190 KiB

Open AccessEditor’s ChoiceReview

ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives

by Giuseppe Manco, Giuseppina Lacerra, Elena Porzio and Giuliana Catara

Biomolecules 2022, 12(3), 443; https://doi.org/10.3390/biom12030443 - 13 Mar 2022

Cited by 8 | Viewed by 3550

Abstract

Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. [...] Read more.

Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules, regulating a multitude of key functional processes as diverse as DNA damage repair (DDR), transcriptional regulation, intracellular transport, immune and stress responses, and cell survival. Additionally, due to the emerging role of ADP-ribosylation in pathological processes, ADP-ribosyltransferases (ARTs), the enzymes involved in ADPr, are attracting growing interest as new drug targets. In this review, an overview of human ARTs and their related biological functions is provided, mainly focusing on the regulation of ADP-ribosyltransferase Diphtheria toxin-like enzymes (ARTD)-dependent RNA functions. Finally, in order to unravel novel gene functional relationships, we propose the analysis of an inventory of human gene clusters, including ARTDs, which share conserved sequences at 3′ untranslated regions (UTRs). Full article

(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)

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16 pages, 5471 KiB

Open AccessEditor’s ChoiceArticle

Antagonistic L1 Adhesion Molecule Mimetic Compounds Inhibit Glioblastoma Cell Migration In Vitro

by Vini Nagaraj, Mirai Mikhail, Micol Baronio, Alessia Gatto, Ashana Nayak, Thomas Theis, Ugo Cavallaro and Melitta Schachner

Biomolecules 2022, 12(3), 439; https://doi.org/10.3390/biom12030439 - 12 Mar 2022

Cited by 5 | Viewed by 2278

Abstract

Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the consequences of neuronal degeneration in mouse and zebrafish models. Counter-indicative features of L1 were found in tumor progression: the more [...] Read more.

Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the consequences of neuronal degeneration in mouse and zebrafish models. Counter-indicative features of L1 were found in tumor progression: the more L1 is expressed, the more tumor cells migrate and increase their metastatic potential. L1′s metastatic potential is further evidenced by its promotion of epithelial–mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy. These unfortunate features are indicated by observations that cells that normally do not express L1 are induced to express it when becoming malignant. With the aim to ameliorate the devastating functions of L1 in tumors, we designed an alternative approach to counteract tumor cell migration. Libraries of small organic compounds were screened using the ELISA competition approach similar to the one that we used for identifying L1 agonistic mimetics. Whereas in the former approach, a function-triggering monoclonal antibody was used for screening libraries, we here used the function-inhibiting monoclonal antibody 324 that reduces the migration of neurons. We now show that the L1 antagonistic mimetics anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol inhibit the migration of cultured tumor cells in an L1-dependent manner, raising hopes for therapy. Full article

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26 pages, 4898 KiB

Open AccessEditor’s ChoiceReview

The Mechanisms of Restenosis and Relevance to Next Generation Stent Design

by Jessie Clare, Justin Ganly, Christina A. Bursill, Huseyin Sumer, Peter Kingshott and Judy B. de Haan

Biomolecules 2022, 12(3), 430; https://doi.org/10.3390/biom12030430 - 10 Mar 2022

Cited by 25 | Viewed by 4772

Abstract

Stents are lifesaving mechanical devices that re-establish essential blood flow to the coronary circulation after significant vessel occlusion due to coronary vessel disease or thrombolytic blockade. Improvements in stent surface engineering over the last 20 years have seen significant reductions in complications arising [...] Read more.

Stents are lifesaving mechanical devices that re-establish essential blood flow to the coronary circulation after significant vessel occlusion due to coronary vessel disease or thrombolytic blockade. Improvements in stent surface engineering over the last 20 years have seen significant reductions in complications arising due to restenosis and thrombosis. However, under certain conditions such as diabetes mellitus (DM), the incidence of stent-mediated complications remains 2–4-fold higher than seen in non-diabetic patients. The stents with the largest market share are designed to target the mechanisms behind neointimal hyperplasia (NIH) through anti-proliferative drugs that prevent the formation of a neointima by halting the cell cycle of vascular smooth muscle cells (VSMCs). Thrombosis is treated through dual anti-platelet therapy (DAPT), which is the continual use of aspirin and a P2Y₁₂ inhibitor for 6–12 months. While the most common stents currently in use are reasonably effective at treating these complications, there is still significant room for improvement. Recently, inflammation and redox stress have been identified as major contributing factors that increase the risk of stent-related complications following percutaneous coronary intervention (PCI). The aim of this review is to examine the mechanisms behind inflammation and redox stress through the lens of PCI and its complications and to establish whether tailored targeting of these key mechanistic pathways offers improved outcomes for patients, particularly those where stent placement remains vulnerable to complications. In summary, our review highlights the most recent and promising research being undertaken in understanding the mechanisms of redox biology and inflammation in the context of stent design. We emphasize the benefits of a targeted mechanistic approach to decrease all-cause mortality, even in patients with diabetes. Full article

(This article belongs to the Special Issue Endothelial Inflammation and Cardiovascular Dysfunction: Oxidative, Nitrosative and Reticulum Stress)

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29 pages, 1310 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Nuclear-Mitochondrial Interactions

by Brittni R. Walker and Carlos T. Moraes

Biomolecules 2022, 12(3), 427; https://doi.org/10.3390/biom12030427 - 10 Mar 2022

Cited by 31 | Viewed by 5676

Abstract

Mitochondria, the cell’s major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the [...] Read more.

Mitochondria, the cell’s major energy producers, also act as signaling hubs, interacting with other organelles both directly and indirectly. Despite having its own circular genome, the majority of mitochondrial proteins are encoded by nuclear DNA. To respond to changes in cell physiology, the mitochondria must send signals to the nucleus, which can, in turn, upregulate gene expression to alter metabolism or initiate a stress response. This is known as retrograde signaling. A variety of stimuli and pathways fall under the retrograde signaling umbrella. Mitochondrial dysfunction has already been shown to have severe implications for human health. Disruption of retrograde signaling, whether directly associated with mitochondrial dysfunction or cellular environmental changes, may also contribute to pathological deficits. In this review, we discuss known signaling pathways between the mitochondria and the nucleus, examine the possibility of direct contacts, and identify pathological consequences of an altered relationship. Full article

(This article belongs to the Special Issue Mitochondria as a Key Organelle for Novel Treatments Targeting Metabolic Diseases and Aging)

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21 pages, 2987 KiB

Open AccessEditor’s ChoiceReview

Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases

by Stephanie Diaz, Kankan Wang, Benita Sjögren and Xing Liu

Biomolecules 2022, 12(3), 416; https://doi.org/10.3390/biom12030416 - 8 Mar 2022

Cited by 9 | Viewed by 4394

Abstract

Maintenance of protein homeostasis is crucial for virtually every aspect of eukaryotic biology. The ubiquitin-proteasome system (UPS) represents a highly regulated quality control machinery that protects cells from a variety of stress conditions as well as toxic proteins. A large body of evidence [...] Read more.

Maintenance of protein homeostasis is crucial for virtually every aspect of eukaryotic biology. The ubiquitin-proteasome system (UPS) represents a highly regulated quality control machinery that protects cells from a variety of stress conditions as well as toxic proteins. A large body of evidence has shown that UPS dysfunction contributes to the pathogenesis of cardiovascular diseases. This review highlights the latest findings regarding the physiological and pathological roles of cullin-RING ubiquitin ligases (CRLs), an essential player in the UPS, in the cardiovascular system. To inspire potential therapeutic invention, factors regulating CRL activities are also discussed. Full article

(This article belongs to the Special Issue The Ubiquitin Proteasome System (UPS) in Pathogenesis and Diseases)

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13 pages, 3014 KiB

Open AccessEditor’s ChoiceArticle

β-Sheet to Random Coil Transition in Self-Assembling Peptide Scaffolds Promotes Proteolytic Degradation

by Elsa Genové, Nausika Betriu and Carlos E. Semino

Biomolecules 2022, 12(3), 411; https://doi.org/10.3390/biom12030411 - 7 Mar 2022

Cited by 6 | Viewed by 2558

Abstract

One of the most desirable properties that biomaterials designed for tissue engineering or drug delivery applications should fulfill is biodegradation and resorption without toxicity. Therefore, there is an increasing interest in the development of biomaterials able to be enzymatically degraded once implanted at [...] Read more.

One of the most desirable properties that biomaterials designed for tissue engineering or drug delivery applications should fulfill is biodegradation and resorption without toxicity. Therefore, there is an increasing interest in the development of biomaterials able to be enzymatically degraded once implanted at the injury site or once delivered to the target organ. In this paper, we demonstrate the protease sensitivity of self-assembling amphiphilic peptides, in particular, RAD16-I (AcN-RADARADARADARADA-CONH₂), which contains four potential cleavage sites for trypsin. We detected that when subjected to thermal denaturation, the peptide secondary structure suffers a transition from β-sheet to random coil. We also used Matrix-Assisted Laser Desorption/Ionization-Time-Of-Flight (MALDI-TOF) to detect the proteolytic breakdown products of samples subjected to incubation with trypsin as well as atomic force microscopy (AFM) to visualize the effect of the degradation on the nanofiber scaffold. Interestingly, thermally treated samples had a higher extent of degradation than non-denatured samples, suggesting that the transition from β-sheet to random coil leaves the cleavage sites accessible and susceptible to protease degradation. These results indicate that the self-assembling peptide can be reduced to short peptide sequences and, subsequently, degraded to single amino acids, constituting a group of naturally biodegradable materials optimal for their application in tissue engineering and regenerative medicine. Full article

(This article belongs to the Special Issue Biomolecules and Materials Based Approaches in Biomedical Field)

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16 pages, 2424 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Evidence for Enhanced Efficacy of Passive Immunotherapy against Beta-Amyloid in CD33-Negative 5xFAD Mice

by Kathrin Gnoth, Stefanie Geissler, Julia Feldhaus, Nadine Taudte, Victoria Ilse, Sebastian Zürner, Sebastian Greiser, Ulf-Dietrich Braumann, Jens-Ulrich Rahfeld, Holger Cynis and Stephan Schilling

Biomolecules 2022, 12(3), 399; https://doi.org/10.3390/biom12030399 - 4 Mar 2022

Cited by 1 | Viewed by 2627

Abstract

Passive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). Among the different antibodies under development, those targeting post-translationally modified Aβ peptides might combine efficient reduction in beta-amyloid accompanied by lower sequestration in peripheral compartments and thus anticipated and [...] Read more.

Passive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). Among the different antibodies under development, those targeting post-translationally modified Aβ peptides might combine efficient reduction in beta-amyloid accompanied by lower sequestration in peripheral compartments and thus anticipated and reduced treatment-related side effects. In that regard, we recently demonstrated that the antibody-mediated targeting of isoD7-modified Aβ peptides leads to the attenuation of AD-like amyloid pathology in 5xFAD mice. In order to assess novel strategies to enhance the efficacy of passive vaccination approaches, we investigated the role of CD33 for Aβ phagocytosis in transgenic mice treated with an isoD7-Aβ antibody. We crossbred 5xFAD transgenic mice with CD33 knock out (CD33KO) mice and compared the amyloid pathology in the different genotypes of the crossbreds. The knockout of CD33 in 5xFAD mice leads to a significant reduction in Aβ plaques and concomitant rescue of behavioral deficits. Passive immunotherapy of 5xFAD/CD33KO showed a significant increase in plaque-surrounding microglia compared to 5xFAD treated with the antibody. Additionally, we observed a stronger lowering of Aβ plaque load after passive immunotherapy in 5xFAD/CD33KO mice. The data suggest an additive effect of passive immunotherapy and CD33KO in terms of lowering Aβ pathology. Hence, a combination of CD33 antagonists and monoclonal antibodies might represent a strategy to enhance efficacy of passive immunotherapy in AD. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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13 pages, 1597 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Amino Acid Signaling for TOR in Eukaryotes: Sensors, Transducers, and a Sustainable Agricultural fuTORe

by Nanticha Lutt and Jacob O. Brunkard

Biomolecules 2022, 12(3), 387; https://doi.org/10.3390/biom12030387 - 2 Mar 2022

Cited by 11 | Viewed by 3429

Abstract

Eukaryotic cells monitor and regulate metabolism through the atypical protein kinase target of rapamycin (TOR) regulatory hub. TOR is activated by amino acids in animals and fungi through molecular signaling pathways that have been extensively defined in the past ten years. Very recently, [...] Read more.

Eukaryotic cells monitor and regulate metabolism through the atypical protein kinase target of rapamycin (TOR) regulatory hub. TOR is activated by amino acids in animals and fungi through molecular signaling pathways that have been extensively defined in the past ten years. Very recently, several studies revealed that TOR is also acutely responsive to amino acid metabolism in plants, but the mechanisms of amino acid sensing are not yet established. In this review, we summarize these discoveries, emphasizing the diversity of amino acid sensors in human cells and highlighting pathways that are indirectly sensitive to amino acids, i.e., how TOR monitors changes in amino acid availability without a bona fide amino acid sensor. We then discuss the relevance of these model discoveries to plant biology. As plants can synthesize all proteinogenic amino acids from inorganic precursors, we focus on the possibility that TOR senses both organic metabolites and inorganic nutrients. We conclude that an evolutionary perspective on nutrient sensing by TOR benefits both agricultural and biomedical science, contributing to ongoing efforts to generate crops for a sustainable agricultural future. Full article

(This article belongs to the Collection TOR Signaling Pathway)

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17 pages, 1199 KiB

Open AccessEditor’s ChoiceReview

Potential of Using Infrapatellar–Fat–Pad–Derived Mesenchymal Stem Cells for Therapy in Degenerative Arthritis: Chondrogenesis, Exosomes, and Transcription Regulation

by Hsiu-Jung Liao, Chih-Hung Chang, Chi-Ying F. Huang and Hui-Ting Chen

Biomolecules 2022, 12(3), 386; https://doi.org/10.3390/biom12030386 - 1 Mar 2022

Cited by 11 | Viewed by 4142

Abstract

Infrapatellar fat pad–derived mesenchymal stem cells (IPFP-MSCs) are a type of adipose-derived stem cell (ADSC). They potentially contribute to cartilage regeneration and modulation of the immune microenvironment in patients with osteoarthritis (OA). The ability of IPFP-MSCs to increase chondrogenic capacity has been reported [...] Read more.

Infrapatellar fat pad–derived mesenchymal stem cells (IPFP-MSCs) are a type of adipose-derived stem cell (ADSC). They potentially contribute to cartilage regeneration and modulation of the immune microenvironment in patients with osteoarthritis (OA). The ability of IPFP-MSCs to increase chondrogenic capacity has been reported to be greater, less age dependent, and less affected by inflammatory changes than that of other MSCs. Transcription-regulatory factors strictly regulate the cartilage differentiation of MSCs. However, few studies have explored the effect of transcriptional factors on IPFP-MSC-based neocartilage formation, cartilage engineering, and tissue functionality during and after chondrogenesis. Instead of intact MSCs, MSC-derived extracellular vesicles could be used for the treatment of OA. Furthermore, exosomes are increasingly being considered the principal therapeutic agent in MSC secretions that is responsible for the regenerative and immunomodulatory functions of MSCs in cartilage repair. The present study provides an overview of advancements in enhancement strategies for IPFP-MSC chondrogenic differentiation, including the effects of transcriptional factors, the modulation of released exosomes, delivery mechanisms for MSCs, and ethical and regulatory points concerning the development of MSC products. This review will contribute to the understanding of the IPFP-MSC chondrogenic differentiation process and enable the improvement of IPFP-MSC-based cartilage tissue engineering. Full article

(This article belongs to the Collection Mesenchymal Stem Cell Fate and Potential Therapy)

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51 pages, 5141 KiB

Open AccessEditor’s ChoiceArticle

IMGT^®Homo sapiens IG and TR Loci, Gene Order, CNV and Haplotypes: New Concepts as a Paradigm for Jawed Vertebrates Genome Assemblies

by Marie-Paule Lefranc and Gérard Lefranc

Biomolecules 2022, 12(3), 381; https://doi.org/10.3390/biom12030381 - 28 Feb 2022

Cited by 5 | Viewed by 3060

Abstract

IMGT^®, the international ImMunoGeneTics information system^®, created in 1989, by Marie-Paule Lefranc (Université de Montpellier and CNRS), marked the advent of immunoinformatics, a new science which emerged at the interface between immunogenetics and bioinformatics for the study of the [...] Read more.

IMGT^®, the international ImMunoGeneTics information system^®, created in 1989, by Marie-Paule Lefranc (Université de Montpellier and CNRS), marked the advent of immunoinformatics, a new science which emerged at the interface between immunogenetics and bioinformatics for the study of the adaptive immune responses. IMGT^® is based on a standardized nomenclature of the immunoglobulin (IG) and T cell receptor (TR) genes and alleles from fish to humans and on the IMGT unique numbering for the variable (V) and constant (C) domains of the immunoglobulin superfamily (IgSF) of vertebrates and invertebrates, and for the groove (G) domain of the major histocompatibility (MH) and MH superfamily (MhSF) proteins. IMGT^® comprises 7 databases, 17 tools and more than 25,000 pages of web resources for sequences, genes and structures, based on the IMGT Scientific chart rules generated from the IMGT-ONTOLOGY axioms and concepts. IMGT^® reference directories are used for the analysis of the NGS high-throughput expressed IG and TR repertoires (natural, synthetic and/or bioengineered) and for bridging sequences, two-dimensional (2D) and three-dimensional (3D) structures. This manuscript focuses on the IMGT^®Homo sapiens IG and TR loci, gene order, copy number variation (CNV) and haplotypes new concepts, as a paradigm for jawed vertebrates genome assemblies. Full article

(This article belongs to the Collection Feature Papers in Synthetic Biology and Bioengineering)

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19 pages, 3457 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of Membrane Lipids in Light-Activation of Drosophila TRP Channels

by Rita Gutorov, Ben Katz, Elisheva Rhodes-Mordov, Rachel Zaguri, Tal Brandwine-Shemmer and Baruch Minke

Biomolecules 2022, 12(3), 382; https://doi.org/10.3390/biom12030382 - 28 Feb 2022

Cited by 2 | Viewed by 3185

Abstract

Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to [...] Read more.

Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to play a fundamental role in channel activation and regulation. A prominent example is the Drosophila TRP and TRP-like (TRPL) channels, which are predominantly expressed in the visual system of Drosophila. Light activation of the TRP and TRPL channels, the founding members of the TRP channel superfamily, requires activation of phospholipase Cβ (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) into Diacylglycerol (DAG) and Inositol 1, 4,5-trisphosphate (IP₃). However, the events required for channel gating downstream of PLC activation are still under debate and led to several hypotheses regarding the mechanisms by which lipids gate the channels. Despite many efforts, compelling evidence of the involvement of DAG accumulation, PIP₂ depletion or IP₃-mediated Ca²⁺ release in light activation of the TRP/TRPL channels are still lacking. Exogeneous application of poly unsaturated fatty acids (PUFAs), a product of DAG hydrolysis was demonstrated as an efficient way to activate the Drosophila TRP/TRPL channels. However, compelling evidence for the involvement of PUFAs in physiological light-activation of the TRP/TRPL channels is still lacking. Light-induced mechanical force generation was measured in photoreceptor cells prior to channel opening. This mechanical force depends on PLC activity, suggesting that the enzymatic activity of PLC converting PIP₂ into DAG generates membrane tension, leading to mechanical gating of the channels. In this review, we will present the roles of membrane lipids in light activation of Drosophila TRP channels and present the many advantages of this model system in the exploration of TRP channel activation under physiological conditions. Full article

(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)

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20 pages, 2822 KiB

Open AccessEditor’s ChoiceArticle

Recognition of ATT Triplex and DNA:RNA Hybrid Structures by Benzothiazole Ligands

by Iva Zonjić, Lidija-Marija Tumir, Ivo Crnolatac, Filip Šupljika, Livio Racané, Sanja Tomić and Marijana Radić Stojković

Biomolecules 2022, 12(3), 374; https://doi.org/10.3390/biom12030374 - 27 Feb 2022

Cited by 2 | Viewed by 3104

Abstract

Interactions of an array of nucleic acid structures with a small series of benzothiazole ligands (bis-benzothiazolyl-pyridines—group 1, 2-thienyl/2-benzothienyl-substituted 6-(2-imidazolinyl)benzothiazoles—group 2, and three 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazoles—group 3) were screened by competition dialysis. Due to the involvement of DNA:RNA hybrids and triplex helices in many essential [...] Read more.

Interactions of an array of nucleic acid structures with a small series of benzothiazole ligands (bis-benzothiazolyl-pyridines—group 1, 2-thienyl/2-benzothienyl-substituted 6-(2-imidazolinyl)benzothiazoles—group 2, and three 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazoles—group 3) were screened by competition dialysis. Due to the involvement of DNA:RNA hybrids and triplex helices in many essential functions in cells, this study’s main aim is to detect benzothiazole-based moieties with selective binding or spectroscopic response to these nucleic structures compared to regular (non-hybrid) DNA and RNA duplexes and single-stranded forms. Complexes of nucleic acids and benzothiazoles, selected by this method, were characterized by UV/Vis, fluorescence and circular dichroism (CD) spectroscopy, isothermal titration calorimetry, and molecular modeling. Two compounds (1 and 6) from groups 1 and 2 demonstrated the highest affinities against 13 nucleic acid structures, while another compound (5) from group 2, despite lower affinities, yielded higher selectivity among studied compounds. Compound 1 significantly inhibited RNase H. Compound 6 could differentiate between B- (binding of 6 dimers inside minor groove) and A-type (intercalation) helices by an induced CD signal, while both 5 and 6 selectively stabilized ATT triplex in regard to AT duplex. Compound 3 induced strong condensation-like changes in CD spectra of AT-rich DNA sequences. Full article

(This article belongs to the Special Issue Polynucleotides)

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15 pages, 1350 KiB

Open AccessEditor’s ChoiceReview

Metallothionein and Cadmium Toxicology—Historical Review and Commentary

by Monica Nordberg and Gunnar F. Nordberg

Biomolecules 2022, 12(3), 360; https://doi.org/10.3390/biom12030360 - 24 Feb 2022

Cited by 64 | Viewed by 5522

Abstract

More than one and a half centuries ago, adverse human health effects were reported after use of a cadmium-containing silver polishing agent. Long-term cadmium exposure gives rise to kidney or bone disease, reproductive toxicity and cancer in animals and humans. At present, high [...] Read more.

More than one and a half centuries ago, adverse human health effects were reported after use of a cadmium-containing silver polishing agent. Long-term cadmium exposure gives rise to kidney or bone disease, reproductive toxicity and cancer in animals and humans. At present, high human exposures to cadmium occur in small-scale mining, underlining the need for preventive measures. This is particularly urgent in view of the growing demand for minerals and metals in global climate change mitigation. This review deals with a specific part of cadmium toxicology that is important for understanding when toxic effects appear and, thus, is crucial for risk assessment. The discovery of the low-molecular-weight protein metallothionein (MT) in 1957 was an important milestone because, when this protein binds cadmium, it modifies cellular cadmium toxicity. The present authors contributed evidence in the 1970s concerning cadmium binding to MT and synthesis of the protein in tissues. We showed that binding of cadmium to metallothionein in tissues prevented some toxic effects, but that metallothionein can increase the transport of cadmium to the kidneys. Special studies showed the importance of the Cd/Zn ratio in MT for expression of toxicity in the kidneys. We also developed models of cadmium toxicokinetics based on our MT-related findings. This model combined with estimates of tissue levels giving rise to toxicity, made it possible to calculate expected risks in relation to exposure. Other scientists developed these models further and international organizations have successfully used these amended models in recent publications. Our contributions in recent decades included studies in humans of MT-related biomarkers showing the importance of MT gene expression in lymphocytes and MT autoantibodies for risks of Cd-related adverse effects in cadmium-exposed population groups. In a study of the impact of zinc status on the risk of kidney dysfunction in a cadmium-exposed group, the risks were low when zinc status was good and high when zinc status was poor. The present review summarizes this evidence in a risk assessment context and calls for its application in order to improve preventive measures against adverse effects of cadmium exposures in humans and animals. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2021)

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15 pages, 6819 KiB

Open AccessEditor’s ChoiceArticle

Correlation of Serum Acylcarnitines with Clinical Presentation and Severity of Coronary Artery Disease

by Olga Deda, Eleftherios Panteris, Thomas Meikopoulos, Olga Begou, Thomai Mouskeftara, Efstratios Karagiannidis, Andreas S. Papazoglou, Georgios Sianos, Georgios Theodoridis and Helen Gika

Biomolecules 2022, 12(3), 354; https://doi.org/10.3390/biom12030354 - 23 Feb 2022

Cited by 15 | Viewed by 2624

Abstract

Recent studies support that acylcarnitines exert a significant role in cardiovascular disease development and progression. The aim of this metabolomics-based study was to investigate the association of serum acylcarnitine levels with coronary artery disease (CAD) severity, as assessed via SYNTAX Score. Within the [...] Read more.

Recent studies support that acylcarnitines exert a significant role in cardiovascular disease development and progression. The aim of this metabolomics-based study was to investigate the association of serum acylcarnitine levels with coronary artery disease (CAD) severity, as assessed via SYNTAX Score. Within the context of the prospective CorLipid trial (NCT04580173), the levels of 13 circulating acylcarnitines were accurately determined through a newly developed HILIC-MS/MS method in 958 patients undergoing coronary angiography in the AHEPA University Hospital of Thessaloniki, Greece. Patients presenting with acute coronary syndrome had significantly lower median acylcarnitine C8, C10, C16, C18:1 and C18:2 values, compared to patients with chronic coronary syndrome (p = 0.012, 0.007, 0.018, 0.011 and <0.001, respectively). Among CAD subgroups, median C5 levels were significantly decreased in unstable angina compared to STEMI (p = 0.026), while median C10, C16, C18:1 and C18:2 levels were higher in stable angina compared to STEMI (p = 0.019 p = 0.012, p = 0.013 and p < 0.001, respectively). Moreover, median C2, C3, C4 and C8 levels were significantly elevated in patients with diabetes mellitus (p < 0.001, <0.001, 0.029 and 0.011, respectively). Moreover, short-chain acylcarnitine C2, C4, C5 and C6 levels were elevated in patients with heavier calcification and lower left ventricular ejection fraction (LVEF) % (all p-values less than 0.05). With regard to CAD severity, median C4 and C5 levels were elevated and C16 and C18:2 levels were reduced in the high CAD complexity group with SYNTAX Score > 22 (p = 0.002, 0.024, 0.044 and 0.012, respectively), indicating a potential prognostic capability of those metabolites and of the ratio C4/C18:2 for the prediction of CAD severity. In conclusion, serum acylcarnitines could serve as clinically useful biomarkers leading to a more individualized management of patients with CAD, once further clinically oriented metabolomics-based studies provide similar evidence. Full article

(This article belongs to the Special Issue Cutting-Edge Research on the Analysis of Small Biomolecules in Foods, Plants, and Biological Samples)

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12 pages, 901 KiB

Open AccessEditor’s ChoiceReview

Glucose- and Non-Glucose-Induced Mitochondrial Dysfunction in Diabetic Kidney Disease

by Marie Ito, Margaret Zvido Gurumani, Sandra Merscher and Alessia Fornoni

Biomolecules 2022, 12(3), 351; https://doi.org/10.3390/biom12030351 - 23 Feb 2022

Cited by 14 | Viewed by 3243

Abstract

Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic kidney disease (DKD). In this review, we will discuss mitochondrial dysfunction observed in preclinical models of DKD as well as in clinical DKD with a focus on oxidative phosphorylation (OXPHOS), [...] Read more.

Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic kidney disease (DKD). In this review, we will discuss mitochondrial dysfunction observed in preclinical models of DKD as well as in clinical DKD with a focus on oxidative phosphorylation (OXPHOS), mitochondrial reactive oxygen species (mtROS), biogenesis, fission and fusion, mitophagy and urinary mitochondrial biomarkers. Both glucose- and non-glucose-induced mitochondrial dysfunction will be discussed. In terms of glucose-induced mitochondrial dysfunction, the energetic shift from OXPHOS to aerobic glycolysis, called the Warburg effect, occurs and the resulting toxic intermediates of glucose metabolism contribute to DKD-induced injury. In terms of non-glucose-induced mitochondrial dysfunction, we will review the roles of lipotoxicity, hypoxia and vasoactive pathways, including endothelin-1 (Edn1)/Edn1 receptor type A signaling pathways. Although the relative contribution of each of these pathways to DKD remains unclear, the goal of this review is to highlight the complexity of mitochondrial dysfunction in DKD and to discuss how markers of mitochondrial dysfunction could help us stratify patients at risk for DKD. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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24 pages, 2687 KiB

Open AccessEditor’s ChoiceReview

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

by Kristen E. Rohli, Cierra K. Boyer, Sandra E. Blom and Samuel B. Stephens

Biomolecules 2022, 12(2), 335; https://doi.org/10.3390/biom12020335 - 20 Feb 2022

Cited by 16 | Viewed by 4863

Abstract

Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). [...] Read more.

Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D. Full article

(This article belongs to the Special Issue The Pancreatic Beta Cell)

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16 pages, 1162 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Targeting the Endocannabinoidome in Pancreatic Cancer

by Valerio Falasca and Marco Falasca

Biomolecules 2022, 12(2), 320; https://doi.org/10.3390/biom12020320 - 17 Feb 2022

Cited by 6 | Viewed by 3988

Abstract

Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when [...] Read more.

Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when the tumour has locally advanced or metastasised. PDAC is resistant to most of the available chemotherapy and radiation therapy treatments, making surgery the most potent curative treatment. The desmoplastic tumour microenvironment contributes to determining PDAC pathophysiology, immune response and therapeutic efficacy. The existing therapeutic approaches such as FDA-approved chemotherapeutics, gemcitabine, abraxane and folfirinox, prolong survival marginally and are accompanied by adverse effects. Several studies suggest the role of cannabinoids as anti-cancer agents. Cannabinoid receptors are known to be expressed in pancreatic cells, with a higher expression reported in pancreatic cancer patients. Therefore, pharmacological targeting of the endocannabinoid system might offer therapeutic benefits in pancreatic cancer. In addition, emerging data suggest that cannabinoids in combination with chemotherapy can increase survival in transgenic pancreatic cancer murine models. This review provides an overview of the regulation of the expanded endocannabinoid system, or endocannabinoidome, in PDAC and will explore the potential of targeting this system for novel anticancer approaches. Full article

(This article belongs to the Collection Recent Advances in Pancreatic Cancer)

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19 pages, 7615 KiB

Open AccessEditor’s ChoiceReview

Cytoplasmic and Nuclear Functions of cIAP1

by Aymeric Zadoroznyj and Laurence Dubrez

Biomolecules 2022, 12(2), 322; https://doi.org/10.3390/biom12020322 - 17 Feb 2022

Cited by 9 | Viewed by 3234

Abstract

Cellular inhibitor of apoptosis 1 (cIAP1) is a cell signaling regulator of the IAP family. Through its E3-ubiquitine ligase activity, it has the ability to activate intracellular signaling pathways, modify signal transduction pathways by changing protein-protein interaction networks, and stop signal transduction by [...] Read more.

Cellular inhibitor of apoptosis 1 (cIAP1) is a cell signaling regulator of the IAP family. Through its E3-ubiquitine ligase activity, it has the ability to activate intracellular signaling pathways, modify signal transduction pathways by changing protein-protein interaction networks, and stop signal transduction by promoting the degradation of critical components of signaling pathways. Thus, cIAP1 appears to be a potent determinant of the response of cells, enabling their rapid adaptation to changing environmental conditions or intra- or extracellular stresses. It is expressed in almost all tissues, found in the cytoplasm, membrane and/or nucleus of cells. cIAP1 regulates innate immunity by controlling signaling pathways mediated by tumor necrosis factor receptor superfamily (TNFRs), some cytokine receptors and pattern recognition-receptors (PRRs). Although less documented, cIAP1 has also been involved in the regulation of cell migration and in the control of transcriptional programs. Full article

(This article belongs to the Special Issue State-of-the-Art Cell Death in France 2020-2021)

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42 pages, 1981 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

by Sarah Koushyar, Valerie S. Meniel, Toby J. Phesse and Helen B. Pearson

Biomolecules 2022, 12(2), 309; https://doi.org/10.3390/biom12020309 - 15 Feb 2022

Cited by 18 | Viewed by 5355

Abstract

Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence [...] Read more.

Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance. Full article

(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)

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19 pages, 1166 KiB

Open AccessEditor’s ChoiceReview

An Introduction to Bacterial Biofilms and Their Proteases, and Their Roles in Host Infection and Immune Evasion

by Juan Sebastián Ramírez-Larrota and Ulrich Eckhard

Biomolecules 2022, 12(2), 306; https://doi.org/10.3390/biom12020306 - 14 Feb 2022

Cited by 22 | Viewed by 4955

Abstract

Bacterial biofilms represent multicellular communities embedded in a matrix of extracellular polymeric substances, conveying increased resistance against environmental stress factors but also antibiotics. They are shaped by secreted enzymes such as proteases, which can aid pathogenicity by degrading host proteins of the connective [...] Read more.

Bacterial biofilms represent multicellular communities embedded in a matrix of extracellular polymeric substances, conveying increased resistance against environmental stress factors but also antibiotics. They are shaped by secreted enzymes such as proteases, which can aid pathogenicity by degrading host proteins of the connective tissue or the immune system. Importantly, both secreted proteases and the capability of biofilm formation are considered key virulence factors. In this review, we focus on the basic aspects of proteolysis and protein secretion, and highlight various secreted bacterial proteases involved in biofilm establishment and dispersal, and how they aid bacteria in immune evasion by degrading immunoglobulins and components of the complement system. Thus, secreted proteases represent not only prominent antimicrobial targets but also enzymes that can be used for dedicated applications in biotechnology and biomedicine, including their use as laundry detergents, in mass spectrometry for the glycoprofiling of antibodies, and the desensitization of donor organs intended for positive crossmatch patients. Full article

(This article belongs to the Special Issue New Insights into Proteases and Chaperones in Pathogenic Microorganisms)

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22 pages, 2330 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Impact of Non-Coding RNAs on Chemotherapeutic Resistance in Oral Cancer

by Karen Yamaguchi, Tomofumi Yamamoto, Junichiro Chikuda, Tatsuo Shirota and Yusuke Yamamoto

Biomolecules 2022, 12(2), 284; https://doi.org/10.3390/biom12020284 - 9 Feb 2022

Cited by 9 | Viewed by 3113

Abstract

Drug resistance in oral cancer is one of the major problems in oral cancer therapy because therapeutic failure directly results in tumor recurrence and eventually in metastasis. Accumulating evidence has demonstrated the involvement of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long [...] Read more.

Drug resistance in oral cancer is one of the major problems in oral cancer therapy because therapeutic failure directly results in tumor recurrence and eventually in metastasis. Accumulating evidence has demonstrated the involvement of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in processes related to the development of drug resistance. A number of studies have shown that ncRNAs modulate gene expression at the transcriptional or translational level and regulate biological processes, such as epithelial-to-mesenchymal transition, apoptosis, DNA repair and drug efflux, which are tightly associated with drug resistance acquisition in many types of cancer. Interestingly, these ncRNAs are commonly detected in extracellular vesicles (EVs) and are known to be delivered into surrounding cells. This intercellular communication via EVs is currently considered to be important for acquired drug resistance. Here, we review the recent advances in the study of drug resistance in oral cancer by mainly focusing on the function of ncRNAs, since an increasing number of studies have suggested that ncRNAs could be therapeutic targets as well as biomarkers for cancer diagnosis. Full article

(This article belongs to the Special Issue Non-coding RNAs in Cancer Biology)

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15 pages, 1301 KiB

Open AccessEditor’s ChoiceArticle

Genetic Variants of Matrix Metalloproteinase and Sepsis: The Need Speed Study

by Nicola Fiotti, Filippo Mearelli, Filippo Giorgio Di Girolamo, Luigi Mario Castello, Alessio Nunnari, Salvatore Di Somma, Enrico Lupia, Efrem Colonetti, Maria Lorenza Muiesan, Giuseppe Montrucchio, Carlo Giansante, Gian Carlo Avanzi and Gianni Biolo

Biomolecules 2022, 12(2), 279; https://doi.org/10.3390/biom12020279 - 9 Feb 2022

Cited by 4 | Viewed by 1874

Abstract

Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 [...] Read more.

Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis. Prevalence of MMP8 rs11225395 G/G genotype was higher in sepsis patients than in those with non-infective Systemic Inflammatory Reaction Syndrome (35.6 vs. 26%, hazard ratio, HR 1.56, 95% C.I. 1.04–2.42, p = 0.032). G/G patients developed less hyperthermia (p = 0.041), even after stratification for disease severity (p = 0.003). Patients carrying the 6A allele in MMP3 rs3025058 had a higher probability of microbiologically-proven sepsis (HR 1.4. 95%C.I. 1.01–1.94, p = 0.044), particularly when due to virus (H.R. 2.14, 95% C.I. 1.06–4.31, p = 0.046), while MMP-1 G/G genotype patients carried a higher risk for intracellular bacteria (Chlamydia, Mycoplasma, and Legionella, H.R. 6.46, 95% C.I. 1.58–26.41, p = 0.003). Neither severity of sepsis at presentation, nor 30-day mortality were influenced by the investigated variants or their haplotype. MMP8 rs11225395 G/G carriers have lower temperature at presentation and a more than 50% increased susceptibility to sepsis. Among patients with sepsis, carriers of MMP1 rs1799750 G/G have an increased susceptibility for intracellular pathogen infections, while virus serology is more often positive in those with the MMP3 rs3025058 A/A genotype. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 2.0)

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11 pages, 2585 KiB

Open AccessEditor’s ChoiceArticle

Matrix Metalloproteinase 7 Expression and Apical Epithelial Defects in Atp8b1 Mutant Mouse Model of Pulmonary Fibrosis

by Emma Westermann-Clark, Ramani Soundararajan, Jutaro Fukumoto, Sahebgowda Sidramagowda Patil, Timothy M. Stearns, Smita Saji, Alexander Czachor, Helena Hernandez-Cuervo, Mason Breitzig, Sudarshan Krishnamurthy, Richard F. Lockey and Narasaiah Kolliputi

Biomolecules 2022, 12(2), 283; https://doi.org/10.3390/biom12020283 - 9 Feb 2022

Cited by 2 | Viewed by 2133

Abstract

Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared [...] Read more.

Abnormalities in airway epithelia and lung parenchyma are found in Atp8b1 mutant mice, which develop pulmonary fibrosis after hyperoxic insult. Microarray and ingenuity pathway analysis (IPA) show numerous transcripts involved in ciliogenesis are downregulated in 14-month (14 M) -old Atp8b1 mouse lung compared with wild-type C57BL/6. Lung epithelium of Atp8b1 mice demonstrate apical abnormalities of ciliated and club cells in the bronchial epithelium on transmission electron microscopy (TEM). Matrix metalloproteinase 7 (MMP7) regulates of ciliogenesis and is a biomarker for idiopathic pulmonary fibrosis (IPF) in humans. Mmp7 transcript and protein expression are significantly upregulated in 14 M Atp8b1 mutant mouse lung. MMP7 expression is also increased in bronchoalveolar lavage fluid (BAL). Immunohistochemistry is localized MMP7 to bronchial epithelial cells in the Atp8b1 mutant. In conclusion, MMP7 is upregulated in the aged Atp8b1 mouse model, which displays abnormal ciliated cell and club cell morphology. This mouse model can facilitate the exploration of the role of MMP7 in epithelial integrity and ciliogenesis in IPF. The Atp8b1 mutant mouse is proposed as a model for IPF. Full article

(This article belongs to the Collection Feature Papers in Section Molecular Medicine)

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21 pages, 44025 KiB

Open AccessEditor’s ChoiceArticle

A Comparative Evaluation of the Structural and Dynamic Properties of Insect Odorant Binding Proteins

by George Tzotzos

Biomolecules 2022, 12(2), 282; https://doi.org/10.3390/biom12020282 - 9 Feb 2022

Cited by 1 | Viewed by 2147

Abstract

Insects devote a major part of their metabolic resources to the production of odorant binding proteins (OBPs). Although initially, these proteins were implicated in the solubilisation, binding and transport of semiochemicals to olfactory receptors, it is now recognised that they may play diverse, [...] Read more.

Insects devote a major part of their metabolic resources to the production of odorant binding proteins (OBPs). Although initially, these proteins were implicated in the solubilisation, binding and transport of semiochemicals to olfactory receptors, it is now recognised that they may play diverse, as yet uncharacterised, roles in insect physiology. The structures of these OBPs, the majority of which are known as “classical” OBPs, have shed some light on their potential functional roles. However, the dynamic properties of these proteins have received little attention despite their functional importance. Structural dynamics are encoded in the native protein fold and enable the adaptation of proteins to substrate binding. This paper provides a comparative review of the structural and dynamic properties of OBPs, making use of sequence/structure analysis, statistical and theoretical physics-based methods. It provides a new layer of information and additional methodological tools useful in unravelling the relationship between structure, dynamics and function of insect OBPs. The dynamic properties of OBPs, studied by means of elastic network models, reflect the similarities/dissimilarities observed in their respective structures and provides insights regarding protein motions that may have important implications for ligand recognition and binding. Furthermore, it was shown that the OBPs studied in this paper share conserved structural ‘core’ that may be of evolutionary and functional importance. Full article

(This article belongs to the Special Issue Insect Receptors: Biochemical, Physiological and Molecular Studies)

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