Biomolecules

Review

27 pages, 4242 KiB

Open AccessEditor’s ChoiceReview

Phototheranostics Using Erythrocyte-Based Particles

by Taylor Hanley, Raviraj Vankayala, Chi-Hua Lee, Jack C. Tang, Joshua M. Burns and Bahman Anvari

Biomolecules 2021, 11(5), 729; https://doi.org/10.3390/biom11050729 - 13 May 2021

Cited by 13 | Viewed by 3974

Abstract

There has been a recent increase in the development of delivery systems based on red blood cells (RBCs) for light-mediated imaging and therapeutic applications. These constructs are able to take advantage of the immune evasion properties of the RBC, while the addition of [...] Read more.

There has been a recent increase in the development of delivery systems based on red blood cells (RBCs) for light-mediated imaging and therapeutic applications. These constructs are able to take advantage of the immune evasion properties of the RBC, while the addition of an optical cargo allows the particles to be activated by light for a number of promising applications. Here, we review some of the common fabrication methods to engineer these constructs. We also present some of the current light-based applications with potential for clinical translation, and offer some insight into future directions in this exciting field. Full article

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

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20 pages, 1093 KiB

Open AccessEditor’s ChoiceReview

The Pentose Phosphate Pathway in Yeasts–More Than a Poor Cousin of Glycolysis

by Laura-Katharina Bertels, Lucía Fernández Murillo and Jürgen J. Heinisch

Biomolecules 2021, 11(5), 725; https://doi.org/10.3390/biom11050725 - 12 May 2021

Cited by 47 | Viewed by 12688

Abstract

The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6-phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the [...] Read more.

The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6-phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the reversible transketolase and transaldolase reactions, which interchange PPP metabolites with glycolysis. While the oxidative branch is vital to cope with oxidative stress, the non-oxidative branch provides precursors for the synthesis of nucleic, fatty and aromatic amino acids. For glucose catabolism in the baker’s yeast Saccharomyces cerevisiae, where its components were first discovered and extensively studied, the PPP plays only a minor role. In contrast, PPP and glycolysis contribute almost equally to glucose degradation in other yeasts. We here summarize the data available for the PPP enzymes focusing on S. cerevisiae and Kluyveromyces lactis, and describe the phenotypes of gene deletions and the benefits of their overproduction and modification. Reference to other yeasts and to the importance of the PPP in their biotechnological and medical applications is briefly being included. We propose future studies on the PPP in K. lactis to be of special interest for basic science and as a host for the expression of human disease genes. Full article

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

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18 pages, 1997 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Regulation of Tissue Inflammation by 12-Lipoxygenases

by Abhishek Kulkarni, Jerry L. Nadler, Raghavendra G. Mirmira and Isabel Casimiro

Biomolecules 2021, 11(5), 717; https://doi.org/10.3390/biom11050717 - 11 May 2021

Cited by 49 | Viewed by 6367

Abstract

Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant [...] Read more.

Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells—a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role. Full article

(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)

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16 pages, 1491 KiB

Open AccessEditor’s ChoiceReview

Salicylic Acid Biosynthesis and Metabolism: A Divergent Pathway for Plants and Bacteria

by Awdhesh Kumar Mishra and Kwang-Hyun Baek

Biomolecules 2021, 11(5), 705; https://doi.org/10.3390/biom11050705 - 9 May 2021

Cited by 60 | Viewed by 13293

Abstract

Salicylic acid (SA) is an active secondary metabolite that occurs in bacteria, fungi, and plants. SA and its derivatives (collectively called salicylates) are synthesized from chorismate (derived from shikimate pathway). SA is considered an important phytohormone that regulates various aspects of plant growth, [...] Read more.

Salicylic acid (SA) is an active secondary metabolite that occurs in bacteria, fungi, and plants. SA and its derivatives (collectively called salicylates) are synthesized from chorismate (derived from shikimate pathway). SA is considered an important phytohormone that regulates various aspects of plant growth, environmental stress, and defense responses against pathogens. Besides plants, a large number of bacterial species, such as Pseudomonas, Bacillus, Azospirillum, Salmonella, Achromobacter, Vibrio, Yersinia, and Mycobacteria, have been reported to synthesize salicylates through the NRPS/PKS biosynthetic gene clusters. This bacterial salicylate production is often linked to the biosynthesis of small ferric-ion-chelating molecules, salicyl-derived siderophores (known as catecholate) under iron-limited conditions. Although bacteria possess entirely different biosynthetic pathways from plants, they share one common biosynthetic enzyme, isochorismate synthase, which converts chorismate to isochorismate, a common precursor for synthesizing SA. Additionally, SA in plants and bacteria can undergo several modifications to carry out their specific functions. In this review, we will systematically focus on the plant and bacterial salicylate biosynthesis and its metabolism. Full article

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23 pages, 1302 KiB

Open AccessEditor’s ChoiceReview

Biostimulants Application: A Low Input Cropping Management Tool for Sustainable Farming of Vegetables

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

Biomolecules 2021, 11(5), 698; https://doi.org/10.3390/biom11050698 - 7 May 2021

Cited by 82 | Viewed by 9634

Abstract

Biostimulants, are a diverse class of compounds including substances or microorganism which have positive impacts on plant growth, yield and chemical composition as well as boosting effects to biotic and abiotic stress tolerance. The major plant biostimulants are hydrolysates of plant or animal [...] Read more.

Biostimulants, are a diverse class of compounds including substances or microorganism which have positive impacts on plant growth, yield and chemical composition as well as boosting effects to biotic and abiotic stress tolerance. The major plant biostimulants are hydrolysates of plant or animal protein and other compounds that contain nitrogen, humic substances, extracts of seaweeds, biopolymers, compounds of microbial origin, phosphite, and silicon, among others. The mechanisms involved in the protective effects of biostimulants are varied depending on the compound and/or crop and mostly related with improved physiological processes and plant morphology aspects such as the enhanced root formation and elongation, increased nutrient uptake, improvement in seed germination rates and better crop establishment, increased cation exchange, decreased leaching, detoxification of heavy metals, mechanisms involved in stomatal conductance and plant transpiration or the stimulation of plant immune systems against stressors. The aim of this review was to provide an overview of the application of plant biostimulants on different crops within the framework of sustainable crop management, aiming to gather critical information regarding their positive effects on plant growth and yield, as well as on the quality of the final product. Moreover, the main limitations of such practice as well as the future prospects of biostimulants research will be 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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34 pages, 21908 KiB

Open AccessEditor’s ChoiceReview

SARS-CoV-2 M^pro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

by Andrea Citarella, Angela Scala, Anna Piperno and Nicola Micale

Biomolecules 2021, 11(4), 607; https://doi.org/10.3390/biom11040607 - 19 Apr 2021

Cited by 113 | Viewed by 11698

Abstract

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective [...] Read more.

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO’s main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (M^pro) are becoming more and more promising candidates. M^pro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 M^pro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 M^pro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds. Full article

(This article belongs to the Special Issue State-of-the-Art Highlighting Antiviral Therapy and Viral Diseases Diagnosis in Italy 2020–2021)

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35 pages, 3533 KiB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Cholinesterase Modeling and Simulation

by Danna De Boer, Nguyet Nguyen, Jia Mao, Jessica Moore and Eric J. Sorin

Biomolecules 2021, 11(4), 580; https://doi.org/10.3390/biom11040580 - 15 Apr 2021

Cited by 40 | Viewed by 7652

Abstract

The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the [...] Read more.

The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The inhibitory activities of myriad compounds have been computationally assessed, primarily through Monte Carlo-based docking calculations and molecular dynamics simulations. Pharmaceutical compounds examined herein include FDA-approved therapeutics and their derivatives, as well as several other prescription drug derivatives. Cholinesterase interactions with both narcotics and organophosphate compounds are discussed, with the latter focusing primarily on molecular recognition studies of potential therapeutic value and on improving our understanding of the reactivation of cholinesterases that are bound to toxins. This review also explores the inhibitory properties of several other organic and biological moieties, as well as advancements in virtual screening methodologies with respect to these enzymes. Full article

(This article belongs to the Special Issue Cholinesterase Research)

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27 pages, 12234 KiB

Open AccessEditor’s ChoiceReview

The 40-Year Mystery of Insect Odorant-Binding Proteins

by Karen Rihani, Jean-François Ferveur and Loïc Briand

Biomolecules 2021, 11(4), 509; https://doi.org/10.3390/biom11040509 - 30 Mar 2021

Cited by 94 | Viewed by 8101

Abstract

The survival of insects depends on their ability to detect molecules present in their environment. Odorant-binding proteins (OBPs) form a family of proteins involved in chemoreception. While OBPs were initially found in olfactory appendages, recently these proteins were discovered in other chemosensory and [...] Read more.

The survival of insects depends on their ability to detect molecules present in their environment. Odorant-binding proteins (OBPs) form a family of proteins involved in chemoreception. While OBPs were initially found in olfactory appendages, recently these proteins were discovered in other chemosensory and non-chemosensory organs. OBPs can bind, solubilize and transport hydrophobic stimuli to chemoreceptors across the aqueous sensilla lymph. In addition to this broadly accepted “transporter role”, OBPs can also buffer sudden changes in odorant levels and are involved in hygro-reception. The physiological roles of OBPs expressed in other body tissues, such as mouthparts, pheromone glands, reproductive organs, digestive tract and venom glands, remain to be investigated. This review provides an updated panorama on the varied structural aspects, binding properties, tissue expression and functional roles of insect OBPs. Full article

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

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14 pages, 318 KiB

Open AccessEditor’s ChoiceReview

Current Status and Future Perspectives of Androgen Receptor Inhibition Therapy for Prostate Cancer: A Comprehensive Review

by Tae Jin Kim, Young Hwa Lee and Kyo Chul Koo

Biomolecules 2021, 11(4), 492; https://doi.org/10.3390/biom11040492 - 25 Mar 2021

Cited by 23 | Viewed by 4244

Abstract

The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of [...] Read more.

The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of treatment in patients with hormone-sensitive prostate cancer (HSPC). However, treatment response is short-lived, and the majority of patients ultimately progress to castration-resistant prostate cancer (CRPC). Surmountable data from clinical trials have shown that the maintenance of AR signaling in the castration environment is accountable for disease progression. Study results indicate multiple factors and survival pathways involved in PCa. Based on these findings, the alternative molecular pathways involved in PCa progression can be manipulated to improve current regimens and develop novel treatment modalities in the management of CRPC. In this review, the interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition. Full article

(This article belongs to the Special Issue Androgen Receptors in Health and Diseases)

17 pages, 2273 KiB

Open AccessEditor’s ChoiceReview

Antiviral Cyanometabolites—A Review

by Hanna Mazur-Marzec, Marta Cegłowska, Robert Konkel and Krzysztof Pyrć

Biomolecules 2021, 11(3), 474; https://doi.org/10.3390/biom11030474 - 22 Mar 2021

Cited by 31 | Viewed by 5143

Abstract

Global processes, such as climate change, frequent and distant travelling and population growth, increase the risk of viral infection spread. Unfortunately, the number of effective and accessible medicines for the prevention and treatment of these infections is limited. Therefore, in recent years, efforts [...] Read more.

Global processes, such as climate change, frequent and distant travelling and population growth, increase the risk of viral infection spread. Unfortunately, the number of effective and accessible medicines for the prevention and treatment of these infections is limited. Therefore, in recent years, efforts have been intensified to develop new antiviral medicines or vaccines. In this review article, the structure and activity of the most promising antiviral cyanobacterial products are presented. The antiviral cyanometabolites are mainly active against the human immunodeficiency virus (HIV) and other enveloped viruses such as herpes simplex virus (HSV), Ebola or the influenza viruses. The majority of the metabolites are classified as lectins, monomeric or dimeric proteins with unique amino acid sequences. They all show activity at the nanomolar range but differ in carbohydrate specificity and recognize a different epitope on high mannose oligosaccharides. The cyanobacterial lectins include cyanovirin-N (CV-N), scytovirin (SVN), microvirin (MVN), Microcystisviridis lectin (MVL), and Oscillatoria agardhii agglutinin (OAA). Cyanobacterial polysaccharides, peptides, and other metabolites also have potential to be used as antiviral drugs. The sulfated polysaccharide, calcium spirulan (CA-SP), inhibited infection by enveloped viruses, stimulated the immune system’s response, and showed antitumor activity. Microginins, the linear peptides, inhibit angiotensin-converting enzyme (ACE), therefore, their use in the treatment of COVID-19 patients with injury of the ACE2 expressing organs is considered. In addition, many cyanobacterial extracts were revealed to have antiviral activities, but the active agents have not been identified. This fact provides a good basis for further studies on the therapeutic potential of these microorganisms. Full article

(This article belongs to the Special Issue Biomolecules from Alga: Biological Effect and Pharmacological Properties)

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29 pages, 12461 KiB

Open AccessEditor’s ChoiceReview

Neuropathology of Animal Prion Diseases

by Leonor Orge, Carla Lima, Carla Machado, Paula Tavares, Paula Mendonça, Paulo Carvalho, João Silva, Maria de Lurdes Pinto, Estela Bastos, Jorge Cláudio Pereira, Nuno Gonçalves-Anjo, Adelina Gama, Alexandra Esteves, Anabela Alves, Ana Cristina Matos, Fernanda Seixas, Filipe Silva, Isabel Pires, Luis Figueira, Madalena Vieira-Pinto, Roberto Sargo and Maria dos Anjos Pires Show full author list Hide full author list

Biomolecules 2021, 11(3), 466; https://doi.org/10.3390/biom11030466 - 21 Mar 2021

Cited by 19 | Viewed by 6652

Abstract

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrP^C) into a misfolded pathological isoform (PrP^Sc or [...] Read more.

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrP^C) into a misfolded pathological isoform (PrP^Sc or prion- proteinaceous infectious particle) that self-propagates by conformational conversion of PrP^C. Yet by an unknown mechanism, PrP^C can fold into different PrP^Sc conformers that may result in different prion strains that display specific disease phenotype (incubation time, clinical signs and lesion profile). Although the pathways for neurodegeneration as well as the involvement of brain inflammation in these diseases are not well understood, the spongiform changes, neuronal loss, gliosis and accumulation of PrP^Sc are the characteristic neuropathological lesions. Scrapie affecting small ruminants was the first identified TSE and has been considered the archetype of prion diseases, though atypical and new animal prion diseases continue to emerge highlighting the importance to investigate the lesion profile in naturally affected animals. In this report, we review the neuropathology and the neuroinflammation of animal prion diseases in natural hosts from scrapie, going through the zoonotic bovine spongiform encephalopathy (BSE), the chronic wasting disease (CWD) to the newly identified camel prion disease (CPD). Full article

(This article belongs to the Special Issue Prion Diseases: A Natural Model for Neurodegenerative Disorders)

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37 pages, 4133 KiB

Open AccessEditor’s ChoiceReview

New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota

by Marina Lorente-Picón and Ariadna Laguna

Biomolecules 2021, 11(3), 433; https://doi.org/10.3390/biom11030433 - 15 Mar 2021

Cited by 40 | Viewed by 10758

Abstract

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, and for which no disease-modifying treatments exist. Neurodegeneration and neuropathology in different brain areas are manifested as both motor and non-motor symptoms [...] Read more.

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, and for which no disease-modifying treatments exist. Neurodegeneration and neuropathology in different brain areas are manifested as both motor and non-motor symptoms in patients. Recent interest in the gut–brain axis has led to increasing research into the gut microbiota changes in PD patients and their impact on disease pathophysiology. As evidence is piling up on the effects of gut microbiota in disease development and progression, another front of action has opened up in relation to the potential usage of microbiota-based therapeutic strategies in treating gastrointestinal alterations and possibly also motor symptoms in PD. This review provides status on the different strategies that are in the front line (i.e., antibiotics; probiotics; prebiotics; synbiotics; dietary interventions; fecal microbiota transplantation, live biotherapeutic products), and discusses the opportunities and challenges the field of microbiome research in PD is facing. Full article

(This article belongs to the Section Cellular Biochemistry)

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20 pages, 3844 KiB

Open AccessEditor’s ChoiceReview

RAS Nanoclusters: Dynamic Signaling Platforms Amenable to Therapeutic Intervention

by Que N. Van, Priyanka Prakash, Rebika Shrestha, Trent E. Balius, Thomas J. Turbyville and Andrew G. Stephen

Biomolecules 2021, 11(3), 377; https://doi.org/10.3390/biom11030377 - 3 Mar 2021

Cited by 16 | Viewed by 4092

Abstract

RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes. RAS proteins are localized to the plasma membrane and function as molecular switches, turned on by partners that receive extracellular mitogenic signals. In the on-state, [...] Read more.

RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes. RAS proteins are localized to the plasma membrane and function as molecular switches, turned on by partners that receive extracellular mitogenic signals. In the on-state, they activate intracellular signal transduction cascades. Membrane-bound RAS molecules segregate into multimers, known as nanoclusters. These nanoclusters, held together through weak protein–protein and protein–lipid associations, are highly dynamic and respond to cellular input signals and fluctuations in the local lipid environment. Disruption of RAS nanoclusters results in downregulation of RAS-mediated mitogenic signaling. In this review, we discuss the propensity of RAS proteins to display clustering behavior and the interfaces that are associated with these assemblies. Strategies to therapeutically disrupt nanocluster formation or the stabilization of signaling incompetent RAS complexes are discussed. Full article

(This article belongs to the Special Issue Recent Insights into the Regulation and Structure of RAS Membrane Signaling Complexes—Emerging Drug Targeting Opportunities)

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31 pages, 2324 KiB

Open AccessEditor’s ChoiceReview

by Jason Tallis, Sharn Shelley, Hans Degens and Cameron Hill

Biomolecules 2021, 11(3), 372; https://doi.org/10.3390/biom11030372 - 2 Mar 2021

Cited by 23 | Viewed by 6823

Abstract

Obesity is a global epidemic and coupled with the unprecedented growth of the world’s older adult population, a growing number of individuals are both old and obese. Whilst both ageing and obesity are associated with an increased prevalence of chronic health conditions and [...] Read more.

Obesity is a global epidemic and coupled with the unprecedented growth of the world’s older adult population, a growing number of individuals are both old and obese. Whilst both ageing and obesity are associated with an increased prevalence of chronic health conditions and a substantial economic burden, evidence suggests that the coincident effects exacerbate negative health outcomes. A significant contributor to such detrimental effects may be the reduction in the contractile performance of skeletal muscle, given that poor muscle function is related to chronic disease, poor quality of life and all-cause mortality. Whilst the effects of ageing and obesity independently on skeletal muscle function have been investigated, the combined effects are yet to be thoroughly explored. Given the importance of skeletal muscle to whole-body health and physical function, the present study sought to provide a review of the literature to: (1) summarise the effect of obesity on the age-induced reduction in skeletal muscle contractile function; (2) understand whether obesity effects on skeletal muscle are similar in young and old muscle; (3) consider the consequences of these changes to whole-body functional performance; (4) outline important future work along with the potential for targeted intervention strategies to mitigate potential detrimental effects. Full article

(This article belongs to the Special Issue The Molecular and Physiological Mechanisms Responsible for The Interaction between Aging, Muscle, and Other Tissues)

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35 pages, 9016 KiB

Open AccessEditor’s ChoiceReview

Molecular Targets and Strategies for Inhibition of the Bacterial Type III Secretion System (T3SS); Inhibitors Directly Binding to T3SS Components

by Julia A. Hotinger, Heather A. Pendergrass and Aaron E. May

Biomolecules 2021, 11(2), 316; https://doi.org/10.3390/biom11020316 - 19 Feb 2021

Cited by 29 | Viewed by 9561

Abstract

The type III secretion system (T3SS) is a virulence apparatus used by many Gram-negative pathogenic bacteria to cause infections. Pathogens utilizing a T3SS are responsible for millions of infections yearly. Since many T3SS knockout strains are incapable of causing systemic infection, the T3SS [...] Read more.

The type III secretion system (T3SS) is a virulence apparatus used by many Gram-negative pathogenic bacteria to cause infections. Pathogens utilizing a T3SS are responsible for millions of infections yearly. Since many T3SS knockout strains are incapable of causing systemic infection, the T3SS has emerged as an attractive anti-virulence target for therapeutic design. The T3SS is a multiprotein molecular syringe that enables pathogens to inject effector proteins into host cells. These effectors modify host cell mechanisms in a variety of ways beneficial to the pathogen. Due to the T3SS’s complex nature, there are numerous ways in which it can be targeted. This review will be focused on the direct targeting of components of the T3SS, including the needle, translocon, basal body, sorting platform, and effector proteins. Inhibitors will be considered a direct inhibitor if they have a binding partner that is a T3SS component, regardless of the inhibitory effect being structural or functional. Full article

(This article belongs to the Special Issue Virulence Systems of Human Pathogens as Targets for Novel Therapeutics and Prophylactics)

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26 pages, 2158 KiB

Open AccessEditor’s ChoiceReview

Organ Fibrosis and Autoimmunity: The Role of Inflammation in TGFβ-Dependent EMT

by Margherita Sisto, Domenico Ribatti and Sabrina Lisi

Biomolecules 2021, 11(2), 310; https://doi.org/10.3390/biom11020310 - 18 Feb 2021

Cited by 64 | Viewed by 4653

Abstract

Recent advances in our understanding of the molecular pathways that control the link of inflammation with organ fibrosis and autoimmune diseases point to the epithelial to mesenchymal transition (EMT) as the common association in the progression of these diseases characterized by an intense [...] Read more.

Recent advances in our understanding of the molecular pathways that control the link of inflammation with organ fibrosis and autoimmune diseases point to the epithelial to mesenchymal transition (EMT) as the common association in the progression of these diseases characterized by an intense inflammatory response. EMT, a process in which epithelial cells are gradually transformed to mesenchymal cells, is a major contributor to the pathogenesis of fibrosis. Importantly, the chronic inflammatory microenvironment has emerged as a decisive factor in the induction of pathological EMT. Transforming growth factor-β (TGF-β), a multifunctional cytokine, plays a crucial role in the induction of fibrosis, often associated with chronic phases of inflammatory diseases, contributing to marked fibrotic changes that severely impair normal tissue architecture and function. The understanding of molecular mechanisms underlying EMT-dependent fibrosis has both a basic and a translational relevance, since it may be useful to design therapies aimed at counteracting organ deterioration and failure. To this end, we reviewed the recent literature to better elucidate the molecular response to inflammatory/fibrogenic signals in autoimmune diseases in order to further the specific regulation of EMT-dependent fibrosis in more targeted therapies. Full article

(This article belongs to the Collection TGF-Beta Signaling in Tissue Fibrosis and Cancer)

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23 pages, 2410 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Irisin and Incretin Hormones: Similarities, Differences, and Implications in Type 2 Diabetes and Obesity

by Nicola Marrano, Giuseppina Biondi, Anna Borrelli, Angelo Cignarelli, Sebastio Perrini, Luigi Laviola, Francesco Giorgino and Annalisa Natalicchio

Biomolecules 2021, 11(2), 286; https://doi.org/10.3390/biom11020286 - 15 Feb 2021

Cited by 22 | Viewed by 5466

Abstract

Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different [...] Read more.

Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different organs and tissues. Irisin, a myokine released in response to a high-fat diet and exercise, enhances GSIS. Similar to GLP-1, irisin augments insulin biosynthesis and promotes accrual of β-cell functional mass. In addition, irisin and GLP-1 share comparable pleiotropic effects and activate similar intracellular pathways. The insulinotropic and extra-pancreatic effects of GLP-1 are reduced in type 2 diabetes (T2D) patients but preserved at pharmacological doses. GLP-1 receptor agonists (GLP-1RAs) are therefore among the most widely used antidiabetes drugs, also considered for their cardiovascular benefits and ability to promote weight loss. Irisin levels are lower in T2D patients, and in diabetic and/or obese animal models irisin administration improves glycemic control and promotes weight loss. Interestingly, recent evidence suggests that both GLP-1 and irisin are also synthesized within the pancreatic islets, in α- and β-cells, respectively. This review aims to describe the similarities between GLP-1 and irisin and to propose a new potential axis–involving the gut, muscle, and endocrine pancreas that controls energy homeostasis. Full article

(This article belongs to the Special Issue Pancreatic Islets of Langerhans: Not Only Beta-Cells)

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35 pages, 1355 KiB

Open AccessEditor’s ChoiceReview

Hormonal Regulation of Oligodendrogenesis I: Effects across the Lifespan

by Kimberly L. P. Long, Jocelyn M. Breton, Matthew K. Barraza, Olga S. Perloff and Daniela Kaufer

Biomolecules 2021, 11(2), 283; https://doi.org/10.3390/biom11020283 - 14 Feb 2021

Cited by 19 | Viewed by 6722

Abstract

The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by [...] Read more.

The brain’s capacity to respond to changing environments via hormonal signaling is critical to fine-tuned function. An emerging body of literature highlights a role for myelin plasticity as a prominent type of experience-dependent plasticity in the adult brain. Myelin plasticity is driven by oligodendrocytes (OLs) and their precursor cells (OPCs). OPC differentiation regulates the trajectory of myelin production throughout development, and importantly, OPCs maintain the ability to proliferate and generate new OLs throughout adulthood. The process of oligodendrogenesis, the creation of new OLs, can be dramatically influenced during early development and in adulthood by internal and environmental conditions such as hormones. Here, we review the current literature describing hormonal regulation of oligodendrogenesis within physiological conditions, focusing on several classes of hormones: steroid, peptide, and thyroid hormones. We discuss hormonal regulation at each stage of oligodendrogenesis and describe mechanisms of action, where known. Overall, the majority of hormones enhance oligodendrogenesis, increasing OPC differentiation and inducing maturation and myelin production in OLs. The mechanisms underlying these processes vary for each hormone but may ultimately converge upon common signaling pathways, mediated by specific receptors expressed across the OL lineage. However, not all of the mechanisms have been fully elucidated, and here, we note the remaining gaps in the literature, including the complex interactions between hormonal systems and with the immune system. In the companion manuscript in this issue, we discuss the implications of hormonal regulation of oligodendrogenesis for neurological and psychiatric disorders characterized by white matter loss. Ultimately, a better understanding of the fundamental mechanisms of hormonal regulation of oligodendrogenesis across the entire lifespan, especially in vivo, will progress both basic and translational research. Full article

(This article belongs to the Special Issue Hormonal Regulation of Neurogenesis in Adults)

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34 pages, 3326 KiB

Open AccessEditor’s ChoiceReview

Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules

by Chiara Lanzillotta and Fabio Di Domenico

Biomolecules 2021, 11(2), 266; https://doi.org/10.3390/biom11020266 - 11 Feb 2021

Cited by 18 | Viewed by 3840

Abstract

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development [...] Read more.

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed. Full article

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

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15 pages, 1400 KiB

Open AccessEditor’s ChoiceReview

The Role of Interferons in the Pathogenesis of Sjögren’s Syndrome and Future Therapeutic Perspectives

by Nicoletta Del Papa, Antonina Minniti, Maurizio Lorini, Vincenzo Carbonelli, Wanda Maglione, Francesca Pignataro, Nicola Montano, Roberto Caporali and Claudio Vitali

Biomolecules 2021, 11(2), 251; https://doi.org/10.3390/biom11020251 - 9 Feb 2021

Cited by 27 | Viewed by 3939

Abstract

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type [...] Read more.

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS. Full article

(This article belongs to the Special Issue Emerging Molecular Targets in Sjogren’s Syndrome)

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15 pages, 2371 KiB

Open AccessEditor’s ChoiceReview

Control of Gene Expression by Exosome-Derived Non-Coding RNAs in Cancer Angiogenesis and Lymphangiogenesis

by Valeria Arcucci, Steven A. Stacker and Marc G. Achen

Biomolecules 2021, 11(2), 249; https://doi.org/10.3390/biom11020249 - 9 Feb 2021

Cited by 17 | Viewed by 3037

Abstract

Tumour angiogenesis and lymphangiogenesis are hallmarks of cancer and have been associated with tumour progression, tumour metastasis and poor patient prognosis. Many factors regulate angiogenesis and lymphangiogenesis in cancer including non-coding RNAs which are a category of RNAs that do not encode proteins [...] Read more.

Tumour angiogenesis and lymphangiogenesis are hallmarks of cancer and have been associated with tumour progression, tumour metastasis and poor patient prognosis. Many factors regulate angiogenesis and lymphangiogenesis in cancer including non-coding RNAs which are a category of RNAs that do not encode proteins and have important regulatory functions at transcriptional and post-transcriptional levels. Non-coding RNAs can be encapsulated in extracellular vesicles called exosomes which are secreted by tumour cells or other cells in the tumour microenvironment and can then be taken up by the endothelial cells of blood vessels and lymphatic vessels. The “delivery” of these non-coding RNAs to endothelial cells in tumours can facilitate tumour angiogenesis and lymphangiogenesis. Here we review recent findings about exosomal non-coding RNAs, specifically microRNAs and long non-coding RNAs, which regulate tumour angiogenesis and lymphangiogenesis in cancer. We then focus on the potential use of these molecules as cancer biomarkers and opportunities for exploiting ncRNAs for the treatment of cancer. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 808 KiB

Open AccessEditor’s ChoiceReview

TRPM4 in Cancer—A New Potential Drug Target

by Anna Borgström, Christine Peinelt and Paulina Stokłosa

Biomolecules 2021, 11(2), 229; https://doi.org/10.3390/biom11020229 - 5 Feb 2021

Cited by 27 | Viewed by 6016

Abstract

Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, [...] Read more.

Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca²⁺-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca²⁺ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels: Markers and Therapeutic Targets for Cancer?)

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38 pages, 2533 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Hulks and the Deadpools of the Cytokinin Universe: A Dual Strategy for Cytokinin Production, Translocation, and Signal Transduction

by Tomáš Hluska, Lucia Hlusková and R. J. Neil Emery

Biomolecules 2021, 11(2), 209; https://doi.org/10.3390/biom11020209 - 3 Feb 2021

Cited by 34 | Viewed by 6481

Abstract

Cytokinins are plant hormones, derivatives of adenine with a side chain at the N⁶-position. They are involved in many physiological processes. While the metabolism of trans-zeatin and isopentenyladenine, which are considered to be highly active cytokinins, has been extensively studied, [...] Read more.

Cytokinins are plant hormones, derivatives of adenine with a side chain at the N⁶-position. They are involved in many physiological processes. While the metabolism of trans-zeatin and isopentenyladenine, which are considered to be highly active cytokinins, has been extensively studied, there are others with less obvious functions, such as cis-zeatin, dihydrozeatin, and aromatic cytokinins, which have been comparatively neglected. To help explain this duality, we present a novel hypothesis metaphorically comparing various cytokinin forms, enzymes of CK metabolism, and their signalling and transporter functions to the comics superheroes Hulk and Deadpool. Hulk is a powerful but short-lived creation, whilst Deadpool presents a more subtle and enduring force. With this dual framework in mind, this review compares different cytokinin metabolites, and their biosynthesis, translocation, and sensing to illustrate the different mechanisms behind the two CK strategies. This is put together and applied to a plant developmental scale and, beyond plants, to interactions with organisms of other kingdoms, to highlight where future study can benefit the understanding of plant fitness and productivity. Full article

(This article belongs to the Special Issue Phytohormones 2020)

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15 pages, 2917 KiB

Open AccessEditor’s ChoiceReview

Structural Insights into Substrate Recognition and Processing by the 20S Proteasome

by Indrajit Sahu and Michael H. Glickman

Biomolecules 2021, 11(2), 148; https://doi.org/10.3390/biom11020148 - 24 Jan 2021

Cited by 35 | Viewed by 5750

Abstract

Four decades of proteasome research have yielded extensive information on ubiquitin-dependent proteolysis. The archetype of proteasomes is a 20S barrel-shaped complex that does not rely on ubiquitin as a degradation signal but can degrade substrates with a considerable unstructured stretch. Since roughly half [...] Read more.

Four decades of proteasome research have yielded extensive information on ubiquitin-dependent proteolysis. The archetype of proteasomes is a 20S barrel-shaped complex that does not rely on ubiquitin as a degradation signal but can degrade substrates with a considerable unstructured stretch. Since roughly half of all proteasomes in most eukaryotic cells are free 20S complexes, ubiquitin-independent protein degradation may coexist with ubiquitin-dependent degradation by the highly regulated 26S proteasome. This article reviews recent advances in our understanding of the biochemical and structural features that underlie the proteolytic mechanism of 20S proteasomes. The two outer α-rings of 20S proteasomes provide a number of potential docking sites for loosely folded polypeptides. The binding of a substrate can induce asymmetric conformational changes, trigger gate opening, and initiate its own degradation through a protease-driven translocation mechanism. Consequently, the substrate translocates through two additional narrow apertures augmented by the β-catalytic active sites. The overall pulling force through the two annuli results in a protease-like unfolding of the substrate and subsequent proteolysis in the catalytic chamber. Although both proteasomes contain identical β-catalytic active sites, the differential translocation mechanisms yield distinct peptide products. Nonoverlapping substrate repertoires and product outcomes rationalize cohabitation of both proteasome complexes in cells. Full article

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

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13 pages, 7084 KiB

Open AccessEditor’s ChoiceReview

Exploring the Intracrine Functions of VEGF-A

by Sophie Wiszniak and Quenten Schwarz

Biomolecules 2021, 11(1), 128; https://doi.org/10.3390/biom11010128 - 19 Jan 2021

Cited by 45 | Viewed by 7295

Abstract

Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and [...] Read more.

Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed “intracrine”, and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF): From Basic Mechanisms to Clinical Significance and Drug Development)

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13 pages, 1376 KiB

Open AccessEditor’s ChoiceReview

Breakdown of Filamentous Myofibrils by the UPS–Step by Step

by Dina Aweida and Shenhav Cohen

Biomolecules 2021, 11(1), 110; https://doi.org/10.3390/biom11010110 - 15 Jan 2021

Cited by 13 | Viewed by 5960

Abstract

Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, [...] Read more.

Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, protein aggregates, and cell surface proteins; and the ubiquitin-proteasome system (UPS), which promotes degradation of mainly soluble proteins. Recent findings indicate that more complex protein structures, such as filamentous assemblies, which are not accessible to the catalytic core of the proteasome in vitro, can be efficiently degraded by this proteolytic machinery in systemic catabolic states in vivo. Mechanisms that loosen the filamentous structure seem to be activated first, hence increasing the accessibility of protein constituents to the UPS. In this review, we will discuss the mechanisms underlying the disassembly and loss of the intricate insoluble filamentous myofibrils, which are responsible for muscle contraction, and whose degradation by the UPS causes weakness and disability in aging and disease. Several lines of evidence indicate that myofibril breakdown occurs in a strictly ordered and controlled manner, and the function of AAA-ATPases is crucial for their disassembly and loss. Full article

(This article belongs to the Special Issue Looking Back and Ahead: Emerging Concepts in Ubiquitin and UBLs)

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39 pages, 11703 KiB

Open AccessEditor’s ChoiceReview

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

by Béla Kiss, István Laszlovszky, Balázs Krámos, András Visegrády, Amrita Bobok, György Lévay, Balázs Lendvai and Viktor Román

Biomolecules 2021, 11(1), 104; https://doi.org/10.3390/biom11010104 - 14 Jan 2021

Cited by 38 | Viewed by 6986

Abstract

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 [...] Read more.

Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy. Full article

(This article belongs to the Special Issue Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases)

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22 pages, 3123 KiB

Open AccessEditor’s ChoiceReview

Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries

by Bobbi Fleiss, Juliette Van Steenwinckel, Cindy Bokobza, Isabelle K. Shearer, Emily Ross-Munro and Pierre Gressens

Biomolecules 2021, 11(1), 99; https://doi.org/10.3390/biom11010099 - 13 Jan 2021

Cited by 41 | Viewed by 5019

Abstract

Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, [...] Read more.

Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these. Full article

(This article belongs to the Special Issue Microglia in Neurodegeneration)

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21 pages, 799 KiB

Open AccessEditor’s ChoiceReview

Cytokines and Chemokines in SARS-CoV-2 Infections—Therapeutic Strategies Targeting Cytokine Storm

by Alexandra Pum, Maria Ennemoser, Tiziana Adage and Andreas J. Kungl

Biomolecules 2021, 11(1), 91; https://doi.org/10.3390/biom11010091 - 12 Jan 2021

Cited by 67 | Viewed by 6217

Abstract

The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences [...] Read more.

The recently identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the cause of coronavirus disease (COVID-19) and the associated ongoing pandemic, frequently leads to severe respiratory distress syndrome and pneumonia with fatal consequences. Although several factors of this infection and its consequences are not completely clear, the presence and involvement of specific chemokines is undoubtedly crucial for the development and progression of COVID-19. Cytokine storm and the often-resulting cytokine release syndrome (CRS) are pathophysiological hallmarks in COVID-19 infections related to its most severe and fatal cases. In this hyperinflammatory event, chemokines and other cytokines are highly upregulated and are therefore not fulfilling their beneficial function in the host response anymore but causing harmful effects. Here, we present the recent views on the involvement of chemokines and selected cytokines in COVID-19 and the therapeutics currently in clinical development targeting or interfering with them, discussing their potentials in the treatment of COVID-19 infections. Full article

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

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18 pages, 306 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Efficacy and Safety of Mesenchymal Stem/Stromal Cell Therapy for Inflammatory Bowel Diseases: An Up-to-Date Systematic Review

by Jeffrey Zheng-Hsien Ko, Sheeva Johnson and Maneesh Dave

Biomolecules 2021, 11(1), 82; https://doi.org/10.3390/biom11010082 - 11 Jan 2021

Cited by 35 | Viewed by 4586

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut that can lead to severe gastrointestinal symptoms, malnutrition, and complications such as fistulas and cancer. Mesenchymal stem/stromal cells (MSCs) are being investigated as a novel therapy for IBD and have been [...] Read more.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gut that can lead to severe gastrointestinal symptoms, malnutrition, and complications such as fistulas and cancer. Mesenchymal stem/stromal cells (MSCs) are being investigated as a novel therapy for IBD and have been demonstrated to be safe and effective for perianal fistulizing Crohn’s disease (PFCD). This systematic review aims to present the most recent studies on the safety and efficacy of MSC therapy in IBD. A detailed search strategy of clinical trials on MSCs and IBD was performed on PubMed, with 32 studies selected for inclusion in this review. The newest studies on local MSC injection for PFCD continue to support long-term efficacy while maintaining a favorable safety profile. The evidence for systemic MSC infusion in luminal IBD remains mixed due to marked methodological heterogeneity and unclear safety profiles. Although further studies are needed to better establish the role of this novel treatment modality, MSCs are proving to be a very exciting addition to the limited therapies available for IBD. Full article

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

23 pages, 1417 KiB

Open AccessEditor’s ChoiceReview

Glycosaminoglycans in Tissue Engineering: A Review

by Harkanwalpreet Sodhi and Alyssa Panitch

Biomolecules 2021, 11(1), 29; https://doi.org/10.3390/biom11010029 - 29 Dec 2020

Cited by 79 | Viewed by 11992

Abstract

Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key [...] Read more.

Glycosaminoglycans are native components of the extracellular matrix that drive cell behavior and control the microenvironment surrounding cells, making them promising therapeutic targets for a myriad of diseases. Recent studies have shown that recapitulation of cell interactions with the extracellular matrix are key in tissue engineering, where the aim is to mimic and regenerate endogenous tissues. Because of this, incorporation of glycosaminoglycans to drive stem cell fate and promote cell proliferation in engineered tissues has gained increasing attention. This review summarizes the role glycosaminoglycans can play in tissue engineering and the recent advances in their use in these constructs. We also evaluate the general trend of research in this niche and provide insight into its future directions. Full article

(This article belongs to the Special Issue Exploring the Multifaceted Roles of Glycosaminoglycans (GAGs) - New Advances and Further Challenges)

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18 pages, 1208 KiB

Open AccessEditor’s ChoiceReview

Nanobodies Right in the Middle: Intrabodies as Toolbox to Visualize and Modulate Antigens in the Living Cell

by Teresa R. Wagner and Ulrich Rothbauer

Biomolecules 2020, 10(12), 1701; https://doi.org/10.3390/biom10121701 - 21 Dec 2020

Cited by 24 | Viewed by 5393

Abstract

In biomedical research, there is an ongoing demand for new technologies to elucidate disease mechanisms and develop novel therapeutics. This requires comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, post-translational modifications and dynamic interactions of cellular [...] Read more.

In biomedical research, there is an ongoing demand for new technologies to elucidate disease mechanisms and develop novel therapeutics. This requires comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, post-translational modifications and dynamic interactions of cellular components. Traceable intracellular binding molecules provide new opportunities for real-time cellular diagnostics. Most prominently, intrabodies derived from antibody fragments of heavy-chain only antibodies of camelids (nanobodies) have emerged as highly versatile and attractive probes to study and manipulate antigens within the context of living cells. In this review, we provide an overview on the selection, delivery and usage of intrabodies to visualize and monitor cellular antigens in living cells and organisms. Additionally, we summarize recent advances in the development of intrabodies as cellular biosensors and their application to manipulate disease-related cellular processes. Finally, we highlight switchable intrabodies, which open entirely new possibilities for real-time cell-based diagnostics including live-cell imaging, target validation and generation of precisely controllable binding reagents for future therapeutic applications. Full article

(This article belongs to the Special Issue The Therapeutic and Diagnostic Potential of Nanobodies)

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23 pages, 1846 KiB

Open AccessEditor’s ChoiceReview

Cell-Free DNA-Methylation-Based Methods and Applications in Oncology

by Francesca Galardi, Francesca De Luca, Dario Romagnoli, Chiara Biagioni, Erica Moretti, Laura Biganzoli, Angelo Di Leo, Ilenia Migliaccio, Luca Malorni and Matteo Benelli

Biomolecules 2020, 10(12), 1677; https://doi.org/10.3390/biom10121677 - 15 Dec 2020

Cited by 35 | Viewed by 8710

Abstract

Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm [...] Read more.

Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm being more prevalent, pervasive, and cell- and tumor-type specific than genomics, for which established cfDNA assays already exist. Herein, we report on recent advances on experimental strategies for the analysis of DNAm in cfDNA samples. We describe the main steps of DNAm-based analysis workflows, including pre-analytics of cfDNA samples, DNA treatment, assays for DNAm evaluation, and methods for data analysis. We report on protocols, biomolecular techniques, and computational strategies enabling DNAm evaluation in the context of cfDNA analysis, along with practical considerations on input sample requirements and costs. We provide an overview on existing studies exploiting cell-free DNAm biomarkers for the detection and monitoring of cancer in early and advanced settings, for the evaluation of drug resistance, and for the identification of the cell-of-origin of tumors. Finally, we report on DNAm-based tests approved for clinical use and summarize their performance in the context of liquid biopsy. Full article

(This article belongs to the Special Issue Epigenetics in Cancer)

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25 pages, 2374 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy

by Faheem Shaik, Gary A. Cuthbert, Shervanthi Homer-Vanniasinkam, Stephen P. Muench, Sreenivasan Ponnambalam and Michael A. Harrison

Biomolecules 2020, 10(12), 1673; https://doi.org/10.3390/biom10121673 - 15 Dec 2020

Cited by 46 | Viewed by 6781

Abstract

Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in [...] Read more.

Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in many disease states, including tumour development and progression, there is much interest in understanding the mechanistic basis for how VEGF-A regulates cell and tissue function. VEGF-A binds with high affinity to two VEGF receptor tyrosine kinases (VEGFR1, VEGFR2) and with lower affinity to co-receptors called neuropilin-1 and neuropilin-2 (NRP1, NRP2). Here, we use a structural viewpoint to summarise our current knowledge of VEGF-VEGFR activation and signal transduction. As targeting VEGF-VEGFR activation holds much therapeutic promise, we examine the structural basis for anti-angiogenic therapy using small-molecule compounds such as tyrosine kinase inhibitors that block VEGFR activation and downstream signalling. This review provides a rational basis towards reconciling VEGF and VEGFR structure and function in developing new therapeutics for a diverse range of ailments. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor (VEGF): From Basic Mechanisms to Clinical Significance and Drug Development)

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30 pages, 1797 KiB

Open AccessEditor’s ChoiceReview

An Inside Job: Applications of Intracellular Single Domain Antibodies

by Eline Soetens, Marlies Ballegeer and Xavier Saelens

Biomolecules 2020, 10(12), 1663; https://doi.org/10.3390/biom10121663 - 12 Dec 2020

Cited by 17 | Viewed by 4288

Abstract

Sera of camelid species contain a special kind of antibody that consists only of heavy chains. The variable antigen binding domain of these heavy chain antibodies can be expressed as a separate entity, called a single domain antibody that is characterized by its [...] Read more.

Sera of camelid species contain a special kind of antibody that consists only of heavy chains. The variable antigen binding domain of these heavy chain antibodies can be expressed as a separate entity, called a single domain antibody that is characterized by its small size, high solubility and oftentimes exceptional stability. Because of this, most single domain antibodies fold correctly when expressed in the reducing environment of the cytoplasm, and thereby retain their antigen binding specificity. Single domain antibodies can thus be used to target a broad range of intracellular proteins. Such intracellular single domain antibodies are also known as intrabodies, and have proven to be highly useful tools for basic research by allowing visualization, disruption and even targeted degradation of intracellular proteins. Furthermore, intrabodies can be used to uncover prospective new therapeutic targets and have the potential to be applied in therapeutic settings in the future. In this review we provide a brief overview of recent advances in the field of intracellular single domain antibodies, focusing on their use as research tools and potential therapeutic applications. Special attention is given to the available methods that allow delivery of single domain antibodies into cells. Full article

(This article belongs to the Special Issue The Therapeutic and Diagnostic Potential of Nanobodies)

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26 pages, 1612 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Cx43 and the Actin Cytoskeleton: Novel Roles and Implications for Cell-Cell Junction-Based Barrier Function Regulation

by Randy E. Strauss and Robert G. Gourdie

Biomolecules 2020, 10(12), 1656; https://doi.org/10.3390/biom10121656 - 10 Dec 2020

Cited by 20 | Viewed by 4326

Abstract

Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this [...] Read more.

Barrier function is a vital homeostatic mechanism employed by epithelial and endothelial tissue. Diseases across a wide range of tissue types involve dynamic changes in transcellular junctional complexes and the actin cytoskeleton in the regulation of substance exchange across tissue compartments. In this review, we focus on the contribution of the gap junction protein, Cx43, to the biophysical and biochemical regulation of barrier function. First, we introduce the structure and canonical channel-dependent functions of Cx43. Second, we define barrier function and examine the key molecular structures fundamental to its regulation. Third, we survey the literature on the channel-dependent roles of connexins in barrier function, with an emphasis on the role of Cx43 and the actin cytoskeleton. Lastly, we discuss findings on the channel-independent roles of Cx43 in its associations with the actin cytoskeleton and focal adhesion structures highlighted by PI3K signaling, in the potential modulation of cellular barriers. Mounting evidence of crosstalk between connexins, the cytoskeleton, focal adhesion complexes, and junctional structures has led to a growing appreciation of how barrier-modulating mechanisms may work together to effect solute and cellular flux across tissue boundaries. This new understanding could translate into improved therapeutic outcomes in the treatment of barrier-associated diseases. Full article

(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)

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28 pages, 2942 KiB

Open AccessEditor’s ChoiceReview

Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

by Daniel Liedtke, Christine Hofmann, Franz Jakob, Eva Klopocki and Stephanie Graser

Biomolecules 2020, 10(12), 1648; https://doi.org/10.3390/biom10121648 - 8 Dec 2020

Cited by 21 | Viewed by 5100

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and [...] Read more.

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish. Full article

(This article belongs to the Section Molecular Medicine)

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30 pages, 5094 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells

by Paulina Podkalicka, Jacek Stępniewski, Olga Mucha, Neli Kachamakova-Trojanowska, Józef Dulak and Agnieszka Łoboda

Biomolecules 2020, 10(12), 1614; https://doi.org/10.3390/biom10121614 - 29 Nov 2020

Cited by 27 | Viewed by 5266

Abstract

Inadequate supply of oxygen (O₂) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages [...] Read more.

Inadequate supply of oxygen (O₂) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages of embryonic development. In culture, hypoxic conditions may facilitate the derivation of embryonic stem cells (ESCs) and the generation of induced pluripotent stem cells (iPSCs), which may serve as a valuable tool for disease modeling. Endothelial cells (ECs), multifunctional components of vascular structures, may be obtained from iPSCs and subsequently used in various (hypoxia-related) disease models to investigate vascular dysfunctions. Although iPSC-ECs demonstrated functionality in vitro and in vivo, ongoing studies are conducted to increase the efficiency of differentiation and to establish the most productive protocols for the application of patient-derived cells in clinics. In this review, we highlight recent discoveries on the role of hypoxia in the derivation of ESCs and the generation of iPSCs. We also summarize the existing protocols of hypoxia-driven differentiation of iPSCs toward ECs and discuss their possible applications in disease modeling and treatment of hypoxia-related disorders. Full article

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

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19 pages, 3119 KiB

Open AccessEditor’s ChoiceReview

Sequence Features of Mitochondrial Transporter Protein Families

by Gergely Gyimesi and Matthias A. Hediger

Biomolecules 2020, 10(12), 1611; https://doi.org/10.3390/biom10121611 - 28 Nov 2020

Cited by 24 | Viewed by 5941

Abstract

Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical SLC25 (solute carrier family 25) mitochondrial carriers, the past decade has led to the discovery of [...] Read more.

Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical SLC25 (solute carrier family 25) mitochondrial carriers, the past decade has led to the discovery of additional protein families with numerous members that exhibit IMM localization and transporter-like properties. These include mitochondrial pyruvate carriers, sideroflexins, and mitochondrial cation/H⁺ exchangers. These transport proteins were linked to vital physiological functions and disease. Their structures and transport mechanisms are, however, still largely unknown and understudied. Protein sequence analysis per se can often pinpoint hotspots that are of functional or structural importance. In this review, we summarize current knowledge about the sequence features of mitochondrial transporters with a special focus on the newly included SLC54, SLC55 and SLC56 families of the SLC solute carrier superfamily. Taking a step further, we combine sequence conservation analysis with transmembrane segment and secondary structure prediction methods to extract residue positions and sequence motifs that likely play a role in substrate binding, binding site gating or structural stability. We hope that our review will help guide future experimental efforts by the scientific community to unravel the transport mechanisms and structures of these novel mitochondrial carriers. Full article

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

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32 pages, 1883 KiB

Open AccessEditor’s ChoiceReview

The Human Epidermal Basement Membrane: A Shaped and Cell Instructive Platform That Aging Slowly Alters

by Eva Roig-Rosello and Patricia Rousselle

Biomolecules 2020, 10(12), 1607; https://doi.org/10.3390/biom10121607 - 27 Nov 2020

Cited by 62 | Viewed by 16198

Abstract

One of the most important functions of skin is to act as a protective barrier. To fulfill this role, the structural integrity of the skin depends on the dermal-epidermal junction—a complex network of extracellular matrix macromolecules that connect the outer epidermal layer to [...] Read more.

One of the most important functions of skin is to act as a protective barrier. To fulfill this role, the structural integrity of the skin depends on the dermal-epidermal junction—a complex network of extracellular matrix macromolecules that connect the outer epidermal layer to the underlying dermis. This junction provides both a structural support to keratinocytes and a specific niche that mediates signals influencing their behavior. It displays a distinctive microarchitecture characterized by an undulating pattern, strengthening dermal-epidermal connectivity and crosstalk. The optimal stiffness arising from the overall molecular organization, together with characteristic anchoring complexes, keeps the dermis and epidermis layers extremely well connected and capable of proper epidermal renewal and regeneration. Due to intrinsic and extrinsic factors, a large number of structural and biological changes accompany skin aging. These changes progressively weaken the dermal–epidermal junction substructure and affect its functions, contributing to the gradual decline in overall skin physiology. Most changes involve reduced turnover or altered enzymatic or non-enzymatic post-translational modifications, compromising the mechanical properties of matrix components and cells. This review combines recent and older data on organization of the dermal-epidermal junction, its mechanical properties and role in mechanotransduction, its involvement in regeneration, and its fate during the aging process. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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22 pages, 798 KiB

Open AccessEditor’s ChoiceReview

Post-Myocardial Infarction Ventricular Remodeling Biomarkers—The Key Link between Pathophysiology and Clinic

by Maria-Madălina Bostan, Cristian Stătescu, Larisa Anghel, Ionela-Lăcrămioara Șerban, Elena Cojocaru and Radu Sascău

Biomolecules 2020, 10(11), 1587; https://doi.org/10.3390/biom10111587 - 23 Nov 2020

Cited by 25 | Viewed by 6528

Abstract

Studies in recent years have shown increased interest in developing new methods of evaluation, but also in limiting post infarction ventricular remodeling, hoping to improve ventricular function and the further evolution of the patient. This is the point where biomarkers have proven effective [...] Read more.

Studies in recent years have shown increased interest in developing new methods of evaluation, but also in limiting post infarction ventricular remodeling, hoping to improve ventricular function and the further evolution of the patient. This is the point where biomarkers have proven effective in early detection of remodeling phenomena. There are six main processes that promote the remodeling and each of them has specific biomarkers that can be used in predicting the evolution (myocardial necrosis, neurohormonal activation, inflammatory reaction, hypertrophy and fibrosis, apoptosis, mixed processes). Some of the biomarkers such as creatine kinase–myocardial band (CK-MB), troponin, and N-terminal-pro type B natriuretic peptide (NT-proBNP) were so convincing that they immediately found their place in the post infarction patient evaluation protocol. Others that are related to more complex processes such as inflammatory biomarkers, atheroma plaque destabilization biomarkers, and microRNA are still being studied, but the results so far are promising. This article aims to review the markers used so far, but also the existing data on new markers that could be considered, taking into consideration the most important studies that have been conducted so far. Full article

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

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32 pages, 741 KiB

Open AccessEditor’s ChoiceReview

Astrocytic Connexin43 Channels as Candidate Targets in Epilepsy Treatment

by Laura Walrave, Mathieu Vinken, Luc Leybaert and Ilse Smolders

Biomolecules 2020, 10(11), 1578; https://doi.org/10.3390/biom10111578 - 20 Nov 2020

Cited by 28 | Viewed by 4957

Abstract

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 [...] Read more.

In epilepsy research, emphasis is put on exploring non-neuronal targets such as astrocytic proteins, since many patients remain pharmacoresistant to current treatments, which almost all target neuronal mechanisms. This paper reviews available data on astrocytic connexin43 (Cx43) signaling in seizures and epilepsy. Cx43 is a widely expressed transmembrane protein and the constituent of gap junctions (GJs) and hemichannels (HCs), allowing intercellular and extracellular communication, respectively. A plethora of research papers show altered Cx43 mRNA levels, protein expression, phosphorylation state, distribution and/or functional coupling in human epileptic tissue and experimental models. Human Cx43 mutations are linked to seizures as well, as 30% of patients with oculodentodigital dysplasia (ODDD), a rare genetic condition caused by mutations in the GJA1 gene coding for Cx43 protein, exhibit neurological symptoms including seizures. Cx30/Cx43 double knock-out mice show increased susceptibility to evoked epileptiform events in brain slices due to impaired GJ-mediated redistribution of K⁺ and glutamate and display a higher frequency of spontaneous generalized chronic seizures in an epilepsy model. Contradictory, Cx30/Cx43 GJs can traffic nutrients to high-energy demanding neurons and initiate astrocytic Ca²⁺ waves and hyper synchronization, thereby supporting proconvulsant effects. The general connexin channel blocker carbenoxolone and blockers from the fenamate family diminish epileptiform activity in vitro and improve seizure outcome in vivo. In addition, interventions with more selective peptide inhibitors of HCs display anticonvulsant actions. To conclude, further studies aiming to disentangle distinct roles of HCs and GJs are necessary and tools specifically targeting Cx43 HCs may facilitate the search for novel epilepsy treatments. Full article

(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)

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34 pages, 8748 KiB

Open AccessEditor’s ChoiceReview

Clinical Applications of Patient-Specific 3D Printed Models in Cardiovascular Disease: Current Status and Future Directions

by Zhonghua Sun

Biomolecules 2020, 10(11), 1577; https://doi.org/10.3390/biom10111577 - 20 Nov 2020

Cited by 44 | Viewed by 5862

Abstract

Three-dimensional (3D) printing has been increasingly used in medicine with applications in many different fields ranging from orthopaedics and tumours to cardiovascular disease. Realistic 3D models can be printed with different materials to replicate anatomical structures and pathologies with high accuracy. 3D printed [...] Read more.

Three-dimensional (3D) printing has been increasingly used in medicine with applications in many different fields ranging from orthopaedics and tumours to cardiovascular disease. Realistic 3D models can be printed with different materials to replicate anatomical structures and pathologies with high accuracy. 3D printed models generated from medical imaging data acquired with computed tomography, magnetic resonance imaging or ultrasound augment the understanding of complex anatomy and pathology, assist preoperative planning and simulate surgical or interventional procedures to achieve precision medicine for improvement of treatment outcomes, train young or junior doctors to gain their confidence in patient management and provide medical education to medical students or healthcare professionals as an effective training tool. This article provides an overview of patient-specific 3D printed models with a focus on the applications in cardiovascular disease including: 3D printed models in congenital heart disease, coronary artery disease, pulmonary embolism, aortic aneurysm and aortic dissection, and aortic valvular disease. Clinical value of the patient-specific 3D printed models in these areas is presented based on the current literature, while limitations and future research in 3D printing including bioprinting of cardiovascular disease are highlighted. Full article

(This article belongs to the Special Issue Usefulness and Clinical Applications of 3D Printing in Cardiovascular Diseases)

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34 pages, 807 KiB

Open AccessEditor’s ChoiceReview

Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders

by María S. García-Gutiérrez, Francisco Navarrete, Ani Gasparyan, Amaya Austrich-Olivares, Francisco Sala and Jorge Manzanares

Biomolecules 2020, 10(11), 1575; https://doi.org/10.3390/biom10111575 - 19 Nov 2020

Cited by 142 | Viewed by 52005

Abstract

The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) [...] Read more.

The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB₁r and CB₂r), 5-HT_1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders. Full article

(This article belongs to the Special Issue The Endocannabinoid System in Health and Disease)

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14 pages, 1289 KiB

Open AccessEditor’s ChoiceReview

Ferroptosis in Friedreich’s Ataxia: A Metal-Induced Neurodegenerative Disease

by Piergiorgio La Rosa, Sara Petrillo, Maria Teresa Fiorenza, Enrico Silvio Bertini and Fiorella Piemonte

Biomolecules 2020, 10(11), 1551; https://doi.org/10.3390/biom10111551 - 13 Nov 2020

Cited by 22 | Viewed by 4458

Abstract

Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player [...] Read more.

Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich’s Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress. Full article

(This article belongs to the Special Issue Biomolecules Controlling Transition Metals Derangement and Metal-Based Compounds as Therapeutic Approach for Cancer and Neurodegeneration)

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20 pages, 3216 KiB

Open AccessEditor’s ChoiceReview

Hyaluronan: Metabolism and Function

by Takashi Kobayashi, Theerawut Chanmee and Naoki Itano

Biomolecules 2020, 10(11), 1525; https://doi.org/10.3390/biom10111525 - 7 Nov 2020

Cited by 152 | Viewed by 13013

Abstract

As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis [...] Read more.

As a major polysaccharide component of the extracellular matrix, hyaluronan plays essential roles in the organization of tissue architecture and the regulation of cellular functions, such as cell proliferation and migration, through interactions with cell-surface receptors and binding molecules. Metabolic pathways for biosynthesis and degradation tightly control the turnover rate, concentration, and molecular size of hyaluronan in tissues. Despite the relatively simple chemical composition of this polysaccharide, its wide range of molecular weights mediate diverse functions that depend on molecular size and tissue concentration. Genetic engineering and pharmacological approaches have demonstrated close associations between hyaluronan metabolism and functions in many physiological and pathological events, including morphogenesis, wound healing, and inflammation. Moreover, emerging evidence has suggested that the accumulation of hyaluronan extracellular matrix and fragments due to the altered expression of hyaluronan synthases and hyaluronidases potentiates cancer development and progression by remodeling the tumor microenvironment. In addition to the well-known functions exerted by extracellular hyaluronan, recent metabolomic approaches have also revealed that its synthesis can regulate cellular functions via the reprogramming of cellular metabolism. This review highlights the current advances in knowledge on the biosynthesis and catabolism of hyaluronan and describes the diverse functions associated with hyaluronan metabolism. Full article

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

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24 pages, 1511 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Structural Conservation and Adaptation of the Bacterial Flagella Motor

by Brittany L. Carroll and Jun Liu

Biomolecules 2020, 10(11), 1492; https://doi.org/10.3390/biom10111492 - 29 Oct 2020

Cited by 25 | Viewed by 9372

Abstract

Many bacteria require flagella for the ability to move, survive, and cause infection. The flagellum is a complex nanomachine that has evolved to increase the fitness of each bacterium to diverse environments. Over several decades, molecular, biochemical, and structural insights into the flagella [...] Read more.

Many bacteria require flagella for the ability to move, survive, and cause infection. The flagellum is a complex nanomachine that has evolved to increase the fitness of each bacterium to diverse environments. Over several decades, molecular, biochemical, and structural insights into the flagella have led to a comprehensive understanding of the structure and function of this fascinating nanomachine. Notably, X-ray crystallography, cryo-electron microscopy (cryo-EM), and cryo-electron tomography (cryo-ET) have elucidated the flagella and their components to unprecedented resolution, gleaning insights into their structural conservation and adaptation. In this review, we focus on recent structural studies that have led to a mechanistic understanding of flagellar assembly, function, and evolution. Full article

(This article belongs to the Special Issue Perspectives on Bacterial Flagellar Motor)

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19 pages, 1107 KiB

Open AccessEditor’s ChoiceReview

Protective Effects of Epigallocatechin Gallate (EGCG) on Endometrial, Breast, and Ovarian Cancers

by Yun-Ju Huang, Kai-Lee Wang, Hsin-Yuan Chen, Yi-Fen Chiang and Shih-Min Hsia

Biomolecules 2020, 10(11), 1481; https://doi.org/10.3390/biom10111481 - 25 Oct 2020

Cited by 43 | Viewed by 7119

Abstract

Green tea and its major bioactive component, (−)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly antiproliferation, antimetastasis, and apoptosis induction. Many studies have widely investigated the anticancer and synergistic effects of EGCG due to the side effects of conventional cytotoxic agents. This review [...] Read more.

Green tea and its major bioactive component, (−)-epigallocatechin gallate (EGCG), possess diverse biological properties, particularly antiproliferation, antimetastasis, and apoptosis induction. Many studies have widely investigated the anticancer and synergistic effects of EGCG due to the side effects of conventional cytotoxic agents. This review summarizes recent knowledge of underlying mechanisms of EGCG on protective roles for endometrial, breast, and ovarian cancers based on both in vitro and in vivo animal studies. EGCG has the ability to regulate many pathways, including the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), inhibition of nuclear factor-κB (NF-κB), and protection against epithelial–mesenchymal transition (EMT). EGCG has also been found to interact with DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which affect epigenetic modifications. Finally, the action of EGCG may exert a suppressive effect on gynecological cancers and have beneficial effects on auxiliary therapies for known drugs. Thus, future clinical intervention studies with EGCG will be necessary to more and clear evidence for the benefit to these cancers. Full article

(This article belongs to the Special Issue Biomolecules and Cancer Prevention)

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32 pages, 2420 KiB

Open AccessEditor’s ChoiceReview

Updating Phospholipase A₂ Biology

by Makoto Murakami, Hiroyasu Sato and Yoshitaka Taketomi

Biomolecules 2020, 10(10), 1457; https://doi.org/10.3390/biom10101457 - 19 Oct 2020

Cited by 122 | Viewed by 11108

Abstract

The phospholipase A₂ (PLA₂) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA₂ has the capacity to hydrolyze the sn-2 position of glycerophospholipids [...] Read more.

The phospholipase A₂ (PLA₂) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA₂ has the capacity to hydrolyze the sn-2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA₂ reaction. PLA₂ enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA₂-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA₂ superfamily, focusing particularly on the novel roles of PLA₂s in vivo. Full article

(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)

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22 pages, 1142 KiB

Open AccessEditor’s ChoiceReview

Ubiquitomics: An Overview and Future

by George Vere, Rachel Kealy, Benedikt M. Kessler and Adan Pinto-Fernandez

Biomolecules 2020, 10(10), 1453; https://doi.org/10.3390/biom10101453 - 17 Oct 2020

Cited by 22 | Viewed by 6380

Abstract

Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is a key post-translational modification that determines the fate, function, and turnover of most cellular proteins. Ubiquitin modification exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected [...] Read more.

Covalent attachment of ubiquitin, a small globular polypeptide, to protein substrates is a key post-translational modification that determines the fate, function, and turnover of most cellular proteins. Ubiquitin modification exists as mono- or polyubiquitin chains involving multiple ways how ubiquitin C-termini are connected to lysine, perhaps other amino acid side chains, and N-termini of proteins, often including branching of the ubiquitin chains. Understanding this enormous complexity in protein ubiquitination, the so-called ‘ubiquitin code’, in combination with the

\sim

1000 enzymes involved in controlling ubiquitin recognition, conjugation, and deconjugation, calls for novel developments in analytical techniques. Here, we review different headways in the field mainly driven by mass spectrometry and chemical biology, referred to as “ubiquitomics”, aiming to understand this system’s biological diversity. Full article

(This article belongs to the Special Issue Looking Back and Ahead: Emerging Concepts in Ubiquitin and UBLs)

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