Biomolecules

32 pages, 27417 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Immunoaffinity Capillary Electrophoresis in the Era of Proteoforms, Liquid Biopsy and Preventive Medicine: A Potential Impact in the Diagnosis and Monitoring of Disease Progression

by Norberto A. Guzman and Daniel E. Guzman

Biomolecules 2021, 11(10), 1443; https://doi.org/10.3390/biom11101443 - 1 Oct 2021

Cited by 12 | Viewed by 4299

Abstract

Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in [...] Read more.

Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in identification and characterization of a distinct functional pool of proteins known as proteoforms. Proteoforms are defined as all of the different molecular forms of a protein derived from a single gene caused by genetic variations, alternative spliced RNA transcripts and post-translational modifications. Monitoring the structural changes of each proteoform of a particular protein is essential to elucidate the complex molecular mechanisms that guide the course of disease. Clinical proteomics therefore holds the potential to offer further insight into disease pathology, progression, and prevention. Nevertheless, more technologically advanced diagnostic methods are needed to improve the reliability and clinical applicability of proteomics in preventive medicine. In this manuscript, we review the use of immunoaffinity capillary electrophoresis (IACE) as an emerging powerful diagnostic tool to isolate, separate, detect and characterize proteoform biomarkers obtained from liquid biopsy. IACE is an affinity capture-separation technology capable of isolating, concentrating and analyzing a wide range of biomarkers present in biological fluids. Isolation and concentration of target analytes is accomplished through binding to one or more biorecognition affinity ligands immobilized to a solid support, while separation and analysis are achieved by high-resolution capillary electrophoresis (CE) coupled to one or more detectors. IACE has the potential to generate rapid results with significant accuracy, leading to reliability and reproducibility in diagnosing and monitoring disease. Additionally, IACE has the capability of monitoring the efficacy of therapeutic agents by quantifying companion and complementary protein biomarkers. With advancements in telemedicine and artificial intelligence, the implementation of proteoform biomarker detection and analysis may significantly improve our capacity to identify medical conditions early and intervene in ways that improve health outcomes for individuals and populations. Full article

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

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21 pages, 4112 KiB

Open AccessEditor’s ChoiceReview

Pyrroloquinoline-Quinone Is More Than an Antioxidant: A Vitamin-like Accessory Factor Important in Health and Disease Prevention

by Karen R. Jonscher, Winyoo Chowanadisai and Robert B. Rucker

Biomolecules 2021, 11(10), 1441; https://doi.org/10.3390/biom11101441 - 30 Sep 2021

Cited by 40 | Viewed by 16345

Abstract

Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or [...] Read more.

Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or conditional vitamins. For example, the absence of PQQ in diets produces a response like a vitamin-related deficiency with recovery upon PQQ repletion in a dose-dependent manner. Moreover, potential health benefits, such as improved metabolic flexibility and immuno-and neuroprotection, are associated with PQQ supplementation. Here, we address PQQ’s role as an enzymatic cofactor or accessory factor and highlight mechanisms underlying PQQ’s actions. We review both large scale and targeted datasets demonstrating that a neonatal or perinatal PQQ deficiency reduces mitochondria content and mitochondrial-related gene expression. Data are reviewed that suggest PQQ’s modulation of lactate acid and perhaps other dehydrogenases enhance NAD+-dependent sirtuin activity, along with the sirtuin targets, such as PGC-1

α

, NRF-1, NRF-2 and TFAM; thus, mediating mitochondrial functions. Taken together, current observations suggest vitamin-like PQQ has strong potential as a potent therapeutic nutraceutical. Full article

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14 pages, 4574 KiB

Open AccessEditor’s ChoiceArticle

Fatty Acids Rescue the Thermogenic Function of Sympathetically Denervated Brown Fat

by Qiang Cao, Shirong Wang, Huan Wang, Xin Cui, Jia Jing, Liqing Yu, Hang Shi and Bingzhong Xue

Biomolecules 2021, 11(10), 1428; https://doi.org/10.3390/biom11101428 - 29 Sep 2021

Cited by 5 | Viewed by 2793

Abstract

Sympathetic nervous system (SNS) innervation into brown adipose tissue (BAT) has been viewed as an impetus for brown fat thermogenesis. However, we surprisingly discovered that BAT SNS innervation is dispensable for mice to maintain proper body temperature during a prolonged cold exposure. Here [...] Read more.

Sympathetic nervous system (SNS) innervation into brown adipose tissue (BAT) has been viewed as an impetus for brown fat thermogenesis. However, we surprisingly discovered that BAT SNS innervation is dispensable for mice to maintain proper body temperature during a prolonged cold exposure. Here we aimed to uncover the physiological factors compensating for maintaining brown fat thermogenesis in the absence of BAT innervation. After an initial decline of body temperature during cold exposure, mice with SNS surgical denervation in interscapular BAT gradually recovered their temperature comparable to that of sham-operated mice. The surgically denervated BAT also maintained a sizable uncoupling protein 1 (UCP1) protein along with basal norepinephrine (NE) at a similar level to that of sham controls, which were associated with increased circulating NE. Furthermore, the denervated mice exhibited increased free fatty acid levels in circulation. Indeed, surgical denervation of mice with CGI-58 deletion in adipocytes, a model lacking lipolytic capacity to release fatty acids from WAT, dramatically reduced BAT UCP1 protein and rendered the mice susceptible to cold. We conclude that circulating fatty acids and NE may serve as key factors for maintaining BAT thermogenic function and body temperature in the absence of BAT sympathetic innervation. Full article

(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)

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28 pages, 1647 KiB

Open AccessEditor’s ChoiceReview

Obesity–An Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances

by Erind Gjermeni, Anna S. Kirstein, Florentien Kolbig, Michael Kirchhof, Linnaeus Bundalian, Julius L. Katzmann, Ulrich Laufs, Matthias Blüher, Antje Garten and Diana Le Duc

Biomolecules 2021, 11(10), 1426; https://doi.org/10.3390/biom11101426 - 29 Sep 2021

Cited by 42 | Viewed by 21884

Abstract

Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, [...] Read more.

Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored. Full article

(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)

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23 pages, 3520 KiB

Open AccessEditor’s ChoiceArticle

NBD2 Is Required for the Rescue of Mutant F508del CFTR by a Thiazole-Based Molecule: A Class II Corrector for the Multi-Drug Therapy of Cystic Fibrosis

by Chiara Brandas, Alessandra Ludovico, Alice Parodi, Oscar Moran, Enrico Millo, Elena Cichero and Debora Baroni

Biomolecules 2021, 11(10), 1417; https://doi.org/10.3390/biom11101417 - 28 Sep 2021

Cited by 9 | Viewed by 2704

Abstract

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel that regulates epithelial surface fluid secretion. The deletion of phenylalanine at position 508 (F508del) is the most common CFTR mutation. F508del CFTR is characterized [...] Read more.

Cystic fibrosis (CF) is caused by loss-of-function mutations in the CF transmembrane conductance regulator (CFTR) protein, an anion channel that regulates epithelial surface fluid secretion. The deletion of phenylalanine at position 508 (F508del) is the most common CFTR mutation. F508del CFTR is characterized by folding and trafficking defects, resulting in decreased functional expression of the protein on the plasma membrane. Several classes of small molecules, named correctors, have been developed to rescue defective F508del CFTR. Although individual correctors failed to improve the clinical status of CF patients carrying the F508del mutation, better results were obtained using correctors combinations. These results were obtained according to the premise that the administration of correctors having different sites of action should enhance F508del CFTR rescue. We investigated the putative site of action of an aminoarylthiazole 4-(3-chlorophenyl)-N-(3-(methylthio)phenyl)thiazol-2-amine, named FCG, with proven CFTR corrector activity, and its synergistic effect with the corrector VX809. We found that neither the total expression nor the maturation of WT CFTR transiently expressed in human embryonic kidney 293 cells was influenced by FCG, administrated alone or in combination with VX809. On the contrary, FCG was able to enhance F508del CFTR total expression, and its combination with VX809 provided a further effect, being able to increase not only the total expression but also the maturation of the mutant protein. Analyses on different CFTR domains and groups of domains, heterologously expressed in HEK293 cells, show that NBD2 is necessary for FCG corrector activity. Molecular modelling analyses suggest that FCG interacts with a putative region located into the NBD2, ascribing this molecule to class II correctors. Our study indicates that the continuous development and testing of combinations of correctors targeting different structural and functional defects of mutant CFTR is the best strategy to ensure a valuable therapeutic perspective to a larger cohort of CF patients. Full article

(This article belongs to the Special Issue An Update on CFTR Drug Discovery: Opportunities and Challenges)

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17 pages, 1618 KiB

Open AccessEditor’s ChoiceReview

A Proteomic View of Cellular and Molecular Effects of Cannabis

by Morteza Abyadeh, Vivek Gupta, Joao A. Paulo, Veer Gupta, Nitin Chitranshi, Angela Godinez, Danit Saks, Mafruha Hasan, Ardeshir Amirkhani, Matthew McKay, Ghasem H. Salekdeh, Paul A. Haynes, Stuart L. Graham and Mehdi Mirzaei

Biomolecules 2021, 11(10), 1411; https://doi.org/10.3390/biom11101411 - 27 Sep 2021

Cited by 18 | Viewed by 6520

Abstract

Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known [...] Read more.

Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known as cannabinoids against several diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease, schizophrenia and glaucoma; these have prompted changes in medicinal cannabis legislation. The relaxation of legal restrictions and increased socio-cultural acceptance has led to its increase in both medicinal and recreational usage. Several biochemically active components of cannabis have a range of effects on the biological system. There is an urgent need for more research to better understand the molecular and biochemical effects of cannabis at a cellular level, to understand fully its implications as a pharmaceutical drug. Proteomics technology is an efficient tool to rigorously elucidate the mechanistic effects of cannabis on the human body in a cell and tissue-specific manner, drawing conclusions associated with its toxicity as well as therapeutic benefits, safety and efficacy profiles. This review provides a comprehensive overview of both in vitro and in vivo proteomic studies involving the cellular and molecular effects of cannabis and cannabis-derived compounds. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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22 pages, 2584 KiB

Open AccessEditor’s ChoiceReview

TRP Channels as Sensors of Aldehyde and Oxidative Stress

by Katharina E. M. Hellenthal, Laura Brabenec, Eric R. Gross and Nana-Maria Wagner

Biomolecules 2021, 11(10), 1401; https://doi.org/10.3390/biom11101401 - 24 Sep 2021

Cited by 21 | Viewed by 4779

Abstract

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade [...] Read more.

The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options. Full article

(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)

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30 pages, 8651 KiB

Open AccessEditor’s ChoiceArticle

Multifunctionality of Nanosized Calcium Apatite Dual-Doped with Li⁺/Eu³⁺ Ions Related to Cell Culture Studies and Cytotoxicity Evaluation In Vitro

by Paulina Sobierajska, Blazej Pozniak, Marta Tikhomirov, Julia Miller, Lucyna Mrowczynska, Agata Piecuch, Justyna Rewak-Soroczynska, Agata Dorotkiewicz-Jach, Zuzanna Drulis-Kawa and Rafal J. Wiglusz

Biomolecules 2021, 11(9), 1388; https://doi.org/10.3390/biom11091388 - 21 Sep 2021

Cited by 12 | Viewed by 3139

Abstract

Li⁺/Eu³⁺ dual-doped calcium apatite analogues were fabricated using a microwave stimulated hydrothermal technique. XRPD, FT-IR, micro-Raman spectroscopy, TEM and SAED measurements indicated that obtained apatites are single-phased, crystallize with a hexagonal structure, have similar morphology and nanometric size as well [...] Read more.

Li⁺/Eu³⁺ dual-doped calcium apatite analogues were fabricated using a microwave stimulated hydrothermal technique. XRPD, FT-IR, micro-Raman spectroscopy, TEM and SAED measurements indicated that obtained apatites are single-phased, crystallize with a hexagonal structure, have similar morphology and nanometric size as well as show red luminescence. Lithium effectively modifies the local symmetry of optical active sites and, thus, affects the emission efficiency. Moreover, the hydrodynamic size and surface charge of the nanoparticles have been extensively studied. The protein adsorption (lysozyme, LSZ; bovine serum albumin, BSA) on the nanoparticle surface depended on the type of cationic dopant (Li⁺, Eu³⁺) and anionic group (OH⁻, Cl⁻, F⁻) of the apatite matrix. Interaction with LSZ resulted in a positive zeta potential, and the nanoparticles had the lowest hydrodynamic size in this protein medium. The cytotoxicity assessment was carried out on the human osteosarcoma cell line (U2OS), murine macrophages (J774.E), as well as human red blood cells (RBCs). The studied apatites were not cytotoxic to RBCs and J774.E cells; however, at higher concentrations of nanoparticles, cytotoxicity was observed against the U2OS cell line. No antimicrobial activity was detected against Gram-negative bacteria with one exception for P. aeruginosa treated with Li⁺-doped fluorapatite. Full article

(This article belongs to the Section Biological and Bio- Materials)

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30 pages, 2095 KiB

Open AccessEditor’s ChoiceReview

Stress-Induced Epstein-Barr Virus Reactivation

by Daniel G. Sausen, Maimoona S. Bhutta, Elisa S. Gallo, Harel Dahari and Ronen Borenstein

Biomolecules 2021, 11(9), 1380; https://doi.org/10.3390/biom11091380 - 18 Sep 2021

Cited by 45 | Viewed by 13579

Abstract

Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough [...] Read more.

Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough understanding of this virus, and the interplay between stress and the immune system, is essential to establish effective treatment. This review will provide a summary of the interaction between both psychological and cellular stressors resulting in EBV reactivation. It will examine mechanisms by which EBV establishes and maintains latency and will conclude with a brief overview of treatments targeting EBV. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)

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31 pages, 2899 KiB

Open AccessEditor’s ChoiceArticle

Theory and Practice of Coarse-Grained Molecular Dynamics of Biologically Important Systems

by Adam Liwo, Cezary Czaplewski, Adam K. Sieradzan, Agnieszka G. Lipska, Sergey A. Samsonov and Rajesh K. Murarka

Biomolecules 2021, 11(9), 1347; https://doi.org/10.3390/biom11091347 - 11 Sep 2021

Cited by 34 | Viewed by 5644

Abstract

Molecular dynamics with coarse-grained models is nowadays extensively used to simulate biomolecular systems at large time and size scales, compared to those accessible to all-atom molecular dynamics. In this review article, we describe the physical basis of coarse-grained molecular dynamics, the coarse-grained force [...] Read more.

Molecular dynamics with coarse-grained models is nowadays extensively used to simulate biomolecular systems at large time and size scales, compared to those accessible to all-atom molecular dynamics. In this review article, we describe the physical basis of coarse-grained molecular dynamics, the coarse-grained force fields, the equations of motion and the respective numerical integration algorithms, and selected practical applications of coarse-grained molecular dynamics. We demonstrate that the motion of coarse-grained sites is governed by the potential of mean force and the friction and stochastic forces, resulting from integrating out the secondary degrees of freedom. Consequently, Langevin dynamics is a natural means of describing the motion of a system at the coarse-grained level and the potential of mean force is the physical basis of the coarse-grained force fields. Moreover, the choice of coarse-grained variables and the fact that coarse-grained sites often do not have spherical symmetry implies a non-diagonal inertia tensor. We describe selected coarse-grained models used in molecular dynamics simulations, including the most popular MARTINI model developed by Marrink’s group and the UNICORN model of biological macromolecules developed in our laboratory. We conclude by discussing examples of the application of coarse-grained molecular dynamics to study biologically important processes. Full article

(This article belongs to the Collection Biomolecules In Silico: Contemporary Advances in Computational Approaches to Investigating the Molecular Dynamics of Biological Systems)

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18 pages, 2554 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Regulation of Rab GTPases by Phosphorylation

by Lejia Xu, Yuki Nagai, Yotaro Kajihara, Genta Ito and Taisuke Tomita

Biomolecules 2021, 11(9), 1340; https://doi.org/10.3390/biom11091340 - 10 Sep 2021

Cited by 18 | Viewed by 5193

Abstract

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated [...] Read more.

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation. Full article

(This article belongs to the Collection Recent Advances in Protein Phosphorylation)

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18 pages, 873 KiB

Open AccessEditor’s ChoiceReview

Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association

by Maxime Teixeira, Razan Sheta, Walid Idi and Abid Oueslati

Biomolecules 2021, 11(9), 1333; https://doi.org/10.3390/biom11091333 - 9 Sep 2021

Cited by 25 | Viewed by 4823

Abstract

Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such [...] Read more.

Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)

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25 pages, 4160 KiB

Open AccessEditor’s ChoiceReview

Amylomaltases in Extremophilic Microorganisms

by Claudia Leoni, Bruno A. R. Gattulli, Graziano Pesole, Luigi R. Ceci and Mariateresa Volpicella

Biomolecules 2021, 11(9), 1335; https://doi.org/10.3390/biom11091335 - 9 Sep 2021

Cited by 8 | Viewed by 3549

Abstract

Amylomaltases (4-α-glucanotransferases, E.C. 2.4.1.25) are enzymes which can perform a double-step catalytic process, resulting in a transglycosylation reaction. They hydrolyse glucosidic bonds of α-1,4′-d-glucans and transfer the glucan portion with the newly available anomeric carbon to the 4′-position of an α-1,4′- [...] Read more.

Amylomaltases (4-α-glucanotransferases, E.C. 2.4.1.25) are enzymes which can perform a double-step catalytic process, resulting in a transglycosylation reaction. They hydrolyse glucosidic bonds of α-1,4′-d-glucans and transfer the glucan portion with the newly available anomeric carbon to the 4′-position of an α-1,4′-d-glucan acceptor. The intramolecular reaction produces a cyclic α-1,4′-glucan. Amylomaltases can be found only in prokaryotes, where they are involved in glycogen degradation and maltose metabolism. These enzymes are being studied for possible biotechnological applications, such as the production of (i) sugar substitutes; (ii) cycloamyloses (molecules larger than cyclodextrins), which could potentially be useful as carriers and encapsulating agents for hydrophobic molecules and also as effective protein chaperons; and (iii) thermoreversible starch gels, which could be used as non-animal gelatin substitutes. Extremophilic prokaryotes have been investigated for the identification of amylomaltases to be used in the starch modifying processes, which require high temperatures or extreme conditions. The aim of this article is to present an updated overview of studies on amylomaltases from extremophilic Bacteria and Archaea, including data about their distribution, activity, potential industrial application and structure. Full article

(This article belongs to the Collection Feature Papers in Enzymology)

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42 pages, 2047 KiB

Open AccessEditor’s ChoiceReview

Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation

by Stefanie Haberecht-Müller, Elke Krüger and Jens Fielitz

Biomolecules 2021, 11(9), 1327; https://doi.org/10.3390/biom11091327 - 8 Sep 2021

Cited by 43 | Viewed by 6173

Abstract

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein [...] Read more.

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed. Full article

(This article belongs to the Special Issue Regulating Proteasome Activity)

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33 pages, 11064 KiB

Open AccessEditor’s ChoiceArticle

Identification of a Region in the Common Amino-terminal Domain of Hendra Virus P, V, and W Proteins Responsible for Phase Transition and Amyloid Formation

by Edoardo Salladini, Frank Gondelaud, Juliet F. Nilsson, Giulia Pesce, Christophe Bignon, Maria Grazia Murrali, Roxane Fabre, Roberta Pierattelli, Andrey V. Kajava, Branka Horvat, Denis Gerlier, Cyrille Mathieu and Sonia Longhi

Biomolecules 2021, 11(9), 1324; https://doi.org/10.3390/biom11091324 - 7 Sep 2021

Cited by 13 | Viewed by 3969

Abstract

Henipaviruses are BSL-4 zoonotic pathogens responsible in humans for severe encephalitis. Their V protein is a key player in the evasion of the host innate immune response. We previously showed that the Henipavirus V proteins consist of a long intrinsically disordered N-terminal domain [...] Read more.

Henipaviruses are BSL-4 zoonotic pathogens responsible in humans for severe encephalitis. Their V protein is a key player in the evasion of the host innate immune response. We previously showed that the Henipavirus V proteins consist of a long intrinsically disordered N-terminal domain (NTD) and a β-enriched C-terminal domain (CTD). The CTD is critical for V binding to DDB1, which is a cellular protein that is a component of the ubiquitin ligase E3 complex, as well as binding to MDA5 and LGP2, which are two host sensors of viral RNA. Here, we serendipitously discovered that the Hendra virus V protein undergoes a liquid-to-hydrogel phase transition and identified the V region responsible for this phenomenon. This region, referred to as PNT3 and encompassing residues 200–310, was further investigated using a combination of biophysical and structural approaches. Congo red binding assays, together with negative-staining transmisison electron microscopy (TEM) studies, show that PNT3 forms amyloid-like fibrils. Fibrillation abilities are dramatically reduced in a rationally designed PNT3 variant in which a stretch of three contiguous tyrosines, falling within an amyloidogenic motif, were replaced by three alanines. Worthy to note, Congo red staining experiments provided hints that these amyloid-like fibrils form not only in vitro but also in cellula after transfection or infection. The present results set the stage for further investigations aimed at assessing the functional role of phase separation and fibrillation by the Henipavirus V proteins. Full article

(This article belongs to the Collection Protein Intrinsic Disorder: Role in Signaling, Regulation and Membrane-Less Organelle Formation)

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19 pages, 1102 KiB

Open AccessEditor’s ChoiceReview

Lumican in Carcinogenesis—Revisited

by Eirini-Maria Giatagana, Aikaterini Berdiaki, Aristidis Tsatsakis, George N. Tzanakakis and Dragana Nikitovic

Biomolecules 2021, 11(9), 1319; https://doi.org/10.3390/biom11091319 - 6 Sep 2021

Cited by 27 | Viewed by 4687

Abstract

Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of [...] Read more.

Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of the ECM and are established biological mediators. Notably, lumican is involved in cellular processes associated with tumorigeneses, such as EMT (epithelial-to-mesenchymal transition), cellular proliferation, migration, invasion, and adhesion. Furthermore, lumican is expressed in various cancer tissues and is reported to have a positive or negative correlation with tumor progression. This review focuses on significant advances achieved regardingthe role of lumican in the tumor biology. Here, the effects of lumican on cancer cell growth, invasion, motility, and metastasis are discussed, as well as the repercussions on autophagy and apoptosis. Finally, in light of the available data, novel roles for lumican as a cancer prognosis marker, chemoresistance regulator, and cancer therapy target are proposed. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

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24 pages, 2989 KiB

Open AccessEditor’s ChoiceArticle

Systemic Copper Disorders Influence the Olfactory Function in Adult Rats: Roles of Altered Adult Neurogenesis and Neurochemical Imbalance

by Sherleen Xue-Fu Adamson, Wei Zheng, Zeynep Sena Agim, Sarah Du, Sheila Fleming, Jonathan Shannahan and Jason Cannon

Biomolecules 2021, 11(9), 1315; https://doi.org/10.3390/biom11091315 - 6 Sep 2021

Cited by 6 | Viewed by 3362

Abstract

Disrupted systemic copper (Cu) homeostasis underlies neurodegenerative diseases with early symptoms including olfactory dysfunction. This study investigated the impact of Cu dyshomeostasis on olfactory function, adult neurogenesis, and neurochemical balance. Models of Cu deficiency (CuD) and Cu overload (CuO) were established by feeding [...] Read more.

Disrupted systemic copper (Cu) homeostasis underlies neurodegenerative diseases with early symptoms including olfactory dysfunction. This study investigated the impact of Cu dyshomeostasis on olfactory function, adult neurogenesis, and neurochemical balance. Models of Cu deficiency (CuD) and Cu overload (CuO) were established by feeding adult rats with Cu-restricted diets plus ip. injection of a Cu chelator (ammonium tetrathiomolybdate) and excess Cu, respectively. CuD reduced Cu levels in the olfactory bulb (OB), subventricular zone (SVZ), rostral migratory stream (RMS), and striatum, while CuO increased Cu levels in these areas. The buried pellet test revealed both CuD and CuO prolonged the latency to uncover food. CuD increased neural proliferation and stem cells in the SVZ and newly differentiated neurons in the OB, whereas CuO caused opposite alterations, suggesting a “switch”-type function of Cu in regulating adult neurogenesis. CuO increased GABA in the OB, while both CuD and CuO reduced DOPAC, HVA, 5-HT and the DA turnover rate in olfactory-associated brain regions. Altered mRNA expression of Cu transport and storage proteins in tested brain areas were observed under both conditions. Together, results support an association between systemic Cu dyshomeostasis and olfactory dysfunction. Specifically, altered adult neurogenesis along the SVZ-RMS-OB pathway and neurochemical imbalance could be the factors that may contribute to olfactory dysfunction. Full article

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

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37 pages, 888 KiB

Open AccessEditor’s ChoiceReview

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

by Reed Berlet, Stefan Anthony, Beverly Brooks, Zhen-Jie Wang, Nadia Sadanandan, Alex Shear, Blaise Cozene, Bella Gonzales-Portillo, Blake Parsons, Felipe Esparza Salazar, Alma R. Lezama Toledo, Germán Rivera Monroy, Joaquín Vega Gonzales-Portillo and Cesario V. Borlongan

Biomolecules 2021, 11(9), 1316; https://doi.org/10.3390/biom11091316 - 6 Sep 2021

Cited by 19 | Viewed by 6468

Abstract

Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new [...] Read more.

Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke. Full article

(This article belongs to the Special Issue Protection, Plasticity, and Physical Rehabilitation in Ischemic Injury)

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14 pages, 687 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Heart Organoids and Engineered Heart Tissues: Novel Tools for Modeling Human Cardiac Biology and Disease

by Yonatan R. Lewis-Israeli, Aaron H. Wasserman and Aitor Aguirre

Biomolecules 2021, 11(9), 1277; https://doi.org/10.3390/biom11091277 - 26 Aug 2021

Cited by 27 | Viewed by 6346

Abstract

Organoids are three-dimensional in vitro cell constructs that recapitulate organ properties and structure to a significant extent. They constitute particularly useful models to study unapproachable states in humans, such as embryonic and fetal development, or early disease progression in adults. In recent years [...] Read more.

Organoids are three-dimensional in vitro cell constructs that recapitulate organ properties and structure to a significant extent. They constitute particularly useful models to study unapproachable states in humans, such as embryonic and fetal development, or early disease progression in adults. In recent years organoids have been implemented to model a wide range of different organs and disease conditions. However, the technology for their fabrication and application to cardiovascular studies has been lagging significantly when compared to other organoid types (e.g., brain, pancreas, kidney, intestine). This is a surprising fact since cardiovascular disease (CVD) and congenital heart disease (CHD) constitute the leading cause of mortality and morbidity in the developed world, and the most common birth defect in humans, respectively, and collectively constitute one of the largest unmet medical needs in the modern world. There is a critical need to establish in vitro models of the human heart that faithfully recapitulate its biology and function, thus enabling basic and translational studies to develop new therapeutics. Generating heart organoids that truly resemble the heart has proven difficult due to its complexity, but significant progress has been made recently to overcome this obstacle. In this review, we will discuss progress in novel heart organoid generation methods, the advantages and disadvantages of each approach, and their translational applications for advancing cardiovascular studies and the treatment of heart disorders. Full article

(This article belongs to the Section Synthetic Biology and Bioengineering)

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15 pages, 15351 KiB

Open AccessEditor’s ChoiceArticle

3D Bioprinting Mesenchymal Stem Cell-Derived Neural Tissues Using a Fibrin-Based Bioink

by Milena Restan Perez, Ruchi Sharma, Nadia Zeina Masri and Stephanie Michelle Willerth

Biomolecules 2021, 11(8), 1250; https://doi.org/10.3390/biom11081250 - 21 Aug 2021

Cited by 20 | Viewed by 5574

Abstract

Current treatments for neurodegenerative diseases aim to alleviate the symptoms experienced by patients; however, these treatments do not cure the disease nor prevent further degeneration. Improvements in current disease-modeling and drug-development practices could accelerate effective treatments for neurological diseases. To that end, 3D [...] Read more.

Current treatments for neurodegenerative diseases aim to alleviate the symptoms experienced by patients; however, these treatments do not cure the disease nor prevent further degeneration. Improvements in current disease-modeling and drug-development practices could accelerate effective treatments for neurological diseases. To that end, 3D bioprinting has gained significant attention for engineering tissues in a rapid and reproducible fashion. Additionally, using patient-derived stem cells, which can be reprogrammed to neural-like cells, could generate personalized neural tissues. Here, adipose tissue-derived mesenchymal stem cells (MSCs) were bioprinted using a fibrin-based bioink and the microfluidic RX1 bioprinter. These tissues were cultured for 12 days in the presence of SB431542 (SB), LDN-193189 (LDN), purmorphamine (puro), fibroblast growth factor 8 (FGF8), fibroblast growth factor-basic (bFGF), and brain-derived neurotrophic factor (BDNF) to induce differentiation to dopaminergic neurons (DN). The constructs were analyzed for expression of neural markers, dopamine release, and electrophysiological activity. The cells expressed DN-specific and early neuronal markers (tyrosine hydroxylase (TH) and class III beta-tubulin (TUJ1), respectively) after 12 days of differentiation. Additionally, the tissues exhibited immature electrical signaling after treatment with potassium chloride (KCl). Overall, this work shows the potential of bioprinting engineered neural tissues from patient-derived MSCs, which could serve as an important tool for personalized disease models and drug-screening. Full article

(This article belongs to the Special Issue Extracellular Matrix-Based Bioinks for 3D Bioprinting Applications)

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10 pages, 801 KiB

Open AccessEditor’s ChoiceReview

Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside?

by Cecilia Marini, Vanessa Cossu, Matteo Bauckneht, Francesco Lanfranchi, Stefano Raffa, Anna Maria Orengo, Silvia Ravera, Silvia Bruno and Gianmario Sambuceti

Biomolecules 2021, 11(8), 1231; https://doi.org/10.3390/biom11081231 - 18 Aug 2021

Cited by 11 | Viewed by 4435

Abstract

Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This [...] Read more.

Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This action is most often attributed to a well-documented blockage of oxidative phosphorylation (OXPHOS) caused by a direct interference of metformin on Complex I function. Nevertheless, several other pleiotropic actions seem to contribute to the anticancer potential of this biguanide. In particular, in vitro and in vivo experimental studies recently documented that metformin selectively inhibits the uptake of 2-[18F]-Fluoro-2-Deoxy-D-Glucose (FDG), via an impaired catalytic function of the enzyme hexose-6P-dehydrogenase (H6PD). H6PD triggers a still largely uncharacterized pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER) that has been found to play a pivotal role in feeding the NADPH reductive power for both cellular proliferation and antioxidant responses. Regardless of its exploitability in the clinical setting, this metformin action might configure the ER metabolism as a potential target for innovative therapeutic strategies in patients with solid cancers and potentially modifies the current interpretative model of FDG uptake, attributing PET/CT capability to predict cancer aggressiveness to the activation of H6PD catalytic function. Full article

(This article belongs to the Special Issue Metformin and Cancer)

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24 pages, 2434 KiB

Open AccessEditor’s ChoiceReview

Perineuronal Nets and Metal Cation Concentrations in the Microenvironments of Fast-Spiking, Parvalbumin-Expressing GABAergic Interneurons: Relevance to Neurodevelopment and Neurodevelopmental Disorders

by Jessica A. Burket, Jason D. Webb and Stephen I. Deutsch

Biomolecules 2021, 11(8), 1235; https://doi.org/10.3390/biom11081235 - 18 Aug 2021

Cited by 17 | Viewed by 6156

Abstract

Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local [...] Read more.

Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range. Full article

(This article belongs to the Special Issue Clinical Phenotype of Autism Spectrum Disorder: Development and Delivery of Therapeutic Biomolecules to the CNS)

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26 pages, 1588 KiB

Open AccessEditor’s ChoiceReview

Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets

by Phuong Linh Nguyen and Jungsook Cho

Biomolecules 2021, 11(8), 1232; https://doi.org/10.3390/biom11081232 - 18 Aug 2021

Cited by 27 | Viewed by 10853

Abstract

High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine [...] Read more.

High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings. Full article

(This article belongs to the Special Issue New Developments in Histamine Research)

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14 pages, 565 KiB

Open AccessEditor’s ChoiceArticle

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

by Chin-Hsiao Tseng

Biomolecules 2021, 11(8), 1226; https://doi.org/10.3390/biom11081226 - 17 Aug 2021

Cited by 7 | Viewed by 3066

Abstract

The risk of malignant brain tumors associated with metformin use has rarely been investigated in humans. This retrospective cohort study investigated such an association. Patients with new-onset type 2 diabetes mellitus diagnosed from 1999 to 2005 in the nationwide database of Taiwan’s national [...] Read more.

The risk of malignant brain tumors associated with metformin use has rarely been investigated in humans. This retrospective cohort study investigated such an association. Patients with new-onset type 2 diabetes mellitus diagnosed from 1999 to 2005 in the nationwide database of Taiwan’s national health insurance were used to enroll study subjects. We first identified an unmatched cohort of 153,429 ever users and 16,222 never users of metformin. A cohort of 16,222 ever users and 16,222 never users matched on propensity score was then created from this unmatched cohort. All patients were followed up from 1 January 2006 until 31 December 2011. The incidence density was calculated and hazard ratios were derived from Cox regression incorporated with the inverse probability of treatment weighting using a propensity score. The results showed that 27 never users and 155 ever users developed malignant brain tumors in the unmatched cohort. The incidence rate was 37.11 per 100,000 person-years in never users and 21.39 per 100,000 person-years in ever users. The overall hazard ratio comparing ever users versus never users was 0.574 (95% confidence interval: 0.381–0.863). The respective hazard ratios comparing the first (<27.13 months), second (27.13–58.33 months), and third (>58.33 months) tertiles of cumulative duration of metformin therapy versus never users were 0.897 (0.567–1.421), 0.623 (0.395–0.984), and 0.316 (0.192–0.518). In the matched cohort, the overall hazard ratio was 0.317 (0.149–0.673) and the respective hazard ratios were 0.427 (0.129–1.412), 0.509 (0.196–1.322), and 0.087 (0.012–0.639) for the first, second, and third tertile of cumulative duration of metformin therapy. In conclusion, this study shows a risk reduction of malignant brain tumors associated with metformin use in a dose–response pattern. The risk reduction is more remarkable when metformin has been used for approximately 2–5 years. Full article

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38 pages, 11203 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Chalcones: Synthetic Chemistry Follows Where Nature Leads

by Hiba A. Jasim, Lutfun Nahar, Mohammad A. Jasim, Sharon A. Moore, Kenneth J. Ritchie and Satyajit D. Sarker

Biomolecules 2021, 11(8), 1203; https://doi.org/10.3390/biom11081203 - 13 Aug 2021

Cited by 76 | Viewed by 8430

Abstract

Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of [...] Read more.

Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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16 pages, 3140 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Uptake of Biotinylated Spermine in Astrocytes: Effect of Cx43 siRNA, HIV-Tat Protein and Polyamine Transport Inhibitor on Polyamine Uptake

by Christian J. Malpica-Nieves, Yomarie Rivera, David E. Rivera-Aponte, Otto Phanstiel, Rüdiger W. Veh, Misty J. Eaton and Serguei N. Skatchkov

Biomolecules 2021, 11(8), 1187; https://doi.org/10.3390/biom11081187 - 11 Aug 2021

Cited by 11 | Viewed by 3306

Abstract

Polyamines (PAs) are polycationic biomolecules containing multiple amino groups. Patients with HIV-associated neurocognitive disorder (HAND) have high concentrations of the polyamine N-acetylated spermine in their brain and cerebral spinal fluid (CSF) and have increased PA release from astrocytes. These effects are due to [...] Read more.

Polyamines (PAs) are polycationic biomolecules containing multiple amino groups. Patients with HIV-associated neurocognitive disorder (HAND) have high concentrations of the polyamine N-acetylated spermine in their brain and cerebral spinal fluid (CSF) and have increased PA release from astrocytes. These effects are due to the exposure to HIV-Tat. In healthy adult brain, PAs are accumulated but not synthesized in astrocytes, suggesting that PAs must enter astrocytes to be N-acetylated and released. Therefore, we tested if Cx43 hemichannels (Cx43-HCs) are pathways for PA flux in control and HIV-Tat-treated astrocytes. We used biotinylated spermine (b-SPM) to examine polyamine uptake. We found that control astrocytes and those treated with siRNA-Cx43 took up b-SPM, similarly suggesting that PA uptake is via a transporter/channel other than Cx43-HCs. Surprisingly, astrocytes pretreated with both HIV-Tat and siRNA-Cx43 showed increased accumulation of b-SPM. Using a novel polyamine transport inhibitor (PTI), trimer 44NMe, we blocked b-SPM uptake, showing that PA uptake is via a PTI-sensitive transport mechanism such as organic cation transporter. Our data suggest that Cx43 HCs are not a major pathway for b-SPM uptake in the condition of normal extracellular calcium concentration but may be involved in the release of PAs to the extracellular space during viral infection. Full article

(This article belongs to the Special Issue Polyamines in the Central Nervous System: Neurons, Glial Cells and Diseases)

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16 pages, 3067 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Targeting of Native Proteins to the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway: An Expanding Repertoire of Regulated Substrates

by Deepa Kumari and Jeffrey L. Brodsky

Biomolecules 2021, 11(8), 1185; https://doi.org/10.3390/biom11081185 - 11 Aug 2021

Cited by 20 | Viewed by 6516

Abstract

All proteins are subject to quality control processes during or soon after their synthesis, and these cellular quality control pathways play critical roles in maintaining homeostasis in the cell and in organism health. Protein quality control is particularly vital for those polypeptides that [...] Read more.

All proteins are subject to quality control processes during or soon after their synthesis, and these cellular quality control pathways play critical roles in maintaining homeostasis in the cell and in organism health. Protein quality control is particularly vital for those polypeptides that enter the endoplasmic reticulum (ER). Approximately one-quarter to one-third of all proteins synthesized in eukaryotic cells access the ER because they are destined for transport to the extracellular space, because they represent integral membrane proteins, or because they reside within one of the many compartments of the secretory pathway. However, proteins that mature inefficiently are subject to ER-associated degradation (ERAD), a multi-step pathway involving the chaperone-mediated selection, ubiquitination, and extraction (or “retrotranslocation”) of protein substrates from the ER. Ultimately, these substrates are degraded by the cytosolic proteasome. Interestingly, there is an increasing number of native enzymes and metabolite and solute transporters that are also targeted for ERAD. While some of these proteins may transiently misfold, the ERAD pathway also provides a route to rapidly and quantitatively downregulate the levels and thus the activities of a variety of proteins that mature or reside in the ER. Full article

(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)

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17 pages, 3903 KiB

Open AccessEditor’s ChoiceArticle

Development and Evaluation of Gellan Gum/Silk Fibroin/Chondroitin Sulfate Ternary Injectable Hydrogel for Cartilage Tissue Engineering

by Seongwon Lee, Joohee Choi, Jina Youn, Younghun Lee, Wooyoup Kim, Seungho Choe, Jeongeun Song, Rui L. Reis and Gilson Khang

Biomolecules 2021, 11(8), 1184; https://doi.org/10.3390/biom11081184 - 11 Aug 2021

Cited by 35 | Viewed by 4627

Abstract

Hydrogel is in the spotlight as a useful biomaterial in the field of drug delivery and tissue engineering due to its similar biological properties to a native extracellular matrix (ECM). Herein, we proposed a ternary hydrogel of gellan gum (GG), silk fibroin (SF), [...] Read more.

Hydrogel is in the spotlight as a useful biomaterial in the field of drug delivery and tissue engineering due to its similar biological properties to a native extracellular matrix (ECM). Herein, we proposed a ternary hydrogel of gellan gum (GG), silk fibroin (SF), and chondroitin sulfate (CS) as a biomaterial for cartilage tissue engineering. The hydrogels were fabricated with a facile combination of the physical and chemical crosslinking method. The purpose of this study was to find the proper content of SF and GG for the ternary matrix and confirm the applicability of the hydrogel in vitro and in vivo. The chemical and mechanical properties were measured to confirm the suitability of the hydrogel for cartilage tissue engineering. The biocompatibility of the hydrogels was investigated by analyzing the cell morphology, adhesion, proliferation, migration, and growth of articular chondrocytes-laden hydrogels. The results showed that the higher proportion of GG enhanced the mechanical properties of the hydrogel but the groups with over 0.75% of GG exhibited gelling temperatures over 40 °C, which was a harsh condition for cell encapsulation. The 0.3% GG/3.7% SF/CS and 0.5% GG/3.5% SF/CS hydrogels were chosen for the in vitro study. The cells that were encapsulated in the hydrogels did not show any abnormalities and exhibited low cytotoxicity. The biochemical properties and gene expression of the encapsulated cells exhibited positive cell growth and expression of cartilage-specific ECM and genes in the 0.5% GG/3.5% SF/CS hydrogel. Overall, the study of the GG/SF/CS ternary hydrogel with an appropriate content showed that the combination of GG, SF, and CS can synergistically promote articular cartilage defect repair and has considerable potential for application as a biomaterial in cartilage tissue engineering. Full article

(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)

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16 pages, 3974 KiB

Open AccessEditor’s ChoiceArticle

Design and Evaluation of Synthetic RNA-Based Incoherent Feed-Forward Loop Circuits

by Seongho Hong, Dohyun Jeong, Jordan Ryan, Mathias Foo, Xun Tang and Jongmin Kim

Biomolecules 2021, 11(8), 1182; https://doi.org/10.3390/biom11081182 - 10 Aug 2021

Cited by 11 | Viewed by 4818

Abstract

RNA-based regulators are promising tools for building synthetic biological systems that provide a powerful platform for achieving a complex regulation of transcription and translation. Recently, de novo-designed synthetic RNA regulators, such as the small transcriptional activating RNA (STAR), toehold switch (THS), and three-way [...] Read more.

RNA-based regulators are promising tools for building synthetic biological systems that provide a powerful platform for achieving a complex regulation of transcription and translation. Recently, de novo-designed synthetic RNA regulators, such as the small transcriptional activating RNA (STAR), toehold switch (THS), and three-way junction (3WJ) repressor, have been utilized to construct RNA-based synthetic gene circuits in living cells. In this work, we utilized these regulators to construct type 1 incoherent feed-forward loop (IFFL) circuits in vivo and explored their dynamic behaviors. A combination of a STAR and 3WJ repressor was used to construct an RNA-only IFFL circuit. However, due to the fast kinetics of RNA–RNA interactions, there was no significant timescale difference between the direct activation and the indirect inhibition, that no pulse was observed in the experiments. These findings were confirmed with mechanistic modeling and simulation results for a wider range of conditions. To increase delay in the inhibition pathway, we introduced a protein synthesis process to the circuit and designed an RNA–protein hybrid IFFL circuit using THS and TetR protein. Simulation results indicated that pulse generation could be achieved with this RNA–protein hybrid model, and this was further verified with experimental realization in E. coli. Our findings demonstrate that while RNA-based regulators excel in speed as compared to protein-based regulators, the fast reaction kinetics of RNA-based regulators could also undermine the functionality of a circuit (e.g., lack of significant timescale difference). The agreement between experiments and simulations suggests that the mechanistic modeling can help debug issues and validate the hypothesis in designing a new circuit. Moreover, the applicability of the kinetic parameters extracted from the RNA-only circuit to the RNA–protein hybrid circuit also indicates the modularity of RNA-based regulators when used in a different context. We anticipate the findings of this work to guide the future design of gene circuits that rely heavily on the dynamics of RNA-based regulators, in terms of both modeling and experimental realization. Full article

(This article belongs to the Special Issue Nucleic Acids: Applications in the Fields of Diagnostics, Therapeutics, Synthetic Biology, and Beyond)

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17 pages, 1237 KiB

Open AccessEditor’s ChoiceArticle

Insight into Calcium-Binding Motifs of Intrinsically Disordered Proteins

by Estella A. Newcombe, Catarina B. Fernandes, Jeppe E. Lundsgaard, Inna Brakti, Kresten Lindorff-Larsen, Annette E. Langkilde, Karen Skriver and Birthe B. Kragelund

Biomolecules 2021, 11(8), 1173; https://doi.org/10.3390/biom11081173 - 9 Aug 2021

Cited by 12 | Viewed by 4530

Abstract

Motifs within proteins help us categorize their functions. Intrinsically disordered proteins (IDPs) are rich in short linear motifs, conferring them many different roles. IDPs are also frequently highly charged and, therefore, likely to interact with ions. Canonical calcium-binding motifs, such as the EF-hand, [...] Read more.

Motifs within proteins help us categorize their functions. Intrinsically disordered proteins (IDPs) are rich in short linear motifs, conferring them many different roles. IDPs are also frequently highly charged and, therefore, likely to interact with ions. Canonical calcium-binding motifs, such as the EF-hand, often rely on the formation of stabilizing flanking helices, which are a key characteristic of folded proteins, but are absent in IDPs. In this study, we probe the existence of a calcium-binding motif relevant to IDPs. Upon screening several carefully selected IDPs using NMR spectroscopy supplemented with affinity quantification by colorimetric assays, we found calcium-binding motifs in IDPs which could be categorized into at least two groups—an Excalibur-like motif, sequentially similar to the EF-hand loop, and a condensed-charge motif carrying repetitive negative charges. The motifs show an affinity for calcium typically in the ~100 μM range relevant to regulatory functions and, while calcium binding to the condensed-charge motif had little effect on the overall compaction of the IDP chain, calcium binding to Excalibur-like motifs resulted in changes in compaction. Thus, calcium binding to IDPs may serve various structural and functional roles that have previously been underreported. Full article

(This article belongs to the Collection Protein Intrinsic Disorder: Role in Signaling, Regulation and Membrane-Less Organelle Formation)

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28 pages, 1784 KiB

Open AccessEditor’s ChoiceReview

Therapy Approaches for Stargardt Disease

by Elena Piotter, Michelle E McClements and Robert E MacLaren

Biomolecules 2021, 11(8), 1179; https://doi.org/10.3390/biom11081179 - 9 Aug 2021

Cited by 31 | Viewed by 9596

Abstract

Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over [...] Read more.

Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide. Full article

(This article belongs to the Special Issue Nucleic Acids: Applications in the Fields of Diagnostics, Therapeutics, Synthetic Biology, and Beyond)

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22 pages, 4016 KiB

Open AccessEditor’s ChoiceArticle

Characterization of the Skeletal Muscle Secretome Reveals a Role for Extracellular Vesicles and IL1α/IL1β in Restricting Fibro/Adipogenic Progenitor Adipogenesis

by Simone Vumbaca, Giulio Giuliani, Valeria Fiorentini, Flavia Tortolici, Andrea Cerquone Perpetuini, Federica Riccio, Simona Sennato, Cesare Gargioli, Claudia Fuoco, Luisa Castagnoli and Gianni Cesareni

Biomolecules 2021, 11(8), 1171; https://doi.org/10.3390/biom11081171 - 8 Aug 2021

Cited by 12 | Viewed by 4289

Abstract

Repeated mechanical stress causes injuries in the adult skeletal muscle that need to be repaired. Although muscle regeneration is a highly efficient process, it fails in some pathological conditions, compromising tissue functionality. This may be caused by aberrant cell–cell communication, resulting in the [...] Read more.

Repeated mechanical stress causes injuries in the adult skeletal muscle that need to be repaired. Although muscle regeneration is a highly efficient process, it fails in some pathological conditions, compromising tissue functionality. This may be caused by aberrant cell–cell communication, resulting in the deposition of fibrotic and adipose infiltrates. Here, we investigate in vivo changes in the profile of skeletal muscle secretome during the regeneration process to suggest new targetable regulatory circuits whose failure may lead to tissue degeneration in pathological conditions. We describe the kinetic variation of expression levels of 76 secreted proteins during the regeneration process. In addition, we profile the gene expression of immune cells, endothelial cells, satellite cells, and fibro-adipogenic progenitors. This analysis allowed us to annotate each cell-type with the cytokines and receptors they have the potential to synthetize, thus making it possible to draw a cell–cell interaction map. We next selected 12 cytokines whose receptors are expressed in FAPs and tested their ability to modulate FAP adipogenesis and proliferation. We observed that IL1α and IL1β potently inhibit FAP adipogenesis, while EGF and BTC notably promote FAP proliferation. In addition, we characterized the cross-talk mediated by extracellular vesicles (EVs). We first monitored the modulation of muscle EV cargo during tissue regeneration. Using a single-vesicle flow cytometry approach, we observed that EVs differentially affect the uptake of RNA and proteins into their lumen. We also investigated the EV capability to interact with SCs and FAPs and to modulate their proliferation and differentiation. We conclude that both cytokines and EVs secreted during muscle regeneration have the potential to modulate adipogenic differentiation of FAPs. The results of our approach provide a system-wide picture of mechanisms that control cell fate during the regeneration process in the muscle niche. Full article

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

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12 pages, 692 KiB

Open AccessEditor’s ChoiceReview

Neutrophil in the Pancreatic Tumor Microenvironment

by Lin Jin, Hong Sun Kim and Jiaqi Shi

Biomolecules 2021, 11(8), 1170; https://doi.org/10.3390/biom11081170 - 7 Aug 2021

Cited by 31 | Viewed by 5836

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed. Full article

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

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19 pages, 13260 KiB

Open AccessEditor’s ChoiceArticle

Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa

by T.J. Hollingsworth, Meredith G. Hubbard, Hailey J. Levi, William White, Xiangdi Wang, Raven Simpson, Monica M. Jablonski and Alecia K. Gross

Biomolecules 2021, 11(8), 1163; https://doi.org/10.3390/biom11081163 - 6 Aug 2021

Cited by 11 | Viewed by 3326

Abstract

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple [...] Read more.

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

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22 pages, 4261 KiB

Open AccessEditor’s ChoiceReview

The Bigger Picture: Why Oral Mucosa Heals Better Than Skin

by Maaike Waasdorp, Bastiaan P. Krom, Floris J. Bikker, Paul P. M. van Zuijlen, Frank B. Niessen and Susan Gibbs

Biomolecules 2021, 11(8), 1165; https://doi.org/10.3390/biom11081165 - 6 Aug 2021

Cited by 67 | Viewed by 13098

Abstract

Wound healing is an essential process to restore tissue integrity after trauma. Large skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in disfigurements and reduced joint mobility. Such adverse healing outcomes are less common in the oral mucosa, [...] Read more.

Wound healing is an essential process to restore tissue integrity after trauma. Large skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in disfigurements and reduced joint mobility. Such adverse healing outcomes are less common in the oral mucosa, which generally heals faster compared to skin. Several studies have identified differences between oral and skin wound healing. Most of these studies however focus only on a single stage of wound healing or a single cell type. The aim of this review is to provide an extensive overview of wound healing in skin versus oral mucosa during all stages of wound healing and including all cell types and molecules involved in the process and also taking into account environmental specific factors such as exposure to saliva and the microbiome. Next to intrinsic properties of resident cells and differential expression of cytokines and growth factors, multiple external factors have been identified that contribute to oral wound healing. It can be concluded that faster wound closure, the presence of saliva, a more rapid immune response, and increased extracellular matrix remodeling all contribute to the superior wound healing and reduced scar formation in oral mucosa, compared to skin. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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12 pages, 631 KiB

Open AccessEditor’s ChoiceArticle

Influence of the Levels of Arsenic, Cadmium, Mercury and Lead on Overall Survival in Lung Cancer

by Sandra Pietrzak, Janusz Wójcik, Piotr Baszuk, Wojciech Marciniak, Małgorzata Wojtyś, Tadeusz Dębniak, Cezary Cybulski, Jacek Gronwald, Jacek Alchimowicz, Bartłomiej Masojć, Piotr Waloszczyk, Darko Gajić, Tomasz Grodzki, Anna Jakubowska, Rodney J. Scott, Jan Lubiński and Marcin R. Lener

Biomolecules 2021, 11(8), 1160; https://doi.org/10.3390/biom11081160 - 5 Aug 2021

Cited by 30 | Viewed by 3092

Abstract

The effects of heavy metals on cancer risk have been widely studied in recent decades, but there is limited data on the effects of these elements on cancer survival. In this research, we examined whether blood concentrations of the heavy metals arsenic, cadmium, [...] Read more.

The effects of heavy metals on cancer risk have been widely studied in recent decades, but there is limited data on the effects of these elements on cancer survival. In this research, we examined whether blood concentrations of the heavy metals arsenic, cadmium, mercury and lead were associated with the overall survival of lung cancer patients. The study group consisted of 336 patients with lung cancer who were prospectively observed. Blood concentrations of heavy metals were measured to study the relationship between their levels and overall survival using Cox proportional hazards analysis. The hazard ratio of death from all causes was 0.99 (p = 0.94) for arsenic, 1.37 (p = 0.15) for cadmium, 1.55 (p = 0.04) for mercury, and 1.18 (p = 0.47) for lead in patients from the lowest concentration quartile, compared with those in the highest quartile. Among the patients with stage IA disease, this relationship was statistically significant (HR = 7.36; p < 0.01) for cadmium levels in the highest quartile (>1.97–7.77 µg/L) compared to quartile I (0.23–0.57 µg/L, reference). This study revealed that low blood cadmium levels <1.47 µg/L are probably associated with improved overall survival in treated patients with stage IA disease. Full article

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15 pages, 2155 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells

by Trevor Teafatiller, Sudhanshu Agrawal, Gabriela De Robles, Farah Rahmatpanah, Veedamali S. Subramanian and Anshu Agrawal

Biomolecules 2021, 11(8), 1148; https://doi.org/10.3390/biom11081148 - 3 Aug 2021

Cited by 17 | Viewed by 4705

Abstract

Vitamin C is well documented to have antiviral functions; however, there is limited information about its effect on airway epithelial cells—the first cells to encounter infections. Here, we examined the effect of vitamin C on human bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) [...] Read more.

Vitamin C is well documented to have antiviral functions; however, there is limited information about its effect on airway epithelial cells—the first cells to encounter infections. Here, we examined the effect of vitamin C on human bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) cells, and observed that sodium-dependent vitamin C transporter 2 (SVCT2) was the primary vitamin C transporter. Transcriptomic analysis revealed that treating BEAS-2B cells with vitamin C led to a significant upregulation of several metabolic pathways and interferon-stimulated genes (ISGs) along with a downregulation of pathways involved in lung injury and inflammation. Remarkably, vitamin C also enhanced the expression of the viral-sensing receptors retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA-5), which was confirmed at the protein and functional levels. In addition, the lungs of l-gulono-γ-lactone oxidase knockout (GULO-KO) mice also displayed a marked decrease in these genes compared to wild-type controls. Collectively, our findings indicate that vitamin C acts at multiple levels to exert its antiviral and protective functions in the lungs. Full article

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

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15 pages, 1532 KiB

Open AccessEditor’s ChoiceReview

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

by Aikaterini Skandalaki, Panagiotis Sarantis and Stamatios Theocharis

Biomolecules 2021, 11(8), 1142; https://doi.org/10.3390/biom11081142 - 2 Aug 2021

Cited by 18 | Viewed by 3702

Abstract

Pregnane X Receptor (PXR) belongs to the nuclear receptors’ superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR’s regulation. Antineoplastic [...] Read more.

Pregnane X Receptor (PXR) belongs to the nuclear receptors’ superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR’s regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomolecules—Recent Advances in Understanding of Molecular Pathology and Therapeutics of Cancer)

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11 pages, 974 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Ocular Gene Delivery Landscape

by Bhubanananda Sahu, Isha Chug and Hemant Khanna

Biomolecules 2021, 11(8), 1135; https://doi.org/10.3390/biom11081135 - 1 Aug 2021

Cited by 14 | Viewed by 5472

Abstract

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These [...] Read more.

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These examinations have revealed new information about the benefits as well as restrictions to using drug-delivery routes to the different parts of the eye. In this article, we will discuss a brief history of gene therapy and its importance to the eye and ocular delivery landscape that is currently being investigated, and provide insights into their advantages and disadvantages. Efficient delivery routes and vehicle are crucial for an effective, safe, and longer-lasting therapy. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

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23 pages, 3202 KiB

Open AccessEditor’s ChoiceReview

Transportation of Single-Domain Antibodies through the Blood–Brain Barrier

by Eduardo Ruiz-López and Alberto J. Schuhmacher

Biomolecules 2021, 11(8), 1131; https://doi.org/10.3390/biom11081131 - 31 Jul 2021

Cited by 44 | Viewed by 10590

Abstract

Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for [...] Read more.

Single-domain antibodies derive from the heavy-chain-only antibodies of Camelidae (camel, dromedary, llama, alpaca, vicuñas, and guananos; i.e., nanobodies) and cartilaginous fishes (i.e., VNARs). Their small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. Nevertheless, numerous neurological diseases and brain pathologies, including cancer, result in BBB leakiness favoring single-domain antibodies uptake into the CNS. Some single-domain antibodies have been reported to naturally cross the BBB. In addition, different strategies and methods to deliver both nanobodies and VNARs into the brain parenchyma can be exploited when the BBB is intact. These include device-based and physicochemical disruption of the BBB, receptor and adsorptive-mediated transcytosis, somatic gene transfer, and the use of carriers/shuttles such as cell-penetrating peptides, liposomes, extracellular vesicles, and nanoparticles. Approaches based on single-domain antibodies are reaching the clinic for other diseases. Several tailoring methods can be followed to favor the transport of nanobodies and VNARs to the CNS, avoiding the limitations imposed by the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies. Full article

(This article belongs to the Special Issue Bioinspired and Biomimicking Materials for Biomedical Applications)

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36 pages, 3020 KiB

Open AccessEditor’s ChoiceReview

Understanding and Exploiting Post-Translational Modifications for Plant Disease Resistance

by Catherine Gough and Ari Sadanandom

Biomolecules 2021, 11(8), 1122; https://doi.org/10.3390/biom11081122 - 30 Jul 2021

Cited by 16 | Viewed by 5612

Abstract

Plants are constantly threatened by pathogens, so have evolved complex defence signalling networks to overcome pathogen attacks. Post-translational modifications (PTMs) are fundamental to plant immunity, allowing rapid and dynamic responses at the appropriate time. PTM regulation is essential; pathogen effectors often disrupt PTMs [...] Read more.

Plants are constantly threatened by pathogens, so have evolved complex defence signalling networks to overcome pathogen attacks. Post-translational modifications (PTMs) are fundamental to plant immunity, allowing rapid and dynamic responses at the appropriate time. PTM regulation is essential; pathogen effectors often disrupt PTMs in an attempt to evade immune responses. Here, we cover the mechanisms of disease resistance to pathogens, and how growth is balanced with defence, with a focus on the essential roles of PTMs. Alteration of defence-related PTMs has the potential to fine-tune molecular interactions to produce disease-resistant crops, without trade-offs in growth and fitness. Full article

(This article belongs to the Collection Cellular and Molecular Mechanisms Governing Stress Response in Plants)

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17 pages, 2188 KiB

Open AccessEditor’s ChoiceReview

How Inflammation Pathways Contribute to Cell Death in Neuro-Muscular Disorders

by Sara Salucci, Anna Bartoletti Stella, Michela Battistelli, Sabrina Burattini, Alberto Bavelloni, Lucio Ildebrando Cocco, Pietro Gobbi and Irene Faenza

Biomolecules 2021, 11(8), 1109; https://doi.org/10.3390/biom11081109 - 28 Jul 2021

Cited by 11 | Viewed by 4028

Abstract

Neuro-muscular disorders include a variety of diseases induced by genetic mutations resulting in muscle weakness and waste, swallowing and breathing difficulties. However, muscle alterations and nerve depletions involve specific molecular and cellular mechanisms which lead to the loss of motor-nerve or skeletal-muscle function, [...] Read more.

Neuro-muscular disorders include a variety of diseases induced by genetic mutations resulting in muscle weakness and waste, swallowing and breathing difficulties. However, muscle alterations and nerve depletions involve specific molecular and cellular mechanisms which lead to the loss of motor-nerve or skeletal-muscle function, often due to an excessive cell death. Morphological and molecular studies demonstrated that a high number of these disorders seem characterized by an upregulated apoptosis which significantly contributes to the pathology. Cell death involvement is the consequence of some cellular processes that occur during diseases, including mitochondrial dysfunction, protein aggregation, free radical generation, excitotoxicity and inflammation. The latter represents an important mediator of disease progression, which, in the central nervous system, is known as neuroinflammation, characterized by reactive microglia and astroglia, as well the infiltration of peripheral monocytes and lymphocytes. Some of the mechanisms underlying inflammation have been linked to reactive oxygen species accumulation, which trigger mitochondrial genomic and respiratory chain instability, autophagy impairment and finally neuron or muscle cell death. This review discusses the main inflammatory pathways contributing to cell death in neuro-muscular disorders by highlighting the main mechanisms, the knowledge of which appears essential in developing therapeutic strategies to prevent the consequent neuron loss and muscle wasting. Full article

(This article belongs to the Special Issue Inflammatory Pathways in Neuro-Muscular Degeneration, Metabolic Syndromes, Cancer and Infection)

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17 pages, 3960 KiB

Open AccessEditor’s ChoiceArticle

Sirtuin 1, Visfatin and IL-27 Serum Levels of Type 1 Diabetic Females in Relation to Cardiovascular Parameters and Autoimmune Thyroid Disease

by Magdalena Łukawska-Tatarczuk, Edward Franek, Leszek Czupryniak, Ilona Joniec-Maciejak, Agnieszka Pawlak, Ewa Wojnar, Jakub Zieliński, Dagmara Mirowska-Guzel and Beata Mrozikiewicz-Rakowska

Biomolecules 2021, 11(8), 1110; https://doi.org/10.3390/biom11081110 - 28 Jul 2021

Cited by 12 | Viewed by 3465

Abstract

The loss of cardioprotection observed in premenopausal, diabetic women may result from the interplay between epigenetic, metabolic, and immunological factors. The aim of this study was to evaluate the concentration of sirtuin 1, visfatin, and IL-27 in relation to cardiovascular parameters and Hashimoto’s [...] Read more.

The loss of cardioprotection observed in premenopausal, diabetic women may result from the interplay between epigenetic, metabolic, and immunological factors. The aim of this study was to evaluate the concentration of sirtuin 1, visfatin, and IL-27 in relation to cardiovascular parameters and Hashimoto’s disease (HD) in young, asymptomatic women with type 1 diabetes mellitus (T1DM). Thyroid ultrasound, carotid intima-media thickness (cIMT) measurement, electrocardiography, and echocardiography were performed in 50 euthyroid females with T1DM (28 with HD and 22 without concomitant diseases) and 30 controls. The concentrations of serum sirtuin 1, visfatin and IL-27 were assessed using ELISA. The T1DM and HD group had higher cIMT (p = 0.018) and lower left ventricular global longitudinal strain (p = 0.025) compared to females with T1DM exclusively. In women with a double diagnosis, the sirtuin 1 and IL-27 concentrations were non-significantly higher than in other groups and significantly positively correlated with each other (r = 0.445, p = 0.018) and thyroid volume (r = 0.511, p = 0.005; r = 0.482, p = 0.009, respectively) and negatively correlated with relative wall thickness (r = –0.451, p = 0.016; r = –0.387, p = 0.041, respectively). These relationships were not observed in the control group nor for the visfatin concentration. These results suggest that sirtuin 1 and IL-27 contribute to the pathogenesis of early cardiac dysfunction in women with T1DM and HD. Full article

(This article belongs to the Special Issue Molecular Biomarkers In Cardiology 2021)

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18 pages, 496 KiB

Open AccessEditor’s ChoiceReview

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing – Review

by Gabriel Dorado, Sergio Gálvez, Teresa E. Rosales, Víctor F. Vásquez and Pilar Hernández

Biomolecules 2021, 11(8), 1111; https://doi.org/10.3390/biom11081111 - 28 Jul 2021

Cited by 27 | Viewed by 7178

Abstract

Recent developments have revolutionized the study of biomolecules. Among them are molecular markers, amplification and sequencing of nucleic acids. The latter is classified into three generations. The first allows to sequence small DNA fragments. The second one increases throughput, reducing turnaround and pricing, [...] Read more.

Recent developments have revolutionized the study of biomolecules. Among them are molecular markers, amplification and sequencing of nucleic acids. The latter is classified into three generations. The first allows to sequence small DNA fragments. The second one increases throughput, reducing turnaround and pricing, and is therefore more convenient to sequence full genomes and transcriptomes. The third generation is currently pushing technology to its limits, being able to sequence single molecules, without previous amplification, which was previously impossible. Besides, this represents a new revolution, allowing researchers to directly sequence RNA without previous retrotranscription. These technologies are having a significant impact on different areas, such as medicine, agronomy, ecology and biotechnology. Additionally, the study of biomolecules is revealing interesting evolutionary information. That includes deciphering what makes us human, including phenomena like non-coding RNA expansion. All this is redefining the concept of gene and transcript. Basic analyses and applications are now facilitated with new genome editing tools, such as CRISPR. All these developments, in general, and nucleic-acid sequencing, in particular, are opening a new exciting era of biomolecule analyses and applications, including personalized medicine, and diagnosis and prevention of diseases for humans and other animals. Full article

(This article belongs to the Section Molecular Genetics)

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21 pages, 3477 KiB

Open AccessEditor’s ChoiceReview

Oxidative Power: Tools for Assessing LPMO Activity on Cellulose

by Federica Calderaro, Loes E. Bevers and Marco A. van den Berg

Biomolecules 2021, 11(8), 1098; https://doi.org/10.3390/biom11081098 - 26 Jul 2021

Cited by 13 | Viewed by 5401

Abstract

Lytic polysaccharide monooxygenases (LPMOs) have sparked a lot of research regarding their fascinating mode-of-action. Particularly, their boosting effect on top of the well-known cellulolytic enzymes in lignocellulosic hydrolysis makes them industrially relevant targets. As more characteristics of LPMO and its key role have [...] Read more.

Lytic polysaccharide monooxygenases (LPMOs) have sparked a lot of research regarding their fascinating mode-of-action. Particularly, their boosting effect on top of the well-known cellulolytic enzymes in lignocellulosic hydrolysis makes them industrially relevant targets. As more characteristics of LPMO and its key role have been elucidated, the need for fast and reliable methods to assess its activity have become clear. Several aspects such as its co-substrates, electron donors, inhibiting factors, and the inhomogeneity of lignocellulose had to be considered during experimental design and data interpretation, as they can impact and often hamper outcomes. This review provides an overview of the currently available methods to measure LPMO activity, including their potential and limitations, and it is illustrated with practical examples. Full article

(This article belongs to the Special Issue Oxygenases: Exploiting Their Catalytic Power)

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29 pages, 1626 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Nitric Oxide-Dependent Pathways as Critical Factors in the Consequences and Recovery after Brain Ischemic Hypoxia

by Joanna M Wierońska, Paulina Cieślik and Leszek Kalinowski

Biomolecules 2021, 11(8), 1097; https://doi.org/10.3390/biom11081097 - 26 Jul 2021

Cited by 49 | Viewed by 5656

Abstract

Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO^•), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the [...] Read more.

Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO^•), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the development of pathological changes after stroke. One of the early consequences of a sudden interruption in the cerebral blood flow is the massive production of reactive oxygen and nitrogen species (ROS/RNS) in neurons due to NO^• synthase uncoupling, which leads to neurotoxicity. Progression of apoptotic or necrotic neuronal damage activates reactive astrocytes and attracts microglia or lymphocytes to migrate to place of inflammation. Those inflammatory cells start to produce large amounts of inflammatory proteins, including pathological, inducible form of NOS (iNOS), which generates nitrosative stress that further contributes to brain tissue damage, forming vicious circle of detrimental processes in the late stage of ischemia. S-nitrosylation, hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent genes activated in reactive astrocytes play essential roles in this process. The review summarizes the roles of NO^•-dependent pathways in the early and late aftermath of stroke and treatments based on the stimulation or inhibition of particular NO^• synthases and the stabilization of HIF-1α activity. Full article

(This article belongs to the Special Issue Hypoxia and Hypoxia-Inducible Factors in Human Endothelium)

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27 pages, 832 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in the Molecular Effects of Biostimulants in Plants: An Overview

by Miguel Baltazar, Sofia Correia, Kieran J. Guinan, Neerakkal Sujeeth, Radek Bragança and Berta Gonçalves

Biomolecules 2021, 11(8), 1096; https://doi.org/10.3390/biom11081096 - 25 Jul 2021

Cited by 80 | Viewed by 14437

Abstract

As the world develops and population increases, so too does the demand for higher agricultural output with lower resources. Plant biostimulants appear to be one of the more prominent sustainable solutions, given their natural origin and their potential to substitute conventional methods in [...] Read more.

As the world develops and population increases, so too does the demand for higher agricultural output with lower resources. Plant biostimulants appear to be one of the more prominent sustainable solutions, given their natural origin and their potential to substitute conventional methods in agriculture. Classified based on their source rather than constitution, biostimulants such as humic substances (HS), protein hydrolysates (PHs), seaweed extracts (SWE) and microorganisms have a proven potential in improving plant growth, increasing crop production and quality, as well as ameliorating stress effects. However, the multi-molecular nature and varying composition of commercially available biostimulants presents challenges when attempting to elucidate their underlying mechanisms. While most research has focused on the broad effects of biostimulants in crops, recent studies at the molecular level have started to unravel the pathways triggered by certain products at the cellular and gene level. Understanding the molecular influences involved could lead to further refinement of these treatments. This review comprises the most recent findings regarding the use of biostimulants in plants, with particular focus on reports of their molecular influence. Full article

(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)

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20 pages, 3086 KiB

Open AccessEditor’s ChoiceArticle

Altered L-Arginine Metabolic Pathways in Gastric Cancer: Potential Therapeutic Targets and Biomarkers

by Iwona Bednarz-Misa, Mariusz G. Fleszar, Paulina Fortuna, Łukasz Lewandowski, Magdalena Mierzchała-Pasierb, Dorota Diakowska and Małgorzata Krzystek-Korpacka

Biomolecules 2021, 11(8), 1086; https://doi.org/10.3390/biom11081086 - 23 Jul 2021

Cited by 19 | Viewed by 4057

Abstract

There is a pressing need for molecular targets and biomarkers in gastric cancer (GC). We aimed at identifying aberrations in L-arginine metabolism with therapeutic and diagnostic potential. Systemic metabolites were quantified using mass spectrometry in 293 individuals and enzymes’ gene expression was quantified [...] Read more.

There is a pressing need for molecular targets and biomarkers in gastric cancer (GC). We aimed at identifying aberrations in L-arginine metabolism with therapeutic and diagnostic potential. Systemic metabolites were quantified using mass spectrometry in 293 individuals and enzymes’ gene expression was quantified in 29 paired tumor-normal samples using qPCR and referred to cancer pathology and molecular landscape. Patients with cancer or benign disorders had reduced systemic arginine, citrulline, and ornithine and elevated symmetric dimethylarginine and dimethylamine. Citrulline and ornithine depletion was accentuated in metastasizing cancers. Metabolite diagnostic panel had 91% accuracy in detecting cancer and 70% accuracy in differentiating cancer from benign disorders. Gastric tumors had upregulated NOS2 and downregulated ASL, PRMT2, ORNT1, and DDAH1 expression. NOS2 upregulation was less and ASL downregulation was more pronounced in metastatic cancers. Tumor ASL and PRMT2 expression was inversely related to local advancement. Enzyme up- or downregulation was greater or significant solely in cardia subtype. Metabolic reprogramming in GC includes aberrant L-arginine metabolism, reflecting GC subtype and pathology, and is manifested by altered interplay of its intermediates and enzymes. Exploiting L-arginine metabolic pathways for diagnostic and therapeutic purposes is warranted. Functional studies on ASL, PRMT2, and ORNT1 in GC are needed. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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14 pages, 1240 KiB

Open AccessEditor’s ChoiceReview

Epigenetic Alterations in Pancreatic Cancer Metastasis

by Sarah S. Wang, Jihao Xu, Keely Y. Ji and Chang-Il Hwang

Biomolecules 2021, 11(8), 1082; https://doi.org/10.3390/biom11081082 - 22 Jul 2021

Cited by 30 | Viewed by 5662

Abstract

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA [...] Read more.

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Pancreatic ductal adenocarcinoma (PDA) is the most common (90%) and aggressive type of pancreatic cancer. Genomic analyses of PDA specimens have identified the recurrent genetic mutations that drive PDA initiation and progression. However, the underlying mechanisms that further drive PDA metastasis remain elusive. Despite many attempts, no recurrent genetic mutation driving PDA metastasis has been found, suggesting that PDA metastasis is driven by epigenetic fluctuations rather than genetic factors. Therefore, establishing epigenetic mechanisms of PDA metastasis would facilitate the development of successful therapeutic interventions. In this review, we provide a comprehensive overview on the role of epigenetic mechanisms in PDA as a critical contributor on PDA progression and metastasis. In particular, we explore the recent advancements elucidating the role of nucleosome remodeling, histone modification, and DNA methylation in the process of cancer metastasis. Full article

(This article belongs to the Section Molecular Medicine)

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Open AccessEditor’s ChoiceReview

Neutrophil Elastase and Chronic Lung Disease

by Judith A. Voynow and Meagan Shinbashi

Biomolecules 2021, 11(8), 1065; https://doi.org/10.3390/biom11081065 - 21 Jul 2021

Cited by 86 | Viewed by 12795

Abstract

Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and [...] Read more.

Neutrophil elastase (NE) is a major inflammatory protease released by neutrophils and is present in the airways of patients with cystic fibrosis (CF), chronic obstructive pulmonary disease, non-CF bronchiectasis, and bronchopulmonary dysplasia. Although NE facilitates leukocyte transmigration to the site of infection and is required for clearance of Gram-negative bacteria, it also activates inflammation when released into the airway milieu in chronic inflammatory airway diseases. NE exposure induces airway remodeling with increased mucin expression and secretion and impaired ciliary motility. NE interrupts epithelial repair by promoting cellular apoptosis and senescence and it activates inflammation directly by increasing cytokine expression and release, and indirectly by triggering extracellular trap release and exosome release, which magnify protease activity and inflammation in the airway. NE inhibits innate immune function by digesting opsonins and opsonin receptors, degrading innate immune proteins such as lactoferrin, and inhibiting macrophage phagocytosis. Importantly, NE-directed therapies have not yet been effective in preventing the pathologic sequelae of NE exposure, but new therapies are being developed that offer both direct antiprotease activity and multifunctional anti-inflammatory properties. Full article

(This article belongs to the Collection Feature Papers in Enzymology)

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