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Open AccessArticle

The Effects of Adiponectin on the Behavior of B-Cell Leukemia Cells: Insights from an In Vitro Study

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Biomedicines 2023, 11(9), 2585; https://doi.org/10.3390/biomedicines11092585 (registering DOI) - 21 Sep 2023

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Abstract

Background: Non-Hodgkin’s lymphoma (NHL), the most frequent hematological neoplasm worldwide, represents a heterogeneous group of malignancies. The etiology of NHL remains to be fully elucidated, but the role of adipose tissue (AT) in immune function via the secretion of adipokines was recently [...] Read more.

Background: Non-Hodgkin’s lymphoma (NHL), the most frequent hematological neoplasm worldwide, represents a heterogeneous group of malignancies. The etiology of NHL remains to be fully elucidated, but the role of adipose tissue (AT) in immune function via the secretion of adipokines was recently recognized. Among adipokines, adiponectin has garnered attention for its beneficial properties. This study aimed to explore the in vitro effects of AdipoRon, an adiponectin agonist, on JVM-2, a lymphoblast cell line used as a representative disease model. Methods: JVM-2 cells were treated with different concentrations of AdipoRon to evaluate its effects on viability (via an MTT test), cell cycle distribution (via an FACS analysis), invasiveness (via a Matrigel assay) and colony-forming ability; protein expression was assessed via a real-time PCR (qPCR) and/or Western blotting (WB). Results: We found that the prolonged exposure of JVM-2 cells to AdipoRon led to a reduction in their viability due to a cytostatic effect. Additionally, AdipoRon stimulated both the formation of cell colonies and the expression of E-cadherin. Interestingly, the administration of AdipoRon increased the invasive potential of JVM-2 cells. Conclusions: Our findings indicate that adiponectin is involved in the regulation of different cellular processes of JVM-2 cells, supporting its potential association with a pro-tumorigenic phenotype and indicating that it might contribute to the increased aggressiveness and metastatic potential of B lymphoma cells. However, additional studies are required to fully understand the molecular mechanisms of adiponectin’s actions on lymphoblasts and whether it may represent a marker of disease. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Evaluation of the Effectiveness of an Innovative Polycomponent Formulation on Adult and Aged Human Dermal Fibroblasts

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Francesca Rosaria Augello

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Biomedicines 2023, 11(9), 2410; https://doi.org/10.3390/biomedicines11092410 - 28 Aug 2023

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Abstract

Skin aging is a dynamic process that determines structural alterations in ECM and reduction in dermal fibroblasts. The recent availability on the market of an innovative polycomponent formulation (KARISMA Rh Collagen^® FACE, K) containing noncrosslinked high-molecular-weight hyaluronic acid (HMW-HA), a human recombinant [...] Read more.

Skin aging is a dynamic process that determines structural alterations in ECM and reduction in dermal fibroblasts. The recent availability on the market of an innovative polycomponent formulation (KARISMA Rh Collagen^® FACE, K) containing noncrosslinked high-molecular-weight hyaluronic acid (HMW-HA), a human recombinant polypeptide of collagen-1 alpha chain, and carboxymethyl cellulose (CMC), attracted our scientific interest in evaluating its biomolecular effects on human dermal adult and aged fibroblasts. After treatment with increasing K concentrations, cell proliferation, collagen I, prolyl 4-hydroxylase (P4HA1), an essential protein in collagen biosynthesis, and α-SMA levels were assessed. The fibroblast contractility, TGF-β1 levels, and oxidative stress markers were also evaluated. K formulation exposure led to a significant and dose-dependent increase in the proliferation and migration of adult fibroblasts. Of note, the K exposure counteracted the H₂O₂-induced aging by promoting cell proliferation, reducing β-galactosidase activity, and neutralizing the aging-associated oxidative damage. Moreover, an increase in collagen I, P4HA1, α-SMA, TGF-β1 levels, and improved contractility of adult and aged fibroblasts were observed after treatment. Overall, our results show evidence that the K treatment is efficacious in improving biological functions in adult fibroblasts and suppressing the biomolecular events associated with H₂O₂-induced cellular aging, thus supporting the regenerative and bio-revitalizing action of the K formulation helpful in preventing or treating skin aging. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Serum Urate Levels and Ultrasound Characteristics of Carotid Atherosclerosis across Obesity Phenotypes

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Biomedicines 2023, 11(7), 1897; https://doi.org/10.3390/biomedicines11071897 - 04 Jul 2023

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Abstract

Background: Existing evidence suggests a close link among high levels of serum urate (SU), obesity and carotid atherosclerosis. The aim of the present study was to evaluate the interrelations between SU levels and carotid atherosclerosis in subjects with different obesity phenotypes. Methods: In [...] Read more.

Background: Existing evidence suggests a close link among high levels of serum urate (SU), obesity and carotid atherosclerosis. The aim of the present study was to evaluate the interrelations between SU levels and carotid atherosclerosis in subjects with different obesity phenotypes. Methods: In this study, a total of 2076 subjects (mean age 48.1 ± 13.1 years; 1307 women) were recruited: 59 with general obesity, 616 with central obesity, 715 with mixed (general–central) obesity and 686 non-obese. Anthropometric measurements, vascular risk factors, blood biochemistry analysis (including SU levels), and carotid ultrasound were performed. Ultrasound assessment included evaluation of intima-media thickness (IMT) and plaque characteristics, including number, total area and type (vulnerable vs. stable) of plaques. Results: After adjustment for potential confounders, the highest levels of SU were observed in subjects with mixed obesity, followed by subjects with central obesity, general obesity and the non-obese (309.4 ± 82.2 vs. 301.2 ± 73.1 vs. 272.9 ± 61.8 vs. 234.2 ± 59.8 μmol/L, respectively; F = 149.2, post hoc p < 0.001). Similarly, subjects with mixed and central obesity presented higher values of IMT compared to subjects with general obesity and the non-obese (0.68 ± 0.16 vs. 0.67 ± 0.16 vs. 0.62 ± 0.14 vs. 0.57 ± 0.13 mm, respectively; F = 54.2, post hoc p < 0.001). No difference in number, total area and type of plaques among obesity groups were attested (all p > 0.05). Significantly higher IMT values were observed in subjects with increased SU levels compared to subjects with normal SU levels (0.70 ± 0.10 vs. 0.62 ± 0.14 mm, p = 0.02) only within the central obesity group. Increasing levels of SU were associated with a higher frequency of increased IMT only in subjects with central obesity (OR 1.033, 95% CI 1.025–1.041). Similarly, SU levels yielded a satisfactory performance in detecting subjects with increased IMT (AUC 0.65, 95% CI 0.50–0.73, subjects with carotid plaques (0.62, 95% CI 0.55–0.68) and subjects with vulnerable plaque types (0.68, 0.59–0.76) only within the central obesity group. Conclusions: Among the studied obesity types, the association between SU levels and markers of carotid atherosclerosis was of particular significance in subjects with central obesity. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Continuous Glucose Monitoring as an Additional Tool in Early Cystic Fibrosis-Related Diabetes Monitoring and in Evaluation of Short-Term Sitagliptin Response

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Fernando Sebastian-Valles

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José Alfonso Arranz Martín

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Rosa María Girón

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Carolina Knott-Torcal

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Miguel Antonio Sampedro-Nuñez

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Jose Carlos Martin-Adan

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Jessica Jiménez-Díaz

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Mónica Marazuela

Biomedicines 2023, 11(6), 1754; https://doi.org/10.3390/biomedicines11061754 - 19 Jun 2023

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Abstract

Cystic fibrosis-related diabetes (CFRD) is a complication associated with a negative prognosis in patients with cystic fibrosis (CF). Although the oral glucose tolerance test (OGTT) is the widely recommended screening test for CFRD diagnosis, continuous glucose monitoring (CGM) is increasingly considered a useful [...] Read more.

Cystic fibrosis-related diabetes (CFRD) is a complication associated with a negative prognosis in patients with cystic fibrosis (CF). Although the oral glucose tolerance test (OGTT) is the widely recommended screening test for CFRD diagnosis, continuous glucose monitoring (CGM) is increasingly considered a useful and easy-to-perform test for diagnosis and follow-up in clinical practice. Regarding CFRD treatment, although insulin is the classic approved pharmacological option, incretins could also be a helpful alternative in early stages. CGM could be also a useful tool to measure the early response to this therapy. METHODS: We studied 25 CF patients with abnormal OGTT results and compared glucose and insulin levels during the OGTTs with CGM results as a tool for early CFRD diagnosis. In addition, we evaluated glycaemic control with CGM before and after treatment with sitagliptin. RESULTS: A correlation was found between lower plasma insulin levels during the OGTTs and higher average sensor glucose (p = 0.009) and hyperglycaemic excursions (p = 0.017). The CGM data on sitagliptin treatment (n = 25) showed an average glycaemic improvement from 124.2 to 117.2 mg/dL (p = 0.002) with a 5.6-point standard deviation of glucose decrease (p < 0.001). Hyperglycaemic excursions ≥200 mg/dL diminished 57.1% (p = 0.021). Both time in range and time above 180 mg/dL improved during treatment (p = 0.036 and p = 0.006, respectively). CONCLUSION: CGM is a useful tool that offers valuable information for both the diagnosis and the management of CFRD. Lower plasma insulin levels during OGTTs are associated with a poor ambulatory glucose profile in CGM. Sitagliptin could play an important role in the treatment of the early stages of CFRD. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Measurement of Aβ Amyloid Plaques and Tau Protein in Postmortem Human Alzheimer’s Disease Brain by Autoradiography Using [¹⁸F]Flotaza, [¹²⁵I]IBETA, [^124/125I]IPPI and Immunohistochemistry Analysis Using QuPath

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Biomedicines 2023, 11(4), 1033; https://doi.org/10.3390/biomedicines11041033 - 27 Mar 2023

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High-resolution scans of immunohistochemical (IHC) stains of Alzheimer’s disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aβ plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aβ plaques [...] Read more.

High-resolution scans of immunohistochemical (IHC) stains of Alzheimer’s disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aβ plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aβ plaques and Tau is essential to understand the progression of AD pathology. Our goal was to develop a quantitative method for the analysis of IHC–autoradiography images. Postmortem anterior cingulate (AC) and corpus callosum (CC) from AD and control (CN) subjects were IHC stained with anti-Aβ for Aβ plaques and autoradiography with [¹⁸F]flotaza and [¹²⁵I]IBETA for Aβ plaques. For Tau, [¹²⁴I]IPPI, a new radiotracer, was synthesized and evaluated in the AD brain. For Tau imaging, brain slices were IHC stained with anti-Tau and autoradiography using [¹²⁵I]IPPI and [¹²⁴I]IPPI. Annotations for Aβ plaques and Tau using QuPath for training and pixel classifiers were generated to measure the percent of the area of Aβ plaques and Tau in each slice. The binding of [¹²⁴I]IPPI was observed in all AD brains with an AC/CC ratio > 10. Selectivity to Tau was shown by blocking [¹²⁴I]IPPI with MK-6240. Percent positivity for Aβ plaques was 4–15%, and for Tau, it was 1.3 to 35%. All IHC Aβ plaque-positive subjects showed [¹⁸F]flotaza and [¹²⁵I]IBETA binding with a positive linear correlation (r² > 0.45). Tau-positive subjects showed [^124/125I]IPPI binding with a stronger positive linear correlation (r² > 0.80). This quantitative IHC–autoradiography approach provides an accurate measurement of Aβ plaques and Tau within and across subjects. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

A Single Arm Clinical Study on the Effects of Continuous Erythropoietin Receptor Activator Treatment in Non-Dialysis Patients with Chronic Heart Failure and Renal Anemia

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Biomedicines 2023, 11(3), 946; https://doi.org/10.3390/biomedicines11030946 - 20 Mar 2023

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Erythropoiesis-stimulating agents improve the NYHA functional class and decrease the hospital readmission rates for heart failure; however, little is known about the influence of continuous erythropoietin receptor activator (CERA) on the heart. Therefore, a prospective study was conducted to investigate the effects of [...] Read more.

Erythropoiesis-stimulating agents improve the NYHA functional class and decrease the hospital readmission rates for heart failure; however, little is known about the influence of continuous erythropoietin receptor activator (CERA) on the heart. Therefore, a prospective study was conducted to investigate the effects of CERA on cardiac and renal function and oxidative stress in chronic heart failure with renal anemia. Sixty patients with chronic heart failure and renal anemia were enrolled and received CERA for 12 months. The primary endpoints were hemoglobin (Hb) and hematocrit, and the secondary endpoints were: (1) atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP); (2) NYHA class; (3) echocardiography; (4) blood urea nitrogen, creatinine, cystatin C, and urinary albumin; (5) high-sensitivity C-reactive protein; (6) oxidized low-density lipoprotein (Ox-LDL); and (7) renin, angiotensin-II, and aldosterone. There was a significant difference in the Hb levels measured before and after CERA administration. The BNP, ANP, NYHA, left ventricular mass index, renal function, and Ox-LDL decreased significantly after CERA administration. This study shows that CERA improves anemia and reduces renal impairment, as well as cardiac and oxidative stress. The result of this study is useful for a study in which switching from CERA to a new renal anemia drug, hypoxia-inducible factor prolyl-hydroxylase inhibitor, is investigated. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Novel Potential Markers of Myofibroblast Differentiation Revealed by Single-Cell RNA Sequencing Analysis of Mesenchymal Stromal Cells in Profibrotic and Adipogenic Conditions

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Konstantin Kulebyakin

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Pyotr Tyurin-Kuzmin

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Natalia Kalinina

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Anastasia Efimenko

Biomedicines 2023, 11(3), 840; https://doi.org/10.3390/biomedicines11030840 - 10 Mar 2023

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Mesenchymal stromal cells (MSCs) are the key regulators of tissue homeostasis and repair after damage. Accumulating evidence indicates the dual contribution of MSCs into the development of fibrosis induced by chronic injury: these cells can suppress the fibrotic process due to paracrine activity, [...] Read more.

Mesenchymal stromal cells (MSCs) are the key regulators of tissue homeostasis and repair after damage. Accumulating evidence indicates the dual contribution of MSCs into the development of fibrosis induced by chronic injury: these cells can suppress the fibrotic process due to paracrine activity, but their promoting role in fibrosis by differentiating into myofibroblasts has also been demonstrated. Many model systems reproducing fibrosis have shown the ability of peroxisome proliferator-activated receptor (PPAR) agonists to reverse myofibroblast differentiation. Thus, the differentiation of multipotent cells into myofibroblasts and adipocytes can be considered as processes that require the activation of opposite patterns of gene expression. To test this hypothesis, we analyzed single cell RNA-Seq transcriptome of human adipose tissue MSCs after stimulation of the myofibroblast or adipogenic differentiation and revealed several genes that changed their expression in a reciprocal manner upon these conditions. We validated the expression of selected genes by RT-PCR, and evaluated the upregulation of several relevant proteins using immunocytochemistry, refining the results obtained by RNA-Seq analysis. We have shown, for the first time, the expression of neurotrimin (NTM), previously studied mainly in the nervous tissue, in human adipose tissue MSCs, and demonstrated its increased gene expression and clustering of membrane receptors upon the stimulation of myofibroblast differentiation. We also showed an increased level of CHD3 (Chromodomain-Helicase-DNA-binding protein 3) in MSCs under profibrotic conditions, while retinol dehydrogenase-10 (RDH10) was detected only in MSCs after adipogenic induction, which contradicted the data of transcriptomic analysis and again highlights the need to validate the data obtained by omics methods. Our findings suggest the further analysis of the potential contribution of neurotrimin and CHD3 in the regulation of myofibroblast differentiation and the development of fibrosis. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Synthesis, In Vitro Biological Evaluation of Antiproliferative and Neuroprotective Effects and In Silico Studies of Novel 16E-Arylidene-5α,6α-epoxyepiandrosterone Derivatives

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Vanessa Brito

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Mariana Marques

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Marta Esteves

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Catarina Serra-Almeida

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Biomedicines 2023, 11(3), 812; https://doi.org/10.3390/biomedicines11030812 - 07 Mar 2023

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Steroids constitute an important class of pharmacologically active molecules, playing key roles in human physiology. Within this group, 16E-arylideneandrostane derivatives have been reported as potent anti-cancer agents for the treatment of leukemia, breast and prostate cancers, and brain tumors. Additionally, 5α,6α-epoxycholesterol [...] Read more.

Steroids constitute an important class of pharmacologically active molecules, playing key roles in human physiology. Within this group, 16E-arylideneandrostane derivatives have been reported as potent anti-cancer agents for the treatment of leukemia, breast and prostate cancers, and brain tumors. Additionally, 5α,6α-epoxycholesterol is an oxysterol with several biological activities, including regulation of cell proliferation and cholesterol homeostasis. Interestingly, pregnenolone derivatives combining these two modifications were described as potential neuroprotective agents. In this research, novel 16E-arylidene-5α,6α-epoxyepiandrosterone derivatives were synthesized from dehydroepiandrosterone by aldol condensation with different aldehydes followed by a diastereoselective 5α,6α-epoxidation. Their cytotoxicity was evaluated on tumoral and non-tumoral cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, the assessment of the neuroprotective activity of these derivatives was performed in a dopaminergic neuronal cell line (N27), at basal conditions, and in the presence of the neurotoxin 6-hydroxydopamine (6-OHDA). Interestingly, some of these steroids had selective cytotoxic effects in tumoral cell lines, with an IC₅₀ of 3.47 µM for the 2,3-dichlorophenyl derivative in the breast cancer cell line (MCF-7). The effects of this functionalized epoxide on cell proliferation (Ki67 staining), cell necrosis (propidium iodide staining), as well as the analysis of the nuclear area and near neighbor distance in MCF-7 cells, were analyzed. From this set of biological studies, strong evidence of the activation of apoptosis was found. In contrast, no significant neuroprotection against 6-OHDA-induced neurotoxicity was observed for the less cytotoxic steroids in N27 cells. Lastly, molecular docking simulations were achieved to verify the potential affinity of these compounds against important targets of steroidal drugs (androgen receptor, estrogen receptor α, and 5α-reductase type 2, 17α-hydroxylase-17,20-lyase and aromatase enzymes). This in silico study predicted a strong affinity between most novel steroidal derivatives and 5α-reductase and 17α-hydroxylase-17,20-lyase enzymes. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Computational and Preclinical Analysis of 2-(4-Methyl)benzylidene-4,7-dimethyl Indan-1-one (IPX-18): A Novel Arylidene Indanone Small Molecule with Anti-Inflammatory Activity via NF-κB and Nrf2 Signaling

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Reem M. Gahtani

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Ahmad Shaikh

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Hossam Kamli

Biomedicines 2023, 11(3), 716; https://doi.org/10.3390/biomedicines11030716 - 27 Feb 2023

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Abstract

Background: The adverse effects of anti-inflammatory drugs urges the search for new anti-inflammatory agents. This study aims at the preclinical analysis of the in-house synthesized small molecule IPX-18. Human whole blood (HWB), peripheral blood mononuclear cells (PBMCs), and neutrophils were used. Rat basophil [...] Read more.

Background: The adverse effects of anti-inflammatory drugs urges the search for new anti-inflammatory agents. This study aims at the preclinical analysis of the in-house synthesized small molecule IPX-18. Human whole blood (HWB), peripheral blood mononuclear cells (PBMCs), and neutrophils were used. Rat basophil cells (RBL-2H3) were used to assess degranulation. Binding stability to NF-κB-p50 was predicted using computational docking and molecular dynamic simulations. Essential signaling proteins were evaluated through flow cytometry. Results: IPX-18 inhibited the release of TNF-α with an IC₅₀ value of 298.8 nM and 96.29 nM in the HWB and PBMCs, respectively. The compound depicted an IC₅₀ value of 217.6 nM in the HWB and of 103.7 nM in the PBMCs for IFN-γ inhibition. IL-2 release and IL-8 release were inhibited by IPX-18 in the HWB and PBMCs. The compound controlled the migration of and the elastase in the activated neutrophils. The IC₅₀ value for basophil activation through the FcεRI receptor assay was found to be 91.63 nM. IPX-18 inhibited RBL-2H3-degranulation with an IC₅₀ value of 98.52 nM. The computational docking analysis predicted that IPX-18 would effectively bind NF-κB-p50. NF-κB-phosphorylation in the activated RBL-2H3 cells was decreased, and the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were increased with IPX-18 treatment. Conclusions: IPX-18 demonstrated efficacy in mediating the effector cells’ inflammatory responses through NF-κB/Nrf2 signaling. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

An Artificial Placenta Experimental System in Sheep: Critical Issues for Successful Transition and Survival up to One Week

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Sergio Sanchez-Martinez

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Yolanda J. D. de Roo-Puente

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Maria del Mar Velilla

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Biomedicines 2023, 11(3), 702; https://doi.org/10.3390/biomedicines11030702 - 24 Feb 2023

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Objective: To describe the development of an artificial placenta (AP) system in sheep with learning curve and main bottlenecks to allow survival up to one week. Methods: A total of 28 fetal sheep were transferred to an AP system at 110–115 days of [...] Read more.

Objective: To describe the development of an artificial placenta (AP) system in sheep with learning curve and main bottlenecks to allow survival up to one week. Methods: A total of 28 fetal sheep were transferred to an AP system at 110–115 days of gestation. The survival goal in the AP system was increased progressively in three consecutive study groups: 1–3 h (n = 8), 4–24 h (n = 10) and 48–168 h (n = 10). Duration of cannulation procedure, technical complications, pH, lactate, extracorporeal circulation (EC) circuit flows, fetal heart rate, and outcomes across experiments were compared. Results: There was a progressive reduction in cannulation complications (75%, 50% and 0%, p = 0.004), improvement in initial pH (7.20 ± 0.06, 7.31 ± 0.04 and 7.33 ± 0.02, p = 0.161), and increment in the rate of experiments reaching survival goal (25%, 70% and 80%, p = 0.045). In the first two groups, cannulation accidents, air bubbles in the extracorporeal circuit, and thrombotic complications were the most common cause of AP system failure. Conclusions: Achieving a reproducible experimental setting for an AP system is extremely challenging, time- and effort-consuming, and requires a highly multidisciplinary team. As a result of the learning curve, we achieved reproducible transition and survival up to 7 days. Extended survival requires improving instrumentation with custom-designed devices. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Autopsies Revealed Pathological Features of COVID-19 in Unvaccinated vs. Vaccinated Patients

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Biomedicines 2023, 11(2), 551; https://doi.org/10.3390/biomedicines11020551 - 14 Feb 2023

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Background: In Italy, by the end of 2021, a new pandemic wave led to increased hospitalizations and death, even in some vaccinated people. We aimed to investigate the death of COVID-19-vaccinated patients who acquired infection and developed severe disease, and to assess [...] Read more.

Background: In Italy, by the end of 2021, a new pandemic wave led to increased hospitalizations and death, even in some vaccinated people. We aimed to investigate the death of COVID-19-vaccinated patients who acquired infection and developed severe disease, and to assess differences with fatal COVID-19 in unvaccinated subjects by studying the pathological events triggered by SARS-CoV-2. Methods: Detailed autoptic examination was performed on five fully vaccinated compared to five unvaccinated patients. Histopathological analysis focused on the lung and heart, the two major affected organs. Results: COVID-19 caused, or contributed to death, in all the unvaccinated cases. By contrast, in vaccinated group, pre-existing pathologies played a major role, and death was not COVID-19-related in four out of five patients. These patients did not show the histological features of SARS-CoV-2 lung damage. Diffuse inflammatory macrophages infiltration recently emerged as the main feature of COVID-19 cardiac injury. Interestingly, the most striking difference between the two groups was the absence of increased macrophage infiltration in the heart of vaccinated patients. Conclusions: Results of this study confirm the efficacy of anti-SARS-CoV-2 vaccination in protecting organs from injury and support the need to maintain an adequate immune response by booster dose administration. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Exploring the Phospholipid Transport Mechanism of ATP8A1-CDC50

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Biomedicines 2023, 11(2), 546; https://doi.org/10.3390/biomedicines11020546 - 13 Feb 2023

Viewed by 1032

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P4-ATPase translocates lipids from the exoplasmic to the cytosolic plasma membrane leaflet to maintain lipid asymmetry distribution in eukaryotic cells. P4-ATPase is associated with severe neurodegenerative and metabolic diseases such as neurological and motor disorders. Thus, it is important to understand its transport [...] Read more.

P4-ATPase translocates lipids from the exoplasmic to the cytosolic plasma membrane leaflet to maintain lipid asymmetry distribution in eukaryotic cells. P4-ATPase is associated with severe neurodegenerative and metabolic diseases such as neurological and motor disorders. Thus, it is important to understand its transport mechanism. However, even with progress in X-ray diffraction and cryo-electron microscopy techniques, it is difficult to obtain the dynamic information of the phospholipid transport process in detail. There are still some problems required to be resolved: (1) when does the lipid transport happen? (2) How do the key residues on the transmembrane helices contribute to the free energy of important states? In this work, we explore the phospholipid transport mechanism using a coarse-grained model and binding free energy calculations. We obtained the free energy landscape by coupling the protein conformational changes and the phospholipid transport event, taking ATP8A1-CDC50 (the typical subtype of P4-ATPase) as the research object. According to the results, we found that the phospholipid would bind to the ATP8A1-CDC50 at the early stage when ATP8A1-CDC50 changes from E2P to E2Pi-PL state. We also found that the electrostatic effects play crucial roles in the phospholipid transport process. The information obtained from this work could help us in designing novel drugs for P-type flippase disorders. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Antimicrobial and Antiviral Compounds of Phlomis viscosa Poiret

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Biomedicines 2023, 11(2), 441; https://doi.org/10.3390/biomedicines11020441 - 02 Feb 2023

Cited by 1 | Viewed by 880

Abstract

Phlomis viscosa Poiret (an evergreen shrub) represents a valuable source of medicinal compounds. In this study, we discovered compounds with antimicrobial and antiviral properties. The aim of this study was to identify compounds of P. viscosa and estimate the antimicrobial and antiviral activity [...] Read more.

Phlomis viscosa Poiret (an evergreen shrub) represents a valuable source of medicinal compounds. In this study, we discovered compounds with antimicrobial and antiviral properties. The aim of this study was to identify compounds of P. viscosa and estimate the antimicrobial and antiviral activity of its phytochemicals. The volatile compounds were identified using gas chromatography/mass spectrometry (GC/MS) analysis. For the identification of nonvolatile components of the extracts, high-performance liquid chromatography (HPLC), liquid chromatography–electrospray ionization-mass spectrometry (LC-ESI-MS) and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF-MS) were applied. Quercetin 3-O-rutinoside and hesperidin caused a significant decrease in the bacterial concentration of Agrobacterium tumefaciens, Xylella fastidiosa and Pseudomonas syringae (p < 0.001). The growth of drug-resistant microorganisms (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Serratia marcescens and Salmonella enteritidis) was inhibited by quercetin 3-O-rutinoside, quercetin 3-O-arabinoside and hesperidin. In addition, these compounds demonstrated antiquorum-sensing properties. Diosmin, hesperidin and quercetin 3-O-arabinoside significantly inhibited varicella zoster virus (VZV) (p < 0.001). Quercetin 3-O-rutinoside and quercetin 3-O-arabinoside were effective against herpes simplex virus 1 (HSV-1), including mutant strains. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Biomacromolecular Profile in Human Primary Retinal Pigment Epithelial Cells—A Study of Oxidative Stress and Autophagy by Synchrotron-Based FTIR Microspectroscopy

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Biomedicines 2023, 11(2), 300; https://doi.org/10.3390/biomedicines11020300 - 21 Jan 2023

Viewed by 917

Abstract

Synchrotron radiation-based Fourier Transform Infrared (SR-FTIR) microspectroscopy is a non-destructive and chemically sensitive technique for the rapid detection of changes in the different components of the cell’s biomacromolecular profile. Reactive oxygen species and oxidative stress may cause damage to the DNA, RNA, and [...] Read more.

Synchrotron radiation-based Fourier Transform Infrared (SR-FTIR) microspectroscopy is a non-destructive and chemically sensitive technique for the rapid detection of changes in the different components of the cell’s biomacromolecular profile. Reactive oxygen species and oxidative stress may cause damage to the DNA, RNA, and proteins in the retinal pigment epithelium (RPE), which can further lead to age-related macular degeneration (AMD) and visual loss in the elderly. In this study, human primary RPEs (hRPEs) were used to study AMD pathogenesis by using an established in vitro cellular model of the disease. Autophagy—a mechanism of intracellular degradation, which is altered during AMD, was studied in the hRPEs by using the autophagy inducer rapamycin and treated with the autophagy inhibitor bafilomycin A1. In addition, oxidative stress was induced by the hydrogen peroxide (H₂O₂) treatment of hRPEs. By using SR-FTIR microspectroscopy and multivariate analyses, the changes in the phosphate groups of nucleic acids, Amide I and II of the proteins, the carbonyl groups, and the lipid status in the hRPEs showed a significantly different pattern under oxidative stress/autophagy induction and inhibition. This biomolecular fingerprint can be evaluated in future drug discovery studies affecting autophagy and oxidative stress in AMD. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Hepatoprotective Efficacy of Cycloastragenol Alleviated the Progression of Liver Fibrosis in Carbon-Tetrachloride-Treated Mice

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Theerut Luangmonkong

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Pittaya Puphancharoensuk

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Varisara Tongsongsang

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Peter Olinga

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Warisara Parichatikanond

Biomedicines 2023, 11(1), 231; https://doi.org/10.3390/biomedicines11010231 - 16 Jan 2023

Viewed by 1395

Abstract

The continuous death of hepatocytes induced by various etiologies leads to an aberrant tissue healing process and promotes the progression of liver fibrosis and ultimately chronic liver diseases. To date, effective treatments to delay this harmful process remain an unmet clinical need. Cycloastragenol [...] Read more.

The continuous death of hepatocytes induced by various etiologies leads to an aberrant tissue healing process and promotes the progression of liver fibrosis and ultimately chronic liver diseases. To date, effective treatments to delay this harmful process remain an unmet clinical need. Cycloastragenol is an active phytochemical substance isolated from Astragalus membranaceus, a plant used in traditional Chinese medicine to protect the liver. Therefore, our study aimed to elucidate the efficacy of cycloastragenol on carbon-tetrachloride (CCl₄)-induced liver fibrosis in mice. We found that cycloastragenol at 200 mg/kg dosage exhibited anti-fibrotic efficacy as demonstrated by a decrease in collagen deposition, downregulation of mRNA expression of collagen type 1, and a reduction in the content of total collagens. In addition, cycloastragenol further augmented the levels of anti-fibrotic matrix metalloproteinases (Mmps), that is, Mmp8, proMmp9, and Mmp12, which play a pivotal role in fibrosis resolution. According to histological analysis and serum markers of hepatotoxicity, cycloastragenol protected the livers from damage and mitigated the increment of serum alanine aminotransferase and bilirubin implicating hepatoprotective efficacy against CCl₄. Moreover, cycloastragenol upregulated the mRNA expression of interleukin 6, a pleiotropic cytokine plays a vital role in the promotion of hepatocyte regeneration. In conclusion, cycloastragenol alleviated the progression of liver fibrosis in CCl₄-treated mice and its anti-fibrotic efficacy was mainly due to the hepatoprotective efficacy. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

Development and Characterization of Phage-Display-Derived Novel Human Monoclonal Antibodies against the Receptor Binding Domain of SARS-CoV-2

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Biomedicines 2022, 10(12), 3274; https://doi.org/10.3390/biomedicines10123274 - 17 Dec 2022

Cited by 1 | Viewed by 4206

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in an ongoing global pandemic crisis, caused by the life-threatening illness coronavirus disease 2019 (COVID-19). Thus, the rapid development of monoclonal antibodies (mAbs) to cope with COVID-19 is urgently necessary. In this study, we used [...] Read more.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in an ongoing global pandemic crisis, caused by the life-threatening illness coronavirus disease 2019 (COVID-19). Thus, the rapid development of monoclonal antibodies (mAbs) to cope with COVID-19 is urgently necessary. In this study, we used phage display to develop four human mAbs specific to the receptor-binding domain (RBD) of SARS-CoV-2. Our intensive in vitro functional analyses demonstrated that K102.1, an anti-SARS-CoV-2 RBD-specific mAb, exerted potent neutralizing activity against pseudoviral and live viral infection and the interaction between SARS-CoV-2 RBD and human angiotensin-converting enzyme 2. Monotherapy with K102.1 also revealed the therapeutic potential against SARS-CoV-2 infection in vivo. Further, this study developed a sandwich enzyme-linked immunosorbent assay with a non-competing mAb pair, K102.1 and K102.2, that accurately detected the RBDs of SARS-CoV-2 wild-type and variants with high sensitivity in the picomolar range. These findings suggest that the phage-display-based mAb selection from an established antibody library may be an effective strategy for the rapid development of mAbs against the constantly evolving SARS-CoV-2. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessArticle

TNBC Therapeutics Based on Combination of Fusarochromanone with EGFR Inhibitors

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Biomedicines 2022, 10(11), 2906; https://doi.org/10.3390/biomedicines10112906 - 12 Nov 2022

Viewed by 980

Abstract

Fusarochromanone is an experimental drug with unique and potent anti-cancer activity. Current cancer therapies often incorporate a combination of drugs to increase efficacy and decrease the development of drug resistance. In this study, we used drug combinations and cellular phenotypic screens to address [...] Read more.

Fusarochromanone is an experimental drug with unique and potent anti-cancer activity. Current cancer therapies often incorporate a combination of drugs to increase efficacy and decrease the development of drug resistance. In this study, we used drug combinations and cellular phenotypic screens to address important questions about FC101′s mode of action and its potential therapeutic synergies in triple negative breast cancer (TNBC). We hypothesized that FC101′s activity against TNBC is similar to the mTOR inhibitor, everolimus, because FC101 downregulates the phosphorylation of two mTOR substrates, S6K and S6. Since everolimus synergistically enhances the anti-cancer activities of two known EGFR inhibitors (erlotinib or lapatinib) in TNBC, we performed analogous studies with FC101. Phenotypic cellular assays helped assess whether FC101 acts similarly to everolimus, in both single and combination treatments with the two inhibitors. FC101 outperformed all other single treatments in both cell proliferation and viability assays. However, unlike everolimus, FC101 produced a sustained decrease in cell viability in drug washout studies. None of the other drugs were able to maintain comparable effects upon removal. Although we observed slightly additive effects when the TNBC cells were treated with FC101 and the two EGFR inhibitors, those effects were not truly synergistic in the manner displayed with everolimus. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Odontogenic Chronic Rhinosinusitis: Structured Histopathology Evidence in Different Patho-Physiological Mechanisms

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Biomedicines 2022, 10(11), 2768; https://doi.org/10.3390/biomedicines10112768 - 31 Oct 2022

Viewed by 909

Abstract

An increased odontogenic chronic rhinosinusitis (oCRS) occurrence rate has quite recently been reported, likely due to an intensification of conservative dental surgery and implantology. The main aim of the study was to report for the first time the structured histopathological characteristics of the [...] Read more.

An increased odontogenic chronic rhinosinusitis (oCRS) occurrence rate has quite recently been reported, likely due to an intensification of conservative dental surgery and implantology. The main aim of the study was to report for the first time the structured histopathological characteristics of the surgical specimens of oCRS. Possible associations between histopathological features and oCRS patho-physiological mechanisms were also evaluated. Structured histopathology features were investigated in the sinonasal mucosa tissue of 42 consecutive oCRS patients. Mean tissue eosinophil counts were significantly different between oCRS with radicular cysts, dental implants, or other dental diseases (p = 0.0118): mean tissue eosinophil count was higher in oCRS with dental implants. Sub-epithelial edema score and squamous metaplasia presence were significantly different when comparing the above-mentioned sub-cohorts of oCRS (p = 0.0099 and p = 0.0258). In particular, squamous metaplasia was more present in oCRS cases with radicular cysts than in those with a dental implant (p = 0.0423). Fibrosis presence was significantly different comparing the three sub-cohorts of oCRS (p = 0.0408), too. This preliminary evidence supports the hypothesis that: (i) structural histopathology can become a useful tool for clinic-pathological practice in diagnostic, therapeutic, and prognostic terms in CRS; (ii) that oCRS, as CRS in general, is a histo-pathologically heterogeneous disease; (iii) oCRS resulting from dental implants disorders can frequently be characterized as a CRS with a rich tissue eosinophilic component. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Modulatory Effects of NBF1, an Algal Fiber-Rich Bioformula, on Adiponectin and C-Reactive Protein Levels, and Its Therapeutic Prospects for Metabolic Syndrome and Type-2 Diabetes Patients

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Nlandu Roger Ngatu

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Mitsunori Ikeda

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Daniel Kuezina Tonduangu

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Severin Luzitu Nangana

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Tomohiro Hirao

Biomedicines 2022, 10(10), 2572; https://doi.org/10.3390/biomedicines10102572 - 14 Oct 2022

Viewed by 1243

Abstract

An unhealthy diet can lead to the development of metabolic disorders. C-reactive protein (CRP) has been reported to be an inflammatory component of metabolic disorders. Additionally, reduced adiponectin (APN) levels is known as a predictor of metabolic disorders. We report on the beneficial [...] Read more.

An unhealthy diet can lead to the development of metabolic disorders. C-reactive protein (CRP) has been reported to be an inflammatory component of metabolic disorders. Additionally, reduced adiponectin (APN) levels is known as a predictor of metabolic disorders. We report on the beneficial effects of NBF1, an algal fiber-rich formula, on CRP, APN, and diabetes markers. Additionally, associations between dietary nutrients, CRP, and APN were investigated. A dietary survey that used a brief self-administered diet history questionnaire, a validated 58-item fixed-portion-type questionnaire, and a 4-week placebo-controlled dietary intervention were carried out. The latter consisted of a twice daily intake of 3 g of sujiaonori alga-based powder as a supplement (NBF1, n = 16), whereas the placebo group received the same amount of corn starch powder (n = 15). CRP and APN levels were assayed by ELISA. Clinical cases comprising three subjects with metabolic disorders treated with NBF1, including two type 2 diabetes mellitus patients and one subject with hypercholesterolemia, are also reported. They received 2.1g NBF1 once daily for 12 weeks. Intakes of algal fiber and n-3 PUFA were positively associated with the increase of APN, and n-3PUFA intake was inversely associated with CRP. All cases had improved metabolic health profile. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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UniStArt: A 12-Month Prospective Observational Study of Body Weight, Dietary Intake, and Physical Activity Levels in Australian First-Year University Students

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Nina A. Wilson

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Anthony Villani

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Sze-Yen Tan

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Evangeline Mantzioris

Biomedicines 2022, 10(9), 2241; https://doi.org/10.3390/biomedicines10092241 - 09 Sep 2022

Viewed by 989

Abstract

Background: Students in the United States gain weight significantly during their first year of university, however limited data are available for Australian students. Methods: This 12-month observational study was conducted to monitor monthly body weight and composition, as well as quarterly eating behaviours, [...] Read more.

Background: Students in the United States gain weight significantly during their first year of university, however limited data are available for Australian students. Methods: This 12-month observational study was conducted to monitor monthly body weight and composition, as well as quarterly eating behaviours, dietary intake, physical activity, sedentary behaviours, and basal metabolic rate changes amongst first-year Australian university students. Participants were first-year university students over 18 years. Results: Twenty-two first-year university students (5 males and 17 females) completed the study. Female students gained weight significantly at two, three, and four-months (+0.9 kg; +1.5 kg; +1.1 kg, p < 0.05). Female waist circumference (2.5 cm increase at three-months, p = 0.012), and body fat also increased (+0.9%, p = 0.026 at three-months). Intakes of sugar, saturated fat (both >10% of total energy), and sodium exceeded recommended levels (>2000 mg) at 12-months. Greater sedentary behaviours were observed amongst male students throughout the study (p <0.05). Conclusions: Female students are at risk of unfavourable changes in body composition during the first year of university, while males are at risk of increased sedentary behaviours. High intakes of saturated fat, sugars, and sodium warrant future interventions in such a vulnerable group. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Formal Meta-Analysis of Hypoxic Gene Expression Profiles Reveals a Universal Gene Signature

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Laura Puente-Santamaria

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Lucia Sanchez-Gonzalez

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Biomedicines 2022, 10(9), 2229; https://doi.org/10.3390/biomedicines10092229 - 08 Sep 2022

Cited by 1 | Viewed by 1330

Abstract

Integrating transcriptional profiles results in identifying gene expression signatures that are more robust than those obtained for individual datasets. However, a direct comparison of datasets derived from heterogeneous experimental conditions is problematic, hence their integration requires applying of specific meta-analysis techniques. The transcriptional [...] Read more.

Integrating transcriptional profiles results in identifying gene expression signatures that are more robust than those obtained for individual datasets. However, a direct comparison of datasets derived from heterogeneous experimental conditions is problematic, hence their integration requires applying of specific meta-analysis techniques. The transcriptional response to hypoxia has been the focus of intense research due to its central role in tissue homeostasis and prevalent diseases. Accordingly, many studies have determined the gene expression profile of hypoxic cells. Yet, despite this wealth of information, little effort has been made to integrate these datasets to produce a robust hypoxic signature. We applied a formal meta-analysis procedure to datasets comprising 430 RNA-seq samples from 43 individual studies including 34 different cell types, to derive a pooled estimate of the effect of hypoxia on gene expression in human cell lines grown ingin vitro. This approach revealed that a large proportion of the transcriptome is significantly regulated by hypoxia (8556 out of 20,888 genes identified across studies). However, only a small fraction of the differentially expressed genes (1265 genes, 15%) show an effect size that, according to comparisons to gene pathways known to be regulated by hypoxia, is likely to be biologically relevant. By focusing on genes ubiquitously expressed, we identified a signature of 291 genes robustly and consistently regulated by hypoxia. Overall, we have developed a robust gene signature that characterizes the transcriptomic response of human cell lines exposed to hypoxia in vitro by applying a formal meta-analysis to gene expression profiles. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Identification of Germinal Neurofibromin Hotspots

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Biomedicines 2022, 10(8), 2044; https://doi.org/10.3390/biomedicines10082044 - 21 Aug 2022

Cited by 2 | Viewed by 1678

Abstract

Neurofibromin is engaged in many cellular processes and when the proper protein functioning is impaired, it causes neurofibromatosis type 1 (NF1), one of the most common inherited neurological disorders. Recent advances in sequencing and screening of the NF1 gene have increased [...] Read more.

Neurofibromin is engaged in many cellular processes and when the proper protein functioning is impaired, it causes neurofibromatosis type 1 (NF1), one of the most common inherited neurological disorders. Recent advances in sequencing and screening of the NF1 gene have increased the number of detected variants. However, the correlation of these variants with the clinic remains poorly understood. In this study, we analyzed 4610 germinal NF1 variants annotated in ClinVar and determined on exon level the mutational spectrum and potential pathogenic regions. Then, a binomial and sliding windows test using 783 benign and 938 pathogenic NF1 variants were analyzed against functional and structural regions of neurofibromin. The distribution of synonymous, missense, and frameshift variants are statistically significant in certain regions of neurofibromin suggesting that the type of variant and its associated phenotype may depend on protein disorder. Indeed, there is a negative correlation between the pathogenic fraction prediction and the disorder data, suggesting that the higher an intrinsically disordered region is, the lower the pathogenic fraction is and vice versa. Most pathogenic variants are associated to NF1 and our analysis suggests that GRD, CSRD, TBD, and Armadillo1 domains are hotspots in neurofibromin. Knowledge about NF1 genotype–phenotype correlations can provide prognostic guidance and aid in organ-specific surveillance. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Identification of Human Breast Adipose Tissue Progenitors Displaying Distinct Differentiation Potentials and Interactions with Cancer Cells

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Pascal Peraldi

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Agnès Loubat

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Bérengère Chignon-Sicard

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Christian Dani

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Annie Ladoux

Biomedicines 2022, 10(8), 1928; https://doi.org/10.3390/biomedicines10081928 - 09 Aug 2022

Cited by 1 | Viewed by 1421

Abstract

Breast adipose tissue (AT) participates in the physiological evolution and remodeling of the mammary gland due to its high plasticity. It is also a favorable microenvironment for breast cancer progression. However, information on the properties of human breast adipose progenitor cells (APCs) involved [...] Read more.

Breast adipose tissue (AT) participates in the physiological evolution and remodeling of the mammary gland due to its high plasticity. It is also a favorable microenvironment for breast cancer progression. However, information on the properties of human breast adipose progenitor cells (APCs) involved in breast physiology or pathology is scant. We performed differential enzymatic dissociation of human breast AT lobules. We isolated and characterized two populations of APCs. Here we report that these distinct breast APC populations selectively expressed markers suitable for characterization. The population preferentially expressing ALPL (MSCA1) showed higher adipogenic potential. The population expressing higher levels of INHBA and CD142 acquired myofibroblast characteristics upon TGF-β treatment and a myo-cancer-associated fibroblast profile in the presence of breast cancer cells. This population expressed the immune checkpoint CD274 (PD-L1) and facilitated the expansion of breast cancer mammospheres compared with the adipogenic population. Indeed, the breast, as with other fat depots, contains distinct types of APCs with differences in their ability to specialize. This indicates that they were differentially involved in breast remodeling. Their interactions with breast cancer cells revealed differences in the potential for tumor dissemination and estrogen receptor expression, and these differences might be relevant to improve therapies targeting the tumor microenvironment. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Post-Bariatric Hypoglycemia Is Associated with Endothelial Dysfunction and Increased Oxidative Stress

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Matteo Nicola Dario Di Minno

Biomedicines 2022, 10(4), 916; https://doi.org/10.3390/biomedicines10040916 - 16 Apr 2022

Cited by 3 | Viewed by 1839

Abstract

Post-bariatric hypoglycemia (PBH) is a potentially serious complication that may occur after bariatric surgery. Recurrent hypoglycemia may exert detrimental effects on vascular function. The aim of the present study was to evaluate endothelial function and oxygen reactive compounds in patients who experience PBH [...] Read more.

Post-bariatric hypoglycemia (PBH) is a potentially serious complication that may occur after bariatric surgery. Recurrent hypoglycemia may exert detrimental effects on vascular function. The aim of the present study was to evaluate endothelial function and oxygen reactive compounds in patients who experience PBH compared with controls. We performed a cross-sectional study on subjects with PBH (HYPO) and those without (NO-HYPO), detected by seven-day continuous glucose monitoring (CGM) performed at least twelve months after bariatric surgery. We enrolled 28 post-bariatric subjects (17.9% males, mean age 40.6 ± 10.7 years), with 18 in the HYPO group and 10 in the NO-HYPO group. In the two groups, we measured brachial artery flow-mediated dilation (FMD), oxidized low-density lipoproteins (oxLDL) and reactive oxygen metabolites (D-ROMs). The HYPO group had significantly lower FMD values than the NO-HYPO group (3.8% ± 3.0 vs. 10.5% ± 2.0, p < 0.001). A significant correlation was found between FMD and the time spent in hypoglycemia (rho = −0.648, p < 0.001), the number of hypoglycemic events (rho = −0.664, p < 0.001) and the mean glucose nadir (rho = 0.532, p = 0.004). The HYPO group showed significantly higher levels of D-ROMs (416.2 ± 88.7 UCARR vs. 305.5 ± 56.3 UCARR, p < 0.001) and oxLDLs (770.5 ± 49.7 µEq/L vs. 725.1 ± 51.6 µEq/L, p = 0.035) compared to the NO-HYPO group. In the multiple linear regression analysis, hypoglycemia independently predicted FMD values (β = −0.781, p < 0.001), D-ROMs (β = 0.548, p = 0.023) and oxLDL levels (β = 0.409, p = 0.031). PBH is associated with impaired endothelial function accompanied by increased oxidative stress. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessReview

Circulating Surfactant Protein D: A Biomarker for Acute Lung Injury?

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Biomedicines 2023, 11(9), 2517; https://doi.org/10.3390/biomedicines11092517 - 12 Sep 2023

Viewed by 323

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening lung diseases in critically ill patients. The lack of prognostic biomarkers has halted detection methods and effective therapy development. Quantitative biomarker-based approaches in the systemic circulation have been proposed as a [...] Read more.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening lung diseases in critically ill patients. The lack of prognostic biomarkers has halted detection methods and effective therapy development. Quantitative biomarker-based approaches in the systemic circulation have been proposed as a means of enhancing diagnostic strategies as well as pharmacotherapy in a patient-specific manner. Pulmonary surfactants are complex mixtures made up of lipids and proteins, which are secreted into the alveolar space by epithelial type II cells under normal and pathological conditions. In this review, we summarize the current knowledge of SP-D in lung injury from both preclinical and clinical studies. Among surfactant proteins, surfactant protein-D (SP-D) has been more widely studied in ALI and ARDS. Recent studies have reported that SP-D has a superior discriminatory ability compared to other lung epithelial proteins for the diagnosis of ARDS, which could reflect the severity of lung injury. Furthermore, we shed light on recombinant SP-D treatment and its benefits as a potential drug for ALI, and we encourage further studies to translate SP-D into clinical use for diagnosis and treatment. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Chronic Wound Management: From Gauze to Homologous Cellular Matrix

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Valentin Popescu

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Victor Cauni

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Marius Septimiu Petrutescu

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Maria Madalina Rustin

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Raluca Bocai

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Cristina Rachila Turculet

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Horia Doran

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Traian Patrascu

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Angela Madalina Lazar

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Dragos Cretoiu

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Valentin Nicolae Varlas

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Bogdan Mastalier

Biomedicines 2023, 11(9), 2457; https://doi.org/10.3390/biomedicines11092457 - 04 Sep 2023

Viewed by 450

Abstract

Background: Chronic wounds are a significant health problem with devastating consequences for patients’ physical, social, and mental health, increasing healthcare systems’ costs. Their prolonged healing times, economic burden, diminished quality of life, increased infection risk, and impact on patients’ mobility and functionality make [...] Read more.

Background: Chronic wounds are a significant health problem with devastating consequences for patients’ physical, social, and mental health, increasing healthcare systems’ costs. Their prolonged healing times, economic burden, diminished quality of life, increased infection risk, and impact on patients’ mobility and functionality make them a major concern for healthcare professionals. Purpose: This review offers a multi-perspective analysis of the medical literature focusing on chronic wound management. Methods used: We evaluated 48 articles from the last 21 years registered in the MEDLINE and Global Health databases. The articles included in our study had a minimum of 20 citations, patients > 18 years old, and focused on chronic, complex, and hard-to-heal wounds. Extracted data were summarized into a narrative synthesis using the same health-related quality of life instrument. Results: We evaluated the efficacy of existing wound care therapies from classical methods to modern concepts, and wound care products to regenerative medicine that uses a patient’s pluripotent stem cells and growth factors. Regenerative medicine and stem cell therapies, biologic dressings and scaffolds, negative pressure wound therapy (NPWT), electrical stimulation, topical growth factors and cytokines, hyperbaric oxygen therapy (HBOT), advanced wound dressings, artificial intelligence (AI), and digital wound management are all part of the new arsenal of wound healing. Conclusion: Periodic medical evaluation and proper use of modern wound care therapies, including the use of plasma-derived products [such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF)] combined with proper systemic support (adequate protein levels, blood sugar, vitamins involved in tissue regeneration, etc.) are the key to a faster wound healing, and, with the help of AI, can reach the fastest healing rate possible. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Zinc Finger E-Box Binding Homeobox Family: Non-Coding RNA and Epigenetic Regulation in Gliomas

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Bartosz Lenda

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Marta Żebrowska-Nawrocka

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Grzegorz Turek

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Ewa Balcerczak

Biomedicines 2023, 11(5), 1364; https://doi.org/10.3390/biomedicines11051364 - 05 May 2023

Viewed by 1174

Abstract

Gliomas are the most common malignant brain tumours. Among them, glioblastoma (GBM) is a grade four tumour with a median survival of approximately 15 months and still limited treatment options. Although a classical epithelial to mesenchymal transition (EMT) is not the case in [...] Read more.

Gliomas are the most common malignant brain tumours. Among them, glioblastoma (GBM) is a grade four tumour with a median survival of approximately 15 months and still limited treatment options. Although a classical epithelial to mesenchymal transition (EMT) is not the case in glioma due to its non-epithelial origin, the EMT-like processes may contribute largely to the aggressive and highly infiltrative nature of these tumours, thus promoting invasive phenotype and intracranial metastasis. To date, many well-known EMT transcription factors (EMT-TFs) have been described with clear, biological functions in glioma progression. Among them, EMT-related families of molecules such as SNAI, TWIST and ZEB are widely cited, well-established oncogenes considering both epithelial and non-epithelial tumours. In this review, we aimed to summarise the current knowledge with a regard to functional experiments considering the impact of miRNA and lncRNA as well as other epigenetic modifications, with a main focus on ZEB1 and ZEB2 in gliomas. Although we explored various molecular interactions and pathophysiological processes, such as cancer stem cell phenotype, hypoxia-induced EMT, tumour microenvironment and TMZ-resistant tumour cells, there is still a pressing need to elucidate the molecular mechanisms by which EMT-TFs are regulated in gliomas, which will enable researchers to uncover novel therapeutic targets as well as improve patients’ diagnosis and prognostication. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Cardiac Resynchronization Therapy and Left Atrial Remodeling: A Novel Insight?

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Alexandru Scafa-Udriște

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Maria Dorobantu

Biomedicines 2023, 11(4), 1156; https://doi.org/10.3390/biomedicines11041156 - 12 Apr 2023

Viewed by 808

Abstract

Cardiac resynchronization therapy (CRT) restores ventricular dyssynchrony, improving left ventricle (LV) systolic function, symptoms, and outcome in patients with heart failure, systolic dysfunction, and prolonged QRS interval. The left atrium (LA) plays tremendous roles in maintaining cardiac function, being often inflicted in various [...] Read more.

Cardiac resynchronization therapy (CRT) restores ventricular dyssynchrony, improving left ventricle (LV) systolic function, symptoms, and outcome in patients with heart failure, systolic dysfunction, and prolonged QRS interval. The left atrium (LA) plays tremendous roles in maintaining cardiac function, being often inflicted in various cardiovascular diseases. LA remodeling implies structural—dilation, functional—altered phasic functions, and strain and electrical—atrial fibrillation remodeling. Until now, several important studies have approached the relationship between LA and CRT. LA volumes can predict responsiveness to CRT, being also associated with improved outcome in these patients. LA function and strain parameters have been shown to improve after CRT, especially in those who were positive responders to it. Further studies still need to be conducted to comprehensively characterize the impact of CRT on LA phasic function and strain, and, also, in conjunction with its impact on functional mitral regurgitation and LV diastolic dysfunction. The aim of this review was to provide an overview of current available data regarding the relation between CRT and LA remodeling. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Cardiac Resynchronization Therapy and Hypertrophic Cardiomyopathy: A Comprehensive Review

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Biomedicines 2023, 11(2), 350; https://doi.org/10.3390/biomedicines11020350 - 26 Jan 2023

Viewed by 1312

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited primary myocardial disease characterized by asymmetrical/symmetrical left ventricle (LV) hypertrophy, with or without LV outflow tract (LVOT) dynamic obstruction, and poor prognosis. Cardiac resynchronization therapy (CRT) has emerged as a minimally invasive tool for patients with heart [...] Read more.

Hypertrophic cardiomyopathy (HCM) is an inherited primary myocardial disease characterized by asymmetrical/symmetrical left ventricle (LV) hypertrophy, with or without LV outflow tract (LVOT) dynamic obstruction, and poor prognosis. Cardiac resynchronization therapy (CRT) has emerged as a minimally invasive tool for patients with heart failure (HF) with decreased LV ejection fraction (LVEF) and prolonged QRS duration of over 120 ms with or without left bundle branch block (LBBB). Several HCM patients are at risk of developing LBBB because of disease progression or secondary to septal myomectomy, while others might develop HF with decreased LVEF, alleged end-stage/dilated HCM, especially those with thin myofilament mutations. Several studies have shown that patients with myectomy-induced LBBB might benefit from left bundle branch pacing or CRT to relieve symptoms, improve exercise capacity, and increase LVEF. Otherwise, patients with end-stage/dilated HCM and prolonged QRS interval could gain from CRT in terms of NYHA class improvement, LV systolic performance increase and, to some degree, LV reverse remodeling. Moreover, several electrical and imaging parameters might aid proper selection and stratification of HCM patients to benefit from CRT. Nonetheless, current available data are scarce and further studies are still required to accurately clarify the view. This review reassesses the importance of CRT in patients with HCM based on current research by contrasting and contextualizing data from various published studies. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessReview

Retinal Pigment Epithelium Cell Development: Extrapolating Basic Biology to Stem Cell Research

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Biomedicines 2023, 11(2), 310; https://doi.org/10.3390/biomedicines11020310 - 23 Jan 2023

Cited by 1 | Viewed by 3280

Abstract

The retinal pigment epithelium (RPE) forms an important cellular monolayer, which contributes to the normal physiology of the eye. Damage to the RPE leads to the development of degenerative diseases, such as age-related macular degeneration (AMD). Apart from acting as a physical barrier [...] Read more.

The retinal pigment epithelium (RPE) forms an important cellular monolayer, which contributes to the normal physiology of the eye. Damage to the RPE leads to the development of degenerative diseases, such as age-related macular degeneration (AMD). Apart from acting as a physical barrier between the retina and choroidal blood vessels, the RPE is crucial in maintaining photoreceptor (PR) and visual functions. Current clinical intervention to treat early stages of AMD includes stem cell-derived RPE transplantation, which is still in its early stages of evolution. Therefore, it becomes essential to derive RPEs which are functional and exhibit features as observed in native human RPE cells. The conventional strategy is to use the knowledge obtained from developmental studies using various animal models and stem cell-based exploratory studies to understand RPE biogenies and developmental trajectory. This article emphasises such studies and aims to present a comprehensive understanding of the basic biology, including the genetics and molecular pathways of RPE development. It encompasses basic developmental biology and stem cell-based developmental studies to uncover RPE differentiation. Knowledge of the in utero developmental cues provides an inclusive methodology required for deriving RPEs using stem cells. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessReview

The Molecular Pharmacology of Phloretin: Anti-Inflammatory Mechanisms of Action

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Solomon Habtemariam

Biomedicines 2023, 11(1), 143; https://doi.org/10.3390/biomedicines11010143 - 06 Jan 2023

Cited by 6 | Viewed by 1749

Abstract

The isolation of phlorizin from the bark of an apple tree in 1835 led to a flurry of research on its inhibitory effect on glucose transporters in the intestine and kidney. Using phlorizin as a prototype drug, antidiabetic agents with more selective inhibitory [...] Read more.

The isolation of phlorizin from the bark of an apple tree in 1835 led to a flurry of research on its inhibitory effect on glucose transporters in the intestine and kidney. Using phlorizin as a prototype drug, antidiabetic agents with more selective inhibitory activity towards glucose transport at the kidney have subsequently been developed. In contrast, its hydrolysis product in the body, phloretin, which is also found in the apple plant, has weak antidiabetic properties. Phloretin, however, displays a range of pharmacological effects including antibacterial, anticancer, and cellular and organ protective properties both in vitro and in vivo. In this communication, the molecular basis of its anti-inflammatory mechanisms that attribute to its pharmacological effects is scrutinised. These include inhibiting the signalling pathways of inflammatory mediators’ expression that support its suppressive effect in immune cells overactivation, obesity-induced inflammation, arthritis, endothelial, myocardial, hepatic, renal and lung injury, and inflammation in the gut, skin, and nervous system, among others. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessReview

Extracorporeal Carbon Dioxide Removal: From Pathophysiology to Clinical Applications; Focus on Combined Continuous Renal Replacement Therapy

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Biomedicines 2023, 11(1), 142; https://doi.org/10.3390/biomedicines11010142 - 05 Jan 2023

Cited by 1 | Viewed by 2132

Abstract

Lung-protective ventilation (LPV) with low tidal volumes can significantly increase the survival of patients with acute respiratory distress syndrome (ARDS) by limiting ventilator-induced lung injuries. However, one of the main concerns regarding the use of LPV is the risk of developing hypercapnia and [...] Read more.

Lung-protective ventilation (LPV) with low tidal volumes can significantly increase the survival of patients with acute respiratory distress syndrome (ARDS) by limiting ventilator-induced lung injuries. However, one of the main concerns regarding the use of LPV is the risk of developing hypercapnia and respiratory acidosis, which may limit the clinical application of this strategy. This is the reason why different extracorporeal CO₂ removal (ECCO₂R) techniques and devices have been developed. They include low-flow or high-flow systems that may be performed with dedicated platforms or, alternatively, combined with continuous renal replacement therapy (CRRT). ECCO₂R has demonstrated effectiveness in controlling PaCO₂ levels, thus allowing LPV in patients with ARDS from different causes, including those affected by Coronavirus disease 2019 (COVID-19). Similarly, the suitability and safety of combined ECCO₂R and CRRT (ECCO₂R–CRRT), which provides CO₂ removal and kidney support simultaneously, have been reported in both retrospective and prospective studies. However, due to the complexity of ARDS patients and the limitations of current evidence, the actual impact of ECCO₂R on patient outcome still remains to be defined. In this review, we discuss the main principles of ECCO₂R and its clinical application in ARDS patients, in particular looking at clinical experiences of combined ECCO₂R–CRRT treatments. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessReview

COVID-19 in Patients with Hematologic Diseases

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Ilaria Carola Casetti

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Oscar Borsani

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Elisa Rumi

Biomedicines 2022, 10(12), 3069; https://doi.org/10.3390/biomedicines10123069 - 29 Nov 2022

Cited by 2 | Viewed by 1774

Abstract

The COVID-19 outbreak had a strong impact on people’s lives all over the world. Patients with hematologic diseases have been heavily affected by the pandemic, because their immune system may be compromised due to anti-cancer or immunosuppressive therapies and because diagnosis and treatment [...] Read more.

The COVID-19 outbreak had a strong impact on people’s lives all over the world. Patients with hematologic diseases have been heavily affected by the pandemic, because their immune system may be compromised due to anti-cancer or immunosuppressive therapies and because diagnosis and treatment of their baseline conditions were delayed during lockdowns. Hematologic malignancies emerged very soon as risk factors for severe COVID-19 infection, increasing the mortality rate. SARS-CoV2 can also induce or exacerbate immune-mediated cytopenias, such as autoimmune hemolytic anemias, complement-mediated anemias, and immune thrombocytopenia. Active immunization with vaccines has been shown to be the best prophylaxis of severe COVID-19 in hematologic patients. However, the immune response to vaccines may be significantly impaired, especially in those receiving anti-CD20 monoclonal antibodies or immunosuppressive agents. Recently, antiviral drugs and monoclonal antibodies have become available for pre-exposure and post-exposure prevention of severe COVID-19. As adverse events after vaccines are extremely rare, the cost–benefit ratio is largely in favor of vaccination, even in patients who might be non-responders; in the hematological setting, all patients should be considered at high risk of developing complications due to SARS-CoV2 infection and should be offered all the therapies aimed to prevent them. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessReview

Medical Records: A Historical Narrative

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Jacek Lorkowski

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Mieczyslaw Pokorski

Biomedicines 2022, 10(10), 2594; https://doi.org/10.3390/biomedicines10102594 - 17 Oct 2022

Cited by 3 | Viewed by 3173

Abstract

The history of medical records is thousand-year-long, with earlier roots in ancient civilizations. Until the 19th century, medical records mainly served educational purposes, later assuming other roles such as in insurance or legal procedures. This article comprehensively describes and reviews the development of [...] Read more.

The history of medical records is thousand-year-long, with earlier roots in ancient civilizations. Until the 19th century, medical records mainly served educational purposes, later assuming other roles such as in insurance or legal procedures. This article comprehensively describes and reviews the development of medical records from ancient to modern times in Europe and North America, reflecting alterations and adaptations compliant with the mental and technological capabilities of a given period. We searched PubMed and Google Scholar databases to collect pertinent articles. English articles or those having English abstracts were considered. The search terms included “Medical Records,” “Health Records,” “History of Medicine,” and “eHealth” and covered the last hundred years. References were also picked out from the identified articles. Overall, 600 articles were identified, 158 of which were judged thematically relevant. The general conclusion is that medical records undergo a revolutionary change from paper-based to electronic format, which reflects the development of eHealth systems. The migration process to eHealth records involves the use of artificial intelligence (AI) algorithms that streamline medical services by using faster and simpler working methods. AI benefits both patients and providers as it improves patient management and communication among medical centers, spares resources, identifies contamination or infections, and limits health costs. These advantages have become pointedly apparent during the recent COVID-19 scourge. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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The Biosynthesis and Medicinal Properties of Taraxerol

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Biomedicines 2022, 10(4), 807; https://doi.org/10.3390/biomedicines10040807 - 30 Mar 2022

Cited by 7 | Viewed by 1951

Abstract

Taraxerol is a pentacyclic triterpenoid that is actively produced by some higher plants as part of a defense mechanism. The biosynthesis of taraxerol in plants occurs through the mevalonate pathway in the cytosol, in which dimethylallyl diphosphate (DMAPP) and isopentyl pyrophosphate (IPP) are [...] Read more.

Taraxerol is a pentacyclic triterpenoid that is actively produced by some higher plants as part of a defense mechanism. The biosynthesis of taraxerol in plants occurs through the mevalonate pathway in the cytosol, in which dimethylallyl diphosphate (DMAPP) and isopentyl pyrophosphate (IPP) are first produced, followed by squalene. Squalene is the primary precursor for the synthesis of triterpenoids, including taraxerol, β-amyrin, and lupeol, which are catalyzed by taraxerol synthase. Taraxerol has been extensively investigated for its medicinal and pharmacological properties, and various biotechnological approaches have been established to produce this compound using in vitro techniques. This review provides an in-depth summary of the hypothesized taraxerol biosynthetic pathway, the medicinal properties of taraxerol, and recent developments on tissue culture for the in vitro production of taraxerol. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessSystematic Review

Efficacy and Safety of [¹⁷⁷Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor-Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review

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Berna Degirmenci Polack

Biomedicines 2023, 11(4), 1024; https://doi.org/10.3390/biomedicines11041024 - 27 Mar 2023

Viewed by 1292

Abstract

Background: We have performed a systematic review to evaluate the efficacy and safety of [¹⁷⁷Lu]Lu-DOTA-TATE, a radioligand therapy, in advanced somatostatin receptor-positive pheochromocytoma/paraganglioma (PPGL), thymic neuroendocrine tumor (NET), bronchial NET, unknown primary NET, or medullary thyroid carcinoma (MTC). Methods: Studies identified [...] Read more.

Background: We have performed a systematic review to evaluate the efficacy and safety of [¹⁷⁷Lu]Lu-DOTA-TATE, a radioligand therapy, in advanced somatostatin receptor-positive pheochromocytoma/paraganglioma (PPGL), thymic neuroendocrine tumor (NET), bronchial NET, unknown primary NET, or medullary thyroid carcinoma (MTC). Methods: Studies identified in PubMed from inception to 13 May 2021 must have assessed [¹⁷⁷Lu]Lu-DOTA-TATE as a single agent and reported outcome data for the specific NET types of interest. Results: Two independent reviewers performed the screening and data extraction, resulting in 16 publications: PPGL (n = 7), bronchial NETs (n = 6; one also included NETs of unknown origin), and MTC (n = 3). Overall, [¹⁷⁷Lu]Lu-DOTA-TATE offers encouraging antitumor activity (overall tumor response rates and disease control rates) across NET types. Safety was favorable with most adverse events mild to moderate in severity, transient, and consistent with those seen in patients with gastroenteropancreatic (GEP)-NETs. Conclusions: [¹⁷⁷Lu]Lu-DOTA-TATE has been used effectively in clinical practice to treat NETs of non-GEP origin. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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Open AccessSystematic Review

Serum Magnesium Levels in Patients with Obstructive Sleep Apnoea: A Systematic Review and Meta-Analysis

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Zahraa Al Wadee

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Soo Liang Ooi

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Sok Cheon Pak

Biomedicines 2022, 10(9), 2273; https://doi.org/10.3390/biomedicines10092273 - 14 Sep 2022

Cited by 1 | Viewed by 1692

Abstract

Aims: Obstructive sleep apnoea (OSA) affects patients’ quality of life and health. Magnesium (Mg) is an essential mineral and a potent antioxidant. Mg deficiency can worsen oxidative stress caused by sleep deprivation or disorders. The impact of OSA on serum Mg levels and [...] Read more.

Aims: Obstructive sleep apnoea (OSA) affects patients’ quality of life and health. Magnesium (Mg) is an essential mineral and a potent antioxidant. Mg deficiency can worsen oxidative stress caused by sleep deprivation or disorders. The impact of OSA on serum Mg levels and its health consequences remain unclear. Data Synthesis: This study systematically reviewed clinical studies investigating the serum Mg levels of OSA patients and the potential relationships with other biomarkers. Six articles were included for qualitative synthesis and quantitative analysis. Two out of four studies that compared OSA patients to healthy controls found them to have significantly lower serum Mg levels. Our meta-analysis with three studies shows that patients with OSA had significantly lower serum Mg with an effect size of −1.22 (95% CI: −2.24, −0.21). However, the mean serum Mg level of OSA patients (n = 251) pooled from five studies (1.90 mg/dL, 95% CI: 1.77, 2.04) does not differ significantly from the normal range between 1.82 to 2.30 mg/dL. OSA severity appears to affect serum Mg negatively. Serum Mg levels generally improve after treatment, coinciding with the improvement of OSA severity. Low serum Mg levels correlate with the worsening of cardiovascular risk biomarkers of C-reactive protein, ischaemia-modified albumin, and carotid intima-media thickness. The serum Mg levels also potentially correlate with biomarkers for lipid profile, glucose metabolism, calcium, and heavy metals. Conclusions: Sleep deprivation appears to deplete Mg levels of OSA patients, making them at risk of Mg deficiency, which potentially increases systemic inflammation and the risk of cardiovascular and metabolic diseases. Full article

(This article belongs to the Special Issue Biomedicines: 10th Anniversary)

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