Biomolecules

Review

22 pages, 8209 KiB

Open AccessEditor’s ChoiceReview

Cell-Adhesion Properties of β-Subunits in the Regulation of Cardiomyocyte Sodium Channels

by Samantha C. Salvage, Christopher L.-H. Huang and Antony P. Jackson

Biomolecules 2020, 10(7), 989; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10070989 - 1 Jul 2020

Cited by 14 | Viewed by 5649

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel α-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel α-subunit isoform, with a smaller expression [...] Read more.

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel α-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel α-subunit isoform, with a smaller expression of neuronal Nav channels. Four distinct regulatory β-subunits (β1–4) bind to the Nav channel α-subunits. Previous work has emphasised the β-subunits as direct Nav channel gating modulators. However, there is now increasing appreciation of additional roles played by these subunits. In this review, we focus on β-subunits as homophilic and heterophilic cell-adhesion molecules and the implications for cardiomyocyte function. Based on recent cryogenic electron microscopy (cryo-EM) data, we suggest that the β-subunits interact with Nav1.5 in a different way from their binding to other Nav channel isoforms. We believe this feature may facilitate trans-cell-adhesion between β1-associated Nav1.5 subunits on the intercalated disc and promote ephaptic conduction between cardiomyocytes. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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32 pages, 2345 KiB

Open AccessEditor’s ChoiceReview

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

by Yves Jossin

Biomolecules 2020, 10(6), 964; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10060964 - 26 Jun 2020

Cited by 100 | Viewed by 9077

Abstract

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human [...] Read more.

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders. Full article

(This article belongs to the Special Issue Reelin, a Hub Protein during Nervous System Development?)

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28 pages, 1235 KiB

Open AccessEditor’s ChoiceReview

The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives

by Emiliano Panieri, Pelin Telkoparan-Akillilar, Sibel Suzen and Luciano Saso

Biomolecules 2020, 10(5), 791; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050791 - 20 May 2020

Cited by 52 | Viewed by 5899

Abstract

The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic [...] Read more.

The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review. Full article

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

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32 pages, 1311 KiB

Open AccessEditor’s ChoiceReview

Carbapenemases: Transforming Acinetobacter baumannii into a Yet More Dangerous Menace

by Maria Soledad Ramirez, Robert A. Bonomo and Marcelo E. Tolmasky

Biomolecules 2020, 10(5), 720; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050720 - 6 May 2020

Cited by 122 | Viewed by 11941

Abstract

Acinetobacter baumannii is a common cause of serious nosocomial infections. Although community-acquired infections are observed, the vast majority occur in people with preexisting comorbidities. A. baumannii emerged as a problematic pathogen in the 1980s when an increase in virulence, difficulty in treatment due [...] Read more.

Acinetobacter baumannii is a common cause of serious nosocomial infections. Although community-acquired infections are observed, the vast majority occur in people with preexisting comorbidities. A. baumannii emerged as a problematic pathogen in the 1980s when an increase in virulence, difficulty in treatment due to drug resistance, and opportunities for infection turned it into one of the most important threats to human health. Some of the clinical manifestations of A. baumannii nosocomial infection are pneumonia; bloodstream infections; lower respiratory tract, urinary tract, and wound infections; burn infections; skin and soft tissue infections (including necrotizing fasciitis); meningitis; osteomyelitis; and endocarditis. A. baumannii has an extraordinary genetic plasticity that results in a high capacity to acquire antimicrobial resistance traits. In particular, acquisition of resistance to carbapenems, which are among the antimicrobials of last resort for treatment of multidrug infections, is increasing among A. baumannii strains compounding the problem of nosocomial infections caused by this pathogen. It is not uncommon to find multidrug-resistant (MDR, resistance to at least three classes of antimicrobials), extensively drug-resistant (XDR, MDR plus resistance to carbapenems), and pan-drug-resistant (PDR, XDR plus resistance to polymyxins) nosocomial isolates that are hard to treat with the currently available drugs. In this article we review the acquired resistance to carbapenems by A. baumannii. We describe the enzymes within the OXA, NDM, VIM, IMP, and KPC groups of carbapenemases and the coding genes found in A. baumannii clinical isolates. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

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30 pages, 1274 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Novel Applications of Mesenchymal Stem Cell-Derived Exosomes for Myocardial Infarction Therapeutics

by Sho Joseph Ozaki Tan, Juliana Ferreria Floriano, Laura Nicastro, Costanza Emanueli and Francesco Catapano

Biomolecules 2020, 10(5), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050707 - 2 May 2020

Cited by 58 | Viewed by 6902

Abstract

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts. Full article

(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)

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82 pages, 15127 KiB

Open AccessEditor’s ChoiceReview

Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

by Karim Zuhra, Fiona Augsburger, Tomas Majtan and Csaba Szabo

Biomolecules 2020, 10(5), 697; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050697 - 30 Apr 2020

Cited by 125 | Viewed by 11962

Abstract

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen [...] Read more.

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H₂S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models. Full article

(This article belongs to the Special Issue H₂S, Polysulfides, and Enzymes: Physiological and Pathological Aspects)

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21 pages, 1138 KiB

Open AccessEditor’s ChoiceReview

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment

by Eun Seong Hwang and Seon Beom Song

Biomolecules 2020, 10(5), 687; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050687 - 29 Apr 2020

Cited by 68 | Viewed by 18110

Abstract

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects [...] Read more.

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD⁺) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD⁺ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM. Full article

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

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17 pages, 728 KiB

Open AccessEditor’s ChoiceReview

The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

by Evangelos Koustas, Panagiotis Sarantis, Athanasios G. Papavassiliou and Michalis V. Karamouzis

Biomolecules 2020, 10(5), 666; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050666 - 25 Apr 2020

Cited by 31 | Viewed by 5178

Abstract

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary [...] Read more.

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors. Full article

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

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15 pages, 1210 KiB

Open AccessEditor’s ChoiceReview

Antimicrobial and Antibiofilm Peptides

by Angela Di Somma, Antonio Moretta, Carolina Canè, Arianna Cirillo and Angela Duilio

Biomolecules 2020, 10(4), 652; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040652 - 23 Apr 2020

Cited by 150 | Viewed by 10548

Abstract

The increasing onset of multidrug-resistant bacteria has propelled microbiology research towards antimicrobial peptides as new possible antibiotics from natural sources. Antimicrobial peptides are short peptides endowed with a broad range of activity against both Gram-positive and Gram-negative bacteria and are less prone to [...] Read more.

The increasing onset of multidrug-resistant bacteria has propelled microbiology research towards antimicrobial peptides as new possible antibiotics from natural sources. Antimicrobial peptides are short peptides endowed with a broad range of activity against both Gram-positive and Gram-negative bacteria and are less prone to trigger resistance. Besides their activity against planktonic bacteria, many antimicrobial peptides also show antibiofilm activity. Biofilms are ubiquitous in nature, having the ability to adhere to virtually any surface, either biotic or abiotic, including medical devices, causing chronic infections that are difficult to eradicate. The biofilm matrix protects bacteria from hostile environments, thus contributing to the bacterial resistance to antimicrobial agents. Biofilms are very difficult to treat, with options restricted to the use of large doses of antibiotics or the removal of the infected device. Antimicrobial peptides could represent good candidates to develop new antibiofilm drugs as they can act at different stages of biofilm formation, on disparate molecular targets and with various mechanisms of action. These include inhibition of biofilm formation and adhesion, downregulation of quorum sensing factors, and disruption of the pre-formed biofilm. This review focuses on the proprieties of antimicrobial and antibiofilm peptides, with a particular emphasis on their mechanism of action, reporting several examples of peptides that over time have been shown to have activity against biofilm. Full article

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41 pages, 3186 KiB

Open AccessEditor’s ChoiceReview

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases

by Laura Toma, Gabriela Maria Sanda, Loredan Stefan Niculescu, Mariana Deleanu, Anca Volumnia Sima and Camelia Sorina Stancu

Biomolecules 2020, 10(4), 641; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040641 - 21 Apr 2020

Cited by 45 | Viewed by 6920

Abstract

Atherosclerosis is the main process behind cardiovascular diseases (CVD), maladies which continue to be responsible for up to 70% of death worldwide. Despite the ongoing development of new and potent drugs, their incomplete efficacy, partial intolerance and numerous side effects make the search [...] Read more.

Atherosclerosis is the main process behind cardiovascular diseases (CVD), maladies which continue to be responsible for up to 70% of death worldwide. Despite the ongoing development of new and potent drugs, their incomplete efficacy, partial intolerance and numerous side effects make the search for new alternatives worthwhile. The focus of the scientific world turned to the potential of natural active compounds to prevent and treat CVD. Essential for effective prevention or treatment based on phytochemicals is to know their mechanisms of action according to their bioavailability and dosage. The present review is focused on the latest data about phenolic compounds and aims to collect and correlate the reliable existing knowledge concerning their molecular mechanisms of action to counteract important risk factors that contribute to the initiation and development of atherosclerosis: dyslipidemia, and oxidative and inflammatory-stress. The selection of phenolic compounds was made to prove their multiple benefic effects and endorse them as CVD remedies, complementary to allopathic drugs. The review also highlights some aspects that still need clear scientific explanations and draws up some new molecular approaches to validate phenolic compounds for CVD complementary therapy in the near future. Full article

(This article belongs to the Special Issue Phytochemical Omics in Medicinal Plants)

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19 pages, 762 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Photobiomodulation for Parkinson’s Disease in Animal Models: A Systematic Review

by Farzad Salehpour and Michael R Hamblin

Biomolecules 2020, 10(4), 610; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040610 - 15 Apr 2020

Cited by 45 | Viewed by 7352

Abstract

Photobiomodulation (PBM) might be an effective treatment for Parkinson’s disease (PD) in human patients. PBM of the brain uses red or near infrared light delivered from a laser or an LED at relatively low power densities, onto the head (or other body parts) [...] Read more.

Photobiomodulation (PBM) might be an effective treatment for Parkinson’s disease (PD) in human patients. PBM of the brain uses red or near infrared light delivered from a laser or an LED at relatively low power densities, onto the head (or other body parts) to stimulate the brain and prevent degeneration of neurons. PD is a progressive neurodegenerative disease involving the loss of dopamine-producing neurons in the substantia nigra deep within the brain. PD is a movement disorder that also shows various other symptoms affecting the brain and other organs. Treatment involves dopamine replacement therapy or electrical deep brain stimulation. The present systematic review covers reports describing the use of PBM to treat laboratory animal models of PD, in an attempt to draw conclusions about the best choice of parameters and irradiation techniques. There have already been clinical trials of PBM reported in patients, and more are expected in the coming years. PBM is particularly attractive as it is a non-pharmacological treatment, without any major adverse effects (and very few minor ones). Full article

(This article belongs to the Special Issue Photobiomodulation for Parkinson's Disease)

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18 pages, 1234 KiB

Open AccessEditor’s ChoiceReview

High-Density Lipoproteins Are Bug Scavengers

by Olivier Meilhac, Sébastien Tanaka and David Couret

Biomolecules 2020, 10(4), 598; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040598 - 12 Apr 2020

Cited by 52 | Viewed by 6828

Abstract

Lipoproteins were initially defined according to their composition (lipids and proteins) and classified according to their density (from very low- to high-density lipoproteins—HDLs). Whereas their capacity to transport hydrophobic lipids in a hydrophilic environment (plasma) is not questionable, their primitive function of cholesterol [...] Read more.

Lipoproteins were initially defined according to their composition (lipids and proteins) and classified according to their density (from very low- to high-density lipoproteins—HDLs). Whereas their capacity to transport hydrophobic lipids in a hydrophilic environment (plasma) is not questionable, their primitive function of cholesterol transporter could be challenged. All lipoproteins are reported to bind and potentially neutralize bacterial lipopolysaccharides (LPS); this is particularly true for HDL particles. In addition, HDL levels are drastically decreased under infectious conditions such as sepsis, suggesting a potential role in the clearance of bacterial material and, particularly, LPS. Moreover, "omics" technologies have unveiled significant changes in HDL composition in different inflammatory states, ranging from acute inflammation occurring during septic shock to low-grade inflammation associated with moderate endotoxemia such as periodontal disease or obesity. In this review, we will discuss HDL modifications associated with exposure to pathogens including bacteria, viruses and parasites, with a special focus on sepsis and the potential of HDL therapy in this context. Low-grade inflammation associated with atherosclerosis, periodontitis or metabolic syndrome may also highlight the protective role of HDLs in theses pathologies by other mechanisms than the reverse transport of cholesterol. Full article

(This article belongs to the Special Issue High-Density Lipoprotein (HDL): The Role of Reverse Cholesterol Transport in Human Health and Disease)

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21 pages, 2361 KiB

Open AccessEditor’s ChoiceReview

New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future?

by Nerea M. Molina, Alberto Sola-Leyva, Maria Jose Saez-Lara, Julio Plaza-Diaz, Aleksandra Tubić-Pavlović, Barbara Romero, Ana Clavero, Juan Mozas-Moreno, Juan Fontes and Signe Altmäe

Biomolecules 2020, 10(4), 593; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040593 - 11 Apr 2020

Cited by 93 | Viewed by 14766

Abstract

Current knowledge suggests that the uterus harbours its own microbiota, where the microbes could influence the uterine functions in health and disease; however, the core uterine microbial composition and the host-microbial relationships remain to be fully elucidated. Different studies are indicating, based on [...] Read more.

Current knowledge suggests that the uterus harbours its own microbiota, where the microbes could influence the uterine functions in health and disease; however, the core uterine microbial composition and the host-microbial relationships remain to be fully elucidated. Different studies are indicating, based on next-generation sequencing techniques, that microbial dysbiosis could be associated with several gynaecological disorders, such as endometriosis, chronic endometritis, dysfunctional menstrual bleeding, endometrial cancer, and infertility. Treatments using antibiotics and probiotics and/or prebiotics for endometrial microbial dysbiosis are being applied. Nevertheless there is no unified protocol for assessing the endometrial dysbiosis and no optimal treatment protocol for the established dysbiosis. With this review we outline the microbes (mostly bacteria) identified in the endometrial microbiome studies, the current treatments offered for bacterial dysbiosis in the clinical setting, and the future possibilities such as pro- and prebiotics and microbial transplants for modifying uterine microbial composition. Full article

(This article belongs to the Special Issue Relevant Biomolecules for Germ Cells and Fertilization)

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15 pages, 1105 KiB

Open AccessEditor’s ChoiceReview

Methionine Dependence of Cancer

by Peter Kaiser

Biomolecules 2020, 10(4), 568; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040568 - 8 Apr 2020

Cited by 106 | Viewed by 9486

Abstract

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish [...] Read more.

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed. Full article

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

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24 pages, 1776 KiB

Open AccessEditor’s ChoiceReview

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

by Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Julio Manuel Martinez-Moreno, Maria Monsalve, Adrian Mario Ramos, Maria Dolores Sanchez-Niño, Marta Ruiz-Ortega, Alberto Ortiz and Ana Belen Sanz

Biomolecules 2020, 10(2), 347; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020347 - 24 Feb 2020

Cited by 124 | Viewed by 19805

Abstract

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and [...] Read more.

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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34 pages, 7528 KiB

Open AccessEditor’s ChoiceReview

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

by Simona Neri and Rosa Maria Borzì

Biomolecules 2020, 10(2), 340; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020340 - 21 Feb 2020

Cited by 74 | Viewed by 8937

Abstract

Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of [...] Read more.

Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of clinical conditions. MSC use frequently requires in vitro expansion, thus exposing cells to replicative senescence. Aging of MSCs (both in vivo and in vitro) can affect not only their replicative potential, but also their properties, like immunomodulation and secretory profile, thus possibly compromising their therapeutic effect. It is therefore of critical importance to unveil the underlying mechanisms of MSC senescence and to define shared methods to assess MSC aging status. The present review will focus on current scientific knowledge about MSC aging mechanisms, control and effects, including possible anti-aging treatments. Full article

(This article belongs to the Special Issue New Targets and Strategies in Regenerative Medicine)

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21 pages, 2655 KiB

Open AccessEditor’s ChoiceReview

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

by Shuya Kasai, Sunao Shimizu, Yota Tatara, Junsei Mimura and Ken Itoh

Biomolecules 2020, 10(2), 320; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020320 - 17 Feb 2020

Cited by 285 | Viewed by 21110

Abstract

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence [...] Read more.

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS. Full article

(This article belongs to the Special Issue Emerging Role of Mitochondrial Reactive Oxygen Species in Cellular Signaling)

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24 pages, 2267 KiB

Open AccessEditor’s ChoiceReview

p53’s Extended Reach: The Mutant p53 Secretome

by Evangelos Pavlakis and Thorsten Stiewe

Biomolecules 2020, 10(2), 307; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020307 - 15 Feb 2020

Cited by 38 | Viewed by 9119

Abstract

p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous [...] Read more.

p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization. Full article

(This article belongs to the Special Issue Recent Advances in p53)

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15 pages, 1351 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Allogeneic CAR-T Cells

by Dong Wook Kim and Je-Yoel Cho

Biomolecules 2020, 10(2), 263; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020263 - 10 Feb 2020

Cited by 73 | Viewed by 10709

Abstract

In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of [...] Read more.

In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of genes encoding scFv, a co-stimulatory domain (CD28 or TNFRSF9), and CD247 signaling domains for T cell proliferation and activation. Principally, CAR-T cells are activated by recognizing TAA by scFv on the T cell surface, and then signaling domains inside cells connected by scFv are subsequently activated to induce downstream signaling pathways involving T cell proliferation, activation, and production of cytokines. Many efforts have been made to increase the efficacy and persistence and also to decrease T cell exhaustion. Overall, allogeneic and universal CAR-T generation has attracted much attention because of their wide and prompt usage for patients. In this review, we summarized the current techniques for generation of allogeneic and universal CAR-T cells along with their disadvantages and limitations that still need to be overcome. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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14 pages, 1400 KiB

Open AccessEditor’s ChoiceReview

Copper Ions and Parkinson’s Disease: Why Is Homeostasis So Relevant?

by Marco Bisaglia and Luigi Bubacco

Biomolecules 2020, 10(2), 195; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020195 - 29 Jan 2020

Cited by 112 | Viewed by 9005

Abstract

The involvement of copper in numerous physiological processes makes this metal ion essential for human life. Alterations in copper homeostasis might have deleterious consequences, and several neurodegenerative disorders, including Parkinson’s disease (PD), have been associated with impaired copper levels. In the present review, [...] Read more.

The involvement of copper in numerous physiological processes makes this metal ion essential for human life. Alterations in copper homeostasis might have deleterious consequences, and several neurodegenerative disorders, including Parkinson’s disease (PD), have been associated with impaired copper levels. In the present review, we describe the molecular mechanisms through which copper can exert its toxicity, by considering how it can interfere with other cellular processes known to play a role in PD, such as dopamine metabolism, oxidative stress, and α-synuclein aggregation. The recent experimental evidence that associates copper deficiency and the formation of superoxide dismutase 1 (SOD1) aggregates with the progression of PD is also discussed together with its therapeutic implication. Overall, the recent discoveries described in this review show how either copper deficiency or excessive levels can promote detrimental effects, highlighting the importance of preserving copper homeostasis and opening unexplored therapeutic avenues in the definition of novel disease-modifying drugs. Full article

(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)

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21 pages, 11760 KiB

Open AccessEditor’s ChoiceReview

The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective

by Nicolai P. Ostberg, Mohammad A. Zafar, Bulat A. Ziganshin and John A. Elefteriades

Biomolecules 2020, 10(2), 182; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020182 - 24 Jan 2020

Cited by 78 | Viewed by 9759

Abstract

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural [...] Read more.

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on genes that have been linked to dissection at diameters <5.0 cm, the current lower bound for surgical intervention. Genetic screening tests to identify patients with TAAD associated mutations that place them at high risk for dissection are also discussed. Full article

(This article belongs to the Special Issue Genetics of Cardiovascular Disorders)

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16 pages, 1861 KiB

Open AccessFeature PaperEditor’s ChoiceReview

FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

by Paula Tapial Martínez, Pilar López Navajas and Daniel Lietha

Biomolecules 2020, 10(2), 179; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10020179 - 24 Jan 2020

Cited by 115 | Viewed by 11527

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK [...] Read more.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK is autoinhibited in the cytosol, but activated upon localisation into a protein complex, known as focal adhesion complex. This complex forms upon cell adhesion to the extracellular matrix (ECM) at the cytoplasmic side of the plasma membrane at sites of ECM attachment. FAK is anchored to the complex via multiple sites, including direct interactions with specific membrane lipids and connector proteins that attach focal adhesions to the actin cytoskeleton. In migrating cells, the contraction of actomyosin stress fibres attached to the focal adhesion complex apply a force to the complex, which is likely transmitted to the FAK protein, causing stretching of the FAK molecule. In this review we discuss the current knowledge of the FAK structure and how specific structural features are involved in the regulation of FAK signalling. We focus on two major regulatory mechanisms known to contribute to FAK activation, namely interactions with membrane lipids and stretching forces applied to FAK, and discuss how they might induce structural changes that facilitate FAK activation. Full article

(This article belongs to the Special Issue Focal Adhesion Kinase and Its Role in Cell, Molecular Biology, Cell Mechanics, and Bioengineering)

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16 pages, 403 KiB

Open AccessEditor’s ChoiceReview

Polysaccharide-Based Formulations for Healing of Skin-Related Wound Infections: Lessons from Animal Models and Clinical Trials

by Diogo Marcelo Lima Ribeiro, Alexsander Rodrigues Carvalho Júnior, Gustavo Henrique Rodrigues Vale de Macedo, Vitor Lopes Chagas, Lucas dos Santos Silva, Brenda da Silva Cutrim, Deivid Martins Santos, Bruno Luis Lima Soares, Adrielle Zagmignan, Rita de Cássia Mendonça de Miranda, Priscilla Barbosa Sales de Albuquerque and Luís Cláudio Nascimento da Silva

Biomolecules 2020, 10(1), 63; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10010063 - 30 Dec 2019

Cited by 65 | Viewed by 6547

Abstract

Skin injuries constitute a gateway for pathogenic bacteria that can be either part of tissue microbiota or acquired from the environmental. These microorganisms (such as Acinetobacter baumannii, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus aureus) produce virulence factors that impair tissue integrity and [...] Read more.

Skin injuries constitute a gateway for pathogenic bacteria that can be either part of tissue microbiota or acquired from the environmental. These microorganisms (such as Acinetobacter baumannii, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus aureus) produce virulence factors that impair tissue integrity and sustain the inflammatory phase leading for establishment of chronic wounds. The high levels of antimicrobial resistance have limited the therapeutic arsenal for combatting skin infections. Thus, the treatment of non-healing chronic wounds is a huge challenge for health services worldwide, imposing great socio-economic damage to the affected individuals. This scenario has encouraged the use of natural polymers, such as polysaccharide, in order to develop new formulations (membranes, nanoparticles, hydrogels, scaffolds) to be applied in the treatment of skin infections. In this non-exhaustive review, we discuss the applications of polysaccharide-based formulations in the healing of infected wounds in animal models and clinical trials. The formulations discussed in this review were prepared using alginate, cellulose, chitosan, and hyaluronic acid. In addition to have healing actions per se, these polysaccharide formulations can act as transdermal drug delivery systems, controlling the release of active ingredients (such as antimicrobial and healing agents). The papers show that these polysaccharides-based formulations are efficient in controlling infection and improve the healing, even in chronic infected wounds. These data should positively impact the design of new dressings to treat skin infections. Full article

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25 pages, 13439 KiB

Open AccessEditor’s ChoiceReview

Contribution of Non-Saccharomyces Yeasts to Wine Freshness. A Review

by Antonio Morata, Carlos Escott, María Antonia Bañuelos, Iris Loira, Juan Manuel del Fresno, Carmen González and José Antonio Suárez-Lepe

Biomolecules 2020, 10(1), 34; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10010034 - 25 Dec 2019

Cited by 90 | Viewed by 9505

Abstract

Freshness, although it is a concept difficult to define in wines, can be understood as a combination of different circumstances. Organolepticwise, bluish red, floral and fruity, more acidic and full-bodied wines, are perceived as younger and fresher by consumers. In traditional winemaking processes, [...] Read more.

Freshness, although it is a concept difficult to define in wines, can be understood as a combination of different circumstances. Organolepticwise, bluish red, floral and fruity, more acidic and full-bodied wines, are perceived as younger and fresher by consumers. In traditional winemaking processes, these attributes are hard to boost if no other technology or biotechnology is involved. In this regard, the right selection of yeast strains plays an important role in meeting these parameters and obtaining wines with fresher profiles. Another approach in getting fresh wines is through the use of novel non-thermal technologies during winemaking. Herein, the contributions of non-Saccharomyces yeasts and emerging technologies to these parameters are reviewed and discussed. Full article

(This article belongs to the Special Issue Biochemistry of Wine and Beer)

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17 pages, 834 KiB

Open AccessEditor’s ChoiceReview

A Sight to Wheat Bran: High Value-Added Products

by Agne Katileviciute, Gediminas Plakys, Aida Budreviciute, Kamil Onder, Samar Damiati and Rimantas Kodzius

Biomolecules 2019, 9(12), 887; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120887 - 17 Dec 2019

Cited by 59 | Viewed by 8994

Abstract

Recently more consideration has been given to the use of renewable materials and agricultural residues. Wheat production is increasing yearly and correspondingly, the volume of by-products from the wheat process is increasing, as well. It is important to find the use of the [...] Read more.

Recently more consideration has been given to the use of renewable materials and agricultural residues. Wheat production is increasing yearly and correspondingly, the volume of by-products from the wheat process is increasing, as well. It is important to find the use of the residuals for higher value-added products, and not just for the food industry or animal feed purposes as it is happening now. Agricultural residue of the roller milled wheat grain is a wheat bran description. The low-cost of wheat bran and its composition assortment provides a good source of substrate for various enzymes and organic acids production and other biotechnological applications. The main purpose of this review article is to look into recent trends, developments, and applications of wheat bran. Full article

(This article belongs to the Special Issue Application of Biotechnological Techniques Aimed to Obtain Bioactive Compounds from Food Industry By-Products)

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25 pages, 2417 KiB

Open AccessEditor’s ChoiceReview

Fatty Acids of Marine Mollusks: Impact of Diet, Bacterial Symbiosis and Biosynthetic Potential

by Natalia V. Zhukova

Biomolecules 2019, 9(12), 857; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120857 - 11 Dec 2019

Cited by 47 | Viewed by 5501

Abstract

The n-3 and n-6 polyunsaturated fatty acid (PUFA) families are essential for important physiological processes. Their major source are marine ecosystems. The fatty acids (FAs) from phytoplankton, which are the primary producer of organic matter and PUFAs, are transferred into consumers via food [...] Read more.

The n-3 and n-6 polyunsaturated fatty acid (PUFA) families are essential for important physiological processes. Their major source are marine ecosystems. The fatty acids (FAs) from phytoplankton, which are the primary producer of organic matter and PUFAs, are transferred into consumers via food webs. Mollusk FAs have attracted the attention of researchers that has been driven by their critical roles in aquatic ecology and their importance as sources of essential PUFAs. The main objective of this review is to focus on the most important factors and causes determining the biodiversity of the mollusk FAs, with an emphasis on the key relationship of these FAs with the food spectrum and trophic preference. The marker FAs of trophic sources are also of particular interest. The discovery of new symbioses involving invertebrates and bacteria, which are responsible for nutrition of the host, deserves special attention. The present paper also highlights recent research into the molecular and biochemical mechanisms of PUFA biosynthesis in marine mollusks. The biosynthetic capacities of marine mollusks require a well-grounded evaluation. Full article

(This article belongs to the Special Issue Fatty Acids in Natural Ecosystems and Human Nutrition)

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33 pages, 1639 KiB

Open AccessEditor’s ChoiceReview

Metformin: The Answer to Cancer in a Flower? Current Knowledge and Future Prospects of Metformin as an Anti-Cancer Agent in Breast Cancer

by Samson Mathews Samuel, Elizabeth Varghese, Peter Kubatka, Chris R. Triggle and Dietrich Büsselberg

Biomolecules 2019, 9(12), 846; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120846 - 9 Dec 2019

Cited by 58 | Viewed by 8337

Abstract

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast [...] Read more.

Interest has grown in studying the possible use of well-known anti-diabetic drugs as anti-cancer agents individually or in combination with, frequently used, chemotherapeutic agents and/or radiation, owing to the fact that diabetes heightens the risk, incidence, and rapid progression of cancers, including breast cancer, in an individual. In this regard, metformin (1, 1-dimethylbiguanide), well known as ‘Glucophage’ among diabetics, was reported to be cancer preventive while also being a potent anti-proliferative and anti-cancer agent. While meta-analysis studies reported a lower risk and incidence of breast cancer among diabetic individuals on a metformin treatment regimen, several in vitro, pre-clinical, and clinical studies reported the efficacy of using metformin individually as an anti-cancer/anti-tumor agent or in combination with chemotherapeutic drugs or radiation in the treatment of different forms of breast cancer. However, unanswered questions remain with regards to areas such as cancer treatment specific therapeutic dosing of metformin, specificity to cancer cells at high concentrations, resistance to metformin therapy, efficacy of combinatory therapeutic approaches, post-therapeutic relapse of the disease, and efficacy in cancer prevention in non-diabetic individuals. In the current article, we discuss the biology of metformin and its molecular mechanism of action, the existing cellular, pre-clinical, and clinical studies that have tested the anti-tumor potential of metformin as a potential anti-cancer/anti-tumor agent in breast cancer therapy, and outline the future prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer drug in the treatment of breast cancer. Full article

(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)

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26 pages, 4264 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Polysaccharide-Based Systems for Targeted Stem Cell Differentiation and Bone Regeneration

by Markus Witzler, Dominik Büchner, Sarah Hani Shoushrah, Patrick Babczyk, Juliana Baranova, Steffen Witzleben, Edda Tobiasch and Margit Schulze

Biomolecules 2019, 9(12), 840; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120840 - 6 Dec 2019

Cited by 35 | Viewed by 6070

Abstract

Bone tissue engineering is an ever-changing, rapidly evolving, and highly interdisciplinary field of study, where scientists try to mimic natural bone structure as closely as possible in order to facilitate bone healing. New insights from cell biology, specifically from mesenchymal stem cell differentiation [...] Read more.

Bone tissue engineering is an ever-changing, rapidly evolving, and highly interdisciplinary field of study, where scientists try to mimic natural bone structure as closely as possible in order to facilitate bone healing. New insights from cell biology, specifically from mesenchymal stem cell differentiation and signaling, lead to new approaches in bone regeneration. Novel scaffold and drug release materials based on polysaccharides gain increasing attention due to their wide availability and good biocompatibility to be used as hydrogels and/or hybrid components for drug release and tissue engineering. This article reviews the current state of the art, recent developments, and future perspectives in polysaccharide-based systems used for bone regeneration. Full article

(This article belongs to the Special Issue New Targets and Strategies in Regenerative Medicine)

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27 pages, 2320 KiB

Open AccessEditor’s ChoiceReview

Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium

by Marek Samec, Alena Liskova, Lenka Koklesova, Veronika Mestanova, Maria Franekova, Monika Kassayova, Bianka Bojkova, Sona Uramova, Pavol Zubor, Katarina Janikova, Jan Danko, Samson Mathews Samuel, Dietrich Büsselberg and Peter Kubatka

Biomolecules 2019, 9(12), 829; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120829 - 5 Dec 2019

Cited by 20 | Viewed by 5909

Abstract

Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated [...] Read more.

Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell’s epigenome. The potential antineoplastic activity of plant natural substances mediated by their action on posttranslational histone modifications (PHMs) is currently a highly evaluated area of cancer research. PHMs play an important role in maintaining chromatin structure and regulating gene expression. Aberrations in PHMs are directly linked to the process of carcinogenesis in cancer such as breast (BC), prostate (PC), and colorectal (CRC) cancer, common malignant diseases in terms of incidence and mortality among both men and women. This review summarizes the effects of plant phytochemicals (isolated or mixtures) on cancer-associated PHMs (mainly modulation of acetylation and methylation) resulting in alterations of chromatin structure that are related to the regulation of transcription activity of specific oncogenes, which are crucial in the development of BC, PC, and CRC. Significant effectiveness of natural compounds in the modulation of aberrant PHMs were confirmed by a number of in vitro or in vivo studies in preclinical cancer research. However, evidence concerning PHMs-modulating abilities of plant-based natural substances in clinical trials is insufficient. Full article

(This article belongs to the Special Issue Plant-Derived Natural Compounds in the Management of Cancer: Significance and Challenges)

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35 pages, 6586 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Actual and Potential Aroma of Winemaking Grapes

by Vicente Ferreira and Ricardo Lopez

Biomolecules 2019, 9(12), 818; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120818 - 3 Dec 2019

Cited by 91 | Viewed by 8631

Abstract

This review intends to rationalize the knowledge related to the aroma of grapes and to the aroma of wine with specific origin in molecules formed in grapes. The actual flavor of grapes is formed by the few free aroma molecules already found in [...] Read more.

This review intends to rationalize the knowledge related to the aroma of grapes and to the aroma of wine with specific origin in molecules formed in grapes. The actual flavor of grapes is formed by the few free aroma molecules already found in the pulp and in the skin, plus by those aroma molecules quickly formed by enzymatic/catalytic reactions. The review covers key aroma components of aromatic grapes, raisins and raisinized grapes, and the aroma components responsible from green and vegetal notes. This knowledge is used to explain the flavor properties of neutral grapes. The aroma potential of grape is the consequence of five different systems/pools of specific aroma precursors that during fermentation and/or aging, release wine varietal aroma. In total, 27 relevant wine aroma compounds can be considered that proceed from grape specific precursors. Some of them are immediately formed during fermentation, while some others require long aging time to accumulate. Precursors are glycosides, glutathionyl and cysteinyl conjugates, and other non-volatile molecules. Full article

(This article belongs to the Special Issue Biochemistry of Wine and Beer)

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24 pages, 3892 KiB

Open AccessEditor’s ChoiceReview

Biomaterials for In Situ Tissue Regeneration: A Review

by Saba Abdulghani and Geoffrey R. Mitchell

Biomolecules 2019, 9(11), 750; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110750 - 19 Nov 2019

Cited by 146 | Viewed by 12983

Abstract

This review focuses on a somewhat unexplored strand of regenerative medicine, that is in situ tissue engineering. In this approach manufactured scaffolds are implanted in the injured region for regeneration within the patient. The scaffold is designed to attract cells to the required [...] Read more.

This review focuses on a somewhat unexplored strand of regenerative medicine, that is in situ tissue engineering. In this approach manufactured scaffolds are implanted in the injured region for regeneration within the patient. The scaffold is designed to attract cells to the required volume of regeneration to subsequently proliferate, differentiate, and as a consequence develop tissue within the scaffold which in time will degrade leaving just the regenerated tissue. This review highlights the wealth of information available from studies of ex-situ tissue engineering about the selection of materials for scaffolds. It is clear that there are great opportunities for the use of additive manufacturing to prepare complex personalized scaffolds and we speculate that by building on this knowledge and technology, the development of in situ tissue engineering could rapidly increase. Ex-situ tissue engineering is handicapped by the need to develop the tissue in a bioreactor where the conditions, however optimized, may not be optimum for accelerated growth and maintenance of the cell function. We identify that in both methodologies the prospect of tissue regeneration has created much promise but delivered little outside the scope of laboratory-based experiments. We propose that the design of the scaffolds and the materials selected remain at the heart of developments in this field and there is a clear need for predictive modelling which can be used in the design and optimization of materials and scaffolds. Full article

(This article belongs to the Special Issue New Targets and Strategies in Regenerative Medicine)

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18 pages, 1971 KiB

Open AccessFeature PaperEditor’s ChoiceReview

A Perspective on the Development of TGF-β Inhibitors for Cancer Treatment

by Linh Khanh Huynh, Christopher John Hipolito and Peter ten Dijke

Biomolecules 2019, 9(11), 743; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110743 - 17 Nov 2019

Cited by 129 | Viewed by 12210

Abstract

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages [...] Read more.

Transforming growth factor (TGF)-β is a secreted multifunctional cytokine that signals via plasma membrane TGF-β type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-β signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-β can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-β in cancer cells are blocked, TGF-β signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-β signaling in cancer and summarize the clinical status of TGF-β signaling inhibitors that interfere with TGF−β bioavailability, TGF-β/receptor interaction, or TGF-β receptor kinase function. Moreover, we will discuss targeting of TGF-β signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs. Full article

(This article belongs to the Special Issue TGF-Beta Signaling in Physiology and Pathology)

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26 pages, 2934 KiB

Open AccessEditor’s ChoiceReview

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements

by Vaishali Aggarwal, Hardeep Singh Tuli, Ayşegül Varol, Falak Thakral, Mukerrem Betul Yerer, Katrin Sak, Mehmet Varol, Aklank Jain, Md. Asaduzzaman Khan and Gautam Sethi

Biomolecules 2019, 9(11), 735; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110735 - 13 Nov 2019

Cited by 762 | Viewed by 20674

Abstract

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor [...] Read more.

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies. Full article

(This article belongs to the Special Issue Antitumor Agents from Natural Sources)

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14 pages, 1265 KiB

Open AccessEditor’s ChoiceReview

Algae: Critical Sources of Very Long-Chain Polyunsaturated Fatty Acids

by John L. Harwood

Biomolecules 2019, 9(11), 708; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110708 - 6 Nov 2019

Cited by 101 | Viewed by 10449

Abstract

Polyunsaturated fatty acids (PUFAs), which are divided into n-3 and n-6 classes, are essential for good health in humans and many animals. They are metabolised to lipid mediators, such as eicosanoids, resolvins and protectins. Increasing interest has been paid to the 20 or [...] Read more.

Polyunsaturated fatty acids (PUFAs), which are divided into n-3 and n-6 classes, are essential for good health in humans and many animals. They are metabolised to lipid mediators, such as eicosanoids, resolvins and protectins. Increasing interest has been paid to the 20 or 22 carbon very long chain PUFAs, since these compounds can be used to form lipid mediators and, thus, avoid inefficient formation of dietary plant PUFAs. The ultimate sources of very long chain PUFAs are algae, which are consumed by fish and then by humans. In this review, I describe the biosynthesis of very long chain PUFAs by algae and how this synthesis can be manipulated for commercial purposes. Ultimately, the production of algal oils is critical for ecosystems worldwide, as well as for human dietary lipids. Full article

(This article belongs to the Special Issue Lipids of Marine Algae)

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17 pages, 1223 KiB

Open AccessEditor’s ChoiceReview

Cell Fate Control by Translation: mRNA Translation Initiation as a Therapeutic Target for Cancer Development and Stem Cell Fate Control

by Hyun-Jung Kim

Biomolecules 2019, 9(11), 665; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110665 - 29 Oct 2019

Cited by 14 | Viewed by 7894

Abstract

Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and [...] Read more.

Translation of mRNA is an important process that controls cell behavior and gene regulation because proteins are the functional molecules that determine cell types and function. Cancer develops as a result of genetic mutations, which lead to the production of abnormal proteins and the dysregulation of translation, which in turn, leads to aberrant protein synthesis. In addition, the machinery that is involved in protein synthesis plays critical roles in stem cell fate determination. In the current review, recent advances in the understanding of translational control, especially translational initiation in cancer development and stem cell fate control, are described. Therapeutic targets of mRNA translation such as eIF4E, 4EBP, and eIF2, for cancer treatment or stem cell fate regulation are reviewed. Upstream signaling pathways that regulate and affect translation initiation were introduced. It is important to regulate the expression of protein for normal cell behavior and development. mRNA translation initiation is a key step to regulate protein synthesis, therefore, identifying and targeting molecules that are critical for protein synthesis is necessary and beneficial to develop cancer therapeutics and stem cells fate regulation. Full article

(This article belongs to the Special Issue New Insights on Translational Machinery in Protein Synthesis and Beyond)

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20 pages, 3272 KiB

Open AccessEditor’s ChoiceReview

The Roles of Notch Signaling in Liver Development and Disease

by Joshua M. Adams and Hamed Jafar-Nejad

Biomolecules 2019, 9(10), 608; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9100608 - 14 Oct 2019

Cited by 61 | Viewed by 7859

Abstract

The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch [...] Read more.

The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch activity in proper liver development and function. Specifically, we discuss the latest discoveries on how Notch, in conjunction with other signaling pathways, aids in proper liver development, regeneration and repair. In addition, we review the latest in the role of Notch signaling in the pathogenesis of liver fibrosis and chronic liver disease. Finally, recent evidence has shed light on the emerging connection between Notch signaling and glucose and lipid metabolism. We hope that highlighting the major advances in the roles of Notch signaling in the liver will stimulate further research in this exciting field and generate additional ideas for therapeutic manipulation of the Notch pathway in liver diseases. Full article

(This article belongs to the Special Issue Cell Type- and Context-Specific Roles and Regulation of Notch Signaling)

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21 pages, 3200 KiB

Open AccessEditor’s ChoiceReview

Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges

by José Martínez-González, Saray Varona, Laia Cañes, María Galán, Ana M Briones, Victoria Cachofeiro and Cristina Rodríguez

Biomolecules 2019, 9(10), 610; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9100610 - 14 Oct 2019

Cited by 38 | Viewed by 6441

Abstract

Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. [...] Read more.

Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. Besides this structural role, in the last years, novel biological properties have been attributed to these enzymes, which can critically influence cardiovascular function. LOX and LOXLs control cell proliferation, migration, adhesion, differentiation, oxidative stress, and transcriptional regulation and, thereby, their dysregulation has been linked to a myriad of cardiovascular pathologies. Lysyl oxidase could modulate virtually all stages of the atherosclerotic process, from endothelial dysfunction and plaque progression to calcification and rupture of advanced and complicated plaques, and contributes to vascular stiffness in hypertension. The alteration of LOX/LOXLs expression underlies the development of other vascular pathologies characterized by a destructive remodeling of the ECM, such as aneurysm and artery dissections, and contributes to the adverse myocardial remodeling and dysfunction in hypertension, myocardial infarction, and obesity. This review examines the most recent advances in the study of LOX and LOXLs biology and their pathophysiological role in cardiovascular diseases with special emphasis on their potential as therapeutic targets. Full article

(This article belongs to the Special Issue Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities)

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28 pages, 1485 KiB

Open AccessEditor’s ChoiceReview

Function, Regulation and Biological Roles of PI3Kγ Variants

by Bernd Nürnberg and Sandra Beer-Hammer

Biomolecules 2019, 9(9), 427; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090427 - 30 Aug 2019

Cited by 27 | Viewed by 5104

Abstract

Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. [...] Read more.

Phosphatidylinositide 3-kinase (PI3K) γ is the only class IB PI3K member playing significant roles in the G-protein-dependent regulation of cell signaling in health and disease. Originally found in the immune system, increasing evidence suggest a wide array of functions in the whole organism. PI3Kγ occur as two different heterodimeric variants: PI3Kγ (p87) and PI3Kγ (p101), which share the same p110γ catalytic subunit but differ in their associated non-catalytic subunit. Here we concentrate on specific PI3Kγ features including its regulation and biological functions. In particular, the roles of its non-catalytic subunits serving as the main regulators determining specificity of class IB PI3Kγ enzymes are highlighted. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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26 pages, 2247 KiB

Open AccessEditor’s ChoiceReview

For Better or Worse: The Potential for Dose Limiting the On-Target Toxicity of PI 3-Kinase Inhibitors

by Christina M. Buchanan, Kate L. Lee and Peter R. Shepherd

Biomolecules 2019, 9(9), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090402 - 22 Aug 2019

Cited by 15 | Viewed by 6064

Abstract

The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key [...] Read more.

The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key role PI 3-kinases play in many normal cell functions, there is significant potential for the disruption of essential cellular functions by PI 3-kinase inhibitors in normal tissues; so-called on-target drug toxicity. It is, therefore, no surprise that progress within the clinical development of PI 3-kinase inhibitors as single-agent anti-cancer therapies has been slowed by the difficulty of identifying a therapeutic window. The aim of this review is to place the cellular, tissue and whole-body effects of PI 3-kinase inhibition in the context of understanding the potential for dose limiting on-target toxicities and to introduce possible strategies to overcome these. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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16 pages, 965 KiB

Open AccessEditor’s ChoiceReview

There Is Treasure Everywhere: Reductive Plastid Evolution in Apicomplexa in Light of Their Close Relatives

by Eric D. Salomaki and Martin Kolisko

Biomolecules 2019, 9(8), 378; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080378 - 19 Aug 2019

Cited by 19 | Viewed by 6389

Abstract

The phylum Apicomplexa (Alveolates) comprises a group of host-associated protists, predominately intracellular parasites, including devastating parasites like Plasmodium falciparum, the causative agent of malaria. One of the more fascinating characteristics of Apicomplexa is their highly reduced (and occasionally lost) remnant plastid, termed [...] Read more.

The phylum Apicomplexa (Alveolates) comprises a group of host-associated protists, predominately intracellular parasites, including devastating parasites like Plasmodium falciparum, the causative agent of malaria. One of the more fascinating characteristics of Apicomplexa is their highly reduced (and occasionally lost) remnant plastid, termed the apicoplast. Four core metabolic pathways are retained in the apicoplast: heme synthesis, iron–sulfur cluster synthesis, isoprenoid synthesis, and fatty acid synthesis. It has been suggested that one or more of these pathways are essential for plastid and plastid genome retention. The past decade has witnessed the discovery of several apicomplexan relatives, and next-generation sequencing efforts are revealing that they retain variable plastid metabolic capacities. These data are providing clues about the core genes and pathways of reduced plastids, while at the same time further confounding our view on the evolutionary history of the apicoplast. Here, we examine the evolutionary history of the apicoplast, explore plastid metabolism in Apicomplexa and their close relatives, and propose that the differences among reduced plastids result from a game of endosymbiotic roulette. Continued exploration of the Apicomplexa and their relatives is sure to provide new insights into the evolution of the apicoplast and apicomplexans as a whole. Full article

(This article belongs to the Special Issue Evolutionary and Molecular Aspects of Plastid Endosymbioses)

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30 pages, 5117 KiB

Open AccessEditor’s ChoiceReview

Tannins: Prospectives and Actual Industrial Applications

by Antonio Pizzi

Biomolecules 2019, 9(8), 344; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080344 - 5 Aug 2019

Cited by 179 | Viewed by 12345

Abstract

The origin of tannins, their historical evolution, their different types, and their applications are described. Old and established applications are described, as well as the future applications which are being developed at present and that promise to have an industrial impact in the [...] Read more.

The origin of tannins, their historical evolution, their different types, and their applications are described. Old and established applications are described, as well as the future applications which are being developed at present and that promise to have an industrial impact in the future. The chemistry of some of these applications is discussed where it is essential to understand the tannins and their derivates role. The essential points of each application, their drawbacks, and their chance of industrial application are briefly discussed. The article presents historical applications of tannins, such as leather, or traditional medicine, and more recent applications. Full article

(This article belongs to the Special Issue Perspectives on Tannins)

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18 pages, 1060 KiB

Open AccessEditor’s ChoiceReview

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

by Bart Vanhaesebroeck, Benoit Bilanges, Ralitsa R. Madsen, Katie L. Dale, Evelyn Lau and Elina Vladimirou

Biomolecules 2019, 9(8), 331; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080331 - 1 Aug 2019

Cited by 9 | Viewed by 5037

Abstract

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase that [...] Read more.

Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase that opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancer-cell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which—even if occurring in a low fraction of the cell population—might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic. Full article

(This article belongs to the Special Issue Phosphoinositide 3-kinase, a Field in Transition)

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22 pages, 8183 KiB

Open AccessEditor’s ChoiceReview

Metabolic Innovations Underpinning the Origin and Diversification of the Diatom Chloroplast

by Tomomi Nonoyama, Elena Kazamia, Hermanus Nawaly, Xia Gao, Yoshinori Tsuji, Yusuke Matsuda, Chris Bowler, Tsuyoshi Tanaka and Richard G. Dorrell

Biomolecules 2019, 9(8), 322; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080322 - 30 Jul 2019

Cited by 27 | Viewed by 6944

Abstract

Of all the eukaryotic algal groups, diatoms make the most substantial contributions to photosynthesis in the contemporary ocean. Understanding the biological innovations that have occurred in the diatom chloroplast may provide us with explanations to the ecological success of this lineage and clues [...] Read more.

Of all the eukaryotic algal groups, diatoms make the most substantial contributions to photosynthesis in the contemporary ocean. Understanding the biological innovations that have occurred in the diatom chloroplast may provide us with explanations to the ecological success of this lineage and clues as to how best to exploit the biology of these organisms for biotechnology. In this paper, we use multi-species transcriptome datasets to compare chloroplast metabolism pathways in diatoms to other algal lineages. We identify possible diatom-specific innovations in chloroplast metabolism, including the completion of tocopherol synthesis via a chloroplast-targeted tocopherol cyclase, a complete chloroplast ornithine cycle, and chloroplast-targeted proteins involved in iron acquisition and CO₂ concentration not shared between diatoms and their closest relatives in the stramenopiles. We additionally present a detailed investigation of the chloroplast metabolism of the oil-producing diatom Fistulifera solaris, which is of industrial interest for biofuel production. These include modified amino acid and pyruvate hub metabolism that might enhance acetyl-coA production for chloroplast lipid biosynthesis and the presence of a chloroplast-localised squalene synthesis pathway unknown in other diatoms. Our data provides valuable insights into the biological adaptations underpinning an ecologically critical lineage, and how chloroplast metabolism can change even at a species level in extant algae. Full article

(This article belongs to the Special Issue Evolutionary and Molecular Aspects of Plastid Endosymbioses)

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25 pages, 1185 KiB

Open AccessEditor’s ChoiceReview

Cell Intrinsic and Extrinsic Mechanisms of Caveolin-1-Enhanced Metastasis

by America Campos, Renato Burgos-Ravanal, María Fernanda González, Ricardo Huilcaman, Lorena Lobos González and Andrew Frederick Geoffery Quest

Biomolecules 2019, 9(8), 314; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080314 - 29 Jul 2019

Cited by 35 | Viewed by 8732

Abstract

Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. [...] Read more.

Caveolin-1 (CAV1) is a scaffolding protein with a controversial role in cancer. This review will initially discuss earlier studies focused on the role as a tumor suppressor before elaborating subsequently on those relating to function of the protein as a promoter of metastasis. Different mechanisms are summarized illustrating how CAV1 promotes such traits upon expression in cancer cells (intrinsic mechanisms). More recently, it has become apparent that CAV1 is also a secreted protein that can be included into exosomes where it plays a significant role in determining cargo composition. Thus, we will also discuss how CAV1 containing exosomes from metastatic cells promote malignant traits in more benign recipient cells (extrinsic mechanisms). This ability appears, at least in part, attributable to the transfer of specific cargos present due to CAV1 rather than the transfer of CAV1 itself. The evolution of how our perception of CAV1 function has changed since its discovery is summarized graphically in a time line figure. Full article

(This article belongs to the Special Issue Beyond Lipid Rafts and Caveolae: From Caveolae Compartmentalization of Signal Transduction to Medicine)

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14 pages, 1151 KiB

Open AccessEditor’s ChoiceReview

Gangliosides: The Double-Edge Sword of Neuro-Ectodermal Derived Tumors

by Sumeyye Cavdarli, Sophie Groux-Degroote and Philippe Delannoy

Biomolecules 2019, 9(8), 311; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080311 - 27 Jul 2019

Cited by 49 | Viewed by 6945

Abstract

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to [...] Read more.

Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are mostly localized at the plasma membrane in lipid raft domains and implicated in many cellular signaling pathways mostly by interacting with tyrosine kinase receptors. Gangliosides are divided into four series according to the number of sialic acid residues, which can be also modified by O-acetylation. Both ganglioside expression and sialic acid modifications can be modified in pathological conditions such as cancer, which can induce either pro-cancerous or anti-cancerous effects. In this review, we summarize the specific functions of gangliosides in neuro-ectodermal derived tumors, and their roles in reprogramming the lipidomic profile of cell membrane occurring with the induction of epithelial-mesenchymal transition. Full article

(This article belongs to the Special Issue Bioactive Lipids in Health and Disease)

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23 pages, 2555 KiB

Open AccessEditor’s ChoiceReview

Flagella-Driven Motility of Bacteria

by Shuichi Nakamura and Tohru Minamino

Biomolecules 2019, 9(7), 279; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9070279 - 14 Jul 2019

Cited by 194 | Viewed by 23803

Abstract

The bacterial flagellum is a helical filamentous organelle responsible for motility. In bacterial species possessing flagella at the cell exterior, the long helical flagellar filament acts as a molecular screw to generate thrust. Meanwhile, the flagella of spirochetes reside within the periplasmic space [...] Read more.

The bacterial flagellum is a helical filamentous organelle responsible for motility. In bacterial species possessing flagella at the cell exterior, the long helical flagellar filament acts as a molecular screw to generate thrust. Meanwhile, the flagella of spirochetes reside within the periplasmic space and not only act as a cytoskeleton to determine the helicity of the cell body, but also rotate or undulate the helical cell body for propulsion. Despite structural diversity of the flagella among bacterial species, flagellated bacteria share a common rotary nanomachine, namely the flagellar motor, which is located at the base of the filament. The flagellar motor is composed of a rotor ring complex and multiple transmembrane stator units and converts the ion flux through an ion channel of each stator unit into the mechanical work required for motor rotation. Intracellular chemotactic signaling pathways regulate the direction of flagella-driven motility in response to changes in the environments, allowing bacteria to migrate towards more desirable environments for their survival. Recent experimental and theoretical studies have been deepening our understanding of the molecular mechanisms of the flagellar motor. In this review article, we describe the current understanding of the structure and dynamics of the bacterial flagellum. Full article

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

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54 pages, 1623 KiB

Open AccessEditor’s ChoiceReview

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

by Marianna Tosato and Valerio Di Marco

Biomolecules 2019, 9(7), 269; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9070269 - 9 Jul 2019

Cited by 45 | Viewed by 8674

Abstract

The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson’s disease (PD) therapy in the year range 2014–2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or [...] Read more.

The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson’s disease (PD) therapy in the year range 2014–2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules. Stoichiometries and stability constants of the complexes have been reported; values of the cologarithm of the concentration of free metal ion at equilibrium (pM), and of the dissociation constant K_d (both computed at pH = 7.4 and at total metal and ligand concentrations of 10⁻⁶ and 10⁻⁵ mol/L, respectively), charge and stoichiometry of the most abundant metal–ligand complexes existing at physiological conditions, have been obtained. A rigorous definition of the reported amounts is given, the possible usefulness of this data is described, and the need to characterize the metal–ligand speciation of PD drugs is underlined. Full article

(This article belongs to the Special Issue Advances in Parkinson's Disease Drugs)

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20 pages, 2390 KiB

Open AccessEditor’s ChoiceReview

Mechanism of the Formation of Electronically Excited Species by Oxidative Metabolic Processes: Role of Reactive Oxygen Species

by Pavel Pospíšil, Ankush Prasad and Marek Rác

Biomolecules 2019, 9(7), 258; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9070258 - 5 Jul 2019

Cited by 66 | Viewed by 7347

Abstract

It is well known that biological systems, such as microorganisms, plants, and animals, including human beings, form spontaneous electronically excited species through oxidative metabolic processes. Though the mechanism responsible for the formation of electronically excited species is still not clearly understood, several lines [...] Read more.

It is well known that biological systems, such as microorganisms, plants, and animals, including human beings, form spontaneous electronically excited species through oxidative metabolic processes. Though the mechanism responsible for the formation of electronically excited species is still not clearly understood, several lines of evidence suggest that reactive oxygen species (ROS) are involved in the formation of electronically excited species. This review attempts to describe the role of ROS in the formation of electronically excited species during oxidative metabolic processes. Briefly, the oxidation of biomolecules, such as lipids, proteins, and nucleic acids by ROS initiates a cascade of reactions that leads to the formation of triplet excited carbonyls formed by the decomposition of cyclic (1,2-dioxetane) and linear (tetroxide) high-energy intermediates. When chromophores are in proximity to triplet excited carbonyls, the triplet-singlet and triplet-triplet energy transfers from triplet excited carbonyls to chromophores result in the formation of singlet and triplet excited chromophores, respectively. Alternatively, when molecular oxygen is present, the triplet-singlet energy transfer from triplet excited carbonyls to molecular oxygen initiates the formation of singlet oxygen. Understanding the mechanism of the formation of electronically excited species allows us to use electronically excited species as a marker for oxidative metabolic processes in cells. Full article

(This article belongs to the Section Cellular Biochemistry)

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17 pages, 1455 KiB

Open AccessEditor’s ChoiceReview

Site-Specific Incorporation of Unnatural Amino Acids into Escherichia coli Recombinant Protein: Methodology Development and Recent Achievement

by Sviatlana Smolskaya and Yaroslav A. Andreev

Biomolecules 2019, 9(7), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9070255 - 28 Jun 2019

Cited by 57 | Viewed by 9402

Abstract

More than two decades ago a general method to genetically encode noncanonical or unnatural amino acids (NAAs) with diverse physical, chemical, or biological properties in bacteria, yeast, animals and mammalian cells was developed. More than 200 NAAs have been incorporated into recombinant proteins [...] Read more.

More than two decades ago a general method to genetically encode noncanonical or unnatural amino acids (NAAs) with diverse physical, chemical, or biological properties in bacteria, yeast, animals and mammalian cells was developed. More than 200 NAAs have been incorporated into recombinant proteins by means of non-endogenous aminoacyl-tRNA synthetase (aa-RS)/tRNA pair, an orthogonal pair, that directs site-specific incorporation of NAA encoded by a unique codon. The most established method to genetically encode NAAs in Escherichia coli is based on the usage of the desired mutant of Methanocaldococcus janaschii tyrosyl-tRNA synthetase (MjTyrRS) and cognate suppressor tRNA. The amber codon, the least-used stop codon in E. coli, assigns NAA. Until very recently the genetic code expansion technology suffered from a low yield of targeted proteins due to both incompatibilities of orthogonal pair with host cell translational machinery and the competition of suppressor tRNA with release factor (RF) for binding to nonsense codons. Here we describe the latest progress made to enhance nonsense suppression in E. coli with the emphasis on the improved expression vectors encoding for an orthogonal aa-RA/tRNA pair, enhancement of aa-RS and suppressor tRNA efficiency, the evolution of orthogonal EF-Tu and attempts to reduce the effect of RF1. Full article

(This article belongs to the Section Synthetic Biology and Bioengineering)

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13 pages, 1202 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Hunt for Degrons of the 26S Proteasome

by Hadar Ella, Yuval Reiss and Tommer Ravid

Biomolecules 2019, 9(6), 230; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060230 - 13 Jun 2019

Cited by 18 | Viewed by 5875

Abstract

Since the discovery of ubiquitin conjugation as a cellular mechanism that triggers proteasomal degradation, the mode of substrate recognition by the ubiquitin-ligation system has been the holy grail of research in the field. This entails the discovery of recognition determinants within protein substrates, [...] Read more.

Since the discovery of ubiquitin conjugation as a cellular mechanism that triggers proteasomal degradation, the mode of substrate recognition by the ubiquitin-ligation system has been the holy grail of research in the field. This entails the discovery of recognition determinants within protein substrates, which are part of a degron, and explicit E3 ubiquitin (Ub)-protein ligases that trigger their degradation. Indeed, many protein substrates and their cognate E3′s have been discovered in the past 40 years. In the course of these studies, various degrons have been randomly identified, most of which are acquired through post-translational modification, typically, but not exclusively, protein phosphorylation. Nevertheless, acquired degrons cannot account for the vast diversity in cellular protein half-life times. Obviously, regulation of the proteome is largely determined by inherent degrons, that is, determinants integral to the protein structure. Inherent degrons are difficult to predict since they consist of diverse sequence and secondary structure features. Therefore, unbiased methods have been employed for their discovery. This review describes the history of degron discovery methods, including the development of high throughput screening methods, state of the art data acquisition and data analysis. Additionally, it summarizes major discoveries that led to the identification of cognate E3 ligases and hitherto unrecognized complexities of degron function. Finally, we discuss future perspectives and what still needs to be accomplished towards achieving the goal of understanding how the eukaryotic proteome is regulated via coordinated action of components of the ubiquitin-proteasome system. Full article

(This article belongs to the Special Issue The Broader Cellular Impact of Proteasome-CSN-eIf3 (PCI) Complexes)

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