Biomolecules

Review

21 pages, 1356 KiB

Open AccessEditor’s ChoiceReview

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

by Sarah J. Backe, Rebecca A. Sager, Katherine A. Meluni, Mark R. Woodford, Dimitra Bourboulia and Mehdi Mollapour

Biomolecules 2022, 12(7), 928; https://doi.org/10.3390/biom12070928 - 1 Jul 2022

Cited by 2 | Viewed by 3175

Abstract

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and [...] Read more.

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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20 pages, 6070 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Monoterpenes as Sirtuin-1 Activators: Therapeutic Potential in Aging and Related Diseases

by Cátia Sousa and Alexandrina Ferreira Mendes

Biomolecules 2022, 12(7), 921; https://doi.org/10.3390/biom12070921 - 30 Jun 2022

Cited by 5 | Viewed by 3641

Abstract

Sirtuin 1 (SIRT) is a class III, NAD⁺-dependent histone deacetylase that also modulates the activity of numerous non-histone proteins through deacylation. SIRT1 plays critical roles in regulating and integrating cellular energy metabolism, response to stress, and circadian rhythm by modulating epigenetic [...] Read more.

Sirtuin 1 (SIRT) is a class III, NAD⁺-dependent histone deacetylase that also modulates the activity of numerous non-histone proteins through deacylation. SIRT1 plays critical roles in regulating and integrating cellular energy metabolism, response to stress, and circadian rhythm by modulating epigenetic and transcriptional regulation, mitochondrial homeostasis, proteostasis, telomere maintenance, inflammation, and the response to hypoxia. SIRT1 expression and activity decrease with aging, and enhancing its activity extends life span in various organisms, including mammals, and improves many age-related diseases, including cancer, metabolic, cardiovascular, neurodegenerative, respiratory, musculoskeletal, and renal diseases, but the opposite, that is, aggravation of various diseases, such as some cancers and neurodegenerative diseases, has also been reported. Accordingly, many natural and synthetic SIRT1 activators and inhibitors have been developed. Known SIRT1 activators of natural origin are mainly polyphenols. Nonetheless, various classes of non-polyphenolic monoterpenoids have been identified as inducers of SIRT1 expression and/or activity. This narrative review discusses current information on the evidence that supports the role of those compounds as SIRT1 activators and their potential both as tools for research and as pharmaceuticals for therapeutic application in age-related diseases. Full article

(This article belongs to the Collection Feature Papers in Chemical Biology)

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29 pages, 1408 KiB

Open AccessEditor’s ChoiceReview

Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network

by Gabriel Ichim, Benjamin Gibert, Sahil Adriouch, Catherine Brenner, Nathalie Davoust, Solange Desagher, David Devos, Svetlana Dokudovskaya, Laurence Dubrez, Jérôme Estaquier, Germain Gillet, Isabelle Guénal, Philippe P. Juin, Guido Kroemer, Patrick Legembre, Romain Levayer, Stéphen Manon, Patrick Mehlen, Olivier Meurette, Olivier Micheau, Bernard Mignotte, Florence Nguyen-Khac, Nikolay Popgeorgiev, Jean-Luc Poyet, Muriel Priault, Jean-Ehrland Ricci, Franck B. Riquet, Santos A. Susin, Magali Suzanne, Pierre Vacher, Ludivine Walter and Bertrand Mollereau Show full author list Hide full author list

Biomolecules 2022, 12(7), 901; https://doi.org/10.3390/biom12070901 - 28 Jun 2022

Cited by 3 | Viewed by 3621

Abstract

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated [...] Read more.

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy. Full article

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

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23 pages, 1612 KiB

Open AccessEditor’s ChoiceReview

Getting Closer to Decrypting the Phase Transitions of Bacterial Biomolecules

by Katarzyna Sołtys, Aneta Tarczewska, Dominika Bystranowska and Nikola Sozańska

Biomolecules 2022, 12(7), 907; https://doi.org/10.3390/biom12070907 - 28 Jun 2022

Cited by 8 | Viewed by 4185

Abstract

Liquid–liquid phase separation (LLPS) of biomolecules has emerged as a new paradigm in cell biology, and the process is one proposed mechanism for the formation of membraneless organelles (MLOs). Bacterial cells have only recently drawn strong interest in terms of studies on both [...] Read more.

Liquid–liquid phase separation (LLPS) of biomolecules has emerged as a new paradigm in cell biology, and the process is one proposed mechanism for the formation of membraneless organelles (MLOs). Bacterial cells have only recently drawn strong interest in terms of studies on both liquid-to-liquid and liquid-to-solid phase transitions. It seems that these processes drive the formation of prokaryotic cellular condensates that resemble eukaryotic MLOs. In this review, we present an overview of the key microbial biomolecules that undergo LLPS, as well as the formation and organization of biomacromolecular condensates within the intracellular space. We also discuss the current challenges in investigating bacterial biomacromolecular condensates. Additionally, we highlight a summary of recent knowledge about the participation of bacterial biomolecules in a phase transition and provide some new in silico analyses that can be helpful for further investigations. Full article

(This article belongs to the Special Issue Molecular Phase Transitions in Physiology and Pathology: Freezing and Precipitation in Biology)

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17 pages, 2276 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Multifaceted Role of Aquaporin-9 in Health and Its Potential as a Clinical Biomarker

by Inês V. da Silva, Sabino Garra, Giuseppe Calamita and Graça Soveral

Biomolecules 2022, 12(7), 897; https://doi.org/10.3390/biom12070897 - 27 Jun 2022

Cited by 27 | Viewed by 3060

Abstract

Aquaporins (AQPs) are transmembrane channels essential for water, energy, and redox homeostasis, with proven involvement in a variety of pathophysiological conditions such as edema, glaucoma, nephrogenic diabetes insipidus, oxidative stress, sepsis, cancer, and metabolic dysfunctions. The 13 AQPs present in humans are widely [...] Read more.

Aquaporins (AQPs) are transmembrane channels essential for water, energy, and redox homeostasis, with proven involvement in a variety of pathophysiological conditions such as edema, glaucoma, nephrogenic diabetes insipidus, oxidative stress, sepsis, cancer, and metabolic dysfunctions. The 13 AQPs present in humans are widely distributed in all body districts, drawing cell lineage-specific expression patterns closely related to cell native functions. Compelling evidence indicates that AQPs are proteins with great potential as biomarkers and targets for therapeutic intervention. Aquaporin-9 (AQP9) is the most expressed in the liver, with implications in general metabolic and redox balance due to its aquaglyceroporin and peroxiporin activities, facilitating glycerol and hydrogen peroxide (H₂O₂) diffusion across membranes. AQP9 is also expressed in other tissues, and their altered expression is described in several human diseases, such as liver injury, inflammation, cancer, infertility, and immune disorders. The present review compiles the current knowledge of AQP9 implication in diseases and highlights its potential as a new biomarker for diagnosis and prognosis in clinical medicine. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomolecules—Advances in Biomarkers, Therapeutics and Prevention)

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Graphical abstract

13 pages, 1806 KiB

Open AccessEditor’s ChoiceReview

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

by Abhinav Joshi, Takeshi Ito, Didier Picard and Len Neckers

Biomolecules 2022, 12(7), 880; https://doi.org/10.3390/biom12070880 - 24 Jun 2022

Cited by 10 | Viewed by 3665

Abstract

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in [...] Read more.

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone’s nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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19 pages, 865 KiB

Open AccessEditor’s ChoiceReview

Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties

by Marco Fabbrini, Federica D’Amico, Monica Barone, Gabriele Conti, Mariachiara Mengoli, Patrizia Brigidi and Silvia Turroni

Biomolecules 2022, 12(7), 875; https://doi.org/10.3390/biom12070875 - 23 Jun 2022

Cited by 23 | Viewed by 3764

Abstract

Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, [...] Read more.

Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, and it is generally reported that a substantial elevation of their plasma concentration can only be achieved when they are consumed at pharmacological levels. Even so, positive effects have been reported associated with an average dietary consumption of several nutraceutical classes, meaning that the primary compound might not be solely responsible for all the biological effects. The in vivo activities of such biomolecules might be carried out by metabolites derived from gut microbiota fermentative transformation. This review discusses the structure and properties of phenolic nutraceuticals (i.e., polyphenols and tannins) and the putative role of the human gut microbiota in influencing the beneficial effects of such compounds. Full article

(This article belongs to the Special Issue Bioactive Natural Compounds against Animal and Human Pathogens)

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15 pages, 1411 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Life and Death Decisions—The Many Faces of Autophagy in Cell Survival and Cell Death

by Ge Yu and Daniel J. Klionsky

Biomolecules 2022, 12(7), 866; https://doi.org/10.3390/biom12070866 - 21 Jun 2022

Cited by 20 | Viewed by 2866

Abstract

Autophagy is a process conserved from yeast to humans. Since the discovery of autophagy, its physiological role in cell survival and cell death has been intensively investigated. The inherent ability of the autophagy machinery to sequester, deliver, and degrade cytoplasmic components enables autophagy [...] Read more.

Autophagy is a process conserved from yeast to humans. Since the discovery of autophagy, its physiological role in cell survival and cell death has been intensively investigated. The inherent ability of the autophagy machinery to sequester, deliver, and degrade cytoplasmic components enables autophagy to participate in cell survival and cell death in multiple ways. The primary role of autophagy is to send cytoplasmic components to the vacuole or lysosomes for degradation. By fine-tuning autophagy, the cell regulates the removal and recycling of cytoplasmic components in response to various stress or signals. Recent research has shown the implications of the autophagy machinery in other pathways independent of lysosomal degradation, expanding the pro-survival role of autophagy. Autophagy also facilitates certain forms of regulated cell death. In addition, there is complex crosstalk between autophagy and regulated cell death pathways, with a number of genes shared between them, further suggesting a deeper connection between autophagy and cell death. Finally, the mitochondrion presents an example where the cell utilizes autophagy to strike a balance between cell survival and cell death. In this review, we consider the current knowledge on the physiological role of autophagy as well as its regulation and discuss the multiple functions of autophagy in cell survival and cell death. Full article

(This article belongs to the Special Issue The Many Faces of Autophagy: Balancing Survival and Cell Death)

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11 pages, 812 KiB

Open AccessEditor’s ChoiceReview

CPLANE Complex and Ciliopathies

by Jesús Eduardo Martín-Salazar and Diana Valverde

Biomolecules 2022, 12(6), 847; https://doi.org/10.3390/biom12060847 - 17 Jun 2022

Cited by 11 | Viewed by 2503

Abstract

Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some [...] Read more.

Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and RSG1 for cilia formation. Defects in these genes have been linked to a malfunction of intraflagellar transport and defects in the planar cell polarity, as well as defective activation of the Hedgehog signalling pathway. These faults lead to defective cilium formation, resulting in ciliopathies, including orofacial–digital syndrome (OFDS) and Bardet–Biedl syndrome (BBS). Considering the close relationship, between the CPLANE complex and cilium formation, it can be expected that defects in the genes that encode subunits of the CPLANE complex may be related to other ciliopathies. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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32 pages, 1340 KiB

Open AccessEditor’s ChoiceReview

NAFLD: Mechanisms, Treatments, and Biomarkers

by Fatiha Nassir

Biomolecules 2022, 12(6), 824; https://doi.org/10.3390/biom12060824 - 13 Jun 2022

Cited by 123 | Viewed by 14659

Abstract

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason [...] Read more.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments. Full article

(This article belongs to the Special Issue Mechanisms of Nonalcoholic Liver Diseases)

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21 pages, 3295 KiB

Open AccessEditor’s ChoiceReview

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

by Anna Ananchenko, Toka O. K. Hussein, Deepansh Mody, Mackenzie J. Thompson and John E. Baenziger

Biomolecules 2022, 12(6), 814; https://doi.org/10.3390/biom12060814 - 10 Jun 2022

Cited by 7 | Viewed by 3351

Abstract

Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function [...] Read more.

Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs. Here, we update our evolving understanding of pLGIC–lipid interactions highlighting newly identified modes of lipid binding along with the mechanistic understanding derived from the new structural data. Full article

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

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32 pages, 9181 KiB

Open AccessEditor’s ChoiceReview

Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present

by Sarah E. Huff, Jordan M. Winter and Chris G. Dealwis

Biomolecules 2022, 12(6), 815; https://doi.org/10.3390/biom12060815 - 10 Jun 2022

Cited by 19 | Viewed by 4559

Abstract

Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR [...] Read more.

Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors. Full article

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

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24 pages, 2138 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

by Carla Rodriguez-Mogeda, Sabela Rodríguez-Lorenzo, Jiji Attia, Jack van Horssen, Maarten E. Witte and Helga E. de Vries

Biomolecules 2022, 12(6), 800; https://doi.org/10.3390/biom12060800 - 7 Jun 2022

Cited by 11 | Viewed by 5518

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of [...] Read more.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood–brain-, blood–meningeal-, and blood–cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease. Full article

(This article belongs to the Special Issue The Central Nervous System Barriers in Health and Disease)

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27 pages, 2164 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Nano-Based Approved Pharmaceuticals for Cancer Treatment: Present and Future Challenges

by Francisco Rodríguez, Pablo Caruana, Noa De la Fuente, Pía Español, María Gámez, Josep Balart, Elisa Llurba, Ramón Rovira, Raúl Ruiz, Cristina Martín-Lorente, José Luis Corchero and María Virtudes Céspedes

Biomolecules 2022, 12(6), 784; https://doi.org/10.3390/biom12060784 - 4 Jun 2022

Cited by 66 | Viewed by 6848

Abstract

Cancer is one of the main causes of death worldwide. To date, and despite the advances in conventional treatment options, therapy in cancer is still far from optimal due to the non-specific systemic biodistribution of antitumor agents. The inadequate drug concentrations at the [...] Read more.

Cancer is one of the main causes of death worldwide. To date, and despite the advances in conventional treatment options, therapy in cancer is still far from optimal due to the non-specific systemic biodistribution of antitumor agents. The inadequate drug concentrations at the tumor site led to an increased incidence of multiple drug resistance and the appearance of many severe undesirable side effects. Nanotechnology, through the development of nanoscale-based pharmaceuticals, has emerged to provide new and innovative drugs to overcome these limitations. In this review, we provide an overview of the approved nanomedicine for cancer treatment and the rationale behind their designs and applications. We also highlight the new approaches that are currently under investigation and the perspectives and challenges for nanopharmaceuticals, focusing on the tumor microenvironment and tumor disseminate cells as the most attractive and effective strategies for cancer treatments. Full article

(This article belongs to the Special Issue Applications of Nanoparticles in Tumor Therapy)

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19 pages, 2670 KiB

Open AccessEditor’s ChoiceReview

TRAP1 Chaperones the Metabolic Switch in Cancer

by Laura A. Wengert, Sarah J. Backe, Dimitra Bourboulia, Mehdi Mollapour and Mark R. Woodford

Biomolecules 2022, 12(6), 786; https://doi.org/10.3390/biom12060786 - 4 Jun 2022

Cited by 18 | Viewed by 4143

Abstract

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in [...] Read more.

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or ‘clients’. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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11 pages, 303 KiB

Open AccessEditor’s ChoiceReview

Classical and Unexpected Effects of Ultra-Micronized PEA in Neuromuscular Function

by Pierangelo Cifelli, Gabriele Ruffolo, Marco Ceccanti, Chiara Cambieri, Laura Libonati, Eleonora Palma and Maurizio Inghilleri

Biomolecules 2022, 12(6), 758; https://doi.org/10.3390/biom12060758 - 29 May 2022

Cited by 1 | Viewed by 2340

Abstract

Recently, the endocannabinoid system has attracted growing attention from the scientific community for its involvement in homeostatic and pathological processes as they pertains to human physiology. Among the constituents of the endocannabinoid system, the molecule palmitoyl ethanolamide has particularly been studied for its [...] Read more.

Recently, the endocannabinoid system has attracted growing attention from the scientific community for its involvement in homeostatic and pathological processes as they pertains to human physiology. Among the constituents of the endocannabinoid system, the molecule palmitoyl ethanolamide has particularly been studied for its ability to reduce several inflammatory processes involving the central nervous system. Here, we reviewed published literature and summarized the main targets of the palmitoyl ethanolamide, along with its unique possible mechanisms for restoring correct functioning of the central nervous system. Moreover, we have highlighted a less-known characteristic of palmitoyl ethanolamide, namely its ability to modulate the function of the neuromuscular junction by binding to acetylcholine receptors in different experimental conditions. Indeed, there are several studies that have highlighted how ultra-micronized palmitoyl ethanolamide is an interesting nutraceutical support for the treatment of pathological neuromuscular conditions, specifically when the normal activity of the acetylcholine receptor is altered. Although further multicentric clinical trials are needed to confirm the efficacy of ultra-micronized palmitoyl ethanolamide in improving symptoms of neuromuscular diseases, all the literature reviewed here strongly supports the ability of this endocannabinoid-like molecule to modulate the acetylcholine receptors thus resulting as a valid support for the treatment of human neuromuscular diseases. Full article

(This article belongs to the Special Issue To Go Where Nature Leads: Focus on Palmitoylethanolamide and Related ALIAmides As Innovative Approach to Neuroinflammatory and Pain-Related Disease States in Honor of Doctor Francesco Della Valle)

11 pages, 1733 KiB

Open AccessEditor’s ChoiceReview

Neuromuscular Active Zone Structure and Function in Healthy and Lambert-Eaton Myasthenic Syndrome States

by Scott P. Ginebaugh, Yomna Badawi, Tyler B. Tarr and Stephen D. Meriney

Biomolecules 2022, 12(6), 740; https://doi.org/10.3390/biom12060740 - 24 May 2022

Cited by 3 | Viewed by 2745

Abstract

The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within [...] Read more.

The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within AZs, the relationships between the voltage-gated calcium channels and docked synaptic vesicles govern the probability of acetylcholine release during single action potentials, and the short-term plasticity characteristics during short, high frequency trains of action potentials. Understanding these relationships is important not only for healthy synapses, but also to better understand the pathophysiology of neuromuscular diseases. In particular, we are interested in Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder in which neurotransmitter release from the NMJ decreases, leading to severe muscle weakness. In LEMS, the reduced neurotransmission is traditionally thought to be caused by the antibody-mediated removal of presynaptic voltage-gated calcium channels. However, recent experimental data and AZ computer simulations have predicted that a disruption in the normally highly organized active zone structure, and perhaps autoantibodies to other presynaptic proteins, contribute significantly to pathological effects in the active zone and the characteristics of chemical transmitters. Full article

(This article belongs to the Special Issue The Neuromuscular Junction in Health and Disease)

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20 pages, 1082 KiB

Open AccessEditor’s ChoiceReview

Innate Immunity: A Balance between Disease and Adaption to Stress

by Irene Faenza and William L. Blalock

Biomolecules 2022, 12(5), 737; https://doi.org/10.3390/biom12050737 - 23 May 2022

Cited by 8 | Viewed by 4088

Abstract

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation [...] Read more.

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving adaptation. Full article

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

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20 pages, 2502 KiB

Open AccessFeature PaperEditor’s ChoiceReview

PPARα Signaling: A Candidate Target in Psychiatric Disorder Management

by Simona Scheggi, Graziano Pinna, Giulia Braccagni, Maria Graziella De Montis and Carla Gambarana

Biomolecules 2022, 12(5), 723; https://doi.org/10.3390/biom12050723 - 20 May 2022

Cited by 8 | Viewed by 3983

Abstract

Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in [...] Read more.

Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD. Full article

(This article belongs to the Special Issue Role of PPARs in Neurological and Psychiatric Disorders)

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22 pages, 3607 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Evidence of Failed Resolution Mechanisms in Arrhythmogenic Inflammation, Fibrosis and Right Heart Disease

by Rim Younes, Charles-Alexandre LeBlanc and Roddy Hiram

Biomolecules 2022, 12(5), 720; https://doi.org/10.3390/biom12050720 - 19 May 2022

Cited by 5 | Viewed by 5086

Abstract

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can [...] Read more.

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can lead to chronic inflammatory disorders due to aggravation of structural damages, development of a fibrous area, and loss of function. Various human conditions show a typical unresolved inflammatory profile. Inflammatory diseases include cancer, neurodegenerative disease, asthma, right heart disease, atherosclerosis, myocardial infarction, or atrial fibrillation. New evidence has started to emerge on the role, including pro-resolution involvement of chemical mediators in the acute phase of inflammation. Although flourishing knowledge is available about the role of specialized pro-resolving mediators in neurodegenerative diseases, atherosclerosis, obesity, or hepatic fibrosis, little is known about their efficacy to combat inflammation-associated arrhythmogenic cardiac disorders. It has been shown that resolvins, including RvD1, RvE1, or Mar1, are bioactive mediators of resolution. Resolvins can stop neutrophil activation and infiltration, stimulate monocytes polarization into anti-inflammatory-M2-macrophages, and activate macrophage phagocytosis of inflammation-debris and neutrophils to promote efferocytosis and clearance. This review aims to discuss the paradigm of failed-resolution mechanisms (FRM) potentially promoting arrhythmogenicity in right heart disease-induced inflammatory status. 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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38 pages, 1515 KiB

Open AccessEditor’s ChoiceReview

Cerebral Iron Deposition in Neurodegeneration

by Petr Dusek, Tim Hofer, Jan Alexander, Per M. Roos and Jan O. Aaseth

Biomolecules 2022, 12(5), 714; https://doi.org/10.3390/biom12050714 - 17 May 2022

Cited by 49 | Viewed by 18226

Abstract

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance [...] Read more.

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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19 pages, 814 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy

by Melania Lo Iacono, Chiara Modica, Gaetana Porcelli, Ornella Roberta Brancato, Giampaolo Muratore, Paola Bianca, Miriam Gaggianesi, Alice Turdo, Veronica Veschi, Matilde Todaro, Simone Di Franco and Giorgio Stassi

Biomolecules 2022, 12(5), 702; https://doi.org/10.3390/biom12050702 - 14 May 2022

Cited by 6 | Viewed by 3122

Abstract

The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells [...] Read more.

The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells (CSCs), drive cancer progression by releasing metabolites and inflammatory adipokines. In this review, we highlight the mechanisms underlying the bidirectional crosstalk among CAAs, CSCs, and stromal cells. Moreover, we focus on the recent advances in the therapeutic targeting of adipocyte-released factors as an innovative strategy to counteract cancer progression. Full article

(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)

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26 pages, 872 KiB

Open AccessEditor’s ChoiceReview

Kinases on Double Duty: A Review of UniProtKB Annotated Bifunctionality within the Kinome

by Aziz M. Rangwala, Victoria R. Mingione, George Georghiou and Markus A. Seeliger

Biomolecules 2022, 12(5), 685; https://doi.org/10.3390/biom12050685 - 11 May 2022

Cited by 2 | Viewed by 2907

Abstract

Phosphorylation facilitates the regulation of all fundamental biological processes, which has triggered extensive research of protein kinases and their roles in human health and disease. In addition to their phosphotransferase activity, certain kinases have evolved to adopt additional catalytic functions, while others have [...] Read more.

Phosphorylation facilitates the regulation of all fundamental biological processes, which has triggered extensive research of protein kinases and their roles in human health and disease. In addition to their phosphotransferase activity, certain kinases have evolved to adopt additional catalytic functions, while others have completely lost all catalytic activity. We searched the Universal Protein Resource Knowledgebase (UniProtKB) database for bifunctional protein kinases and focused on kinases that are critical for bacterial and human cellular homeostasis. These kinases engage in diverse functional roles, ranging from environmental sensing and metabolic regulation to immune-host defense and cell cycle control. Herein, we describe their dual catalytic activities and how they contribute to disease pathogenesis. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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26 pages, 1472 KiB

Open AccessEditor’s ChoiceReview

Biomarker Characterization and Prediction of Virulence and Antibiotic Resistance from Helicobacter pylori Next Generation Sequencing Data

by Joana S. Vital, Luís Tanoeiro, Ricardo Lopes-Oliveira and Filipa F. Vale

Biomolecules 2022, 12(5), 691; https://doi.org/10.3390/biom12050691 - 11 May 2022

Cited by 18 | Viewed by 4158

Abstract

The Gram-negative bacterium Helicobacter pylori colonizes c.a. 50% of human stomachs worldwide and is the major risk factor for gastric adenocarcinoma. Its high genetic variability makes it difficult to identify biomarkers of early stages of infection that can reliably predict its outcome. Moreover, [...] Read more.

The Gram-negative bacterium Helicobacter pylori colonizes c.a. 50% of human stomachs worldwide and is the major risk factor for gastric adenocarcinoma. Its high genetic variability makes it difficult to identify biomarkers of early stages of infection that can reliably predict its outcome. Moreover, the increasing antibiotic resistance found in H. pylori defies therapy, constituting a major human health problem. Here, we review H. pylori virulence factors and genes involved in antibiotic resistance, as well as the technologies currently used for their detection. Furthermore, we show that next generation sequencing may lead to faster characterization of virulence factors and prediction of the antibiotic resistance profile, thus contributing to personalized treatment and management of H. pylori-associated infections. With this new approach, more and permanent data will be generated at a lower cost, opening the future to new applications for H. pylori biomarker identification and antibiotic resistance prediction. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomolecules—Advances in Biomarkers, Therapeutics and Prevention)

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14 pages, 1230 KiB

Open AccessEditor’s ChoiceReview

Role of TFEB in Autophagy and the Pathogenesis of Liver Diseases

by Shengmin Yan

Biomolecules 2022, 12(5), 672; https://doi.org/10.3390/biom12050672 - 6 May 2022

Cited by 17 | Viewed by 4291

Abstract

The transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. Mechanistic target of rapamycin (mTOR)-mediated phosphorylation on TFEB is known to regulate TFEB subcellular localization and activity at the lysosomal surface. Recent studies have shown that TFEB also plays [...] Read more.

The transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. Mechanistic target of rapamycin (mTOR)-mediated phosphorylation on TFEB is known to regulate TFEB subcellular localization and activity at the lysosomal surface. Recent studies have shown that TFEB also plays a critical role in physiological processes such as lipid metabolism, and dysfunction of TFEB has been observed in the pathogenesis of several diseases. Owing to its ability to improve disease status in murine models, TFEB has attracted attention as a therapeutic target for diseases. In this review, we will present the regulation of TFEB and its role in the pathogenesis of liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). Full article

(This article belongs to the Special Issue Lipid and Glucose Metabolism in Liver Diseases)

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20 pages, 1290 KiB

Open AccessEditor’s ChoiceReview

Loricrin at the Boundary between Inside and Outside

by Yosuke Ishitsuka and Dennis R. Roop

Biomolecules 2022, 12(5), 673; https://doi.org/10.3390/biom12050673 - 6 May 2022

Cited by 4 | Viewed by 3959

Abstract

Cornification is a specialized mode of the cell-death program exclusively allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name (“lorica” meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes [...] Read more.

Cornification is a specialized mode of the cell-death program exclusively allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name (“lorica” meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes the maturation of the epidermal structure through organizing covalent cross-linkages, endowing the epidermis with the protection against oxidative injuries. By reviewing cornification mechanisms, we seek to classify ichthyosiform dermatoses based on their function, rather than clinical manifestations. We also reviewed recent mechanistic insights into the Kelch-like erythroid cell-derived protein with the cap “n” collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in skin health and diseases, as LOR and NRF2 coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of cross-talking between keratinocytes and epidermal resident leukocytes, dissecting an LOR immunomodulatory function. Full article

(This article belongs to the Special Issue Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II)

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17 pages, 604 KiB

Open AccessEditor’s ChoiceReview

Effects of Palmitoylethanolamide on Neurodegenerative Diseases: A Review from Rodents to Humans

by Eugenia Landolfo, Debora Cutuli, Laura Petrosini and Carlo Caltagirone

Biomolecules 2022, 12(5), 667; https://doi.org/10.3390/biom12050667 - 5 May 2022

Cited by 12 | Viewed by 5370

Abstract

Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different [...] Read more.

Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different types of neuropathic pain, such as fibromyalgia, osteoarthritis, carpal tunnel syndrome, and many other conditions. The properties of PEA, especially of its micronized or ultra-micronized forms maximizing bioavailability and efficacy, have sparked a series of innovative research to evaluate its possible application as therapeutic agent for neurodegenerative diseases. Neurodegenerative diseases are widespread throughout the world, and although they are numerous and different, they share common patterns of conditions that result from progressive damage to the brain areas involved in mobility, muscle coordination and strength, mood, and cognition. The present review is aimed at illustrating in vitro and in vivo research, as well as human studies, using PEA treatment, alone or in combination with other compounds, in the presence of neurodegeneration. Namely, attention has been paid to the effects of PEA in counteracting neuroinflammatory conditions and in slowing down the progression of diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. Literature research demonstrated the efficacy of PEA in addressing the damage typical of major neurodegenerative diseases. Full article

(This article belongs to the Special Issue To Go Where Nature Leads: Focus on Palmitoylethanolamide and Related ALIAmides As Innovative Approach to Neuroinflammatory and Pain-Related Disease States in Honor of Doctor Francesco Della Valle)

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8 pages, 597 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Lyso-IP: Uncovering Pathogenic Mechanisms of Lysosomal Dysfunction

by Chase Chen, Ellen Sidransky and Yu Chen

Biomolecules 2022, 12(5), 616; https://doi.org/10.3390/biom12050616 - 21 Apr 2022

Cited by 7 | Viewed by 5855

Abstract

Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage [...] Read more.

Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage diseases but also in a host of others, including common neurodegenerative disorders, such as Alzheimer disease and Parkinson disease. New technological advances have significantly increased our ability to rapidly isolate lysosomes from cells in recent years. The development of the Lyso-IP approach and similar methods now allow for lysosomal purification within ten minutes. Multiple studies using the Lyso-IP approach have revealed novel insights into the pathogenic mechanisms of lysosomal disorders, including Niemann-Pick type C disease, showing the immense potential for this technique. Future applications of rapid lysosomal isolation techniques are likely to greatly enhance our understanding of lysosomal dysfunction in rare and common neurodegeneration causes. Full article

(This article belongs to the Special Issue Upscaling the Basic Knowledge of Lysosomal Storage Disorders: Novel Insights into the Pathogenic Mechanisms and Emerging Therapeutic Approaches)

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11 pages, 667 KiB

Open AccessEditor’s ChoiceReview

Making Invisible RNA Visible: Discriminative Sequencing Methods for RNA Molecules with Specific Terminal Formations

by Megumi Shigematsu and Yohei Kirino

Biomolecules 2022, 12(5), 611; https://doi.org/10.3390/biom12050611 - 20 Apr 2022

Cited by 5 | Viewed by 2479

Abstract

Next generation sequencing of RNA molecules (RNA-seq) has become a common tool to characterize the expression profiles of RNAs and their regulations in normal physiological processes and diseases. Although increasingly accumulating RNA-seq data are widely available through publicly accessible sites, most of the [...] Read more.

Next generation sequencing of RNA molecules (RNA-seq) has become a common tool to characterize the expression profiles of RNAs and their regulations in normal physiological processes and diseases. Although increasingly accumulating RNA-seq data are widely available through publicly accessible sites, most of the data for short non-coding RNAs (sncRNAs) have been obtained for microRNA (miRNA) analyses by standard RNA-seq, which only capture the sncRNAs with 5′-phosphate (5′-P) and 3′-hydroxyl (3′-OH) ends. The sncRNAs with other terminal formations such as those with a 5′-hydroxyl end (5′-OH), a 3′-phosphate (3′-P) end, or a 2′,3′-cyclic phosphate end (2′,3′-cP) cannot be efficiently amplified and sequenced by standard RNA-seq. Due to the invisibility in standard RNA-seq data, these non-miRNA-sncRNAs have been a hidden component in the transcriptome. However, as the functional significances of these sncRNAs have become increasingly apparent, specific RNA-seq methods compatible with various terminal formations of sncRNAs have been developed and started shedding light on the previously unrecognized sncRNAs that lack 5′-P/3′-OH ends. In this review, we summarize the expanding world of sncRNAs with various terminal formations and the strategic approaches of specific RNA-seq methods to distinctively characterize their expression profiles. Full article

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

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23 pages, 5768 KiB

Open AccessEditor’s ChoiceReview

Advances towards Understanding the Mechanism of Action of the Hsp90 Complex

by Chrisostomos Prodromou and Dennis M. Bjorklund

Biomolecules 2022, 12(5), 600; https://doi.org/10.3390/biom12050600 - 19 Apr 2022

Cited by 23 | Viewed by 4017

Abstract

Hsp90 (Heat Shock Protein 90) is an ATP (Adenosine triphosphate) molecular chaperone responsible for the activation and maturation of client proteins. The mechanism by which Hsp90 achieves such activation, involving structurally diverse client proteins, has remained enigmatic. However, recent advances using structural techniques, [...] Read more.

Hsp90 (Heat Shock Protein 90) is an ATP (Adenosine triphosphate) molecular chaperone responsible for the activation and maturation of client proteins. The mechanism by which Hsp90 achieves such activation, involving structurally diverse client proteins, has remained enigmatic. However, recent advances using structural techniques, together with advances in biochemical studies, have not only defined the chaperone cycle but have shed light on its mechanism of action. Hsp90 hydrolysis of ATP by each protomer may not be simultaneous and may be dependent on the specific client protein and co-chaperone complex involved. Surprisingly, Hsp90 appears to remodel client proteins, acting as a means by which the structure of the client protein is modified to allow its subsequent refolding to an active state, in the case of kinases, or by making the client protein competent for hormone binding, as in the case of the GR (glucocorticoid receptor). This review looks at selected examples of client proteins, such as CDK4 (cyclin-dependent kinase 4) and GR, which are activated according to the so-called ‘remodelling hypothesis’ for their activation. A detailed description of these activation mechanisms is paramount to understanding how Hsp90-associated diseases develop. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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14 pages, 1564 KiB

Open AccessEditor’s ChoiceReview

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

by Yoichiro Abe and Masato Yasui

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

Cited by 16 | Viewed by 4048

Abstract

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

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

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

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19 pages, 940 KiB

Open AccessEditor’s ChoiceReview

Potential Effects of Natural H₂S-Donors in Hypertension Management

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

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

Cited by 17 | Viewed by 3327

Abstract

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

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

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

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15 pages, 4081 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 6 | Viewed by 3901

Abstract

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

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

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

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21 pages, 2081 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Frédéric Checler and Cristine Alves da Costa

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

Cited by 4 | Viewed by 3259

Abstract

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

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

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

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18 pages, 4471 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 14 | Viewed by 3012

Abstract

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

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

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

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14 pages, 3464 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Velia Garcia, Yasiru Randika Perera and Walter Jacob Chazin

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

Cited by 11 | Viewed by 4910

Abstract

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

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

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

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11 pages, 1158 KiB

Open AccessEditor’s ChoiceReview

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

by Hadar Peeri and Hinanit Koltai

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

Cited by 16 | Viewed by 7302

Abstract

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

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

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

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27 pages, 3494 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

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

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

Cited by 10 | Viewed by 10439

Abstract

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

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

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

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30 pages, 2036 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 13 | Viewed by 4018

Abstract

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

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

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

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25 pages, 7004 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 76 | Viewed by 15050

Abstract

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

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

β

-d-glucose to d-glucono-

δ

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

δ

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

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

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24 pages, 2520 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 18 | Viewed by 5692

Abstract

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

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

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

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13 pages, 287 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 4 | Viewed by 3515

Abstract

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

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

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

25 pages, 3696 KiB

Open AccessEditor’s ChoiceReview

Endogenous Human Proteins Interfering with Amyloid Formation

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

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

Cited by 7 | Viewed by 3471

Abstract

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

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

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23 pages, 1190 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 9 | Viewed by 3693

Abstract

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

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

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

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26 pages, 4898 KiB

Open AccessEditor’s ChoiceReview

The Mechanisms of Restenosis and Relevance to Next Generation Stent Design

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

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

Cited by 27 | Viewed by 5065

Abstract

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

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

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

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29 pages, 1310 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Nuclear-Mitochondrial Interactions

by Brittni R. Walker and Carlos T. Moraes

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

Cited by 34 | Viewed by 6012

Abstract

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

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

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

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21 pages, 2987 KiB

Open AccessEditor’s ChoiceReview

Roles of Cullin-RING Ubiquitin Ligases in Cardiovascular Diseases

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

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

Cited by 10 | Viewed by 4560

Abstract

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

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

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

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13 pages, 1597 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Nanticha Lutt and Jacob O. Brunkard

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

Cited by 11 | Viewed by 3563

Abstract

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

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

(This article belongs to the Collection TOR Signaling Pathway)

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17 pages, 1199 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 11 | Viewed by 4261

Abstract

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

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

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

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19 pages, 3457 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

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

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

Cited by 3 | Viewed by 3300

Abstract

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

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

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

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