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Biomedicines
Volume 9
Issue 2
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Biomedicines, Volume 9, Issue 2 (February 2021) – 132 articles

Cover Story (view full-size image): Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative diseases characterized by aggregation of protein inclusion. PD is characterized by Lewy bodies inclusions, where α-synuclein (α-syn) is the major constituent. Accumulations of tau protein and beta-amyloid protein are the main cause of AD. Multiple sclerosis is the result of inflammation and immune-mediated processes that provoke demyelination. In all these disorders, autophagy and mitophagy play a fundamental role. View this paper
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35 pages, 2183 KiB  
Review
Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases
by Nuno Santos Leal and Luís Miguel Martins
Biomedicines 2021, 9(2), 227; https://doi.org/10.3390/biomedicines9020227 - 23 Feb 2021
Cited by 25 | Viewed by 5592
Abstract
The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical [...] Read more.
The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria–ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer’s disease as well as Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer’s disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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25 pages, 2899 KiB  
Review
β-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies
by Ahmad Al-Mrabeh
Biomedicines 2021, 9(2), 226; https://doi.org/10.3390/biomedicines9020226 - 23 Feb 2021
Cited by 17 | Viewed by 4018
Abstract
Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of β-cell dysfunction and recovery in T2DM [...] Read more.
Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of β-cell dysfunction and recovery in T2DM are discussed in the context of abnormal hepatic lipid metabolism and cardiovascular health. (i) In normal health, continuous exposure of the pancreas to nutrient stimulus increases the demand on β-cells. In the long term, this will not only stress β-cells and decrease their insulin secretory capacity, but also will blunt the cellular response to insulin. (ii) At the pre-diabetes stage, β-cells compensate for insulin resistance through hypersecretion of insulin. This increases the metabolic burden on the stressed β-cells and changes hepatic lipoprotein metabolism and adipose tissue function. (iii) If this lipotoxic hyperinsulinemic environment is not removed, β-cells start to lose function, and CVD risk rises due to lower lipoprotein clearance. (iv) Once developed, T2DM can be reversed by weight loss, a process described recently as remission. However, the precise mechanism(s) by which calorie restriction causes normalization of lipoprotein metabolism and restores β-cell function are not fully established. Understanding the pathophysiological and molecular basis of β-cell failure and recovery during remission is critical to reduce β-cell burden and loss of function. The aim of this review is to highlight the link between lipoprotein export and lipid-driven β-cell dysfunction in T2DM and how this is related to cardiovascular health. A second aim is to understand the mechanisms of β-cell recovery after weight loss, and to explore new areas of research for developing more targeted future therapies to prevent T2DM and the associated CVD events. Full article
(This article belongs to the Special Issue Diabetes Complications: From Pathophysiology to Novel Therapeutic Approaches)
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20 pages, 1480 KiB  
Review
Energy, Entropy and Quantum Tunneling of Protons and Electrons in Brain Mitochondria: Relation to Mitochondrial Impairment in Aging-Related Human Brain Diseases and Therapeutic Measures
by James P. Bennett, Jr. and Isaac G. Onyango
Biomedicines 2021, 9(2), 225; https://doi.org/10.3390/biomedicines9020225 - 22 Feb 2021
Cited by 12 | Viewed by 4828
Abstract
Adult human brains consume a disproportionate amount of energy substrates (2–3% of body weight; 20–25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered [...] Read more.
Adult human brains consume a disproportionate amount of energy substrates (2–3% of body weight; 20–25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered by the proton gradient generated from proton-coupled electron transfer (PCET) in the multi-complex electron transport chain (ETC). ETC catalysis rates are reduced in brains from humans with neurodegenerative diseases (NDDs). Declines of ETC function in NDDs may result from combinations of nitrative stress (NS)–oxidative stress (OS) damage; mitochondrial and/or nuclear genomic mutations of ETC/OXPHOS genes; epigenetic modifications of ETC/OXPHOS genes; or defects in importation or assembly of ETC/OXPHOS proteins or complexes, respectively; or alterations in mitochondrial dynamics (fusion, fission, mitophagy). Substantial free energy is gained by direct O2-mediated oxidation of NADH. Traditional ETC mechanisms require separation between O2 and electrons flowing from NADH/FADH2 through the ETC. Quantum tunneling of electrons and much larger protons may facilitate this separation. Neuronal death may be viewed as a local increase in entropy requiring constant energy input to avoid. The ATP requirement of the brain may partially be used for avoidance of local entropy increase. Mitochondrial therapeutics seeks to correct deficiencies in ETC and OXPHOS. Full article
(This article belongs to the Special Issue Mitochondria and Brain Disease)
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20 pages, 7772 KiB  
Article
Anomalous Angiogenesis in Retina
by Rocío Vega, Manuel Carretero and Luis L Bonilla
Biomedicines 2021, 9(2), 224; https://doi.org/10.3390/biomedicines9020224 - 22 Feb 2021
Cited by 9 | Viewed by 4281
Abstract
Age-related macular degeneration (AMD) may cause severe loss of vision or blindness, particularly in elderly people. Exudative AMD is characterized by the angiogenesis of blood vessels growing from underneath the macula, crossing the blood–retina barrier (which comprises Bruch’s membrane (BM) and the retinal [...] Read more.
Age-related macular degeneration (AMD) may cause severe loss of vision or blindness, particularly in elderly people. Exudative AMD is characterized by the angiogenesis of blood vessels growing from underneath the macula, crossing the blood–retina barrier (which comprises Bruch’s membrane (BM) and the retinal pigmentation epithelium (RPE)), leaking blood and fluid into the retina and knocking off photoreceptors. Here, we simulate a computational model of angiogenesis from the choroid blood vessels via a cellular Potts model, as well as BM, RPE cells, drusen deposits and photoreceptors. Our results indicate that improving AMD may require fixing the impaired lateral adhesion between RPE cells and with BM, as well as diminishing Vessel Endothelial Growth Factor (VEGF) and Jagged proteins that affect the Notch signaling pathway. Our numerical simulations suggest that anti-VEGF and anti-Jagged therapies could temporarily halt exudative AMD while addressing impaired cellular adhesion, which could be more effective over a longer time-span. Full article
(This article belongs to the Special Issue Angiogenesis and Inflammation in Biological Barriers)
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14 pages, 286 KiB  
Review
Are Sarcopenia and Cognitive Dysfunction Comorbid after Stroke in the Context of Brain–Muscle Crosstalk?
by Sophia X. Sui, Brenton Hordacre and Julie A. Pasco
Biomedicines 2021, 9(2), 223; https://doi.org/10.3390/biomedicines9020223 - 22 Feb 2021
Cited by 8 | Viewed by 3629
Abstract
Stroke is a leading cause of death and disability and is responsible for a significant economic burden. Sarcopenia and cognitive dysfunction are common consequences of stroke, but there is less awareness of the concurrency of these conditions. In addition, few reviews are available [...] Read more.
Stroke is a leading cause of death and disability and is responsible for a significant economic burden. Sarcopenia and cognitive dysfunction are common consequences of stroke, but there is less awareness of the concurrency of these conditions. In addition, few reviews are available to guide clinicians and researchers on how to approach sarcopenia and cognitive dysfunction as comorbidities after stroke, including how to assess and manage them and implement interventions to improve health outcomes. This review synthesises current knowledge about the relationship between post-stroke sarcopenia and cognitive dysfunction, including the physiological pathways, assessment tools, and interventions involved. Full article
(This article belongs to the Special Issue Recent Advances in Brain Vascular Diseases Management and Therapy)
12 pages, 3462 KiB  
Article
Neuropeptide Substance P Enhances Skin Wound Healing In Vitro and In Vivo under Hypoxia
by Suneel Kumar, Yuying Tan and Francois Berthiaume
Biomedicines 2021, 9(2), 222; https://doi.org/10.3390/biomedicines9020222 - 22 Feb 2021
Cited by 10 | Viewed by 3455
Abstract
Pressure ulcers (PUs) or sores are a secondary complication of diabetic neuropathy and traumatic spinal cord injury (SCI). PUs tend to occur in soft tissues located around bony prominences and may heal slowly or not at all. A common mechanism underlying impaired healing [...] Read more.
Pressure ulcers (PUs) or sores are a secondary complication of diabetic neuropathy and traumatic spinal cord injury (SCI). PUs tend to occur in soft tissues located around bony prominences and may heal slowly or not at all. A common mechanism underlying impaired healing of PUs may be dysfunction of the local neurovascular system including deficiency of essential neuropeptides, such as substance P (SP). Previous studies indicate that disturbance in cutaneous sensory innervation leads to a defect in all stages of wound healing, as is the case after SCI. It is hypothesized that nerve fibers enhance wound healing by promoting initial inflammation via the releasing of neuropeptides such as SP. Therefore, we investigated whether exogenous SP improves skin wound healing using in vitro and in vivo models. For in vitro studies, the effects of SP on keratinocyte proliferation and wound closure after a scratch injury were studied under normoxia (pO2 ~21%) or hypoxia (pO2 ~1%) and in presence of normal serum (10% v/v) or low serum (1% v/v) concentrations. Hypoxia and low serum both significantly slowed cell proliferation and wound closure. Under combined low serum and hypoxia, used to mimic the nutrient- and oxygen-poor environment of chronic wounds, SP (10−7 M) significantly enhanced cell proliferation and wound closure rate. For in vivo studies, two full-thickness excisional wounds were created with a 5 mm biopsy punch on the dorsum on either side of the midline of 15-week-old C57BL/6J male and female mice. Immediately, wounds were treated topically with one dose of 0.5 μg SP or PBS vehicle. The data suggest a beneficial role in wound closure and reepithelization, and thus enhanced wound healing, in male and female mice. Taken together, exogenously applied neuropeptide SP enhanced wound healing via cell proliferation and migration in vitro and in vivo. Thus, exogenous SP may be a useful strategy to explore further for treating PUs in SCI and diabetic patients. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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19 pages, 501 KiB  
Review
Metabolic Diseases and Down Syndrome: How Are They Linked Together?
by Manon Moreau, Soukaina Benhaddou, Rodolphe Dard, Stefania Tolu, Rim Hamzé, François Vialard, Jamileh Movassat and Nathalie Janel
Biomedicines 2021, 9(2), 221; https://doi.org/10.3390/biomedicines9020221 - 22 Feb 2021
Cited by 32 | Viewed by 6801
Abstract
Down syndrome is a genetic disorder caused by the presence of a third copy of chromosome 21, associated with intellectual disabilities. Down syndrome is associated with anomalies of both the nervous and endocrine systems. Over the past decades, dramatic advances in Down syndrome [...] Read more.
Down syndrome is a genetic disorder caused by the presence of a third copy of chromosome 21, associated with intellectual disabilities. Down syndrome is associated with anomalies of both the nervous and endocrine systems. Over the past decades, dramatic advances in Down syndrome research and treatment have helped to extend the life expectancy of these patients. Improved life expectancy is obviously a positive outcome, but it is accompanied with the need to address previously overlooked complications and comorbidities of Down syndrome, including obesity and diabetes, in order to improve the quality of life of Down syndrome patients. In this focused review, we describe the associations between Down syndrome and comorbidities, obesity and diabetes, and we discuss the understanding of proposed mechanisms for the association of Down syndrome with metabolic disorders. Drawing molecular mechanisms through which Type 1 diabetes and Type 2 diabetes could be linked to Down syndrome could allow identification of novel drug targets and provide therapeutic solutions to limit the development of metabolic and cognitive disorders. Full article
(This article belongs to the Special Issue Diabetes Complications: From Pathophysiology to Novel Therapeutic Approaches)
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25 pages, 4085 KiB  
Review
Zinc: Multidimensional Effects on Living Organisms
by Math P. Cuajungco, Maria Soledad Ramirez and Marcelo E. Tolmasky
Biomedicines 2021, 9(2), 208; https://doi.org/10.3390/biomedicines9020208 - 22 Feb 2021
Cited by 50 | Viewed by 5694
Abstract
Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but it may also exist in a labile or chelatable (free ion) form. Zinc plays a [...] Read more.
Zinc is a redox-inert trace element that is second only to iron in abundance in biological systems. In cells, zinc is typically buffered and bound to metalloproteins, but it may also exist in a labile or chelatable (free ion) form. Zinc plays a critical role in prokaryotes and eukaryotes, ranging from structural to catalytic to replication to demise. This review discusses the influential properties of zinc on various mechanisms of bacterial proliferation and synergistic action as an antimicrobial element. We also touch upon the significance of zinc among eukaryotic cells and how it may modulate their survival and death through its inhibitory or modulatory effect on certain receptors, enzymes, and signaling proteins. A brief discussion on zinc chelators is also presented, and chelating agents may be used with or against zinc to affect therapeutics against human diseases. Overall, the multidimensional effects of zinc in cells attest to the growing number of scientific research that reveal the consequential prominence of this remarkable transition metal in human health and disease. Full article
(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)
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13 pages, 1019 KiB  
Review
Transmembrane 163 (TMEM163) Protein: A New Member of the Zinc Efflux Transporter Family
by Daniel J. Styrpejko and Math P. Cuajungco
Biomedicines 2021, 9(2), 220; https://doi.org/10.3390/biomedicines9020220 - 21 Feb 2021
Cited by 13 | Viewed by 3646
Abstract
A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The mammalian solute carrier 30 (SLC30) family, with ten current members, controls zinc efflux transport in cells. TMEM163, a recently reported zinc transporter, [...] Read more.
A growing body of evidence continues to demonstrate the vital roles that zinc and its transporters play on human health. The mammalian solute carrier 30 (SLC30) family, with ten current members, controls zinc efflux transport in cells. TMEM163, a recently reported zinc transporter, has similar characteristics in both predicted transmembrane domain structure and function to the cation diffusion facilitator (CDF) protein superfamily. This review discusses past and present data indicating that TMEM163 is a zinc binding protein that transports zinc in cells. We provide a brief background on TMEM163’s discovery, transport feature, protein interactome, and similarities, as well as differences, with known SLC30 (ZnT) protein family. We also examine recent reports that implicate TMEM163 directly or indirectly in various human diseases such as Parkinson’s disease, Mucolipidosis type IV and diabetes. Overall, the role of TMEM163 protein in zinc metabolism is beginning to be realized, and based on current evidence, we propose that it is likely a new CDF member belonging to mammalian SLC30 (ZnT) zinc efflux transporter proteins. Full article
(This article belongs to the Special Issue Zinc and Copper in Human Health and Disease)
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17 pages, 3249 KiB  
Article
The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD
by Elena Gargaun, Sestina Falcone, Guilhem Solé, Julien Durigneux, Andoni Urtizberea, Jean Marie Cuisset, Sofia Benkhelifa-Ziyyat, Laura Julien, Anne Boland, Florian Sandron, Vincent Meyer, Jean François Deleuze, David Salgado, Jean-Pierre Desvignes, Christophe Béroud, Anatole Chessel, Alexia Blesius, Martin Krahn, Nicolas Levy, France Leturcq and France Pietri-Rouxeladd Show full author list remove Hide full author list
Biomedicines 2021, 9(2), 219; https://doi.org/10.3390/biomedicines9020219 - 20 Feb 2021
Cited by 6 | Viewed by 4210
Abstract
In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are [...] Read more.
In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion. Full article
(This article belongs to the Special Issue Non-coding RNAs in Health and Disease)
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21 pages, 3929 KiB  
Article
The Antibacterial Activity of Human Amniotic Membrane against Multidrug-Resistant Bacteria Associated with Urinary Tract Infections: New Insights from Normal and Cancerous Urothelial Models
by Taja Železnik Ramuta, Larisa Tratnjek, Aleksandar Janev, Katja Seme, Marjanca Starčič Erjavec and Mateja Erdani Kreft
Biomedicines 2021, 9(2), 218; https://doi.org/10.3390/biomedicines9020218 - 20 Feb 2021
Cited by 21 | Viewed by 3942
Abstract
Urinary tract infections (UTIs) represent a serious global health issue, especially due to emerging multidrug-resistant UTI-causing bacteria. Recently, we showed that the human amniotic membrane (hAM) could be a candidate for treatments and prevention of UPEC and Staphylococcus aureus infections. However, its role [...] Read more.
Urinary tract infections (UTIs) represent a serious global health issue, especially due to emerging multidrug-resistant UTI-causing bacteria. Recently, we showed that the human amniotic membrane (hAM) could be a candidate for treatments and prevention of UPEC and Staphylococcus aureus infections. However, its role against multidrug-resistant bacteria, namely methicillin-resistant S. aureus (MRSA), extended-spectrum beta-lactamases (ESBL) producing Escherichia coli and Klebsiella pneumoniae, vancomycin-resistant Enterococci (VRE), carbapenem-resistant Acinetobacter baumannii, and Pseudomonas aeruginosa has not yet been thoroughly explored. Here, we demonstrate for the first time that the hAM homogenate had antibacterial activity against 7 out of 11 tested multidrug-resistant strains, the greatest effect was on MRSA. Using novel approaches, its activity against MRSA was further evaluated in a complex microenvironment of normal and cancerous urinary bladder urothelia. Even short-term incubation in hAM homogenate significantly decreased the number of bacteria in MRSA-infected urothelial models, while it did not affect the viability, number, and ultrastructure of urothelial cells. The hAM patches had no antibacterial activity against any of the tested strains, which further exposes the importance of the hAM preparation. Our study substantially contributes to basic knowledge on the antibacterial activity of hAM and reveals its potential to be used as an antibacterial agent against multidrug-resistant bacteria. Full article
(This article belongs to the Section Drug Discovery and Development)
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20 pages, 3945 KiB  
Article
Urinary Cyclophilin A as Marker of Tubular Cell Death and Kidney Injury
by Ramio Cabello, Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Ana M. Lopez-Diaz, Susana Carrasco, Ignacio Mahillo, Carmen Gonzalez-Enguita, Maria D. Sanchez-Niño, Alberto Ortiz and Ana B. Sanz
Biomedicines 2021, 9(2), 217; https://doi.org/10.3390/biomedicines9020217 - 20 Feb 2021
Cited by 12 | Viewed by 3665
Abstract
Background: Despite the term acute kidney injury (AKI), clinical biomarkers for AKI reflect function rather than injury and independent markers of injury are needed. Tubular cell death, including necroptotic cell death, is a key feature of AKI. Cyclophilin A (CypA) is an intracellular [...] Read more.
Background: Despite the term acute kidney injury (AKI), clinical biomarkers for AKI reflect function rather than injury and independent markers of injury are needed. Tubular cell death, including necroptotic cell death, is a key feature of AKI. Cyclophilin A (CypA) is an intracellular protein that has been reported to be released during necroptosis. We have now explored CypA as a potential marker for kidney injury in cultured tubular cells and in clinical settings of ischemia-reperfusion injury (IRI), characterized by limitations of current diagnostic criteria for AKI. Methods: CypA was analyzed in cultured human and murine proximal tubular epithelial cells exposed to chemical hypoxia, hypoxia/reoxygenation (H/R) or other cell death (apoptosis, necroptosis, ferroptosis) inducers. Urinary levels of CypA (uCypA) were analyzed in patients after nephron sparing surgery (NSS) in which the contralateral kidney is not disturbed and kidney grafts with initial function. Results: Intracellular CypA remained unchanged while supernatant CypA increased in parallel to cell death induction. uCypA levels were higher in NSS patients with renal artery clamping (that is, with NSS-IRI) than in no clamping (NSS-no IRI), and in kidney transplantation (KT) recipients (KT-IRI) even in the presence of preserved or improving kidney function, while this was not the case for urinary Neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, higher uCypA levels in NSS patients were associated with longer surgery duration and the incidence of AKI increased from 10% when using serum creatinine (sCr) or urinary output criteria to 36% when using high uCypA levels in NNS clamping patients. Conclusions: CypA is released by kidney tubular cells during different forms of cell death, and uCypA increased during IRI-induced clinical kidney injury independently from kidney function parameters. Thus, uCypA is a potential biomarker of kidney injury, which is independent from decreased kidney function. Full article
(This article belongs to the Section Biomedical Materials and Nanomedicine)
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25 pages, 1517 KiB  
Review
Mitochondrial Oxidative Stress and “Mito-Inflammation”: Actors in the Diseases
by Simone Patergnani, Esmaa Bouhamida, Sara Leo, Paolo Pinton and Alessandro Rimessi
Biomedicines 2021, 9(2), 216; https://doi.org/10.3390/biomedicines9020216 - 20 Feb 2021
Cited by 86 | Viewed by 7803
Abstract
A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front [...] Read more.
A decline in mitochondrial redox homeostasis has been associated with the development of a wide range of inflammatory-related diseases. Continue discoveries demonstrate that mitochondria are pivotal elements to trigger inflammation and stimulate innate immune signaling cascades to intensify the inflammatory response at front of different stimuli. Here, we review the evidence that an exacerbation in the levels of mitochondrial-derived reactive oxygen species (ROS) contribute to mito-inflammation, a new concept that identifies the compartmentalization of the inflammatory process, in which the mitochondrion acts as central regulator, checkpoint, and arbitrator. In particular, we discuss how ROS contribute to specific aspects of mito-inflammation in different inflammatory-related diseases, such as neurodegenerative disorders, cancer, pulmonary diseases, diabetes, and cardiovascular diseases. Taken together, these observations indicate that mitochondrial ROS influence and regulate a number of key aspects of mito-inflammation and that strategies directed to reduce or neutralize mitochondrial ROS levels might have broad beneficial effects on inflammatory-related diseases. Full article
(This article belongs to the Special Issue Oxidative Stress and Inflammation: From Mechanisms to Therapeutic Approaches 2.0)
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24 pages, 5514 KiB  
Article
Reclassification of Kidney Clear Cell Carcinoma Based on Immune Cell Gene-Related DNA CpG Pairs
by Qizhan Luo and Thomas-Alexander Vögeli
Biomedicines 2021, 9(2), 215; https://doi.org/10.3390/biomedicines9020215 - 20 Feb 2021
Cited by 2 | Viewed by 2347
Abstract
Background: A new method was developed based on the relative ranking of gene expression level, overcoming the flaw of the batch effect, and having reliable results in various studies. In the current study, we defined the two methylation sites as a pair. The [...] Read more.
Background: A new method was developed based on the relative ranking of gene expression level, overcoming the flaw of the batch effect, and having reliable results in various studies. In the current study, we defined the two methylation sites as a pair. The methylation level in a specific sample was subject to pairwise comparison to calculate a score for each CpGs-pair. The score was defined as a CpGs-pair score. If the first immune-related CpG value was higher than the second one in a specific CpGs-pair, the output score of this immune-related CpGs-pair was 1; otherwise, the output score was 0. This study aimed to construct a new classification of Kidney Clear Cell Carcinoma (KIRC) based on DNA CpGs (methylation sites) pairs. Methods: In this study, the biomarkers of 28 kinds of immune infiltration cells and corresponding methylation sites were acquired. The methylation data were compared between KIRC and normal tissue samples, and differentially methylated sites (DMSs) were obtained. Then, DNA CpGs-pairs were obtained according to the pairs of DMSs. In total, 441 DNA CpGs-pairs were utilized to construct a classification using unsupervised clustering analysis. We also analyzed the potential mechanism and therapy of different subtypes, and validated them in a testing set. Results: The classification of KIRC contained three subgroups. The clinicopathological features were different across three subgroups. The distribution of immune cells, immune checkpoints and immune-related mechanisms were significantly different across the three clusters. The mutation and copy number variation (CNV) were also different. The clinicopathological features and potential mechanism in the testing dataset were consistent with those in the training set. Conclusions: Our findings provide a new accurate and stable classification for developing personalized treatments for the new specific subtypes. Full article
(This article belongs to the Special Issue Immune Checkpoints and Autoimmunity)
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13 pages, 477 KiB  
Article
Reinforcement Learning for Radiotherapy Dose Fractioning Automation
by Grégoire Moreau, Vincent François-Lavet, Paul Desbordes and Benoît Macq
Biomedicines 2021, 9(2), 214; https://doi.org/10.3390/biomedicines9020214 - 19 Feb 2021
Cited by 10 | Viewed by 3813
Abstract
External beam radiotherapy cancer treatment aims to deliver dose fractions to slowly destroy a tumor while avoiding severe side effects in surrounding healthy tissues. To automate the dose fraction schedules, this paper investigates how deep reinforcement learning approaches (based on deep Q network [...] Read more.
External beam radiotherapy cancer treatment aims to deliver dose fractions to slowly destroy a tumor while avoiding severe side effects in surrounding healthy tissues. To automate the dose fraction schedules, this paper investigates how deep reinforcement learning approaches (based on deep Q network and deep deterministic policy gradient) can learn from a model of a mixture of tumor and healthy cells. A 2D tumor growth simulation is used to simulate radiation effects on tissues and thus training an agent to automatically optimize dose fractionation. Results show that initiating treatment with large dose per fraction, and then gradually reducing it, is preferred to the standard approach of using a constant dose per fraction. Full article
(This article belongs to the Special Issue New Insights in Radiotherapy)
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22 pages, 1510 KiB  
Review
Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva
by Francesc Ventura, Eleanor Williams, Makoto Ikeya, Alex N. Bullock, Peter ten Dijke, Marie-José Goumans and Gonzalo Sanchez-Duffhues
Biomedicines 2021, 9(2), 213; https://doi.org/10.3390/biomedicines9020213 - 19 Feb 2021
Cited by 9 | Viewed by 5133
Abstract
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I [...] Read more.
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages. Full article
(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)
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24 pages, 2225 KiB  
Review
Imaging Inflammation with Positron Emission Tomography
by Janette Iking, Magdalena Staniszewska, Lukas Kessler, Jasmin M. Klose, Katharina Lückerath, Wolfgang P. Fendler, Ken Herrmann and Christoph Rischpler
Biomedicines 2021, 9(2), 212; https://doi.org/10.3390/biomedicines9020212 - 19 Feb 2021
Cited by 37 | Viewed by 5681
Abstract
The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and [...] Read more.
The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and management of inflammation. Imaging can provide insights into individual and temporospatial biology and grade of inflammation which can be of diagnostic, therapeutic, and prognostic value. There is therefore an urgent need to evaluate and understand current approaches and potential applications for imaging of inflammation. This review discusses radiotracers for positron emission tomography (PET) that have been used to image inflammation in cardiovascular diseases and other inflammatory conditions with a special emphasis on radiotracers that have already been successfully applied in clinical settings. Full article
(This article belongs to the Special Issue Advanced Research in Molecular Imaging of Immunity and Inflammation)
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13 pages, 2436 KiB  
Article
Statins Directly Influence the Polarization of Adipose Tissue Macrophages: A Role in Chronic Inflammation
by Sona Kauerova, Hana Bartuskova, Barbora Muffova, Libor Janousek, Jiri Fronek, Marek Petras, Rudolf Poledne and Ivana Kralova Lesna
Biomedicines 2021, 9(2), 211; https://doi.org/10.3390/biomedicines9020211 - 19 Feb 2021
Cited by 11 | Viewed by 3256
Abstract
Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we [...] Read more.
Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we showed that statins are able to decrease the proportion of pro-inflammatory macrophages (CD14+16+CD36high) in visceral adipose tissue in humans. In the present study including 118 healthy individuals (living kidney donors), a very close relationship between the pro-inflammatory macrophage proportion and LDL cholesterol levels was found. This was confirmed after adjustment for the most important risk factors. The effect of statins on the proportion of pro-inflammatory macrophages was also confirmed in an experimental model of the Prague hereditary hypercholesterolemia rat. A direct anti-inflammatory effect of fluvastatin on human macrophage polarization in vitro was documented. Based on modifying the LDL cholesterol concentrations, statins are suggested to decrease the cholesterol inflow through the lipid raft of macrophages in adipose tissue and hypercholesterolemia to enhance the pro-inflammatory macrophage phenotype polarization. On the contrary, due to their opposite effect, statins respond with anti-inflammatory activity, affecting the whole organism. Full article
(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)
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12 pages, 3328 KiB  
Review
Clinical Application and Efficacy of Silver Drug in Ophthalmology: A Literature Review and New Formulation of EYE Drops with Drug Silver (I) Complex of Metronidazole with Improved Dosage Form
by Arleta Waszczykowska, Dominik Żyro, Justyn Ochocki and Piotr Jurowski
Biomedicines 2021, 9(2), 210; https://doi.org/10.3390/biomedicines9020210 - 19 Feb 2021
Cited by 14 | Viewed by 5007
Abstract
The use of silver preparations in medicine is becoming increasingly popular. The basic aim of this evaluation was to review the literature on the clinical (in vivo) and antibacterial potential of silver preparations in ophthalmic diseases. The second goal was to summarize the [...] Read more.
The use of silver preparations in medicine is becoming increasingly popular. The basic aim of this evaluation was to review the literature on the clinical (in vivo) and antibacterial potential of silver preparations in ophthalmic diseases. The second goal was to summarize the results of experimental research on the use of silver preparations in ophthalmology. The third objective was to present a method for stabilizing eye drops containing silver (I) complex. Analysis of the pH stability of the silver (I) complex with metronidazole in the prepared dosage form (eye drops) was carried out. Most silver preparations are clinically used for topical application. Few experimental results indicate the usefulness of intraocular or systemic administration of silver (I) preparations as an alternative or additional therapy in infectious and angiogenic eye diseases. The development of a new formulation increases the stability of the dosage form. New forms of silver (I) products will certainly find application in the treatment of many ophthalmic diseases. One of the most important features of the silver (I) complex is its capacity to break down bacterial resistance. The new eye drops formula can significantly improve comfort of use. Due to their chemical nature, silver (I) compounds are difficult to stabilize, especially in the finished dosage form. Full article
(This article belongs to the Section Molecular and Translational Medicine)
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16 pages, 3167 KiB  
Article
Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties
by Hansol Joo, Mi-Kyung Oh, Ji Yeon Kang, Hyun Sung Park, Dong-Hoon Chae, Jieun Kim, Jong-Hee Lee, Hee Min Yoo, Uimook Choi, Do-Kyun Kim, Hakmo Lee, Sungjoo Kim and Kyung-Rok Yu
Biomedicines 2021, 9(2), 209; https://doi.org/10.3390/biomedicines9020209 - 18 Feb 2021
Cited by 15 | Viewed by 4140
Abstract
Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human [...] Read more.
Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton’s jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-β1 (TGFβ), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis. Full article
(This article belongs to the Special Issue Novel Therapeutic Approaches in Inflammatory Bowel Diseases)
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17 pages, 3946 KiB  
Article
BECN1 and BRCA1 Deficiency Sensitizes Ovarian Cancer to Platinum Therapy and Confers Better Prognosis
by Amreen Salwa, Alessandra Ferraresi, Menaka Chinthakindi, Letizia Vallino, Chiara Vidoni, Danny N. Dhanasekaran and Ciro Isidoro
Biomedicines 2021, 9(2), 207; https://doi.org/10.3390/biomedicines9020207 - 18 Feb 2021
Cited by 17 | Viewed by 3045
Abstract
Background: BRCA1, BECN1 and TP53 are three tumor suppressor genes located on chromosome 17 and frequently found deleted, silenced, or mutated in many cancers. These genes are involved in autophagy, apoptosis, and drug resistance in ovarian cancer. Haploinsufficiency or loss-of-function of either TP53 [...] Read more.
Background: BRCA1, BECN1 and TP53 are three tumor suppressor genes located on chromosome 17 and frequently found deleted, silenced, or mutated in many cancers. These genes are involved in autophagy, apoptosis, and drug resistance in ovarian cancer. Haploinsufficiency or loss-of-function of either TP53, BRCA1 or BECN1 correlates with enhanced predisposition to cancer development and progression, and chemoresistance. Expectedly, the combined altered expression of these three tumor suppressor genes worsens the prognosis of ovarian cancer patients. However, whether such a genotypic pattern indeed affects the chemo-responsiveness to standard chemotherapy thus worsening patients’ survival has not been validated in a large cohort of ovarian cancer patients. Aim: We interrogated datasets from the TCGA database to analyze how the expression of these three tumor suppressor genes impacts on the clinical response to platinum-based chemotherapy thus affecting the survival of ovarian cancer patients. Results and conclusion: Compared to EOC with homozygous expression of BECN1 and BRCA1, tumors expressing low mRNA expression of these two tumor suppressor genes (either because of shallow (monoallelic) co-deletion or of promoter hypermethylation), showed higher sensitivity to platinum-based therapies and were associated with a better prognosis of ovarian cancer-bearing patients. This outcome was independent of TP53 status, though it was statistically more significant in the cohort of patients with mutated TP53. Thus, sensitivity to platinum therapy (and probably to other chemotherapeutics) correlates with low expression of a combination of critical tumor suppressor genes. Our study highlights the importance of thoroughly assessing the genetic lesions of the most frequently mutated genes to stratify the patients in view of a personalized therapy. More importantly, the present findings suggest that targeting the function of both BECN1 and BRCA1 could be a strategy to restore chemosensitivity in refractory tumors. Full article
(This article belongs to the Special Issue Role of Biomarkers and Targeted Therapy in the Management of Ovarian Cancer)
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16 pages, 1959 KiB  
Article
Zoom in on Antibody Aggregates: A Potential Pitfall in the Search of Rare EV Populations
by Rikke W. Rasmussen, Jaco Botha, Frederik Prip, Mathilde Sanden, Morten H. Nielsen and Aase Handberg
Biomedicines 2021, 9(2), 206; https://doi.org/10.3390/biomedicines9020206 - 18 Feb 2021
Cited by 4 | Viewed by 2578
Abstract
High-resolution flow cytometers (hFCM) are used for the detection of extracellular vesicles (EV) in various biological fluids. Due to the increased sensitivity of hFCM, new artifacts with the potential of interfering with data interpretation are introduced, such as detection of antibody aggregates. The [...] Read more.
High-resolution flow cytometers (hFCM) are used for the detection of extracellular vesicles (EV) in various biological fluids. Due to the increased sensitivity of hFCM, new artifacts with the potential of interfering with data interpretation are introduced, such as detection of antibody aggregates. The aim of this study was to investigate the extent of aggregates in labels commonly used for the characterization of EVs by hFCM. Furthermore, we aimed to compare the efficacy of centrifugation and filtering treatments to remove aggregates, as well as to quantify the effect of the treatments in reducing aggregates. For this purpose, we labeled phosphate buffered saline (PBS) with fluorescently conjugated protein labels and antibodies after submitting them to 5, 10, or 30 min centrifugation, filtering or washed filtering. We investigated samples by hFCM and quantified the amount of aggregates found in PBS labeled with untreated and pre-treated labels. We found a varying amount of aggregates in all labels investigated, and further that filtering is most efficient in removing all but the smallest aggregates. Filtering protein labels can reduce the extent of aggregates; however, how much remains depends on the specific labels and their combination. Therefore, it is still necessary to include appropriate controls in a hFCM study of EVs. Full article
(This article belongs to the Special Issue The Role of Extracellular Vesicles in Pathogenesis and Therapeutic Strategies)
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14 pages, 3089 KiB  
Article
Loss of parla Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish
by Rawan Merhi, Michael Kalyn, Amanda Zhu-Pawlowsky and Marc Ekker
Biomedicines 2021, 9(2), 205; https://doi.org/10.3390/biomedicines9020205 - 18 Feb 2021
Cited by 11 | Viewed by 4181
Abstract
The presenilin-associated rhomboid-like (PARL) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The PARL gene product is a mitochondrial intramembrane cleaving protease that acts on a number of mitochondrial proteins involved [...] Read more.
The presenilin-associated rhomboid-like (PARL) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The PARL gene product is a mitochondrial intramembrane cleaving protease that acts on a number of mitochondrial proteins involved in mitochondrial morphology, apoptosis, and mitophagy. To date, functional and genetic studies of PARL have been mainly performed in mammals. However, little is known about PARL function and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafish genome comprises two PARL paralogs: parla and parlb. Here, we established a loss-of-function mutation in parla via CRISPR/Cas9-mediated mutagenesis. We examined DA neuron numbers in the adult brain and expression of genes associated with DA neuron function in larvae and adults. We show that loss of parla function results in loss of DA neurons, mainly in the olfactory bulb. Changes in the levels of tyrosine hydroxylase transcripts supported this neuronal loss. Expression of fis1, a gene involved in mitochondrial fission, was increased in parla mutants. Finally, we showed that loss of parla function translates into impaired olfaction and altered locomotion parameters. These results suggest a role for parla in the development and/or maintenance of DA neuron function in zebrafish. Full article
(This article belongs to the Special Issue Dopamine in Health and Disease)
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21 pages, 1435 KiB  
Review
Role of Adenosine and Purinergic Receptors in Myocardial Infarction: Focus on Different Signal Transduction Pathways
by Maria Cristina Procopio, Rita Lauro, Chiara Nasso, Scipione Carerj, Francesco Squadrito, Alessandra Bitto, Gianluca Di Bella, Antonio Micari, Natasha Irrera and Francesco Costa
Biomedicines 2021, 9(2), 204; https://doi.org/10.3390/biomedicines9020204 - 18 Feb 2021
Cited by 16 | Viewed by 4555
Abstract
Myocardial infarction (MI) is a dramatic event often caused by atherosclerotic plaque erosion or rupture and subsequent thrombotic occlusion of a coronary vessel. The low supply of oxygen and nutrients in the infarcted area may result in cardiomyocytes necrosis, replacement of intact myocardium [...] Read more.
Myocardial infarction (MI) is a dramatic event often caused by atherosclerotic plaque erosion or rupture and subsequent thrombotic occlusion of a coronary vessel. The low supply of oxygen and nutrients in the infarcted area may result in cardiomyocytes necrosis, replacement of intact myocardium with non-contractile fibrous tissue and left ventricular (LV) function impairment if blood flow is not quickly restored. In this review, we summarized the possible correlation between adenosine system, purinergic system and Wnt/β-catenin pathway and their role in the pathogenesis of cardiac damage following MI. In this context, several pathways are involved and, in particular, the adenosine receptors system shows different interactions between its members and purinergic receptors: their modulation might be effective not only for a normal functional recovery but also for the treatment of heart diseases, thus avoiding fibrosis, reducing infarcted area and limiting scaring. Similarly, it has been shown that Wnt/β catenin pathway is activated following myocardial injury and its unbalanced activation might promote cardiac fibrosis and, consequently, LV systolic function impairment. In this regard, the therapeutic benefits of Wnt inhibitors use were highlighted, thus demonstrating that Wnt/β-catenin pathway might be considered as a therapeutic target to prevent adverse LV remodeling and heart failure following MI. Full article
(This article belongs to the Special Issue Advances in Adenosine Receptor Research)
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16 pages, 4603 KiB  
Article
Platelet-Derived Growth Factor Stimulated Migration of Bone Marrow Mesenchymal Stem Cells into an Injectable Gelatin-Hydroxyphenyl Propionic Acid Matrix
by Wanting Niu, Teck Chuan Lim, Abdulmonem Alshihri, Ravikumar Rajappa, Lishan Wang, Motoichi Kurisawa and Myron Spector
Biomedicines 2021, 9(2), 203; https://doi.org/10.3390/biomedicines9020203 - 17 Feb 2021
Cited by 10 | Viewed by 3081
Abstract
Bone marrow mesenchymal stem cells (bMSCs) are responsible in the repair of injured tissue through differentiation into multiple cell types and secretion of paracrine factors, and thus have a broad application profile in tissue engineering/regenerative medicine, especially for the musculoskeletal system. The lesion [...] Read more.
Bone marrow mesenchymal stem cells (bMSCs) are responsible in the repair of injured tissue through differentiation into multiple cell types and secretion of paracrine factors, and thus have a broad application profile in tissue engineering/regenerative medicine, especially for the musculoskeletal system. The lesion due to injury or disease may be a closed irregular-shaped cavity deep within tissue necessitating an injectable biomaterial permissive of host (endogenous) cell migration, proliferation and differentiation. Gelatin-hydroxyphenyl propionic acid (Gtn-HPA) is a natural biopolymer hydrogel which is covalently cross-linked by horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) in situ and can be delivered to the lesion by needle injection. Growth factors and cytokines can be directly incorporated into the gel or into nano- and micro-particles, which can be employed for sustained release of biomolecules while maintaining their bioactivity. In this study, we selected polyelectrolyte complex nanoparticles (PCNs) prepared with dextran sulfate and chitosan as the carrier for platelet-derived growth factor (PDGF)-BB and stromal cell-derived factor (SDF)-1α, which have been tested effectively in recruiting stem cells. Our in vitro results showed a high degree of viability of bMSCs through the process of Gtn-HPA covalent cross-linking gelation. The Gtn-HPA matrix was highly permissive of bMSC migration, proliferation, and differentiation. PDGF-BB (20 ng/mL) directly incorporated into the gel and, alternatively, released from PCNs stimulated bMSC migration and proliferation. There were only small differences in the results for the direct incorporation of PDGF into the gel compared with its release from PCNs, and for increased doses of the growth factor (200 ng/mL and 2 µg/mL). In contrast, SDF-1α elicited an increase in migration and proliferation only when released from PCNs; its effect on migration was notably less than PDGF-BB. The in vitro results demonstrate that PDGF-BB substantially increases migration of bMSCs into Gtn-HPA and their proliferation in the gel, and that these benefits can be derived from incorporation of a relatively low dose of the growth factor directly into the gel. These findings commend the use of Gtn-HPA/PDGF-BB as an injectable therapeutic agent to treat defects in musculoskeletal tissues. Full article
(This article belongs to the Special Issue Hydrogels for Biomedical Application)
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13 pages, 1006 KiB  
Review
Non-Genetically Encoded Epitopes Are Relevant Targets in Autoimmune Diabetes
by Hai Nguyen, Perrin Guyer, Ruth A. Ettinger and Eddie A. James
Biomedicines 2021, 9(2), 202; https://doi.org/10.3390/biomedicines9020202 - 17 Feb 2021
Cited by 8 | Viewed by 2637
Abstract
Islet antigen reactive T cells play a key role in promoting beta cell destruction in type 1 diabetes (T1D). Self-reactive T cells are typically deleted through negative selection in the thymus or deviated to a regulatory phenotype. Nevertheless, those processes are imperfect such [...] Read more.
Islet antigen reactive T cells play a key role in promoting beta cell destruction in type 1 diabetes (T1D). Self-reactive T cells are typically deleted through negative selection in the thymus or deviated to a regulatory phenotype. Nevertheless, those processes are imperfect such that even healthy individuals have a reservoir of potentially autoreactive T cells. What remains less clear is how tolerance is lost to insulin and other beta cell specific antigens. Islet autoantibodies, the best predictor of disease risk, are known to recognize classical antigens such as proinsulin, GAD65, IA-2, and ZnT8. These antibodies are thought to be supported by the expansion of autoreactive CD4+ T cells that recognize these same antigenic targets. However, recent studies have identified new classes of non-genetically encoded epitopes that may reflect crucial gaps in central and peripheral tolerance. Notably, some of these specificities, including epitopes from enzymatically post-translationally modified antigens and hybrid insulin peptides, are present at relatively high frequencies in the peripheral blood of patients with T1D. We conclude that CD4+ T cells that recognize non-genetically encoded epitopes are likely to make an important contribution to the progression of islet autoimmunity in T1D. We further propose that these classes of neo-epitopes should be considered as possible targets for strategies to induce antigen specific tolerance. Full article
(This article belongs to the Special Issue Antigen-Specific Immunotherapies for Autoimmune Disease)
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12 pages, 1722 KiB  
Article
The ElonginB/C-Cullin5-SOCS-Box-Complex Is a Potential Biomarker for Growth Hormone Disorders
by Wilhelm Gossing, Lars Radke, Henrik Biering, Sven Diederich, Knut Mai and Marcus Frohme
Biomedicines 2021, 9(2), 201; https://doi.org/10.3390/biomedicines9020201 - 17 Feb 2021
Cited by 3 | Viewed by 2575
Abstract
Insulin-like growth factor 1 (IGF-1) is the standard biochemical marker for the diagnosis and treatment control of acromegaly and growth hormone deficiency (GHD). However, its limitations necessitate the screening for new specific and sensitive biomarkers. The elonginB/C-cullin5-SOCS-box-complex (ECS-complex) (an intracellular five-protein complex) is [...] Read more.
Insulin-like growth factor 1 (IGF-1) is the standard biochemical marker for the diagnosis and treatment control of acromegaly and growth hormone deficiency (GHD). However, its limitations necessitate the screening for new specific and sensitive biomarkers. The elonginB/C-cullin5-SOCS-box-complex (ECS-complex) (an intracellular five-protein complex) is stimulated by circulating growth hormone (GH) and regulates GH receptor levels through a negative feedback loop. It mediates the cells’ sensitivity for GH and therefore, represents a potent new biomarker for those diseases. In this study, individual ECS-complex proteins were measured in whole blood samples of patients with acromegaly (n = 32) or GHD (n = 12) via ELISA and compared to controls. Hierarchical clustering of the results revealed that by combining the three ECS-complex proteins suppressor of cytokine signaling 2 (SOCS2), cullin-5 and ring-box protein 2 (Rbx-2), 93% of patient samples could be separated from controls, despite many patients having a normal IGF-1 or not receiving medical treatment. SOCS2 showed the best individual diagnostic performance with an overall accuracy of 0.93, while the combination of the three proteins correctly identified all patients and controls. This resulted in perfect sensitivity and specificity for all patient groups, which demonstrates potential benefits of the ECS-complex proteins as clinical biomarkers for the diagnostics of GH-related diseases and substantiates their important role in GH metabolism. Full article
(This article belongs to the Special Issue Advanced Research in Endocrine Tumor: Molecular Pathology, Biomarker and Target Therapy)
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22 pages, 913 KiB  
Review
Antiviral Effects of Polyphenols from Marine Algae
by Natalya N. Besednova, Boris G. Andryukov, Tatyana S. Zaporozhets, Sergey P. Kryzhanovsky, Ludmila N. Fedyanina, Tatyana A. Kuznetsova, Tatyana N. Zvyagintseva and Mikhail Yu. Shchelkanov
Biomedicines 2021, 9(2), 200; https://doi.org/10.3390/biomedicines9020200 - 17 Feb 2021
Cited by 57 | Viewed by 5459
Abstract
The disease-preventive and medicinal properties of plant polyphenolic compounds have long been known. As active ingredients, they are used to prevent and treat many noncommunicable diseases. In recent decades, marine macroalgae have attracted the attention of biotechnologists and pharmacologists as a promising and [...] Read more.
The disease-preventive and medicinal properties of plant polyphenolic compounds have long been known. As active ingredients, they are used to prevent and treat many noncommunicable diseases. In recent decades, marine macroalgae have attracted the attention of biotechnologists and pharmacologists as a promising and almost inexhaustible source of polyphenols. This heterogeneous group of compounds contains many biopolymers with unique structure and biological properties that exhibit high anti-infective activity. In the present review, the authors focus on the antiviral potential of polyphenolic compounds (phlorotannins) from marine algae and consider the mechanisms of their action as well as other biological properties of these compounds that have effects on the progress and outcome of viral infections. Effective nutraceuticals, to be potentially developed on the basis of algal polyphenols, can also be used in the complex therapy of viral diseases. It is necessary to extend in vivo studies on laboratory animals, which subsequently will allow proceeding to clinical tests. Polyphenolic compounds have a great potential as active ingredients to be used for the creation of new antiviral pharmaceutical substances. Full article
(This article belongs to the Special Issue Anti-inflammatory Activity of Plant Polyphenols 2.0)
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13 pages, 1642 KiB  
Article
Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis
by Urara Tanaka, Shunichi Kajioka, Livia S. Finoti, Daniela B. Palioto, Denis F. Kinane and Manjunatha R. Benakanakere
Biomedicines 2021, 9(2), 199; https://doi.org/10.3390/biomedicines9020199 - 17 Feb 2021
Cited by 14 | Viewed by 3248
Abstract
DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) [...] Read more.
DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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20 pages, 5221 KiB  
Review
Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides
by Sang Yeol Lee
Biomedicines 2021, 9(2), 198; https://doi.org/10.3390/biomedicines9020198 - 17 Feb 2021
Cited by 13 | Viewed by 3201
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes which cleave extracellular matrix (ECM) and other substrates. They are deeply involved in both cancer metastasis and human chronic inflammatory diseases such as osteoarthritis and Crohn’s disease. Regulation of MMPs is closely associated with signaling molecules, especially [...] Read more.
Matrix metalloproteinases (MMPs) are proteolytic enzymes which cleave extracellular matrix (ECM) and other substrates. They are deeply involved in both cancer metastasis and human chronic inflammatory diseases such as osteoarthritis and Crohn’s disease. Regulation of MMPs is closely associated with signaling molecules, especially mitogen-activated protein kinases (MAPKs), including three representative kinases, extracellular signal regulated kinases (ERK), p38 and c-Jun N-terminal kinases (JNK). Ginseng (Panax sp.) is a plant which has been traditionally used for medicinal applications. Ginsenosides are major metabolites which have potentials to treat various human diseases. In this review, the pharmacological effects of ginsenosides have been rigorously investigated; these include anti-metastatic and anti-inflammatory activities of ginsenosides associated with suppression of MMPs via regulation of various signaling pathways. This will highlight the importance of MMPs as therapeutic targets for anti-metastatic and anti-inflammatory drug development based on ginsenosides. Full article
(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Diseases)
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