Biomedicines

17 pages, 3330 KiB

Open AccessReview

Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases

by Eunsik Yun, Yunjin Kook, Kyung Hyun Yoo, Keun Il Kim, Myeong-Sok Lee, Jongmin Kim and Aram Lee

Biomedicines 2020, 8(12), 639; https://doi.org/10.3390/biomedicines8120639 - 21 Dec 2020

Cited by 25 | Viewed by 5367

Abstract

Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy [...] Read more.

Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy have been mainly used as therapy owing to these characteristics, their effectiveness does not meet expectations. Therefore, a better understanding of the etiology and new therapeutic approaches are needed. Endothelial cells (ECs) line the inner walls of blood vessels and maintain vascular homeostasis by protecting vascular cells from pathological stimuli. Chronic stimulation of ECs by various factors, including pro-inflammatory cytokines and hypoxia, leads to ECs undergoing an imbalance of endothelial homeostasis, which results in endothelial dysfunction and is closely associated with vascular diseases. Emerging studies suggest that endothelial to mesenchymal transition (EndMT) contributes to endothelial dysfunction and plays a key role in the pathogenesis of vascular diseases. EndMT is a process by which ECs lose their markers and show mesenchymal-like morphological changes, and gain mesenchymal cell markers. Despite the efforts to elucidate these molecular mechanisms, the role of EndMT in the pathogenesis of lung disease still requires further investigation. Here, we review the importance of EndMT in the pathogenesis of pulmonary vascular diseases and discuss various signaling pathways and mediators involved in the EndMT process. Furthermore, we will provide insight into the therapeutic potential of targeting EndMT. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From Pathophysiology to Novel Therapeutic Approaches)

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12 pages, 1146 KiB

Open AccessEditor’s ChoiceArticle

Advanced Glycation End Products (AGE) and Soluble Forms of AGE Receptor: Emerging Role as Mortality Risk Factors in CKD

by Elena Dozio, Simone Vettoretti, Lara Caldiroli, Silvia Nerini-Molteni, Lorenza Tacchini, Federico Ambrogi, Piergiorgio Messa and Massimiliano M. Corsi Romanelli

Biomedicines 2020, 8(12), 638; https://doi.org/10.3390/biomedicines8120638 - 21 Dec 2020

Cited by 29 | Viewed by 3346

Abstract

Advanced glycation end-products (AGE) can promote chronic kidney disease (CKD) progression and CKD-related morbidities. The soluble receptor for AGE (sRAGE) is a potential biomarker of inflammation and oxidative stress. Here, we explored the role of AGE, glycated albumin, sRAGE and its different forms, [...] Read more.

Advanced glycation end-products (AGE) can promote chronic kidney disease (CKD) progression and CKD-related morbidities. The soluble receptor for AGE (sRAGE) is a potential biomarker of inflammation and oxidative stress. Here, we explored the role of AGE, glycated albumin, sRAGE and its different forms, cRAGE and esRAGE, as prognostic factors for mortality in 111 advanced CKD patients. The median follow-up time was 39 months. AGE were quantified by fluorescence, sRAGE and its forms by ELISA. Malnutrition was screened by the Malnutrition Inflammation Score (MIS). The Cox proportional hazards regression model was used to assess the association of variables with all-cause mortality. Mean levels of sRAGE, esRAGE and cRAGE were 2318 ± 1224, 649 ± 454 and 1669 ± 901 pg/mL. The mean value of cRAGE/esRAGE was 2.82 ± 0.96. AGE were 3026 ± 766 AU and MIS 6.0 ± 4.7. eGFR correlated negatively with AGE, sRAGE, esRAGE and cRAGE, but not with cRAGE/esRAGE. Twenty-eight patients died. No difference was observed between diabetic and non-diabetic patients. Starting dialysis was not associated with enhanced risk of death. AGE, esRAGE and cRAGE/esRAGE were independently associated with all-cause mortality. AGE, esRAGE and cRAGE/esRAGE may help to stratify overall mortality risk. Implementing the clinical evaluation of CKD patients by quantifying these biomarkers can help to improve patient outcomes. Full article

(This article belongs to the Special Issue Biomarkers in Chronic Kidney Disease)

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24 pages, 1187 KiB

Open AccessReview

STAT3 and p53: Dual Target for Cancer Therapy

by Thu-Huyen Pham, Hyo-Min Park, Jinju Kim, Jin Tae Hong and Do-Young Yoon

Biomedicines 2020, 8(12), 637; https://doi.org/10.3390/biomedicines8120637 - 21 Dec 2020

Cited by 37 | Viewed by 5863

Abstract

The tumor suppressor p53 is considered the “guardian of the genome” that can protect cells against cancer by inducing cell cycle arrest followed by cell death. However, STAT3 is constitutively activated in several human cancers and plays crucial roles in promoting cancer cell [...] Read more.

The tumor suppressor p53 is considered the “guardian of the genome” that can protect cells against cancer by inducing cell cycle arrest followed by cell death. However, STAT3 is constitutively activated in several human cancers and plays crucial roles in promoting cancer cell proliferation and survival. Hence, STAT3 and p53 have opposing roles in cellular pathway regulation, as activation of STAT3 upregulates the survival pathway, whereas p53 triggers the apoptotic pathway. Constitutive activation of STAT3 and gain or loss of p53 function due to mutations are the most frequent events in numerous cancer types. Several studies have reported the association of STAT3 and/or p53 mutations with drug resistance in cancer treatment. This review discusses the relationship between STAT3 and p53 status in cancer, the molecular mechanism underlying the negative regulation of p53 by STAT3, and vice versa. Moreover, it underlines prospective therapies targeting both STAT3 and p53 to enhance chemotherapeutic outcomes. Full article

(This article belongs to the Special Issue Role of STAT3 in Oncogenesis)

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17 pages, 10752 KiB

Open AccessArticle

Biocompatibility and Immune Response of a Newly Developed Volume-Stable Magnesium-Based Barrier Membrane in Combination with a PVD Coating for Guided Bone Regeneration (GBR)

by Larissa Steigmann, Ole Jung, Wolfgang Kieferle, Sanja Stojanovic, Annica Proehl, Oliver Görke, Steffen Emmert, Stevo Najman, Mike Barbeck and Daniel Rothamel

Biomedicines 2020, 8(12), 636; https://doi.org/10.3390/biomedicines8120636 - 20 Dec 2020

Cited by 20 | Viewed by 3785

Abstract

To date, there are no bioresorbable alternatives to non-resorbable and volume-stable membranes in the field of dentistry for guided bone or tissue regeneration (GBR/GTR). Even magnesium (Mg) has been shown to constitute a favorable biomaterial for the development of stabilizing structures. However, it [...] Read more.

To date, there are no bioresorbable alternatives to non-resorbable and volume-stable membranes in the field of dentistry for guided bone or tissue regeneration (GBR/GTR). Even magnesium (Mg) has been shown to constitute a favorable biomaterial for the development of stabilizing structures. However, it has been described that it is necessary to prevent premature degradation to ensure both the functionality and the biocompatibility of such Mg implants. Different coating strategies have already been developed, but most of them did not provide the desired functionality. The present study analyses a new approach based on ion implantation (II) with PVD coating for the passivation of a newly developed Mg membrane for GBR/GTR procedures. To demonstrate comprehensive biocompatibility and successful passivation of the Mg membranes, untreated Mg (MG) and coated Mg (MG-Co) were investigated in vitro and in vivo. Thereby a collagen membrane with an already shown biocompatibility was used as control material. All investigations were performed according to EN ISO 10993 regulations. The in vitro results showed that both the untreated and PVD-coated membranes were not cytocompatible. However, both membrane types fulfilled the requirements for in vivo biocompatibility. Interestingly, the PVD coating did not have an influence on the gas cavity formation compared to the uncoated membrane, but it induced lower numbers of anti-inflammatory macrophages in comparison to the pure Mg membrane and the collagen membrane. In contrast, the pure Mg membrane provoked an immune response that was fully comparable to the collagen membrane. Altogether, this study shows that pure magnesium membranes represent a promising alternative compared to the nonresorbable volume-stable materials for GBR/GTR therapy. Full article

(This article belongs to the Special Issue Soft and Hard Tissue Regeneration)

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16 pages, 3433 KiB

Open AccessArticle

Fatty Acid Binding Protein 5 Mediates Cell Death by Psychosine Exposure through Mitochondrial Macropores Formation in Oligodendrocytes

by An Cheng, Ichiro Kawahata and Kohji Fukunaga

Biomedicines 2020, 8(12), 635; https://doi.org/10.3390/biomedicines8120635 - 20 Dec 2020

Cited by 18 | Viewed by 4007

Abstract

Oligodendrocytes, the myelinating cells in the central nervous system (CNS), are critical for producing myelin throughout the CNS. The loss of oligodendrocytes is associated with multiple neurodegenerative disorders mediated by psychosine. However, the involvement of psychosine in the critical biochemical pathogenetic mechanism of [...] Read more.

Oligodendrocytes, the myelinating cells in the central nervous system (CNS), are critical for producing myelin throughout the CNS. The loss of oligodendrocytes is associated with multiple neurodegenerative disorders mediated by psychosine. However, the involvement of psychosine in the critical biochemical pathogenetic mechanism of the loss of oligodendrocytes and myelin in krabbe disease (KD) remains unclear. Here, we addressed how oligodendrocytes are induced by psychosine treatment in both KG-1C human oligodendroglial cells and mouse oligodendrocyte precursor cells. We found that fatty acid binding protein 5 (FABP5) expressed in oligodendrocytes accelerates mitochondria-induced glial death by inducing mitochondrial macropore formation through voltage-dependent anion channels (VDAC-1) and BAX. These two proteins mediate mitochondrial outer membrane permeabilization, thereby leading to the release of mitochondrial DNA and cytochrome C into the cytosol, and the activation of apoptotic caspases. Furthermore, we confirmed that the inhibition of FABP5 functions by shRNA and FABP5-specific ligands blocking mitochondrial macropore formation, thereby rescuing psychosine-induced oligodendrocyte death. Taken together, we identified FABP5 as a critical factor in mitochondrial injury associated with psychosine-induced apoptosis in oligodendrocytes. Full article

(This article belongs to the Special Issue Mitochondria and Brain Disease)

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21 pages, 2553 KiB

Open AccessArticle

Modulation of Early Host Innate Immune Response by an Avipox Vaccine Virus’ Lateral Body Protein

by Efstathios S. Giotis, Stephen M. Laidlaw, Susanna R. Bidgood, David Albrecht, Jemima J. Burden, Rebecca C. Robey, Jason Mercer and Michael A. Skinner

Biomedicines 2020, 8(12), 634; https://doi.org/10.3390/biomedicines8120634 - 19 Dec 2020

Cited by 5 | Viewed by 3881

Abstract

The avian pathogen fowlpox virus (FWPV) has been successfully used as a vaccine vector in poultry and humans, but relatively little is known about its ability to modulate host antiviral immune responses in these hosts, which are replication-permissive and nonpermissive, respectively. FWPV is [...] Read more.

The avian pathogen fowlpox virus (FWPV) has been successfully used as a vaccine vector in poultry and humans, but relatively little is known about its ability to modulate host antiviral immune responses in these hosts, which are replication-permissive and nonpermissive, respectively. FWPV is highly resistant to avian type I interferon (IFN) and able to completely block the host IFN-response. Microarray screening of host IFN-regulated gene expression in cells infected with 59 different, nonessential FWPV gene knockout mutants revealed that FPV184 confers immunomodulatory capacity. We report that the FPV184-knockout virus (FWPVΔ184) induces the cellular IFN response as early as 2 h postinfection. The wild-type, uninduced phenotype can be rescued by transient expression of FPV184 in FWPVΔ184-infected cells. Ectopic expression of FPV184 inhibited polyI:C activation of the chicken IFN-β promoter and IFN-α activation of the chicken Mx1 promoter. Confocal and correlative super-resolution light and electron microscopy demonstrated that FPV184 has a functional nuclear localisation signal domain and is packaged in the lateral bodies of the virions. Taken together, these results provide a paradigm for a late poxvirus structural protein packaged in the lateral bodies, capable of suppressing IFN induction early during the next round of infection. Full article

(This article belongs to the Special Issue Poxviruses: From Pathophysiology to Novel Therapeutic Approaches)

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19 pages, 1974 KiB

Open AccessReview

Role of CD146 (MCAM) in Physiological and Pathological Angiogenesis—Contribution of New Antibodies for Therapy

by Ahmad Joshkon, Xavier Heim, Cléa Dubrou, Richard Bachelier, Wael Traboulsi, Jimmy Stalin, Hussein Fayyad-Kazan, Bassam Badran, Alexandrine Foucault-Bertaud, Aurelie S. Leroyer, Nathalie Bardin and Marcel Blot-Chabaud

Biomedicines 2020, 8(12), 633; https://doi.org/10.3390/biomedicines8120633 - 19 Dec 2020

Cited by 29 | Viewed by 4951

Abstract

The fundamental role of cell adhesion molecules in mediating various biological processes as angiogenesis has been well-documented. CD146, an adhesion molecule of the immunoglobulin superfamily, and its soluble form, constitute major players in both physiological and pathological angiogenesis. A growing body of evidence [...] Read more.

The fundamental role of cell adhesion molecules in mediating various biological processes as angiogenesis has been well-documented. CD146, an adhesion molecule of the immunoglobulin superfamily, and its soluble form, constitute major players in both physiological and pathological angiogenesis. A growing body of evidence shows soluble CD146 to be significantly elevated in the serum or interstitial fluid of patients with pathologies related to deregulated angiogenesis, as autoimmune diseases, obstetric and ocular pathologies, and cancers. To block the undesirable effects of this molecule, therapeutic antibodies have been developed. Herein, we review the multifaceted functions of CD146 in physiological and pathological angiogenesis and summarize the interest of using monoclonal antibodies for therapeutic purposes. Full article

(This article belongs to the Special Issue Angiogenesis and Inflammation in Biological Barriers)

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12 pages, 1716 KiB

Open AccessArticle

Local Vascularization during Orthodontic Tooth Movement in a Split Mouth Rat Model—A MRI Study

by Peter Proff, Agnes Schröder, Lisa Seyler, Franziska Wolf, Yüksel Korkmaz, Tobias Bäuerle, Lina Gölz and Christian Kirschneck

Biomedicines 2020, 8(12), 632; https://doi.org/10.3390/biomedicines8120632 - 19 Dec 2020

Cited by 5 | Viewed by 2688

Abstract

Orthodontic tooth movement to therapeutically align malpositioned teeth is supposed to impact blood flow in the surrounding tissues. Here, we evaluated actual vascularization in the tension area of the periodontal ligament during experimental tooth movement in rats (N = 8) with magnetic [...] Read more.

Orthodontic tooth movement to therapeutically align malpositioned teeth is supposed to impact blood flow in the surrounding tissues. Here, we evaluated actual vascularization in the tension area of the periodontal ligament during experimental tooth movement in rats (N = 8) with magnetic resonance imaging (MRI). We inserted an elastic band between the left upper first and the second rat molar; the right side was not treated and served as control. After four days of tooth movement, we recorded T1-weighted morphologic and dynamic-contrast-enhanced MRI sequences with an animal-specific 7 Tesla MRI to assess of local vascularization. Furthermore, we quantified osteoclasts and monocytes in the periodontal ligament, which are crucial for orthodontic tooth movement, root resorptions as undesirable side effects, as well as the extent of tooth movement using paraffine histology and micro-CT analysis. Data were tested for normal distribution with Shapiro–Wilk tests followed by either a two-tailed paired t-test or a Wilcoxon matched-pairs signed rank test. Significant orthodontic tooth movement was induced within the four days of treatment, as evidenced by increased osteoclast and monocyte activity in the periodontal ligament as well as by µCT analysis. Contrast enhancement was increased at the orthodontically-treated side distally of the moved upper first left molar, indicating increased vascularization at the tension side of the periodontal ligament. Accordingly, we detected reduced time-to-peak and washout rates. Our study using MRI to directly assess local vascularization thus seems to confirm the hypothesis that perfusion is enhanced in tension zones of the periodontal ligament during orthodontic tooth movement. Full article

(This article belongs to the Special Issue Models for Oral Biology Research)

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12 pages, 1665 KiB

Open AccessArticle

Novel Pathogenic Variants of the AIRE Gene in Two Autoimmune Polyendocrine Syndrome Type I Cases with Atypical Presentation: Role of the NGS in Diagnostic Pathway and Review of the Literature

by Luigia Cinque, Cristina Angeletti, Alfredo Orrico, Stefano Castellana, Lucia Ferrito, Cristina Ciuoli, Tommaso Mazza, Marco Castori and Vito Guarnieri

Biomedicines 2020, 8(12), 631; https://doi.org/10.3390/biomedicines8120631 - 19 Dec 2020

Cited by 3 | Viewed by 2748

Abstract

Background. Autoimmune polyglandular syndrome type 1 (APS-1) with or without reversible metaphyseal dysplasia is a rare genetic disorder due to inactivating variants of the autoimmune regulator, AIRE, gene. Clinical variability of APS-1 relates to pleiotropy, and the general dysfunction of self-tolerance to [...] Read more.

Background. Autoimmune polyglandular syndrome type 1 (APS-1) with or without reversible metaphyseal dysplasia is a rare genetic disorder due to inactivating variants of the autoimmune regulator, AIRE, gene. Clinical variability of APS-1 relates to pleiotropy, and the general dysfunction of self-tolerance to organ-specific antigens and autoimmune reactions towards peripheral tissues caused by the underlying molecular defect. Thus, early recognition of the syndrome is often delayed, mostly in cases with atypical presentation, and the molecular confirm through the genetic analysis of the AIRE gene might be of great benefit. Methods. Our methods were to investigate, with a multigene panel next generation sequencing approach, two clinical cases, both presenting with idiopathic hypoparathyroidism, also comprising the AIRE gene; as well as to comment our findings as part of a more extensive review of literature data. Results. In the first clinical case, two compound heterozygote pathogenic variants of the AIRE gene were identified, thus indicating an autosomal recessive inheritance of the disease. In the second case, only one AIRE gene variant was found and an atypical dominant negative form of APS-1 suggested, later confirmed by further medical ascertainments. Conclusions. APS-1 might present with variable and sometimes monosymptomatic presentations and, if not recognized, might associate with severe complications. In this context, next generation diagnostics focused on a set of genes causative of partially overlapping disorders may allow early diagnosis. Full article

(This article belongs to the Special Issue Novelties in Parathyroid Gland Diseases)

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15 pages, 3210 KiB

Open AccessEditor’s ChoiceArticle

Increased Encapsulation Efficiency of Methotrexate in Liposomes for Rheumatoid Arthritis Therapy

by Diana Guimarães, Jennifer Noro, Ana Loureiro, Franck Lager, Gilles Renault, Artur Cavaco-Paulo and Eugénia Nogueira

Biomedicines 2020, 8(12), 630; https://doi.org/10.3390/biomedicines8120630 - 18 Dec 2020

Cited by 29 | Viewed by 5756

Abstract

Methotrexate (MTX) is a common drug used to treat rheumatoid arthritis. Due to the excessive side effects, encapsulation of MTX in liposomes is considered an effective delivery system, reducing drug toxicity, while maintaining its efficacy. The ethanol injection method is an interesting technique [...] Read more.

Methotrexate (MTX) is a common drug used to treat rheumatoid arthritis. Due to the excessive side effects, encapsulation of MTX in liposomes is considered an effective delivery system, reducing drug toxicity, while maintaining its efficacy. The ethanol injection method is an interesting technique for liposome production, due to its simplicity, fast implementation, and reproducibility. However, this method occasionally requires the extrusion process, to obtain suitable size distribution, and achieve a low level of MTX encapsulation. Here, we develop a novel pre-concentration method, based on the principles of the ethanol injection, using an initial aqueous volume of 20% and 1:1 ratio of organic:aqueous phase (v/v). The liposomes obtained present small values of size and polydispersity index, without the extrusion process, and a higher MTX encapsulation (efficiency higher than 30%), suitable characteristics for in vivo application. The great potential of MTX to interact at the surface of the lipid bilayer was shown by nuclear magnetic resonance (NMR) studies, revealing mutual interactions between the drug and the main phospholipid via hydrogen bonding. In vivo experiments reveal that liposomes encapsulating MTX significantly increase the biological benefit in arthritic mice. This approach shows a significant advance in MTX therapeutic applications. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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15 pages, 4015 KiB

Open AccessArticle

Detailed Characterization of the Cooperative Binding of Piperine with Heat Shock Protein 70 by Molecular Biophysical Approaches

by Gabriel Zazeri, Ana Paula Ribeiro Povinelli, Marcelo de Freitas Lima and Marinônio Lopes Cornélio

Biomedicines 2020, 8(12), 629; https://doi.org/10.3390/biomedicines8120629 - 18 Dec 2020

Cited by 5 | Viewed by 2774

Abstract

In this work, for the first time, details of the complex formed by heat shock protein 70 (HSP70) independent nucleotide binding domain (NBD) and piperine were characterized through experimental and computational molecular biophysical methods. Fluorescence spectroscopy results revealed positive cooperativity between the two [...] Read more.

In this work, for the first time, details of the complex formed by heat shock protein 70 (HSP70) independent nucleotide binding domain (NBD) and piperine were characterized through experimental and computational molecular biophysical methods. Fluorescence spectroscopy results revealed positive cooperativity between the two binding sites. Circular dichroism identified secondary conformational changes. Molecular dynamics along with molecular mechanics Poisson Boltzmann surface area (MM/PBSA) reinforced the positive cooperativity, showing that the affinity of piperine for NBD increased when piperine occupied both binding sites instead of one. The spontaneity of the complexation was demonstrated through the Gibbs free energy (∆G < 0 kJ/mol) for different temperatures obtained experimentally by van’t Hoff analysis and computationally by umbrella sampling with the potential of mean force profile. Furthermore, the mean forces which drove the complexation were disclosed by van’t Hoff and MM/PBSA as being the non-specific interactions. In conclusion, the work revealed characteristics of NBD and piperine interaction, which may support further drug discover studies. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Target Identification and Drug Discovery)

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21 pages, 4209 KiB

Open AccessArticle

3D-Hepatocyte Culture Applied to Parasitology: Immune Activation of Canine Hepatic Spheroids Exposed to Leishmania infantum

by Armanda V. Rodrigues, Graça Alexandre-Pires, Ana Valério-Bolas, David Santos-Mateus, Mariana Rafael-Fernandes, Maria A. Pereira, Dário Ligeiro, Telmo Nunes, Raquel Alves-Azevedo, Marcos Santos, Isabel Pereira da Fonseca and Gabriela Santos-Gomes

Biomedicines 2020, 8(12), 628; https://doi.org/10.3390/biomedicines8120628 - 18 Dec 2020

Cited by 6 | Viewed by 2906

Abstract

The application of innovative three-dimensional (3D) spheroids cell culture strategy to Parasitology offers the opportunity to closely explore host–parasite interactions. Here we present a first report on the application of 3D hepatic spheroids to unravel the immune response of canine hepatocytes exposed to [...] Read more.

The application of innovative three-dimensional (3D) spheroids cell culture strategy to Parasitology offers the opportunity to closely explore host–parasite interactions. Here we present a first report on the application of 3D hepatic spheroids to unravel the immune response of canine hepatocytes exposed to Leishmania infantum. The liver, usually considered a major metabolic organ, also performs several important immunological functions and constitutes a target organ for L. infantum infection, the etiological agent of canine leishmaniasis (CanL), and a parasitic disease of major veterinary and public health concern. 3D hepatic spheroids were able to sense and immunologically react to L. infantum parasites, generating an innate immune response by increasing nitric oxide (NO) production and enhancing toll-like receptor (TLR) 2 and interleukin-10 gene expression. The immune response orchestrated by canine hepatocytes also lead to the impairment of several cytochrome P450 (CYP450) with possible implications for liver natural xenobiotic metabolization capacity. The application of meglumine antimoniate (MgA) increased the inflammatory response of 3D hepatic spheroids by inducing the expression of Nucleotide oligomerization domain (NOD) -like receptors 1 and NOD2 and TLR2, TLR4, and TLR9 and enhancing gene expression of tumour necrosis factor α. It is therefore suggested that hepatocytes are key effector cells and can activate and orchestrate the immune response to L. infantum parasites. Full article

(This article belongs to the Special Issue Parasitic Infection and Immunity)

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18 pages, 3373 KiB

Open AccessArticle

Comparative Analysis of the Transcriptome, Proteome, and miRNA Profile of Kupffer Cells and Monocytes

by Andrey Elchaninov, Anastasia Lokhonina, Maria Nikitina, Polina Vishnyakova, Andrey Makarov, Irina Arutyunyan, Anastasiya Poltavets, Evgenia Kananykhina, Sergey Kovalchuk, Evgeny Karpulevich, Galina Bolshakova, Gennady Sukhikh and Timur Fatkhudinov

Biomedicines 2020, 8(12), 627; https://doi.org/10.3390/biomedicines8120627 - 18 Dec 2020

Cited by 11 | Viewed by 4075

Abstract

Macrophage populations in most mammalian organs consist of cells of different origin. Resident macrophages originate from erythromyeloid precursors of the yolk sac wall; maintenance of the numbers of such macrophages in postnatal ontogenesis is practically independent of bone marrow haematopoiesis. The largest populations [...] Read more.

Macrophage populations in most mammalian organs consist of cells of different origin. Resident macrophages originate from erythromyeloid precursors of the yolk sac wall; maintenance of the numbers of such macrophages in postnatal ontogenesis is practically independent of bone marrow haematopoiesis. The largest populations of the resident macrophages of embryonic origin are found in the central nervous system (microglia) and liver (Kupffer cells). In contrast, skin dermis and mucous membranes become predominantly colonized by bone marrow-derived monocytes that show pronounced functional and phenotypic plasticity. In the present study, we compared Kupffer cells and monocytes using the immunophenotype, gene expression profile, proteome, and pool of microRNA. The observed differences did not consider the resident liver macrophages as purely M2 macrophages or state that monocytes have purely M1 features. Monocytes show signs of high plasticity and sensitivity to pathogen-associated molecular patterns (e.g., high levels of transcription for Tlr 2, 4, 7, and 8). In contrast, the resident liver macrophages were clearly involved in the regulation of specific organ functions (nitrogen metabolism, complement system protein synthesis). Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease)

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13 pages, 1906 KiB

Open AccessEditor’s ChoiceArticle

Evidence of SARS-CoV-2 Transcriptional Activity in Cardiomyocytes of COVID-19 Patients without Clinical Signs of Cardiac Involvement

by Gaetano Pietro Bulfamante, Gianluca Lorenzo Perrucci, Monica Falleni, Elena Sommariva, Delfina Tosi, Carla Martinelli, Paola Songia, Paolo Poggio, Stefano Carugo and Giulio Pompilio

Biomedicines 2020, 8(12), 626; https://doi.org/10.3390/biomedicines8120626 - 18 Dec 2020

Cited by 64 | Viewed by 6203

Abstract

Aims: A considerable proportion of patients affected by coronavirus respiratory disease (COVID-19) develop cardiac injury. The viral impact in cardiomyocytes deserves, however, further investigations, especially in asymptomatic patients. Methods: We investigated for SARS-CoV-2 presence and activity in heart tissues of six consecutive COVID-19 [...] Read more.

Aims: A considerable proportion of patients affected by coronavirus respiratory disease (COVID-19) develop cardiac injury. The viral impact in cardiomyocytes deserves, however, further investigations, especially in asymptomatic patients. Methods: We investigated for SARS-CoV-2 presence and activity in heart tissues of six consecutive COVID-19 patients deceased from respiratory failure showing no signs of cardiac involvement and with no history of heart disease. Cardiac autopsy samples were collected within 2 h after death, and then analysed by digital PCR, Western blot, immunohistochemistry, immunofluorescence, RNAScope, and transmission electron microscopy assays. Results: The presence of SARS-CoV-2 into cardiomyocytes was invariably detected in all assays. A variable pattern of cardiomyocyte injury was observed, spanning from absence of cell death and subcellular alterations hallmarks, to intracellular oedema and sarcomere ruptures. In addition, we found active viral transcription in cardiomyocytes, by detecting both sense and antisense SARS-CoV-2 spike RNA. Conclusions: In this autopsy analysis of patients with no clinical signs of cardiac involvement, the presence of SARS-CoV-2 in cardiomyocytes has been detected, determining variable patterns of intracellular damage. These findings suggest the need for cardiologic surveillance in surviving COVID-19 patients not displaying a cardiac phenotype. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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14 pages, 1964 KiB

Open AccessArticle

HDL-Mediated Cholesterol Efflux and Plasma Loading Capacities Are Altered in Subjects with Metabolically- but Not Genetically Driven Non-Alcoholic Fatty Liver Disease (NAFLD)

by Alessia Di Costanzo, Annalisa Ronca, Laura D’Erasmo, Matteo Manfredini, Francesco Baratta, Daniele Pastori, Michele Di Martino, Fabrizio Ceci, Francesco Angelico, Maria Del Ben, Chiara Pavanello, Marta Turri, Laura Calabresi, Elda Favari and Marcello Arca

Biomedicines 2020, 8(12), 625; https://doi.org/10.3390/biomedicines8120625 - 18 Dec 2020

Cited by 22 | Viewed by 3611

Abstract

Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether [...] Read more.

Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether CEC and CLC differ between metabolically- vs. genetically-determined NAFLD. Methods: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type PNPLA3 genotype (Group M), 10 patients with genetic NAFLD carrying M148M PNPLA3 genotype (Group G), and 10 controls PNPLA3 wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. Results: Compared with Group G, Group M showed reduced total CEC (−18.6%; p < 0.001) as well as that mediated by cholesterol transporters (−25.3% ABCA1; −16.3% ABCG1; −14.8% aqueous diffusion; all p < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (p < 0.001). Conclusions: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired. Full article

(This article belongs to the Special Issue High-Density Lipoproteins and Cardiovascular Disease: The Good, the Bad, and the Future)

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14 pages, 20979 KiB

Open AccessArticle

High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition

by Miriam Sartages, Ebel Floridia, Mar García-Colomer, Cristina Iglesias, Manuel Macía, Patricia Peñas, Pierre-Olivier Couraud, Ignacio A. Romero, Babette Weksler, Celia M. Pombo and Juan Zalvide

Biomedicines 2020, 8(12), 624; https://doi.org/10.3390/biomedicines8120624 - 17 Dec 2020

Cited by 2 | Viewed by 2741

Abstract

Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively [...] Read more.

Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically. Full article

(This article belongs to the Section Drug Discovery and Development)

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12 pages, 840 KiB

Open AccessReview

The Role of Corticotropin-Releasing Hormone at Peripheral Nociceptors: Implications for Pain Modulation

by Haiyan Zheng, Ji Yeon Lim, Jae Young Seong and Sun Wook Hwang

Biomedicines 2020, 8(12), 623; https://doi.org/10.3390/biomedicines8120623 - 17 Dec 2020

Cited by 11 | Viewed by 6133

Abstract

Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for [...] Read more.

Peripheral nociceptors and their synaptic partners utilize neuropeptides for signal transmission. Such communication tunes the excitatory and inhibitory function of nociceptor-based circuits, eventually contributing to pain modulation. Corticotropin-releasing hormone (CRH) is the initiator hormone for the conventional hypothalamic-pituitary-adrenal axis, preparing our body for stress insults. Although knowledge of the expression and functional profiles of CRH and its receptors and the outcomes of their interactions has been actively accumulating for many brain regions, those for nociceptors are still under gradual investigation. Currently, based on the evidence of their expressions in nociceptors and their neighboring components, several hypotheses for possible pain modulations are emerging. Here we overview the historical attention to CRH and its receptors on the peripheral nociception and the recent increases in information regarding their roles in tuning pain signals. We also briefly contemplate the possibility that the stress-response paradigm can be locally intrapolated into intercellular communication that is driven by nociceptor neurons. Such endeavors may contribute to a more precise view of local peptidergic mechanisms of peripheral pain modulation. Full article

(This article belongs to the Special Issue Neuropathic Pain: Therapy and Mechanisms)

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13 pages, 1776 KiB

Open AccessArticle

Validation of the Particle-Based Multi-Analyte Technology for Detection of Anti-PhosphatidylSerine/Prothrombin Antibodies

by Massimo Radin, Irene Cecchi, Silvia Grazietta Foddai, Elena Rubini, Alice Barinotti, Carlos Ramirez, Andrea Seaman, Dario Roccatello, Michael Mahler and Savino Sciascia

Biomedicines 2020, 8(12), 622; https://doi.org/10.3390/biomedicines8120622 - 17 Dec 2020

Cited by 7 | Viewed by 2849

Abstract

Among “extra-criteria” antiphospholipid (aPL) antibodies, anti-phosphatidylserine/prothrombin (aPS/PT) antibodies, are considered a part of risk assessment strategies when investigating patients suspected of having antiphospholipid syndrome (APS). aPL detection is currently performed by solid-phase assays to identify anti-cardiolipin (aCL), anti-β2glycoprotein I (aβ2GPI) and aPS/PT antibodies, [...] Read more.

Among “extra-criteria” antiphospholipid (aPL) antibodies, anti-phosphatidylserine/prothrombin (aPS/PT) antibodies, are considered a part of risk assessment strategies when investigating patients suspected of having antiphospholipid syndrome (APS). aPL detection is currently performed by solid-phase assays to identify anti-cardiolipin (aCL), anti-β2glycoprotein I (aβ2GPI) and aPS/PT antibodies, but new techniques are emerging. Among these, particle-based multi-analyte technology (PMAT), which allows the full automation and simultaneous digital detection of autoantibodies and proteins, including IgG, IgA and IgM isotypes of aCL, aβ2GPI and aPS/PT. The aim of this study was to investigate the agreement of aPS/PT testing between enzyme-linked immunosorbent assay (ELISA) and the PMAT platform. A total of 94 patients were enrolled in the study, including 71 patients with confirmed APS and 23 “aPL carriers”. aPS/PT IgG showed a moderate binomial agreement between ELISA and PMAT (k = 0.57, 95% CI 0.45–0.75), and aPS/PT IgM showed a moderate agreement (k = 0.60, 95% CI 0.45–0.75). Moreover, when considering the continuous agreement, both aPS/PT IgG and IgM showed a statistically significant correlation between ELISA and PMAT (Spearman’s correlation = 0.69, p < 0.001 and 0.72, p < 0.001, respectively). This study demonstrates that PMAT technology is a reliable method for aPS/PT IgG and IgM testing when compared to the available commercial ELISA kit. Full article

(This article belongs to the Special Issue Antiphospholipid Syndrome: From Pathophysiology to Novel Therapeutic Approaches)

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36 pages, 1871 KiB

Open AccessReview

Current Trends in Cancer Immunotherapy

by Ivan Y. Filin, Valeriya V. Solovyeva, Kristina V. Kitaeva, Catrin S. Rutland and Albert A. Rizvanov

Biomedicines 2020, 8(12), 621; https://doi.org/10.3390/biomedicines8120621 - 17 Dec 2020

Cited by 35 | Viewed by 7981

Abstract

The search for an effective drug to treat oncological diseases, which have become the main scourge of mankind, has generated a lot of methods for studying this affliction. It has also become a serious challenge for scientists and clinicians who have needed to [...] Read more.

The search for an effective drug to treat oncological diseases, which have become the main scourge of mankind, has generated a lot of methods for studying this affliction. It has also become a serious challenge for scientists and clinicians who have needed to invent new ways of overcoming the problems encountered during treatments, and have also made important discoveries pertaining to fundamental issues relating to the emergence and development of malignant neoplasms. Understanding the basics of the human immune system interactions with tumor cells has enabled new cancer immunotherapy strategies. The initial successes observed in immunotherapy led to new methods of treating cancer and attracted the attention of the scientific and clinical communities due to the prospects of these methods. Nevertheless, there are still many problems that prevent immunotherapy from calling itself an effective drug in the fight against malignant neoplasms. This review examines the current state of affairs for each immunotherapy method, the effectiveness of the strategies under study, as well as possible ways to overcome the problems that have arisen and increase their therapeutic potentials. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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20 pages, 622 KiB

Open AccessReview

High-Density Lipoprotein-Targeted Therapies for Heart Failure

by Mudit Mishra and Bart De Geest

Biomedicines 2020, 8(12), 620; https://doi.org/10.3390/biomedicines8120620 - 16 Dec 2020

Cited by 8 | Viewed by 3821

Abstract

The main and common constituents of high-density lipoproteins (HDLs) are apolipoprotein A-I, cholesterol, and phospholipids. Biochemical heterogeneity of HDL particles is based on the variable presence of one or more representatives of at least 180 proteins, 200 lipid species, and 20 micro RNAs. [...] Read more.

The main and common constituents of high-density lipoproteins (HDLs) are apolipoprotein A-I, cholesterol, and phospholipids. Biochemical heterogeneity of HDL particles is based on the variable presence of one or more representatives of at least 180 proteins, 200 lipid species, and 20 micro RNAs. HDLs are circulating multimolecular platforms that perform divergent functions whereby the potential of HDL-targeted interventions for treatment of heart failure can be postulated based on its pleiotropic effects. Several murine studies have shown that HDLs exert effects on the myocardium, which are completely independent of any impact on coronary arteries. Overall, HDL-targeted therapies exert a direct positive lusitropic effect on the myocardium, inhibit the development of cardiac hypertrophy, suppress interstitial and perivascular myocardial fibrosis, increase capillary density in the myocardium, and prevent the occurrence of heart failure. In four distinct murine models, HDL-targeted interventions were shown to be a successful treatment for both pre-existing heart failure with reduced ejection fraction (HFrEF) and pre-existing heart failure with preserved ejection fraction (HFrEF). Until now, the effect of HDL-targeted interventions has not been evaluated in randomized clinical trials in heart failure patients. As HFpEF represents an important unmet therapeutic need, this is likely the preferred therapeutic domain for clinical translation. Full article

(This article belongs to the Special Issue Novel Insights in Clinical Diagnosis and Therapies of Heart Failure)

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13 pages, 5024 KiB

Open AccessArticle

Novel Medicine for Endometriosis and Its Therapeutic Effect in a Mouse Model

by Young Sang Kim, Yu Jin Kim, Myung Joo Kim, Sang Jin Lee, Hwang Kwon and Jae Ho Lee

Biomedicines 2020, 8(12), 619; https://doi.org/10.3390/biomedicines8120619 - 16 Dec 2020

Cited by 13 | Viewed by 9913

Abstract

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their [...] Read more.

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their combination (Dienogest + Cabergoline). We established a mouse model mimicking human endometriosis. The mice with endometriosis were then treated with a single drug (Dienogest or Cabergoline) or both drugs (Dienogest + Cabergoline) for 14 days. An immunohistological study was then performed to analyze inflammatory lesions in the recipient mice. Real-time polymerase chain reaction (RT-PCR) and Western blotting were also performed to determine the levels of genes and proteins in inflammatory lesions to assess the recovery of endometriosis. Histologic staining showed that all medication groups showed a clear decrease in the inflammatory phenotype in the uterus, peritoneum, and intestine. Gene and protein expression analysis showed a therapeutic effect in all medication groups. In conclusion, Cabergoline had a therapeutic effect similar to that of Dienogest and could be used as an alternative to Dienogest during ART for patients with infertility; compared to the individual drugs, the combination treatment has a synergistic effect on endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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26 pages, 8986 KiB

Open AccessReview

Photo-Based Nanomedicines Using Polymeric Systems in the Field of Cancer Imaging and Therapy

by Patihul Husni, Yuseon Shin, Jae Chang Kim, Kioh Kang, Eun Seong Lee, Yu Seok Youn, Taofik Rusdiana and Kyung Taek Oh

Biomedicines 2020, 8(12), 618; https://doi.org/10.3390/biomedicines8120618 - 16 Dec 2020

Cited by 9 | Viewed by 3741

Abstract

The use of photo-based nanomedicine in imaging and therapy has grown rapidly. The property of light in converting its energy into different forms has been exploited in the fields of optical imaging (OI) and phototherapy (PT) for diagnostic and therapeutic applications. The development [...] Read more.

The use of photo-based nanomedicine in imaging and therapy has grown rapidly. The property of light in converting its energy into different forms has been exploited in the fields of optical imaging (OI) and phototherapy (PT) for diagnostic and therapeutic applications. The development of nanotechnology offers numerous advantages to overcome the challenges of OI and PT. Accordingly, in this review, we shed light on common photosensitive agents (PSAs) used in OI and PT; these include fluorescent and bioluminescent PSAs for OI or PT agents for photodynamic therapy (PDT) and photothermal therapy (PTT). We also describe photo-based nanotechnology systems that can be used in photo-based diagnostics and therapies by using various polymeric systems. Full article

(This article belongs to the Special Issue Advanced Nanomedicines for Optical Imaging and Phototherapy)

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22 pages, 8455 KiB

Open AccessArticle

Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Restructures the Immune Contexture to Improve Checkpoint Blockade Efficacy

by Nancy D. Ebelt, Edith Zuniga, Monica Marzagalli, Vic Zamloot, Bruce R. Blazar, Ravi Salgia and Edwin R. Manuel

Biomedicines 2020, 8(12), 617; https://doi.org/10.3390/biomedicines8120617 - 16 Dec 2020

Cited by 15 | Viewed by 3028

Abstract

Therapeutic options for non-small cell lung cancer (NSCLC) treatment have changed dramatically in recent years with the advent of novel immunotherapeutic approaches. Among these, immune checkpoint blockade (ICB) using monoclonal antibodies has shown tremendous promise in approximately 20% of patients. In order to [...] Read more.

Therapeutic options for non-small cell lung cancer (NSCLC) treatment have changed dramatically in recent years with the advent of novel immunotherapeutic approaches. Among these, immune checkpoint blockade (ICB) using monoclonal antibodies has shown tremendous promise in approximately 20% of patients. In order to better predict patients that will respond to ICB treatment, biomarkers such as tumor-associated CD8⁺ T cell frequency, tumor checkpoint protein status and mutational burden have been utilized, however, with mixed success. In this study, we hypothesized that significantly altering the suppressive tumor immune landscape in NSCLC could potentially improve ICB efficacy. Using sub-therapeutic doses of our Salmonella typhimurium-based therapy targeting the suppressive molecule indoleamine 2,3-dioxygenase (shIDO-ST) in tumor-bearing mice, we observed dramatic changes in immune subset phenotypes that included increases in antigen presentation markers, decreased regulatory T cell frequency and overall reduced checkpoint protein expression. Combination shIDO-ST treatment with anti-PD-1/CTLA-4 antibodies enhanced tumor growth control, compared to either treatment alone, which was associated with significant intratumoral infiltration by CD8⁺ and CD4⁺ T cells. Ultimately, we show that increases in antigen presentation markers and infiltration by T cells is correlated with significantly increased survival in NSCLC patients. These results suggest that the success of ICB therapy may be more accurately predicted by taking into account multiple factors such as potential for antigen presentation and immune subset repertoire in addition to markers already being considered. Alternatively, combination treatment with agents such as shIDO-ST could be used to create a more conducive tumor microenvironment for improving responses to ICB. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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19 pages, 2735 KiB

Open AccessArticle

Enhancing Mechanical Properties and Biological Performances of Injectable Bioactive Glass by Gelatin and Chitosan for Bone Small Defect Repair

by Mehri Sohrabi, Bijan Eftekhari Yekta, Hamidreza Rezaie, Mohammad Reza Naimi-Jamal, Ajay Kumar, Andrea Cochis, Marta Miola and Lia Rimondini

Biomedicines 2020, 8(12), 616; https://doi.org/10.3390/biomedicines8120616 - 15 Dec 2020

Cited by 22 | Viewed by 3950

Abstract

Bioactive glass (BG) represents a promising biomaterial for bone healing; here injectable BG pastes biological properties were improved by the addition of gelatin or chitosan, as well as mechanical resistance was enhanced by adding 10 or 20 wt% 3-Glycidyloxypropyl trimethoxysilane (GPTMS) cross-linker. Composite [...] Read more.

Bioactive glass (BG) represents a promising biomaterial for bone healing; here injectable BG pastes biological properties were improved by the addition of gelatin or chitosan, as well as mechanical resistance was enhanced by adding 10 or 20 wt% 3-Glycidyloxypropyl trimethoxysilane (GPTMS) cross-linker. Composite pastes exhibited bioactivity as apatite formation was observed by Scanning Electron Microscopy (SEM) and X-Ray Diffraction (XRD) after 14 days immersion in simulated body fluid (SBF); moreover, polymers did not enhance degradability as weight loss was >10% after 30 days in physiological conditions. BG-gelatin-20 wt% GPTMS composites demonstrated the highest compressive strength (4.8 ± 0.5 MPa) in comparison with the bulk control paste made of 100% BG in water (1.9 ± 0.1 MPa). Cytocompatibility was demonstrated towards human mesenchymal stem cells (hMSC), osteoblasts progenitors, and endothelial cells. The presence of 20 wt% GPTMS conferred antibacterial properties thus inhibiting the joint pathogens Staphylococcus aureus and Staphylococcus epidermidis infection. Finally, hMSC osteogenesis was successfully supported in a 3D model as demonstrated by alkaline phosphatase release and osteogenic genes expression. Full article

(This article belongs to the Special Issue Bone Tissue Regeneration: Biology and Strategies)

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31 pages, 803 KiB

Open AccessReview

Can Blood-Circulating Factors Unveil and Delay Your Biological Aging?

by Natalia Rybtsova, Tatiana Berezina, Alexander Kagansky and Stanislav Rybtsov

Biomedicines 2020, 8(12), 615; https://doi.org/10.3390/biomedicines8120615 - 15 Dec 2020

Cited by 23 | Viewed by 6479

Abstract

According to the World Health Organization, the population of over 60 will double in the next 30 years in the developed countries, which will enforce a further raise of the retirement age and increase the burden on the healthcare system. Therefore, there is [...] Read more.

According to the World Health Organization, the population of over 60 will double in the next 30 years in the developed countries, which will enforce a further raise of the retirement age and increase the burden on the healthcare system. Therefore, there is an acute issue of maintaining health and prolonging active working longevity, as well as implementation of early monitoring and prevention of premature aging and age-related disorders to avoid early disability. Traditional indicators of biological age are not always informative and often require extensive and expensive analysis. The study of blood factors is a simple and easily accessible way to assess individual health and supplement the traditional indicators of a person’s biological age with new objective criteria. With age, the processes of growth and development, tissue regeneration and repair decline; they are gradually replaced by enhanced catabolism, inflammatory cell activity, and insulin resistance. The number of senescent cells supporting the inflammatory loop rises; cellular clearance by autophagy and mitophagy slows down, resulting in mitochondrial and cellular damage and dysfunction. Monitoring of circulated blood factors not only reflects these processes, but also allows suggesting medical intervention to prevent or decelerate the development of age-related diseases. We review the age-related blood factors discussed in recent publications, as well as approaches to slowing aging for healthy and active longevity. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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16 pages, 3493 KiB

Open AccessArticle

Shockwave Therapy Modulates the Expression of BMP2 for Prevention of Bone and Cartilage Loss in the Lower Limbs of Postmenopausal Osteoporosis Rat Model

by Shan-Ling Hsu, Wen-Yi Chou, Chieh-Cheng Hsu, Jih-Yang Ko, Shun-Wun Jhan, Ching-Jen Wang, Meng-Shiou Lee, Tsai-Chin Hsu and Jai-Hong Cheng

Biomedicines 2020, 8(12), 614; https://doi.org/10.3390/biomedicines8120614 - 15 Dec 2020

Cited by 7 | Viewed by 2629

Abstract

Osteoporosis (OP) causes bone loss and weakness, increasing the risk of bone fracture. In this study, rats were divided into Sham, OP, SW(F) (0.25 mJ/mm² with 1600 impulses to the left medial femur), and SW(T) (0.25 mJ/mm² with 1600 impulses to [...] Read more.

Osteoporosis (OP) causes bone loss and weakness, increasing the risk of bone fracture. In this study, rats were divided into Sham, OP, SW(F) (0.25 mJ/mm² with 1600 impulses to the left medial femur), and SW(T) (0.25 mJ/mm² with 1600 impulses to the left medial tibia). The bone strength results following SW(T) were better than SW(F) in the modulus, extension at peak load, handleability, and strain at break. SW(T) had the best prevention for bone loss in both lower limbs of ovariectomized (OVX) rats. The cartilage cellular matrixes of both knees were improved in SW(T) and SW(F) compared to that of OP. Serum bone morphogenetic protein 2 (BMP2) in rats undergoing SW(T) or SW(F) was significantly improved compared to that in Sham and OP. The expressions of BMP2, BMP4, and SMAD family member 4 (Smad4) in addition to the Wnt family member 3A (Wnt3a) and Cyclin D1 signaling key factors were significantly induced in the cartilage of both knees by shockwave (SW). SW(T) presented the best efficacy to induce serum BMP2 to prevent bone loss from both lower limbs. Here, we display the protective effects of SW therapy to induce BMP2, BMP4, Smad4, Wnt3a, and Cyclin D1 signaling factors for cartilage loss in both knees of OVX rats. Full article

(This article belongs to the Special Issue Bone Tissue Regeneration: Biology and Strategies)

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16 pages, 260 KiB

Open AccessReview

Combined Cell Therapy in the Treatment of Neurological Disorders

by Daria D. Namestnikova, Elvira A. Cherkashova, Kirill K. Sukhinich, Ilya L. Gubskiy, Georgy E. Leonov, Leonid V. Gubsky, Alexander G. Majouga and Konstantin N. Yarygin

Biomedicines 2020, 8(12), 613; https://doi.org/10.3390/biomedicines8120613 - 15 Dec 2020

Cited by 11 | Viewed by 3307

Abstract

Cell therapy of neurological diseases is gaining momentum. Various types of stem/progenitor cells and their derivatives have shown positive therapeutic results in animal models of neurological disorders and in clinical trials. Each tested cell type proved to have its advantages and flaws and [...] Read more.

Cell therapy of neurological diseases is gaining momentum. Various types of stem/progenitor cells and their derivatives have shown positive therapeutic results in animal models of neurological disorders and in clinical trials. Each tested cell type proved to have its advantages and flaws and unique cellular and molecular mechanism of action, prompting the idea to test combined transplantation of two or more types of cells (combined cell therapy). This review summarizes the results of combined cell therapy of neurological pathologies reported up to this point. The number of papers describing experimental studies or clinical trials addressing this subject is still limited. However, its successful application to the treatment of neurological pathologies including stroke, spinal cord injury, neurodegenerative diseases, Duchenne muscular dystrophy, and retinal degeneration has been reported in both experimental and clinical studies. The advantages of combined cell therapy can be realized by simple summation of beneficial effects of different cells. Alternatively, one kind of cells can support the survival and functioning of the other by enhancing the formation of optimum environment or immunomodulation. No significant adverse events were reported. Combined cell therapy is a promising approach for the treatment of neurological disorders, but further research needs to be conducted. Full article

(This article belongs to the Section Gene and Cell Therapy)

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15 pages, 1193 KiB

Open AccessReview

Anti-c-myc RNAi-Based Onconanotherapeutics

by Saffiya Habib, Mario Ariatti and Moganavelli Singh

Biomedicines 2020, 8(12), 612; https://doi.org/10.3390/biomedicines8120612 - 15 Dec 2020

Cited by 14 | Viewed by 3841

Abstract

Overexpression of the c-myc proto-oncogene features prominently in most human cancers. Early studies established that inhibiting the expression of oncogenic c-myc, produced potent anti-cancer effects. This gave rise to the notion that an appropriate c-myc silencing agent might provide a broadly applicable [...] Read more.

Overexpression of the c-myc proto-oncogene features prominently in most human cancers. Early studies established that inhibiting the expression of oncogenic c-myc, produced potent anti-cancer effects. This gave rise to the notion that an appropriate c-myc silencing agent might provide a broadly applicable and more effective form of cancer treatment than is currently available. The endogenous mechanism of RNA interference (RNAi), through which small RNA molecules induce gene silencing by binding to complementary mRNA transcripts, represents an attractive avenue for c-myc inhibition. However, the development of a clinically viable, anti-c-myc RNAi-based platform is largely dependent upon the design of an appropriate carrier of the effector nucleic acids. To date, organic and inorganic nanoparticles were assessed both in vitro and in vivo, as carriers of small interfering RNA (siRNA), DICER-substrate siRNA (DsiRNA), and short hairpin RNA (shRNA) expression plasmids, directed against the c-myc oncogene. We review here the various anti-c-myc RNAi-based nanosystems that have come to the fore, especially between 2005 and 2020. Full article

(This article belongs to the Special Issue Novel Anti-cancer Agents and Cellular Targets and Their Mechanism(s) of Action)

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20 pages, 352 KiB

Open AccessReview

Genetic and Acquired Heterotopic Ossification: A Translational Tale of Mice and Men

by Serena Cappato, Riccardo Gamberale, Renata Bocciardi and Silvia Brunelli

Biomedicines 2020, 8(12), 611; https://doi.org/10.3390/biomedicines8120611 - 14 Dec 2020

Cited by 22 | Viewed by 4715

Abstract

Heterotopic ossification is defined as an aberrant formation of bone in extraskeletal soft tissue, for which both genetic and acquired conditions are known. This pathologic process may occur in many different sites such as the skin, subcutaneous tissue, skeletal muscle and fibrous tissue [...] Read more.

Heterotopic ossification is defined as an aberrant formation of bone in extraskeletal soft tissue, for which both genetic and acquired conditions are known. This pathologic process may occur in many different sites such as the skin, subcutaneous tissue, skeletal muscle and fibrous tissue adjacent to joints, ligaments, walls of blood vessels, mesentery and other. The clinical spectrum of this disorder is wide: lesions may range from small foci of ossification to massive deposits of bone throughout the body, typical of the progressive genetically determined conditions such as fibrodysplasia ossificans progressiva, to mention one of the most severe and disabling forms. The ectopic bone formation may be regarded as a failed tissue repair process in response to a variety of triggers and evolving towards bone formation through a multistage differentiation program, with several steps common to different clinical presentations and distinctive features. In this review, we aim at providing a comprehensive view of the genetic and acquired heterotopic ossification disorders by detailing the clinical and molecular features underlying the different human conditions in comparison with the corresponding, currently available mouse models. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches)

16 pages, 3388 KiB

Open AccessArticle

Examination of Oral Squamous Cell Carcinoma and Precancerous Lesions Using Proximity Extension Assay and Salivary RNA Quantification

by Beáta Scholtz, Doan Vo Minh, Csongor Kiss, Ildikó Tar, Ajneesh Kumar, József Tőzsér, Éva Csősz and Ildikó Márton

Biomedicines 2020, 8(12), 610; https://doi.org/10.3390/biomedicines8120610 - 14 Dec 2020

Cited by 8 | Viewed by 3403

Abstract

Saliva is an easy-to access body fluid with high diagnostic potential. The utilization of saliva for oral cancer diagnosis can be an attractive possibility. Besides the oral cancer, it is important to better understand the precancerous lesions such as oral lichen planus (OLP) [...] Read more.

Saliva is an easy-to access body fluid with high diagnostic potential. The utilization of saliva for oral cancer diagnosis can be an attractive possibility. Besides the oral cancer, it is important to better understand the precancerous lesions such as oral lichen planus (OLP) and leukoplakia (OLK). In order to examine the changes of salivary proteins in controls, patients with oral cancer, and patients with precancerous conditions, proximity extension assay was utilized. Some proteins and functions were characteristic to the examined groups and can serve as a starting point for further biomarker studies. The different nature of OLK and OLP was demonstrated, showing the malignant transformation and the inflammation as the prominent biological processes in the OLK and OLP, respectively. The salivary level of IL6 was verified using quantitative ELISA and the mRNA level was also studied. Elevated IL6 levels could be detected in precancerous groups compared to controls. Full article

(This article belongs to the Special Issue Models for Oral Biology Research)

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Biomedicines, Volume 8, Issue 12 (December 2020) – 110 articles

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