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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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Review

35 pages, 1443 KiB  
Review
The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models
by Barbara Kosmowska and Jadwiga Wardas
Biomolecules 2021, 11(12), 1813; https://doi.org/10.3390/biom11121813 - 2 Dec 2021
Cited by 9 | Viewed by 5125
Abstract
Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we [...] Read more.
Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we show that current ET pharmacotherapy often does not sufficiently alleviate disease symptoms and is completely ineffective in more than 30% of patients. At present, deep brain stimulation of the motor thalamus is the most effective ET treatment. However, like any brain surgery, it can cause many undesirable side effects; thus, it is only performed in patients with an advanced disease who are not responsive to drugs. Therefore, it seems extremely important to look for new strategies for treating ET. The purpose of this review is to summarize the current knowledge on the pathomechanism of ET based on studies in animal models of the disease, as well as to present and discuss the results of research available to date on various substances affecting dopamine (mainly D3) or adenosine A1 receptors, which, due to their ability to modulate harmaline-induced tremor, may provide the basis for the development of new potential therapies for ET in the future. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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21 pages, 1857 KiB  
Review
New Insights into the Role of Cysteine Cathepsins in Neuroinflammation
by Anja Pišlar, Lara Bolčina and Janko Kos
Biomolecules 2021, 11(12), 1796; https://doi.org/10.3390/biom11121796 - 30 Nov 2021
Cited by 9 | Viewed by 3046
Abstract
Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that [...] Read more.
Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that aggravate neurodegeneration. To date, most research on neuroinflammation has focused on the role of cysteine cathepsins, the largest cathepsin family. Cysteine cathepsins are primarily responsible for protein degradation in lysosomes; however, they also play a role in regulating a number of other important physiological and pathological processes. This review focuses on the functional roles of cysteine cathepsins in the central nervous system during neuroinflammation, with an emphasis on their roles in the polarization of microglia and neuroinflammation signaling, which in turn causes neuronal death and thus neurodegeneration. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)
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12 pages, 649 KiB  
Review
Role of Intestinal Alkaline Phosphatase in Innate Immunity
by Sudha B. Singh and Henry C. Lin
Biomolecules 2021, 11(12), 1784; https://doi.org/10.3390/biom11121784 - 29 Nov 2021
Cited by 23 | Viewed by 4474
Abstract
Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel [...] Read more.
Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel disease IBD, necrotizing enterocolitis, and metabolic syndrome and that exogenous IAP supplementation improves the outcomes associated with these disorders. Additionally, studies using transgenic IAP-knock out (IAP-KO) mouse models further support the importance of the defensive role of IAP in the intestine. Supplementation of exogenous IAP and cellular overexpression of IAP have also been used in vitro to dissect out the downstream mechanisms of this protein in mammalian cell lines. Some of the innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of gut barrier integrity, regulation of gut microbial communities and its anti-inflammatory roles. A novel function of IAP recently identified is the induction of autophagy. Due to its critical role in the gut physiology and its excellent safety profile, IAP has been used in phase 2a clinical trials for treating conditions such as sepsis-associated acute kidney injury. Many excellent reviews discuss the role of IAP in physiology and pathophysiology and here we extend these to include recent updates on this important host defense protein and discuss its role in innate immunity via its effects on bacteria as well as on host cells. We will also discuss the relationship between IAP and autophagy and how these two pathways may act in concert to protect the gut. Full article
(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)
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25 pages, 2446 KiB  
Review
Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension
by Bastien Masson, David Montani, Marc Humbert, Véronique Capuano and Fabrice Antigny
Biomolecules 2021, 11(12), 1781; https://doi.org/10.3390/biom11121781 - 27 Nov 2021
Cited by 14 | Viewed by 3308
Abstract
Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies [...] Read more.
Pulmonary arterial hypertension (PAH) is a severe and multifactorial disease. PAH pathogenesis mostly involves pulmonary arterial endothelial and pulmonary arterial smooth muscle cell (PASMC) dysfunction, leading to alterations in pulmonary arterial tone and distal pulmonary vessel obstruction and remodeling. Unfortunately, current PAH therapies are not curative, and therapeutic approaches mostly target endothelial dysfunction, while PASMC dysfunction is under investigation. In PAH, modifications in intracellular Ca2+ homoeostasis could partly explain PASMC dysfunction. One of the most crucial actors regulating Ca2+ homeostasis is store-operated Ca2+ channels, which mediate store-operated Ca2+ entry (SOCE). This review focuses on the main actors of SOCE in human and experimental PASMC, their contribution to PAH pathogenesis, and their therapeutic potential in PAH. Full article
(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)
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34 pages, 2512 KiB  
Review
The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor
by Alamelu G. Bharadwaj, Emma Kempster and David M. Waisman
Biomolecules 2021, 11(12), 1772; https://doi.org/10.3390/biom11121772 - 26 Nov 2021
Cited by 11 | Viewed by 3469
Abstract
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound [...] Read more.
The generation of the serine protease plasmin is initiated by the binding of its zymogenic precursor, plasminogen, to cell surface receptors. The proteolytic activity of plasmin, generated at the cell surface, plays a crucial role in several physiological processes, including fibrinolysis, angiogenesis, wound healing, and the invasion of cells through both the basement membrane and extracellular matrix. The seminal observation by Albert Fischer that cancer cells, but not normal cells in culture, produce large amounts of plasmin formed the basis of current-day observations that plasmin generation can be hijacked by cancer cells to allow tumor development, progression, and metastasis. Thus, the cell surface plasminogen-binding receptor proteins are critical to generating plasmin proteolytic activity at the cell surface. This review focuses on one of the twelve well-described plasminogen receptors, S100A10, which, when in complex with its regulatory partner, annexin A2 (ANXA2), forms the ANXA2/S100A10 heterotetrameric complex referred to as AIIt. We present the theme that AIIt is the quintessential cellular plasminogen receptor since it regulates the formation and the destruction of plasmin. We also introduce the term oncogenic plasminogen receptor to define those plasminogen receptors directly activated during cancer progression. We then discuss the research establishing AIIt as an oncogenic plasminogen receptor-regulated during EMT and activated by oncogenes such as SRC, RAS, HIF1α, and PML-RAR and epigenetically by DNA methylation. We further discuss the evidence derived from animal models supporting the role of S100A10 in tumor progression and oncogenesis. Lastly, we describe the potential of S100A10 as a biomarker for cancer diagnosis and prognosis. Full article
(This article belongs to the Special Issue Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer)
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25 pages, 4177 KiB  
Review
Piezoelectric Signals in Vascularized Bone Regeneration
by Delfo D’Alessandro, Claudio Ricci, Mario Milazzo, Giovanna Strangis, Francesca Forli, Gabriele Buda, Mario Petrini, Stefano Berrettini, Mohammed Jasim Uddin, Serena Danti and Paolo Parchi
Biomolecules 2021, 11(11), 1731; https://doi.org/10.3390/biom11111731 - 20 Nov 2021
Cited by 31 | Viewed by 5612
Abstract
The demand for bone substitutes is increasing in Western countries. Bone graft substitutes aim to provide reconstructive surgeons with off-the-shelf alternatives to the natural bone taken from humans or animal species. Under the tissue engineering paradigm, biomaterial scaffolds can be designed by incorporating [...] Read more.
The demand for bone substitutes is increasing in Western countries. Bone graft substitutes aim to provide reconstructive surgeons with off-the-shelf alternatives to the natural bone taken from humans or animal species. Under the tissue engineering paradigm, biomaterial scaffolds can be designed by incorporating bone stem cells to decrease the disadvantages of traditional tissue grafts. However, the effective clinical application of tissue-engineered bone is limited by insufficient neovascularization. As bone is a highly vascularized tissue, new strategies to promote both osteogenesis and vasculogenesis within the scaffolds need to be considered for a successful regeneration. It has been demonstrated that bone and blood vases are piezoelectric, namely, electric signals are locally produced upon mechanical stimulation of these tissues. The specific effects of electric charge generation on different cells are not fully understood, but a substantial amount of evidence has suggested their functional and physiological roles. This review summarizes the special contribution of piezoelectricity as a stimulatory signal for bone and vascular tissue regeneration, including osteogenesis, angiogenesis, vascular repair, and tissue engineering, by considering different stem cell sources entailed with osteogenic and angiogenic potential, aimed at collecting the key findings that may enable the development of successful vascularized bone replacements useful in orthopedic and otologic surgery. Full article
(This article belongs to the Special Issue New Insights into Stem Cell Regulation)
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18 pages, 958 KiB  
Review
Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era
by Mattia Zaghi, Federica Banfi, Edoardo Bellini and Alessandro Sessa
Biomolecules 2021, 11(11), 1713; https://doi.org/10.3390/biom11111713 - 17 Nov 2021
Cited by 4 | Viewed by 2752
Abstract
The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and [...] Read more.
The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and rare genomic variants and to perform detailed phenotypic characterizations of both physiological organs and experimental models. Recent years have seen the introduction of multiple techniques using NGS to profile transcription, DNA and chromatin modifications, protein binding, etc., that are now allowing us to profile cells in bulk or even at a single-cell level. Although rare and ultra-rare diseases only affect a few people, each of these diseases represent scholarly cases from which a great deal can be learned about the pathological and physiological function of genes, pathways, and mechanisms. Therefore, for rare diseases, state-of-the-art investigations using NGS have double valence: their genomic cause (new variants) and the characterize the underlining the mechanisms associated with them (discovery of gene function) can be found. In a non-exhaustive manner, this review will outline the main usage of NGS-based techniques for the diagnosis and characterization of neurodevelopmental disorders (NDDs), under whose umbrella many rare and ultra-rare diseases fall. Full article
(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)
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19 pages, 2572 KiB  
Review
Co-Evolution of Breast Milk Lipid Signaling and Thermogenic Adipose Tissue
by Tamás Röszer
Biomolecules 2021, 11(11), 1705; https://doi.org/10.3390/biom11111705 - 16 Nov 2021
Cited by 7 | Viewed by 3226
Abstract
Breastfeeding is a unique and defining behavior of mammals and has a fundamental role in nourishing offspring by supplying a lipid-rich product that is utilized to generate heat and metabolic fuel. Heat generation from lipids is a feature of newborn mammals and is [...] Read more.
Breastfeeding is a unique and defining behavior of mammals and has a fundamental role in nourishing offspring by supplying a lipid-rich product that is utilized to generate heat and metabolic fuel. Heat generation from lipids is a feature of newborn mammals and is mediated by the uncoupling of mitochondrial respiration in specific fat depots. Breastfeeding and thermogenic adipose tissue have a shared evolutionary history: both have evolved in the course of homeothermy evolution; breastfeeding mammals are termed “thermolipials”, meaning “animals with warm fat”. Beyond its heat-producing capacity, thermogenic adipose tissue is also necessary for proper lipid metabolism and determines adiposity in offspring. Recent advances have demonstrated that lipid metabolism in infants is orchestrated by breast milk lipid signals, which establish mother-to-child signaling and control metabolic development in the infant. Breastfeeding rates are declining worldwide, and are paralleled by an alarming increase in childhood obesity, which at least in part may have its roots in the impaired metabolic control by breast milk lipid signals. Full article
(This article belongs to the Special Issue Breast Milk-Derived Biomolecules in Human Health)
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22 pages, 2366 KiB  
Review
Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
by Louise Pinet, Nadine Assrir and Carine van Heijenoort
Biomolecules 2021, 11(11), 1690; https://doi.org/10.3390/biom11111690 - 14 Nov 2021
Cited by 2 | Viewed by 2399
Abstract
ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal [...] Read more.
ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features. Full article
(This article belongs to the Collection Protein Intrinsic Disorder: Role in Signaling, Regulation and Membrane-Less Organelle Formation)
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11 pages, 1607 KiB  
Review
An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate’s Emerging Roles in Cell Proliferation and Survival
by Iiro Taneli Helenius, Hanumantha Rao Madala and Jing-Ruey Joanna Yeh
Biomolecules 2021, 11(11), 1666; https://doi.org/10.3390/biom11111666 - 10 Nov 2021
Cited by 11 | Viewed by 3046
Abstract
A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable [...] Read more.
A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate–aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, aspartate can become a limiting factor for tumor growth and cancer cell survival. Notably, aspartate availability has been associated with sensitivity or resistance to various therapeutics that are presently in the clinic or in clinical trials, arguing for a critical need for more effective aspartate-targeting approaches. In this review, we present current knowledge of the metabolic roles of aspartate in cancer cells and describe how cancer cells maintain aspartate levels under different metabolic states. We also highlight several promising aspartate level-modulating agents that are currently under investigation. Full article
(This article belongs to the Special Issue Role of the Mitochondrial Stress Response in Human Cancer Progression)
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19 pages, 1175 KiB  
Review
miRNA as a Modulator of Immunotherapy and Immune Response in Melanoma
by Mai-Huong Thi Nguyen, Yueh-Hsia Luo, An-Lun Li, Jen-Chieh Tsai, Kun-Lin Wu, Pei-Jung Chung and Nianhan Ma
Biomolecules 2021, 11(11), 1648; https://doi.org/10.3390/biom11111648 - 8 Nov 2021
Cited by 15 | Viewed by 3219
Abstract
Immune checkpoint inhibitors are a promising therapy for the treatment of cancers, including melanoma, that improved benefit clinical outcomes. However, a subset of melanoma patients do not respond or acquire resistance to immunotherapy, which limits their clinical applicability. Recent studies have explored the [...] Read more.
Immune checkpoint inhibitors are a promising therapy for the treatment of cancers, including melanoma, that improved benefit clinical outcomes. However, a subset of melanoma patients do not respond or acquire resistance to immunotherapy, which limits their clinical applicability. Recent studies have explored the reasons related to the resistance of melanoma to immune checkpoint inhibitors. Of note, miRNAs are the regulators of not only cancer progression but also of the response between cancer cells and immune cells. Investigation of miRNA functions within the tumor microenvironment have suggested that miRNAs could be considered as key partners in immunotherapy. Here, we reviewed the known mechanism by which melanoma induces resistance to immunotherapy and the role of miRNAs in immune responses and the microenvironment. Full article
(This article belongs to the Special Issue MicroRNAs - Small Molecules with Great Potential in Tumorigenesis)
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21 pages, 17965 KiB  
Review
The Synthesis and Biological Evaluation of D-Ring-Modified Vitamin D Analogues
by Fumihiro Kawagoe, Sayuri Mototani and Atsushi Kittaka
Biomolecules 2021, 11(11), 1639; https://doi.org/10.3390/biom11111639 - 4 Nov 2021
Cited by 9 | Viewed by 2134
Abstract
The vitamin D3 structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D3. Many efforts have been made to date [...] Read more.
The vitamin D3 structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D3. Many efforts have been made to date to assess the possible clinical use of vitamin D. Some organic chemists focused on the D-ring structure of vitamin D and synthesized D-ring-modified vitamin D analogues, and their biological activities were studied. This review summarizes the synthetic methodologies of D-ring-modified vitamin D analogues, except for seco-D, and their preliminary biological profiles. Full article
(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)
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15 pages, 1541 KiB  
Review
Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation
by Divya Guntur, Horst Olschewski, Péter Enyedi, Réka Csáki, Andrea Olschewski and Chandran Nagaraj
Biomolecules 2021, 11(11), 1629; https://doi.org/10.3390/biom11111629 - 3 Nov 2021
Cited by 9 | Viewed by 3473
Abstract
Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) [...] Read more.
Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options. Full article
(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)
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17 pages, 1300 KiB  
Review
KCNQ1OT1: An Oncogenic Long Noncoding RNA
by Patrice Cagle, Qi Qi, Suryakant Niture and Deepak Kumar
Biomolecules 2021, 11(11), 1602; https://doi.org/10.3390/biom11111602 - 29 Oct 2021
Cited by 31 | Viewed by 3994
Abstract
Long noncoding RNAs (lncRNAs) are transcripts greater than 200 nucleotides that do not code for proteins but regulate gene expression. Recent studies indicate that lncRNAs are involved in the modulation of biological functions in human disease. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) encodes [...] Read more.
Long noncoding RNAs (lncRNAs) are transcripts greater than 200 nucleotides that do not code for proteins but regulate gene expression. Recent studies indicate that lncRNAs are involved in the modulation of biological functions in human disease. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) encodes a lncRNA from the opposite strand of KCNQ1 in the CDKN1C/KCNQ1OT1 cluster that is reported to play a vital role in the development and progression of cancer. KCNQ1OT1 regulates cancer cell proliferation, cell cycle, migration and invasion, metastasis, glucose metabolism, and immune evasion. The aberrant expression of KCNQ1OT1 in cancer patients is associated with poor prognosis and decreased survival. This review summarizes recent literature related to the biological functions and molecular mechanisms of KCNQ1OT1 in various human cancers, including colorectal, bladder, breast, oral, melanoma, osteosarcoma, lung, glioma, ovarian, liver, acute myeloid leukemia, prostate, and gastric. We also discuss the role of KCNQ1OT1 as a promising diagnostic biomarker and a novel therapeutic target in human cancers. Full article
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18 pages, 1045 KiB  
Review
Bioprinting Au Natural: The Biologics of Bioinks
by Kelsey Willson, Anthony Atala and James J. Yoo
Biomolecules 2021, 11(11), 1593; https://doi.org/10.3390/biom11111593 - 28 Oct 2021
Cited by 14 | Viewed by 2604
Abstract
The development of appropriate bioinks is a complex task, dependent on the mechanical and biochemical requirements of the final construct and the type of printer used for fabrication. The two most common tissue printers are micro-extrusion and digital light projection printers. Here we [...] Read more.
The development of appropriate bioinks is a complex task, dependent on the mechanical and biochemical requirements of the final construct and the type of printer used for fabrication. The two most common tissue printers are micro-extrusion and digital light projection printers. Here we briefly discuss the required characteristics of a bioink for each of these printing processes. However, physical printing is only a short window in the lifespan of a printed construct—the system must support and facilitate cellular development after it is printed. To that end, we provide a broad overview of some of the biological molecules currently used as bioinks. Each molecule has advantages for specific tissues/cells, and potential disadvantages are discussed, along with examples of their current use in the field. Notably, it is stressed that active researchers are trending towards the use of composite bioinks. Utilizing the strengths from multiple materials is highlighted as a key component of bioink development. Full article
(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)
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18 pages, 727 KiB  
Review
Self-Attention-Based Models for the Extraction of Molecular Interactions from Biological Texts
by Prashant Srivastava, Saptarshi Bej, Kristina Yordanova and Olaf Wolkenhauer
Biomolecules 2021, 11(11), 1591; https://doi.org/10.3390/biom11111591 - 27 Oct 2021
Cited by 11 | Viewed by 3039
Abstract
For any molecule, network, or process of interest, keeping up with new publications on these is becoming increasingly difficult. For many cellular processes, the amount molecules and their interactions that need to be considered can be very large. Automated mining of publications can [...] Read more.
For any molecule, network, or process of interest, keeping up with new publications on these is becoming increasingly difficult. For many cellular processes, the amount molecules and their interactions that need to be considered can be very large. Automated mining of publications can support large-scale molecular interaction maps and database curation. Text mining and Natural-Language-Processing (NLP)-based techniques are finding their applications in mining the biological literature, handling problems such as Named Entity Recognition (NER) and Relationship Extraction (RE). Both rule-based and Machine-Learning (ML)-based NLP approaches have been popular in this context, with multiple research and review articles examining the scope of such models in Biological Literature Mining (BLM). In this review article, we explore self-attention-based models, a special type of Neural-Network (NN)-based architecture that has recently revitalized the field of NLP, applied to biological texts. We cover self-attention models operating either at the sentence level or an abstract level, in the context of molecular interaction extraction, published from 2019 onwards. We conducted a comparative study of the models in terms of their architecture. Moreover, we also discuss some limitations in the field of BLM that identifies opportunities for the extraction of molecular interactions from biological text. Full article
(This article belongs to the Special Issue Computational Approaches for the Study of Biomolecular Networks)
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18 pages, 1424 KiB  
Review
CB2 Receptor Involvement in the Treatment of Substance Use Disorders
by Francisco Navarrete, María S. García-Gutiérrez, Ani Gasparyan, Daniela Navarro and Jorge Manzanares
Biomolecules 2021, 11(11), 1556; https://doi.org/10.3390/biom11111556 - 20 Oct 2021
Cited by 14 | Viewed by 2639
Abstract
The pharmacological modulation of the cannabinoid receptor 2 (CB2r) has emerged as a promising potential therapeutic option in addiction. The purpose of this review was to determine the functional involvement of CB2r in the effects produced by drugs of abuse at the central [...] Read more.
The pharmacological modulation of the cannabinoid receptor 2 (CB2r) has emerged as a promising potential therapeutic option in addiction. The purpose of this review was to determine the functional involvement of CB2r in the effects produced by drugs of abuse at the central nervous system (CNS) level by assessing evidence from preclinical and clinical studies. In rodents, several reports suggest the functional involvement of CB2r in the effects produced by drugs of abuse such as alcohol, cocaine, or nicotine. In addition, the discovery of CB2r in brain areas that are part of the reward system supports the relevance of CB2r in the field of addiction. Interestingly, animal studies support that the CB2r regulates anxiety and depression behavioral traits. Due to its frequent comorbidity with neuropsychiatric disorders, these pharmacological actions may be of great interest in managing SUD. Preliminary clinical trials are focused on exploring the therapeutic potential of modulating CB2r in treating addictive disorders. These promising results support the development of new pharmacological tools regulating the CB2r that may help to increase the therapeutic success in the management of SUD. Full article
(This article belongs to the Special Issue Translational Biomarkers in Addictive Disorders)
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16 pages, 999 KiB  
Review
MicroRNAs and Metabolism: Revisiting the Warburg Effect with Emphasis on Epigenetic Background and Clinical Applications
by Zsuzsanna Gaál
Biomolecules 2021, 11(10), 1531; https://doi.org/10.3390/biom11101531 - 17 Oct 2021
Cited by 5 | Viewed by 3750
Abstract
Since the well-known hallmarks of cancer were described by Hanahan and Weinberg, fundamental advances of molecular genomic technologies resulted in the discovery of novel puzzle pieces in the multistep pathogenesis of cancer. MicroRNAs are involved in the altered epigenetic pattern and metabolic phenotype [...] Read more.
Since the well-known hallmarks of cancer were described by Hanahan and Weinberg, fundamental advances of molecular genomic technologies resulted in the discovery of novel puzzle pieces in the multistep pathogenesis of cancer. MicroRNAs are involved in the altered epigenetic pattern and metabolic phenotype of malignantly transformed cells. They contribute to the initiation, progression and metastasis-formation of cancers, also interacting with oncogenes, tumor-suppressor genes and epigenetic modifiers. Metabolic reprogramming of cancer cells results from the dysregulation of a complex network, in which microRNAs are located at central hubs. MicroRNAs regulate the expression of several metabolic enzymes, including tumor-specific isoforms. Therefore, they have a direct impact on the levels of metabolites, also influencing epigenetic pattern due to the metabolite cofactors of chromatin modifiers. Targets of microRNAs include numerous epigenetic enzymes, such as sirtuins, which are key regulators of cellular metabolic homeostasis. A better understanding of reversible epigenetic and metabolic alterations opened up new horizons in the personalized treatment of cancer. MicroRNA expression levels can be utilized in differential diagnosis, prognosis stratification and prediction of chemoresistance. The therapeutic modulation of microRNA levels is an area of particular interest that provides a promising tool for restoring altered metabolism of cancer cells. Full article
(This article belongs to the Special Issue MicroRNAs - Small Molecules with Great Potential in Tumorigenesis)
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23 pages, 2779 KiB  
Review
Decoding Stem Cells: An Overview on Planarian Stem Cell Heterogeneity and Lineage Progression
by M. Dolores Molina and Francesc Cebrià
Biomolecules 2021, 11(10), 1532; https://doi.org/10.3390/biom11101532 - 17 Oct 2021
Cited by 14 | Viewed by 6681
Abstract
Planarians are flatworms capable of whole-body regeneration, able to regrow any missing body part after injury or amputation. The extraordinary regenerative capacity of planarians is based upon the presence in the adult of a large population of somatic pluripotent stem cells. These cells, [...] Read more.
Planarians are flatworms capable of whole-body regeneration, able to regrow any missing body part after injury or amputation. The extraordinary regenerative capacity of planarians is based upon the presence in the adult of a large population of somatic pluripotent stem cells. These cells, called neoblasts, offer a unique system to study the process of stem cell specification and differentiation in vivo. In recent years, FACS-based isolation of neoblasts, RNAi functional analyses as well as high-throughput approaches such as single-cell sequencing have allowed a rapid progress in our understanding of many different aspects of neoblast biology. Here, we summarize our current knowledge on the molecular signatures that define planarian neoblasts heterogeneity, which includes a percentage of truly pluripotent stem cells, and guide the commitment of pluripotent neoblasts into lineage-specific progenitor cells, as well as their differentiation into specific planarian cell types. Full article
(This article belongs to the Special Issue New Insights into Stem Cell Regulation)
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34 pages, 8749 KiB  
Review
Hyaluronic Acid: A Key Ingredient in the Therapy of Inflammation
by Andreia Marinho, Cláudia Nunes and Salette Reis
Biomolecules 2021, 11(10), 1518; https://doi.org/10.3390/biom11101518 - 15 Oct 2021
Cited by 134 | Viewed by 11678
Abstract
Hyaluronic acid (HA) is a natural polymer, produced endogenously by the human body, which has unique physicochemical and biological properties, exhibiting desirable biocompatibility and biodegradability. Therefore, it has been widely studied for possible applications in the area of inflammatory diseases. Although exogenous HA [...] Read more.
Hyaluronic acid (HA) is a natural polymer, produced endogenously by the human body, which has unique physicochemical and biological properties, exhibiting desirable biocompatibility and biodegradability. Therefore, it has been widely studied for possible applications in the area of inflammatory diseases. Although exogenous HA has been described as unable to restore or replace the properties and activities of endogenous HA, it can still provide satisfactory pain relief. This review aims to discuss the advances that have been achieved in the treatment of inflammatory diseases using hyaluronic acid as a key ingredient, essentially focusing on studies carried out between the years 2017 and 2021. Full article
(This article belongs to the Special Issue Hyaluronic Acid in Human Medicine)
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28 pages, 2663 KiB  
Review
Alternative Pre-mRNA Splicing of the Mu Opioid Receptor Gene, OPRM1: Insight into Complex Mu Opioid Actions
by Shan Liu, Wen-Jia Kang, Anna Abrimian, Jin Xu, Luca Cartegni, Susruta Majumdar, Patrick Hesketh, Alex Bekker and Ying-Xian Pan
Biomolecules 2021, 11(10), 1525; https://doi.org/10.3390/biom11101525 - 15 Oct 2021
Cited by 12 | Viewed by 3664
Abstract
Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, [...] Read more.
Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating multiple splice variants or isoforms via a variety of alternative splicing events. These OPRM1 splice variants can be categorized into three major types based on the receptor structure: (1) full-length 7 transmembrane (TM) C-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating the distinct actions of various mu opioids. More importantly, the OPRM1 variants can be targeted for development of novel opioid analgesics that are potent against multiple types of pain, but devoid of many side-effects associated with traditional opiates. In this review, we provide an overview of OPRM1 alternative splicing and its functional relevance in opioid pharmacology. Full article
(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)
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11 pages, 932 KiB  
Review
Hyperbaric Oxygen Treatment—From Mechanisms to Cognitive Improvement
by Irit Gottfried, Nofar Schottlender and Uri Ashery
Biomolecules 2021, 11(10), 1520; https://doi.org/10.3390/biom11101520 - 15 Oct 2021
Cited by 50 | Viewed by 8975
Abstract
Hyperbaric oxygen treatment (HBOT)—the medical use of oxygen at environmental pressure greater than one atmosphere absolute—is a very effective therapy for several approved clinical situations, such as carbon monoxide intoxication, incurable diabetes or radiation-injury wounds, and smoke inhalation. In recent years, it has [...] Read more.
Hyperbaric oxygen treatment (HBOT)—the medical use of oxygen at environmental pressure greater than one atmosphere absolute—is a very effective therapy for several approved clinical situations, such as carbon monoxide intoxication, incurable diabetes or radiation-injury wounds, and smoke inhalation. In recent years, it has also been used to improve cognition, neuro-wellness, and quality of life following brain trauma and stroke. This opens new avenues for the elderly, including the treatment of neurological and neurodegenerative diseases and improvement of cognition and brain metabolism in cases of mild cognitive impairment. Alongside its integration into clinics, basic research studies have elucidated HBOT’s mechanisms of action and its effects on cellular processes, transcription factors, mitochondrial function, oxidative stress, and inflammation. Therefore, HBOT is becoming a major player in 21st century research and clinical treatments. The following review will discuss the basic mechanisms of HBOT, and its effects on cellular processes, cognition, and brain disorders. Full article
(This article belongs to the Special Issue Oxygen Therapy)
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19 pages, 1784 KiB  
Review
Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery
by Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Júnior, Cecilia Bucci and Emanuele Marzetti
Biomolecules 2021, 11(10), 1508; https://doi.org/10.3390/biom11101508 - 13 Oct 2021
Cited by 64 | Viewed by 7442
Abstract
Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational [...] Read more.
Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery. Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Neuroinflammation)
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30 pages, 1439 KiB  
Review
Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis
by Michael Hecker, Jan Bühring, Brit Fitzner, Paulus Stefan Rommer and Uwe Klaus Zettl
Biomolecules 2021, 11(10), 1510; https://doi.org/10.3390/biom11101510 - 13 Oct 2021
Cited by 20 | Viewed by 5877
Abstract
Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative [...] Read more.
Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS. Full article
(This article belongs to the Special Issue The Molecular Mechanisms and Therapeutics in Multiple Sclerosis)
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12 pages, 1141 KiB  
Review
Osteogenesis Imperfecta: Current and Prospective Therapies
by Malwina Botor, Agnieszka Fus-Kujawa, Marta Uroczynska, Karolina L. Stepien, Anna Galicka, Katarzyna Gawron and Aleksander L. Sieron
Biomolecules 2021, 11(10), 1493; https://doi.org/10.3390/biom11101493 - 10 Oct 2021
Cited by 34 | Viewed by 10648
Abstract
Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a [...] Read more.
Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI. Full article
(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)
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23 pages, 4315 KiB  
Review
DNA End Joining: G0-ing to the Core
by Richard L. Frock, Cheyenne Sadeghi, Jodie Meng and Jing L. Wang
Biomolecules 2021, 11(10), 1487; https://doi.org/10.3390/biom11101487 - 9 Oct 2021
Cited by 10 | Viewed by 4684
Abstract
Humans have evolved a series of DNA double-strand break (DSB) repair pathways to efficiently and accurately rejoin nascently formed pairs of double-stranded DNA ends (DSEs). In G0/G1-phase cells, non-homologous end joining (NHEJ) and alternative end joining (A-EJ) operate to support covalent rejoining of [...] Read more.
Humans have evolved a series of DNA double-strand break (DSB) repair pathways to efficiently and accurately rejoin nascently formed pairs of double-stranded DNA ends (DSEs). In G0/G1-phase cells, non-homologous end joining (NHEJ) and alternative end joining (A-EJ) operate to support covalent rejoining of DSEs. While NHEJ is predominantly utilized and collaborates extensively with the DNA damage response (DDR) to support pairing of DSEs, much less is known about A-EJ collaboration with DDR factors when NHEJ is absent. Non-cycling lymphocyte progenitor cells use NHEJ to complete V(D)J recombination of antigen receptor genes, initiated by the RAG1/2 endonuclease which holds its pair of targeted DSBs in a synapse until each specified pair of DSEs is handed off to the NHEJ DSB sensor complex, Ku. Similar to designer endonuclease DSBs, the absence of Ku allows for A-EJ to access RAG1/2 DSEs but with random pairing to complete their repair. Here, we describe recent insights into the major phases of DSB end joining, with an emphasis on synapsis and tethering mechanisms, and bring together new and old concepts of NHEJ vs. A-EJ and on RAG2-mediated repair pathway choice. Full article
(This article belongs to the Collection DNA Repair and Immune Response)
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35 pages, 2833 KiB  
Review
Coordination of RNA Processing Regulation by Signal Transduction Pathways
by Veronica Ruta, Vittoria Pagliarini and Claudio Sette
Biomolecules 2021, 11(10), 1475; https://doi.org/10.3390/biom11101475 - 7 Oct 2021
Cited by 9 | Viewed by 3797
Abstract
Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as [...] Read more.
Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules. Full article
(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)
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17 pages, 1939 KiB  
Review
Natural Products Are a Promising Source for Anthelmintic Drug Discovery
by K. L. T. Dilrukshi Jayawardene, Enzo A. Palombo and Peter R. Boag
Biomolecules 2021, 11(10), 1457; https://doi.org/10.3390/biom11101457 - 4 Oct 2021
Cited by 34 | Viewed by 7226
Abstract
Parasitic nematodes infect almost all forms of life. In the human context, parasites are one of the major causative factors for physical and intellectual growth retardation in the developing world. In the agricultural setting, parasites have a great economic impact through a reduction [...] Read more.
Parasitic nematodes infect almost all forms of life. In the human context, parasites are one of the major causative factors for physical and intellectual growth retardation in the developing world. In the agricultural setting, parasites have a great economic impact through a reduction in livestock performance or control cost. The main method of controlling these devastating conditions is the use of anthelmintic drugs. Unfortunately, there are only a few anthelmintic drug classes available in the market and significant resistance has developed in most of the parasitic species of livestock. Therefore, development of new anthelmintics with different modes of action is critical for sustainable parasitic control in the future. The drug development pipeline is broadly limited to two types of molecules, namely synthetic compounds and natural plant products. Compared to synthetic compounds, natural products are highly diverse, and many have historically proven valuable in folk medicine to treat various gastrointestinal ailments. This review focus on the use of traditional knowledge-based plant extracts in the development of new therapeutic leads, the approaches used as screening techniques, and common bottlenecks and opportunities in plant-based anthelmintic drug discovery. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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16 pages, 1023 KiB  
Review
Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways
by Robert H. Whitaker and Jeanette Gowen Cook
Biomolecules 2021, 11(10), 1444; https://doi.org/10.3390/biom11101444 - 2 Oct 2021
Cited by 43 | Viewed by 6061
Abstract
Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via [...] Read more.
Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways. Full article
(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)
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14 pages, 722 KiB  
Review
Interactions of HMGB Proteins with the Genome and the Impact on Disease
by Calvin K. Voong, James A. Goodrich and Jennifer F. Kugel
Biomolecules 2021, 11(10), 1451; https://doi.org/10.3390/biom11101451 - 2 Oct 2021
Cited by 28 | Viewed by 4199
Abstract
High Mobility Group Box (HMGB) proteins are small architectural DNA binding proteins that regulate multiple genomic processes such as DNA damage repair, nucleosome sliding, telomere homeostasis, and transcription. In doing so they control both normal cellular functions and impact a myriad of disease [...] Read more.
High Mobility Group Box (HMGB) proteins are small architectural DNA binding proteins that regulate multiple genomic processes such as DNA damage repair, nucleosome sliding, telomere homeostasis, and transcription. In doing so they control both normal cellular functions and impact a myriad of disease states, including cancers and autoimmune diseases. HMGB proteins bind to DNA and nucleosomes to modulate the local chromatin environment, which facilitates the binding of regulatory protein factors to the genome and modulates higher order chromosomal organization. Numerous studies over the years have characterized the structure and function of interactions between HMGB proteins and DNA, both biochemically and inside cells, providing valuable mechanistic insight as well as evidence these interactions influence pathological processes. This review highlights recent studies supporting the roles of HMGB1 and HMGB2 in global organization of the genome, as well as roles in transcriptional regulation and telomere maintenance via interactions with G-quadruplex structures. Moreover, emerging models for how HMGB proteins function as RNA binding proteins are presented. Nuclear HMGB proteins have broad regulatory potential to impact numerous aspects of cellular metabolism in normal and disease states. Full article
(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)
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32 pages, 27417 KiB  
Review
Immunoaffinity Capillary Electrophoresis in the Era of Proteoforms, Liquid Biopsy and Preventive Medicine: A Potential Impact in the Diagnosis and Monitoring of Disease Progression
by Norberto A. Guzman and Daniel E. Guzman
Biomolecules 2021, 11(10), 1443; https://doi.org/10.3390/biom11101443 - 1 Oct 2021
Cited by 12 | Viewed by 4120
Abstract
Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in [...] Read more.
Over the years, multiple biomarkers have been used to aid in disease screening, diagnosis, prognosis, and response to therapy. As of late, protein biomarkers are gaining strength in their role for early disease diagnosis and prognosis in part due to the advancements in identification and characterization of a distinct functional pool of proteins known as proteoforms. Proteoforms are defined as all of the different molecular forms of a protein derived from a single gene caused by genetic variations, alternative spliced RNA transcripts and post-translational modifications. Monitoring the structural changes of each proteoform of a particular protein is essential to elucidate the complex molecular mechanisms that guide the course of disease. Clinical proteomics therefore holds the potential to offer further insight into disease pathology, progression, and prevention. Nevertheless, more technologically advanced diagnostic methods are needed to improve the reliability and clinical applicability of proteomics in preventive medicine. In this manuscript, we review the use of immunoaffinity capillary electrophoresis (IACE) as an emerging powerful diagnostic tool to isolate, separate, detect and characterize proteoform biomarkers obtained from liquid biopsy. IACE is an affinity capture-separation technology capable of isolating, concentrating and analyzing a wide range of biomarkers present in biological fluids. Isolation and concentration of target analytes is accomplished through binding to one or more biorecognition affinity ligands immobilized to a solid support, while separation and analysis are achieved by high-resolution capillary electrophoresis (CE) coupled to one or more detectors. IACE has the potential to generate rapid results with significant accuracy, leading to reliability and reproducibility in diagnosing and monitoring disease. Additionally, IACE has the capability of monitoring the efficacy of therapeutic agents by quantifying companion and complementary protein biomarkers. With advancements in telemedicine and artificial intelligence, the implementation of proteoform biomarker detection and analysis may significantly improve our capacity to identify medical conditions early and intervene in ways that improve health outcomes for individuals and populations. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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21 pages, 4112 KiB  
Review
Pyrroloquinoline-Quinone Is More Than an Antioxidant: A Vitamin-like Accessory Factor Important in Health and Disease Prevention
by Karen R. Jonscher, Winyoo Chowanadisai and Robert B. Rucker
Biomolecules 2021, 11(10), 1441; https://doi.org/10.3390/biom11101441 - 30 Sep 2021
Cited by 36 | Viewed by 15384
Abstract
Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or [...] Read more.
Pyrroloquinoline quinone (PQQ) is associated with biological processes such as mitochondriogenesis, reproduction, growth, and aging. In addition, PQQ attenuates clinically relevant dysfunctions (e.g., those associated with ischemia, inflammation and lipotoxicity). PQQ is novel among biofactors that are not currently accepted as vitamins or conditional vitamins. For example, the absence of PQQ in diets produces a response like a vitamin-related deficiency with recovery upon PQQ repletion in a dose-dependent manner. Moreover, potential health benefits, such as improved metabolic flexibility and immuno-and neuroprotection, are associated with PQQ supplementation. Here, we address PQQ’s role as an enzymatic cofactor or accessory factor and highlight mechanisms underlying PQQ’s actions. We review both large scale and targeted datasets demonstrating that a neonatal or perinatal PQQ deficiency reduces mitochondria content and mitochondrial-related gene expression. Data are reviewed that suggest PQQ’s modulation of lactate acid and perhaps other dehydrogenases enhance NAD+-dependent sirtuin activity, along with the sirtuin targets, such as PGC-1α, NRF-1, NRF-2 and TFAM; thus, mediating mitochondrial functions. Taken together, current observations suggest vitamin-like PQQ has strong potential as a potent therapeutic nutraceutical. Full article
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28 pages, 1647 KiB  
Review
Obesity–An Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances
by Erind Gjermeni, Anna S. Kirstein, Florentien Kolbig, Michael Kirchhof, Linnaeus Bundalian, Julius L. Katzmann, Ulrich Laufs, Matthias Blüher, Antje Garten and Diana Le Duc
Biomolecules 2021, 11(10), 1426; https://doi.org/10.3390/biom11101426 - 29 Sep 2021
Cited by 38 | Viewed by 20585
Abstract
Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, [...] Read more.
Obesity represents a major public health problem with a prevalence increasing at an alarming rate worldwide. Continuous intensive efforts to elucidate the complex pathophysiology and improve clinical management have led to a better understanding of biomolecules like gut hormones, antagonists of orexigenic signals, stimulants of fat utilization, and/or inhibitors of fat absorption. In this article, we will review the pathophysiology and pharmacotherapy of obesity including intersection points to the new generation of antidiabetic drugs. We provide insight into the effectiveness of currently approved anti-obesity drugs and other therapeutic avenues that can be explored. Full article
(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)
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17 pages, 1618 KiB  
Review
A Proteomic View of Cellular and Molecular Effects of Cannabis
by Morteza Abyadeh, Vivek Gupta, Joao A. Paulo, Veer Gupta, Nitin Chitranshi, Angela Godinez, Danit Saks, Mafruha Hasan, Ardeshir Amirkhani, Matthew McKay, Ghasem H. Salekdeh, Paul A. Haynes, Stuart L. Graham and Mehdi Mirzaei
Biomolecules 2021, 11(10), 1411; https://doi.org/10.3390/biom11101411 - 27 Sep 2021
Cited by 16 | Viewed by 6220
Abstract
Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known [...] Read more.
Cannabis (Cannabis sativa), popularly known as marijuana, is the most commonly used psychoactive substance and is considered illicit in most countries worldwide. However, a growing body of research has provided evidence of the therapeutic properties of chemical components of cannabis known as cannabinoids against several diseases including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease, schizophrenia and glaucoma; these have prompted changes in medicinal cannabis legislation. The relaxation of legal restrictions and increased socio-cultural acceptance has led to its increase in both medicinal and recreational usage. Several biochemically active components of cannabis have a range of effects on the biological system. There is an urgent need for more research to better understand the molecular and biochemical effects of cannabis at a cellular level, to understand fully its implications as a pharmaceutical drug. Proteomics technology is an efficient tool to rigorously elucidate the mechanistic effects of cannabis on the human body in a cell and tissue-specific manner, drawing conclusions associated with its toxicity as well as therapeutic benefits, safety and efficacy profiles. This review provides a comprehensive overview of both in vitro and in vivo proteomic studies involving the cellular and molecular effects of cannabis and cannabis-derived compounds. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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22 pages, 2584 KiB  
Review
TRP Channels as Sensors of Aldehyde and Oxidative Stress
by Katharina E. M. Hellenthal, Laura Brabenec, Eric R. Gross and Nana-Maria Wagner
Biomolecules 2021, 11(10), 1401; https://doi.org/10.3390/biom11101401 - 24 Sep 2021
Cited by 21 | Viewed by 4572
Abstract
The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade [...] Read more.
The transient receptor potential (TRP) cation channel superfamily comprises more than 50 channels that play crucial roles in physiological processes. TRP channels are responsive to several exogenous and endogenous biomolecules, with aldehydes emerging as a TRP channel trigger contributing to a cellular cascade that can lead to disease pathophysiology. The body is not only exposed to exogenous aldehydes via tobacco products or alcoholic beverages, but also to endogenous aldehydes triggered by lipid peroxidation. In response to lipid peroxidation from inflammation or organ injury, polyunsaturated fatty acids undergo lipid peroxidation to aldehydes, such as 4-hydroxynonenal. Reactive aldehydes activate TRP channels via aldehyde-induced protein adducts, leading to the release of pro-inflammatory mediators driving the pathophysiology caused by cellular injury, including inflammatory pain and organ reperfusion injury. Recent studies have outlined how aldehyde dehydrogenase 2 protects against aldehyde toxicity through the clearance of toxic aldehydes, indicating that targeting the endogenous aldehyde metabolism may represent a novel treatment strategy. An addition approach can involve targeting specific TRP channel regions to limit the triggering of a cellular cascade induced by aldehydes. In this review, we provide a comprehensive summary of aldehydes, TRP channels, and their interactions, as well as their role in pathological conditions and the different therapeutical treatment options. Full article
(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)
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30 pages, 2095 KiB  
Review
Stress-Induced Epstein-Barr Virus Reactivation
by Daniel G. Sausen, Maimoona S. Bhutta, Elisa S. Gallo, Harel Dahari and Ronen Borenstein
Biomolecules 2021, 11(9), 1380; https://doi.org/10.3390/biom11091380 - 18 Sep 2021
Cited by 42 | Viewed by 12894
Abstract
Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough [...] Read more.
Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough understanding of this virus, and the interplay between stress and the immune system, is essential to establish effective treatment. This review will provide a summary of the interaction between both psychological and cellular stressors resulting in EBV reactivation. It will examine mechanisms by which EBV establishes and maintains latency and will conclude with a brief overview of treatments targeting EBV. Full article
(This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)
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18 pages, 2554 KiB  
Review
The Regulation of Rab GTPases by Phosphorylation
by Lejia Xu, Yuki Nagai, Yotaro Kajihara, Genta Ito and Taisuke Tomita
Biomolecules 2021, 11(9), 1340; https://doi.org/10.3390/biom11091340 - 10 Sep 2021
Cited by 18 | Viewed by 5005
Abstract
Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated [...] Read more.
Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation. Full article
(This article belongs to the Collection Recent Advances in Protein Phosphorylation)
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18 pages, 873 KiB  
Review
Alpha-Synuclein and the Endolysosomal System in Parkinson’s Disease: Guilty by Association
by Maxime Teixeira, Razan Sheta, Walid Idi and Abid Oueslati
Biomolecules 2021, 11(9), 1333; https://doi.org/10.3390/biom11091333 - 9 Sep 2021
Cited by 24 | Viewed by 4617
Abstract
Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such [...] Read more.
Abnormal accumulation of the protein α- synuclein (α-syn) into proteinaceous inclusions called Lewy bodies (LB) is the neuropathological hallmark of Parkinson’s disease (PD) and related disorders. Interestingly, a growing body of evidence suggests that LB are also composed of other cellular components such as cellular membrane fragments and vesicular structures, suggesting that dysfunction of the endolysosomal system might also play a role in LB formation and neuronal degeneration. Yet the link between α-syn aggregation and the endolysosomal system disruption is not fully elucidated. In this review, we discuss the potential interaction between α-syn and the endolysosomal system and its impact on PD pathogenesis. We propose that the accumulation of monomeric and aggregated α-syn disrupt vesicles trafficking, docking, and recycling, leading to the impairment of the endolysosomal system, notably the autophagy-lysosomal degradation pathway. Reciprocally, PD-linked mutations in key endosomal/lysosomal machinery genes (LRRK2, GBA, ATP13A2) also contribute to increasing α-syn aggregation and LB formation. Altogether, these observations suggest a potential synergistic role of α-syn and the endolysosomal system in PD pathogenesis and represent a viable target for the development of disease-modifying treatment for PD and related disorders. Full article
(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration)
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25 pages, 4160 KiB  
Review
Amylomaltases in Extremophilic Microorganisms
by Claudia Leoni, Bruno A. R. Gattulli, Graziano Pesole, Luigi R. Ceci and Mariateresa Volpicella
Biomolecules 2021, 11(9), 1335; https://doi.org/10.3390/biom11091335 - 9 Sep 2021
Cited by 8 | Viewed by 3369
Abstract
Amylomaltases (4-α-glucanotransferases, E.C. 2.4.1.25) are enzymes which can perform a double-step catalytic process, resulting in a transglycosylation reaction. They hydrolyse glucosidic bonds of α-1,4′-d-glucans and transfer the glucan portion with the newly available anomeric carbon to the 4′-position of an α-1,4′- [...] Read more.
Amylomaltases (4-α-glucanotransferases, E.C. 2.4.1.25) are enzymes which can perform a double-step catalytic process, resulting in a transglycosylation reaction. They hydrolyse glucosidic bonds of α-1,4′-d-glucans and transfer the glucan portion with the newly available anomeric carbon to the 4′-position of an α-1,4′-d-glucan acceptor. The intramolecular reaction produces a cyclic α-1,4′-glucan. Amylomaltases can be found only in prokaryotes, where they are involved in glycogen degradation and maltose metabolism. These enzymes are being studied for possible biotechnological applications, such as the production of (i) sugar substitutes; (ii) cycloamyloses (molecules larger than cyclodextrins), which could potentially be useful as carriers and encapsulating agents for hydrophobic molecules and also as effective protein chaperons; and (iii) thermoreversible starch gels, which could be used as non-animal gelatin substitutes. Extremophilic prokaryotes have been investigated for the identification of amylomaltases to be used in the starch modifying processes, which require high temperatures or extreme conditions. The aim of this article is to present an updated overview of studies on amylomaltases from extremophilic Bacteria and Archaea, including data about their distribution, activity, potential industrial application and structure. Full article
(This article belongs to the Collection Feature Papers in Enzymology)
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42 pages, 2047 KiB  
Review
Out of Control: The Role of the Ubiquitin Proteasome System in Skeletal Muscle during Inflammation
by Stefanie Haberecht-Müller, Elke Krüger and Jens Fielitz
Biomolecules 2021, 11(9), 1327; https://doi.org/10.3390/biom11091327 - 8 Sep 2021
Cited by 40 | Viewed by 5825
Abstract
The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein [...] Read more.
The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed. Full article
(This article belongs to the Special Issue Regulating Proteasome Activity)
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19 pages, 1102 KiB  
Review
Lumican in Carcinogenesis—Revisited
by Eirini-Maria Giatagana, Aikaterini Berdiaki, Aristidis Tsatsakis, George N. Tzanakakis and Dragana Nikitovic
Biomolecules 2021, 11(9), 1319; https://doi.org/10.3390/biom11091319 - 6 Sep 2021
Cited by 26 | Viewed by 4438
Abstract
Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of [...] Read more.
Carcinogenesis is a multifactorial process with the input and interactions of environmental, genetic, and metabolic factors. During cancer development, a significant remodeling of the extracellular matrix (ECM) is evident. Proteoglycans (PGs), such as lumican, are glycosylated proteins that participate in the formation of the ECM and are established biological mediators. Notably, lumican is involved in cellular processes associated with tumorigeneses, such as EMT (epithelial-to-mesenchymal transition), cellular proliferation, migration, invasion, and adhesion. Furthermore, lumican is expressed in various cancer tissues and is reported to have a positive or negative correlation with tumor progression. This review focuses on significant advances achieved regardingthe role of lumican in the tumor biology. Here, the effects of lumican on cancer cell growth, invasion, motility, and metastasis are discussed, as well as the repercussions on autophagy and apoptosis. Finally, in light of the available data, novel roles for lumican as a cancer prognosis marker, chemoresistance regulator, and cancer therapy target are proposed. Full article
(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)
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37 pages, 888 KiB  
Review
Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke
by Reed Berlet, Stefan Anthony, Beverly Brooks, Zhen-Jie Wang, Nadia Sadanandan, Alex Shear, Blaise Cozene, Bella Gonzales-Portillo, Blake Parsons, Felipe Esparza Salazar, Alma R. Lezama Toledo, Germán Rivera Monroy, Joaquín Vega Gonzales-Portillo and Cesario V. Borlongan
Biomolecules 2021, 11(9), 1316; https://doi.org/10.3390/biom11091316 - 6 Sep 2021
Cited by 18 | Viewed by 6214
Abstract
Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new [...] Read more.
Stem cell transplantation with rehabilitation therapy presents an effective stroke treatment. Here, we discuss current breakthroughs in stem cell research along with rehabilitation strategies that may have a synergistic outcome when combined together after stroke. Indeed, stem cell transplantation offers a promising new approach and may add to current rehabilitation therapies. By reviewing the pathophysiology of stroke and the mechanisms by which stem cells and rehabilitation attenuate this inflammatory process, we hypothesize that a combined therapy will provide better functional outcomes for patients. Using current preclinical data, we explore the prominent types of stem cells, the existing theories for stem cell repair, rehabilitation treatments inside the brain, rehabilitation modalities outside the brain, and evidence pertaining to the benefits of combined therapy. In this review article, we assess the advantages and disadvantages of using stem cell transplantation with rehabilitation to mitigate the devastating effects of stroke. Full article
(This article belongs to the Special Issue Protection, Plasticity, and Physical Rehabilitation in Ischemic Injury)
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14 pages, 687 KiB  
Review
Heart Organoids and Engineered Heart Tissues: Novel Tools for Modeling Human Cardiac Biology and Disease
by Yonatan R. Lewis-Israeli, Aaron H. Wasserman and Aitor Aguirre
Biomolecules 2021, 11(9), 1277; https://doi.org/10.3390/biom11091277 - 26 Aug 2021
Cited by 27 | Viewed by 6051
Abstract
Organoids are three-dimensional in vitro cell constructs that recapitulate organ properties and structure to a significant extent. They constitute particularly useful models to study unapproachable states in humans, such as embryonic and fetal development, or early disease progression in adults. In recent years [...] Read more.
Organoids are three-dimensional in vitro cell constructs that recapitulate organ properties and structure to a significant extent. They constitute particularly useful models to study unapproachable states in humans, such as embryonic and fetal development, or early disease progression in adults. In recent years organoids have been implemented to model a wide range of different organs and disease conditions. However, the technology for their fabrication and application to cardiovascular studies has been lagging significantly when compared to other organoid types (e.g., brain, pancreas, kidney, intestine). This is a surprising fact since cardiovascular disease (CVD) and congenital heart disease (CHD) constitute the leading cause of mortality and morbidity in the developed world, and the most common birth defect in humans, respectively, and collectively constitute one of the largest unmet medical needs in the modern world. There is a critical need to establish in vitro models of the human heart that faithfully recapitulate its biology and function, thus enabling basic and translational studies to develop new therapeutics. Generating heart organoids that truly resemble the heart has proven difficult due to its complexity, but significant progress has been made recently to overcome this obstacle. In this review, we will discuss progress in novel heart organoid generation methods, the advantages and disadvantages of each approach, and their translational applications for advancing cardiovascular studies and the treatment of heart disorders. Full article
(This article belongs to the Section Synthetic Biology and Bioengineering)
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10 pages, 801 KiB  
Review
Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside?
by Cecilia Marini, Vanessa Cossu, Matteo Bauckneht, Francesco Lanfranchi, Stefano Raffa, Anna Maria Orengo, Silvia Ravera, Silvia Bruno and Gianmario Sambuceti
Biomolecules 2021, 11(8), 1231; https://doi.org/10.3390/biom11081231 - 18 Aug 2021
Cited by 10 | Viewed by 4265
Abstract
Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This [...] Read more.
Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This action is most often attributed to a well-documented blockage of oxidative phosphorylation (OXPHOS) caused by a direct interference of metformin on Complex I function. Nevertheless, several other pleiotropic actions seem to contribute to the anticancer potential of this biguanide. In particular, in vitro and in vivo experimental studies recently documented that metformin selectively inhibits the uptake of 2-[18F]-Fluoro-2-Deoxy-D-Glucose (FDG), via an impaired catalytic function of the enzyme hexose-6P-dehydrogenase (H6PD). H6PD triggers a still largely uncharacterized pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER) that has been found to play a pivotal role in feeding the NADPH reductive power for both cellular proliferation and antioxidant responses. Regardless of its exploitability in the clinical setting, this metformin action might configure the ER metabolism as a potential target for innovative therapeutic strategies in patients with solid cancers and potentially modifies the current interpretative model of FDG uptake, attributing PET/CT capability to predict cancer aggressiveness to the activation of H6PD catalytic function. Full article
(This article belongs to the Special Issue Metformin and Cancer)
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24 pages, 2434 KiB  
Review
Perineuronal Nets and Metal Cation Concentrations in the Microenvironments of Fast-Spiking, Parvalbumin-Expressing GABAergic Interneurons: Relevance to Neurodevelopment and Neurodevelopmental Disorders
by Jessica A. Burket, Jason D. Webb and Stephen I. Deutsch
Biomolecules 2021, 11(8), 1235; https://doi.org/10.3390/biom11081235 - 18 Aug 2021
Cited by 16 | Viewed by 5938
Abstract
Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local [...] Read more.
Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range. Full article
(This article belongs to the Special Issue Clinical Phenotype of Autism Spectrum Disorder: Development and Delivery of Therapeutic Biomolecules to the CNS)
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26 pages, 1588 KiB  
Review
Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets
by Phuong Linh Nguyen and Jungsook Cho
Biomolecules 2021, 11(8), 1232; https://doi.org/10.3390/biom11081232 - 18 Aug 2021
Cited by 25 | Viewed by 10430
Abstract
High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine [...] Read more.
High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings. Full article
(This article belongs to the Special Issue New Developments in Histamine Research)
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38 pages, 11203 KiB  
Review
Chalcones: Synthetic Chemistry Follows Where Nature Leads
by Hiba A. Jasim, Lutfun Nahar, Mohammad A. Jasim, Sharon A. Moore, Kenneth J. Ritchie and Satyajit D. Sarker
Biomolecules 2021, 11(8), 1203; https://doi.org/10.3390/biom11081203 - 13 Aug 2021
Cited by 73 | Viewed by 7821
Abstract
Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of [...] Read more.
Chalcones belong to the flavonoid class of phenolic compounds. They form one of the largest groups of bioactive natural products. The potential anticancer, anti-inflammatory, antimicrobial, antioxidant, and antiparasitic properties of naturally occurring chalcones, and their unique chemical structural features inspired the synthesis of numerous chalcone derivatives. In fact, structural features of chalcones are easy to construct from simple aromatic compounds, and it is convenient to perform structural modifications to generate functionalized chalcone derivatives. Many of these synthetic analogs were shown to possess similar bioactivities as their natural counterparts, but often with an enhanced potency and reduced toxicity. This review article aims to demonstrate how bioinspired synthesis of chalcone derivatives can potentially introduce a new chemical space for exploitation for new drug discovery, justifying the title of this article. However, the focus remains on critical appraisal of synthesized chalcones and their derivatives for their bioactivities, linking to their interactions at the biomolecular level where appropriate, and revealing their possible mechanisms of action. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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16 pages, 3067 KiB  
Review
The Targeting of Native Proteins to the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway: An Expanding Repertoire of Regulated Substrates
by Deepa Kumari and Jeffrey L. Brodsky
Biomolecules 2021, 11(8), 1185; https://doi.org/10.3390/biom11081185 - 11 Aug 2021
Cited by 19 | Viewed by 6301
Abstract
All proteins are subject to quality control processes during or soon after their synthesis, and these cellular quality control pathways play critical roles in maintaining homeostasis in the cell and in organism health. Protein quality control is particularly vital for those polypeptides that [...] Read more.
All proteins are subject to quality control processes during or soon after their synthesis, and these cellular quality control pathways play critical roles in maintaining homeostasis in the cell and in organism health. Protein quality control is particularly vital for those polypeptides that enter the endoplasmic reticulum (ER). Approximately one-quarter to one-third of all proteins synthesized in eukaryotic cells access the ER because they are destined for transport to the extracellular space, because they represent integral membrane proteins, or because they reside within one of the many compartments of the secretory pathway. However, proteins that mature inefficiently are subject to ER-associated degradation (ERAD), a multi-step pathway involving the chaperone-mediated selection, ubiquitination, and extraction (or “retrotranslocation”) of protein substrates from the ER. Ultimately, these substrates are degraded by the cytosolic proteasome. Interestingly, there is an increasing number of native enzymes and metabolite and solute transporters that are also targeted for ERAD. While some of these proteins may transiently misfold, the ERAD pathway also provides a route to rapidly and quantitatively downregulate the levels and thus the activities of a variety of proteins that mature or reside in the ER. Full article
(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)
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28 pages, 1784 KiB  
Review
Therapy Approaches for Stargardt Disease
by Elena Piotter, Michelle E McClements and Robert E MacLaren
Biomolecules 2021, 11(8), 1179; https://doi.org/10.3390/biom11081179 - 9 Aug 2021
Cited by 25 | Viewed by 9144
Abstract
Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over [...] Read more.
Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide. Full article
(This article belongs to the Special Issue Nucleic Acids: Applications in the Fields of Diagnostics, Therapeutics, Synthetic Biology, and Beyond)
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12 pages, 692 KiB  
Review
Neutrophil in the Pancreatic Tumor Microenvironment
by Lin Jin, Hong Sun Kim and Jiaqi Shi
Biomolecules 2021, 11(8), 1170; https://doi.org/10.3390/biom11081170 - 7 Aug 2021
Cited by 28 | Viewed by 5656
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed. Full article
(This article belongs to the Collection Recent Advances in Pancreatic Cancer)
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