Biomolecules

21 pages, 1056 KiB

Open AccessEditor’s ChoiceArticle

Repurposable Drugs That Interact with Steroid Responsive Gene Targets for Inner Ear Disease

by Alexander A. Missner, James Dixon Johns, Shoujun Gu and Michael Hoa

Biomolecules 2022, 12(11), 1641; https://doi.org/10.3390/biom12111641 - 5 Nov 2022

Cited by 5 | Viewed by 3077

Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere’s disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate [...] Read more.

Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere’s disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials. Full article

(This article belongs to the Special Issue Inner Ear Therapeutics)

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19 pages, 1186 KiB

Open AccessEditor’s ChoiceReview

Multi-Layered Regulations on the Chromatin Architectures: Establishing the Tight and Specific Responses of Fission Yeast fbp1 Gene Transcription

by Ryuta Asada and Kouji Hirota

Biomolecules 2022, 12(11), 1642; https://doi.org/10.3390/biom12111642 - 5 Nov 2022

Cited by 4 | Viewed by 3308

Abstract

Transcriptional regulation is pivotal for all living organisms and is required for adequate response to environmental fluctuations and intercellular signaling molecules. For precise regulation of transcription, cells have evolved regulatory systems on the genome architecture, including the chromosome higher-order structure (e.g., chromatin loops), [...] Read more.

Transcriptional regulation is pivotal for all living organisms and is required for adequate response to environmental fluctuations and intercellular signaling molecules. For precise regulation of transcription, cells have evolved regulatory systems on the genome architecture, including the chromosome higher-order structure (e.g., chromatin loops), location of transcription factor (TF)-binding sequences, non-coding RNA (ncRNA) transcription, chromatin configuration (e.g., nucleosome positioning and histone modifications), and the topological state of the DNA double helix. To understand how these genome-chromatin architectures and their regulators establish tight and specific responses at the transcription stage, the fission yeast fbp1 gene has been analyzed as a model system for decades. The fission yeast fbp1 gene is tightly repressed in the presence of glucose, and this gene is induced by over three orders of magnitude upon glucose starvation with a cascade of multi-layered regulations on various levels of genome and chromatin architecture. In this review article, we summarize the multi-layered transcriptional regulatory systems revealed by the analysis of the fission yeast fbp1 gene as a model system. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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17 pages, 19407 KiB

Open AccessEditor’s ChoiceReview

Postbiotics and Their Health Modulatory Biomolecules

by Emma Scott, Kim De Paepe and Tom Van de Wiele

Biomolecules 2022, 12(11), 1640; https://doi.org/10.3390/biom12111640 - 4 Nov 2022

Cited by 83 | Viewed by 10448

Abstract

Postbiotics are a new category of biotics that have the potential to confer health benefits but, unlike probiotics, do not require living cells to induce health effects and thus are not subject to the food safety requirements that apply to live microorganisms. Postbiotics [...] Read more.

Postbiotics are a new category of biotics that have the potential to confer health benefits but, unlike probiotics, do not require living cells to induce health effects and thus are not subject to the food safety requirements that apply to live microorganisms. Postbiotics are defined as a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotic components include short-chain fatty acids, exopolysaccharides, vitamins, teichoic acids, bacteriocins, enzymes and peptides in a non-purified inactivated cell preparation. While research into postbiotics is in its infancy, there is increasing evidence that postbiotics have the potential to modulate human health. Specifically, a number of postbiotics have been shown to improve gut health by strengthening the gut barrier, reducing inflammation and promoting antimicrobial activity against gut pathogens. Additionally, research is being conducted into the potential application of postbiotics to other areas of the body, including the skin, vagina and oral cavity. The purpose of this review is to set out the current research on postbiotics, demonstrate how postbiotics are currently used in commercial products and identify a number of knowledge gaps where further research is needed to identify the potential for future applications of postbiotics. Full article

(This article belongs to the Special Issue Probiotics and Their Metabolites)

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12 pages, 2544 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Polymer-Nanodiscs as a Novel Alignment Medium for High-Resolution NMR-Based Structural Studies of Nucleic Acids

by Bankala Krishnarjuna, Thirupathi Ravula, Edgar M. Faison, Marco Tonelli, Qi Zhang and Ayyalusamy Ramamoorthy

Biomolecules 2022, 12(11), 1628; https://doi.org/10.3390/biom12111628 - 3 Nov 2022

Cited by 8 | Viewed by 4008

Abstract

Residual dipolar couplings (RDCs) are increasingly used for high-throughput NMR-based structural studies and to provide long-range angular constraints to validate and refine structures of various molecules determined by X-ray crystallography and NMR spectroscopy. RDCs of a given molecule can be measured in an [...] Read more.

Residual dipolar couplings (RDCs) are increasingly used for high-throughput NMR-based structural studies and to provide long-range angular constraints to validate and refine structures of various molecules determined by X-ray crystallography and NMR spectroscopy. RDCs of a given molecule can be measured in an anisotropic environment that aligns in an external magnetic field. Here, we demonstrate the first application of polymer-based nanodiscs for the measurement of RDCs from nucleic acids. Polymer-based nanodiscs prepared using negatively charged SMA-EA polymer and zwitterionic DMPC lipids were characterized by size-exclusion chromatography, ¹H NMR, dynamic light-scattering, and ²H NMR. The magnetically aligned polymer-nanodiscs were used as an alignment medium to measure RDCs from a ¹³C/¹⁵N-labeled fluoride riboswitch aptamer using 2D ARTSY-HSQC NMR experiments. The results showed that the alignment of nanodiscs is stable for nucleic acids and nanodisc-induced RDCs fit well with the previously determined solution structure of the riboswitch. These results demonstrate that SMA-EA-based lipid-nanodiscs can be used as a stable alignment medium for high-resolution structural and dynamical studies of nucleic acids, and they can also be applicable to study various other biomolecules and small molecules in general. Full article

(This article belongs to the Collection Feature Papers in Molecular Structure and Dynamics)

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18 pages, 1592 KiB

Open AccessEditor’s ChoiceReview

LRRK2 and Lipid Pathways: Implications for Parkinson’s Disease

by Jasmin Galper, Woojin S. Kim and Nicolas Dzamko

Biomolecules 2022, 12(11), 1597; https://doi.org/10.3390/biom12111597 - 30 Oct 2022

Cited by 15 | Viewed by 5529

Abstract

Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in [...] Read more.

Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed. Full article

(This article belongs to the Special Issue Pathological Roles of LRRK2)

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29 pages, 7575 KiB

Open AccessEditor’s ChoiceReview

Small-Angle Neutron Scattering for Studying Lipid Bilayer Membranes

by William T. Heller

Biomolecules 2022, 12(11), 1591; https://doi.org/10.3390/biom12111591 - 29 Oct 2022

Cited by 7 | Viewed by 4918

Abstract

Small-angle neutron scattering (SANS) is a powerful tool for studying biological membranes and model lipid bilayer membranes. The length scales probed by SANS, being from 1 nm to over 100 nm, are well-matched to the relevant length scales of the bilayer, particularly when [...] Read more.

Small-angle neutron scattering (SANS) is a powerful tool for studying biological membranes and model lipid bilayer membranes. The length scales probed by SANS, being from 1 nm to over 100 nm, are well-matched to the relevant length scales of the bilayer, particularly when it is in the form of a vesicle. However, it is the ability of SANS to differentiate between isotopes of hydrogen as well as the availability of deuterium labeled lipids that truly enable SANS to reveal details of membranes that are not accessible with the use of other techniques, such as small-angle X-ray scattering. In this work, an overview of the use of SANS for studying unilamellar lipid bilayer vesicles is presented. The technique is briefly presented, and the power of selective deuteration and contrast variation methods is discussed. Approaches to modeling SANS data from unilamellar lipid bilayer vesicles are presented. Finally, recent examples are discussed. While the emphasis is on studies of unilamellar vesicles, examples of the use of SANS to study intact cells are also presented. Full article

(This article belongs to the Special Issue Recent Developments in Biophysical Studies of Cell Membranes)

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24 pages, 2648 KiB

Open AccessEditor’s ChoiceArticle

The Role of Ca²⁺ Sparks in Force Frequency Relationships in Guinea Pig Ventricular Myocytes

by Roshan Paudel, Mohsin Saleet Jafri and Aman Ullah

Biomolecules 2022, 12(11), 1577; https://doi.org/10.3390/biom12111577 - 27 Oct 2022

Cited by 2 | Viewed by 3072

Abstract

Calcium sparks are the elementary Ca²⁺ release events in excitation-contraction coupling that underlie the Ca²⁺ transient. The frequency-dependent contractile force generated by cardiac myocytes depends upon the characteristics of the Ca²⁺ transients. A stochastic computational local control model of a [...] Read more.

Calcium sparks are the elementary Ca²⁺ release events in excitation-contraction coupling that underlie the Ca²⁺ transient. The frequency-dependent contractile force generated by cardiac myocytes depends upon the characteristics of the Ca²⁺ transients. A stochastic computational local control model of a guinea pig ventricular cardiomyocyte was developed, to gain insight into mechanisms of force-frequency relationship (FFR). This required the creation of a new three-state RyR2 model that reproduced the adaptive behavior of RyR2, in which the RyR2 channels transition into a different state when exposed to prolonged elevated subspace [Ca²⁺]. The model simulations agree with previous experimental and modeling studies on interval-force relations. Unlike previous common pool models, this local control model displayed stable action potential trains at 7 Hz. The duration and the amplitude of the [Ca²⁺]_myo transients increase in pacing rates consistent with the experiments. The [Ca²⁺]_myo transient reaches its peak value at 4 Hz and decreases afterward, consistent with experimental force-frequency curves. The model predicts, in agreement with previous modeling studies of Jafri and co-workers, diastolic sarcoplasmic reticulum, [Ca²⁺]_sr, and RyR2 adaptation increase with the increased stimulation frequency, producing rising, rather than falling, amplitude of the myoplasmic [Ca²⁺] transients. However, the local control model also suggests that the reduction of the L-type Ca²⁺ current, with an increase in pacing frequency due to Ca²⁺-dependent inactivation, also plays a role in the negative slope of the FFR. In the simulations, the peak Ca²⁺ transient in the FFR correlated with the highest numbers of SR Ca²⁺ sparks: the larger average amplitudes of those sparks, and the longer duration of the Ca²⁺ sparks. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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20 pages, 596 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Molecular Insights into Epigenetics and Cannabinoid Receptors

by Balapal S. Basavarajappa and Shivakumar Subbanna

Biomolecules 2022, 12(11), 1560; https://doi.org/10.3390/biom12111560 - 26 Oct 2022

Cited by 15 | Viewed by 4129

Abstract

The actions of cannabis are mediated by G protein-coupled receptors that are part of an endogenous cannabinoid system (ECS). ECS consists of the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB₁ and CB₂ [...] Read more.

The actions of cannabis are mediated by G protein-coupled receptors that are part of an endogenous cannabinoid system (ECS). ECS consists of the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB₁ and CB₂ cannabinoid receptors. Epigenetics are heritable changes that affect gene expression without changing the DNA sequence, transducing external stimuli in stable alterations of the DNA or chromatin structure. Cannabinoid receptors are crucial candidates for exploring their functions through epigenetic approaches due to their significant roles in health and diseases. Epigenetic changes usually promote alterations in the expression of genes and proteins that can be evaluated by various transcriptomic and proteomic analyses. Despite the exponential growth of new evidence on the critical functions of cannabinoid receptors, much is still unknown regarding the contribution of various genetic and epigenetic factors that regulate cannabinoid receptor gene expression. Recent studies have identified several immediate and long-lasting epigenetic changes, such as DNA methylation, DNA-associated histone proteins, and RNA regulatory networks, in cannabinoid receptor function. Thus, they can offer solutions to many cellular, molecular, and behavioral impairments found after modulation of cannabinoid receptor activities. In this review, we discuss the significant research advances in different epigenetic factors contributing to the regulation of cannabinoid receptors and their functions under both physiological and pathological conditions. Increasing our understanding of the epigenetics of cannabinoid receptors will significantly advance our knowledge and could lead to the identification of novel therapeutic targets and innovative treatment strategies for diseases associated with altered cannabinoid receptor functions. Full article

(This article belongs to the Special Issue New Advances of Cannabinoid Receptors in Health and Disease)

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21 pages, 1443 KiB

Open AccessEditor’s ChoiceReview

Immune Checkpoint Inhibitors and RAS–ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma

by Marta Morante, Atanasio Pandiella, Piero Crespo and Ana Herrero

Biomolecules 2022, 12(11), 1562; https://doi.org/10.3390/biom12111562 - 26 Oct 2022

Cited by 12 | Viewed by 6532

Abstract

Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy [...] Read more.

Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS–ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients. Full article

(This article belongs to the Section Molecular Medicine)

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18 pages, 4211 KiB

Open AccessEditor’s ChoiceArticle

Semicarbazide-Sensitive Amine Oxidase (SSAO) and Lysyl Oxidase (LOX) Association in Rat Aortic Vascular Smooth Muscle Cells

by Vesna Manasieva, Shori Thakur, Lisa A. Lione, Jessal Patel, Anwar Baydoun and John Skamarauskas

Biomolecules 2022, 12(11), 1563; https://doi.org/10.3390/biom12111563 - 26 Oct 2022

Cited by 6 | Viewed by 2699

Abstract

Vascular smooth muscle cells (VSMCs) are the main stromal cells in the medial layer of the vascular wall. These cells produce the extracellular matrix (ECM) and are involved in many pathological changes in the vascular wall. Semicarbazide-sensitive amine oxidase (SSAO) and lysyl oxidase [...] Read more.

Vascular smooth muscle cells (VSMCs) are the main stromal cells in the medial layer of the vascular wall. These cells produce the extracellular matrix (ECM) and are involved in many pathological changes in the vascular wall. Semicarbazide-sensitive amine oxidase (SSAO) and lysyl oxidase (LOX) are vascular enzymes associated with the development of atherosclerosis. In the vascular smooth muscle cells, increased SSAO activity elevates reactive oxygen species (ROS) and induces VSMCs death; increased LOX induces chemotaxis through hydrogen peroxide dependent mechanisms; and decreased LOX contributes to endothelial dysfunction. This study investigates the relationship between SSAO and LOX in VSMCs by studying their activity, protein, and mRNA levels during VSMCs passaging and after silencing the LOX gene, while using their respective substrates and inhibitors. At the basal level, LOX activity decreased with passage and its protein expression was maintained between passages. βAPN abolished LOX activity (** p < 0.01 for 8 vs. 3 and * p < 0.05 for 5 vs. 8) and had no effect on LOX protein and mRNA levels. MDL72527 reduced LOX activity at passage 3 and 5 (^## p < 0.01) and had no effect on LOX protein, and mRNA expression. At the basal level, SSAO activity also decreased with passage, and its protein expression was maintained between passages. MDL72527 abolished SSAO activity (**** p < 0.0001 for 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 5 (** p < 0.01) and 8 (**** p < 0.0001), and Aoc3 mRNA levels at passage 8 (* p < 0.05). βAPN inhibited SSAO activity (**** p < 0.0001 for 5 vs. 3 and 8 vs. 3 and * p < 0.05 for 5 vs. 8), VAP-1 expression at passage 3 (* p < 0.05), and Aoc3 mRNA levels at passage 3 (* p < 0.05). Knockdown of the LOX gene (**** p < 0.0001 for Si6 vs. Sictrl and *** p < 0.001 for Si8 vs. Sictrl) and LOX protein (** p < 0.01 for Si6 and Si8 vs. Sictrl) in VSMCs at passage 3 resulted in a reduction in Aoc3 mRNA (^#### p < 0.0001 for Si6 vs. Sictrl and ^### p < 0.001 for Si8 vs. Sictrl) and VAP-1 protein (^# p < 0.05 for Si8 vs. Sictrl). These novel findings demonstrate a passage dependent decrease in LOX activity and increase in SSAO activity in rat aortic VSMCs and show an association between both enzymes in early passage rat aortic VSMCs, where LOX was identified as a regulator of SSAO activity, protein, and mRNA expression. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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15 pages, 1597 KiB

Open AccessEditor’s ChoiceArticle

Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats

by Silvia Diviccaro, Silvia Giatti, Lucia Cioffi, Eva Falvo, Monika Herian, Donatella Caruso and Roberto Cosimo Melcangi

Biomolecules 2022, 12(11), 1567; https://doi.org/10.3390/biom12111567 - 26 Oct 2022

Cited by 9 | Viewed by 13002

Abstract

The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations [...] Read more.

The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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22 pages, 2842 KiB

Open AccessEditor’s ChoiceArticle

Replicative Instability Drives Cancer Progression

by Benjamin B. Morris, Jason P. Smith, Qi Zhang, Zhijie Jiang, Oliver A. Hampton, Michelle L. Churchman, Susanne M. Arnold, Dwight H. Owen, Jhanelle E. Gray, Patrick M. Dillon, Hatem H. Soliman, Daniel G. Stover, Howard Colman, Arnab Chakravarti, Kenneth H. Shain, Ariosto S. Silva, John L. Villano, Michael A. Vogelbaum, Virginia F. Borges, Wallace L. Akerley, Ryan D. Gentzler, Richard D. Hall, Cindy B. Matsen, C. M. Ulrich, Andrew R. Post, David A. Nix, Eric A. Singer, James M. Larner, Peter Todd Stukenberg, David R. Jones and Marty W. Mayo Show full author list Hide full author list

Biomolecules 2022, 12(11), 1570; https://doi.org/10.3390/biom12111570 - 26 Oct 2022

Cited by 4 | Viewed by 4579

Abstract

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability [...] Read more.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types. Full article

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20 pages, 1745 KiB

Open AccessEditor’s ChoiceReview

Copper-Dependent Kinases and Their Role in Cancer Inception, Progression and Metastasis

by Alessandra Vitaliti, Anastasia De Luca and Luisa Rossi

Biomolecules 2022, 12(10), 1520; https://doi.org/10.3390/biom12101520 - 20 Oct 2022

Cited by 22 | Viewed by 3820

Abstract

In recent years, copper function has been expanded beyond its consolidated role as a cofactor of enzyme catalysis. Recent papers have demonstrated a new dynamic role for copper in the regulation of cell signaling pathways through direct interaction with protein kinases, modulating their [...] Read more.

In recent years, copper function has been expanded beyond its consolidated role as a cofactor of enzyme catalysis. Recent papers have demonstrated a new dynamic role for copper in the regulation of cell signaling pathways through direct interaction with protein kinases, modulating their activity. The activation of these pathways is exacerbated in cancer cells to sustain the different steps of tumor growth and dissemination. This review will focus on a novel proposed role for the transition metal copper as a regulator of cell signaling pathways through direct interaction with known protein kinases, which exhibit binding domains for this metal. Activation of these pathways in cancer cells supports both tumor growth and dissemination. In addition to the description of the results recently reported in the literature on the subject, relevance will be given to the possibility of controlling the cellular levels of copper and its homeostatic regulators. Overall, these findings may be of central relevance in order to propose copper and its homeostatic regulators as possible targets for novel therapies, which may act synergistically to those already existing to control cancer growth and dissemination. Full article

(This article belongs to the Special Issue Kinases Signaling in Cancers)

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12 pages, 3317 KiB

Open AccessEditor’s ChoiceReview

Synthesis of Protein-Oligonucleotide Conjugates

by Emma E. Watson and Nicolas Winssinger

Biomolecules 2022, 12(10), 1523; https://doi.org/10.3390/biom12101523 - 20 Oct 2022

Cited by 7 | Viewed by 4840

Abstract

Nucleic acids and proteins form two of the key classes of functional biomolecules. Through the ability to access specific protein-oligonucleotide conjugates, a broader range of functional molecules becomes accessible which leverages both the programmability and recognition potential of nucleic acids and the structural, [...] Read more.

Nucleic acids and proteins form two of the key classes of functional biomolecules. Through the ability to access specific protein-oligonucleotide conjugates, a broader range of functional molecules becomes accessible which leverages both the programmability and recognition potential of nucleic acids and the structural, chemical and functional diversity of proteins. Herein, we summarize the available conjugation strategies to access such chimeric molecules and highlight some key case study examples within the field to showcase the power and utility of such technology. Full article

(This article belongs to the Collection Feature Papers in Biomacromolecules: Nucleic Acids)

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12 pages, 758 KiB

Open AccessEditor’s ChoiceReview

Cyclosporine A Delivery Platform for Veterinary Ophthalmology—A New Concept for Advanced Ophthalmology

by Martyna Padjasek, Badr Qasem, Anna Cisło-Pakuluk and Krzysztof Marycz

Biomolecules 2022, 12(10), 1525; https://doi.org/10.3390/biom12101525 - 20 Oct 2022

Cited by 9 | Viewed by 4628

Abstract

Cyclosporine A (CsA) is a selective and reversible immunosuppressant agent that is widely used as a medication for a wide spectrum of diseases in humans such as graft versus host disease, non-infectious uveitis, rheumatoid arthritis, psoriasis, and atopic dermatitis. Furthermore, the CsA is [...] Read more.

Cyclosporine A (CsA) is a selective and reversible immunosuppressant agent that is widely used as a medication for a wide spectrum of diseases in humans such as graft versus host disease, non-infectious uveitis, rheumatoid arthritis, psoriasis, and atopic dermatitis. Furthermore, the CsA is used to treat keratoconjunctivitis sicca, chronic superficial keratitis, immune-mediated keratitis and equine recurrent uveitis in animals. The selective activity of Cyclosporine A (CsA) was demonstrated to be an immunomodulation characteristic of T-lymphocyte proliferation and inhibits cytokine gene expression. Moreover, the lipophilic characteristics with poor bioavailability and low solubility in water, besides the side effects, force the need to develop new formulations and devices that will provide adequate penetration into the anterior and posterior segments of the eye. This review aims to summarize the effectiveness and safety of cyclosporine A delivery platforms in veterinary ophthalmology. Full article

(This article belongs to the Special Issue Cyclodextrin-Based Drug Release and Drug Delivery Systems)

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16 pages, 3782 KiB

Open AccessEditor’s ChoiceArticle

The Epigenetic Dimension of Protein Structure Is an Intrinsic Weakness of the AlphaFold Program

by Fodil Azzaz, Nouara Yahi, Henri Chahinian and Jacques Fantini

Biomolecules 2022, 12(10), 1527; https://doi.org/10.3390/biom12101527 - 20 Oct 2022

Cited by 35 | Viewed by 8491

Abstract

One of the most important lessons we have learned from sequencing the human genome is that not all proteins have a 3D structure. In fact, a large part of the human proteome is made up of intrinsically disordered proteins (IDPs) which can adopt [...] Read more.

One of the most important lessons we have learned from sequencing the human genome is that not all proteins have a 3D structure. In fact, a large part of the human proteome is made up of intrinsically disordered proteins (IDPs) which can adopt multiple structures, and therefore, multiple functions, depending on the ligands with which they interact. Under these conditions, one can wonder about the value of algorithms developed for predicting the structure of proteins, in particular AlphaFold, an AI which claims to have solved the problem of protein structure. In a recent study, we highlighted a particular weakness of AlphaFold for membrane proteins. Based on this observation, we have proposed a paradigm, referred to as “Epigenetic Dimension of Protein Structure” (EDPS), which takes into account all environmental parameters that control the structure of a protein beyond the amino acid sequence (hence “epigenetic”). In this new study, we compare the reliability of the AlphaFold and Robetta algorithms’ predictions for a new set of membrane proteins involved in human pathologies. We found that Robetta was generally more accurate than AlphaFold for ascribing a membrane-compatible topology. Raft lipids (e.g., gangliosides), which control the structural dynamics of membrane protein structure through chaperone effects, were identified as major actors of the EDPS paradigm. We conclude that the epigenetic dimension of a protein structure is an intrinsic weakness of AI-based protein structure prediction, especially AlphaFold, which warrants further development. Full article

(This article belongs to the Special Issue Protein Structure Prediction with AlphaFold)

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12 pages, 283 KiB

Open AccessEditor’s ChoiceReview

Prognostic Value of High-Sensitivity Cardiac Troponin in Women

by Giandomenico Bisaccia, Fabrizio Ricci, Mohammed Y. Khanji, Giulia Gaggi, Andrea Di Credico, Sabina Gallina, Angela Di Baldassarre and Barbara Ghinassi

Biomolecules 2022, 12(10), 1496; https://doi.org/10.3390/biom12101496 - 17 Oct 2022

Cited by 1 | Viewed by 4158

Abstract

High-sensitivity cardiac troponin assays have become the gold standard for diagnosing acute and chronic myocardial injury. The detection of troponin levels beyond the 99th percentile is included in the fourth universal definition of myocardial infarction, specifically recommending the use of sex-specific thresholds. Measurable [...] Read more.

High-sensitivity cardiac troponin assays have become the gold standard for diagnosing acute and chronic myocardial injury. The detection of troponin levels beyond the 99th percentile is included in the fourth universal definition of myocardial infarction, specifically recommending the use of sex-specific thresholds. Measurable concentrations below the proposed diagnostic thresholds have been shown to inform prognosis in different categories of inpatients and outpatients. However, clinical investigations from the last twenty years have yielded conflicting results regarding the incremental value of using different cut-offs for men and women. While advocates of a sex-specific approach claim it may help reduce gender bias in cardiovascular medicine, particularly in acute coronary syndromes, other groups question the alleged incremental diagnostic and prognostic value of sex-specific thresholds, ultimately asserting that less is more. In the present review, we aimed to synthesize our current understanding of sex-based differences in cardiac troponin levels and to reappraise the available evidence with regard to (i) the prognostic significance of sex-specific diagnostic thresholds of high-sensitivity cardiac troponin assays compared to common cut-offs in both men and women undergoing cardiovascular disease risk assessment, and (ii) the clinical utility of high-sensitivity cardiac troponin assays for cardiovascular disease prevention in women. Full article

(This article belongs to the Special Issue Biomolecules and Cardiovascular Disease in Women)

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27 pages, 7060 KiB

Open AccessEditor’s ChoiceArticle

Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action

by Diana Duarte, Mariana Nunes, Sara Ricardo and Nuno Vale

Biomolecules 2022, 12(10), 1490; https://doi.org/10.3390/biom12101490 - 16 Oct 2022

Cited by 23 | Viewed by 4497

Abstract

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the [...] Read more.

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster and more economical process. In our previous studies, we developed a novel model of drug combination using antineoplastic and different repurposed drugs. We demonstrated the combinations of doxorubicin (DOX) + artesunate, DOX + chloroquine, paclitaxel (PTX) + fluoxetine, PTX + fluphenazine, and PTX + benztropine induce significant cytotoxicity in Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found that 5-FU + thioridazine and 5-fluorouracil (5-FU) + sertraline can synergistically induce a reduction in the viability of human colorectal adenocarcinoma cell line (HT-29). In this study, we aim to (1) evaluate the biosafety profile of these drug combinations for non-tumoral cells and (2) determine their mechanism of action in cancer cells. To do so, human fetal lung fibroblast cells (MRC-5) fibroblast cells were incubated for 48 h with all drugs, alone and in combination in concentrations of 0.25, 0.5, 1, 2, and 4 times their half-maximal inhibitory concentration (IC₅₀). Cell morphology and viability were evaluated. Next, we designed and constructed a cell microarray to perform immunohistochemistry studies for the evaluation of palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), and nuclear factor-kappa-B (NF-kB) p65 expression. We demonstrate that these combinations are cytotoxic for cancer cells and safe for non-tumoral cells at lower concentrations. Furthermore, it is also demonstrated that PPT1 may have an important role in the mechanism of action of these combinations, as demonstrated by their ability to decrease PPT1 expression. These results support the use of antimalarial and central nervous system (CNS) drugs in combination regimens with chemotherapeutic agents; nevertheless, additional studies are recommended to further explore their complete mechanisms of action. Full article

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13 pages, 2137 KiB

Open AccessEditor’s ChoiceArticle

Gene Delivery of Manf to Beta-Cells of the Pancreatic Islets Protects NOD Mice from Type 1 Diabetes Development

by Kailash Singh, Orian Bricard, Jeason Haughton, Mikaela Björkqvist, Moa Thorstensson, Zhengkang Luo, Loriana Mascali, Emanuela Pasciuto, Chantal Mathieu, James Dooley and Adrian Liston

Biomolecules 2022, 12(10), 1493; https://doi.org/10.3390/biom12101493 - 16 Oct 2022

Cited by 6 | Viewed by 5680

Abstract

In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably [...] Read more.

In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself, coupled with unknown environmental insults priming the autoimmune reaction. While autoimmunity is a primary driver in beta-cell death, there is growing evidence that cellular stress participates in the loss of beta-cells. In the beta-cell fragility model, partial loss of islet mass requires compensatory upregulation of insulin production in the remaining islets, driving a cellular stress capable of triggering apoptosis in the remaining cells. The Glis3-Manf axis has been identified as being pivotal to the relative fragility or robustness of stressed islets, potentially operating in both type 1 and type 2 diabetes. Here, we have used an AAV-based gene delivery system to enhance the expression of the anti-apoptotic protein Manf in the beta-cells of NOD mice. Gene delivery substantially lowered the rate of diabetes development in treated mice. Manf-treated mice demonstrated minimal insulitis and superior preservation of insulin production. Our results demonstrating the therapeutic potential of Manf delivery to enhance beta-cell robustness and avert clinical diabetes. Full article

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

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15 pages, 2595 KiB

Open AccessEditor’s ChoiceArticle

Functional Tuning of Intrinsically Disordered Regions in Human Proteins by Composition Bias

by Kristina Kastano, Pablo Mier, Zsuzsanna Dosztányi, Vasilis J. Promponas and Miguel A. Andrade-Navarro

Biomolecules 2022, 12(10), 1486; https://doi.org/10.3390/biom12101486 - 15 Oct 2022

Cited by 8 | Viewed by 2487

Abstract

Intrinsically disordered regions (IDRs) in protein sequences are flexible, have low structural constraints and as a result have faster rates of evolution. This lack of evolutionary conservation greatly limits the use of sequence homology for the classification and functional assessment of IDRs, as [...] Read more.

Intrinsically disordered regions (IDRs) in protein sequences are flexible, have low structural constraints and as a result have faster rates of evolution. This lack of evolutionary conservation greatly limits the use of sequence homology for the classification and functional assessment of IDRs, as opposed to globular domains. The study of IDRs requires other properties for their classification and functional prediction. While composition bias is not a necessary property of IDRs, compositionally biased regions (CBRs) have been noted as frequent part of IDRs. We hypothesized that to characterize IDRs, it could be helpful to study their overlap with particular types of CBRs. Here, we evaluate this overlap in the human proteome. A total of 2/3 of residues in IDRs overlap CBRs. Considering CBRs enriched in one type of amino acid, we can distinguish CBRs that tend to be fully included within long IDRs (R, H, N, D, P, G), from those that partially overlap shorter IDRs (S, E, K, T), and others that tend to overlap IDR terminals (Q, A). CBRs overlap more often IDRs in nuclear proteins and in proteins involved in liquid-liquid phase separation (LLPS). Study of protein interaction networks reveals the enrichment of CBRs in IDRs by tandem repetition of short linear motifs (rich in S or P), and the existence of E-rich polar regions that could support specific protein interactions with non-specific interactions. Our results open ways to pin down the function of IDRs from their partial compositional biases. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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26 pages, 2182 KiB

Open AccessEditor’s ChoiceReview

Current Challenges for Biological Treatment of Pharmaceutical-Based Contaminants with Oxidoreductase Enzymes: Immobilization Processes, Real Aqueous Matrices and Hybrid Techniques

by Helena Sá, Michele Michelin, Teresa Tavares and Bruna Silva

Biomolecules 2022, 12(10), 1489; https://doi.org/10.3390/biom12101489 - 15 Oct 2022

Cited by 23 | Viewed by 3481

Abstract

The worldwide access to pharmaceuticals and their continuous release into the environment have raised a serious global concern. Pharmaceuticals remain active even at low concentrations, therefore their occurrence in waterbodies may lead to successive deterioration of water quality with adverse impacts on the [...] Read more.

The worldwide access to pharmaceuticals and their continuous release into the environment have raised a serious global concern. Pharmaceuticals remain active even at low concentrations, therefore their occurrence in waterbodies may lead to successive deterioration of water quality with adverse impacts on the ecosystem and human health. To address this challenge, there is currently an evolving trend toward the search for effective methods to ensure efficient purification of both drinking water and wastewater. Biocatalytic transformation of pharmaceuticals using oxidoreductase enzymes, such as peroxidase and laccase, is a promising environmentally friendly solution for water treatment, where fungal species have been used as preferred producers due to their ligninolytic enzymatic systems. Enzyme-catalyzed degradation can transform micropollutants into more bioavailable or even innocuous products. Enzyme immobilization on a carrier generally increases its stability and catalytic performance, allowing its reuse, being a promising approach to ensure applicability to an industrial scale process. Moreover, coupling biocatalytic processes to other treatment technologies have been revealed to be an effective approach to achieve the complete removal of pharmaceuticals. This review updates the state-of-the-art of the application of oxidoreductases enzymes, namely laccase, to degrade pharmaceuticals from spiked water and real wastewater. Moreover, the advances concerning the techniques used for enzyme immobilization, the operation in bioreactors, the use of redox mediators, the application of hybrid techniques, as well as the discussion of transformation mechanisms and ending toxicity, are addressed. Full article

(This article belongs to the Special Issue Fungal Metabolism—Enzymes and Bioactive Compounds II)

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20 pages, 6042 KiB

Open AccessEditor’s ChoiceArticle

Digging into the 3D Structure Predictions of AlphaFold2 with Low Confidence: Disorder and Beyond

by Apolline Bruley, Jean-Paul Mornon, Elodie Duprat and Isabelle Callebaut

Biomolecules 2022, 12(10), 1467; https://doi.org/10.3390/biom12101467 - 13 Oct 2022

Cited by 19 | Viewed by 3712

Abstract

AlphaFold2 (AF2) has created a breakthrough in biology by providing three-dimensional structure models for whole-proteome sequences, with unprecedented levels of accuracy. In addition, the AF2 pLDDT score, related to the model confidence, has been shown to provide a good measure of residue-wise disorder. [...] Read more.

AlphaFold2 (AF2) has created a breakthrough in biology by providing three-dimensional structure models for whole-proteome sequences, with unprecedented levels of accuracy. In addition, the AF2 pLDDT score, related to the model confidence, has been shown to provide a good measure of residue-wise disorder. Here, we combined AF2 predictions with pyHCA, a tool we previously developed to identify foldable segments and estimate their order/disorder ratio, from a single protein sequence. We focused our analysis on the AF2 predictions available for 21 reference proteomes (AFDB v1), in particular on their long foldable segments (>30 amino acids) that exhibit characteristics of soluble domains, as estimated by pyHCA. Among these segments, we provided a global analysis of those with very low pLDDT values along their entire length and compared their characteristics to those of segments with very high pLDDT values. We highlighted cases containing conditional order, as well as cases that could form well-folded structures but escape the AF2 prediction due to a shallow multiple sequence alignment and/or undocumented structure or fold. AF2 and pyHCA can therefore be advantageously combined to unravel cryptic structural features in whole proteomes and to refine predictions for different flavors of disorder. Full article

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

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25 pages, 9721 KiB

Open AccessEditor’s ChoiceReview

Biomimetic Artificial Proton Channels

by Iuliana-Marilena Andrei and Mihail Barboiu

Biomolecules 2022, 12(10), 1473; https://doi.org/10.3390/biom12101473 - 13 Oct 2022

Cited by 8 | Viewed by 3669

Abstract

One of the most common biochemical processes is the proton transfer through the cell membranes, having significant physiological functions in living organisms. The proton translocation mechanism has been extensively studied; however, mechanistic details of this transport are still needed. During the last decades, [...] Read more.

One of the most common biochemical processes is the proton transfer through the cell membranes, having significant physiological functions in living organisms. The proton translocation mechanism has been extensively studied; however, mechanistic details of this transport are still needed. During the last decades, the field of artificial proton channels has been in continuous growth, and understanding the phenomena of how confined water and channel components mediate proton dynamics is very important. Thus, proton transfer continues to be an active area of experimental and theoretical investigations, and acquiring insights into the proton transfer mechanism is important as this enlightenment will provide direct applications in several fields. In this review, we present an overview of the development of various artificial proton channels, focusing mostly on their design, self-assembly behavior, proton transport activity performed on bilayer membranes, and comparison with protein proton channels. In the end, we discuss their potential applications as well as future development and perspectives. Full article

(This article belongs to the Special Issue Proton and Proton-Coupled Transport)

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22 pages, 690 KiB

Open AccessEditor’s ChoiceReview

Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review

by Justin Matheson, Zoe Bourgault and Bernard Le Foll

Biomolecules 2022, 12(10), 1462; https://doi.org/10.3390/biom12101462 - 12 Oct 2022

Cited by 20 | Viewed by 4612

Abstract

Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as [...] Read more.

Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as potential moderators of the neuropsychiatric effects and pharmacokinetics of CBD. In this case, 300 articles were screened, retrieved from searches in PubMed/Medline, Scopus, Google Scholar, PsycInfo and CINAHL, though only 12 met our eligibility criteria: eight studies in preclinical models and four studies in humans. Among the preclinical studies, three suggested that sex may influence long-term effects of gestational or adolescent exposure to CBD; two found no impact of sex on CBD modulation of addiction-relevant effects of Δ⁹-tetrahydrocannabinol (THC); two found antidepressant-like effects of CBD in males only; and one found greater plasma and liver CBD concentrations in females compared to males. Among the human studies, two found no sex difference in CBD pharmacokinetics in patient samples, one found greater plasma CBD concentrations in healthy females compared to males, and one found no evidence of sex differences in the effects of CBD on responses to trauma recall in patients with post-traumatic stress disorder (PTSD). No studies were identified that considered the role of gender in CBD treatment effects. We discuss potential implications and current limitations of the existing literature. Full article

(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)

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15 pages, 1541 KiB

Open AccessEditor’s ChoiceReview

An Overview of Molecular Mechanisms in Fabry Disease

by Federica Amodio, Martina Caiazza, Emanuele Monda, Marta Rubino, Laura Capodicasa, Flavia Chiosi, Vincenzo Simonelli, Francesca Dongiglio, Fabio Fimiani, Nicola Pepe, Cristina Chimenti, Paolo Calabrò and Giuseppe Limongelli

Biomolecules 2022, 12(10), 1460; https://doi.org/10.3390/biom12101460 - 12 Oct 2022

Cited by 23 | Viewed by 7024

Abstract

Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation [...] Read more.

Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers. Full article

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

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31 pages, 3167 KiB

Open AccessEditor’s ChoiceReview

Lung Organoids in Smoking Research: Current Advances and Future Promises

by Hina Agraval and Hong Wei Chu

Biomolecules 2022, 12(10), 1463; https://doi.org/10.3390/biom12101463 - 12 Oct 2022

Cited by 11 | Viewed by 6859

Abstract

Tobacco smoking has been established to contribute to the pathogenesis of various respiratory diseases including chronic obstructive pulmonary disease (COPD), lung cancer, and asthma. However, major hurdles in mechanistic studies on the role of smoking in human lungs remain in part due to [...] Read more.

Tobacco smoking has been established to contribute to the pathogenesis of various respiratory diseases including chronic obstructive pulmonary disease (COPD), lung cancer, and asthma. However, major hurdles in mechanistic studies on the role of smoking in human lungs remain in part due to the lack of ex vivo experimental models and ambiguous data from animal models that can best recapitulate the architecture and pathophysiology of the human lung. Recent development of the lung organoid culture system has opened new avenues for respiratory disease research as organoids are proving to be a sophisticated ex vivo model that functionally and structurally mimics the human lungs better than other traditionally used models. This review will discuss how recent advances in lung organoid systems may help us better determine the injurious and immunological effect of smoking on human lungs and will provide some suggestions for future research directions. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Lung Injury, Repair, and Remodeling)

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25 pages, 1639 KiB

Open AccessEditor’s ChoiceReview

Immunosenescence, Inflammaging, and Lung Senescence in Asthma in the Elderly

by Tomoyuki Soma and Makoto Nagata

Biomolecules 2022, 12(10), 1456; https://doi.org/10.3390/biom12101456 - 11 Oct 2022

Cited by 31 | Viewed by 5282

Abstract

Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related [...] Read more.

Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related alterations of functions in the immune system and lung parenchyma occur throughout life. Alterations with advancing age are promoted by various stimuli, including pathobionts, fungi, viruses, pollutants, and damage-associated molecular patterns derived from impaired cells, abandoned cell debris, and senescent cells. Age-related changes in the innate and adaptive immune response, termed immunosenescence, includes impairment of phagocytosis and antigen presentation, enhancement of proinflammatory mediator generation, and production of senescence-associated secretory phenotype. Immnunosenescence could promote inflammaging (chronic low-grade inflammation) and contribute to late-onset adult asthma and asthma in the elderly, along with age-related pulmonary disease, such as chronic obstructive pulmonary disease and pulmonary fibrosis, due to lung parenchyma senescence. Aged patients with asthma exhibit local and systemic type 2 and non-type 2 inflammation, associated with clinical manifestations. Here, we discuss immunosenescence’s contribution to the immune response and the combination of type 2 inflammation and inflammaging in asthma in the elderly and present an overview of age-related features in the immune system and lung structure. Full article

(This article belongs to the Special Issue Eosinophils in Allergy and Related Diseases—Selected Papers from “The Workshop on Eosinophils in Allergy and Related Diseases 2021”)

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17 pages, 44362 KiB

Open AccessEditor’s ChoiceArticle

Traumatic Brain Injury Leads to Alterations in Contusional Cortical miRNAs Involved in Dementia

by Shahmir Naseer, Laura Abelleira-Hervas, Dhwani Savani, Ross de Burgh, Robertas Aleksynas, Cornelius K. Donat, Nelofer Syed and Magdalena Sastre

Biomolecules 2022, 12(10), 1457; https://doi.org/10.3390/biom12101457 - 11 Oct 2022

Cited by 7 | Viewed by 3306

Abstract

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer’s disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains [...] Read more.

There is compelling evidence that head injury is a significant environmental risk factor for Alzheimer’s disease (AD) and that a history of traumatic brain injury (TBI) accelerates the onset of AD. Amyloid-β plaques and tau aggregates have been observed in the post-mortem brains of TBI patients; however, the mechanisms leading to AD neuropathology in TBI are still unknown. In this study, we hypothesized that focal TBI induces changes in miRNA expression in and around affected areas, resulting in the altered expression of genes involved in neurodegeneration and AD pathology. For this purpose, we performed a miRNA array in extracts from rats subjected to experimental TBI, using the controlled cortical impact (CCI) model. In and around the contusion, we observed alterations of miRNAs associated with dementia/AD, compared to the contralateral side. Specifically, the expression of miR-9 was significantly upregulated, while miR-29b, miR-34a, miR-106b, miR-181a and miR-107 were downregulated. Via qPCR, we confirmed these results in an additional group of injured rats when compared to naïve animals. Interestingly, the changes in those miRNAs were concomitant with alterations in the gene expression of mRNAs involved in amyloid generation and tau pathology, such as β-APP cleaving enzyme (BACE1) and Glycogen synthase-3-β (GSK3β). In addition increased levels of neuroinflammatory markers (TNF-α), glial activation, neuronal loss, and tau phosphorylation were observed in pericontusional areas. Therefore, our results suggest that the secondary injury cascade in TBI affects miRNAs regulating the expression of genes involved in AD dementia. Full article

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

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13 pages, 2585 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Galectin-3 Is a Natural Binding Ligand of MCAM (CD146, MUC18) in Melanoma Cells and Their Interaction Promotes Melanoma Progression

by Yaoyu Pang, Ellen Maxwell, Paulina Sindrewicz-Goral, Andrew Shapanis, Shun Li, Mark Morgan and Lu-Gang Yu

Biomolecules 2022, 12(10), 1451; https://doi.org/10.3390/biom12101451 - 10 Oct 2022

Cited by 9 | Viewed by 4632

Abstract

Melanoma cell adhesion molecule (MCAM, CD146, MUC18) is a heavily glycosylated transmembrane protein and a marker of melanoma metastasis. It is expressed in advanced primary melanoma and metastasis but rarely in benign naevi or normal melanocytes. More and more evidence has shown that [...] Read more.

Melanoma cell adhesion molecule (MCAM, CD146, MUC18) is a heavily glycosylated transmembrane protein and a marker of melanoma metastasis. It is expressed in advanced primary melanoma and metastasis but rarely in benign naevi or normal melanocytes. More and more evidence has shown that activation of the MCAM on cell surface plays a vital role in melanoma progression and metastasis. However, the natural MCAM binding ligand that initiates MCAM activation in melanoma so far remains elusive. This study revealed that galectin-3, a galactoside-binding protein that is commonly overexpressed in many cancers including melanoma, is naturally associated with MCAM on the surface of both skin and uveal melanoma cells. Binding of galectin-3 to MCAM, via O-linked glycans on the MCAM, induces MCAM dimerization and clustering on cell surface and subsequent activation of downstream AKT signalling. This leads to the increases of a number of important steps in melanoma progression of cell proliferation, adhesion, migration, and invasion. Thus, galectin-3 is a natural binding ligand of MCAM in melanoma, and their interaction activates MCAM and promotes MCAM-mediated melanoma progression. Targeting the galectin-3–MCAM interaction may potentially be a useful therapeutic strategy for melanoma treatment. Full article

(This article belongs to the Collection Galectins and Cancer)

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29 pages, 2771 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Introduction to Traditional Medicine and Their Role in Prevention and Treatment of Emerging and Re-Emerging Diseases

by Syed A. A. Rizvi, George P. Einstein, Orien L. Tulp, Frantz Sainvil and Rolando Branly

Biomolecules 2022, 12(10), 1442; https://doi.org/10.3390/biom12101442 - 9 Oct 2022

Cited by 59 | Viewed by 8006

Abstract

Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt [...] Read more.

Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt and mutate over time and antibiotic and antiviral resistance ensues. There are many challenges in treating infections such as failure of the microorganisms to respond to the therapeutic agents, which has led to more chronic infections, complications, and preventable loss of life. Thus, a multidisciplinary approach and collaboration is warranted to create more potent, effective, and versatile therapies to prevent and eradicate the old and newly emerging diseases. In the recent past, natural medicine has proven its effectiveness against various illnesses. Most of the pharmaceutical agents currently used can trace their origin to the natural products in one way, shape, or form. The full potential of natural products is yet to be realized, as numerous natural resources have not been explored and analyzed. This merits continuous support in research and analysis of ancient treatment systems to explore their full potential and employ them as an alternative or principal therapy. Full article

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21 pages, 2253 KiB

Open AccessEditor’s ChoiceArticle

Nusinersen Induces Disease-Severity-Specific Neurometabolic Effects in Spinal Muscular Atrophy

by Francesco Errico, Carmen Marino, Manuela Grimaldi, Tommaso Nuzzo, Valentina Bassareo, Valeria Valsecchi, Chiara Panicucci, Elia Di Schiavi, Tommaso Mazza, Claudio Bruno, Adele D’Amico, Manolo Carta, Anna Maria D’Ursi, Enrico Bertini, Livio Pellizzoni and Alessandro Usiello

Biomolecules 2022, 12(10), 1431; https://doi.org/10.3390/biom12101431 - 6 Oct 2022

Cited by 14 | Viewed by 4381

Abstract

Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid [...] Read more.

Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients. Full article

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

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12 pages, 2039 KiB

Open AccessEditor’s ChoiceArticle

Human Melanocortin-2 Receptor: Identifying a Role for Residues in the TM4, EC2, and TM5 Domains in Activation and Trafficking as a Result of Co-Expression with the Accessory Protein, Mrap1 in Chinese Hamster Ovary Cells

by Perry V. Davis, Ciaran A. Shaughnessy and Robert M. Dores

Biomolecules 2022, 12(10), 1422; https://doi.org/10.3390/biom12101422 - 4 Oct 2022

Cited by 4 | Viewed by 1964

Abstract

Human melanocortin-2 receptor (hMC2R) co-expressed with the accessory protein mouse (m)MRAP1 in Chinese Hamster Ovary (CHO) cells has been used as a model system to investigate the activation and trafficking of hMC2R. A previous study had shown that the N-terminal domain of mMRAP1 [...] Read more.

Human melanocortin-2 receptor (hMC2R) co-expressed with the accessory protein mouse (m)MRAP1 in Chinese Hamster Ovary (CHO) cells has been used as a model system to investigate the activation and trafficking of hMC2R. A previous study had shown that the N-terminal domain of mMRAP1 makes contact with one of the extracellular domains of hMC2R to facilitate activation of hMC2R. A chimeric receptor paradigm was used in which the extracellular domains of hMC2R were replaced with the corresponding domains from Xenopus tropicalis MC1R, a receptor that does not interact with MRAP1, to reveal that EC2 (Extracellular domain 2) is the most likely contact site for hMC2R and mMRAP1 to facilitate activation of the receptor following an ACTH binding event. Prior to activation, mMRAP1 facilitates the trafficking of hMC2R from the ER to the plasma membrane. This process is dependent on the transmembrane domain (TM) of mMRAP1 making contact with one or more TMs of hMC2R. A single alanine substitution paradigm was used to identify residues in TM4 (i.e., I¹⁶³, M¹⁶⁵), EC2 (F¹⁶⁷), and TM5 (F¹⁷⁸) that play a role in the trafficking of hMC2R to the plasma membrane. These results provide further clarification of the activation mechanism for hMC2R. Full article

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

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19 pages, 1558 KiB

Open AccessEditor’s ChoiceArticle

Next-Generation Sequencing Gene Panels in Inheritable Cardiomyopathies and Channelopathies: Prevalence of Pathogenic Variants and Variants of Unknown Significance in Uncommon Genes

by Cristina Mazzaccara, Raffaella Lombardi, Bruno Mirra, Ferdinando Barretta, Maria Valeria Esposito, Fabiana Uomo, Martina Caiazza, Emanuele Monda, Maria Angela Losi, Giuseppe Limongelli, Valeria D’Argenio and Giulia Frisso

Biomolecules 2022, 12(10), 1417; https://doi.org/10.3390/biom12101417 - 3 Oct 2022

Cited by 20 | Viewed by 3057

Abstract

The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of [...] Read more.

The diffusion of next-generation sequencing (NGS)-based approaches allows for the identification of pathogenic mutations of cardiomyopathies and channelopathies in more than 200 different genes. Since genes considered uncommon for a clinical phenotype are also now included in molecular testing, the detection rate of disease-causing variants has increased. Here, we report the prevalence of genetic variants detected by using a NGS custom panel in a cohort of 133 patients with inherited cardiomyopathies (n = 77) or channelopathies (n = 56). We identified 82 variants, of which 50 (61%) were identified in genes without a strong or definitive evidence of disease association according to the NIH-funded Clinical Genome Resource (ClinGen; “uncommon genes”). Among these, 35 (70%) were variants of unknown significance (VUSs), 13 (26%) were pathogenic (P) or likely pathogenic (LP) mutations, and 2 (4%) benign (B) or likely benign (LB) variants according to American College of Medical Genetics (ACMG) classifications. These data reinforce the need for the screening of uncommon genes in order to increase the diagnostic sensitivity of the genetic testing of inherited cardiomyopathies and channelopathies by allowing for the identification of mutations in genes that are not usually explored due to a currently poor association with the clinical phenotype. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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13 pages, 751 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Peripheral Neutrophil-to-Lymphocyte Ratio in Bronchiectasis: A Marker of Disease Severity

by Miguel Ángel Martinez-García, Casilda Olveira, Rosa Girón, Marta García-Clemente, Luis Máiz-Carro, Oriol Sibila, Rafael Golpe, Raúl Méndez, Juan Luis Rodríguez Hermosa, Esther Barreiro, Concepción Prados, Juan Rodríguez López and David de la Rosa

Biomolecules 2022, 12(10), 1399; https://doi.org/10.3390/biom12101399 - 30 Sep 2022

Cited by 17 | Viewed by 3054

Abstract

Most patients with bronchiectasis have a predominantly neutrophilic inflammatory profile, although other cells such as lymphocytes (as controllers of bronchial inflammation) and eosinophils also play a significant pathophysiological role. Easy-to-interpret blood biomarkers with a discriminative capacity for severity or prognosis are needed. The [...] Read more.

Most patients with bronchiectasis have a predominantly neutrophilic inflammatory profile, although other cells such as lymphocytes (as controllers of bronchial inflammation) and eosinophils also play a significant pathophysiological role. Easy-to-interpret blood biomarkers with a discriminative capacity for severity or prognosis are needed. The objective of this study was to assess whether the peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with different outcomes of severity in bronchiectasis. A total of 1369 patients with bronchiectasis from the Spanish Registry of Bronchiectasis were included. To compare groups, the sample was divided into increasing quartiles of NLR ratio. Correlations between quantitative variables were established using Pearson’s P test. A simple linear regression (with the value of exacerbations as a quantitative variable) was used to determine the independent relationship between the number and severity of exacerbations and the NLR ratio. The area under the curve (AUC)-ROC was used to determine the predictive capacity of the NLR for severe bronchiectasis, according to the different multidimensional scores. Mean age: 69 (15) years (66.3% of women). The mean NLR was 2.92 (2.03). A higher NLR was associated with more severe bronchiectasis (with an especially significant discriminative power for severe forms) according to the commonly used scores (FACED, E-FACED and BSI), as well as with poorer quality of life (SGRQ), more comorbidities (Charlson index), infection by pathogenic microorganisms, and greater application of treatment. Furthermore, the NLR correlated better with severity scores than other parameters of systemic inflammation. Finally, it was an independent predictor of the incident number and severity of exacerbations. In conclusion, the NLR is an inexpensive and easy-to-measure marker of systemic inflammation for determining severity and predicting exacerbations (especially the most severe) in patients with bronchiectasis. Full article

(This article belongs to the Section Cellular Biochemistry)

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23 pages, 5725 KiB

Open AccessEditor’s ChoiceArticle

The Multicellular Effects of VDAC1 N-Terminal-Derived Peptide

by Uttpal Anand, Anna Shteinfer-Kuzmine, Gal Sela, Manikandan Santhanam, Benjamin Gottschalk, Rajaa Boujemaa-Paterski, Ohad Medalia, Wolfgang F. Graier and Varda Shoshan-Barmatz

Biomolecules 2022, 12(10), 1387; https://doi.org/10.3390/biom12101387 - 28 Sep 2022

Cited by 8 | Viewed by 3752

Abstract

The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein functions in a variety of mitochondria-linked physiological and pathological processes, including metabolism and cell signaling, as well as in mitochondria-mediated apoptosis. VDAC1 interacts with about 150 proteins to regulate the integration of mitochondrial functions with other [...] Read more.

The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein functions in a variety of mitochondria-linked physiological and pathological processes, including metabolism and cell signaling, as well as in mitochondria-mediated apoptosis. VDAC1 interacts with about 150 proteins to regulate the integration of mitochondrial functions with other cellular activities. Recently, we developed VDAC1-based peptides that have multiple effects on cancer cells and tumors including apoptosis induction. Here, we designed several cell-penetrating VDAC1 N-terminal-derived peptides with the goal of identifying the shortest peptide with improved cellular stability and activity. We identified the D-Δ(1-18)N-Ter-Antp comprising the VDAC1 N-terminal region (19–26 amino acids) fused to the Antp, a cell-penetrating peptide. We demonstrated that this peptide induced apoptosis, autophagy, senescence, cell volume enlargement, and the refusion of divided daughter cells into a single cell, it was responsible for reorganization of actin and tubulin filaments, and increased cell adhesion. In addition, the peptide induced alterations in the expression of proteins associated with cell metabolism, signaling, and division, such as enhancing the expression of nuclear factor kappa B and decreasing the expression of the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha. These cellular effects may result from the peptide interfering with VDAC1 interaction with its interacting proteins, thereby blocking multiple mitochondrial/VDAC1 pathways associated with cell functions. The results of this study further support the role of VDAC1 as a mitochondrial gatekeeper protein in controlling a variety of cell functions via interaction with associated proteins. Full article

(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)

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16 pages, 2061 KiB

Open AccessEditor’s ChoiceReview

Galectin-10 as a Potential Biomarker for Eosinophilic Diseases

by Hiroki Tomizawa, Yoshiyuki Yamada, Misaki Arima, Yui Miyabe, Mineyo Fukuchi, Haruka Hikichi, Rossana C. N. Melo, Takechiyo Yamada and Shigeharu Ueki

Biomolecules 2022, 12(10), 1385; https://doi.org/10.3390/biom12101385 - 27 Sep 2022

Cited by 23 | Viewed by 5633

Abstract

Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms [...] Read more.

Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms Charcot–Leyden crystals, which are observed in various eosinophilic diseases. Accumulating studies have indicated that galectin-10 acts as a new biomarker for disease activity, diagnosis, and treatment effectiveness in asthma, eosinophilic esophagitis, rhinitis, sinusitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis. The extracellular release of galectin-10 is not mediated through conventional secretory processes (piecemeal degranulation or exocytosis), but rather by extracellular trap cell death (ETosis), which is an active cell death program. Eosinophils undergoing ETosis rapidly disintegrate their plasma membranes to release the majority of galectin-10. Therefore, elevated galectin-10 levels in serum and tissue suggest a high degree of eosinophil ETosis. To date, several studies have shown that galectin-10/Charcot–Leyden crystals are more than just markers for eosinophilic inflammation, but play functional roles in immunity. In this review, we focus on the close relationship between eosinophils and galectin-10, highlighting this protein as a potential new biomarker in eosinophilic diseases. Full article

(This article belongs to the Special Issue Eosinophils in Allergy and Related Diseases—Selected Papers from “The Workshop on Eosinophils in Allergy and Related Diseases 2021”)

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13 pages, 2183 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Selecting Multitarget Peptides for Alzheimer’s Disease

by Anne Kasus-Jacobi, Jennifer L. Washburn, Riley B. Laurence and H. Anne Pereira

Biomolecules 2022, 12(10), 1386; https://doi.org/10.3390/biom12101386 - 27 Sep 2022

Cited by 8 | Viewed by 3883

Abstract

Alzheimer’s disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate [...] Read more.

Alzheimer’s disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer’s disease, by targeting both neuroinflammation and neurodegeneration. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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18 pages, 1714 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Radiobiological Aspects of FLASH Radiotherapy

by Eline Hageman, Pei-Pei Che, Max Dahele, Ben J. Slotman and Peter Sminia

Biomolecules 2022, 12(10), 1376; https://doi.org/10.3390/biom12101376 - 26 Sep 2022

Cited by 32 | Viewed by 7375

Abstract

Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical [...] Read more.

Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

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27 pages, 3242 KiB

Open AccessEditor’s ChoiceArticle

A Study on the Nature of SARS-CoV-2 Using the Shell Disorder Models: Reproducibility, Evolution, Spread, and Attenuation

by Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster and Vladimir N. Uversky

Biomolecules 2022, 12(10), 1353; https://doi.org/10.3390/biom12101353 - 23 Sep 2022

Cited by 4 | Viewed by 2808

Abstract

The basic tenets of the shell disorder model (SDM) as applied to COVID-19 are that the harder outer shell of the virus shell (lower PID—percentage of intrinsic disorder—of the membrane protein M, PID_M) and higher flexibility of the inner shell (higher [...] Read more.

The basic tenets of the shell disorder model (SDM) as applied to COVID-19 are that the harder outer shell of the virus shell (lower PID—percentage of intrinsic disorder—of the membrane protein M, PID_M) and higher flexibility of the inner shell (higher PID of the nucleocapsid protein N, PID_N) are correlated with the contagiousness and virulence, respectively. M protects the virion from the anti-microbial enzymes in the saliva and mucus. N disorder is associated with the rapid replication of the virus. SDM predictions are supported by two experimental observations. The first observation demonstrated lesser and greater presence of the Omicron particles in the lungs and bronchial tissues, respectively, as there is a greater level of mucus in the bronchi. The other observation revealed that there are lower viral loads in 2017-pangolin-CoV, which is predicted to have similarly low PID_N as Omicron. The abnormally hard M, which is very rarely seen in coronaviruses, arose from the fecal–oral behaviors of pangolins via exposure to buried feces. Pangolins provide an environment for coronavirus (CoV) attenuation, which is seen in Omicron. Phylogenetic study using M shows that COVID-19-related bat-CoVs from Laos and Omicron are clustered in close proximity to pangolin-CoVs, which suggests the recurrence of interspecies transmissions. Hard M may have implications for long COVID-19, with immune systems having difficulty degrading viral proteins/particles. Full article

(This article belongs to the Special Issue Theme Issue Honoring Scientist Louis Pasteur on His 200th Birthday)

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17 pages, 1437 KiB

Open AccessEditor’s ChoiceReview

Antipsychotic Drug Fluphenazine against Human Cancer Cells

by Diana Duarte and Nuno Vale

Biomolecules 2022, 12(10), 1360; https://doi.org/10.3390/biom12101360 - 23 Sep 2022

Cited by 11 | Viewed by 3887

Abstract

Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical [...] Read more.

Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical trials and data related to their pharmacokinetics is already described, reducing the costs and time associated with the development of new anticancer therapeutics. Several studies suggest that the repurposing of fluphenazine for cancer therapy may be a promising approach, as this drug proved to reduce the viability of diverse cancer cell lines. In this review, intensive research of the literature was performed related to the anticancer potential of fluphenazine in different human cancer cells. We have found several research articles on the cytotoxic effect of fluphenazine in lung, breast, colon, liver, brain, leukemia, oral, ovarian, and skin cancer and have summarized the main findings in this review. Taken together, these findings suggest that fluphenazine may regulate the cell cycle, reduce cell proliferation, and cause apoptosis in several types of cancer cells, besides being an established calmodulin inhibitor. It was also found that this drug is able to target cancer-related proteins, such as ABCB1 and P-glycoprotein as well as to regulate the Akt and Wnt signaling pathways. Some studies also refer this drug causes DNA alterations and interferes with cell invasion and migration ability as well as with ROS generation. Collectively, these results imply that fluphenazine may be a favorable compound for further research in oncologic therapy. Full article

(This article belongs to the Special Issue New Advances in Drug Repurposing for Oncology)

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22 pages, 1872 KiB

Open AccessEditor’s ChoiceReview

GPCRs in Intracellular Compartments: New Targets for Drug Discovery

by Irene Fasciani, Marco Carli, Francesco Petragnano, Francesco Colaianni, Gabriella Aloisi, Roberto Maggio, Marco Scarselli and Mario Rossi

Biomolecules 2022, 12(10), 1343; https://doi.org/10.3390/biom12101343 - 22 Sep 2022

Cited by 34 | Viewed by 5767

Abstract

The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their [...] Read more.

The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their signal transduction is traditionally viewed as a chain of events initiated from the plasma membrane. Furthermore, their intracellular trafficking, internalization, and recycling were considered only to regulate receptor desensitization and cell surface expression. On the contrary, accumulating data strongly suggest that GPCRs also signal from intracellular compartments. GPCRs localize in the membranes of endosomes, nucleus, Golgi and endoplasmic reticulum apparatuses, mitochondria, and cell division compartments. Importantly, from these sites they have shown to orchestrate multiple signals that regulate different cell pathways. In this review, we summarize the current knowledge of this fascinating phenomenon, explaining how GPCRs reach the intracellular sites, are stimulated by the endogenous ligands, and their potential physiological/pathophysiological roles. Finally, we illustrate several mechanisms involved in the modulation of the compartmentalized GPCR signaling by drugs and endogenous ligands. Understanding how GPCR signaling compartmentalization is regulated will provide a unique opportunity to develop novel pharmaceutical approaches to target GPCRs and potentially lead the way towards new therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)

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25 pages, 1978 KiB

Open AccessEditor’s ChoiceReview

From Small Peptides to Large Proteins against Alzheimer’sDisease

by Pasquale Picone, Tiziana Sanfilippo, Sonya Vasto, Sara Baldassano, Rossella Guggino, Domenico Nuzzo, Donatella Bulone, Pier Luigi San Biagio, Emanuela Muscolino, Roberto Monastero, Clelia Dispenza and Daniela Giacomazza

Biomolecules 2022, 12(10), 1344; https://doi.org/10.3390/biom12101344 - 22 Sep 2022

Cited by 8 | Viewed by 2963

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau (p-Tau) located [...] Read more.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau (p-Tau) located in the cytoplasm of neurons. Although the research has made relevant progress in the management of the disease, the treatment is still lacking. Only symptomatic medications exist for the disease, and, in the meantime, laboratories worldwide are investigating disease-modifying treatments for AD. In the present review, results centered on the use of peptides of different sizes involved in AD are presented. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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20 pages, 6474 KiB

Open AccessEditor’s ChoiceArticle

Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo

by Ellaine Salvador, Almuth F. Kessler, Dominik Domröse, Julia Hörmann, Clara Schaeffer, Aiste Giniunaite, Malgorzata Burek, Catherine Tempel-Brami, Tali Voloshin, Alexandra Volodin, Adel Zeidan, Moshe Giladi, Ralf-Ingo Ernestus, Mario Löhr, Carola Y. Förster and Carsten Hagemann

Biomolecules 2022, 12(10), 1348; https://doi.org/10.3390/biom12101348 - 22 Sep 2022

Cited by 31 | Viewed by 6610

Abstract

Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We [...] Read more.

Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy. Full article

(This article belongs to the Special Issue Regulation of the Endothelial Cell Barrier)

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12 pages, 978 KiB

Open AccessEditor’s ChoiceReview

Biomolecular Mechanisms of Cardiorenal Protection with Sodium-Glucose Co-Transporter 2 Inhibitors

by Francesca Romana Prandi, Lucy Barone, Dalgisio Lecis, Martina Belli, Domenico Sergi, Marialucia Milite, Stamatios Lerakis, Francesco Romeo and Francesco Barillà

Biomolecules 2022, 12(10), 1349; https://doi.org/10.3390/biom12101349 - 22 Sep 2022

Cited by 8 | Viewed by 2965

Abstract

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of morbidity and mortality, primarily from cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are novel drugs for the treatment of type 2 DM and [...] Read more.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of morbidity and mortality, primarily from cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are novel drugs for the treatment of type 2 DM and heart failure (HF). SGLT2-Is mediate protective effects on both the renal and cardiovascular systems. This review addresses the current knowledge on the biomolecular mechanisms of the cardiorenal protective effects of SGLT2-Is, which appear to act mainly through non-glucose-mediated pathways. Cardiorenal protection mechanisms lead to reduced chronic renal disease progression and improved myocardial and coronary endothelial function. Concomitantly, it is possible to observe reflected changes in biomarkers linked with diabetic kidney disease and HF. Full article

(This article belongs to the Special Issue Biomarkers Profile and Biomolecular Signaling in Heart Failure and Cardiomyopathies)

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14 pages, 1882 KiB

Open AccessEditor’s ChoiceArticle

Why the Ala-His-His Peptide Is an Appropriate Scaffold to Remove and Redox Silence Copper Ions from the Alzheimer’s-Related Aβ Peptide

by Paulina Gonzalez, Laurent Sabater, Emilie Mathieu, Peter Faller and Christelle Hureau

Biomolecules 2022, 12(10), 1327; https://doi.org/10.3390/biom12101327 - 20 Sep 2022

Cited by 8 | Viewed by 2642

Abstract

The progressive, neurodegenerative Alzheimer’s disease (AD) is the most widespread dementia. Due to the ageing of the population and the current lack of molecules able to prevent or stop the disease, AD will be even more impactful for society in the future. AD [...] Read more.

The progressive, neurodegenerative Alzheimer’s disease (AD) is the most widespread dementia. Due to the ageing of the population and the current lack of molecules able to prevent or stop the disease, AD will be even more impactful for society in the future. AD is a multifactorial disease, and, among other factors, metal ions have been regarded as potential therapeutic targets. This is the case for the redox-competent Cu ions involved in the production of reactive oxygen species (ROS) when bound to the Alzheimer-related Aβ peptide, a process that contributes to the overall oxidative stress and inflammation observed in AD. Here, we made use of peptide ligands to stop the Cu(Aβ)-induced ROS production and we showed why the AHH sequence is fully appropriate, while the two parents, AH and AAH, are not. The AHH peptide keeps its beneficial ability against Cu(Aβ)-induced ROS, even in the presence of Zn^II-competing ions and other biologically relevant ions. The detailed kinetic mechanism by which AHH could exert its action against Cu(Aβ)-induced ROS is also proposed. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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20 pages, 1127 KiB

Open AccessEditor’s ChoiceReview

Roles of Two-Component Signal Transduction Systems in Shigella Virulence

by Martina Pasqua, Marco Coluccia, Yoko Eguchi, Toshihide Okajima, Milena Grossi, Gianni Prosseda, Ryutaro Utsumi and Bianca Colonna

Biomolecules 2022, 12(9), 1321; https://doi.org/10.3390/biom12091321 - 18 Sep 2022

Cited by 22 | Viewed by 5466

Abstract

Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of [...] Read more.

Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of bacterial functions, including cell division, motility, differentiation, biofilm formation, antibiotic resistance, and virulence. Pathogenic bacteria exploit the capabilities of TCSs to reprogram gene expression according to the different niches they encounter during host infection. This review focuses on the role of TCSs in regulating the virulence phenotype of Shigella, an intracellular pathogen responsible for severe human enteric syndrome. The pathogenicity of Shigella is the result of the complex action of a wide number of virulence determinants located on the chromosome and on a large virulence plasmid. In particular, we will discuss how five TCSs, EnvZ/OmpR, CpxA/CpxR, ArcB/ArcA, PhoQ/PhoP, and EvgS/EvgA, contribute to linking environmental stimuli to the expression of genes related to virulence and fitness within the host. Considering the relevance of TCSs in the expression of virulence in pathogenic bacteria, the identification of drugs that inhibit TCS function may represent a promising approach to combat bacterial infections. Full article

(This article belongs to the Special Issue Theme Issue Honoring Scientist Louis Pasteur on His 200th Birthday)

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15 pages, 2227 KiB

Open AccessEditor’s ChoiceArticle

6-Furopyridine Hexamethylene Amiloride Is a Non-Selective P2X7 Receptor Antagonist

by Peter Cuthbertson, Amal Elhage, Dena Al-Rifai, Reece A. Sophocleous, Ross J. Turner, Ashraf Aboelela, Hiwa Majed, Richard S. Bujaroski, Iman Jalilian, Michael J. Kelso, Debbie Watson, Benjamin J. Buckley and Ronald Sluyter

Biomolecules 2022, 12(9), 1309; https://doi.org/10.3390/biom12091309 - 16 Sep 2022

Cited by 7 | Viewed by 2781

Abstract

P2X7 is an extracellular adenosine 5′-triphopshate (ATP)-gated cation channel present on leukocytes, where its activation induces pro-inflammatory cytokine release and ectodomain shedding of cell surface molecules. Human P2X7 can be partially inhibited by amiloride and its derivatives at micromolar concentrations. This study aimed [...] Read more.

P2X7 is an extracellular adenosine 5′-triphopshate (ATP)-gated cation channel present on leukocytes, where its activation induces pro-inflammatory cytokine release and ectodomain shedding of cell surface molecules. Human P2X7 can be partially inhibited by amiloride and its derivatives at micromolar concentrations. This study aimed to screen a library of compounds derived from amiloride or its derivative 5-(N,N-hexamethylene) amiloride (HMA) to identify a potential P2X7 antagonist. 6-Furopyridine HMA (6-FPHMA) was identified as a novel P2X7 antagonist and was characterized further. 6-FPHMA impaired ATP-induced dye uptake into human RPMI8226 multiple myeloma cells and human P2X7-HEK293 cells, in a concentration-dependent, non-competitive manner. Likewise, 6-FPHMA blocked ATP-induced Ca²⁺ fluxes in human P2X7-HEK293 cells in a concentration-dependent, non-competitive manner. 6-FPHMA inhibited ATP-induced dye uptake into human T cells, and interleukin-1β release within human blood and CD23 shedding from RPMI8226 cells. 6-FPHMA also impaired ATP-induced dye uptake into murine P2X7- and canine P2X7-HEK293 cells. However, 6-FPHMA impaired ATP-induced Ca²⁺ fluxes in human P2X4-HEK293 cells and non-transfected HEK293 cells, which express native P2Y₁, P2Y₂ and P2Y₄. In conclusion, 6-FPHMA inhibits P2X7 from multiple species. Its poor selectivity excludes its use as a specific P2X7 antagonist, but further study of amiloride derivatives as P2 receptor antagonists is warranted. Full article

(This article belongs to the Special Issue Feature Paper from Biomolecules Journal Reviewers)

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24 pages, 2979 KiB

Open AccessEditor’s ChoiceArticle

Oviductal Extracellular Vesicles Enhance Porcine In Vitro Embryo Development by Modulating the Embryonic Transcriptome

by Agostinho Soares de Alcântara-Neto, Cristina Cuello, Rustem Uzbekov, Stefan Bauersachs, Pascal Mermillod and Carmen Almiñana

Biomolecules 2022, 12(9), 1300; https://doi.org/10.3390/biom12091300 - 15 Sep 2022

Cited by 21 | Viewed by 3508

Abstract

Oviductal extracellular vesicles (oEVs) have been identified as important components of the oviductal fluid (OF) and have been pointed to as key modulators of gamete/embryo-maternal interactions. Here, we determined the functional impact of oEVs on embryo development and the embryonic transcriptome in porcine. [...] Read more.

Oviductal extracellular vesicles (oEVs) have been identified as important components of the oviductal fluid (OF) and have been pointed to as key modulators of gamete/embryo-maternal interactions. Here, we determined the functional impact of oEVs on embryo development and the embryonic transcriptome in porcine. Experiment 1 examined the effect of oEVs and OF on embryo development. In vitro-produced embryos were cultured with oEVs or OF for 2 or 7 days using an in vitro sequential system or without supplementation (control). Experiment 2 analyzed transcriptomic alterations of EV-treated embryos versus control and the oEVs RNA cargo by RNA-sequencing. Two days of EV treatment enhanced embryo development over time when compared to other treatments. Different RNA expression profiles between embryos treated with EVs for two or seven days and untreated controls were obtained, with 54 and 59 differentially expressed (DE) genes and six and seven DE miRNAs, respectively. In oEV RNA cargo, 12,998 RNAs and 163 miRNAs were identified. Integrative analyses pointed to specific oEV components that might act as modulators of the embryonic transcriptome, such as S100A11, ANXA2 or miR-21-5p. Overall, the findings suggested that oEVs could be a potential strategy to improve porcine IVP outcomes, particularly by using two days of EV treatment. Full article

(This article belongs to the Special Issue Biomolecules in Parental–Embryo Communication and Implantation)

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18 pages, 1763 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Galectokines: The Promiscuous Relationship between Galectins and Cytokines

by Lucía Sanjurjo, Esmee C. Broekhuizen, Rory R. Koenen and Victor L. J. L. Thijssen

Biomolecules 2022, 12(9), 1286; https://doi.org/10.3390/biom12091286 - 13 Sep 2022

Cited by 16 | Viewed by 3237

Abstract

Galectins, a family of glycan-binding proteins, are well-known for their role in shaping the immune microenvironment. They can directly affect the activity and survival of different immune cell subtypes. Recent evidence suggests that galectins also indirectly affect the immune response by binding to [...] Read more.

Galectins, a family of glycan-binding proteins, are well-known for their role in shaping the immune microenvironment. They can directly affect the activity and survival of different immune cell subtypes. Recent evidence suggests that galectins also indirectly affect the immune response by binding to members of another immunoregulatory protein family, i.e., cytokines. Such galectin-cytokine heterodimers, here referred to as galectokines, add a new layer of complexity to the regulation of immune homeostasis. Here, we summarize the current knowledge with regard to galectokine formation and function. We describe the known and potential mechanisms by which galectokines can help to shape the immune microenvironment. Finally, the outstanding questions and challenges for future research regarding the role of galectokines in immunomodulation are discussed. Full article

(This article belongs to the Collection Galectins and Cancer)

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9 pages, 830 KiB

Open AccessEditor’s ChoiceArticle

Plasma Clearance of Intravenously Infused Adrenomedullin in Rats with Acute Renal Failure

by Hiroshi Hosoda, Tsutomu Nakamura and Fumiki Yoshihara

Biomolecules 2022, 12(9), 1281; https://doi.org/10.3390/biom12091281 - 11 Sep 2022

Cited by 1 | Viewed by 2350

Abstract

Plasma adrenomedullin concentrations are reportedly elevated in patients with renal failure; however, the underlying mechanism is unclear. In this study, we investigated the plasma clearance of synthetic human adrenomedullin (AM) in two models of rats with renal dysfunction; one was induced by subcutaneous [...] Read more.

Plasma adrenomedullin concentrations are reportedly elevated in patients with renal failure; however, the underlying mechanism is unclear. In this study, we investigated the plasma clearance of synthetic human adrenomedullin (AM) in two models of rats with renal dysfunction; one was induced by subcutaneous injection of mercury chloride (RD-Ag) and the other by completely blocking bilateral renal blood flow (RD-Bl). Sixty minutes after starting intravenous AM infusion, AM levels in RD-Ag, RD-Bl, and rats with normal renal function (NF) were still increased slightly; however, plasma AM levels in RD-Ag rats were approximately three times as high as in RD-Bl and NF rats. Plasma AM disappearance after the end of treatment was similar among the three groups. Pharmacokinetic analysis revealed that elevated plasma AM in RD-Ag rats may be caused by a reduced volume of distribution. The adrenomedullin functional receptor is composed of heterodimers, including GPCR, CLR (calcitonin receptor-like receptor, CALCRL), and the single transmembrane proteins, RAMP2 or RAMP3 (receptor activity modifying protein). Calcrl expression was downregulated in the lungs and kidneys of RD-Ag rats. Furthermore, the plasma concentration of exogenous AM was elevated in mice deficient in vascular endothelium-specific Ramp2. These results suggest that decreased plasma AM clearance in RD-Ag is not due to impaired renal excretion but to a decreased volume of distribution caused by a reduction in adrenomedullin receptors. Full article

(This article belongs to the Special Issue Advanced Researches in G-Protein-Coupled Receptors (GPCRs) and Their Closely Related Functional Proteins)

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