Biomedicines

12 pages, 1341 KiB

Open AccessEditor’s ChoiceArticle

Protective Role of Combined Polyphenols and Micronutrients against Influenza A Virus and SARS-CoV-2 Infection In Vitro

by Marta De Angelis, David Della-Morte, Gabriele Buttinelli, Angela Di Martino, Francesca Pacifici, Paola Checconi, Luigina Ambrosio, Paola Stefanelli, Anna Teresa Palamara, Enrico Garaci, Camillo Ricordi and Lucia Nencioni

Biomedicines 2021, 9(11), 1721; https://doi.org/10.3390/biomedicines9111721 - 19 Nov 2021

Cited by 22 | Viewed by 4071

Abstract

Polyphenols have been widely studied for their antiviral effect against respiratory virus infections. Among these, resveratrol (RV) has been demonstrated to inhibit influenza virus replication and more recently, it has been tested together with pterostilbene against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [...] Read more.

Polyphenols have been widely studied for their antiviral effect against respiratory virus infections. Among these, resveratrol (RV) has been demonstrated to inhibit influenza virus replication and more recently, it has been tested together with pterostilbene against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present work, we evaluated the antiviral activity of polydatin, an RV precursor, and a mixture of polyphenols and other micronutrients, named A5+, against influenza virus and SARS-CoV-2 infections. To this end, we infected Vero E6 cells and analyzed the replication of both respiratory viruses in terms of viral proteins synthesis and viral titration. We demonstrated that A5+ showed a higher efficacy in inhibiting both influenza virus and SARS-CoV-2 infections compared to polydatin treatment alone. Indeed, post infection treatment significantly decreased viral proteins expression and viral release, probably by interfering with any step of virus replicative cycle. Intriguingly, A5+ treatment strongly reduced IL-6 cytokine production in influenza virus-infected cells, suggesting its potential anti-inflammatory properties during the infection. Overall, these results demonstrate the synergic and innovative antiviral efficacy of A5+ mixture, although further studies are needed to clarify the mechanisms underlying its inhibitory effect. Full article

(This article belongs to the Special Issue Inhibitors of Key Targets of SARS-CoV-2 and Other Coronaviruses)

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18 pages, 3973 KiB

Open AccessEditor’s ChoiceArticle

Relationship between Vitamin D Status and Antibody Response to COVID-19 mRNA Vaccination in Healthy Adults

by Thilo Samson Chillon, Kamil Demircan, Raban Arved Heller, Ines Maria Hirschbil-Bremer, Joachim Diegmann, Manuel Bachmann, Arash Moghaddam and Lutz Schomburg

Biomedicines 2021, 9(11), 1714; https://doi.org/10.3390/biomedicines9111714 - 18 Nov 2021

Cited by 33 | Viewed by 6225

Abstract

The immune response to vaccination with SARS-CoV-2 vaccines varies greatly from person to person. In addition to age, there is evidence that certain micronutrients influence the immune system, particularly vitamin D. Here, we analysed SARS-CoV-2 IgG and neutralisation potency along with 25-hydroxy-cholecalciferol [25(OH)D] [...] Read more.

The immune response to vaccination with SARS-CoV-2 vaccines varies greatly from person to person. In addition to age, there is evidence that certain micronutrients influence the immune system, particularly vitamin D. Here, we analysed SARS-CoV-2 IgG and neutralisation potency along with 25-hydroxy-cholecalciferol [25(OH)D] concentrations in a cohort of healthy German adults from the time of vaccination over 24 weeks. Contrary to our expectations, no significant differences were found in the dynamic increase or decrease of SARS-CoV-2 IgG as a function of the 25(OH)D status. Furthermore, the response to the first or second vaccination, the maximum SARS-CoV-2 IgG concentrations achieved, and the decline in SARS-CoV-2 IgG concentrations over time were not related to 25(OH)D status. We conclude that the vaccination response, measured as SARS-CoV-2 IgG concentration, does not depend on 25(OH)D status in healthy adults with moderate vitamin D status. Full article

(This article belongs to the Special Issue Immunology in COVID-19 Disease: From Pathophysiology to Novel Therapeutic Approaches)

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20 pages, 754 KiB

Open AccessEditor’s ChoiceReview

Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma

by Eun Jin Sun, Miriam Wankell, Pranavan Palamuthusingam, Craig McFarlane and Lionel Hebbard

Biomedicines 2021, 9(11), 1639; https://doi.org/10.3390/biomedicines9111639 - 08 Nov 2021

Cited by 97 | Viewed by 10429

Abstract

Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and [...] Read more.

Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments. Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

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13 pages, 780 KiB

Open AccessEditor’s ChoiceReview

Dyslipidemia, Diabetes and Atherosclerosis: Role of Inflammation and ROS-Redox-Sensitive Factors

by Elham Hasheminasabgorji and Jay C. Jha

Biomedicines 2021, 9(11), 1602; https://doi.org/10.3390/biomedicines9111602 - 03 Nov 2021

Cited by 36 | Viewed by 7543

Abstract

The prevalence of diabetes is growing at an alarming rate with increased disability, morbidity, and often premature mortality because of the various complications of this disorder. Chronic hyperglycemia, dyslipidemia, and other metabolic alterations lead to the development and progression of macro- and microvascular [...] Read more.

The prevalence of diabetes is growing at an alarming rate with increased disability, morbidity, and often premature mortality because of the various complications of this disorder. Chronic hyperglycemia, dyslipidemia, and other metabolic alterations lead to the development and progression of macro- and microvascular complications of diabetes including cardiovascular, retinal and kidney disease. Despite advances in glucose and lipid lowering treatments, a large number of diabetic individuals develop one or more types of these complications, ultimately leading to end-organ damage over the time. Atherosclerosis is the major macro-vascular complications of diabetes and the primary underlying cause of cardiovascular disease (CVD) posing heavy burden on the health care system. In this review, we discuss the involvement of dyslipidemia in the progression of atherosclerosis by activating the pro-inflammatory cytokines and oxidative stress-related factors. In addition, we also provide information on various pharmacological agents that provides protection against diabetic atherosclerosis by reducing inflammation and oxidative stress. Full article

(This article belongs to the Special Issue Advanced and Innovative Therapies of Dyslipidemia)

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45 pages, 6964 KiB

Open AccessEditor’s ChoiceReview

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

by Matthias Niklasch, Peter Zimmermann and Michael Nassal

Biomedicines 2021, 9(11), 1577; https://doi.org/10.3390/biomedicines9111577 - 29 Oct 2021

Cited by 22 | Viewed by 4928

Abstract

Hepatitis B virus (HBV) is a small enveloped DNA virus which replicates its tiny 3.2 kb genome by reverse transcription inside an icosahedral nucleocapsid, formed by a single ~180 amino acid capsid, or core, protein (Cp). HBV causes chronic hepatitis B (CHB), a [...] Read more.

Hepatitis B virus (HBV) is a small enveloped DNA virus which replicates its tiny 3.2 kb genome by reverse transcription inside an icosahedral nucleocapsid, formed by a single ~180 amino acid capsid, or core, protein (Cp). HBV causes chronic hepatitis B (CHB), a severe liver disease responsible for nearly a million deaths each year. Most of HBV’s only seven primary gene products are multifunctional. Though less obvious than for the multi-domain polymerase, P protein, this is equally crucial for Cp with its multiple roles in the viral life-cycle. Cp provides a stable genome container during extracellular phases, allows for directed intracellular genome transport and timely release from the capsid, and subsequent assembly of new nucleocapsids around P protein and the pregenomic (pg) RNA, forming a distinct compartment for reverse transcription. These opposing features are enabled by dynamic post-transcriptional modifications of Cp which result in dynamic structural alterations. Their perturbation by capsid assembly modulators (CAMs) is a promising new antiviral concept. CAMs inappropriately accelerate assembly and/or distort the capsid shell. We summarize the functional, biochemical, and structural dynamics of Cp, and discuss the therapeutic potential of CAMs based on clinical data. Presently, CAMs appear as a valuable addition but not a substitute for existing therapies. However, as part of rational combination therapies CAMs may bring the ambitious goal of a cure for CHB closer to reality. Full article

(This article belongs to the Special Issue Conformational Dynamics of Viral Proteins)

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14 pages, 6616 KiB

Open AccessEditor’s ChoiceArticle

Curcumin and Radiotherapy Exert Synergistic Anti-Glioma Effect In Vitro

by Vasiliki Zoi, Vasiliki Galani, Evrysthenis Vartholomatos, Natalia Zacharopoulou, Eftichia Tsoumeleka, Georgios Gkizas, Georgios Bozios, Pericles Tsekeris, Ieremias Chousidis, Ioannis Leonardos, Andreas G. Tzakos, Athanasios P. Kyritsis and George A. Alexiou

Biomedicines 2021, 9(11), 1562; https://doi.org/10.3390/biomedicines9111562 - 28 Oct 2021

Cited by 17 | Viewed by 2688

Abstract

Curcumin, a bioactive polyphenol, is known to have anticancer properties. In this study, the effectiveness of curcumin pretreatment as a strategy for radio-sensitizing glioblastoma cell lines was explored. For this, U87 and T98 cells were treated with curcumin, exposed to 2 Gy or [...] Read more.

Curcumin, a bioactive polyphenol, is known to have anticancer properties. In this study, the effectiveness of curcumin pretreatment as a strategy for radio-sensitizing glioblastoma cell lines was explored. For this, U87 and T98 cells were treated with curcumin, exposed to 2 Gy or 4 Gy of irradiation, and the combined effect was compared to the antiproliferative effect of each agent when given individually. Cell viability and proliferation were evaluated with the trypan blue exclusion assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The synergistic effects of the combination treatment were analyzed with CompuSyn software. To examine how the co-treatment affected different phases of cell-cycle progression, a cell-cycle analysis via flow cytometry was performed. Treatment with curcumin and radiation significantly reduced cell viability in both U87 and T98 cell lines. The combination treatment arrested both cell lines at the G2/M phase to a higher extent than radiation or curcumin treatment alone. The synergistic effect of curcumin when combined with temozolomide resulted in increased tumor cell death. Our results demonstrate for the first time that low doses of curcumin and irradiation exhibit a strong synergistic anti-proliferative effect on glioblastoma cells in vitro. Therefore, this combination may represent an innovative and promising strategy for the treatment of glioblastoma, and further studies are needed to fully understand the molecular mechanism underlying this effect. Full article

(This article belongs to the Special Issue Anti-inflammatory Activity of Plant Polyphenols 2.0)

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46 pages, 12718 KiB

Open AccessEditor’s ChoiceReview

Smart and Biomimetic 3D and 4D Printed Composite Hydrogels: Opportunities for Different Biomedical Applications

by Samira Malekmohammadi, Negar Sedghi Aminabad, Amin Sabzi, Amir Zarebkohan, Mehdi Razavi, Massoud Vosough, Mahdi Bodaghi and Hajar Maleki

Biomedicines 2021, 9(11), 1537; https://doi.org/10.3390/biomedicines9111537 - 26 Oct 2021

Cited by 53 | Viewed by 6490

Abstract

In recent years, smart/stimuli-responsive hydrogels have drawn tremendous attention for their varied applications, mainly in the biomedical field. These hydrogels are derived from different natural and synthetic polymers but are also composite with various organic and nano-organic fillers. The basic functions of smart [...] Read more.

In recent years, smart/stimuli-responsive hydrogels have drawn tremendous attention for their varied applications, mainly in the biomedical field. These hydrogels are derived from different natural and synthetic polymers but are also composite with various organic and nano-organic fillers. The basic functions of smart hydrogels rely on their ability to change behavior; functions include mechanical, swelling, shaping, hydrophilicity, and bioactivity in response to external stimuli such as temperature, pH, magnetic field, electromagnetic radiation, and biological molecules. Depending on the final applications, smart hydrogels can be processed in different geometries and modalities to meet the complicated situations in biological media, namely, injectable hydrogels (following the sol-gel transition), colloidal nano and microgels, and three dimensional (3D) printed gel constructs. In recent decades smart hydrogels have opened a new horizon for scientists to fabricate biomimetic customized biomaterials for tissue engineering, cancer therapy, wound dressing, soft robotic actuators, and controlled release of bioactive substances/drugs. Remarkably, 4D bioprinting, a newly emerged technology/concept, aims to rationally design 3D patterned biological matrices from synthesized hydrogel-based inks with the ability to change structure under stimuli. This technology has enlarged the applicability of engineered smart hydrogels and hydrogel composites in biomedical fields. This paper aims to review stimuli-responsive hydrogels according to the kinds of external changes and t recent applications in biomedical and 4D bioprinting. Full article

(This article belongs to the Special Issue Bio-Inspired Porous Materials and Biomaterials)

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20 pages, 373 KiB

Open AccessEditor’s ChoiceReview

Psoriasis as an Immune-Mediated and Inflammatory Systemic Disease: From Pathophysiology to Novel Therapeutic Approaches

by Anna Campanati, Andrea Marani, Emanuela Martina, Federico Diotallevi, Giulia Radi and Annamaria Offidani

Biomedicines 2021, 9(11), 1511; https://doi.org/10.3390/biomedicines9111511 - 21 Oct 2021

Cited by 40 | Viewed by 3395

Abstract

Psoriasis is an immune-mediated inflammatory disease, with a chronic relapsing-remitting course, which affects 2–3% of the worldwide population. The progressive acquisitions of the inflammatory pathways involved in the development of psoriasis have led to the identification of the key molecules of the psoriatic [...] Read more.

Psoriasis is an immune-mediated inflammatory disease, with a chronic relapsing-remitting course, which affects 2–3% of the worldwide population. The progressive acquisitions of the inflammatory pathways involved in the development of psoriasis have led to the identification of the key molecules of the psoriatic inflammatory cascade. At the same time, psoriasis therapy has radically evolved with the introduction of target molecules able to modify the natural history of the disease, acting specifically on these inflammatory pathways. For these reasons, biologics have been demonstrated to be drugs able to change the disease’s natural history, as they reduce the inflammatory background to avoid irreversible organ damage and prevent systemic complications. However, several issues related to the use of biologics in patients with systemic comorbidities, remain open. All these data reflect the extraordinary potentiality of biologics, but also the unmet medical need to improve our knowledge on the long-term risk related to continuous use of these drugs, and their administration in special populations. This narrative review aims to highlight both the efficacy and safety profile of biologics in psoriasis, starting from pathophysiology and moving towards their clinical application. Full article

(This article belongs to the Special Issue Immune-Mediated Skin Diseases: From Pathophysiology to Novel Therapeutic Approaches)

38 pages, 2331 KiB

Open AccessEditor’s ChoiceReview

Antitumoral Activities of Curcumin and Recent Advances to ImProve Its Oral Bioavailability

by Marta Claudia Nocito, Arianna De Luca, Francesca Prestia, Paola Avena, Davide La Padula, Lucia Zavaglia, Rosa Sirianni, Ivan Casaburi, Francesco Puoci, Adele Chimento and Vincenzo Pezzi

Biomedicines 2021, 9(10), 1476; https://doi.org/10.3390/biomedicines9101476 - 14 Oct 2021

Cited by 33 | Viewed by 3532

Abstract

Curcumin, a main bioactive component of the Curcuma longa L. rhizome, is a phenolic compound that exerts a wide range of beneficial effects, acting as an antimicrobial, antioxidant, anti-inflammatory and anticancer agent. This review summarizes recent data on curcumin’s ability to interfere with [...] Read more.

Curcumin, a main bioactive component of the Curcuma longa L. rhizome, is a phenolic compound that exerts a wide range of beneficial effects, acting as an antimicrobial, antioxidant, anti-inflammatory and anticancer agent. This review summarizes recent data on curcumin’s ability to interfere with the multiple cell signaling pathways involved in cell cycle regulation, apoptosis and the migration of several cancer cell types. However, although curcumin displays anticancer potential, its clinical application is limited by its low absorption, rapid metabolism and poor bioavailability. To overcome these limitations, several curcumin-based derivatives/analogues and different drug delivery approaches have been developed. Here, we also report the anticancer mechanisms and pharmacokinetic characteristics of some derivatives/analogues and the delivery systems used. These strategies, although encouraging, require additional in vivo studies to support curcumin clinical applications. Full article

(This article belongs to the Special Issue Therapeutic Potential of Plant Secondary Metabolites in the Treatment of Diseases and Drug Development)

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27 pages, 10852 KiB

Open AccessEditor’s ChoiceArticle

β-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight

by Agustín Hidalgo-Gutiérrez, Eliana Barriocanal-Casado, María Elena Díaz-Casado, Pilar González-García, Riccardo Zenezini Chiozzi, Darío Acuña-Castroviejo and Luis Carlos López

Biomedicines 2021, 9(10), 1457; https://doi.org/10.3390/biomedicines9101457 - 13 Oct 2021

Cited by 7 | Viewed by 2713

Abstract

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the [...] Read more.

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remain challenging. Here, we show that beta-resorcylic acid (β-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9^R239X mice. As a consequence, β-RA rescued the phenotype of Coq9^R239X mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with β-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that β-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Disease)

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23 pages, 793 KiB

Open AccessEditor’s ChoiceReview

Biomarkers for Gastric Cancer Screening and Early Diagnosis

by Cristina Herrera-Pariente, Sheyla Montori, Joan Llach, Alex Bofill, Eduardo Albeniz and Leticia Moreira

Biomedicines 2021, 9(10), 1448; https://doi.org/10.3390/biomedicines9101448 - 12 Oct 2021

Cited by 28 | Viewed by 4070

Abstract

Gastric cancer is one of the most common cancers worldwide, with a bad prognosis associated with late-stage diagnosis, significantly decreasing the overall survival. This highlights the importance of early detection to improve the clinical course of these patients. Although screening programs, based on [...] Read more.

Gastric cancer is one of the most common cancers worldwide, with a bad prognosis associated with late-stage diagnosis, significantly decreasing the overall survival. This highlights the importance of early detection to improve the clinical course of these patients. Although screening programs, based on endoscopic or radiologic approaches, have been useful in countries with high incidence, they are not cost-effective in low-incidence populations as a massive screening strategy. Additionally, current biomarkers used in daily routine are not specific and sensitive enough, and most of them are obtained invasively. Thus, it is imperative to discover new noninvasive biomarkers able to diagnose early-stage gastric cancer. In this context, liquid biopsy is a promising strategy. In this review, we briefly discuss some of the potential biomarkers for gastric cancer screening and diagnosis identified in blood, saliva, urine, stool, and gastric juice. Full article

(This article belongs to the Special Issue Gastric Cancer: From Mechanisms to Therapeutic Approaches)

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37 pages, 21184 KiB

Open AccessEditor’s ChoiceReview

Discovery, Optimization, and Clinical Application of Natural Antimicrobial Peptides

by Armando A. Rodríguez, Anselmo Otero-González, Maretchia Ghattas and Ludger Ständker

Biomedicines 2021, 9(10), 1381; https://doi.org/10.3390/biomedicines9101381 - 03 Oct 2021

Cited by 25 | Viewed by 4506

Abstract

Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and [...] Read more.

Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and anticancer activities. During the last 30 years, technological advances have boosted the research on antimicrobial peptides, which have also attracted great interest as an alternative to tackling the antimicrobial resistance scenario mainly provoked by some bacterial and fungal pathogens. However, the introduction of natural AMPs in clinical trials faces challenges such as proteolytic digestion, short half-lives, and cytotoxicity upon systemic and oral application. Therefore, some strategies have been implemented to improve the properties of AMPs aiming to be used as effective therapeutic agents. In the present review, we summarize the discovery path of AMPs, focusing on preclinical development, recent advances in chemical optimization and peptide delivery systems, and their introduction into the market. Full article

(This article belongs to the Special Issue Peptides of Natural Origin as Leads for Drug Discovery: From Native Structures to Peptidomimetics, Peptide-Conjugates, and Peptide-Nanoparticles 2.0)

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21 pages, 2071 KiB

Open AccessEditor’s ChoiceReview

Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function

by Teresa Salvatore, Alfredo Caturano, Raffaele Galiero, Anna Di Martino, Gaetana Albanese, Erica Vetrano, Celestino Sardu, Raffaele Marfella, Luca Rinaldi and Ferdinando Carlo Sasso

Biomedicines 2021, 9(10), 1356; https://doi.org/10.3390/biomedicines9101356 - 29 Sep 2021

Cited by 46 | Viewed by 4683

Abstract

Type 2 diabetes mellitus (T2DM) is a known independent risk factor for atherosclerotic cardiovascular disease (CVD) and solid epidemiological evidence points to heart failure (HF) as one of the most common complications of diabetes. For this reason, it is imperative to consider the [...] Read more.

Type 2 diabetes mellitus (T2DM) is a known independent risk factor for atherosclerotic cardiovascular disease (CVD) and solid epidemiological evidence points to heart failure (HF) as one of the most common complications of diabetes. For this reason, it is imperative to consider the prevention of CV outcomes as an effective goal for the management of diabetic patients, as important as lowering blood glucose. Endothelial dysfunction (ED) is an early event of atherosclerosis involving adhesion molecules, chemokines, and leucocytes to enhance low-density lipoprotein oxidation, platelet activation, and vascular smooth muscle cell proliferation and migration. This abnormal vascular phenotype represents an important risk factor for the genesis of any complication of diabetes, contributing to the pathogenesis of not only macrovascular disease but also microvascular damage. Gliflozins are a novel class of anti-hyperglycemic agents used for the treatment of Type 2 diabetes mellitus (T2DM) that selectively inhibit the sodium glucose transporter 2 (SGLT2) in the kidneys and have provoked large interest in scientific community due to their cardiovascular beneficial effects, whose underlying pathophysiology is still not fully understood. This review aimed to analyze the cardiovascular protective mechanisms of SGLT2 inhibition in patients T2DM and their impact on endothelial function. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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14 pages, 1598 KiB

Open AccessEditor’s ChoiceArticle

Airway Bacteria Quantification Using Polymerase Chain Reaction Combined with Neutrophil and Eosinophil Counts Identifies Distinct COPD Endotypes

by Augusta Beech, Simon Lea, Jian Li, Natalie Jackson, Alex Mulvanny and Dave Singh

Biomedicines 2021, 9(10), 1337; https://doi.org/10.3390/biomedicines9101337 - 27 Sep 2021

Cited by 14 | Viewed by 2151

Abstract

Background: Chronic obstructive pulmonary disease (COPD) inflammatory endotypes are associated with different airway microbiomes. We used quantitative polymerase chain reaction (qPCR) analysis of sputum samples to establish the bacterial load upper limit in healthy controls; these values determined the bacterial colonisation prevalence in [...] Read more.

Background: Chronic obstructive pulmonary disease (COPD) inflammatory endotypes are associated with different airway microbiomes. We used quantitative polymerase chain reaction (qPCR) analysis of sputum samples to establish the bacterial load upper limit in healthy controls; these values determined the bacterial colonisation prevalence in a longitudinal COPD cohort. Bacteriology combined with sputum inflammatory cells counts were used to investigate COPD endotypes. Methods: Sixty COPD patients and 15 healthy non-smoking controls were recruited. Sputum was analysed by qPCR (for Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Psuedomonas aeruginosa) and sputum differential cell counts at baseline and 6 months. Results: At baseline and 6 months, 23.1% and 25.6% of COPD patients were colonised with H. influenzae, while colonisation with other bacterial species was less common, e.g., S. pneumoniae—1.9% and 5.1%, respectively. H. influenzae + ve patients had higher neutrophil counts at baseline (90.1% vs. 67.3%, p < 0.01), with similar results at 6 months. COPD patients with sputum eosinophil counts ≥3% at ≥1 visit rarely showed bacterial colonisation. Conclusions: The prevalence of H. influenzae colonisation was approximately 25%, with low colonisation for other bacterial species. H. influenzae colonisation was associated with sputum neutrophilia, while eosinophilic inflammation and H. influenzae colonisation rarely coexisted. Full article

(This article belongs to the Special Issue Chronic Obstructive Pulmonary Disease (COPD): From Pathophysiology to Novel Therapeutic Approaches)

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31 pages, 6061 KiB

Open AccessEditor’s ChoiceArticle

Robert’s Intragastric Alcohol-Induced Gastric Lesion Model as an Escalated General Peripheral and Central Syndrome, Counteracted by the Stable Gastric Pentadecapeptide BPC 157

by Slaven Gojkovic, Ivan Krezic, Hrvoje Vranes, Helena Zizek, Domagoj Drmic, Lovorka Batelja Vuletic, Marija Milavic, Suncana Sikiric, Irma Stilinovic, Paris Simeon, Mario Knezevic, Toni Kolak, Marijan Tepes, Karol Simonji, Sanja Strbe, Nora Nikolac Gabaj, Ivan Barisic, Emma Grace Oreskovic, Eva Lovric, Antonio Kokot, Anita Skrtic, Alenka Boban Blagaic, Sven Seiwerth and Predrag Sikiric Show full author list Hide full author list

Biomedicines 2021, 9(10), 1300; https://doi.org/10.3390/biomedicines9101300 - 23 Sep 2021

Cited by 19 | Viewed by 3085

Abstract

We redefined Robert’s prototypical cytoprotection model, namely the intragastric administration of 96% alcohol in order to generate a general peripheral and central syndrome similar to that which occurs when major central or peripheral veins are occluded in animal models. With this redefinition, we [...] Read more.

We redefined Robert’s prototypical cytoprotection model, namely the intragastric administration of 96% alcohol in order to generate a general peripheral and central syndrome similar to that which occurs when major central or peripheral veins are occluded in animal models. With this redefinition, we used Robert’s model to examine the cytoprotective effects of the stable gastric pentadecapeptide BPC 157. The intragastric administration of alcohol induced gastric lesions, intracranial (superior sagittal sinus) hypertension, severe brain swelling and lesions, portal and vena caval hypertension, aortal hypotension, severe thrombosis, inferior vena cava and superior mesenteric vein congestion, azygos vein failure (as a failed collateral pathway), electrocardiogram disturbances, and heart, lung, liver and kidney lesions. The use of BPC 157 therapy (10 µg/kg or 10 ng/kg given intraperitoneally 1 min after alcohol) counteracted these deficits rapidly. Specifically, BPC 157 reversed brain swelling and superior mesenteric vein and inferior vena caval congestion, and helped the azygos vein to recover, which improved the collateral blood flow pathway. Microscopically, BPC 157 counteracted brain (i.e., intracerebral hemorrhage with degenerative changes of cerebral and cerebellar neurons), heart (acute subendocardial infarct), lung (parenchymal hemorrhage), liver (congestion), kidney (congestion) and gastrointestinal (epithelium loss, hemorrhagic gastritis) lesions. In addition, this may have taken place along with the activation of specific molecular pathways. In conclusion, these findings clarify and extend the theory of cytoprotection, offer an approach to its practical application, and establish BPC 157 as a prospective cytoprotective treatment. Full article

(This article belongs to the Special Issue Frontiers in Pentadecapeptide BPC 157)

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14 pages, 1925 KiB

Open AccessEditor’s ChoiceArticle

Hydrogen Sulfide Inhibits TMPRSS2 in Human Airway Epithelial Cells: Implications for SARS-CoV-2 Infection

by Giulia Pozzi, Elena Masselli, Giuliana Gobbi, Prisco Mirandola, Luis Taborda-Barata, Luca Ampollini, Paolo Carbognani, Cristina Micheloni, Francesco Corazza, Daniela Galli, Cecilia Carubbi and Marco Vitale

Biomedicines 2021, 9(9), 1273; https://doi.org/10.3390/biomedicines9091273 - 20 Sep 2021

Cited by 22 | Viewed by 3184

Abstract

The COVID-19 pandemic has now affected around 190 million people worldwide, accounting for more than 4 million confirmed deaths. Besides ongoing global vaccination, finding protective and therapeutic strategies is an urgent clinical need. SARS-CoV-2 mostly infects the host organism via the respiratory system, [...] Read more.

The COVID-19 pandemic has now affected around 190 million people worldwide, accounting for more than 4 million confirmed deaths. Besides ongoing global vaccination, finding protective and therapeutic strategies is an urgent clinical need. SARS-CoV-2 mostly infects the host organism via the respiratory system, requiring angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) to enter target cells. Therefore, these surface proteins are considered potential druggable targets. Hydrogen sulfide (H₂S) is a gasotransmitter produced by several cell types and is also part of natural compounds, such as sulfurous waters that are often inhaled as low-intensity therapy and prevention in different respiratory conditions. H₂S is a potent biological mediator, with anti-oxidant, anti-inflammatory, and, as more recently shown, also anti-viral activities. Considering that respiratory epithelial cells can be directly exposed to H₂S by inhalation, here we tested the in vitro effects of H₂S-donors on TMPRSS2 and ACE2 expression in human upper and lower airway epithelial cells. We showed that H₂S significantly reduces the expression of TMPRSS2 without modifying ACE2 expression both in respiratory cell lines and primary human upper and lower airway epithelial cells. Results suggest that inhalational exposure of respiratory epithelial cells to natural H₂S sources may hinder SARS-CoV-2 entry into airway epithelial cells and, consequently, potentially prevent the virus from spreading into the lower respiratory tract and the lung. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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14 pages, 1691 KiB

Open AccessEditor’s ChoiceArticle

Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells

by Bianca Maria Rotoli, Amelia Barilli, Rossana Visigalli, Francesca Ferrari and Valeria Dall’Asta

Biomedicines 2021, 9(9), 1220; https://doi.org/10.3390/biomedicines9091220 - 14 Sep 2021

Cited by 27 | Viewed by 4058

Abstract

Background. Emerging evidences suggest that in severe COVID-19, multi-organ failure is associated with a hyperinflammatory state (the so-called “cytokine storm”) in combination with the development of a prothrombotic state. The central role of endothelial dysfunction in the pathogenesis of the disease is to [...] Read more.

Background. Emerging evidences suggest that in severe COVID-19, multi-organ failure is associated with a hyperinflammatory state (the so-called “cytokine storm”) in combination with the development of a prothrombotic state. The central role of endothelial dysfunction in the pathogenesis of the disease is to date accepted, but the precise mechanisms underlying the associated coagulopathy remain unclear. Whether the alterations in vascular homeostasis directly depend upon the SARS-CoV-2 infection of endothelial cells or, rather, occur secondarily to the activation of the inflammatory response is still a matter of debate. Here, we address the effect of the SARS-CoV-2 spike S1 protein on the activation of human lung microvascular endothelial cells (HLMVEC). In particular, the existence of an endothelium-macrophage crosstalk in the response to the spike protein has been explored. Methods and Results. The effect of the spike protein is addressed in human lung microvascular endothelial cells (HLMVEC), either directly or after incubation with a conditioned medium (CM) of human monocyte-derived macrophages (MDM) previously activated by the spike S1 protein (CM-MDM). Both MDM and HLMVEC are activated in response to the S1 protein, with an increased expression of pro-inflammatory mediators. However, when HLMVEC are exposed to CM-MDM, an enhanced cell activation occurs in terms of the expression of adhesion molecules, pro-coagulant markers, and chemokines. Under this experimental condition, ICAM-1 and VCAM-1, the chemokines CXCL8/IL-8, CCL2/MCP1, and CXCL10/IP-10 as well as the protein tissue factor (TF) are markedly induced. Instead, a decrease of thrombomodulin (THBD) is observed. Conclusion. Our data suggest that pro-inflammatory mediators released by spike-activated macrophages amplify the activation of endothelial cells, likely contributing to the impairment of vascular integrity and to the development of a pro-coagulative endothelium. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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16 pages, 3488 KiB

Open AccessEditor’s ChoiceArticle

Target-Oriented Synthesis of Marine Coelenterazine Derivatives with Anticancer Activity by Applying the Heavy-Atom Effect

by Carla M. Magalhães, Patricia González-Berdullas, Diana Duarte, Ana Salomé Correia, José E. Rodríguez-Borges, Nuno Vale, Joaquim C. G. Esteves da Silva and Luís Pinto da Silva

Biomedicines 2021, 9(9), 1199; https://doi.org/10.3390/biomedicines9091199 - 11 Sep 2021

Cited by 22 | Viewed by 2372

Abstract

Photodynamic therapy (PDT) is an anticancer therapeutic modality with remarkable advantages over more conventional approaches. However, PDT is greatly limited by its dependence on external light sources. Given this, PDT would benefit from new systems capable of a light-free and intracellular photodynamic effect. [...] Read more.

Photodynamic therapy (PDT) is an anticancer therapeutic modality with remarkable advantages over more conventional approaches. However, PDT is greatly limited by its dependence on external light sources. Given this, PDT would benefit from new systems capable of a light-free and intracellular photodynamic effect. Herein, we evaluated the heavy-atom effect as a strategy to provide anticancer activity to derivatives of coelenterazine, a chemiluminescent single-molecule widespread in marine organisms. Our results indicate that the use of the heavy-atom effect allows these molecules to generate readily available triplet states in a chemiluminescent reaction triggered by a cancer marker. Cytotoxicity assays in different cancer cell lines showed a heavy-atom-dependent anticancer activity, which increased in the substituent order of hydroxyl < chlorine < bromine. Furthermore, it was found that the magnitude of this anticancer activity is also dependent on the tumor type, being more relevant toward breast and prostate cancer. The compounds also showed moderate activity toward neuroblastoma, while showing limited activity toward colon cancer. In conclusion, the present results indicate that the application of the heavy-atom effect to marine coelenterazine could be a promising approach for the future development of new and optimized self-activating and tumor-selective sensitizers for light-free PDT. Full article

(This article belongs to the Topic Photodynamic Therapy)

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20 pages, 9295 KiB

Open AccessEditor’s ChoiceArticle

Eradication of Mature Bacterial Biofilms with Concurrent Improvement in Chronic Wound Healing Using Silver Nanoparticle Hydrogel Treatment

by Hanif Haidari, Richard Bright, Sanjay Garg, Krasimir Vasilev, Allison J. Cowin and Zlatko Kopecki

Biomedicines 2021, 9(9), 1182; https://doi.org/10.3390/biomedicines9091182 - 08 Sep 2021

Cited by 36 | Viewed by 6680

Abstract

Biofilm-associated infections are a major cause of impaired wound healing. Despite the broad spectrum of anti-bacterial benefits provided by silver nanoparticles (AgNPs), these materials still cause controversy due to cytotoxicity and a lack of efficacy against mature biofilms. Herein, highly potent ultrasmall AgNPs [...] Read more.

Biofilm-associated infections are a major cause of impaired wound healing. Despite the broad spectrum of anti-bacterial benefits provided by silver nanoparticles (AgNPs), these materials still cause controversy due to cytotoxicity and a lack of efficacy against mature biofilms. Herein, highly potent ultrasmall AgNPs were combined with a biocompatible hydrogel with integrated synergistic functionalities to facilitate elimination of clinically relevant mature biofilms in-vivo combined with improved wound healing capacity. The delivery platform showed a superior release mechanism, reflected by high biocompatibility, hemocompatibility, and extended antibacterial efficacy. In vivo studies using the S. aureus wound biofilm model showed that the AgNP hydrogel (200 µg/g) was highly effective in eliminating biofilm infection and promoting wound repair compared to the controls, including silver sulfadiazine (Ag SD). Treatment of infected wounds with the AgNP hydrogel resulted in faster wound closure (46% closure compared to 20% for Ag SD) and accelerated wound re-epithelization (60% for AgNP), as well as improved early collagen deposition. The AgNP hydrogel did not show any toxicity to tissue and/or organs. These findings suggest that the developed AgNP hydrogel has the potential to be a safe wound treatment capable of eliminating infection and providing a safe yet effective strategy for the treatment of infected wounds. Full article

(This article belongs to the Special Issue New Advances in Complex Wound Management: Biofilms and Emerging Biotechnologies as Effective Therapies)

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10 pages, 1678 KiB

Open AccessEditor’s ChoiceArticle

Comparison of Outcomes between 3 Monthly Brolucizumab and Aflibercept Injections for Polypoidal Choroidal Vasculopathy

by Yoshiko Fukuda, Yoichi Sakurada, Mio Matsubara, Yuka Hasebe, Atsushi Sugiyama, Wataru Kikushima and Kenji Kashiwagi

Biomedicines 2021, 9(9), 1164; https://doi.org/10.3390/biomedicines9091164 - 05 Sep 2021

Cited by 30 | Viewed by 3155

Abstract

We compared the short-term outcomes between 3-monthly aflibercept and brolucizumab injections for treatment-naïve polypoidal choroidal vasculopathy (PCV). A total of 52 eyes were included. Patients received 3 monthly intravitreal aflibercept (n = 38) or intravitreal brolucizumab (n = 14). Indocyanine green [...] Read more.

We compared the short-term outcomes between 3-monthly aflibercept and brolucizumab injections for treatment-naïve polypoidal choroidal vasculopathy (PCV). A total of 52 eyes were included. Patients received 3 monthly intravitreal aflibercept (n = 38) or intravitreal brolucizumab (n = 14). Indocyanine green angiography (ICGA) was performed at baseline and at the 3-month visit. Selection of anti-VEGF agents depended on time. In the brolucizumab-treated group, best-corrected visual acuity (BCVA) improved from 0.27 ± 0.34 (log MAR unit) at baseline to 0.20 ± 0.24 at 3-month visit, which is comparable with the aflibercept-treated group (p = 0.87), after adjustment of confounding factors. Central retinal thickness significantly decreased by 43%−44% in both groups. Subfoveal choroidal thickness also significantly decreased by 20.5% during this interval in the brolucizumab-treated group, which was greater than the aflibercept-treated group. The complete resolution rate of polypoidal lesions on ICGA was significantly higher (p = 0.043) in the brolucizumab-treated group (78.6%) than in the aflibercept-treated group (42.1%). Intraocular inflammation was observed in 14.3% (2/14) in the brolucizumab-treated group only. In short-term follow-up, intravitreal injection of 3-monthly brolucizumab was comparable with aflibercept in terms of BCVA and morphological improvement along with higher resolution of polypoidal lesion(s) on ICGA. Full article

(This article belongs to the Special Issue Anti-angiogenesis Therapeutics in Cancer, Ocular and Skin Disorders)

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17 pages, 5717 KiB

Open AccessEditor’s ChoiceArticle

Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients

by Paolo Macor, Paolo Durigutto, Alessandro Mangogna, Rossana Bussani, Luca De Maso, Stefano D’Errico, Martina Zanon, Nicola Pozzi, Pier Luigi Meroni and Francesco Tedesco

Biomedicines 2021, 9(8), 1003; https://doi.org/10.3390/biomedicines9081003 - 12 Aug 2021

Cited by 43 | Viewed by 3147

Abstract

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to [...] Read more.

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG, and spike protein of SARS-CoV-2. Lung deposits of C1q, C4, C3, and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. FB deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on the hepatic artery and portal vein of the liver. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease and the contribution of the complement system to inflammation and tissue damage. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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15 pages, 2119 KiB

Open AccessEditor’s ChoiceArticle

Primary Tumor Sidedness, RAS and BRAF Mutations and MSI Status as Prognostic Factors in Patients with Colorectal Liver Metastases Treated with Surgery and Thermal Ablation: Results from the Amsterdam Colorectal Liver Met Registry (AmCORE)

by Madelon Dijkstra, Sanne Nieuwenhuizen, Robbert S. Puijk, Florentine E. F. Timmer, Bart Geboers, Evelien A. C. Schouten, Jip Opperman, Hester J. Scheffer, Jan J. J. de Vries, Kathelijn S. Versteeg, Birgit I. Lissenberg-Witte, M. Petrousjka van den Tol and Martijn R. Meijerink

Biomedicines 2021, 9(8), 962; https://doi.org/10.3390/biomedicines9080962 - 05 Aug 2021

Cited by 24 | Viewed by 3279

Abstract

The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, [...] Read more.

The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, and local tumor progression (LTP) following surgery and thermal ablation in patients with colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study included 520 patients, 774 procedures, and 2101 tumors undergoing local treatment (resection and/or thermal ablation) from 2000 to 2021. Outcomes following local treatment were analyzed for primary tumor sidedness of CRC, RAS, and BRAF mutations and MSI status. The Kaplan–Meier method was used to estimate local tumor progression-free survival (LTPFS), local control (LC), distant progression-free survival (DPFS), and overall survival (OS). Uni- and multivariable analyses were performed based on Cox proportional hazards model. The chi-square test was used to analyze complications. Complications (p = 0.485), OS (p = 0.252), LTPFS (p = 0.939), and LC (p = 0.423) was not associated with tumor-sidedness. Compared to right-sided colon cancer (CC) (reference HR 1.000), DPFS was superior for left-sided CC and rectal cancer (p = 0.018) with an HR for left-sided CC of 0.742 (95% CI, 0.596–0.923) and for RC of 0.760 (95% CI, 0.597–0.966). Regarding RAS mutations, no significant difference was found in OS (p = 0.116). DPFS (p = 0.001), LTPFS (p = 0.039), and LC (p = 0.025) were significantly lower in the RAS mutation group. Though no difference in LTPFS was found between RAS wildtype and RAS mutated CRLM following resection (p = 0.532), LTPFS was worse for RAS mutated tumors compared to RAS wildtype following thermal ablation (p = 0.037). OS was significantly lower in the BRAF mutation group (p < 0.001) and in the MSI group (p < 0.001) following local treatment, while both did not affect DPFS, LTPFS, and LC. This AmCORE based study suggests the necessity of wider margins to reduce LTP rates in patients with RAS mutated CRLM, especially for thermal ablation. Upfront knowledge regarding molecular biomarkers may contribute to improved oncological outcomes. Full article

(This article belongs to the Special Issue Colorectal Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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15 pages, 2345 KiB

Open AccessEditor’s ChoiceArticle

Persistent Endothelial Dysfunction in Post-Acute COVID-19 Syndrome: A Case-Control Study

by Pasquale Ambrosino, Ilenia Calcaterra, Antonio Molino, Pasquale Moretta, Roberta Lupoli, Giorgio Alfredo Spedicato, Antimo Papa, Andrea Motta, Mauro Maniscalco and Matteo Nicola Dario Di Minno

Biomedicines 2021, 9(8), 957; https://doi.org/10.3390/biomedicines9080957 - 04 Aug 2021

Cited by 61 | Viewed by 4924

Abstract

Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a [...] Read more.

Background: Endothelial dysfunction has a key role in the pathogenesis of coronavirus disease 2019 (COVID-19) and its disabling complications. We designed a case-control study to assess the alterations of endothelium-dependent flow-mediated dilation (FMD) among convalescent COVID-19 patients. Methods: COVID-19 patients referred to a Pulmonary Rehabilitation Unit within 2 months from swab test negativization were consecutively evaluated for inclusion and compared to controls matched for age, gender, and cardiovascular risk factors. Results: A total of 133 convalescent COVID-19 patients (81.2% males, mean age 61.6 years) and 133 matched controls (80.5% males, mean age 60.4 years) were included. A significantly lower FMD was documented in convalescent COVID-19 patients as compared to controls (3.2% ± 2.6 vs. 6.4% ± 4.1 p < 0.001), confirmed when stratifying the study population according to age and major clinical variables. Among cases, females exhibited significantly higher FMD values as compared to males (6.1% ± 2.9 vs. 2.5% ± 1.9, p < 0.001). Thus, no significant difference was observed between cases and controls in the subgroup analysis on females (6.1% ± 2.9 vs. 5.3% ± 3.4, p = 0.362). Among convalescent COVID-19 patients, FMD showed a direct correlation with arterial oxygen tension (rho = 0.247, p = 0.004), forced expiratory volume in 1 s (rho = 0.436, p < 0.001), forced vital capacity (rho = 0.406, p < 0.001), and diffusing capacity for carbon monoxide (rho = 0.280, p = 0.008). Overall, after adjusting for major confounders, a recent COVID-19 was a major and independent predictor of FMD values (β = −0.427, p < 0.001). Conclusions: Post-acute COVID-19 syndrome is associated with a persistent and sex-biased endothelial dysfunction, directly correlated with the severity of pulmonary impairment. Full article

(This article belongs to the Special Issue COVID-19 And Post-Acute COVID-19 Syndrome: From Pathophysiology to Novel Translational Applications)

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15 pages, 17550 KiB

Open AccessEditor’s ChoiceArticle

3D-Printed Ginsenoside Rb1-Loaded Mesoporous Calcium Silicate/Calcium Sulfate Scaffolds for Inflammation Inhibition and Bone Regeneration

by Cheng-Yu Chen, Ming-You Shie, Alvin Kai-Xing Lee, Yun-Ting Chou, Chun Chiang and Chun-Pin Lin

Biomedicines 2021, 9(8), 907; https://doi.org/10.3390/biomedicines9080907 - 28 Jul 2021

Cited by 17 | Viewed by 2739

Abstract

Bone defects are commonly found in the elderly and athletic population due to systemic diseases such as osteoporosis and trauma. Bone scaffolds have since been developed to enhance bone regeneration by acting as a biological extracellular scaffold for cells. The main advantage of [...] Read more.

Bone defects are commonly found in the elderly and athletic population due to systemic diseases such as osteoporosis and trauma. Bone scaffolds have since been developed to enhance bone regeneration by acting as a biological extracellular scaffold for cells. The main advantage of a bone scaffold lies in its ability to provide various degrees of structural support and growth factors for cellular activities. Therefore, we designed a 3D porous scaffold that can not only provide sufficient mechanical properties but also carry drugs and promote cell viability. Ginsenoside Rb1 (GR) is an extract from panax ginseng, which has been used for bone regeneration and repair since ancient Chinese history. In this study, we fabricated scaffolds using various concentrations of GR with mesoporous calcium silicate/calcium sulfate (MSCS) and investigated the scaffold’s physical and chemical characteristic properties. PrestoBlue, F-actin staining, and ELISA were used to demonstrate the effect of the GR-contained MSCS scaffold on cell proliferation, morphology, and expression of the specific osteogenic-related protein of human dental pulp stem cells (hDPSCs). According to our data, hDPSCs cultivated in GR-contained MSCS scaffold had preferable abilities of proliferation and higher expression of the osteogenic-related protein and could effectively inhibit inflammation. Finally, in vivo performance was assessed using histological results that revealed the GR-contained MSCS scaffolds were able to further achieve more effective hard tissue regeneration than has been the case in the past. Taken together, this study demonstrated that a GR-containing MSCS 3D scaffold could be used as a potential alternative for future bone tissue engineering studies and has good potential for clinical use. Full article

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

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12 pages, 2167 KiB

Open AccessEditor’s ChoiceArticle

Metformin Therapy Effects on the Expression of Sodium-Glucose Cotransporter 2, Leptin, and SIRT6 Levels in Pericoronary Fat Excised from Pre-Diabetic Patients with Acute Myocardial Infarction

by Celestino Sardu, Nunzia D’Onofrio, Michele Torella, Michele Portoghese, Simone Mureddu, Francesco Loreni, Franca Ferraraccio, Iacopo Panarese, Maria Consiglia Trotta, Gianluca Gatta, Marilena Galdiero, Ferdinando Carlo Sasso, Michele D’Amico, Marisa De Feo, Maria Luisa Balestrieri, Giuseppe Paolisso and Raffaele Marfella

Biomedicines 2021, 9(8), 904; https://doi.org/10.3390/biomedicines9080904 - 28 Jul 2021

Cited by 32 | Viewed by 2384

Abstract

Background and purpose: pericoronary fat over-inflammation might lead to the development and destabilization of coronary plaque in patients with pre-diabetes (PDM). Notably, pericoronary fat could over-express the sodium-glucose cotransporter 2 (SGLT2) and leptin, along with decreased sirtuin 6 (SIRT6) expression in PDM vs. [...] Read more.

Background and purpose: pericoronary fat over-inflammation might lead to the development and destabilization of coronary plaque in patients with pre-diabetes (PDM). Notably, pericoronary fat could over-express the sodium-glucose cotransporter 2 (SGLT2) and leptin, along with decreased sirtuin 6 (SIRT6) expression in PDM vs. normoglycemic (NG) patients undergoing coronary artery bypass grafting (CABG) for acute myocardial infarction (AMI). However, in the current study, we evaluated inflammatory markers, SGLT2, SIRT6, and leptin levels in pericoronary fat and, subsequently, 12-month prognosis comparing PDM to NG subjected to CABG for AMI. In addition, we evaluated in PDM patients the effects of metformin therapy on SIRT6 expression, leptin, and SGLT2 levels, and assessed its beneficial effect on nitrotyrosine and inflammatory cytokine levels. Methods: we studied AMI patients referred for CABG, divided into PDM and NG-patients. PDM patients were divided into never-metformin users and metformin users. Finally, we evaluated major adverse cardiac events (MACE) at a 12-month follow-up. Results: the MACE was 9.1% in all PDM and 3% in NG patients (p < 0.05). Metformin users presented a significantly lower MACE rate in PDM than never-metformin users (p < 0.05). PDM showed higher inflammatory cytokines, 3-nitrotyrosine levels, SGLT2, and leptin content, and decreased SIRT6 protein levels in pericoronary fat compared to NG-patients (p < 0.05). PDM never-metformin-users showed higher SGLT2 and leptin levels in pericoronary fat than current-metformin-users (p < 0.05). Conclusions: metformin therapy might ameliorate cardiovascular outcomes by reducing inflammatory parameters, SGLT2, and leptin levels, and finally improving SIRT6 levels in AMI-PDM patients treated with CABG. Full article

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

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19 pages, 6307 KiB

Open AccessEditor’s ChoiceArticle

Elastomeric Cardiowrap Scaffolds Functionalized with Mesenchymal Stem Cells-Derived Exosomes Induce a Positive Modulation in the Inflammatory and Wound Healing Response of Mesenchymal Stem Cell and Macrophage

by Juan Carlos Chachques, Chiara Gardin, Nermine Lila, Letizia Ferroni, Veronique Migonney, Celine Falentin-Daudre, Federica Zanotti, Martina Trentini, Giulia Brunello, Tiberio Rocca, Vincenzo Gasbarro and Barbara Zavan

Biomedicines 2021, 9(7), 824; https://doi.org/10.3390/biomedicines9070824 - 15 Jul 2021

Cited by 20 | Viewed by 3168

Abstract

A challenge in contractile restoration of myocardial scars is one of the principal aims in cardiovascular surgery. Recently, a new potent biological tool used within healing processes is represented by exosomes derived from mesenchymal stem cells (MSCs). These cells are the well-known extracellular [...] Read more.

A challenge in contractile restoration of myocardial scars is one of the principal aims in cardiovascular surgery. Recently, a new potent biological tool used within healing processes is represented by exosomes derived from mesenchymal stem cells (MSCs). These cells are the well-known extracellular nanovesicles released from cells to facilitate cell function and communication. In this work, a combination of elastomeric membranes and exosomes was obtained and tested as a bioimplant. Mesenchymal stem cells (MSCs) and macrophages were seeded into the scaffold (polycaprolactone) and filled with exosomes derived from MSCs. Cells were tested for proliferation with an MTT test, and for wound healing properties and macrophage polarization by gene expression. Moreover, morphological analyses of their ability to colonize the scaffolds surfaces have been further evaluated. Results confirm that exosomes were easily entrapped onto the surface of the elastomeric scaffolds, increasing the wound healing properties and collagen type I and vitronectin of the MSC, and improving the M2 phenotype of the macrophages, mainly thanks to the increase in miRNA124 and decrease in miRNA 125. We can conclude that the enrichment of elastomeric scaffolds functionalized with exosomes is as an effective strategy to improve myocardial regeneration. Full article

(This article belongs to the Special Issue Tissue Engineering in Cardiology)

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12 pages, 604 KiB

Open AccessEditor’s ChoiceArticle

Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-CoV-2

by Laura Pérez-Lago, Teresa Aldámiz-Echevarría, Rita García-Martínez, Leire Pérez-Latorre, Marta Herranz, Pedro J. Sola-Campoy, Julia Suárez-González, Carolina Martínez-Laperche, Iñaki Comas, Fernando González-Candelas, Pilar Catalán, Patricia Muñoz, Darío García de Viedma and on behalf of Gregorio Marañón Microbiology-ID COVID 19 Study Group

Biomedicines 2021, 9(7), 808; https://doi.org/10.3390/biomedicines9070808 - 13 Jul 2021

Cited by 25 | Viewed by 3300

Abstract

A successful Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant, B.1.1.7, has recently been reported in the UK, causing global alarm. Most likely, the new variant emerged in a persistently infected patient, justifying a special focus on these cases. Our aim in this [...] Read more.

A successful Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant, B.1.1.7, has recently been reported in the UK, causing global alarm. Most likely, the new variant emerged in a persistently infected patient, justifying a special focus on these cases. Our aim in this study was to explore certain clinical profiles involving severe immunosuppression that may help explain the prolonged persistence of viable viruses. We present three severely immunosuppressed cases (A, B, and C) with a history of lymphoma and prolonged SARS-CoV-2 shedding (2, 4, and 6 months), two of whom finally died. Whole-genome sequencing of 9 and 10 specimens from Cases A and B revealed extensive within-patient acquisition of diversity, 12 and 28 new single nucleotide polymorphisms, respectively, which suggests ongoing SARS-CoV-2 replication. This diversity was not observed for Case C after analysing 5 sequential nasopharyngeal specimens and one plasma specimen, and was only observed in one bronchoaspirate specimen, although viral viability was still considered based on constant low Ct values throughout the disease and recovery of the virus in cell cultures. The acquired viral diversity in Cases A and B followed different dynamics. For Case A, new single nucleotide polymorphisms were quickly fixed (13–15 days) after emerging as minority variants, while for Case B, higher diversity was observed at a slower emergence: fixation pace (1–2 months). Slower SARS-CoV-2 evolutionary pace was observed for Case A following the administration of hyperimmune plasma. This work adds knowledge on SARS-CoV-2 prolonged shedding in severely immunocompromised patients and demonstrates viral viability, noteworthy acquired intra-patient diversity, and different SARS-CoV-2 evolutionary dynamics in persistent cases. Full article

(This article belongs to the Special Issue Immunology in COVID-19 Disease: From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 2712 KiB

Open AccessEditor’s ChoiceArticle

The Gut Microbiota-Immunity Axis in ALS: A Role in Deciphering Disease Heterogeneity?

by Elena Niccolai, Vincenzo Di Pilato, Giulia Nannini, Simone Baldi, Edda Russo, Elisabetta Zucchi, Ilaria Martinelli, Marta Menicatti, Gianluca Bartolucci, Jessica Mandrioli and Amedeo Amedei

Biomedicines 2021, 9(7), 753; https://doi.org/10.3390/biomedicines9070753 - 29 Jun 2021

Cited by 27 | Viewed by 4580

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder with an unknown etiology and no effective treatment, and is characterized by large phenotypic heterogeneity, including variable sites, ages of symptom onset and rates of disease progression. Increasing data support the role of the microbiota-immunity [...] Read more.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder with an unknown etiology and no effective treatment, and is characterized by large phenotypic heterogeneity, including variable sites, ages of symptom onset and rates of disease progression. Increasing data support the role of the microbiota-immunity axis in the pathogenesis of neurodegenerative diseases. In the present study, we compared the inflammatory and microbiota profile of ALS patients with different clinical characteristics, with healthy family caregivers. Measuring a panel of 30 inflammatory cytokines in serum and fecal samples, we observed a distinct cytokine profile both at the systemic and intestinal level in patients compared to controls and even in patients with different clinical phenotypes and progression rates. The 16S targeted metagenome analysis revealed slight differences in patients compared to controls as well as in patients with slow progression, marked by the reduction of butyrate-producing bacteria and a decrease of the Firmicutes/Bacteroidetes ratio in ALS. Finally, the short chain fatty acid analysis did not show a different distribution among the groups. If confirmed in a larger number of patients, the inflammatory cytokine profile and the microbial composition could be appropriate biomarker candidates for deciphering ALS heterogeneity. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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33 pages, 29125 KiB

Open AccessEditor’s ChoiceArticle

BPC 157 Therapy and the Permanent Occlusion of the Superior Sagittal Sinus in Rat: Vascular Recruitment

by Slaven Gojkovic, Ivan Krezic, Hrvoje Vranes, Helena Zizek, Domagoj Drmic, Katarina Horvat Pavlov, Andrea Petrovic, Lovorka Batelja Vuletic, Marija Milavic, Suncana Sikiric, Irma Stilinovic, Mariam Samara, Mario Knezevic, Ivan Barisic, Ivica Sjekavica, Eva Lovric, Anita Skrtic, Sven Seiwerth and Predrag Sikiric

Biomedicines 2021, 9(7), 744; https://doi.org/10.3390/biomedicines9070744 - 28 Jun 2021

Cited by 24 | Viewed by 6526

Abstract

We show the complex syndrome of the occluded superior sagittal sinus, brain swelling and lesions and multiple peripheral organs lesions in rat. Recovery goes centrally and peripherally, with the stable gastric pentadecapeptide BPC 157, which alleviated peripheral vascular occlusion disturbances, rapidly activating alternative [...] Read more.

We show the complex syndrome of the occluded superior sagittal sinus, brain swelling and lesions and multiple peripheral organs lesions in rat. Recovery goes centrally and peripherally, with the stable gastric pentadecapeptide BPC 157, which alleviated peripheral vascular occlusion disturbances, rapidly activating alternative bypassing pathways. Assessments were gross recording, venography, ECG, pressure, microscopy, biochemistry. The increased pressure in the superior sagittal sinus, portal and caval hypertension, aortal hypotension, arterial and venous thrombosis, severe brain swelling and lesions (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus), particular veins (azygos, superior mesenteric, inferior caval) dysfunction, heart dysfunction, lung congestion as acute respiratory distress syndrome, kidney disturbances, liver failure, and hemorrhagic lesions in gastrointestinal tract were all assessed. Rats received BPC 157 medication (10 µg/kg, 10 ng/kg) intraperitoneally, intragastrically, or topically to the swollen brain at 1 min ligation-time, or at 15 min, 24 h and 48 h ligation-time. BPC 157 therapy rapidly attenuates the brain swelling, rapidly eliminates the increased pressure in the ligated superior sagittal sinus and the severe portal and caval hypertension and aortal hypotension, and rapidly recruits collateral vessels, centrally ((para)sagittal venous collateral circulation) and peripherally (left superior caval vein azygos vein-inferior caval vein). In conclusion, as shown by all assessments, BPC 157 acts against the permanent occlusion of the superior sagittal sinus and syndrome (i.e., brain, heart, lung, liver, kidney, gastrointestinal lesions, thrombosis), given at 1 min, 15 min, 24 h or 48 h ligation-time. BPC 157 therapy rapidly overwhelms the permanent occlusion of the superior sagittal sinus in rat. Full article

(This article belongs to the Special Issue Frontiers in Pentadecapeptide BPC 157)

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16 pages, 1984 KiB

Open AccessEditor’s ChoiceArticle

Clinical Assessment of Endothelial Function in Convalescent COVID-19 Patients Undergoing Multidisciplinary Pulmonary Rehabilitation

by Pasquale Ambrosino, Antonio Molino, Ilenia Calcaterra, Roberto Formisano, Silvia Stufano, Giorgio Alfredo Spedicato, Andrea Motta, Antimo Papa, Matteo Nicola Dario Di Minno and Mauro Maniscalco

Biomedicines 2021, 9(6), 614; https://doi.org/10.3390/biomedicines9060614 - 28 May 2021

Cited by 29 | Viewed by 3791

Abstract

Background: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). Methods: After swab test negativization, [...] Read more.

Background: Growing evidence points to a key role of endothelial dysfunction in the pathogenesis of COVID-19. In this study, we evaluated changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of convalescent COVID-19 patients undergoing pulmonary rehabilitation (PR). Methods: After swab test negativization, convalescent COVID-19 patients referring to a post-acute care facility for PR were consecutively screened for inclusion. Study procedures were performed at the time of hospitalization and discharge. Results: We enrolled 82 convalescent COVID-19 patients (85.4% males, mean age 60.4 years). After PR, a significant improvement in most pulmonary function tests and exercise capacity was documented. FMD changed from 2.48% ± 2.01 to 4.24% ± 2.81 (p < 0.001), corresponding to a 70.9% increase. Significantly higher changes in FMD were found in patients without a history of vascular events as compared to those with (+2.04% ± 2.30 vs. +0.61% ± 1.83, p = 0.013). Values of forced expiratory volume in 1 s (FEV₁%), forced vital capacity (FVC%) and diffusion capacity for carbon monoxide (DLCO%) significantly and directly correlated with FMD both at baseline and after PR. Patients with normal FEV₁% (≥80% predicted) during the overall study period or those normalizing FEV₁% after PR showed a more significant FMD change as compared to patients with persistently impaired FEV₁% (<80% predicted) (p for trend = 0.029). This finding was confirmed in a multivariate analysis. Conclusions: Clinically evaluated endothelial function improves after PR in convalescent COVID-19 patients. A direct and persistent association between the severity of pulmonary and vascular disease can be hypothesized. Endothelial function testing may be useful in the follow-up of convalescent COVID-19 patients. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target)

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29 pages, 10428 KiB

Open AccessEditor’s ChoiceArticle

Occlusion of the Superior Mesenteric Artery in Rats Reversed by Collateral Pathways Activation: Gastric Pentadecapeptide BPC 157 Therapy Counteracts Multiple Organ Dysfunction Syndrome; Intracranial, Portal, and Caval Hypertension; and Aortal Hypotension

by Mario Knezevic, Slaven Gojkovic, Ivan Krezic, Helena Zizek, Dominik Malekinusic, Borna Vrdoljak, Hrvoje Vranes, Tamara Knezevic, Ivan Barisic, Katarina Horvat Pavlov, Domagoj Drmic, Miro Staroveski, Antonija Djuzel, Zoran Rajkovic, Toni Kolak, Ivica Kocman, Eva Lovric, Marija Milavic, Suncana Sikiric, Ante Tvrdeic, Leonardo Patrlj, Sanja Strbe, Antonio Kokot, Alenka Boban Blagaic, Anita Skrtic, Sven Seiwerth and Predrag Sikiric Show full author list Hide full author list

Biomedicines 2021, 9(6), 609; https://doi.org/10.3390/biomedicines9060609 - 26 May 2021

Cited by 21 | Viewed by 3764

Abstract

Gastric pentadecapeptide BPC 157 therapy counteracts multiple organ dysfunction syndrome in rats, which have permanent occlusion of the superior mesenteric artery close to the abdominal aorta. Previously, when confronted with major vessel occlusion, its effect would rapidly activate collateral vessel pathways and resolve [...] Read more.

Gastric pentadecapeptide BPC 157 therapy counteracts multiple organ dysfunction syndrome in rats, which have permanent occlusion of the superior mesenteric artery close to the abdominal aorta. Previously, when confronted with major vessel occlusion, its effect would rapidly activate collateral vessel pathways and resolve major venous occlusion syndromes (Pringle maneuver ischemia, reperfusion, Budd–Chiari syndrome) in rats. This would overwhelm superior mesenteric artery permanent occlusion, and result in local, peripheral, and central disturbances. Methods: Assessments, for 30 min (gross recording, angiography, ECG, pressure, microscopy, biochemistry, and oxidative stress), included the portal hypertension, caval hypertension, and aortal hypotension, and centrally, the superior sagittal sinus hypertension; systemic arterial and venous thrombosis; ECG disturbances; MDA-tissue increase; and multiple organ lesions and disturbances, including the heart, lung, liver, kidney, and gastrointestinal tract, in particular, as well as brain (cortex (cerebral, cerebellar), hypothalamus/thalamus, hippocampus). BPC 157 therapy (/kg, abdominal bath) (10 µg, 10 ng) was given for a 1-min ligation time. Results: BPC 157 rapidly recruits collateral vessels (inferior anterior pancreaticoduodenal artery and inferior mesenteric artery) that circumvent occlusion and ascertains blood flow distant from the occlusion in the superior mesenteric artery. Portal and caval hypertension, aortal hypotension, and, centrally, superior sagittal sinus hypertension were attenuated or eliminated, and ECG disturbances markedly mitigated. BPC 157 therapy almost annihilated venous and arterial thrombosis. Multiple organ lesions and disturbances (i.e., heart, lung, liver, and gastrointestinal tract, in particular, as well as brain) were largely attenuated. Conclusions: Rats with superior mesenteric artery occlusion may additionally undergo BPC 157 therapy as full counteraction of vascular occlusion-induced multiple organ dysfunction syndrome. Full article

(This article belongs to the Special Issue Frontiers in Pentadecapeptide BPC 157)

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29 pages, 1854 KiB

Open AccessEditor’s ChoiceReview

Perspectives of Microscopy Methods for Morphology Characterisation of Extracellular Vesicles from Human Biofluids

by Mladenka Malenica, Marija Vukomanović, Mario Kurtjak, Valentina Masciotti, Simone dal Zilio, Silvio Greco, Marco Lazzarino, Vedrana Krušić, Marko Perčić, Ivana Jelovica Badovinac, Karmen Wechtersbach, Ivona Vidović, Vanja Baričević, Srećko Valić, Pero Lučin, Nika Kojc and Kristina Grabušić

Biomedicines 2021, 9(6), 603; https://doi.org/10.3390/biomedicines9060603 - 26 May 2021

Cited by 40 | Viewed by 7666

Abstract

Extracellular vesicles (EVs) are nanometric membranous structures secreted from almost every cell and present in biofluids. Because EV composition reflects the state of its parental tissue, EVs possess an enormous diagnostic/prognostic potential to reveal pathophysiological conditions. However, a prerequisite for such usage of [...] Read more.

Extracellular vesicles (EVs) are nanometric membranous structures secreted from almost every cell and present in biofluids. Because EV composition reflects the state of its parental tissue, EVs possess an enormous diagnostic/prognostic potential to reveal pathophysiological conditions. However, a prerequisite for such usage of EVs is their detailed characterisation, including visualisation which is mainly achieved by atomic force microscopy (AFM) and electron microscopy (EM). Here we summarise the EV preparation protocols for AFM and EM bringing out the main challenges in the imaging of EVs, both in their natural environment as biofluid constituents and in a saline solution after EV isolation. In addition, we discuss approaches for EV imaging and identify the potential benefits and disadvantages when different AFM and EM methods are applied, including numerous factors that influence the morphological characterisation, standardisation, or formation of artefacts. We also demonstrate the effects of some of these factors by using cerebrospinal fluid as an example of human biofluid with a simpler composition. Here presented comparison of approaches to EV imaging should help to estimate the current state in morphology research of EVs from human biofluids and to identify the most efficient pathways towards the standardisation of sample preparation and microscopy modes. Full article

(This article belongs to the Special Issue Feature Papers in "Biomedical Materials and Nanomedicine")

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15 pages, 1336 KiB

Open AccessEditor’s ChoiceArticle

Association of Calcitriol Supplementation with Reduced COVID-19 Mortality in Patients with Chronic Kidney Disease: A Population-Based Study

by Joaquim Oristrell, Joan Carles Oliva, Isaac Subirana, Enrique Casado, Didier Domínguez, Andrea Toloba, Patricia Aguilera, Joan Esplugues, Pilar Fafián and Maria Grau

Biomedicines 2021, 9(5), 509; https://doi.org/10.3390/biomedicines9050509 - 05 May 2021

Cited by 20 | Viewed by 5275

Abstract

Treatment with calcitriol, the hormonal form of vitamin D, has shown beneficial effects in experimental models of acute lung injury. In this study, we aimed to analyze the associations between calcitriol supplementation and the risk of SARS-CoV2 infection or COVID-19 mortality. Individuals ≥18 [...] Read more.

Treatment with calcitriol, the hormonal form of vitamin D, has shown beneficial effects in experimental models of acute lung injury. In this study, we aimed to analyze the associations between calcitriol supplementation and the risk of SARS-CoV2 infection or COVID-19 mortality. Individuals ≥18 years old living in Catalonia and supplemented with calcitriol from April 2019 to February 2020 were compared with propensity score matched controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality. Associations between calcitriol supplementation and outcome variables were analyzed using multivariable Cox proportional regression. A total of 8076 patients were identified as being on calcitriol treatment. Advanced chronic kidney disease and hypoparathyroidism were the most frequent reasons for calcitriol supplementation in our population. Calcitriol use was associated with reduced risk of SARS-CoV2 infection (HR 0.78 [CI 95% 0.64–0.94], p = 0.010), reduced risk of severe COVID-19 and reduced COVID-19 mortality (HR 0.57 (CI 95% 0.41–0.80), p = 0.001) in patients with advanced chronic kidney disease. In addition, an inverse association between mean daily calcitriol dose and COVID-19 severity or mortality was observed in treated patients, independently of renal function. Our findings point out that patients with advanced chronic kidney disease could benefit from calcitriol supplementation during the COVID-19 pandemic. Full article

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

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20 pages, 3744 KiB

Open AccessEditor’s ChoiceArticle

Alteration in the Cerebrospinal Fluid Lipidome in Parkinson’s Disease: A Post-Mortem Pilot Study

by Joaquín Fernández-Irigoyen, Paz Cartas-Cejudo, Marta Iruarrizaga-Lejarreta and Enrique Santamaría

Biomedicines 2021, 9(5), 491; https://doi.org/10.3390/biomedicines9050491 - 29 Apr 2021

Cited by 28 | Viewed by 4250

Abstract

Lipid metabolism is clearly associated to Parkinson’s disease (PD). Although lipid homeostasis has been widely studied in multiple animal and cellular models, as well as in blood derived from PD individuals, the cerebrospinal fluid (CSF) lipidomic profile in PD remains largely unexplored. In [...] Read more.

Lipid metabolism is clearly associated to Parkinson’s disease (PD). Although lipid homeostasis has been widely studied in multiple animal and cellular models, as well as in blood derived from PD individuals, the cerebrospinal fluid (CSF) lipidomic profile in PD remains largely unexplored. In this study, we characterized the post-mortem CSF lipidomic imbalance between neurologically intact controls (n = 10) and PD subjects (n = 20). The combination of dual extraction with ultra-performance liquid chromatography-electrospray ionization quadrupole-time-of-flight mass spectrometry (UPLC-ESI-qToF-MS/MS) allowed for the monitoring of 257 lipid species across all samples. Complementary multivariate and univariate data analysis identified that glycerolipids (mono-, di-, and triacylglycerides), saturated and mono/polyunsaturated fatty acids, primary fatty amides, glycerophospholipids (phosphatidylcholines, phosphatidylethanolamines), sphingolipids (ceramides, sphingomyelins), N-acylethanolamines and sterol lipids (cholesteryl esters, steroids) were significantly increased in the CSF of PD compared to the control group. Interestingly, CSF lipid dyshomeostasis differed depending on neuropathological staging and disease duration. These results, despite the limitation of being obtained in a small population, suggest extensive CSF lipid remodeling in PD, shedding new light on the deployment of CSF lipidomics as a promising tool to identify potential lipid markers as well as discriminatory lipid species between PD and other atypical parkinsonisms. Full article

(This article belongs to the Special Issue Biomarkers in Neurodegenerative Diseases 2.0)

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22 pages, 3468 KiB

Open AccessEditor’s ChoiceArticle

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

by Giuseppe Caruso, Cristina Benatti, Nicolò Musso, Claudia G. Fresta, Annamaria Fidilio, Giorgia Spampinato, Nicoletta Brunello, Claudio Bucolo, Filippo Drago, Susan M. Lunte, Blake R. Peterson, Fabio Tascedda and Filippo Caraci

Biomedicines 2021, 9(5), 477; https://doi.org/10.3390/biomedicines9050477 - 26 Apr 2021

Cited by 27 | Viewed by 3732

Abstract

Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). In this [...] Read more.

Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of amyloid beta (Aβ) peptides from the brain. Correspondingly, in patients suffering from AD, defects in the capacity of peripheral macrophages to engulf Aβ have been reported. The effects of carnosine on macrophages and oxidative stress associated with AD are consequently of substantial interest for drug discovery in this field. In the present work, a model of stress induced by Aβ1-42 oligomers was investigated using a combination of methods including trypan blue exclusion, microchip electrophoresis with laser-induced fluorescence, flow cytometry, fluorescence microscopy, and high-throughput quantitative real-time PCR. These assays were used to assess the ability of carnosine to protect macrophage cells, modulate oxidative stress, and profile the expression of genes related to inflammation and pro- and antioxidant systems. We found that pre-treatment of RAW 264.7 macrophages with carnosine counteracted cell death and apoptosis induced by Aβ1-42 oligomers by decreasing oxidative stress as measured by levels of intracellular nitric oxide (NO)/reactive oxygen species (ROS) and production of peroxynitrite. This protective activity of carnosine was not mediated by modulation of the canonical inflammatory pathway but instead can be explained by the well-known antioxidant and free-radical scavenging activities of carnosine, enhanced macrophage phagocytic activity, and the rescue of fractalkine receptor CX3CR1. These new findings obtained with macrophages challenged with Aβ1-42 oligomers, along with the well-known multimodal mechanism of action of carnosine in vitro and in vivo, substantiate the therapeutic potential of this dipeptide in the context of AD pathology. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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14 pages, 1208 KiB

Open AccessEditor’s ChoiceArticle

Bromodomain and Extraterminal Protein Inhibitor, Apabetalone (RVX-208), Reduces ACE2 Expression and Attenuates SARS-Cov-2 Infection In Vitro

by Dean Gilham, Audrey L. Smith, Li Fu, Dalia Y. Moore, Abenaya Muralidharan, St. Patrick M. Reid, Stephanie C. Stotz, Jan O. Johansson, Michael Sweeney, Norman C. W. Wong, Ewelina Kulikowski and Dalia El-Gamal

Biomedicines 2021, 9(4), 437; https://doi.org/10.3390/biomedicines9040437 - 18 Apr 2021

Cited by 22 | Viewed by 4792

Abstract

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family [...] Read more.

Effective therapeutics are urgently needed to counter infection and improve outcomes for patients suffering from COVID-19 and to combat this pandemic. Manipulation of epigenetic machinery to influence viral infectivity of host cells is a relatively unexplored area. The bromodomain and extraterminal (BET) family of epigenetic readers have been reported to modulate SARS-CoV-2 infection. Herein, we demonstrate apabetalone, the most clinical advanced BET inhibitor, downregulates expression of cell surface receptors involved in SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2) and dipeptidyl-peptidase 4 (DPP4 or CD26) in SARS-CoV-2 permissive cells. Moreover, we show that apabetalone inhibits SARS-CoV-2 infection in vitro to levels comparable to those of antiviral agents. Taken together, our study supports further evaluation of apabetalone to treat COVID-19, either alone or in combination with emerging therapeutics. Full article

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

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18 pages, 3904 KiB

Open AccessEditor’s ChoiceArticle

Biofabrication of Gingival Fibroblast Cell-Laden Collagen/Strontium-Doped Calcium Silicate 3D-Printed Bi-Layered Scaffold for Osteoporotic Periodontal Regeneration

by Chen-Ying Wang, Yung-Cheng Chiu, Alvin Kai-Xing Lee, Yun-An Lin, Ping-Yi Lin and Ming-You Shie

Biomedicines 2021, 9(4), 431; https://doi.org/10.3390/biomedicines9040431 - 16 Apr 2021

Cited by 39 | Viewed by 3685

Abstract

Periodontal disease is a chronic disease that can lead to lose teeth and even tooth loss if left untreated. Osteoporosis and periodontal disease share similar characteristics and associated factors. Current regenerative techniques for periodontal diseases are ineffective in restoring complete function and structural [...] Read more.

Periodontal disease is a chronic disease that can lead to lose teeth and even tooth loss if left untreated. Osteoporosis and periodontal disease share similar characteristics and associated factors. Current regenerative techniques for periodontal diseases are ineffective in restoring complete function and structural integrity of periodontium due to unwanted migration of cells. In this study, we applied the concept of guided tissue regeneration (GTR) and 3D fabricated gingival fibroblast cell-laden collagen/strontium-doped calcium silicate (SrCS) bi-layer scaffold for periodontal regeneration. The results revealed that the bioactive SrCS had a hydroxyapatite formation on its surface after 14 days of immersion and that SrCS could release Sr and Si ions even after 6 months of immersion. In addition, in vitro results showed that the bi-layer scaffold enhanced secretion of FGF-2, BMP-2, and VEGF from human gingival fibroblasts and increased secretion of osteogenic-related proteins ALP, BSP, and OC from WJMSCs. In vivo studies using animal osteoporotic models showed that the 3D-printed cell-laden collagen/SrCS bi-layer scaffold was able to enhance osteoporotic bone regeneration, as seen from the increased Tb.Th and BV/TV ratio and the histological stains. In conclusion, it can be seen that the bi-layer scaffolds enhanced osteogenesis and further showed that guided periodontal regeneration could be achieved using collagen/SrCS scaffolds, thus making it a potential candidate for future clinical applications. Full article

(This article belongs to the Special Issue Tissue Engineering Updates and Perspective in Dentistry)

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18 pages, 3525 KiB

Open AccessEditor’s ChoiceArticle

Nicotinamide Ameliorates Amyloid Beta-Induced Oxidative Stress-Mediated Neuroinflammation and Neurodegeneration in Adult Mouse Brain

by Inayat Ur Rehman, Riaz Ahmad, Ibrahim Khan, Hyeon Jin Lee, Jungsung Park, Rahat Ullah, Myeong Jun Choi, Hee Young Kang and Myeong Ok Kim

Biomedicines 2021, 9(4), 408; https://doi.org/10.3390/biomedicines9040408 - 10 Apr 2021

Cited by 23 | Viewed by 3280

Abstract

Alzheimer’s disease (AD) is the most predominant age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregates of amyloid beta Aβ_1–42 and tau hyperphosphorylation in the brain. It is considered to be the primary cause of cognitive dysfunction. The aggregation of Aβ [...] Read more.

Alzheimer’s disease (AD) is the most predominant age-related neurodegenerative disease, pathologically characterized by the accumulation of aggregates of amyloid beta Aβ_1–42 and tau hyperphosphorylation in the brain. It is considered to be the primary cause of cognitive dysfunction. The aggregation of Aβ_1–42 leads to neuronal inflammation and apoptosis. Since vitamins are basic dietary nutrients that organisms need for their growth, survival, and other metabolic functions, in this study, the underlying neuroprotective mechanism of nicotinamide (NAM) Vitamin B3 against Aβ_1–42 -induced neurotoxicity was investigated in mouse brains. Intracerebroventricular (i.c.v.) Aβ_1–42 injection elicited neuronal dysfunctions that led to memory impairment and neurodegeneration in mouse brains. After 24 h after Aβ_1–42 injection, the mice were treated with NAM (250 mg/kg intraperitoneally) for 1 week. For biochemical and Western blot studies, the mice were directly sacrificed, while for confocal and “immunohistochemical staining”, mice were perfused transcardially with 4% paraformaldehyde. Our biochemical, immunofluorescence, and immunohistochemical results showed that NAM can ameliorate neuronal inflammation and apoptosis by reducing oxidative stress through lowering malondialdehyde and 2,7-dichlorofluorescein levels in an Aβ_1–42-injected mouse brains, where the regulation of p-JNK further regulated inflammatory marker proteins (TNF-α, IL-1β, transcription factor NF-kB) and apoptotic marker proteins (Bax, caspase 3, PARP1). Furthermore, NAM + Aβ treatment for 1 week increased the amount of survival neurons and reduced neuronal cell death in Nissl staining. We also analyzed memory dysfunction via behavioral studies and the analysis showed that NAM could prevent Aβ_1–42 -induced memory deficits. Collectively, the results of this study suggest that NAM may be a potential preventive and therapeutic candidate for Aβ_1–42 -induced reactive oxygen species (ROS)-mediated neuroinflammation, neurodegeneration, and neurotoxicity in an adult mouse model. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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13 pages, 504 KiB

Open AccessEditor’s ChoiceArticle

Atherosclerotic Plaque Fissuration and Clinical Outcomes in Pre-Diabetics vs. Normoglycemics Patients Affected by Asymptomatic Significant Carotid Artery Stenosis at 2 Years of Follow-Up: Role of microRNAs Modulation: The ATIMIR Study

by Celestino Sardu, Pietro Modugno, Gaetano Castellano, Lucia Scisciola, Michelangela Barbieri, Lella Petrella, Mara Fanelli, Gabriella Macchia, Eugenio Caradonna, Massimo Massetti, Giuseppe Paolisso and Raffaele Marfella

Biomedicines 2021, 9(4), 401; https://doi.org/10.3390/biomedicines9040401 - 08 Apr 2021

Cited by 20 | Viewed by 2542

Abstract

Atherosclerotic plaque instability and rupture in patients with asymptomatic carotid artery stenosis (ACAS) is a leading cause of major adverse cardiac events (MACE). This could be mainly evidenced in patients with pre-diabetes. Indeed, the altered glucose homeostasis and insulin resistance could cause over-inflammation [...] Read more.

Atherosclerotic plaque instability and rupture in patients with asymptomatic carotid artery stenosis (ACAS) is a leading cause of major adverse cardiac events (MACE). This could be mainly evidenced in patients with pre-diabetes. Indeed, the altered glucose homeostasis and insulin resistance could cause over-inflammation of atherosclerotic plaque, favoring its conversion to unstable phenotype with rupture and MACE. Notably, metformin therapy reducing the metabolic distress and the inflammatory burden could reduce MACE in ACAS patients with pre-diabetes. In this setting, the microRNAs (miRs) could be used as molecular biomarkers of atherosclerosis progression, plaque rupture, and worse prognosis in normoglycemics (NG) versus pre-diabetics metformin users (PDMU) versus pre-diabetics non-metformin users (PDNMU). However, our study aimed to investigate a wide miRNA panel in peripheral blood exosomes from patients with ACAS divided in NG versus PDMU versus PDNMU, and to associate the circulating miRNA expression profiles with MACE at 2 years of follow-up after endarterectomy. The study included 234 patients with ACAS divided into NG (n = 125), PDNMU (n = 73), and PDMU (n = 36). The miRs’ expression profiles of circulating exosomes were determined at baseline and at 2 years of follow-up by Affymetrix microarrays from the patients’ plasma samples from any study cohort. Then we collected and analyzed MACE at 2 years of follow-up in NG versus PDMU versus PDNMU. Prediabetics versus NG had over-inflammation (p < 0.05) and over expressed miR-24 and miR-27 at baseline. At 2 years of follow-up, PDNMU versus NG, PDMU versus NG, and PDNMU versus PDMU over-expressed inflammatory markers and miR-24, miR-27, miR-100, miR-126, and miR-133 (p < 0.05). Finally, at the end of follow-up, we observed a significant difference about MACE comparing PDNMU versus NG (n = 27 (36.9%) versus n = 8 (6.4%); p < 0.05), PDNMU versus PDMU (n = 27 (36.9%) versus n = 6 (16.6%); p < 0.05); and PDMU versus NG (n = 6 (16.6%) versus n = 8 (6.4%); p < 0.05). Admission glucose values (HR (hazard ratio) 1.020, CI (confidence of interval) 95% (1.001–1.038), p = 0.029), atheromatous carotid plaque (HR 5.373, CI 95% (1.251–11.079), p = 0.024), and miR-24 (HR 3.842, CI 95% (1.768–19.222), p = 0.011) predicted MACE at 2 years of follow-up. Specific circulating miRs could be over-expressed in pre-diabetics and specifically in PDNMU versus PDMU after endarterectomy. MiR24, hyperglycemia, and atheromatous plaque could predict MACE at 2 years of follow-up. Full article

(This article belongs to the Special Issue microRNAs as Biomarkers of Cardiovascular Diseases)

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20 pages, 3666 KiB

Open AccessEditor’s ChoiceArticle

Absence of Cold-Inducible RNA-Binding Protein (CIRP) Promotes Angiogenesis and Regeneration of Ischemic Tissue by Inducing M2-Like Macrophage Polarization

by Matthias Kübler, Sebastian Beck, Silvia Fischer, Philipp Götz, Konda Kumaraswami, Hellen Ishikawa-Ankerhold, Manuel Lasch and Elisabeth Deindl

Biomedicines 2021, 9(4), 395; https://doi.org/10.3390/biomedicines9040395 - 07 Apr 2021

Cited by 13 | Viewed by 4188

Abstract

Cold-inducible RNA-binding protein (CIRP) is an intracellular RNA-chaperone and extracellular promoter of inflammation, which is increasingly expressed and released under conditions of hypoxia and cold stress. The functional relevance of CIRP for angiogenesis and regeneration of ischemic muscle tissue has never been investigated [...] Read more.

Cold-inducible RNA-binding protein (CIRP) is an intracellular RNA-chaperone and extracellular promoter of inflammation, which is increasingly expressed and released under conditions of hypoxia and cold stress. The functional relevance of CIRP for angiogenesis and regeneration of ischemic muscle tissue has never been investigated and is the topic of the present study. We investigated the role of CIRP employing CIRP deficient mice along with a hindlimb model of ischemia-induced angiogenesis. 1 and 7 days after femoral artery ligation or sham operation, gastrocnemius muscles of CIRP-deficient and wildtype mice were isolated and processed for (immuno-) histological analyses. CIRP deficient mice showed decreased ischemic tissue damage as evidenced by Hematoxylin and Eosin staining, whereas angiogenesis was enhanced as demonstrated by increased capillary/muscle fiber ratio and number of proliferating endothelial (CD31⁺/BrdU⁺) cells on day 7 after surgery. Moreover, CIRP deficiency resulted in a reduction of total leukocyte count (CD45⁺), neutrophils (myeloperoxidase, MPO⁺), neutrophil extracellular traps (NETs) (MPO⁺/CitH3⁺), and inflammatory M1-like polarized macrophages (CD68⁺/MRC1^-), whereas the number of tissue regenerating M2-like polarized macrophages (CD68⁺/MRC1^-) was increased in ischemic tissue samples. In summary, we show that the absence of CIRP ameliorates angiogenesis and regeneration of ischemic muscle tissue, most likely by influencing macrophage polarization in direction to regenerative M2-like macrophages. Full article

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

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22 pages, 3466 KiB

Open AccessEditor’s ChoiceArticle

Mesothelin Expression in Human Tumors: A Tissue Microarray Study on 12,679 Tumors

by Sören Weidemann, Pauline Gagelmann, Natalia Gorbokon, Maximilian Lennartz, Anne Menz, Andreas M. Luebke, Martina Kluth, Claudia Hube-Magg, Niclas C. Blessin, Christoph Fraune, Katharina Möller, Christian Bernreuther, Patrick Lebok, Till S. Clauditz, Frank Jacobsen, Jakob R. Izbicki, Kristina Jansen, Guido Sauter, Ria Uhlig, Waldemar Wilczak, Stefan Steurer, Sarah Minner, Eike Burandt, Rainer H. Krech, David Dum, Till Krech, Andreas H. Marx and Ronald Simon Show full author list Hide full author list

Biomedicines 2021, 9(4), 397; https://doi.org/10.3390/biomedicines9040397 - 07 Apr 2021

Cited by 46 | Viewed by 5858

Abstract

Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor [...] Read more.

Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage (p < 0.0001) and metastasis (p < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN’s prognostic relevance appears to be limited. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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20 pages, 2667 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

by Bruno Rizzuti, Fedora Grande, Filomena Conforti, Ana Jimenez-Alesanco, Laura Ceballos-Laita, David Ortega-Alarcon, Sonia Vega, Hugh T. Reyburn, Olga Abian and Adrian Velazquez-Campoy

Biomedicines 2021, 9(4), 375; https://doi.org/10.3390/biomedicines9040375 - 02 Apr 2021

Cited by 52 | Viewed by 4821

Abstract

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either [...] Read more.

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design. Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease. However, its low in vivo bioavailability calls for modifications to its molecular structure. In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model. Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, K_i = 11 μM). Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145). The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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11 pages, 1096 KiB

Open AccessEditor’s ChoiceArticle

Brain Metabolic Correlates of Persistent Olfactory Dysfunction after SARS-Cov2 Infection

by Maria Isabella Donegani, Alberto Miceli, Matteo Pardini, Matteo Bauckneht, Silvia Chiola, Michele Pennone, Cecilia Marini, Federico Massa, Stefano Raffa, Giulia Ferrarazzo, Dario Arnaldi, Gianmario Sambuceti, Flavio Nobili and Silvia Morbelli

Biomedicines 2021, 9(3), 287; https://doi.org/10.3390/biomedicines9030287 - 12 Mar 2021

Cited by 35 | Viewed by 3757

Abstract

We aimed to evaluate the brain hypometabolic signature of persistent isolated olfactory dysfunction after SARS-CoV-2 infection. Twenty-two patients underwent whole-body [¹⁸F]-FDG PET, including a dedicated brain acquisition at our institution between May and December 2020 following their recovery after SARS-Cov2 infection. [...] Read more.

We aimed to evaluate the brain hypometabolic signature of persistent isolated olfactory dysfunction after SARS-CoV-2 infection. Twenty-two patients underwent whole-body [¹⁸F]-FDG PET, including a dedicated brain acquisition at our institution between May and December 2020 following their recovery after SARS-Cov2 infection. Fourteen of these patients presented isolated persistent hyposmia (smell diskettes olfaction test was used). A voxel-wise analysis (using Statistical Parametric Mapping software version 8 (SPM8)) was performed to identify brain regions of relative hypometabolism in patients with hyposmia with respect to controls. Structural connectivity of these regions was assessed (BCB toolkit). Relative hypometabolism was demonstrated in bilateral parahippocampal and fusiform gyri and in left insula in patients with respect to controls. Structural connectivity maps highlighted the involvement of bilateral longitudinal fasciculi. This study provides evidence of cortical hypometabolism in patients with isolated persistent hyposmia after SARS-Cov2 infection. [¹⁸F]-FDG PET may play a role in the identification of long-term brain functional sequelae of COVID-19. Full article

(This article belongs to the Special Issue Brain Injury and Neurodegeneration: Molecular, Functional, and Translational Approach)

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20 pages, 5515 KiB

Open AccessEditor’s ChoiceArticle

Asiatic Acid Prevents Cognitive Deficits by Inhibiting Calpain Activation and Preserving Synaptic and Mitochondrial Function in Rats with Kainic Acid-Induced Seizure

by Cheng-Wei Lu, Tzu-Yu Lin, Tai-Long Pan, Pei-Wen Wang, Kuan-Ming Chiu, Ming-Yi Lee and Su-Jane Wang

Biomedicines 2021, 9(3), 284; https://doi.org/10.3390/biomedicines9030284 - 10 Mar 2021

Cited by 19 | Viewed by 3028

Abstract

Cognitive impairment is not only associated with seizures but also reported as an adverse effect of antiepileptic drugs. Thus, new molecules that can ameliorate seizures and maintain satisfactory cognitive function should be developed. The antiepileptic potential of asiatic acid, a triterpene derived from [...] Read more.

Cognitive impairment is not only associated with seizures but also reported as an adverse effect of antiepileptic drugs. Thus, new molecules that can ameliorate seizures and maintain satisfactory cognitive function should be developed. The antiepileptic potential of asiatic acid, a triterpene derived from the medicinal herb Centella asiatica, has already been demonstrated; however, its role in epilepsy-related cognitive deficits is yet to be determined. In this study, we evaluated the effects of asiatic acid on cognitive deficits in rats with kainic acid (KA)-induced seizure and explored the potential mechanisms underlying these effects. Our results revealed that asiatic acid administrated intraperitoneally 30 min prior to KA (15 mg/kg) injection ameliorated seizures and significantly improved KA-induced memory deficits, as demonstrated by the results of the Morris water maze test. In addition, asiatic acid ameliorated neuronal damage, inhibited calpain activation, and increased protein kinase B (AKT) activation in the hippocampus of KA-treated rats. Asiatic acid also increased the levels of synaptic proteins and the number of synaptic vesicles as well as attenuated mitochondrial morphology damage in the hippocampus of KA-treated rats. Furthermore, proteomic and Western blot analyses of hippocampal synaptosomes revealed that asiatic acid reversed KA-induced changes in mitochondria function-associated proteins, including lipoamide dehydrogenase, glutamate dehydrogenase 1 (GLUD1), ATP synthase (ATP5A), and mitochondrial deacetylase sirtuin-3 (SIRT3). Our data suggest that asiatic acid can prevent seizures and improve cognitive impairment in KA-treated rats by reducing hippocampal neuronal damage through the inhibition of calpain activation and the elevation of activated AKT, coupled with an increase in synaptic and mitochondrial function. Full article

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

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17 pages, 4761 KiB

Open AccessEditor’s ChoiceArticle

Neuronal Differentiation from Induced Pluripotent Stem Cell-Derived Neurospheres by the Application of Oxidized Alginate-Gelatin-Laminin Hydrogels

by Thomas Distler, Ines Lauria, Rainer Detsch, Clemens M. Sauter, Farina Bendt, Julia Kapr, Stephan Rütten, Aldo R. Boccaccini and Ellen Fritsche

Biomedicines 2021, 9(3), 261; https://doi.org/10.3390/biomedicines9030261 - 05 Mar 2021

Cited by 21 | Viewed by 4976

Abstract

Biodegradable hydrogels that promote stem cell differentiation into neurons in three dimensions (3D) are highly desired in biomedical research to study drug neurotoxicity or to yield cell-containing biomaterials for neuronal tissue repair. Here, we demonstrate that oxidized alginate-gelatin-laminin (ADA-GEL-LAM) hydrogels facilitate neuronal differentiation [...] Read more.

Biodegradable hydrogels that promote stem cell differentiation into neurons in three dimensions (3D) are highly desired in biomedical research to study drug neurotoxicity or to yield cell-containing biomaterials for neuronal tissue repair. Here, we demonstrate that oxidized alginate-gelatin-laminin (ADA-GEL-LAM) hydrogels facilitate neuronal differentiation and growth of embedded human induced pluripotent stem cell (hiPSC) derived neurospheres. ADA-GEL and ADA-GEL-LAM hydrogels exhibiting a stiffness close to ~5 kPa at initial cell culture conditions of 37 °C were prepared. Laminin supplemented ADA-GEL promoted an increase in neuronal differentiation in comparison to pristine ADA-GEL, with enhanced neuron migration from the neurospheres to the bulk 3D hydrogel matrix. The presence of laminin in ADA-GEL led to a more than two-fold increase in the number of neurospheres with migrated neurons. Our findings suggest that laminin addition to oxidized alginate—gelatin hydrogel matrices plays a crucial role to tailor oxidized alginate-gelatin hydrogels suitable for 3D neuronal cell culture applications. Full article

(This article belongs to the Special Issue Hydrogels for Biomedical Application)

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14 pages, 2820 KiB

Open AccessEditor’s ChoiceArticle

Retinal Microvascular Impairment in COVID-19 Bilateral Pneumonia Assessed by Optical Coherence Tomography Angiography

by Jorge González-Zamora, Valentina Bilbao-Malavé, Elsa Gándara, Anna Casablanca-Piñera, Claudia Boquera-Ventosa, Manuel F. Landecho, Javier Zarranz-Ventura and Alfredo García-Layana

Biomedicines 2021, 9(3), 247; https://doi.org/10.3390/biomedicines9030247 - 02 Mar 2021

Cited by 41 | Viewed by 3640

Abstract

The purpose of this study was to evaluate the presence of retinal and microvascular alterations in COVID-19 patients with bilateral pneumonia due to SARS-COV-2 that required hospital admission and compare this with a cohort of age- and sex-matched controls. COVID-19 bilateral pneumonia patients [...] Read more.

The purpose of this study was to evaluate the presence of retinal and microvascular alterations in COVID-19 patients with bilateral pneumonia due to SARS-COV-2 that required hospital admission and compare this with a cohort of age- and sex-matched controls. COVID-19 bilateral pneumonia patients underwent retinal imaging 14 days after hospital discharge with structural optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) measurements. Vessel density (VD) and foveal avascular zone (FAZ) area were evaluated in the superficial, deep capillary plexus (SCP, DCP), and choriocapillaris (CC). After exclusion criteria, only one eye per patient was selected, and 50 eyes (25 patients and 25 controls) were included in the analysis. COVID-19 patients presented significantly thinner ganglion cell layer (GCL) (p = 0.003) and thicker retinal nerve fiber layer (RNFL) compared to controls (p = 0.048), and this RNFL thickening was greater in COVID-19 cases with cotton wool spots (CWS), when compared with patients without CWS (p = 0.032). In both SCP and DCP, COVID-19 patients presented lower VD in the foveal region (p < 0.001) and a greater FAZ area than controls (p = 0.007). These findings suggest that thrombotic and inflammatory phenomena could be happening in the retina of COVID-19 patients. Further research is warranted to analyze the longitudinal evolution of these changes over time as well as their correlation with disease severity. Full article

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

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17 pages, 2859 KiB

Open AccessEditor’s ChoiceArticle

Obesity Affects HDL Metabolism, Composition and Subclass Distribution

by Julia T. Stadler, Sonja Lackner, Sabrina Mörkl, Athina Trakaki, Hubert Scharnagl, Andrea Borenich, Willibald Wonisch, Harald Mangge, Sieglinde Zelzer, Nathalie Meier-Allard, Sandra J. Holasek and Gunther Marsche

Biomedicines 2021, 9(3), 242; https://doi.org/10.3390/biomedicines9030242 - 27 Feb 2021

Cited by 36 | Viewed by 5068

Abstract

Background: Obesity increases the risk of coronary heart disease, partly due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol levels. Functional impairment of HDL may contribute to the increased cardiovascular mortality, but the effect [...] Read more.

Background: Obesity increases the risk of coronary heart disease, partly due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol levels. Functional impairment of HDL may contribute to the increased cardiovascular mortality, but the effect of obesity on composition, structure, and function of HDL is not well understood. Design and Methods: We determined HDL composition, HDL subclass distribution, parameters of HDL function, and activities of most important enzymes involved in lipoprotein remodeling, including lecithin–cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) in relatively young normal weight (n = 26), overweight (n = 22), and obese (n = 20) women. Results: Obesity (body mass index (BMI) ≥ 30) was associated with noticeable changes in LCAT and CETP activities and altered HDL composition, such as decreased apolipoprotein A-I, cholesterol, and phospholipid content, while pro-inflammatory HDL serum amyloid a content was increased. We observed a marked shift towards smaller HDL subclasses in obesity linked to lower anti-oxidative capacity of serum. LCAT activity, HDL subclass distribution, and HDL-cholesterol were associated with soluble leptin receptor, adiponectin, and liver enzyme activities. Of note, most of these alterations were only seen in obese women but not in overweight women. Conclusions: Obesity markedly affects HDL metabolism, composition, and subclass distribution linked to changes in liver and adipose tissue. HDL dysfunction may contribute to increased cardiovascular risk in obesity. Full article

(This article belongs to the Special Issue Lipids and Lipoproteins in Health and Disease: Focus on Targeting Atherosclerosis)

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25 pages, 19829 KiB

Open AccessEditor’s ChoiceArticle

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

by Jutta Ries, Abbas Agaimy, Falk Wehrhan, Christoph Baran, Stella Bolze, Eva Danzer, Silke Frey, Jonathan Jantsch, Tobias Möst, Maike Büttner-Herold, Claudia Wickenhauser, Marco Kesting and Manuel Weber

Biomedicines 2021, 9(2), 194; https://doi.org/10.3390/biomedicines9020194 - 16 Feb 2021

Cited by 24 | Viewed by 3070

Abstract

Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. [...] Read more.

Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (p_E = 0.001; p_S = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions. Full article

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

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33 pages, 4488 KiB

Open AccessEditor’s ChoiceReview

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

by Luca Fania, Dario Didona, Francesca Romana Di Pietro, Sofia Verkhovskaia, Roberto Morese, Giovanni Paolino, Michele Donati, Francesca Ricci, Valeria Coco, Francesco Ricci, Eleonora Candi, Damiano Abeni and Elena Dellambra

Biomedicines 2021, 9(2), 171; https://doi.org/10.3390/biomedicines9020171 - 09 Feb 2021

Cited by 90 | Viewed by 14504

Abstract

Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen’s disease) or an invasive form. A significant cSCC risk factor is advanced [...] Read more.

Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ (e.g., Bowen’s disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management. Full article

(This article belongs to the Special Issue Skin Cancer: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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28 pages, 1799 KiB

Open AccessEditor’s ChoiceReview

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

by Marianna Carinci, Bianca Vezzani, Simone Patergnani, Peter Ludewig, Katrin Lessmann, Tim Magnus, Ilaria Casetta, Maura Pugliatti, Paolo Pinton and Carlotta Giorgi

Biomedicines 2021, 9(2), 169; https://doi.org/10.3390/biomedicines9020169 - 09 Feb 2021

Cited by 39 | Viewed by 5957

Abstract

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen [...] Read more.

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis. Full article

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

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