Biomedicines

16 pages, 1306 KiB

Open AccessArticle

Stress Hormone Corticosterone Controls Metabolic Mitochondrial Performance and Inflammatory Signaling of In Vitro Cultured Sertoli Cells

by Ana M. Silva, Carina T. Ribeiro, Raquel L. Bernardino, Ivana Jarak, Rui A. Carvalho, M. A. Pereira-Sampaio, Diogo B. de Souza, Marco G. Alves and Pedro F. Oliveira

Biomedicines 2022, 10(9), 2331; https://doi.org/10.3390/biomedicines10092331 - 19 Sep 2022

Cited by 1 | Viewed by 1977

Abstract

Stress, as a physiological response, is a major factor that affects several processes, including reproductive functions. The main hormonal players of stress are cortisol (humans) and corticosterone (rodents). Sertoli cells (SCs), as key contributors for the testicular homeostasis maintenance, are extensively challenged by [...] Read more.

Stress, as a physiological response, is a major factor that affects several processes, including reproductive functions. The main hormonal players of stress are cortisol (humans) and corticosterone (rodents). Sertoli cells (SCs), as key contributors for the testicular homeostasis maintenance, are extensively challenged by different hormones, with glucocorticoid corticosterone being the signaling modulator that may impact these cells at different levels. We aimed to characterize how corticosterone modulates SCs energy balance, putting the mitochondrial performance and signaling output in perspective as the cells can disperse to the surroundings. TM4 mouse SCs were cultured in the absence and presence of corticosterone (in nM: 20, 200, and 2000). Cells were assessed for extracellular metabolic fluxes, mitochondrial performance (cell respirometry, mitochondrial potential, and mitochondrial complex expressions and activities), and the expression of androgen and corticosteroid receptors, as well as interleukine-6 (IL-6) and glutathione content. Corticosterone presented a biphasic impact on the extracellular fluxes of metabolites. Low sub-physiological corticosterone stimulated the glycolytic activity of SCs. Still, no alterations were perceived for lactate and alanine production. However, the lactate/alanine ratio was decreased in a dose-dependent mode, opposite to the mitochondrial complex II activity rise and concurrent with the decrease of IL-6 expression levels. Our results suggest that corticosterone finely tuned the energetic profile of mouse SCs, with sub-physiological concentrations promoting glycolytic expenditure, without translating into cell redox power and mitochondrial respiratory chain performance. Corticosterone deeply impacted the expression of the pro-inflammatory IL-6, which may alter cell-to-cell communication in the testis, in the last instance and impact of the spermatogenic performance. Full article

(This article belongs to the Special Issue Hormonal Regulation of Male Reproductive System)

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24 pages, 1296 KiB

Open AccessSystematic Review

Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma

by Luigino Calzetta, Marina Aiello, Annalisa Frizzelli, Elena Pistocchini, Beatrice Ludovica Ritondo, Paola Rogliani and Alfredo Chetta

Biomedicines 2022, 10(9), 2330; https://doi.org/10.3390/biomedicines10092330 - 19 Sep 2022

Cited by 6 | Viewed by 2436

Abstract

Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really [...] Read more.

Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really change the natural course of asthma, including disease remission. Considering the highly heterogeneous nature of asthma, there is a strong need for innovative medications that selectively target components of the inflammatory cascade. The aim of this review was to systematically assess current investigational agents in Phase I and II randomised controlled trials (RCTs) over the last five years. Sixteen classes of novel therapeutic options were identified from 19 RCTs. Drugs belonging to different classes, such as the anti-interleukin (IL)-4Rα inhibitors, anti-IL-5 monoclonal antibodies (mAbs), anti-IL-17A mAbs, anti-thymic stromal lymphopoietin (TSLP) mAbs, epithelial sodium channel (ENaC) inhibitors, bifunctional M₃ receptor muscarinic antagonists/β₂-adrenoceptor agonists (MABAs), and anti-Fel d 1 mAbs, were found to be effective in the treatment of asthma, with lung function being the main assessed outcome across the RCTs. Several novel investigational molecules, particularly biologics, seem promising as future disease-modifying agents; nevertheless, further larger studies are required to confirm positive results from Phase I and II RCTs. Full article

(This article belongs to the Special Issue Pathogenesis and Novel Therapeutics in Asthma)

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14 pages, 3350 KiB

Open AccessArticle

Detection of SARS-CoV-2 Using Reverse Transcription Helicase Dependent Amplification and Reverse Transcription Loop-Mediated Amplification Combined with Lateral Flow Assay

by Aleksandra Anna Zasada, Ewa Mosiej, Marta Prygiel, Maciej Polak, Karol Wdowiak, Kamila Formińska, Robert Ziółkowski, Kamil Żukowski, Kasper Marchlewicz, Adam Nowiński, Julia Nowińska, Waldemar Rastawicki and Elżbieta Malinowska

Biomedicines 2022, 10(9), 2329; https://doi.org/10.3390/biomedicines10092329 - 19 Sep 2022

Cited by 13 | Viewed by 2010

Abstract

Rapid and accurate detection and identification of pathogens in clinical samples is essential for all infection diseases. However, in the case of epidemics, it plays a key role not only in the implementation of effective therapy but also in limiting the spread of [...] Read more.

Rapid and accurate detection and identification of pathogens in clinical samples is essential for all infection diseases. However, in the case of epidemics, it plays a key role not only in the implementation of effective therapy but also in limiting the spread of the epidemic. In this study, we present the application of two nucleic acid isothermal amplification methods—reverse transcription helicase dependent amplification (RT-HDA) and reverse transcription loop-mediated amplification (RT-LAMP)—combined with lateral flow assay as the tools for the rapid detection of SARS-CoV-2, the etiological agent of COVID-19, which caused the ongoing global pandemic. In order to optimize the RT-had, the LOD was 3 genome copies per reaction for amplification conducted for 10–20 min, whereas for RT-LAMP, the LOD was 30–300 genome copies per reaction for a reaction conducted for 40 min. No false-positive results were detected for RT-HDA conducted for 10 to 90 min, but false-positive results occurred when RT-LAMP was conducted for longer than 40 min. We concluded that RT-HDA combined with LFA is more sensitive than RT-LAMP, and it is a good alternative for the development of point-of-care tests for SARS-CoV-2 detection as this method is simple, inexpensive, practical, and does not require qualified personnel to perform the test and interpret its results. Full article

(This article belongs to the Special Issue High Sensitivity Lateral Flow Assays for SARS-CoV-2 and Other Infections)

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23 pages, 5297 KiB

Open AccessArticle

Dexamethasone-Induced Adipose Tissue Redistribution and Metabolic Changes: Is Gene Expression the Main Factor? An Animal Model of Chronic Hypercortisolism

by Flaviane de Fatima Silva, Ayumi Cristina Medeiros Komino, Sandra Andreotti, Gabriela Boltes Reis, Rennan Oliveira Caminhotto, Richardt Gama Landgraf, Gabriel Orefice de Souza, Rogerio Antonio Laurato Sertié, Sheila Collins, Jose Donato, Jr. and Fabio Bessa Lima

Biomedicines 2022, 10(9), 2328; https://doi.org/10.3390/biomedicines10092328 - 19 Sep 2022

Cited by 3 | Viewed by 2066

Abstract

Chronic hypercortisolism has been associated with the development of several metabolic alterations, mostly caused by the effects of chronic glucocorticoid (GC) exposure over gene expression. The metabolic changes can be partially explained by the GC actions on different adipose tissues (ATs), leading to [...] Read more.

Chronic hypercortisolism has been associated with the development of several metabolic alterations, mostly caused by the effects of chronic glucocorticoid (GC) exposure over gene expression. The metabolic changes can be partially explained by the GC actions on different adipose tissues (ATs), leading to central obesity. In this regard, we aimed to characterize an experimental model of iatrogenic hypercortisolism in rats with significant AT redistribution. Male Wistar rats were distributed into control (CT) and GC-treated, which received dexamethasone sodium phosphate (0.5 mg/kg/day) by an osmotic minipump, for 4 weeks. GC-treated rats reproduced several characteristics observed in human hypercortisolism/Cushing’s syndrome, such as HPA axis inhibition, glucose intolerance, insulin resistance, dyslipidemia, hepatic lipid accumulation, and AT redistribution. There was an increase in the mesenteric (meWAT), perirenal (prWAT), and interscapular brown (BAT) ATs mass, but a reduction of the retroperitoneal (rpWAT) mass compared to CT rats. Overexpressed lipolytic and lipogenic gene profiles were observed in white adipose tissue (WAT) of GC rats as BAT dysfunction and whitening. The AT remodeling in response to GC excess showed more importance than the increase of AT mass per se, and it cannot be explained just by GC regulation of gene transcription. Full article

(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)

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9 pages, 711 KiB

Open AccessArticle

Clinical Performance of Self-Collected Nasal Swabs and Antigen Rapid Tests for SARS-CoV-2 Detection in Resource-Poor Settings

by Nádia Sitoe, Júlia Sambo, Nédio Mabunda, Neuza Nguenha, Jorfélia Chilaúle, Júlio Rafael, Anésio Macicame, Imelda Chelene, Chishamiso Mudenyanga, Jillian Sacks, Sofia Viegas, Osvaldo Loquiha and Ilesh Jani

Biomedicines 2022, 10(9), 2327; https://doi.org/10.3390/biomedicines10092327 - 19 Sep 2022

Cited by 1 | Viewed by 1723

Abstract

Background: In resource-poor countries, antigen-based rapid tests (Ag-RDTs) performed at primary healthcare and community settings improved access to SARS-CoV-2 diagnostics. However, the technical skills and biosafety requirements inherent to nasopharyngeal and oropharyngeal (OP) specimens limit the scale-up of SARS-CoV-2 testing. The collection of [...] Read more.

Background: In resource-poor countries, antigen-based rapid tests (Ag-RDTs) performed at primary healthcare and community settings improved access to SARS-CoV-2 diagnostics. However, the technical skills and biosafety requirements inherent to nasopharyngeal and oropharyngeal (OP) specimens limit the scale-up of SARS-CoV-2 testing. The collection of nasal-swabs is programmatically viable, but its performance has not been evaluated in resource-poor settings. Methods: We first evaluated the performance of SteriPack self-collected nasal swabs for the detection of SARS-CoV-2 by real-time PCR in 1498 consecutively enrolled patients with suspected infection. Next, we evaluated the clinical performance of three nasal swab-based Ag-RDTs against real-time PCR on OP specimens. Results: The sensitivity of nasal swabs was 80.6% [95% CI: 75.3–85.2%] compared to OP specimens. There was a good correlation (r = 0.58; p < 0.0001) between Ct values of 213 positive cases obtained using nasal and OP swabs. Our findings show sensitivities of 79.7% [95% CI: 73.3–85.1%] for Panbio COVID-19 Ag-RDT, 59.6% [95% CI: 55.2–63.8%] for COVIOS Ag-RDT, and 78.0% [95% CI: 73.5–82.0%] for the LumiraDx SARS-CoV-2 Ag-RDT. Conclusions: In our setting, the COVIOS Ag-RDT did not meet WHO requirements. Nasal swab-based Ag-RDTs for SARS-CoV-2 detection constitute a viable and accurate diagnostic option in resource-poor settings. Full article

(This article belongs to the Special Issue High Sensitivity Lateral Flow Assays for SARS-CoV-2 and Other Infections)

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23 pages, 5211 KiB

Open AccessArticle

Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing

by Lucía Pérez-Regidor, Joan Guzmán-Caldentey, Nils Oberhauser, Carmen Punzón, Balázs Balogh, José R. Pedro, Eva Falomir, Alessandra Nurisso, Péter Mátyus, J. Carlos Menéndez, Belén de Andrés, Manuel Fresno and Sonsoles Martín-Santamaría

Biomedicines 2022, 10(9), 2326; https://doi.org/10.3390/biomedicines10092326 - 19 Sep 2022

Cited by 2 | Viewed by 2270

Abstract

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 [...] Read more.

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Discovery and Development in Spain)

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Graphical abstract

19 pages, 987 KiB

Open AccessReview

Trends and Perspectives of Biological Drug Approvals by the FDA: A Review from 2015 to 2021

by Alexander C. Martins, Mariana Y. Oshiro, Fernando Albericio, Beatriz G. de la Torre, Gustavo José V. Pereira and Rodrigo V. Gonzaga

Biomedicines 2022, 10(9), 2325; https://doi.org/10.3390/biomedicines10092325 - 19 Sep 2022

Cited by 13 | Viewed by 3886

Abstract

Despite belonging to a relatively new class of pharmaceuticals, biological drugs have been used since the 1980s, when they brought about a breakthrough in the treatment of chronic diseases, especially cancer. They conquered a large space in the pipeline of the pharmaceutical industry [...] Read more.

Despite belonging to a relatively new class of pharmaceuticals, biological drugs have been used since the 1980s, when they brought about a breakthrough in the treatment of chronic diseases, especially cancer. They conquered a large space in the pipeline of the pharmaceutical industry and boosted the innovation portfolio and arsenal of therapeutic compounds available. Here, we report on biological drug approvals by the US Food and Drug Administration (FDA) from 2015 to 2021. The number of drugs included in this class grew over this period, totaling 90 approvals, with an average of 13 authorizations per year. This figure contrasts with previous periods, which registered between 2 and 8 approvals per year. We highlight the great potential and advantages of biological drugs. In this context, these therapeutics show high efficacy and high selectivity, and they have brought about a significant increase in patient survival and a reduction of adverse reactions. The development and production of biopharmaceuticals pose a major challenge because these processes require cutting-edge technology, thereby making the drugs very expensive. However, we believe that, in the near future, biological medicines will be more accessible and new drugs belonging to this class will become available as new technologies emerge. Such advances will enhance the production of these biopharmaceuticals, thereby making the process increasingly profitable and less expensive, thereby bringing about greater availability of these drugs. Full article

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

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13 pages, 1589 KiB

Open AccessArticle

The JAK1/2 Inhibitor Baricitinib Mitigates the Spike-Induced Inflammatory Response of Immune and Endothelial Cells In Vitro

by Amelia Barilli, Rossana Visigalli, Francesca Ferrari, Giulia Recchia Luciani, Maurizio Soli, Valeria Dall’Asta and Bianca Maria Rotoli

Biomedicines 2022, 10(9), 2324; https://doi.org/10.3390/biomedicines10092324 - 19 Sep 2022

Cited by 6 | Viewed by 1737

Abstract

The purpose of this study was to examine the effect of the JAK-STAT inhibitor baricitinib on the inflammatory response of human monocyte-derived macrophages (MDM) and endothelial cells upon exposure to the spike S1 protein from SARS-CoV-2. The effect of the drug has been [...] Read more.

The purpose of this study was to examine the effect of the JAK-STAT inhibitor baricitinib on the inflammatory response of human monocyte-derived macrophages (MDM) and endothelial cells upon exposure to the spike S1 protein from SARS-CoV-2. The effect of the drug has been evaluated on the release of cytokines and chemokines from spike-treated MDM, as well as on the activation of endothelial cells (HUVECs) after exposure to conditioned medium collected from spike-activated MDM. Results obtained indicate that, in MDM, baricitinib prevents the S1-dependent phosphorylation of STAT1 and STAT3, along with the induction of IP-10- and MCP-1 secretion; the release of IL-6 and TNFα is also reduced, while all other mediators tested (IL-1β, IL-8, RANTES, MIP-1α and MIP-1β) are not modified. Baricitinib is, instead, poorly effective on endothelial activation when HUVECs are exposed to supernatants from S1-activated macrophages; the induction of VCAM-1, indeed, is not affected by the drug, while that of ICAM-1 is only poorly inhibited. The drug, however, also exerts protective effects on the endothelium by limiting the expression of pro-inflammatory mediators, specifically IL-6, RANTES and IP-10. No effect of baricitinib has been observed on IL-8 synthesis and, consistently, on neutrophils chemiotaxis. Our in vitro findings reveal that the efficacy of baricitinib is limited, with effects mainly focused on the inhibition of the IL-6-mediated inflammatory loop. Full article

(This article belongs to the Special Issue Non-antiviral Agents for Treatment of COVID-19)

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11 pages, 1332 KiB

Open AccessArticle

Deep Learning for Bone Mineral Density and T-Score Prediction from Chest X-rays: A Multicenter Study

by Yoichi Sato, Norio Yamamoto, Naoya Inagaki, Yusuke Iesaki, Takamune Asamoto, Tomohiro Suzuki and Shunsuke Takahara

Biomedicines 2022, 10(9), 2323; https://doi.org/10.3390/biomedicines10092323 - 19 Sep 2022

Cited by 11 | Viewed by 3614

Abstract

Although the number of patients with osteoporosis is increasing worldwide, diagnosis and treatment are presently inadequate. In this study, we developed a deep learning model to predict bone mineral density (BMD) and T-score from chest X-rays, which are one of the most common, [...] Read more.

Although the number of patients with osteoporosis is increasing worldwide, diagnosis and treatment are presently inadequate. In this study, we developed a deep learning model to predict bone mineral density (BMD) and T-score from chest X-rays, which are one of the most common, easily accessible, and low-cost medical imaging examination methods. The dataset used in this study contained patients who underwent dual-energy X-ray absorptiometry (DXA) and chest radiography at six hospitals between 2010 and 2021. We trained the deep learning model through ensemble learning of chest X-rays, age, and sex to predict BMD using regression and T-score for multiclass classification. We assessed the following two metrics to evaluate the performance of the deep learning model: (1) correlation between the predicted and true BMDs and (2) consistency in the T-score between the predicted class and true class. The correlation coefficients for BMD prediction were hip = 0.75 and lumbar spine = 0.63. The areas under the curves for the T-score predictions of normal, osteopenia, and osteoporosis diagnoses were 0.89, 0.70, and 0.84, respectively. These results suggest that the proposed deep learning model may be suitable for screening patients with osteoporosis by predicting BMD and T-score from chest X-rays. Full article

(This article belongs to the Special Issue Artificial Intelligence in Biological and Biomedical Imaging 2.0)

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15 pages, 1755 KiB

Open AccessBrief Report

Retinol Binding Protein, Sunlight Hours, and the Influenza Virus-Specific Immune Response

by Nehali Patel, Rhiannon R. Penkert, Robert E. Sealy, Sherri L. Surman, Bart G. Jones, Karen Ringwald-Smith, A. Catharine Ross and Julia L. Hurwitz

Biomedicines 2022, 10(9), 2322; https://doi.org/10.3390/biomedicines10092322 - 19 Sep 2022

Cited by 3 | Viewed by 1984

Abstract

Healthy pediatric immune responses depend on adequate vitamin A and D levels. Relationships between solar ultraviolet B (UVB) radiation and vitamin D are well understood, while relationships between sunlight, vitamin A, and its serum escort, retinol binding protein (RBP), are not. A pediatric [...] Read more.

Healthy pediatric immune responses depend on adequate vitamin A and D levels. Relationships between solar ultraviolet B (UVB) radiation and vitamin D are well understood, while relationships between sunlight, vitamin A, and its serum escort, retinol binding protein (RBP), are not. A pediatric clinical study enrolled 2–8-year-old children at various times between September 2016 and March 2017, inclusive, in Memphis, Tennessee. A serum sample from each child was then assayed to examine the influence of season on vitamin levels. We found that RBP and RBP/retinol molar ratios decreased in winter months and RBP/retinol ratios correlated positively with the average daily sunlight hours per month. A food frequency questionnaire given to parents/guardians indicated a shift in dietary intake from plant-based foods to animal-based foods by children between winter and spring months. This translated to higher retinol and zinc (integral to RBP–transthyretin–retinol complexes) in the spring, perhaps explaining the seasonal influence on RBP/retinol. RBP and retinol were associated positively with IgG/IgM and IgA/IgM ratios. RBP and retinol, but not 25(OH)D, also correlated positively with influenza virus-specific antibodies. Retinol correlated negatively, while 25(OH)D correlated positively, with certain serum cytokine/chemokine levels. Significant differences in 25(OH)D, immunoglobulin ratios, and cytokines/chemokines were observed between black and white children. In sum, seasonal changes in dietary foods rich in retinol and zinc may have influenced RBP levels, which in turn influenced innate and adaptive immune responses. Results encourage routine monitoring and reporting of season, RBP, and vitamin levels in future clinical studies, as seasons may affect sunlight exposures, diet, vitamin levels, and immune protection against infectious disease. Full article

(This article belongs to the Special Issue Molecular Research in Infectious Diseases)

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19 pages, 8013 KiB

Open AccessArticle

Level of Amyloid-β (Aβ) Binding Leading to Differential Effects on Resting State Functional Connectivity in Major Brain Networks

by Eva Y. W. Cheung, Anson C. M. Chau, Yat-Fung Shea, Patrick K. C. Chiu, Joseph S. K. Kwan and Henry K. F. Mak

Biomedicines 2022, 10(9), 2321; https://doi.org/10.3390/biomedicines10092321 - 19 Sep 2022

Cited by 2 | Viewed by 1753

Abstract

Introduction: Amyloid-β protein (Aβ) is one of the biomarkers for Alzheimer’s disease (AD). The recent application of interhemispheric functional connectivity (IFC) in resting-state fMRI has been used as a non-invasive diagnostic tool for early dementia. In this study, we focused on the level [...] Read more.

Introduction: Amyloid-β protein (Aβ) is one of the biomarkers for Alzheimer’s disease (AD). The recent application of interhemispheric functional connectivity (IFC) in resting-state fMRI has been used as a non-invasive diagnostic tool for early dementia. In this study, we focused on the level of Aβ accumulated and its effects on the major functional networks, including default mode network (DMN), central executive network (CEN), salience network (SN), self-referential network (SRN) and sensory motor network (SMN). Methods: 58 participants (27 Hi Aβ (HiAmy) and 31 low Aβ (LowAmy)) and 25 healthy controls (HC) were recruited. [¹⁸F]flutemetamol PET/CT was performed for diseased groups, and MRI scanning was done for all participants. Voxel-by-voxel correlation analysis was done for both groups in all networks. Results: In HiAmy, IFC was reduced in all networks except SN. A negative correlation in DMN, CEN, SRN and SMN suggests high Aβ related to IFC reduction; However, a positive correlation in SN suggests high Aβ related to an increase in IFC. In LowAmy, IFC increased in CEN, SMN, SN and SRN. Positive correlation in all major brain networks. Conclusion: The level of Aβ accumulated demonstrated differential effects on IFC in various brain networks. As the treatment to reduce Aβ plaque deposition is available in the market, it may be an option for the HiAmy group to improve their IFC in major brain networks. Full article

(This article belongs to the Special Issue State of the Art: Prerequisites, Prevention and Treatment of Neurodegenerative Diseases)

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13 pages, 325 KiB

Open AccessReview

The Influence of SARS-CoV-2 Infection on Lipid Metabolism—The Potential Use of Lipid-Lowering Agents in COVID-19 Management

by Klaudia Kowalska, Zofia Sabatowska, Joanna Forycka, Ewelina Młynarska, Beata Franczyk and Jacek Rysz

Biomedicines 2022, 10(9), 2320; https://doi.org/10.3390/biomedicines10092320 - 18 Sep 2022

Cited by 11 | Viewed by 2771

Abstract

Several studies have indicated lipid metabolism alterations during COVID-19 infection, specifically a decrease in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) concentrations and an increase in triglyceride (TG) levels during the infection. However, a decline in triglycerides can also be observed in critical [...] Read more.

Several studies have indicated lipid metabolism alterations during COVID-19 infection, specifically a decrease in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) concentrations and an increase in triglyceride (TG) levels during the infection. However, a decline in triglycerides can also be observed in critical cases. A direct correlation can be observed between a decrease in serum cholesterol, HDL-C, LDL-C and TGs, and the severity of the disease; these laboratory findings can serve as potential markers for patient outcomes. The transmission of coronavirus increases proportionally with rising levels of cholesterol in the cell membrane. This is due to the fact that cholesterol increases the number of viral entry spots and the concentration of angiotensin-converting enzyme 2 (ACE2) receptor, crucial for viral penetration. Studies have found that lower HDL-C levels correspond with a higher susceptibility to SARS-CoV-2 infection and infections in general, while higher HDL-C levels were related to a lower risk of developing them. However, extremely high HDL-C levels in serum increase the risk of infectious diseases and is associated with a higher risk of cardiovascular events. Low HDL-C levels are already accepted as a marker for risk stratification in critical illnesses, and higher HDL-C levels prior to the infection is associated with a lower risk of death in older patients. The correlation between LDL-C levels and disease severity is still unclear. However, TG levels were significantly higher in non-surviving severe patients compared to those that survived; therefore, elevated TG-C levels in COVID-19 patients may be considered an indicator of uncontrolled inflammation and an increased risk of death. Full article

(This article belongs to the Special Issue Cardiovascular Diseases and COVID-19)

22 pages, 2925 KiB

Open AccessSystematic Review

Quantitative Measurement of Swallowing Performance Using Iowa Oral Performance Instrument: A Systematic Review and Meta-Analysis

by Raffaella Franciotti, Erica Di Maria, Michele D’Attilio, Giuseppe Aprile, Federica Giulia Cosentino and Vittoria Perrotti

Biomedicines 2022, 10(9), 2319; https://doi.org/10.3390/biomedicines10092319 - 18 Sep 2022

Cited by 10 | Viewed by 5013

Abstract

Swallowing is a complex but stereotyped motor activity aimed at serving two vital purposes: alimentary function and the protection of upper airways. Therefore, any impairment of the swallowing act can represent a significant clinical and personal problem that needs an accurate diagnosis by [...] Read more.

Swallowing is a complex but stereotyped motor activity aimed at serving two vital purposes: alimentary function and the protection of upper airways. Therefore, any impairment of the swallowing act can represent a significant clinical and personal problem that needs an accurate diagnosis by means of reliable and non-invasive techniques. Thus, a systematic review and meta-analysis was performed to investigate the reliability of the Iowa Oral Pressure Instrument (IOPI) in distinguishing healthy controls (HC) from patients affected by swallowing disorders or pathologies and conditions that imply dysphagia. A comprehensive search was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and using PubMed, Scopus, Web of Science, Cochrane, and Lilacs databases. Overall, 271 articles were identified and, after a three-step screening, 33 case-control and interventional studies reporting IOPI measurements were included. The methodological quality of the retrieved studies resulted in being at a low risk of bias. The meta-analysis on case-control studies showed that maximum tongue pressure (MIP) values were always higher in HC than in patients, with an overall effect of the MIP difference of 18.2 KPa (17.7–18.7 KPa CI). This result was also confirmed when the sample was split into adults and children, although the MIP difference between HC and patients was greater in children than in adults (21.0 vs. 15.4 KPa in the MIP mean difference overall effect, respectively). Tongue endurance (TE) showed conflicting results among studies, with an overall effect among studies near zero (0.7 s, 0.2–1.1 s CI) and a slight tendency toward higher TE values in HC than in patients. Among the intervention studies, MIP values were higher after treatment than before, with a better outcome after the experimental tongue training exercise than traditional treatments (the MIP mean difference overall effect was 10.8 and 2.3 KPa, respectively). In conclusion, MIP values can be considered as a reliable measure of swallowing function in adults and in children, with a more marked MIP difference between HC and patients for the children population. MIP measures in patients are also able to detect the best outcome on the tongue function after the training exercise compared to traditional training. Full article

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

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14 pages, 322 KiB

Open AccessReview

Transcriptomic Harmonization as the Way for Suppressing Cross-Platform Bias and Batch Effect

by Nicolas Borisov and Anton Buzdin

Biomedicines 2022, 10(9), 2318; https://doi.org/10.3390/biomedicines10092318 - 18 Sep 2022

Cited by 6 | Viewed by 2242

Abstract

(1) Background: Emergence of methods interrogating gene expression at high throughput gave birth to quantitative transcriptomics, but also posed a question of inter-comparison of expression profiles obtained using different equipment and protocols and/or in different series of experiments. Addressing this issue is challenging, [...] Read more.

(1) Background: Emergence of methods interrogating gene expression at high throughput gave birth to quantitative transcriptomics, but also posed a question of inter-comparison of expression profiles obtained using different equipment and protocols and/or in different series of experiments. Addressing this issue is challenging, because all of the above variables can dramatically influence gene expression signals and, therefore, cause a plethora of peculiar features in the transcriptomic profiles. Millions of transcriptomic profiles were obtained and deposited in public databases of which the usefulness is however strongly limited due to the inter-comparison issues; (2) Methods: Dozens of methods and software packages that can be generally classified as either flexible or predefined format harmonizers have been proposed, but none has become to the date the gold standard for unification of this type of Big Data; (3) Results: However, recent developments evidence that platform/protocol/batch bias can be efficiently reduced not only for the comparisons of limited transcriptomic datasets. Instead, instruments were proposed for transforming gene expression profiles into the universal, uniformly shaped format that can support multiple inter-comparisons for reasonable calculation costs. This forms a basement for universal indexing of all or most of all types of RNA sequencing and microarray hybridization profiles; (4) Conclusions: In this paper, we attempted to overview the landscape of modern approaches and methods in transcriptomic harmonization and focused on the practical aspects of their application. Full article

(This article belongs to the Special Issue Multiomics Approaches for Translational Medicine)

16 pages, 2144 KiB

Open AccessHypothesis

Therapeutic Neuromodulation toward a Critical State May Serve as a General Treatment Strategy

by Simon Arvin, Keisuke Yonehara and Andreas Nørgaard Glud

Biomedicines 2022, 10(9), 2317; https://doi.org/10.3390/biomedicines10092317 - 18 Sep 2022

Viewed by 2809

Abstract

Brain disease has become one of this century’s biggest health challenges, urging the development of novel, more effective treatments. To this end, neuromodulation represents an excellent method to modulate the activity of distinct neuronal regions to alleviate disease. Recently, the medical indications for [...] Read more.

Brain disease has become one of this century’s biggest health challenges, urging the development of novel, more effective treatments. To this end, neuromodulation represents an excellent method to modulate the activity of distinct neuronal regions to alleviate disease. Recently, the medical indications for neuromodulation therapy have expanded through the adoption of the idea that neurological disorders emerge from deficits in systems-level structures, such as brain waves and neural topology. Connections between neuronal regions are thought to fluidly form and dissolve again based on the patterns by which neuronal populations synchronize. Akin to a fire that may spread or die out, the brain’s activity may similarly hyper-synchronize and ignite, such as seizures, or dwindle out and go stale, as in a state of coma. Remarkably, however, the healthy brain remains hedged in between these extremes in a critical state around which neuronal activity maneuvers local and global operational modes. While it has been suggested that perturbations of this criticality could underlie neuropathologies, such as vegetative states, epilepsy, and schizophrenia, a major translational impact is yet to be made. In this hypothesis article, we dissect recent computational findings demonstrating that a neural network’s short- and long-range connections have distinct and tractable roles in sustaining the critical regime. While short-range connections shape the dynamics of neuronal activity, long-range connections determine the scope of the neuronal processes. Thus, to facilitate translational progress, we introduce topological and dynamical system concepts within the framework of criticality and discuss the implications and possibilities for therapeutic neuromodulation guided by topological decompositions. Full article

(This article belongs to the Special Issue Neuromodulation from Theory to Therapy)

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15 pages, 1869 KiB

Open AccessReview

Chloride Ions, Vascular Function and Hypertension

by Kenichi Goto and Takanari Kitazono

Biomedicines 2022, 10(9), 2316; https://doi.org/10.3390/biomedicines10092316 - 18 Sep 2022

Cited by 3 | Viewed by 3790

Abstract

Blood pressure is determined by cardiac output and systemic vascular resistance, and mediators that induce vasoconstriction will increase systemic vascular resistance and thus elevate blood pressure. While peripheral vascular resistance reflects a complex interaction of multiple factors, vascular ion channels and transporters play [...] Read more.

Blood pressure is determined by cardiac output and systemic vascular resistance, and mediators that induce vasoconstriction will increase systemic vascular resistance and thus elevate blood pressure. While peripheral vascular resistance reflects a complex interaction of multiple factors, vascular ion channels and transporters play important roles in the regulation of vascular tone by modulating the membrane potential of vascular cells. In vascular smooth muscle cells, chloride ions (Cl⁻) are a type of anions accumulated by anion exchangers and the anion–proton cotransporter system, and efflux of Cl⁻ through Cl⁻ channels depolarizes the membrane and thereby triggers vasoconstriction. Among these Cl⁻ regulatory pathways, emerging evidence suggests that upregulation of the Ca²⁺-activated Cl⁻ channel TMEM16A in the vasculature contributes to the increased vascular contractility and elevated blood pressure in hypertension. A robust accumulation of intracellular Cl⁻ in vascular smooth muscle cells through the increased activity of Na⁺–K⁺–2Cl⁻ cotransporter 1 (NKCC1) during hypertension has also been reported. Thus, the enhanced activity of both TMEM16A and NKCC1 could act additively and sequentially to increase vascular contractility and hence blood pressure in hypertension. In this review, we discuss recent findings regarding the role of Cl⁻ in the regulation of vascular tone and arterial blood pressure and its association with hypertension, with a particular focus on TMEM16A and NKCC1. Full article

(This article belongs to the Special Issue Animal Models for Study of Pathophysiological Mechanisms of Hypertension and Its Complications)

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13 pages, 2672 KiB

Open AccessArticle

Benzalkonium Chloride, Even at Low Concentrations, Deteriorates Intracellular Metabolic Capacity in Human Conjunctival Fibroblasts

by Yuri Tsugeno, Tatsuya Sato, Megumi Watanabe, Masato Furuhashi, Araya Umetsu, Yosuke Ida, Fumihito Hikage and Hiroshi Ohguro

Biomedicines 2022, 10(9), 2315; https://doi.org/10.3390/biomedicines10092315 - 18 Sep 2022

Cited by 4 | Viewed by 1925

Abstract

The objective of this study was to clarify the effects of benzalkonium chloride (BAC) on two-dimensional (2D) and three-dimensional (3D) cultures of human conjunctival fibroblast (HconF) cells, which are in vitro models replicating the epithelial barrier and the stromal supportive functions of the [...] Read more.

The objective of this study was to clarify the effects of benzalkonium chloride (BAC) on two-dimensional (2D) and three-dimensional (3D) cultures of human conjunctival fibroblast (HconF) cells, which are in vitro models replicating the epithelial barrier and the stromal supportive functions of the human conjunctiva. The cultured HconF cells were subjected to the following analyses in the absence and presence of 10⁻⁵% or 10⁻⁴% concentrations of BAC; (1) the barrier function of the 2D HconF monolayers, as determined by trans-endothelial electrical resistance (TEER) and FITC dextran permeability, (2) real-time metabolic analysis using an extracellular Seahorse flux analyzer, (3) the size and stiffness of 3D HconF spheroids, and (4) the mRNA expression of genes that encode for extracellular matrix (ECM) molecules including collagen (COL)1, 4 and 6, and fibronectin (FN), α-smooth muscle actin (α-SMA), ER stress related genes including the X-box binding protein-1 (XBP1), the spliced XBP1 (sXBP1) glucose regulator protein (GRP)78, GRP94, and the CCAAT/enhancer-binding protein homologous protein (CHOP), hypoxia inducible factor 1α (HIF1α), and Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α). In the presence of BAC, even at low concentrations at 10⁻⁵% or 10⁻⁴%, the maximal respiratory capacity, mitochondrial respiratory reserve, and glycolytic reserve of HconF cells were significantly decreased, although the barrier functions of 2D HconF monolayers, the physical properties of the 3D HconF spheroids, and the mRNA expression of the corresponding genes were not affected. The findings reported herein highlight the fact that BAC, even such low concentrations, may induce unfavorable adverse effects on the cellular metabolic capacity of the human conjunctiva. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Responses to Low-Intensity Exposures)

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10 pages, 4519 KiB

Open AccessArticle

Choroidal and Retinal Thicknesses in Type 2 Diabetes Mellitus with Moderate Diabetic Retinopathy Measured by Swept Source OCT

by Guisela Fernández-Espinosa, Elvira Orduna-Hospital, Ana Boned-Murillo, Maria Dolores Diaz-Barreda, Ana Sanchez-Cano, María Sopeña-Pinilla and Isabel Pinilla

Biomedicines 2022, 10(9), 2314; https://doi.org/10.3390/biomedicines10092314 - 18 Sep 2022

Cited by 5 | Viewed by 1724

Abstract

Background: To study choroidal thickness (CT) in type 2 diabetes mellitus (DM2) patients with moderate diabetic retinopathy (DR) and to correlate with changes in retinal thickness (RT) with swept-source OCT (SS-OCT) compared to healthy subjects. Methods: Fifty-four DM2 patients with moderate DR without [...] Read more.

Background: To study choroidal thickness (CT) in type 2 diabetes mellitus (DM2) patients with moderate diabetic retinopathy (DR) and to correlate with changes in retinal thickness (RT) with swept-source OCT (SS-OCT) compared to healthy subjects. Methods: Fifty-four DM2 patients with moderate DR without diabetic macular edema (DME) and 73 age-matched healthy subjects were evaluated using SS-OCT to measure changes in total RT and CT in the nine areas of the Early Treatment Diabetic Retinopathy Study (ETDRS) macular grid. Results: The mean age was 64.06 ± 11.98 years and 60.79 ± 8.62 years in the diabetic and control groups, respectively. Total RT showed statistically significant differences in the temporal inner area, with higher values in the DM2 group (p = 0.010). CT did not show differences between the groups. There was a significant negative correlation between RT and age in all of the outer ETDRS areas and a positive significant correlation in the central area for the DM2 group. There was also a negative significant correlation between CT and age in all of the ETDRS areas except for the inferior inner area. In the DM2 group, a negative correlation was observed between RT and CT in the central area (p = 0.039) and in both horizontal parafoveal areas (temporal inner, p = 0.028; nasal inner, p= 0.003). Conclusion: DM2 patients with moderate DR have no changes with regard to CT. Both CT and RT decreased with age in DM2, showing a negative correlation between these factors in the central and horizontal parafoveal areas of the ETDRS grid. Full article

(This article belongs to the Special Issue Pathological Mechanisms in Diabetes 2.0)

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22 pages, 1110 KiB

Open AccessReview

Biodegradation of Dental Resin-Based Composite—A Potential Factor Affecting the Bonding Effect: A Narrative Review

by Xinwei Guo, Yiyan Yu, Shang Gao, Zhimin Zhang and Hongyan Zhao

Biomedicines 2022, 10(9), 2313; https://doi.org/10.3390/biomedicines10092313 - 18 Sep 2022

Cited by 10 | Viewed by 3015

Abstract

In recent years, although resin composite has played an important role in the restoration of tooth defects, it still has several disadvantages, including being biodegraded by saliva, bacteria and other enzymes in the oral cavity, which may result in repair failure. This factor [...] Read more.

In recent years, although resin composite has played an important role in the restoration of tooth defects, it still has several disadvantages, including being biodegraded by saliva, bacteria and other enzymes in the oral cavity, which may result in repair failure. This factor is not conducive to the long-term survival of the prosthesis in the mouth. In this article, we review the causes, influencing factors and prevention methods of resin biodegradation. Biodegradation is mainly caused by esterase in saliva and bacteria, which breaks the ester bond in resin and causes the release of monomers. The mechanical properties of the prosthesis can then be affected. Meanwhile, cathepsin and MMPs are activated on the bonding surface, which may decompose the dentin collagen. In addition, neutrophils and residual water on the bonding surface can also aggravate biodegradation. Currently, the primary methods to prevent biodegradation involve adding antibacterial agents to resin, inhibiting the activity of MMPs and enhancing the crosslinking of collagen fibers. All of the above indicates that in the preparation and adhesion of resin materials, attention should be paid to the influence of biodegradation to improve the prosthesis’s service life in the complex environment of the oral cavity. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

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15 pages, 1504 KiB

Open AccessArticle

Photoreactive Coating Material as an Effective and Durable Antimicrobial Composite in Reducing Bacterial Load on Surfaces in Livestock

by Ádám Kerek, Mátyás Sasvári, Ákos Jerzsele, Zoltán Somogyi, László Janovák, Zsolt Abonyi-Tóth and Imre Dékány

Biomedicines 2022, 10(9), 2312; https://doi.org/10.3390/biomedicines10092312 - 17 Sep 2022

Cited by 1 | Viewed by 1443

Abstract

Titanium dioxide (TiO₂) is a well-known photocatalytic compound that can be used to effectively reduce the presence of pathogens in human and animal hospitals via ROS release. The aim of this study was to investigate the efficacy of a polymer-based composite [...] Read more.

Titanium dioxide (TiO₂) is a well-known photocatalytic compound that can be used to effectively reduce the presence of pathogens in human and animal hospitals via ROS release. The aim of this study was to investigate the efficacy of a polymer-based composite layer containing TiO₂ and zinc oxide (ZnO) against Escherichia coli (E. coli) of animal origin. We showed that the photocatalyst coating caused a significant (p < 0.001) reduction in pathogen numbers compared to the control with an average reduction of 94% over 30 min. We used six light sources of different wattages (4 W, 7 W, 9 W, 12 W, 18 W, 36 W) at six distances (35 cm, 100 cm, 150 cm, 200 cm, 250 cm, 300 cm). Samples (n = 2160) were taken in the 36 settings and showed no significant difference in efficacy between light intensity and distance. We also investigated the influence of organic contaminant that resulted in lower activity as well as the effect of a water jet and a high-pressure device on the antibacterial activity. We found that the latter completely removed the coating from the surface, which significantly (p < 0.0001) reduced its antibacterial potential. As a conclusion, light intensity and distance does not reduce the efficacy of the polymer, but the presence of organic contaminants does. Full article

(This article belongs to the Special Issue Drug Discovery for Infectious Diseases)

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10 pages, 1690 KiB

Open AccessArticle

Identification of Hub Genes and Potential Biomarkers for Childhood Asthma by Utilizing an Established Bioinformatic Analysis Approach

by Ichtiarini Nurullita Santri, Lalu Muhammad Irham, Gina Noor Djalilah, Dyah Aryani Perwitasari, Yuniar Wardani, Yohane Vincent Abero Phiri and Wirawan Adikusuma

Biomedicines 2022, 10(9), 2311; https://doi.org/10.3390/biomedicines10092311 - 16 Sep 2022

Cited by 4 | Viewed by 2304

Abstract

Childhood asthma represents a heterogeneous disease resulting from the interaction between genetic factors and environmental exposures. Currently, finding reliable biomarkers is necessary for the clinical management of childhood asthma. However, only a few biomarkers are being used in clinical practice in the pediatric [...] Read more.

Childhood asthma represents a heterogeneous disease resulting from the interaction between genetic factors and environmental exposures. Currently, finding reliable biomarkers is necessary for the clinical management of childhood asthma. However, only a few biomarkers are being used in clinical practice in the pediatric population. In the long run, new biomarkers for asthma in children are required and would help direct therapy approaches. This study aims to identify potential childhood asthma biomarkers using a genetic-driven biomarkers approach. Herein, childhood asthma-associated Single Nucleotide Polymorphisms (SNPs) were utilized from the GWAS database to drive and facilitate the biomarker of childhood asthma. We uncovered 466 childhood asthma-associated loci by extending to proximal SNPs based on r² > 0.8 in Asian populations and utilizing HaploReg version 4.1 to determine 393 childhood asthma risk genes. Next, the functional roles of these genes were subsequently investigated using Gene Ontology (GO) term enrichment analysis, a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and a protein–protein interaction (PPI) network. MCODE and CytoHubba are two Cytoscape plugins utilized to find biomarker genes from functional networks created using childhood asthma risk genes. Intriguingly, 10 hub genes (IL6, IL4, IL2, IL13, PTPRC, IL5, IL33, TBX21, IL2RA, and STAT6) were successfully identified and may have been identified to play a potential role in the pathogenesis of childhood asthma. Among 10 hub genes, we strongly suggest IL6 and IL4 as prospective childhood asthma biomarkers since both of these biomarkers achieved a high systemic score in Cytohubba’s MCC algorithm. In summary, this study offers a valuable genetic-driven biomarker approach to facilitate the potential biomarkers for asthma in children. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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11 pages, 938 KiB

Open AccessArticle

Beneficial Effects of Table Grape Use on Serum Levels of Omega-3 Index and Liver Function: A Randomized Controlled Clinical Trial

by Maria Notarnicola, Valentina De Nunzio, Tamara Lippolis, Valeria Tutino, Anna Maria Cisternino, Palma Aurelia Iacovazzi, Rosa Anna Milella, Marica Gasparro, Roberto Negro, Maurizio Polignano and Maria Gabriella Caruso

Biomedicines 2022, 10(9), 2310; https://doi.org/10.3390/biomedicines10092310 - 16 Sep 2022

Cited by 2 | Viewed by 1937

Abstract

This clinical trial was aimed to investigate the effects of fresh table grape intake on the serum levels of the Omega-3 index, defined as the sum of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) levels. Forty consecutive healthy subjects were randomly assigned to [...] Read more.

This clinical trial was aimed to investigate the effects of fresh table grape intake on the serum levels of the Omega-3 index, defined as the sum of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) levels. Forty consecutive healthy subjects were randomly assigned to the control group, receiving only dietary recommendations, and the grape group receiving a daily dose of 5 g of fresh table grape per kg of body weight, for 21 days. Compared with baseline, the grape treatment produced no significant difference in the serum levels of glucose, liver transaminase, and triglycerides, with the exception of cholesterol value, which was significantly reduced in both control and grape group (180.5 ± 20.32 vs. 196.1 ± 30.0 and 181.4 ± 21.9 vs. 194.3 ± 37.5, respectively). After 4 weeks from the end of grape treatment, the analysis of single fatty acids showed a significant increase in oleic acid content (14.15 ± 1.8 vs. 12.85 ± 1.6, p < 0.05) and a significant induction of the Omega-3 index (8.23 ± 1.9 vs. 6.09 ± 1.2, p < 0.05), associated with increased serum levels of adiponectin (24.09 ± 1.08 vs. 8.8 ± 0.7, p < 0.001). In contrast, the expression of fibroblast growth factor 21 (FGF21), a molecule associated with metabolic syndrome and liver disease, was significantly reduced (37.9 ± 6.8 vs. 107.8 ± 10.1, p < 0.001). The data suggest that the intake of fresh grape improves the Omega-3 index in the serum and exerts beneficial effects on liver function through the overexpression of adiponectin and the reduction in FGF21 levels. Full article

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

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13 pages, 907 KiB

Open AccessArticle

The Role of Intraamygdaloid Oxytocin and D2 Dopamine Receptors in Reinforcement in the Valproate-Induced Autism Rat Model

by Kristóf László, Dávid Vörös, Orsolya Kiss, Bettina Réka László, Tamás Ollmann, László Péczely, Kitti Mintál, Attila Tóth, Anita Kovács, Olga Zagoracz, Erika Kertes, Veronika Kállai, Beáta Berta, Zoltán Karádi and László Lénárd

Biomedicines 2022, 10(9), 2309; https://doi.org/10.3390/biomedicines10092309 - 16 Sep 2022

Cited by 1 | Viewed by 1718

Abstract

Background: autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting around 1 out of 68 children and its incidence shows an increasing tendency. There is currently no effective treatment for ASD. In autism research, the valproate (VPA)-induced autism rodent model is widely accepted. [...] Read more.

Background: autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting around 1 out of 68 children and its incidence shows an increasing tendency. There is currently no effective treatment for ASD. In autism research, the valproate (VPA)-induced autism rodent model is widely accepted. Our previous results showed that intraamygdaloid oxytocin (OT) has anxiolytic effects on rats showing autistic signs under the VPA-induced autism model. Methods: rats were stereotaxically implanted with guide cannulae bilaterally and received intraamygdaloid microinjections. In the present study, we investigated the possible role of intraamygdaloid OT and D2 dopamine (DA) receptors on reinforcement using VPA-treated rats in a conditioned place preference test. OT and/or an OT receptor antagonist or a D2 DA antagonist were microinjected into the central nucleus of the amygdala (CeA). Results: valproate-treated rats receiving 10 ng OT spent significantly longer time in the treatment quadrant during the test session of the conditioned place preference test. Prior treatment with an OT receptor antagonist or with a D2 DA receptor antagonist blocked the positive reinforcing effects of OT. The OT receptor antagonist or D2 DA antagonist in themselves did not influence the time rats spent in the treatment quadrant. Conclusions: Our results show that OT has positive reinforcing effects under the VPA-induced autism rodent model and these effects are OT receptor-specific. Our data also suggest that the DAergic system plays a role in the positive reinforcing effects of OT because the D2 DA receptor antagonist can block these actions. Full article

(This article belongs to the Special Issue Neuropeptides, Dopamine and Their Interactions in Neuroscience)

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13 pages, 1286 KiB

Open AccessArticle

High Prevalence of Primary Aldosteronism in Patients with Type 2 Diabetes Mellitus and Hypertension

by Ernestini Tyfoxylou, Nick Voulgaris, Chris Gravvanis, Sophia Vlachou, Athina Markou, Labrini Papanastasiou, Nikolaos Tentolouris, Eva Kassi, Gregory Kaltsas, George P. Chrousos and George P. Piaditis

Biomedicines 2022, 10(9), 2308; https://doi.org/10.3390/biomedicines10092308 - 16 Sep 2022

Cited by 2 | Viewed by 1655

Abstract

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. The prevalence of hypertension is higher in patients with diabetes mellitus-2 (DM-2). Following the limited existing data, we prospectively investigated the prevalence of aldosterone excess either as autonomous secretion (PA) or as [...] Read more.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. The prevalence of hypertension is higher in patients with diabetes mellitus-2 (DM-2). Following the limited existing data, we prospectively investigated the prevalence of aldosterone excess either as autonomous secretion (PA) or as a hyper-response to stress in hypertensive patients with DM-2 (HDM-2). A total of 137 HDM-2 patients and 61 non-diabetics with essential hypertension who served as controls (EH-C) underwent a combined, overnight diagnostic test, the Dexamethasone–captopril–valsartan test (DCVT) used for the diagnosis of PA and an ultralow dose (0.3 μg) ACTH stimulation test to identify an exaggerated aldosterone response to ACTH stimulation. Twenty-three normotensive individuals served as controls (NC) to define the normal response of aldosterone (ALD) and aldosterone-to-renin ratio (ARR) to the ultralow dose ACTH test. Using post-DCVTALD and ARR from the EH-C, and post-ACTH peak ALD and ARR from the NC, 47 (34.3%) HDM-2 patients were found to have PA, whereas 6 (10.4%) HDM-2 patients without PA (DCVT-negative) exhibited an exaggerated aldosterone response to stress—a prevalence much higher than ever reported. Treatment with mineralocorticoid receptor antagonists (MRAs) induced a significant and permanent reduction of BP in all HDM-2 patients. Early diagnosis and targeted treatment of PA is crucial to prevent any aggravating effect on chronic diabetic complications. Full article

(This article belongs to the Special Issue Recent Advances in Primary Aldosteronism: From Bench to Clinic)

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44 pages, 3300 KiB

Open AccessReview

A Comprehensive Review on Collagen Type I Development of Biomaterials for Tissue Engineering: From Biosynthesis to Bioscaffold

by Ibrahim N. Amirrah, Yogeswaran Lokanathan, Izzat Zulkiflee, M. F. Mohd Razip Wee, Antonella Motta and Mh Busra Fauzi

Biomedicines 2022, 10(9), 2307; https://doi.org/10.3390/biomedicines10092307 - 16 Sep 2022

Cited by 53 | Viewed by 10837

Abstract

Collagen is the most abundant structural protein found in humans and mammals, particularly in the extracellular matrix (ECM). Its primary function is to hold the body together. The collagen superfamily of proteins includes over 20 types that have been identified. Yet, collagen type [...] Read more.

Collagen is the most abundant structural protein found in humans and mammals, particularly in the extracellular matrix (ECM). Its primary function is to hold the body together. The collagen superfamily of proteins includes over 20 types that have been identified. Yet, collagen type I is the major component in many tissues and can be extracted as a natural biomaterial for various medical and biological purposes. Collagen has multiple advantageous characteristics, including varied sources, biocompatibility, sustainability, low immunogenicity, porosity, and biodegradability. As such, collagen-type-I-based bioscaffolds have been widely used in tissue engineering. Biomaterials based on collagen type I can also be modified to improve their functions, such as by crosslinking to strengthen the mechanical property or adding biochemical factors to enhance their biological activity. This review discusses the complexities of collagen type I structure, biosynthesis, sources for collagen derivatives, methods of isolation and purification, physicochemical characteristics, and the current development of collagen-type-I-based scaffolds in tissue engineering applications. The advancement of additional novel tissue engineered bioproducts with refined techniques and continuous biomaterial augmentation is facilitated by understanding the conventional design and application of biomaterials based on collagen type I. Full article

(This article belongs to the Special Issue Biomaterial Modifications and Improvement of Their Biocompatibility)

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21 pages, 1106 KiB

Open AccessReview

Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis

by Ilaria Barchetta, Flavia Agata Cimini, Sara Dule and Maria Gisella Cavallo

Biomedicines 2022, 10(9), 2306; https://doi.org/10.3390/biomedicines10092306 - 16 Sep 2022

Cited by 7 | Viewed by 3256

Abstract

Dipeptidyl peptidase 4 (DPP4) is a molecule implicated in the regulation of metabolic homeostasis and inflammatory processes, and it exerts its main action through its enzymatic activity. DPP4 represents the enzyme most involved in the catabolism of incretin hormones; thus, its activity impacts [...] Read more.

Dipeptidyl peptidase 4 (DPP4) is a molecule implicated in the regulation of metabolic homeostasis and inflammatory processes, and it exerts its main action through its enzymatic activity. DPP4 represents the enzyme most involved in the catabolism of incretin hormones; thus, its activity impacts appetite, energy balance, and the fine regulation of glucose homeostasis. Indeed, DPP4 inhibitors represent a class of antidiabetic agents widely used for the treatment of Type 2 diabetes mellitus (T2DM). DPP4 also acts as an adipokine and is mainly secreted by the adipose tissue, mostly from mature adipocytes of the visceral compartment, where it exerts autocrine and paracrine activities. DPP4 can disrupt insulin signaling within the adipocyte and in other target cells and tissues, where it also favors the development of a proinflammatory environment. This is likely at the basis of the presence of elevated circulating DPP4 levels in several metabolic diseases. In this review, we summarize the most recent evidence of the role of the DPP4 as an adipokine-regulating glucose/insulin metabolism and fat homeostasis, with a particular focus on clinical outcomes associated with its increased secretion in the presence of adipose tissue accumulation and dysfunction. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Recent Advances on Adipokines)

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10 pages, 1015 KiB

Open AccessArticle

Prognostic Role of Post-Induction Fecal Calprotectin Levels in Patients with Inflammatory Bowel Disease Treated with Biological Therapies

by Antonio Facciorusso, Daryl Ramai, Cristina Ricciardelli, Rosa Paolillo, Marcello Maida, Saurabh Chandan, Babu P. Mohan, Viktor Domislovic and Rodolfo Sacco

Biomedicines 2022, 10(9), 2305; https://doi.org/10.3390/biomedicines10092305 - 16 Sep 2022

Cited by 3 | Viewed by 1625

Abstract

Background: There is currently scarce knowledge about markers of early therapeutic response in patients with inflammatory bowel disease (IBD) treated with biologics. The aim of this study was to evaluate the role of fecal calprotectin (FC) as an early predictor of mucosal healing [...] Read more.

Background: There is currently scarce knowledge about markers of early therapeutic response in patients with inflammatory bowel disease (IBD) treated with biologics. The aim of this study was to evaluate the role of fecal calprotectin (FC) as an early predictor of mucosal healing and clinical remission. Methods: Data from a multicenter series of 172 IBD patients treated with biologics between 2017 and 2020 were analyzed. Treatment outcomes were mucosal healing and clinical remission assessed at 2 years. FC levels were assessed at 14 weeks (post-induction), at 6 months, and yearly. The receiver operating characteristic (ROC) curve analysis was performed to calculate the best cut-off in % change of FC levels between post-induction and baseline predicting treatment outcomes. Sensitivity, specificity, and accuracy for several post-induction FC cut-off points were also calculated. Results: At 2 years, mucosal healing was noted in 77 patients (44.7%), of whom were 41 Crohn’s disease (CD) and 36 ulcerative colitis (UC) patients, whereas 106 patients experienced clinical remission (61.6%), of whom were 59 CD and 47 UC patients. Both baseline and post-induction FC levels were significantly higher in non-responders as compared to responders. On the other hand, FC decrease was less pronounced in non-responders. Similar results were observed in all subgroups, namely according to disease (CD vs. UC), or treatment used (TNF-inhibitors vs. vedolizumab). The best cut-off points were −86% in % change in FC levels to predict mucosal healing and −83% for clinical remission. Conclusions: The current study suggests a predictive role of post-induction FC assessment to predict treatment response in IBD patients treated with biologics. Full article

(This article belongs to the Section Cell Biology and Pathology)

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18 pages, 1247 KiB

Open AccessReview

Dynamic Regulation of NF-κB Response in Innate Immunity: The Case of the IMD Pathway in Drosophila

by Alexandre Cammarata-Mouchtouris, Adrian Acker, Akira Goto, Di Chen, Nicolas Matt and Vincent Leclerc

Biomedicines 2022, 10(9), 2304; https://doi.org/10.3390/biomedicines10092304 - 16 Sep 2022

Cited by 12 | Viewed by 3727

Abstract

Metazoans have developed strategies to protect themselves from pathogenic attack. These preserved mechanisms constitute the immune system, composed of innate and adaptive responses. Among the two kinds, the innate immune system involves the activation of a fast response. NF-κB signaling pathways are activated [...] Read more.

Metazoans have developed strategies to protect themselves from pathogenic attack. These preserved mechanisms constitute the immune system, composed of innate and adaptive responses. Among the two kinds, the innate immune system involves the activation of a fast response. NF-κB signaling pathways are activated during infections and lead to the expression of timely-controlled immune response genes. However, activation of NF-κB pathways can be deleterious when uncontrolled. Their regulation is necessary to prevent the development of inflammatory diseases or cancers. The similarity of the NF-κB pathways mediating immune mechanisms in insects and mammals makes Drosophila melanogaster a suitable model for studying the innate immune response and learning general mechanisms that are also relevant for humans. In this review, we summarize what is known about the dynamic regulation of the central NF-κB-pathways and go into detail on the molecular level of the IMD pathway. We report on the role of the nuclear protein Akirin in the regulation of the NF-κB Relish immune response. The use of the Drosophila model allows the understanding of the fine-tuned regulation of this central NF-κB pathway. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches 2.0)

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9 pages, 744 KiB

Open AccessCommunication

Granulocyte Colony-Stimulating Factor Ameliorates Endothelial Activation and Thrombotic Diathesis Biomarkers in a Murine Model of Hind Limb Ischemia

by Angeliki Valatsou, Panagiotis Theofilis, Spyridon Simantiris, Georgia Vogiatzi, Alexandros Briasoulis, Marios Sagris, Evangelos Oikonomou, Alexios S. Antonopoulos, Alkistis Pantopoulou, Narjes Nasiri-Ansari, Elizabeth Fragopoulou, Despoina Perrea, Konstantinos Tsioufis and Dimitris Tousoulis

Biomedicines 2022, 10(9), 2303; https://doi.org/10.3390/biomedicines10092303 - 16 Sep 2022

Viewed by 1388

Abstract

Novel therapies in peripheral arterial disease, such as granulocyte colony-stimulating factor (GCSF) administration, might result in anti-atherosclerotic effects. In this study, we used 10-week-old male ApoE^−/− mice, which were fed an atherosclerosis-inducing diet for four weeks. At the end of the four [...] Read more.

Novel therapies in peripheral arterial disease, such as granulocyte colony-stimulating factor (GCSF) administration, might result in anti-atherosclerotic effects. In this study, we used 10-week-old male ApoE^−/− mice, which were fed an atherosclerosis-inducing diet for four weeks. At the end of the four weeks, hind limb ischemia was induced through left femoral artery ligation, the atherosclerosis-inducing diet was discontinued, and a normal diet was initiated. Mice were then randomized into a control group (intramuscular 0.4 mL normal saline 0.9% for 7 days) and a group in which GCSF was administrated intramuscularly in the left hind limb for 7 days (100 mg/kg). In the GCSF group, but not in the control group, we observed significant reductions in the soluble adhesion molecules (vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1)), sE-Selectin, and plasminogen activator inhibitor (PAI)-1 when they were measured through ELISA on the 1st and the 28th days after hind limb ischemia induction. Therefore, GCSF administration in an atherosclerotic mouse model of hind limb ischemia led to decreases in the biomarkers associated with endothelial activation and thrombosis. These findings warrant further validation in future preclinical studies. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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Open AccessArticle

Sex-Differences in Pain and Opioid Use Disorder Management: A Cross-Sectional Real-World Study

by Mónica Escorial, Javier Muriel, César Margarit, Laura Agulló, Domingo Morales and Ana M. Peiró Peiró

Biomedicines 2022, 10(9), 2302; https://doi.org/10.3390/biomedicines10092302 - 16 Sep 2022

Cited by 4 | Viewed by 2316

Abstract

(1) Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. [...] Read more.

(1) Background: It is essential to focus attention on sex-specific factors which are clinically relevant in pain management, especially with regards to opioid use disorder (OUD) risk. The aim of this study was to explore potential sex-differences in chronic non-cancer pain (CNCP) outpatients. (2) Methods: An observational cross-sectional study was conducted under CNCP outpatients with long-term prescribed opioids (n = 806), wherein 137 patients had an OUD diagnosis (cases, 64% females) and 669 did not (controls, 66% females). Socio-demographic, clinical, and pharmacological outcomes were analyzed. (3) Results: Female controls presented an older age and less intensive pain therapy but higher psychotropic prescriptions and emergency department visits compared to male controls. Meanwhile, cases demonstrated a younger age, higher work disability, double morphine equivalent daily dose, and benzodiazepine use compared with controls. Here, female cases showed an 8% greater substance use disorder (OR 2.04 [1.11–3.76]) and 24% lower tramadol use, while male cases presented a 22% higher fentanyl use (OR 2.97 [1.52–5.81]) and reported the highest number of adverse drug reactions (24%, OR 2.40 [1.12–5.16]) compared with controls. (4) Conclusions: An OUD individual risk profile was evidenced with sex-differences to take into consideration to design equal prevention programs. Full article

(This article belongs to the Special Issue Gender Medicine and Pharmacology)

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Biomedicines, Volume 10, Issue 9 (September 2022) – 277 articles

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