Biomolecules

12 pages, 692 KiB

Open AccessEditor’s ChoiceReview

Neutrophil in the Pancreatic Tumor Microenvironment

by Lin Jin, Hong Sun Kim and Jiaqi Shi

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

Cited by 39 | Viewed by 6852

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

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

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

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19 pages, 13260 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 12 | Viewed by 3940

Abstract

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

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

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

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22 pages, 4261 KiB

Open AccessEditor’s ChoiceReview

The Bigger Picture: Why Oral Mucosa Heals Better Than Skin

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

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

Cited by 106 | Viewed by 17438

Abstract

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

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

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

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12 pages, 631 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 38 | Viewed by 3868

Abstract

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

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

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15 pages, 2155 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells

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

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

Cited by 22 | Viewed by 6082

Abstract

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

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

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

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15 pages, 1532 KiB

Open AccessEditor’s ChoiceReview

Pregnane X Receptor (PXR) Polymorphisms and Cancer Treatment

by Aikaterini Skandalaki, Panagiotis Sarantis and Stamatios Theocharis

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

Cited by 21 | Viewed by 4607

Abstract

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

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

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

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11 pages, 974 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Ocular Gene Delivery Landscape

by Bhubanananda Sahu, Isha Chug and Hemant Khanna

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

Cited by 21 | Viewed by 6313

Abstract

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

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

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

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23 pages, 3202 KiB

Open AccessEditor’s ChoiceReview

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

by Eduardo Ruiz-López and Alberto J. Schuhmacher

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

Cited by 58 | Viewed by 12745

Abstract

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

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

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

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36 pages, 3020 KiB

Open AccessEditor’s ChoiceReview

Understanding and Exploiting Post-Translational Modifications for Plant Disease Resistance

by Catherine Gough and Ari Sadanandom

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

Cited by 23 | Viewed by 6654

Abstract

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

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

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

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17 pages, 3960 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 16 | Viewed by 4002

Abstract

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

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

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

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18 pages, 496 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 41 | Viewed by 9512

Abstract

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

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

(This article belongs to the Section Molecular Genetics)

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17 pages, 2188 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 16 | Viewed by 4963

Abstract

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

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

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

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29 pages, 1626 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Joanna M Wierońska, Paulina Cieślik and Leszek Kalinowski

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

Cited by 61 | Viewed by 6892

Abstract

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

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

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

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21 pages, 3477 KiB

Open AccessEditor’s ChoiceReview

Oxidative Power: Tools for Assessing LPMO Activity on Cellulose

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

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

Cited by 13 | Viewed by 6486

Abstract

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

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

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

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27 pages, 832 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 143 | Viewed by 19853

Abstract

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

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

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

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20 pages, 3086 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 24 | Viewed by 4952

Abstract

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

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

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

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14 pages, 1240 KiB

Open AccessEditor’s ChoiceReview

Epigenetic Alterations in Pancreatic Cancer Metastasis

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

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

Cited by 38 | Viewed by 6692

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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15 pages, 339 KiB

Open AccessEditor’s ChoiceReview

Neutrophil Elastase and Chronic Lung Disease

by Judith A. Voynow and Meagan Shinbashi

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

Cited by 126 | Viewed by 16646

Abstract

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

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

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

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20 pages, 1102 KiB

Open AccessEditor’s ChoiceReview

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

by Ilias Kalafatakis and Domna Karagogeos

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

Cited by 74 | Viewed by 13031

Abstract

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

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

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

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12 pages, 1646 KiB

Open AccessEditor’s ChoiceArticle

Screening for Fatal Traumatic Brain Injuries in Cerebrospinal Fluid Using Blood-Validated CK and CK–MB Immunoassays

by Johann Zwirner, Sven Anders, Simone Bohnert, Ralph Burkhardt, Ugo Da Broi, Niels Hammer, Dirk Pohlers, Rexson Tse and Benjamin Ondruschka

Biomolecules 2021, 11(7), 1061; https://doi.org/10.3390/biom11071061 - 20 Jul 2021

Cited by 9 | Viewed by 5491

Abstract

A single, specific, sensitive biochemical biomarker that can reliably diagnose a traumatic brain injury (TBI) has not yet been found, but combining different biomarkers would be the most promising approach in clinical and postmortem settings. In addition, identifying new biomarkers and developing laboratory [...] Read more.

A single, specific, sensitive biochemical biomarker that can reliably diagnose a traumatic brain injury (TBI) has not yet been found, but combining different biomarkers would be the most promising approach in clinical and postmortem settings. In addition, identifying new biomarkers and developing laboratory tests can be time-consuming and economically challenging. As such, it would be efficient to use established clinical diagnostic assays for postmortem biochemistry. In this study, postmortem cerebrospinal fluid samples from 45 lethal TBI cases and 47 controls were analyzed using commercially available blood-validated assays for creatine kinase (CK) activity and its heart-type isoenzyme (CK–MB). TBI cases with a survival time of up to two hours showed an increase in both CK and CK–MB with moderate (CK–MB: AUC = 0.788, p < 0.001) to high (CK: AUC = 0.811, p < 0.001) diagnostic accuracy. This reflected the excessive increase of the brain-type CK isoenzyme (CK–BB) following a TBI. The results provide evidence that CK immunoassays can be used as an adjunct quantitative test aid in diagnosing acute TBI-related fatalities. Full article

(This article belongs to the Special Issue Postmortem Biochemistry-When Death Matters)

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23 pages, 9050 KiB

Open AccessEditor’s ChoiceArticle

Interaction Mode of the Novel Monobactam AIC499 Targeting Penicillin Binding Protein 3 of Gram-Negative Bacteria

by Stefan Freischem, Immanuel Grimm, Arancha López-Pérez, Dieter Willbold, Burkhard Klenke, Cuong Vuong, Andrew J. Dingley and Oliver H. Weiergräber

Biomolecules 2021, 11(7), 1057; https://doi.org/10.3390/biom11071057 - 19 Jul 2021

Cited by 12 | Viewed by 4465

Abstract

Novel antimicrobial strategies are urgently required because of the rising threat of multi drug resistant bacterial strains and the infections caused by them. Among the available target structures, the so-called penicillin binding proteins are of particular interest, owing to their good accessibility in [...] Read more.

Novel antimicrobial strategies are urgently required because of the rising threat of multi drug resistant bacterial strains and the infections caused by them. Among the available target structures, the so-called penicillin binding proteins are of particular interest, owing to their good accessibility in the periplasmic space, and the lack of homologous proteins in humans, reducing the risk of side effects of potential drugs. In this report, we focus on the interaction of the innovative β-lactam antibiotic AIC499 with penicillin binding protein 3 (PBP3) from Escherichia coli and Pseudomonas aeruginosa. This recently developed monobactam displays broad antimicrobial activity, against Gram-negative strains, and improved resistance to most classes of β-lactamases. By analyzing crystal structures of the respective complexes, we were able to explore the binding mode of AIC499 to its target proteins. In addition, the apo structures determined for PBP3, from P. aeruginosa and the catalytic transpeptidase domain of the E. coli orthologue, provide new insights into the dynamics of these proteins and the impact of drug binding. Full article

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12 pages, 2294 KiB

Open AccessEditor’s ChoiceArticle

Enzymatic and Chemical Syntheses of Vacor Analogs of Nicotinamide Riboside, NMN and NAD

by Lars Jansen Sverkeli, Faisal Hayat, Marie E. Migaud and Mathias Ziegler

Biomolecules 2021, 11(7), 1044; https://doi.org/10.3390/biom11071044 - 16 Jul 2021

Cited by 13 | Viewed by 4735

Abstract

It has recently been demonstrated that the rat poison vacor interferes with mammalian NAD metabolism, because it acts as a nicotinamide analog and is converted by enzymes of the NAD salvage pathway. Thereby, vacor is transformed into the NAD analog vacor adenine dinucleotide [...] Read more.

It has recently been demonstrated that the rat poison vacor interferes with mammalian NAD metabolism, because it acts as a nicotinamide analog and is converted by enzymes of the NAD salvage pathway. Thereby, vacor is transformed into the NAD analog vacor adenine dinucleotide (VAD), a molecule that causes cell toxicity. Therefore, vacor may potentially be exploited to kill cancer cells. In this study, we have developed efficient enzymatic and chemical procedures to produce vacor analogs of NAD and nicotinamide riboside (NR). VAD was readily generated by a base-exchange reaction, replacing the nicotinamide moiety of NAD by vacor, catalyzed by Aplysia californica ADP ribosyl cyclase. Additionally, we present the chemical synthesis of the nucleoside version of vacor, vacor riboside (VR). Similar to the physiological NAD precursor, NR, VR was converted to the corresponding mononucleotide (VMN) by nicotinamide riboside kinases (NRKs). This conversion is quantitative and very efficient. Consequently, phosphorylation of VR by NRKs represents a valuable alternative to produce the vacor analog of NMN, compared to its generation from vacor by nicotinamide phosphoribosyltransferase (NamPT). Full article

(This article belongs to the Special Issue Biotechnological and Biomedical Applications of Enzymes Involved in the Synthesis of Nucleosides and Nucleotides)

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15 pages, 3594 KiB

Open AccessEditor’s ChoiceArticle

Bisphenol a Exposure and Kidney Diseases: Systematic Review, Meta-Analysis, and NHANES 03–16 Study

by Rafael Moreno-Gómez-Toledano, María I. Arenas, Esperanza Vélez-Vélez, Elisabeth Coll, Borja Quiroga, Jordi Bover and Ricardo J. Bosch

Biomolecules 2021, 11(7), 1046; https://doi.org/10.3390/biom11071046 - 16 Jul 2021

Cited by 35 | Viewed by 5357

Abstract

Bisphenol A (BPA) is a compound that is especially widespread in most commonly used objects due to its multiple uses in the plastic industry. However, several data support the need to restrict its use. In recent years, new implications of BPA on the [...] Read more.

Bisphenol A (BPA) is a compound that is especially widespread in most commonly used objects due to its multiple uses in the plastic industry. However, several data support the need to restrict its use. In recent years, new implications of BPA on the renal system have been discovered, which denotes the need to expand studies in patients. To this end, a systematic review and a meta-analysis was performed to explore existing literature that examines the BPA-kidney disease paradigm and to determine what and how future studies will need to be carried out. Our systematic review revealed that only few relevant publications have focused on the problem. However, the subsequent meta-analysis revealed that high blood concentrations of BPA could be a factor in developing kidney disease, at least in people with previous pathologies such as diabetes or hypertension. Furthermore, BPA could also represent a risk factor in healthy people whose urinary excretion is higher. Finally, the data analyzed from the NHANES 03-16 cohort provided new evidence on the possible involvement of BPA in kidney disease. Therefore, our results underline the need to carry out a thorough and methodologically homogeneous study, delving into the relationship between urinary and blood BPA, glomerular filtration rate, and urine albumin-to-creatinine ratio, preferably in population groups at risk, and subsequently in the general population, to solve this relevant conundrum with critical potential implications in Public Health. Full article

(This article belongs to the Special Issue Bisphenol A: An Environmental Factor with an Emerging Role in the Pathophysiology of Renal and Cardiovascular Diseases)

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17 pages, 4263 KiB

Open AccessEditor’s ChoiceArticle

Selenium Nanoparticles as Candidates for Antibacterial Substitutes and Supplements against Multidrug-Resistant Bacteria

by Hee-Won Han, Kapil D. Patel, Jin-Hwan Kwak, Soo-Kyung Jun, Tae-Su Jang, Sung-Hoon Lee, Jonathan Campbell Knowles, Hae-Won Kim, Hae-Hyoung Lee and Jung-Hwan Lee

Biomolecules 2021, 11(7), 1028; https://doi.org/10.3390/biom11071028 - 14 Jul 2021

Cited by 52 | Viewed by 5033

Abstract

In recent years, multidrug-resistant (MDR) bacteria have increased rapidly, representing a major threat to human health. This problem has created an urgent need to identify alternatives for the treatment of MDR bacteria. The aim of this study was to identify the antibacterial activity [...] Read more.

In recent years, multidrug-resistant (MDR) bacteria have increased rapidly, representing a major threat to human health. This problem has created an urgent need to identify alternatives for the treatment of MDR bacteria. The aim of this study was to identify the antibacterial activity of selenium nanoparticles (SeNPs) and selenium nanowires (SeNWs) against MDR bacteria and assess the potential synergistic effects when combined with a conventional antibiotic (linezolid). SeNPs and SeNWs were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), zeta potential, and UV-visible analysis. The antibacterial effects of SeNPs and SeNWs were confirmed by the macro-dilution minimum inhibitory concentration (MIC) test. SeNPs showed MIC values against methicillin-sensitive S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-resistant S. aureus (VRSA), and vancomycin-resistant enterococci (VRE) at concentrations of 20, 80, 320, and >320 μg/mL, respectively. On the other hand, SeNWs showed a MIC value of >320 μg/mL against all tested bacteria. Therefore, MSSA, MRSA, and VRSA were selected for the bacteria to be tested, and SeNPs were selected as the antimicrobial agent for the following experiments. In the time-kill assay, SeNPs at a concentration of 4X MIC (80 and 320 μg/mL) showed bactericidal effects against MSSA and MRSA, respectively. At a concentration of 2X MIC (40 and 160 μg/mL), SeNPs showed bacteriostatic effects against MSSA and bactericidal effects against MRSA, respectively. In the synergy test, SeNPs showed a synergistic effect with linezolid (LZD) through protein degradation against MSSA and MRSA. In conclusion, these results suggest that SeNPs can be candidates for antibacterial substitutes and supplements against MDR bacteria for topical use, such as dressings. However, for use in clinical situations, additional experiments such as toxicity and synergistic mechanism tests of SeNPs are needed. Full article

(This article belongs to the Special Issue Bio-Based Co-Adjuvant Systems for Infection Control)

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18 pages, 594 KiB

Open AccessEditor’s ChoiceReview

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

by Macy L. Sprunger and Meredith E. Jackrel

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

Cited by 29 | Viewed by 11242

Abstract

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

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

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

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16 pages, 3623 KiB

Open AccessEditor’s ChoiceReview

Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives

by Suresh Thangudu and Chia-Hao Su

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

Cited by 52 | Viewed by 9087

Abstract

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

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

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

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38 pages, 4838 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 54 | Viewed by 7207

Abstract

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

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

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

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18 pages, 987 KiB

Open AccessEditor’s ChoiceReview

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

by Kenneth Maiese

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

Cited by 40 | Viewed by 6526

Abstract

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

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

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

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16 pages, 2777 KiB

Open AccessEditor’s ChoiceArticle

Effects of the Clock Modulator Nobiletin on Circadian Rhythms and Pathophysiology in Female Mice of an Alzheimer’s Disease Model

by Eunju Kim, Kazunari Nohara, Marvin Wirianto, Gabriel Escobedo, Jr., Ji Ye Lim, Rodrigo Morales, Seung-Hee Yoo and Zheng Chen

Biomolecules 2021, 11(7), 1004; https://doi.org/10.3390/biom11071004 - 9 Jul 2021

Cited by 36 | Viewed by 5710

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. Various pathogenic mechanisms have been proposed to contribute to disease progression, and recent research provided evidence linking dysregulated circadian rhythms/sleep and energy metabolism with AD. Previously, we found [...] Read more.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. Various pathogenic mechanisms have been proposed to contribute to disease progression, and recent research provided evidence linking dysregulated circadian rhythms/sleep and energy metabolism with AD. Previously, we found that the natural compound Nobiletin (NOB) can directly activate circadian cellular oscillators to promote metabolic health in disease models and healthy aging in naturally aged mice. In the current study, using the amyloid-β AD model APP/PS1, we investigated circadian, metabolic and amyloid characteristics of female mice and the effects of NOB. Female APP/PS1 mice showed reduced sleep bout duration, and NOB treatment exhibited a trend to improve it. While glucose tolerance was unchanged, female APP/PS1 mice displayed exaggerated oxygen consumption and CO2 production, which was mitigated by NOB. Likewise, cold tolerance in APP/PS1 was impaired relative to WT, and interestingly was markedly enhanced in NOB-treated APP/PS1 mice. Although circadian behavioral rhythms were largely unchanged, real-time qPCR analysis revealed altered expression of several core clock genes by NOB in the cerebral cortex, notably Bmal1, Npas2, and Rora. Moreover, NOB was also able to activate various clock-controlled metabolic genes involved in insulin signaling and mitochondrial function, including Igf1, Glut1, Insr, Irs1, Ucp2, and Ucp4. Finally, we observed that NOB attenuated the expression of several AD related genes including App, Bace1, and ApoE, reduced APP protein levels, and strongly ameliorated Aβ pathology in the cortex. Collectively, these results reveal novel genotype differences and importantly beneficial effects of a natural clock-enhancing compound in biological rhythms and related pathophysiology, suggesting the circadian clock as a modifiable target for AD. Full article

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

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26 pages, 872 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 129 | Viewed by 19171

Abstract

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

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

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

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30 pages, 1250 KiB

Open AccessEditor’s ChoiceReview

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

by Renuka Raman, Krishna J. Patel and Kishu Ranjan

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

Cited by 158 | Viewed by 17385

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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15 pages, 1049 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 36 | Viewed by 6033

Abstract

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

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

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

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17 pages, 2690 KiB

Open AccessEditor’s ChoiceReview

TFEB Signalling-Related MicroRNAs and Autophagy

by Davide Corà, Federico Bussolino and Gabriella Doronzo

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

Cited by 20 | Viewed by 5580

Abstract

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

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

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

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13 pages, 2343 KiB

Open AccessEditor’s ChoiceArticle

Receptor Interactions of Angiotensin II and Angiotensin Receptor Blockers—Relevance to COVID-19

by Graham J. Moore, Jose M. Pires, Konstantinos Kelaidonis, Laura Kate Gadanec, Anthony Zulli, Vasso Apostolopoulos and John M. Matsoukas

Biomolecules 2021, 11(7), 979; https://doi.org/10.3390/biom11070979 - 3 Jul 2021

Cited by 22 | Viewed by 3762

Abstract

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino [...] Read more.

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy. Full article

(This article belongs to the Special Issue The Role of Angiotensin in Cardiovascular Disease)

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21 pages, 1685 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 92 | Viewed by 7630

Abstract

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

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

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

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20 pages, 4588 KiB

Open AccessEditor’s ChoiceArticle

Phytochemical Analysis and Anti-Inflammatory Activity of Different Ethanolic Phyto-Extracts of Artemisia annua L.

by Giulia Abate, Leilei Zhang, Mariachiara Pucci, Giulia Morbini, Eileen Mac Sweeney, Giuseppina Maccarinelli, Giovanni Ribaudo, Alessandra Gianoncelli, Daniela Uberti, Maurizio Memo, Luigi Lucini and Andrea Mastinu

Biomolecules 2021, 11(7), 975; https://doi.org/10.3390/biom11070975 - 2 Jul 2021

Cited by 76 | Viewed by 8798

Abstract

Artemisia annua L. (AA) has shown for many centuries important therapeutic virtues associated with the presence of artemisinin (ART). The aim of this study was to identify and quantify ART and other secondary metabolites in ethanolic extracts of AA and evaluate the biological [...] Read more.

Artemisia annua L. (AA) has shown for many centuries important therapeutic virtues associated with the presence of artemisinin (ART). The aim of this study was to identify and quantify ART and other secondary metabolites in ethanolic extracts of AA and evaluate the biological activity in the presence of an inflammatory stimulus. In this work, after the extraction of the aerial parts of AA with different concentrations of ethanol, ART was quantified by HPLC and HPLC-MS. In addition, anthocyanins, flavanols, flavanones, flavonols, lignans, low-molecular-weight phenolics, phenolic acids, stilbenes, and terpenes were identified and semi-quantitatively determined by UHPLC-QTOF-MS untargeted metabolomics. Finally, the viability of human neuroblastoma cells (SH-SY5Y) was evaluated in the presence of the different ethanolic extracts and in the presence of lipopolysaccharide (LPS). The results show that ART is more concentrated in AA samples extracted with 90% ethanol. Regarding the other metabolites, only the anthocyanins are more concentrated in the samples extracted with 90% ethanol. Finally, ART and all AA samples showed a protective action towards the pro-inflammatory stimulus of LPS. In particular, the anti-inflammatory effect of the leaf extract of AA with 90% ethanol was also confirmed at the molecular level since a reduction in TNF-α mRNA gene expression was observed in SH-SY5Y treated with LPS. Full article

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26 pages, 2545 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 26 | Viewed by 4835

Abstract

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

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

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

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18 pages, 5209 KiB

Open AccessEditor’s ChoiceArticle

The Protein Kinase Inhibitor Midostaurin Improves Functional Neurological Recovery and Attenuates Inflammatory Changes Following Traumatic Cervical Spinal Cord Injury

by Mohammad-Masoud Zavvarian, James Hong, Mohamad Khazaei, Jonathon Chon Teng Chio, Jian Wang, Anna Badner and Michael G. Fehlings

Biomolecules 2021, 11(7), 972; https://doi.org/10.3390/biom11070972 - 1 Jul 2021

Cited by 9 | Viewed by 5553

Abstract

Traumatic spinal cord injury (SCI) impairs neuronal function and introduces a complex cascade of secondary pathologies that limit recovery. Despite decades of preclinical and clinical research, there is a shortage of efficacious treatment options to modulate the secondary response to injury. Protein kinases [...] Read more.

Traumatic spinal cord injury (SCI) impairs neuronal function and introduces a complex cascade of secondary pathologies that limit recovery. Despite decades of preclinical and clinical research, there is a shortage of efficacious treatment options to modulate the secondary response to injury. Protein kinases are crucial signaling molecules that mediate the secondary SCI-induced cellular response and present promising therapeutic targets. The objective of this study was to examine the safety and efficacy of midostaurin—a clinically-approved multi-target protein kinase inhibitor—on cervical SCI pathogenesis. High-throughput analyses demonstrated that intraperitoneal midostaurin injection (25 mg/kg) in C6/7 injured Wistar rats altered the local inflammasome and downregulated adhesive and migratory genes at 24 h post-injury. Treated animals also exhibited enhanced recovery and restored coordination between forelimbs and hindlimbs after injury, indicating the synergistic impact of midostaurin and its dimethyl sulfoxide vehicle to improve functional recovery. Furthermore, histological analyses suggested improved tissue preservation and functionality in the treated animals during the chronic phase of injury. This study serves as a proof-of-concept experiment and demonstrates that systemic midostaurin administration is an effective strategy for mitigating cervical secondary SCI damage. Full article

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26 pages, 1376 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Transcriptomic and Epigenomic Landscape in Rett Syndrome

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

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

Cited by 12 | Viewed by 5880

Abstract

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

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

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

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15 pages, 1958 KiB

Open AccessEditor’s ChoiceArticle

Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

by John S. Lazo, Elizabeth R. Sharlow, Robert Cornelison, Duncan J. Hart, Danielle C. Llaneza, Anna J. Mendelson, Ettore J. Rastelli, Nikhil R. Tasker, Charles N. Landen, Jr. and Peter Wipf

Biomolecules 2021, 11(7), 969; https://doi.org/10.3390/biom11070969 - 30 Jun 2021

Cited by 9 | Viewed by 4660

Abstract

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient [...] Read more.

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053. Full article

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

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22 pages, 2152 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 60 | Viewed by 7462

Abstract

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

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

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

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23 pages, 3912 KiB

Open AccessEditor’s ChoiceArticle

Copper Imbalance in Alzheimer’s Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants

by Rosanna Squitti, Mariacarla Ventriglia, Ilaria Simonelli, Cristian Bonvicini, Alfredo Costa, Giulia Perini, Giuliano Binetti, Luisa Benussi, Roberta Ghidoni, Giacomo Koch, Barbara Borroni, Alberto Albanese, Stefano L. Sensi and Mauro Rongioletti

Biomolecules 2021, 11(7), 960; https://doi.org/10.3390/biom11070960 - 29 Jun 2021

Cited by 56 | Viewed by 4789

Abstract

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled [...] Read more.

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation. Full article

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

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15 pages, 1955 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing

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

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

Cited by 38 | Viewed by 7909

Abstract

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

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

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

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23 pages, 1636 KiB

Open AccessEditor’s ChoiceReview

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

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

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

Cited by 40 | Viewed by 9460

Abstract

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

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

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

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20 pages, 2344 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 24 | Viewed by 4732

Abstract

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

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

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

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14 pages, 2217 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Compression Model for Orthodontic Tooth Movement Modulates Human Periodontal Ligament Fibroblast Proliferation, Apoptosis and Cell Cycle

by Julia Brockhaus, Rogerio B. Craveiro, Irma Azraq, Christian Niederau, Sarah K. Schröder, Ralf Weiskirchen, Joachim Jankowski and Michael Wolf

Biomolecules 2021, 11(7), 932; https://doi.org/10.3390/biom11070932 - 23 Jun 2021

Cited by 23 | Viewed by 3921

Abstract

Human Periodontal Ligament Fibroblasts (hPDLF), as part of the periodontal apparatus, modulate inflammation, regeneration and bone remodeling. Interferences are clinically manifested as attachment loss, tooth loosening and root resorption. During orthodontic tooth movement (OTM), remodeling and adaptation of the periodontium is required in [...] Read more.

Human Periodontal Ligament Fibroblasts (hPDLF), as part of the periodontal apparatus, modulate inflammation, regeneration and bone remodeling. Interferences are clinically manifested as attachment loss, tooth loosening and root resorption. During orthodontic tooth movement (OTM), remodeling and adaptation of the periodontium is required in order to enable tooth movement. hPDLF involvement in the early phase-OTM compression side was investigated for a 72-h period through a well-studied in vitro model. Changes in the morphology, cell proliferation and cell death were analyzed. Specific markers of the cell cycle were investigated by RT-qPCR and Western blot. The study showed that the morphology of hPDLF changes towards more unstructured, unsorted filaments under mechanical compression. The total cell numbers were significantly reduced with a higher cell death rate over the whole observation period. hPDLF started to recover to pretreatment conditions after 48 h. Furthermore, key molecules involved in the cell cycle were significantly reduced under compressive force at the gene expression and protein levels. These findings revealed important information for a better understanding of the preservation and remodeling processes within the periodontium through Periodontal Ligament Fibroblasts during orthodontic tooth movement. OTM initially decelerates the hPDLF cell cycle and proliferation. After adapting to environmental changes, human Periodontal Ligament Fibroblasts can regain homeostasis of the periodontium, affecting its reorganization. Full article

(This article belongs to the Special Issue Oral Regenerative Medicine: Current and Future)

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16 pages, 901 KiB

Open AccessEditor’s ChoiceReview

Leptin, Both Bad and Good Actor in Cancer

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

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

Cited by 43 | Viewed by 7076

Abstract

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

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

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

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13 pages, 1794 KiB

Open AccessEditor’s ChoiceArticle

The m⁶A RNA Modification Quantity and mRNA Expression Level of RNA Methylation-Related Genes in Head and Neck Squamous Cell Carcinoma Cell Lines and Patients

by Kamila Romanowska, Agnieszka A. Rawłuszko-Wieczorek, Łukasz Marczak, Agnieszka Kosińska, Wiktoria M. Suchorska and Wojciech Golusiński

Biomolecules 2021, 11(6), 908; https://doi.org/10.3390/biom11060908 - 18 Jun 2021

Cited by 9 | Viewed by 3568

Abstract

RNA methylation at the nitrogen sixth of adenosine (m⁶A, N⁶-methyladenosine) is the most abundant RNA modification which plays a crucial role in all RNA metabolic aspects. Recently, m⁶A modification has been assigned to mediate the biological processes [...] Read more.

RNA methylation at the nitrogen sixth of adenosine (m⁶A, N⁶-methyladenosine) is the most abundant RNA modification which plays a crucial role in all RNA metabolic aspects. Recently, m⁶A modification has been assigned to mediate the biological processes of cancer cells, but their significance in HNSCC development is still poorly described. Thus, the main aim of this study was to globally quantify m⁶A modification by the mass spectrometry approach and determine the mRNA expression level of selected m⁶A RNA methyltransferase (METTL3), demethylase (FTO), and m⁶A readers (YTHDF2, YTHDC2) in 45 HNSCC patients and 4 cell lines (FaDu, Detroit 562, A-253 and SCC-15) using qPCR. In the results, we have not observed differences in the global amount of m⁶A modification and the mRNA level of the selected genes between the cancerous and paired-matched histopathologically unchanged tissues from 45 HNSCC patients. However, we have found a positive correlation between selected RNA methylation machinery genes expression and m⁶A abundance on total RNA and characterized the transcript level of those genes in the HNSCC cell lines. Moreover, the lack of global m⁶A differences between cancerous and histopathologically unchanged tissues suggests that m⁶A alterations in specific RNA sites may specifically influence HNSCC tumorigenesis. Full article

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

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19 pages, 4558 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 15 | Viewed by 5668

Abstract

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

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

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

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25 pages, 2178 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 26 | Viewed by 6037

Abstract

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

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

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

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