Biomolecules

Review

22 pages, 4261 KiB

Open AccessEditor’s ChoiceReview

The Bigger Picture: Why Oral Mucosa Heals Better Than Skin

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

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

Cited by 57 | Viewed by 12354

Abstract

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

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

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

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15 pages, 1532 KiB

Open AccessEditor’s ChoiceReview

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

by Aikaterini Skandalaki, Panagiotis Sarantis and Stamatios Theocharis

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

Cited by 16 | Viewed by 3495

Abstract

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

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

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

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11 pages, 974 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Ocular Gene Delivery Landscape

by Bhubanananda Sahu, Isha Chug and Hemant Khanna

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

Cited by 12 | Viewed by 5304

Abstract

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

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

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

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23 pages, 3202 KiB

Open AccessEditor’s ChoiceReview

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

by Eduardo Ruiz-López and Alberto J. Schuhmacher

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

Cited by 37 | Viewed by 10253

Abstract

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

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

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

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36 pages, 3020 KiB

Open AccessEditor’s ChoiceReview

Understanding and Exploiting Post-Translational Modifications for Plant Disease Resistance

by Catherine Gough and Ari Sadanandom

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

Cited by 12 | Viewed by 5400

Abstract

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

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

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

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17 pages, 2188 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 10 | Viewed by 3866

Abstract

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

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

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

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Graphical abstract

18 pages, 496 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 20 | Viewed by 6739

Abstract

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

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

(This article belongs to the Section Molecular Genetics)

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21 pages, 3477 KiB

Open AccessEditor’s ChoiceReview

Oxidative Power: Tools for Assessing LPMO Activity on Cellulose

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

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

Cited by 13 | Viewed by 5162

Abstract

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

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

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

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29 pages, 1626 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Joanna M Wierońska, Paulina Cieślik and Leszek Kalinowski

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

Cited by 45 | Viewed by 5408

Abstract

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

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

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

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27 pages, 832 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 74 | Viewed by 13415

Abstract

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

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

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

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14 pages, 1240 KiB

Open AccessEditor’s ChoiceReview

Epigenetic Alterations in Pancreatic Cancer Metastasis

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

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

Cited by 28 | Viewed by 5444

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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15 pages, 339 KiB

Open AccessEditor’s ChoiceReview

Neutrophil Elastase and Chronic Lung Disease

by Judith A. Voynow and Meagan Shinbashi

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

Cited by 79 | Viewed by 12098

Abstract

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

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

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

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20 pages, 1102 KiB

Open AccessEditor’s ChoiceReview

Oligodendrocytes and Microglia: Key Players in Myelin Development, Damage and Repair

by Ilias Kalafatakis and Domna Karagogeos

Biomolecules 2021, 11(7), 1058; https://doi.org/10.3390/biom11071058 - 20 Jul 2021

Cited by 41 | Viewed by 9709

Abstract

Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by other glial cell types such as microglia, the brain-resident, macrophage-like innate immune cells. In this review, we summarize how oligodendrocytes orchestrate myelination, [...] Read more.

Oligodendrocytes, the myelin-making cells of the CNS, regulate the complex process of myelination under physiological and pathological conditions, significantly aided by other glial cell types such as microglia, the brain-resident, macrophage-like innate immune cells. In this review, we summarize how oligodendrocytes orchestrate myelination, and especially myelin repair after damage, and present novel aspects of oligodendroglial functions. We emphasize the contribution of microglia in the generation and regeneration of myelin by discussing their beneficial and detrimental roles, especially in remyelination, underlining the cellular and molecular components involved. Finally, we present recent findings towards human stem cell-derived preclinical models for the study of microglia in human pathologies and on the role of microbiome on glial cell functions. Full article

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

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18 pages, 594 KiB

Open AccessEditor’s ChoiceReview

Prion-Like Proteins in Phase Separation and Their Link to Disease

by Macy L. Sprunger and Meredith E. Jackrel

Biomolecules 2021, 11(7), 1014; https://doi.org/10.3390/biom11071014 - 11 Jul 2021

Cited by 21 | Viewed by 9086

Abstract

Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid [...] Read more.

Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid phase separation. Liquid-liquid phase separation is thought to be an important physiological process, but one that is prone to malfunction. Thus, aberrant liquid-to-solid phase transitions may drive protein aggregation and fibrillization, which could give rise to pathological inclusions. Here, we review prions and prion-like proteins, their roles in phase separation and disease, as well as potential therapeutic approaches to counter aberrant phase transitions. Full article

(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)

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16 pages, 3623 KiB

Open AccessEditor’s ChoiceReview

Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives

by Suresh Thangudu and Chia-Hao Su

Biomolecules 2021, 11(7), 1015; https://doi.org/10.3390/biom11071015 - 11 Jul 2021

Cited by 36 | Viewed by 7624

Abstract

Nanomaterial-mediated cancer therapeutics is a fast developing field and has been utilized in potential clinical applications. However, most effective therapies, such as photodynamic therapy (PDT) and radio therapy (RT), are strongly oxygen-dependent, which hinders their practical applications. Later on, several strategies were developed [...] Read more.

Nanomaterial-mediated cancer therapeutics is a fast developing field and has been utilized in potential clinical applications. However, most effective therapies, such as photodynamic therapy (PDT) and radio therapy (RT), are strongly oxygen-dependent, which hinders their practical applications. Later on, several strategies were developed to overcome tumor hypoxia, such as oxygen carrier nanomaterials and oxygen generated nanomaterials. Among these, oxygen species generation on nanozymes, especially catalase (CAT) mimetic nanozymes, convert endogenous hydrogen peroxide (H₂O₂) to oxygen (O₂) and peroxidase (POD) mimetic nanozymes converts endogenous H₂O₂ to water (H₂O) and reactive oxygen species (ROS) in a hypoxic tumor microenvironment is a fascinating approach. The present review provides a detailed examination of past, present and future perspectives of POD mimetic nanozymes for effective oxygen-dependent cancer phototherapeutics. Full article

(This article belongs to the Special Issue Applications of Nanomaterials: Theranostic Imaging in Health and Disease)

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38 pages, 4838 KiB

Open AccessEditor’s ChoiceReview

Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration

by Juan A. Godoy, Juvenal A. Rios, Pol Picón-Pagès, Víctor Herrera-Fernández, Bronte Swaby, Giulia Crepin, Rubén Vicente, Jose M. Fernández-Fernández and Francisco J. Muñoz

Biomolecules 2021, 11(7), 1012; https://doi.org/10.3390/biom11071012 - 10 Jul 2021

Cited by 39 | Viewed by 5731

Abstract

Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission [...] Read more.

Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca²⁺ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca²⁺ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca²⁺ overload results in an increase in mitochondrial Ca²⁺, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases. Full article

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

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18 pages, 987 KiB

Open AccessEditor’s ChoiceReview

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

by Kenneth Maiese

Biomolecules 2021, 11(7), 1002; https://doi.org/10.3390/biom11071002 - 9 Jul 2021

Cited by 32 | Viewed by 5191

Abstract

Neurodegenerative disorders affect fifteen percent of the world’s population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer’s disease, and [...] Read more.

Neurodegenerative disorders affect fifteen percent of the world’s population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer’s disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments. Full article

(This article belongs to the Special Issue Therapeutic Aspects of Circadian Rhythms)

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26 pages, 872 KiB

Open AccessEditor’s ChoiceReview

Probiotics, Prebiotics and Postbiotics on Mitigation of Depression Symptoms: Modulation of the Brain–Gut–Microbiome Axis

by Agata Chudzik, Anna Orzyłowska, Radosław Rola and Greg J. Stanisz

Biomolecules 2021, 11(7), 1000; https://doi.org/10.3390/biom11071000 - 7 Jul 2021

Cited by 76 | Viewed by 14292

Abstract

The brain–gut–microbiome axis is a bidirectional communication pathway between the gut microbiota and the central nervous system. The growing interest in the gut microbiota and mechanisms of its interaction with the brain has contributed to the considerable attention given to the potential use [...] Read more.

The brain–gut–microbiome axis is a bidirectional communication pathway between the gut microbiota and the central nervous system. The growing interest in the gut microbiota and mechanisms of its interaction with the brain has contributed to the considerable attention given to the potential use of probiotics, prebiotics and postbiotics in the prevention and treatment of depressive disorders. This review discusses the up-to-date findings in preclinical and clinical trials regarding the use of pro-, pre- and postbiotics in depressive disorders. Studies in rodent models of depression show that some of them inhibit inflammation, decrease corticosterone level and change the level of neurometabolites, which consequently lead to mitigation of the symptoms of depression. Moreover, certain clinical studies have indicated improvement in mood as well as changes in biochemical parameters in patients suffering from depressive disorders. Full article

(This article belongs to the Special Issue Prebiotics and Probiotics in Health and Disease)

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30 pages, 1250 KiB

Open AccessEditor’s ChoiceReview

COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

by Renuka Raman, Krishna J. Patel and Kishu Ranjan

Biomolecules 2021, 11(7), 993; https://doi.org/10.3390/biom11070993 - 6 Jul 2021

Cited by 137 | Viewed by 15518

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 1049 KiB

Open AccessEditor’s ChoiceReview

Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

by Natasha Ting Lee, Lin Kooi Ong, Prajwal Gyawali, Che Mohd Nasril Che Mohd Nassir, Muzaimi Mustapha, Harshal H. Nandurkar and Maithili Sashindranath

Biomolecules 2021, 11(7), 994; https://doi.org/10.3390/biom11070994 - 6 Jul 2021

Cited by 27 | Viewed by 4745

Abstract

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune [...] Read more.

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain. Full article

(This article belongs to the Special Issue Novel Biomolecules in Neuro-ThromboInflammation)

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17 pages, 2690 KiB

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TFEB Signalling-Related MicroRNAs and Autophagy

by Davide Corà, Federico Bussolino and Gabriella Doronzo

Biomolecules 2021, 11(7), 985; https://doi.org/10.3390/biom11070985 - 4 Jul 2021

Cited by 16 | Viewed by 4259

Abstract

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to [...] Read more.

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions. Full article

(This article belongs to the Special Issue Complexities in microRNA Function: Nuclear Roles, Sequence Variants and Non-canonical Gene Targeting)

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21 pages, 1685 KiB

Open AccessEditor’s ChoiceReview

Endothelial Dysfunction Driven by Hypoxia—The Influence of Oxygen Deficiency on NO Bioavailability

by Anna Janaszak-Jasiecka, Anna Siekierzycka, Agata Płoska, Iwona T. Dobrucki and Leszek Kalinowski

Biomolecules 2021, 11(7), 982; https://doi.org/10.3390/biom11070982 - 3 Jul 2021

Cited by 54 | Viewed by 5536

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The initial stage of CVDs is characterized by endothelial dysfunction, defined as the limited bioavailability of nitric oxide (NO). Thus, any factors that interfere with the synthesis or metabolism of NO in endothelial [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The initial stage of CVDs is characterized by endothelial dysfunction, defined as the limited bioavailability of nitric oxide (NO). Thus, any factors that interfere with the synthesis or metabolism of NO in endothelial cells are involved in CVD pathogenesis. It is well established that hypoxia is both the triggering factor as well as the accompanying factor in cardiovascular disease, and diminished tissue oxygen levels have been reported to influence endothelial NO bioavailability. In endothelial cells, NO is produced by endothelial nitric oxide synthase (eNOS) from L-Arg, with tetrahydrobiopterin (BH₄) as an essential cofactor. Here, we discuss the mechanisms by which hypoxia affects NO bioavailability, including regulation of eNOS expression and activity. What is particularly important is the fact that hypoxia contributes to the depletion of cofactor BH₄ and deficiency of substrate L-Arg, and thus elicits eNOS uncoupling—a state in which the enzyme produces superoxide instead of NO. eNOS uncoupling and the resulting oxidative stress is the major driver of endothelial dysfunction and atherogenesis. Moreover, hypoxia induces impairment in mitochondrial respiration and endothelial cell activation; thus, oxidative stress and inflammation, along with the hypoxic response, contribute to the development of endothelial dysfunction. Full article

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

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26 pages, 2545 KiB

Open AccessEditor’s ChoiceReview

On the Role of Paraoxonase-1 and Chemokine Ligand 2 (C-C motif) in Metabolic Alterations Linked to Inflammation and Disease. A 2021 Update

by Jordi Camps, Helena Castañé, Elisabet Rodríguez-Tomàs, Gerard Baiges-Gaya, Anna Hernández-Aguilera, Meritxell Arenas, Simona Iftimie and Jorge Joven

Biomolecules 2021, 11(7), 971; https://doi.org/10.3390/biom11070971 - 1 Jul 2021

Cited by 20 | Viewed by 3899

Abstract

Infectious and many non-infectious diseases share common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors produce [...] Read more.

Infectious and many non-infectious diseases share common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins, and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, both produce metabolic alterations that influence the pathogenesis of the disease. In this review, we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, inducing migration and infiltration of immune cells in target tissues and disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets. Full article

(This article belongs to the Special Issue Chemokines in Infectious and Non-infectious Diseases)

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26 pages, 1376 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Transcriptomic and Epigenomic Landscape in Rett Syndrome

by Domenico Marano, Salvatore Fioriniello, Maurizio D’Esposito and Floriana Della Ragione

Biomolecules 2021, 11(7), 967; https://doi.org/10.3390/biom11070967 - 30 Jun 2021

Cited by 10 | Viewed by 4866

Abstract

Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein [...] Read more.

Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models. Full article

(This article belongs to the Collection DNA Methylation Dynamics in Health and Disease)

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22 pages, 2152 KiB

Open AccessEditor’s ChoiceReview

Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition

by Taylor C. Brown, Narendra V. Sankpal and William E. Gillanders

Biomolecules 2021, 11(7), 956; https://doi.org/10.3390/biom11070956 - 29 Jun 2021

Cited by 42 | Viewed by 5287

Abstract

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor [...] Read more.

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities. Full article

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

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15 pages, 1955 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing

by Marija Petkovic, Michelle Vang Mouritzen, Biljana Mojsoska and Håvard Jenssen

Biomolecules 2021, 11(7), 952; https://doi.org/10.3390/biom11070952 - 28 Jun 2021

Cited by 26 | Viewed by 6264

Abstract

Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of [...] Read more.

Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of peripheral sensory nervature, inadequate nutrients and blood tissue supply. The most significant hallmark of chronic wounds is heavily aberrant immune skin function. The immune response in humans relies on a large network of signalling molecules and their interactions. Research studies have reported on the dual role of host defence peptides (HDPs), which are also often called antimicrobial peptides (AMPs). Their duality reflects their potential for acting as antibacterial peptides, and as immunodulators that assist in modulating several biological signalling pathways related to processes such as wound healing, autoimmune disease, and others. HDPs may differentially control gene regulation and alter the behaviour of epithelial and immune cells, resulting in modulation of immune responses. In this review, we shed light on the understanding and most recent advances related to molecular mechanisms and immune modulatory features of host defence peptides in human skin wound healing. Understanding their functional role in skin immunity may further inspire topical treatments for chronic wounds. Full article

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

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23 pages, 1636 KiB

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Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

by Antía Custodia, Marta Aramburu-Núñez, Clara Correa-Paz, Adrián Posado-Fernández, Ana Gómez-Larrauri, José Castillo, Antonio Gómez-Muñoz, Tomás Sobrino and Alberto Ouro

Biomolecules 2021, 11(7), 945; https://doi.org/10.3390/biom11070945 - 25 Jun 2021

Cited by 32 | Viewed by 7662

Abstract

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or [...] Read more.

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease. Full article

(This article belongs to the Special Issue Involvement of Sphingolipids in the Pathogenesis of Parkinson's Disease and Parkinsonism)

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20 pages, 2344 KiB

Open AccessEditor’s ChoiceReview

α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

by Simon Oliver Hoppe, Gamze Uzunoğlu and Carmen Nussbaum-Krammer

Biomolecules 2021, 11(7), 931; https://doi.org/10.3390/biom11070931 - 23 Jun 2021

Cited by 17 | Viewed by 3865

Abstract

Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. [...] Read more.

Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. The prion strain hypothesis offers a possible explanation for this conundrum. According to this hypothesis, a single protein sequence is able to misfold into distinct amyloid structures that can cause different pathologies. In fact, a growing body of evidence suggests that conformationally distinct α-Syn assemblies might be the causative agents behind different synucleinopathies. In this review, we provide an overview of research on the strain hypothesis as it applies to synucleinopathies and discuss the potential implications for diagnostic and therapeutic purposes. Full article

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

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16 pages, 901 KiB

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Leptin, Both Bad and Good Actor in Cancer

by Carlos Jiménez-Cortegana, Ana López-Saavedra, Flora Sánchez-Jiménez, Antonio Pérez-Pérez, Jesús Castiñeiras, Juan A. Virizuela-Echaburu, Luis de la de la Cruz-Merino and Víctor Sánchez-Margalet

Biomolecules 2021, 11(6), 913; https://doi.org/10.3390/biom11060913 - 20 Jun 2021

Cited by 32 | Viewed by 5261

Abstract

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the [...] Read more.

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the “obesity paradox”, and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

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19 pages, 4558 KiB

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The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

by Sergey Shityakov, Kentaro Hayashi, Stefan Störk, Verena Scheper, Thomas Lenarz and Carola Y. Förster

Biomolecules 2021, 11(6), 900; https://doi.org/10.3390/biom11060900 - 17 Jun 2021

Cited by 13 | Viewed by 4562

Abstract

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of [...] Read more.

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease. Full article

(This article belongs to the Special Issue Metabolic and Neurotrophic Pathways Driving the Brain-Heart-Axis)

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25 pages, 2178 KiB

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Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

by Ramiz S. Ahmad, Timothy D. Eubank, Slawomir Lukomski and Brian A. Boone

Biomolecules 2021, 11(6), 901; https://doi.org/10.3390/biom11060901 - 17 Jun 2021

Cited by 21 | Viewed by 4879

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease. Full article

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

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11 pages, 574 KiB

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Hydrogen Sulfide (H₂S) and Polysulfide (H₂S_n) Signaling: The First 25 Years

by Hideo Kimura

Biomolecules 2021, 11(6), 896; https://doi.org/10.3390/biom11060896 - 16 Jun 2021

Cited by 80 | Viewed by 4923

Abstract

Since the first description of hydrogen sulfide (H₂S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H₂S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H₂S [...] Read more.

Since the first description of hydrogen sulfide (H₂S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H₂S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H₂S in the brain, suggesting that H₂S may have physiological roles. In 1996, we demonstrated that hydrogen sulfide (H₂S) is a potential signaling molecule, which can be produced by cystathionine β-synthase (CBS) to modify neurotransmission in the brain. Subsequently, we showed that H₂S relaxes vascular smooth muscle in synergy with nitric oxide (NO) and that cystathionine γ-lyase (CSE) is another producing enzyme. This study also opened up a new research area of a crosstalk between H₂S and NO. The cytoprotective effect, anti-inflammatory activity, energy formation, and oxygen sensing by H₂S have been subsequently demonstrated. Two additional pathways for the production of H₂S with 3-mercaptopyruvate sulfurtransferase (3MST) from l- and d-cysteine have been identified. We also discovered that hydrogen polysulfides (H₂S_n, n ≥ 2) are potential signaling molecules produced by 3MST. H₂S_n regulate the activity of ion channels and enzymes, as well as even the growth of tumors. S-Sulfuration (S-sulfhydration) proposed by Snyder is the main mechanism for H₂S/H₂S_n underlying regulation of the activity of target proteins. This mini review focuses on the key findings on H₂S/H₂S_n signaling during the first 25 years. 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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23 pages, 1795 KiB

Open AccessEditor’s ChoiceReview

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition

by Jingjing Sha, Yunpeng Bai, Huy Xuan Ngo, Tatsuo Okui and Takahiro Kanno

Biomolecules 2021, 11(6), 893; https://doi.org/10.3390/biom11060893 - 16 Jun 2021

Cited by 34 | Viewed by 4040

Abstract

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy [...] Read more.

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy drug resistance. EMT-activating transcription factors (EMT-ATFs), such as Snail, TWIST, and ZEB, can activate several different molecular pathways, e.g., PI3K/AKT, NF-κB, and TGF-β. In contrast, the activated oncological signal pathways provide reciprocal feedback that affects the expression of EMT-ATFs, resulting in a peritumoral extracellular environment conducive to cancer cell survival and evasion of the immune system, leading to resistance to multiple chemotherapeutic agents. We present an overview of evidence-based chemotherapy for OC treatment based on the National Comprehensive Cancer Network (NCCN) Chemotherapy Order Templates. We focus on the molecular pathways involved in drug resistance related to the EMT and highlight the signal pathways and transcription factors that may be important for EMT-regulated drug resistance. Rapid progress in antitumor regimens, together with the application of powerful techniques such as high-throughput screening and microRNA technology, will facilitate the development of therapeutic strategies to augment chemotherapy. Full article

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

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10 pages, 1277 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression

by Yves St-Pierre

Biomolecules 2021, 11(6), 879; https://doi.org/10.3390/biom11060879 - 14 Jun 2021

Cited by 11 | Viewed by 3567

Abstract

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial [...] Read more.

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial origin (carcinoma) are among the most frequent and deadly cancer subtypes. Initially described as a p53-induced gene and associated with apoptosis, galectin-7 is now recognized as having a protumorigenic role in many cancer types. Several studies have indeed shown that galectin-7 is associated with aggressive behavior of cancer cells and induces expression of MMP-9, a member of the matrix metalloproteinases (MMP) family known to confer invasive behavior to cancer cells. It is therefore not surprising that many studies have examined its relationships with p53 and MMP-9. However, the relationships between galectin-7 and p53 and MMP-9 are not always clear. This is largely because p53 is often mutated in cancer cells and such mutations drastically change its functions and, consequently, its association with galectin-7. In this review, we discuss the functional relationships between galectin-7, p53 and MMP-9 and reconcile some apparently contradictory observations. A better understanding of these relationships will help to develop a working hypothesis and model that will provide the basis for further research in the hope of establishing a new paradigm for tackling the role of galectin-7 in cancer. Full article

(This article belongs to the Special Issue Cell Biology of Galectins)

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15 pages, 21732 KiB

Open AccessEditor’s ChoiceReview

Welcome to the Family: Identification of the NAD⁺ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25

by Mathias Ziegler, Magnus Monné, Andrey Nikiforov, Gennaro Agrimi, Ines Heiland and Ferdinando Palmieri

Biomolecules 2021, 11(6), 880; https://doi.org/10.3390/biom11060880 - 14 Jun 2021

Cited by 19 | Viewed by 5542

Abstract

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective [...] Read more.

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD⁺ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD⁺ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD⁺ carrier in mammals, a long-standing mystery in NAD⁺ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

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24 pages, 1529 KiB

Open AccessEditor’s ChoiceReview

Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”

by Anna Trzyna and Agnieszka Banaś-Ząbczyk

Biomolecules 2021, 11(6), 878; https://doi.org/10.3390/biom11060878 - 13 Jun 2021

Cited by 93 | Viewed by 7495

Abstract

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides [...] Read more.

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides cytokines, proteins, and growth factors, the therapeutic effect of secretome is hidden in non-coding RNAs such as miR-21, miR-24, and miR-26 carried via exosomes secreted by adequate cells. The whole secretome, including ASC-derived exosomes (ASC-exos) has been proven in many studies to have immunomodulatory, proangiogenic, neurotrophic, and epithelization activity and can potentially be used for neurodegenerative, cardiovascular, respiratory, inflammatory, and autoimmune diseases as well as wound healing treatment. Due to limitations in the use of stem cells in cell-based therapy, its secretome with emphasis on exosomes seems to be a reasonable and safer alternative with increased effectiveness and fewer side effects. Moreover, the great advantage of cell-free therapy is the possibility of biobanking the ASCs secretome. In this review, we focus on the current state of knowledge on the use of the ASCs secretome in stem cell-free therapy. Full article

(This article belongs to the Special Issue Recent Advances in Translational Adipose-Derived Stem Cell Biology)

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23 pages, 3286 KiB

Open AccessEditor’s ChoiceReview

Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

by Sara Chiappalupi, Laura Salvadori, Rosario Donato, Francesca Riuzzi and Guglielmo Sorci

Biomolecules 2021, 11(6), 876; https://doi.org/10.3390/biom11060876 - 12 Jun 2021

Cited by 22 | Viewed by 4027

Abstract

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential [...] Read more.

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin–angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed. Full article

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

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25 pages, 12270 KiB

Open AccessEditor’s ChoiceReview

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

by Christopher L. Cioffi

Biomolecules 2021, 11(6), 864; https://doi.org/10.3390/biom11060864 - 10 Jun 2021

Cited by 9 | Viewed by 4194

Abstract

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal [...] Read more.

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na⁺/Cl⁻-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain. Full article

(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)

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47 pages, 14889 KiB

Open AccessEditor’s ChoiceReview

Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development

by Bodo C. Melnik, Wolfgang Stremmel, Ralf Weiskirchen, Swen Malte John and Gerd Schmitz

Biomolecules 2021, 11(6), 851; https://doi.org/10.3390/biom11060851 - 7 Jun 2021

Cited by 89 | Viewed by 9599

Abstract

Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing [...] Read more.

Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing infant, the majority of recent studies report on the MEV subfraction of milk exosomes (MEX) and their miRNA cargo, which are in the focus of this review. MEX and the dominant miRNA-148a play a key role in intestinal maturation, barrier function and suppression of nuclear factor-κB (NF-κB) signaling and may thus be helpful for the prevention and treatment of necrotizing enterocolitis. MEX and their miRNAs reach the systemic circulation and may impact epigenetic programming of various organs including the liver, thymus, brain, pancreatic islets, beige, brown and white adipose tissue as well as bones. Translational evidence indicates that MEX and their miRNAs control the expression of global cellular regulators such as DNA methyltransferase 1—which is important for the up-regulation of developmental genes including insulin, insulin-like growth factor-1, α-synuclein and forkhead box P3—and receptor-interacting protein 140, which is important for the regulation of multiple nuclear receptors. MEX-derived miRNA-148a and miRNA-30b may stimulate the expression of uncoupling protein 1, the key inducer of thermogenesis converting white into beige/brown adipose tissue. MEX have to be considered as signalosomes derived from the maternal lactation genome emitted to promote growth, maturation, immunological and metabolic programming of the offspring. Deeper insights into milk’s molecular biology allow the conclusion that infants are both “breast-fed” and “breast-programmed”. In this regard, MEX miRNA-deficient artificial formula is not an adequate substitute for breastfeeding, the birthright of all mammals. Full article

(This article belongs to the Special Issue Breast Milk-Derived Biomolecules in Human Health)

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13 pages, 3688 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Glycine Receptors in Spinal Nociceptive Control—An Update

by Hanns Ulrich Zeilhofer, Karolina Werynska, Jacinthe Gingras and Gonzalo E. Yévenes

Biomolecules 2021, 11(6), 846; https://doi.org/10.3390/biom11060846 - 6 Jun 2021

Cited by 21 | Viewed by 5026

Abstract

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid [...] Read more.

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid deleterious side effects such as sedation, addiction, or impaired motor control, which would arise from wide-range facilitation of inhibition. Specific targeting of glycinergic inhibition, which dominates in the spinal cord and parts of the hindbrain, may help reduce these side effects. Selective targeting of the α3 subtype of glycine receptors (GlyRs), which is highly enriched in the superficial layers of the spinal dorsal horn, a key site of nociceptive processing, may help to further narrow down pharmacological intervention on the nociceptive system and increase tolerability. This review provides an update on the physiological properties and functions of α3 subtype GlyRs and on the present state of related drug discovery programs. Full article

(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)

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23 pages, 3522 KiB

Open AccessEditor’s ChoiceReview

Folding and Stability of Ankyrin Repeats Control Biological Protein Function

by Amit Kumar and Jochen Balbach

Biomolecules 2021, 11(6), 840; https://doi.org/10.3390/biom11060840 - 5 Jun 2021

Cited by 21 | Viewed by 5835

Abstract

Ankyrin repeat proteins are found in all three kingdoms of life. Fundamentally, these proteins are involved in protein-protein interaction in order to activate or suppress biological processes. The basic architecture of these proteins comprises repeating modules forming elongated structures. Due to the lack [...] Read more.

Ankyrin repeat proteins are found in all three kingdoms of life. Fundamentally, these proteins are involved in protein-protein interaction in order to activate or suppress biological processes. The basic architecture of these proteins comprises repeating modules forming elongated structures. Due to the lack of long-range interactions, a graded stability among the repeats is the generic properties of this protein family determining both protein folding and biological function. Protein folding intermediates were frequently found to be key for the biological functions of repeat proteins. In this review, we discuss most recent findings addressing this close relation for ankyrin repeat proteins including DARPins, Notch receptor ankyrin repeat domain, IκBα inhibitor of NFκB, and CDK inhibitor p19^INK4d. The role of local folding and unfolding and gradual stability of individual repeats will be discussed during protein folding, protein-protein interactions, and post-translational modifications. The conformational changes of these repeats function as molecular switches for biological regulation, a versatile property for modern drug discovery. Full article

(This article belongs to the Special Issue Protein Folding Stability and Dynamics: Commemorative Issue in Honor of Professor Sir Christopher Dobson (1949–2019))

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17 pages, 360 KiB

Open AccessEditor’s ChoiceReview

MicroRNA as a Novel Biomarker in the Diagnosis of Head and Neck Cancer

by Jacek Kabzinski, Monika Maczynska and Ireneusz Majsterek

Biomolecules 2021, 11(6), 844; https://doi.org/10.3390/biom11060844 - 5 Jun 2021

Cited by 30 | Viewed by 4669

Abstract

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast [...] Read more.

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast and reliable biomarker that allows early diagnosis. This niche can be filled by microRNA, small single-stranded non-coding RNA molecules, which are expressed in response to specific events in the body. This article presents the potential use of microRNAs in the diagnosis of HNSCC, compares the advances in this field to other diseases, especially other cancers, and discusses the detailed use of miRNA as a biomarker in profiling and predicting the treatment outcome with radiotherapy and immunotherapy. Potential problems and difficulties related to the development of this promising technology, and areas on which future research should be focused in order to overcome these difficulties, were also indicated. Full article

(This article belongs to the Special Issue Genetics and Molecular Biology of Head and Neck Cancer)

18 pages, 693 KiB

Open AccessEditor’s ChoiceReview

Sustainable Agriculture Systems in Vegetable Production Using Chitin and Chitosan as Plant Biostimulants

by Mohamad Hesam Shahrajabian, Christina Chaski, Nikolaos Polyzos, Nikolaos Tzortzakis and Spyridon A. Petropoulos

Biomolecules 2021, 11(6), 819; https://doi.org/10.3390/biom11060819 - 31 May 2021

Cited by 103 | Viewed by 9768

Abstract

Chitin and chitosan are natural compounds that are biodegradable and nontoxic and have gained noticeable attention due to their effective contribution to increased yield and agro-environmental sustainability. Several effects have been reported for chitosan application in plants. Particularly, it can be used in [...] Read more.

Chitin and chitosan are natural compounds that are biodegradable and nontoxic and have gained noticeable attention due to their effective contribution to increased yield and agro-environmental sustainability. Several effects have been reported for chitosan application in plants. Particularly, it can be used in plant defense systems against biological and environmental stress conditions and as a plant growth promoter—it can increase stomatal conductance and reduce transpiration or be applied as a coating material in seeds. Moreover, it can be effective in promoting chitinolytic microorganisms and prolonging storage life through post-harvest treatments, or benefit nutrient delivery to plants since it may prevent leaching and improve slow release of nutrients in fertilizers. Finally, it can remediate polluted soils through the removal of cationic and anionic heavy metals and the improvement of soil properties. On the other hand, chitin also has many beneficial effects such as plant growth promotion, improved plant nutrition and ability to modulate and improve plants’ resistance to abiotic and biotic stressors. The present review presents a literature overview regarding the effects of chitin, chitosan and derivatives on horticultural crops, highlighting their important role in modern sustainable crop production; the main limitations as well as the future prospects of applications of this particular biostimulant category are also presented. Full article

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

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22 pages, 871 KiB

Open AccessEditor’s ChoiceReview

Effects of Anthocyanins on Vascular Health

by Ioana Mozos, Corina Flangea, Daliborca C. Vlad, Cristina Gug, Costin Mozos, Dana Stoian, Constantin T. Luca, Jarosław O. Horbańczuk, Olaf K. Horbańczuk and Atanas G. Atanasov

Biomolecules 2021, 11(6), 811; https://doi.org/10.3390/biom11060811 - 30 May 2021

Cited by 50 | Viewed by 6806

Abstract

Cardiovascular disorders are leading mortality causes worldwide, often with a latent evolution. Vascular health depends on endothelial function, arterial stiffness, and the presence of atherosclerotic plaques. Preventive medicine deserves special attention, focusing on modifiable cardiovascular risk factors, including diet. A diet rich in [...] Read more.

Cardiovascular disorders are leading mortality causes worldwide, often with a latent evolution. Vascular health depends on endothelial function, arterial stiffness, and the presence of atherosclerotic plaques. Preventive medicine deserves special attention, focusing on modifiable cardiovascular risk factors, including diet. A diet rich in fruits and vegetables has well-known health benefits, especially due to its polyphenolic components. Anthocyanins, water-soluble flavonoid species, responsible for the red-blue color in plants and commonly found in berries, exert favorable effects on the endothelial function, oxidative stress, inhibit COX-1, and COX-2 enzymes, exert antiatherogenic, antihypertensive, antiglycation, antithrombotic, and anti-inflammatory activity, ameliorate dyslipidemia and arterial stiffness. The present review aims to give a current overview of the mechanisms involved in the vascular protective effect of anthocyanins from the human diet, considering epidemiological data, in vitro and in vivo preclinical research, clinical observational, retrospective, intervention and randomized studies, dietary and biomarker studies, and discussing preventive benefits of anthocyanins and future research directions. Full article

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22 pages, 921 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease

by Emma C. Tovey Crutchfield, Sarah E. Garnish and Joanne M. Hildebrand

Biomolecules 2021, 11(6), 803; https://doi.org/10.3390/biom11060803 - 28 May 2021

Cited by 16 | Viewed by 3947

Abstract

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that [...] Read more.

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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33 pages, 2611 KiB

Open AccessEditor’s ChoiceReview

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

by Igor A. Schepetkin, Mark B. Plotnikov, Andrei I. Khlebnikov, Tatiana M. Plotnikova and Mark T. Quinn

Biomolecules 2021, 11(6), 777; https://doi.org/10.3390/biom11060777 - 22 May 2021

Cited by 43 | Viewed by 5968

Abstract

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are [...] Read more.

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed. Full article

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

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22 pages, 2069 KiB

Open AccessEditor’s ChoiceReview

Mechanisms That Activate 26S Proteasomes and Enhance Protein Degradation

by Alfred L. Goldberg, Hyoung Tae Kim, Donghoon Lee and Galen Andrew Collins

Biomolecules 2021, 11(6), 779; https://doi.org/10.3390/biom11060779 - 22 May 2021

Cited by 21 | Viewed by 6561

Abstract

Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become [...] Read more.

Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become activated by a two-step mechanism requiring an association of the ubiquitin chain with Usp14 and then a loosely folded protein domain with the ATPases. The initial activation step is signaled by Usp14’s UBL domain, and many UBL-domain-containing proteins (e.g., Rad23, Parkin) also activate the proteasome. ZFAND5 is a distinct type of activator that binds ubiquitin conjugates and the proteasome and stimulates proteolysis during muscle atrophy. The proteasome’s activities are also regulated through subunit phosphorylation. Agents that raise cAMP and activate PKA stimulate within minutes Rpn6 phosphorylation and enhance the selective degradation of short-lived proteins. Likewise, hormones, fasting, and exercise, which raise cAMP, activate proteasomes and proteolysis in target tissues. Agents that raise cGMP and activate PKG also stimulate 26S activities but modify different subunit(s) and stimulate also the degradation of long-lived cell proteins. Both kinases enhance the selective degradation of aggregation-prone proteins that cause neurodegenerative diseases. These new mechanisms regulating proteolysis thus have clear physiological importance and therapeutic potential. Full article

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

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21 pages, 1770 KiB

Open AccessEditor’s ChoiceReview

DEER Analysis of GPCR Conformational Heterogeneity

by Matthias Elgeti and Wayne L. Hubbell

Biomolecules 2021, 11(6), 778; https://doi.org/10.3390/biom11060778 - 22 May 2021

Cited by 23 | Viewed by 4917

Abstract

G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor [...] Read more.

G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor basal activity, ligand affinity, intrinsic efficacy and signal bias. These parameters are encoded in characteristic receptor conformations existing in equilibrium and their populations, which are thus of paramount interest for the understanding of receptor (mal-)functions and rational design of improved therapeutics. To this end, the combination of site-directed spin labeling and EPR spectroscopy, in particular double electron–electron resonance (DEER), is exceedingly valuable as it has access to sub-Angstrom spatial resolution and provides a detailed picture of the number and populations of conformations in equilibrium. This review gives an overview of existing DEER studies on GPCRs with a focus on the delineation of structure/function frameworks, highlighting recent developments in data analysis and visualization. We introduce “conformational efficacy” as a parameter to describe ligand-specific shifts in the conformational equilibrium, taking into account the loose coupling between receptor segments observed for different GPCRs using DEER. Full article

(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)

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12 pages, 493 KiB

Open AccessEditor’s ChoiceReview

Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?

by Courtney Griffiths, James Aikins, David Warshal and Olga Ostrovsky

Biomolecules 2021, 11(5), 766; https://doi.org/10.3390/biom11050766 - 20 May 2021

Cited by 17 | Viewed by 4977

Abstract

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. [...] Read more.

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound’s response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications. Full article

(This article belongs to the Special Issue Novel Indications of Epigenetic Therapy in Cancer)

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22 pages, 5131 KiB

Open AccessEditor’s ChoiceReview

A Bittersweet Computational Journey among Glycosaminoglycans

by Giulia Paiardi, Maria Milanesi, Rebecca C. Wade, Pasqualina D’Ursi and Marco Rusnati

Biomolecules 2021, 11(5), 739; https://doi.org/10.3390/biom11050739 - 15 May 2021

Cited by 10 | Viewed by 3960

Abstract

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of [...] Read more.

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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