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Biomedicines, Volume 10, Issue 3 (March 2022) – 215 articles

Cover Story (view full-size image): Mitochondrial toxicity induced by some anticancer drugs, including certain RTKIs and PIs, is a major mechanism underlying the increased risk of cardiovascular events secondary to their use. These cardiac mitochondrial impairments are due to different mechanisms, generally altering mitochondrial respiratory chains and mitochondrial dynamics, and are reflected by dramatic changes in ROS generation and lipid formation that lead to mitochondrial oxidative/nitrative stress, eventually culminating in cell death. Notably, PI-mediated mitochondrial dysfunction might also be explained by the recently described process of the extraction of misfolded proteins from mitochondria and their subsequent degradation in proteasomes, called mitochondria-associated degradation. View this paper
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14 pages, 1224 KiB  
Article
Mechanistic Insights into Inorganic Nitrite-Mediated Vasodilation of Isolated Aortic Rings under Oxidative/Hypertensive Conditions and S-Nitros(yl)ation of Proteins in Germ-Free Mice
by Paul Stamm, Sanela Kalinovic, Matthias Oelze, Sebastian Steven, Alexander Czarnowski, Miroslava Kvandova, Franziska Bayer, Christoph Reinhardt, Thomas Münzel and Andreas Daiber
Biomedicines 2022, 10(3), 730; https://doi.org/10.3390/biomedicines10030730 - 21 Mar 2022
Cited by 1 | Viewed by 2328
Abstract
The prevalence and clinical importance of arterial hypertension are still growing. Inorganic nitrite (NO2) represents an attractive dietary antihypertensive agent, but its metabolism and mode of action, which we aimed to investigate with the present study, are not completely understood. [...] Read more.
The prevalence and clinical importance of arterial hypertension are still growing. Inorganic nitrite (NO2) represents an attractive dietary antihypertensive agent, but its metabolism and mode of action, which we aimed to investigate with the present study, are not completely understood. Isolated aortic rings from rats were treated ex vivo with oxidants, and rats were infused in vivo with angiotensin-II. Vascular responses to acetylcholine (ACh) and nitrite were assessed by isometric tension recording. The loss of vasodilatory potency in response to oxidants was much more pronounced for ACh as compared to nitrite ex vivo (but not in vivo with angiotensin-II). This effect may be caused by the redox regulation of conversion to xanthine oxidase (XO). Conventionally raised and germ-free mice were treated with nitrite by gavage, which did not improve ACh-mediated vasodilation, but did increase the plasma levels of S-nitros(yl)ated proteins in the conventionally-raised, but not in the germ-free mice. In conclusion, inorganic nitrite represents a dietary drug option to treat arterial hypertension in addition to already established pharmacological treatment. Short-term oxidative stress did not impair the vasodilatory properties of nitrite, which may be beneficial in cardiovascular disease patients. The gastrointestinal microbiome appears to play a key role in nitrite metabolism and bioactivation. Full article
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15 pages, 2979 KiB  
Systematic Review
Putative Role of the Lung–Brain Axis in the Pathogenesis of COVID-19-Associated Respiratory Failure: A Systematic Review
by Francesco Gentile, Tommaso Bocci, Silvia Coppola, Tommaso Pozzi, Leo Modafferi, Alberto Priori and Davide Chiumello
Biomedicines 2022, 10(3), 729; https://doi.org/10.3390/biomedicines10030729 - 21 Mar 2022
Cited by 5 | Viewed by 4033
Abstract
The emergence of SARS-CoV-2 and its related disease caused by coronavirus (COVID-19) has posed a huge threat to the global population, with millions of deaths and the creation of enormous social and healthcare pressure. Several studies have shown that besides respiratory illness, other [...] Read more.
The emergence of SARS-CoV-2 and its related disease caused by coronavirus (COVID-19) has posed a huge threat to the global population, with millions of deaths and the creation of enormous social and healthcare pressure. Several studies have shown that besides respiratory illness, other organs may be damaged as well, including the heart, kidneys, and brain. Current evidence reports a high frequency of neurological manifestations in COVID-19, with significant prognostic implications. Importantly, emerging literature is showing that the virus may spread to the central nervous system through neuronal routes, hitting the brainstem and cardiorespiratory centers, potentially exacerbating the respiratory illness. In this systematic review, we searched public databases for all available evidence and discuss current clinical and pre-clinical data on the relationship between the lung and brain during COVID-19. Acknowledging the involvement of these primordial brain areas in the pathogenesis of the disease may fuel research on the topic and allow the development of new therapeutic strategies. Full article
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26 pages, 659 KiB  
Review
Detection of TERT Promoter Mutations as a Prognostic Biomarker in Gliomas: Methodology, Prospects, and Advances
by Tsimur Hasanau, Eduard Pisarev, Olga Kisil, Naosuke Nonoguchi, Florence Le Calvez-Kelm and Maria Zvereva
Biomedicines 2022, 10(3), 728; https://doi.org/10.3390/biomedicines10030728 - 21 Mar 2022
Cited by 15 | Viewed by 6782
Abstract
This article reviews the existing approaches to determining the TERT promoter mutational status in patients with various tumoral diseases of the central nervous system. The operational characteristics of the most common methods and their transferability in medical practice for the selection or monitoring [...] Read more.
This article reviews the existing approaches to determining the TERT promoter mutational status in patients with various tumoral diseases of the central nervous system. The operational characteristics of the most common methods and their transferability in medical practice for the selection or monitoring of personalized treatments based on the TERT status and other related molecular biomarkers in patients with the most common tumors, such as glioblastoma, oligodendroglioma, and astrocytoma, are compared. The inclusion of new molecular markers in the course of CNS clinical management requires their rapid and reliable assessment. Availability of molecular evaluation of gliomas facilitates timely decisions regarding patient follow-up with the selection of the most appropriate treatment protocols. Significant progress in the inclusion of molecular biomarkers for their subsequent clinical application has been made since 2016 when the WHO CNS classification first used molecular markers to classify gliomas. In this review, we consider the methodological approaches used to determine mutations in the promoter region of the TERT gene in tumors of the central nervous system. In addition to classical molecular genetical methods, other methods for determining TERT mutations based on mass spectrometry, magnetic resonance imaging, next-generation sequencing, and nanopore sequencing are reviewed with an assessment of advantages and disadvantages. Beyond that, noninvasive diagnostic methods based on the determination of the mutational status of the TERT promoter are discussed. Full article
(This article belongs to the Special Issue Telomerase: Role in Health and Aging)
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14 pages, 34007 KiB  
Article
Evaluation of AIF-1 (Allograft Inflammatory Factor-1) as a Biomarker of Crohn’s Disease Severity
by Luis G. Guijarro, David Cano-Martínez, M. Val Toledo-Lobo, Lidia Ruiz-Llorente, María Chaparro, Iván Guerra, Marisa Iborra, José Luis Cabriada, Luis Bujanda, Carlos Taxonera, Valle García-Sánchez, Ignacio Marín-Jiménez, Manuel Barreiro-de Acosta, Isabel Vera, María Dolores Martín-Arranz, Francisco Mesonero, Laura Sempere, Fernando Gomollón, Joaquín Hinojosa, Sofía Zoullas, Jorge Monserrat, Cesar Menor-Salvan, Melchor Alvarez-Mon, Javier P. Gisbert, Miguel A. Ortega and Borja Hernández-Breijoadd Show full author list remove Hide full author list
Biomedicines 2022, 10(3), 727; https://doi.org/10.3390/biomedicines10030727 - 21 Mar 2022
Cited by 5 | Viewed by 2405
Abstract
Background: Recently, increased tissue levels of AIF-1 have been shown in experimental colitis, supporting its role in intestinal inflammation. Therefore, we studied the levels of AIF-1 in Crohn’s disease (CD). Methods: This study included 33 patients with CD (14 men and 19 women) [...] Read more.
Background: Recently, increased tissue levels of AIF-1 have been shown in experimental colitis, supporting its role in intestinal inflammation. Therefore, we studied the levels of AIF-1 in Crohn’s disease (CD). Methods: This study included 33 patients with CD (14 men and 19 women) who participated in the PREDICROHN project, a prospective multicenter study of the Spanish Group of Inflammatory bowel disease (GETECCU). Results: This article demonstrates declines with respect to baseline levels of serum AIF-1 in Crohn’s disease (CD) patients after 14 weeks of treatment with anti-TNFs. Furthermore, in patients with active CD (HB ≥ 5), serum AIF-1 levels were significantly higher than those in patients without activity (HB ≤ 4). The study of serum AIF-1 in the same cohort, revealed an area under the ROC curve (AUC) value of AUC = 0.66 (p = 0.014), while for the CRP (C-reactive protein), (AUC) value of 0.69 (p = 0.0066), indicating a similar ability to classify CD patients by their severity. However, the combination of data on serum levels of AIF-1 and CRP improves the predictive ability of these analyses for classifying CD patients as active (HB ≥ 5) or inactive (HB ≤ 4). When we used the odds ratio (OR) formula, we observed that patients with CRP > 5 mg/L or AIF-1 > 200 pg/mL or both conditions were 13 times more likely to show HB ≥ 5 (active CD) than were those with both markers below these thresholds. Conclusion: The development of an algorithm that includes serum levels of AIF-1 and CRP could be useful for assessing Crohn’s disease severity. Full article
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22 pages, 7688 KiB  
Review
Some Insights into the Regulation of Cardiac Physiology and Pathology by the Hippo Pathway
by Daniela Ramaccini, Gaia Pedriali, Mariasole Perrone, Esmaa Bouhamida, Lorenzo Modesti, Mariusz R. Wieckowski, Carlotta Giorgi, Paolo Pinton and Giampaolo Morciano
Biomedicines 2022, 10(3), 726; https://doi.org/10.3390/biomedicines10030726 - 21 Mar 2022
Cited by 3 | Viewed by 2888
Abstract
The heart is one of the most fascinating organs in living beings. It beats up to 100,000 times a day throughout the lifespan, without resting. The heart undergoes profound anatomical, biochemical, and functional changes during life, from hypoxemic fetal stages to a completely [...] Read more.
The heart is one of the most fascinating organs in living beings. It beats up to 100,000 times a day throughout the lifespan, without resting. The heart undergoes profound anatomical, biochemical, and functional changes during life, from hypoxemic fetal stages to a completely differentiated four-chambered cardiac muscle. In the middle, many biological events occur after and intersect with each other to regulate development, organ size, and, in some cases, regeneration. Several studies have defined the essential roles of the Hippo pathway in heart physiology through the regulation of apoptosis, autophagy, cell proliferation, and differentiation. This molecular route is composed of multiple components, some of which were recently discovered, and is highly interconnected with multiple known prosurvival pathways. The Hippo cascade is evolutionarily conserved among species, and in addition to its regulatory roles, it is involved in disease by drastically changing the heart phenotype and its function when its components are mutated, absent, or constitutively activated. In this review, we report some insights into the regulation of cardiac physiology and pathology by the Hippo pathway. Full article
(This article belongs to the Special Issue Key Processes in Health and Disease Regulated by the Hippo Pathway)
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23 pages, 797 KiB  
Review
Circular RNAs as Potential Biomarkers in Breast Cancer
by Fatima Domenica Elisa De Palma, Francesco Salvatore, Jonathan G. Pol, Guido Kroemer and Maria Chiara Maiuri
Biomedicines 2022, 10(3), 725; https://doi.org/10.3390/biomedicines10030725 - 21 Mar 2022
Cited by 26 | Viewed by 4363
Abstract
Due to the high heterogeneity and initially asymptomatic nature of breast cancer (BC), the management of this disease depends on imaging together with immunohistochemical and molecular evaluations. These tests allow early detection of BC and patient stratification as they guide clinicians in prognostication [...] Read more.
Due to the high heterogeneity and initially asymptomatic nature of breast cancer (BC), the management of this disease depends on imaging together with immunohistochemical and molecular evaluations. These tests allow early detection of BC and patient stratification as they guide clinicians in prognostication and treatment decision-making. Circular RNAs (circRNAs) represent a class of newly identified long non-coding RNAs. These molecules have been described as key regulators of breast carcinogenesis and progression. Moreover, circRNAs play a role in drug resistance and are associated with clinicopathological features in BC. Accumulating evidence reveals a clinical interest in deregulated circRNAs as diagnostic, prognostic and predictive biomarkers. Furthermore, due to their covalently closed structure, circRNAs are highly stable and easily detectable in body fluids, making them ideal candidates for use as non-invasive biomarkers. Herein, we provide an overview of the biogenesis and pleiotropic functions of circRNAs, and report on their clinical relevance in BC. Full article
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31 pages, 4263 KiB  
Review
A Bioinformatics-Assisted Review on Iron Metabolism and Immune System to Identify Potential Biomarkers of Exercise Stress-Induced Immunosuppression
by Diego A. Bonilla, Yurany Moreno, Jorge L. Petro, Diego A. Forero, Salvador Vargas-Molina, Adrián Odriozola-Martínez, Carlos A. Orozco, Jeffrey R. Stout, Eric S. Rawson and Richard B. Kreider
Biomedicines 2022, 10(3), 724; https://doi.org/10.3390/biomedicines10030724 - 21 Mar 2022
Cited by 10 | Viewed by 5137
Abstract
The immune function is closely related to iron (Fe) homeostasis and allostasis. The aim of this bioinformatics-assisted review was twofold; (i) to update the current knowledge of Fe metabolism and its relationship to the immune system, and (ii) to perform a prediction analysis [...] Read more.
The immune function is closely related to iron (Fe) homeostasis and allostasis. The aim of this bioinformatics-assisted review was twofold; (i) to update the current knowledge of Fe metabolism and its relationship to the immune system, and (ii) to perform a prediction analysis of regulatory network hubs that might serve as potential biomarkers during stress-induced immunosuppression. Several literature and bioinformatics databases/repositories were utilized to review Fe metabolism and complement the molecular description of prioritized proteins. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to build a protein-protein interactions network for subsequent network topology analysis. Importantly, Fe is a sensitive double-edged sword where two extremes of its nutritional status may have harmful effects on innate and adaptive immunity. We identified clearly connected important hubs that belong to two clusters: (i) presentation of peptide antigens to the immune system with the involvement of redox reactions of Fe, heme, and Fe trafficking/transport; and (ii) ubiquitination, endocytosis, and degradation processes of proteins related to Fe metabolism in immune cells (e.g., macrophages). The identified potential biomarkers were in agreement with the current experimental evidence, are included in several immunological/biomarkers databases, and/or are emerging genetic markers for different stressful conditions. Although further validation is warranted, this hybrid method (human-machine collaboration) to extract meaningful biological applications using available data in literature and bioinformatics tools should be highlighted. Full article
(This article belongs to the Special Issue Bioinformatics and Its Application in Biomedicine)
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13 pages, 2926 KiB  
Article
Production and Secretion of Gelsolin by Both Human Macrophage- and Fibroblast-like Synoviocytes and GSN Modulation in the Synovial Fluid of Patients with Various Forms of Arthritis
by Jessica Feldt, Martin Schicht, Jessica Welss, Kolja Gelse, Stefan Sesselmann, Michael Tsokos, Eileen Socher, Fabian Garreis, Thomas Müller and Friedrich Paulsen
Biomedicines 2022, 10(3), 723; https://doi.org/10.3390/biomedicines10030723 - 21 Mar 2022
Cited by 2 | Viewed by 2253
Abstract
Gelsolin (GSN) is an actin-binding protein involved in cell formation, metabolism and wound closure processes. Since this protein is known to play a role in arthritis, here we investigate how the synovial membrane with its specific synoviocytes contributes to the expression of GSN [...] Read more.
Gelsolin (GSN) is an actin-binding protein involved in cell formation, metabolism and wound closure processes. Since this protein is known to play a role in arthritis, here we investigate how the synovial membrane with its specific synoviocytes contributes to the expression of GSN and how the amount of GSN expressed is modulated by different types of arthritis. Synovial membranes from adult healthy subjects and patients with rheumatoid arthritis (RA) and osteoarthritis (OA) are analyzed by immunofluorescence, Western blot and ELISA. Macrophage-like synoviocytes (MLS) and fibroblast-like synoviocytes (FLS) were isolated, cultured and analyzed for their potential to produce and secrete GSN. In addition, the GSN concentrations in the synovial fluid of various forms of arthritis are determined by ELISA. GSN is produced by the healthy and arthritic synovial membranes. Both forms of synoviocytes (MLS and FLS) release GSN. The results show that there is a significant reduction in GSN in the synovial fluid in adult patients with OA. This reduction is also detectable in adult patients with RA but is not as evident. In juvenile arthritis, there is a slight increase in GSN concentration in the synovial fluid. This study shows that primary MLS and FLS express GSN and that these cells, in addition to articular chondrocytes, contribute to GSN levels in synovial fluid. Furthermore, GSN concentrations are modulated in different types of arthritis. Further studies are needed to fully understand how GSN is involved in joint homeostasis. Full article
(This article belongs to the Section Immunology and Immunotherapy)
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21 pages, 4442 KiB  
Article
Anticancer Effects with Molecular Docking Confirmation of Newly Synthesized Isatin Sulfonamide Molecular Hybrid Derivatives against Hepatic Cancer Cell Lines
by Mahmoud Eldeeb, Eman F. Sanad, Ahmed Ragab, Yousry A. Ammar, Khaled Mahmoud, Mamdouh M. Ali and Nadia M. Hamdy
Biomedicines 2022, 10(3), 722; https://doi.org/10.3390/biomedicines10030722 - 20 Mar 2022
Cited by 36 | Viewed by 4019
Abstract
The current study investigated the cytotoxic effect of ten sulfonamide-derived isatins, following molecular hybridization, based on the association principles, on hepatocellular carcinoma (HCC) HepG2 and Huh7 cell lines, compared for safety using human normal retina pigmented epithelial (RPE-1) cells. The ten compounds showed [...] Read more.
The current study investigated the cytotoxic effect of ten sulfonamide-derived isatins, following molecular hybridization, based on the association principles, on hepatocellular carcinoma (HCC) HepG2 and Huh7 cell lines, compared for safety using human normal retina pigmented epithelial (RPE-1) cells. The ten compounds showed variable in vitro cytotoxicity on HepG2 and Huh7 cells, using the MTT assay. Four compounds (4/10) were highly cytotoxic to both HepG2 and HuH7. However, only 3 of these 4 were of the highest safety margin on RPE-1 cells in vitro and in the in vivo acute (14-day) oral toxicity study. These later, superior three compounds’ structures are 3-hydroxy-3-(2-oxo-2-(p-tolyl)ethyl)-5-(piperidin-1-ylsulfonyl)indolin-2-one (3a), N-(4-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4b), and N-(3-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4c). The half-maximal inhibitory concentration (IC50) of the tested compounds (3a, 4b, and 4c) on HepG2 cells were approximately 16.8, 44.7, and 39.7 μM, respectively. The 3a, 4b, and 4c compounds significantly decreased the angiogenic marker epithelial growth factor receptor (EGFR) level and that was further confirmed via molecular docking inside the EFGR active site (PDB: 1M17). The binding free energies ranged between −19.21 and −21.74 Kcal/mol compared to Erlotinib (−25.65 Kcal/mol). The most promising compounds, 3a, 4b, and 4c, showed variable anticancer potential on “hallmarks of cancer”, significant cytotoxicity, and apoptotic anti-angiogenic and anti-invasive effects, manifested as suppression of Bcl-2, urokinase plasminogen activation, and heparanase expression in HepG2-treated cells’ lysate, compared to non-treated HepG2 cells. In conclusion, compound “3a” is highly comparable to doxorubicin regarding cell cycle arrest at G2/M, the pre-G0 phases and early and late apoptosis induction and is comparable to Erlotinib regarding binding to EGFR active site. Therefore, the current study could suggest that compound “3a” is, hopefully, the most safe and active synthesized isatin sulfonamide derivative for HCC management. Full article
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20 pages, 6444 KiB  
Article
Activation of Voltage-Gated Na+ Current by GV-58, a Known Activator of CaV Channels
by Hsin-Yen Cho, Pei-Chun Chen, Tzu-Hsien Chuang, Meng-Cheng Yu and Sheng-Nan Wu
Biomedicines 2022, 10(3), 721; https://doi.org/10.3390/biomedicines10030721 - 20 Mar 2022
Cited by 4 | Viewed by 1657
Abstract
GV-58 ((2R)-2-[(6-{[(5-methylthiophen-2-yl)methyl]amino}-9-propyl-9H-purin-2-yl)amino]butan-1-ol) is recognized to be an activator of N- and P/Q-type Ca2+ currents. However, its modulatory actions on other types of ionic currents in electrically excitable cells remain largely unanswered. This study was undertaken to explore the possible modifications [...] Read more.
GV-58 ((2R)-2-[(6-{[(5-methylthiophen-2-yl)methyl]amino}-9-propyl-9H-purin-2-yl)amino]butan-1-ol) is recognized to be an activator of N- and P/Q-type Ca2+ currents. However, its modulatory actions on other types of ionic currents in electrically excitable cells remain largely unanswered. This study was undertaken to explore the possible modifications caused by GV-58 in ionic currents (e.g., voltage-gated Na+ current [INa], A-type K+ current [IK(A)], and erg-mediated K+ current [IK(erg)]) identified from pituitary GH3 lactotrophs. GH3 cell exposure to GV-58 enhanced the transient and late components of INa with varying potencies; consequently, the EC50 values of GV-58 required for its differential increase in peak and late INa in GH3 cells were estimated to be 8.9 and 2.6 μM, respectively. The INa in response to brief depolarizing pulse was respectively stimulated or suppressed by GV-58 or tetrodotoxin, but it failed to be altered by ω-conotoxin MVIID. Cell exposure to this compound increased the recovery of INa inactivation evoked by two-pulse protocol based on a geometrics progression; however, in its presence, there was a slowing in the inactivation rate of current decay evoked by a train of depolarizing pulses. The existence of GV-58 also resulted in an increase in the amplitude of ramp-induced resurgent and window INa. The presence of this compound inhibited IK(A) magnitude, accompanied by a shortening in inactivation time course of the current; however, it mildly decreased IK(erg). Under current-clamp conditions, GV-58 increased the frequency of spontaneous action potentials in GH3 cells. Moreover, in NSC-34 motor neuron-like cells, the presence of GV-58 not only raised INa amplitude but also reduced current inactivation. Taken together, the overall work provides a noticeable yet unidentified finding which implies that, in addition to its agonistic effect on Ca2+ currents, GV-58 may concertedly modify the amplitude and gating kinetics of INa in electrically excitable cells, hence modifiying functional activities in these cells. Full article
(This article belongs to the Special Issue Actions of Small Molecules on Varying Type of Membrane Ion Channels)
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11 pages, 458 KiB  
Article
Metabolic Syndrome but Not Fatty Liver-Associated Genetic Variants Correlates with Glomerular Renal Function Decline in Patients with Non-Alcoholic Fatty Liver Disease
by Francesco Baratta, Laura D’Erasmo, Alessia Di Costanzo, Ilaria Umbro, Daniele Pastori, Francesco Angelico and Maria Del Ben
Biomedicines 2022, 10(3), 720; https://doi.org/10.3390/biomedicines10030720 - 19 Mar 2022
Cited by 5 | Viewed by 2316
Abstract
The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in [...] Read more.
The association between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) has been extensively demonstrated. Recent studies have focused attention on the role of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism in the association between NAFLD and CKD in non-metabolic adults and children, but the genetic impact on NAFLD-CKD association is still a matter of debate. The aim of the study was to investigate the impact of PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and glucokinase regulatory protein (GCKR) gene variants rather than metabolic syndrome features on renal function in a large population of NAFLD patients. The present study is a post hoc analysis of the Plinio Study (ClinicalTrials.gov: NCT04036357). PNPLA3, TM6SF2MBOAT7 and GCKR genes were analyzed by using real-time PCR with TaqMan probes. Glomerular filtration rate (GFR) was estimated with CKD-EPI. We analyzed 538 NAFLD; 47.2% had GFR < 90 mL/min/1.73 m2 while 5.9% had GFR < 60 mL/min/1.73 m2. The distribution of genotypes was superimposable according to GFR cut-offs. Results from the multivariable regression model did not show any correlation between genotypes and renal function. Conversely, metabolic syndrome was highly associated with GFR < 90 mL/min/1.73 m2 (odds ratio (OR): 1.58 [1.10–2.28]) and arterial hypertension with GFR < 60 mL/min/1.73 m2 (OR: 1.50 [1.05–2.14]). In conclusion, the association between NAFLD and CKD might be related to the shared metabolic risk factors rather than the genetic NAFLD background. Full article
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13 pages, 1368 KiB  
Article
Prognostic Value of Mid-Regional Proadrenomedullin Sampled at Presentation and after 72 Hours in Septic Patients Presenting to the Emergency Department: An Observational Two-Center Study
by Paolo Bima, Giorgia Montrucchio, Valeria Caramello, Francesca Rumbolo, Stefania Dutto, Sarah Boasso, Anita Ferraro, Luca Brazzi, Enrico Lupia, Adriana Boccuzzi, Giulio Mengozzi, Fulvio Morello and Stefania Battista
Biomedicines 2022, 10(3), 719; https://doi.org/10.3390/biomedicines10030719 - 19 Mar 2022
Cited by 8 | Viewed by 1771
Abstract
The prognostic value of mid-regional proADM (MR-proADM) in septic patients presenting to the emergency department (ED) is not well established. In this prospective observational study enrolling septic patients evaluated in two EDs, MR-proADM was measured at arrival (t0) and after 72 h (t72). [...] Read more.
The prognostic value of mid-regional proADM (MR-proADM) in septic patients presenting to the emergency department (ED) is not well established. In this prospective observational study enrolling septic patients evaluated in two EDs, MR-proADM was measured at arrival (t0) and after 72 h (t72). MR-proADM%change was calculated as follows: (MR-proADMt72h − MR-proADMt0)/MR-proADMt0. In total, 147 patients were included in the study, including 109 with a final diagnosis of sepsis and 38 with septic shock, according to the Sepsis-3 criteria. The overall 28-day mortality (outcome) rate was 12.9%. The AUC for outcome prognostication was 0.66 (95% CI 0.51–0.80) for MR-proADMt0, 0.77 (95% CI 0.63–0.92) for MR-proADMt72 and 0.74 (95% CI 0.64–0.84) for MR-proADM%change. MR-proADMt0 ≥ 2.78 nmol/L, MR-proADMt72 ≥ 2.7 nmol/L and MR-proADM%change ≥ −15.2% showed statistically significant log-rank test results and sensitivity/specificity of 81/65%, 69/80% and 75/70% respectively. In regression analysis, MR-proADM%change was a significant outcome predictor both in univariate and multivariate analysis, after adjustment for age, SOFA and APACHEII scores, providing up to 80% of added prognostic value. In conclusion, time trends of MR-proADM may provide additional insights for patient risk stratification over single sampling. MR-proADM levels sampled both at presentation and after 72 h predicted 28-day survival in septic patients presenting to the ED. Full article
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16 pages, 1270 KiB  
Article
First-Trimester Screening for Fetal Growth Restriction and Small-for-Gestational-Age Pregnancies without Preeclampsia Using Cardiovascular Disease-Associated MicroRNA Biomarkers
by Ilona Hromadnikova, Katerina Kotlabova and Ladislav Krofta
Biomedicines 2022, 10(3), 718; https://doi.org/10.3390/biomedicines10030718 - 19 Mar 2022
Cited by 17 | Viewed by 2989
Abstract
The goal of the study was to determine the early diagnostical potential of cardiovascular disease-associated microRNAs for prediction of small-for-gestational-age (SGA) and fetal growth restriction (FGR) without preeclampsia (PE). The whole peripheral venous blood samples were collected within 10 to 13 weeks of [...] Read more.
The goal of the study was to determine the early diagnostical potential of cardiovascular disease-associated microRNAs for prediction of small-for-gestational-age (SGA) and fetal growth restriction (FGR) without preeclampsia (PE). The whole peripheral venous blood samples were collected within 10 to 13 weeks of gestation from singleton Caucasian pregnancies within the period November 2012 to March 2020. The case-control retrospective study, nested in a cohort, involved all pregnancies diagnosed with SGA (n = 37) or FGR (n = 82) without PE and 80 appropriate-for-gestational age (AGA) pregnancies selected with regard to equality of sample storage time. Gene expression of 29 cardiovascular disease-associated microRNAs was assessed using real-time RT-PCR. Upregulation of miR-16-5p, miR-20a-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, and miR-195-5p was observed in SGA or FGR pregnancies at 10.0% false positive rate (FPR). Upregulation of miR-1-3p, miR-20b-5p, miR-126-3p, miR-130b-3p, and miR-499a-5p was observed in SGA pregnancies only at 10.0% FPR. Upregulation of miR-145-5p, miR-342-3p, and miR-574-3p was detected in FGR pregnancies at 10.0% FPR. The combination of four microRNA biomarkers (miR-1-3p, miR-20a-5p, miR-146a-5p, and miR-181a-5p) was able to identify 75.68% SGA pregnancies at 10.0% FPR in early stages of gestation. The detection rate of SGA pregnancies without PE increased 4.67-fold (75.68% vs. 16.22%) when compared with the routine first-trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation. The combination of seven microRNA biomarkers (miR-16-5p, miR-20a-5p, miR-145-5p, miR-146a-5p, miR-181a-5p, miR-342-3p, and miR-574-3p) was able to identify 42.68% FGR pregnancies at 10.0% FPR in early stages of gestation. The detection rate of FGR pregnancies without PE increased 1.52-fold (42.68% vs. 28.05%) when compared with the routine first-trimester screening for PE and/or FGR based on the criteria of the Fetal Medicine Foundation. Cardiovascular disease-associated microRNAs represent promising early biomarkers with very suitable predictive potential for SGA or FGR without PE to be implemented into the routine screening programs. Full article
(This article belongs to the Topic Pathogenesis of Pregnancy-Related Complications)
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14 pages, 2253 KiB  
Article
Combined HP 13C Pyruvate and 13C-Glucose Fluxomic as a Potential Marker of Response to Targeted Therapies in YUMM1.7 Melanoma Xenografts
by Chantale Farah, Marie-Aline Neveu, Caner Yelek, Caroline Bouzin, Bernard Gallez, Jean-François Baurain, Lionel Mignion and Bénédicte F. Jordan
Biomedicines 2022, 10(3), 717; https://doi.org/10.3390/biomedicines10030717 - 19 Mar 2022
Cited by 4 | Viewed by 2421
Abstract
A vast majority of BRAF V600E mutated melanoma patients will develop resistance to combined BRAF/MEK inhibition after initial clinical response. Resistance to targeted therapy is described to be accompanied by specific metabolic changes in melanoma. The aim of this work was to evaluate [...] Read more.
A vast majority of BRAF V600E mutated melanoma patients will develop resistance to combined BRAF/MEK inhibition after initial clinical response. Resistance to targeted therapy is described to be accompanied by specific metabolic changes in melanoma. The aim of this work was to evaluate metabolic imaging using 13C-MRS (Magnetic Resonance Spectroscopy) as a marker of response to BRAF/MEK inhibition in a syngeneic melanoma model. Tumor growth was significantly delayed in mice bearing YUMM1.7 melanoma xenografts treated with the BRAF inhibitor vemurafenib, and/or with the MEK inhibitor trametinib, in comparison with the control group. 13C-MRS was performed in vivo after injection of hyperpolarized (HP) 13C-pyruvate, at baseline and 24 h after treatment, to evaluate dynamic changes in pyruvate-lactate exchange. Furthermore, ex vivo 13C-MRS steady state metabolic tracing experiments were performed after U-13C-glucose or 5-13C-glutamine injection, 24 h after treatment. The HP 13C-lactate-to-pyruvate ratio was not modified in response to BRAF/MEK inhibition, whereas the production of 13C-lactate from 13C-glucose was significantly reduced 24 h after treatment with vemurafenib, trametinib, or with the combined inhibitors. Conversely, 13C-glutamine metabolism was not modified in response to BRAF/MEK inhibition. In conclusion, we identified 13C-glucose fluxomic as a potential marker of response to BRAF/MEK inhibition in YUMM1.7 melanoma xenografts. Full article
(This article belongs to the Special Issue Advanced Research in Molecular Imaging of Immunity and Inflammation)
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23 pages, 1438 KiB  
Review
Immune Mechanism of Epileptogenesis and Related Therapeutic Strategies
by María José Aguilar-Castillo, Pablo Cabezudo-García, Nicolas Lundahl Ciano-Petersen, Guillermina García-Martin, Marta Marín-Gracia, Guillermo Estivill-Torrús and Pedro Jesús Serrano-Castro
Biomedicines 2022, 10(3), 716; https://doi.org/10.3390/biomedicines10030716 - 19 Mar 2022
Cited by 9 | Viewed by 3504
Abstract
Immunologic and neuroinflammatory pathways have been found to play a major role in the pathogenesis of many neurological disorders such as epilepsy, proposing the use of novel therapeutic strategies. In the era of personalized medicine and in the face of the exhaustion of [...] Read more.
Immunologic and neuroinflammatory pathways have been found to play a major role in the pathogenesis of many neurological disorders such as epilepsy, proposing the use of novel therapeutic strategies. In the era of personalized medicine and in the face of the exhaustion of anti-seizure therapeutic resources, it is worth looking at the current or future possibilities that neuroimmunomodulator or anti-inflammatory therapy can offer us in the management of patients with epilepsy. For this reason, we performed a narrative review on the recent advances on the basic epileptogenic mechanisms related to the activation of immunity or neuroinflammation with special attention to current and future opportunities for novel treatments in epilepsy. Neuroinflammation can be considered a universal phenomenon and occurs in structural, infectious, post-traumatic, autoimmune, or even genetically based epilepsies. The emerging research developed in recent years has allowed us to identify the main molecular pathways involved in these processes. These molecular pathways could constitute future therapeutic targets for epilepsy. Different drugs current or in development have demonstrated their capacity to inhibit or modulate molecular pathways involved in the immunologic or neuroinflammatory mechanisms described in epilepsy. Some of them should be tested in the future as possible antiepileptic drugs. Full article
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19 pages, 717 KiB  
Review
Involvement of Il-33 in the Pathogenesis and Prognosis of Major Respiratory Viral Infections: Future Perspectives for Personalized Therapy
by Giuseppe Murdaca, Francesca Paladin, Alessandro Tonacci, Matteo Borro, Monica Greco, Alessandra Gerosa, Stefania Isola, Alessandro Allegra and Sebastiano Gangemi
Biomedicines 2022, 10(3), 715; https://doi.org/10.3390/biomedicines10030715 - 19 Mar 2022
Cited by 14 | Viewed by 2895
Abstract
Interleukin (IL)-33 is a key cytokine involved in type-2 immunity and allergic airway disease. At the level of lung epithelial cells, where it is clearly expressed, IL-33 plays an important role in both innate and adaptive immune responses in mucosal organs. It has [...] Read more.
Interleukin (IL)-33 is a key cytokine involved in type-2 immunity and allergic airway disease. At the level of lung epithelial cells, where it is clearly expressed, IL-33 plays an important role in both innate and adaptive immune responses in mucosal organs. It has been widely demonstrated that in the course of respiratory virus infections, the release of IL-33 increases, with consequent pro-inflammatory effects and consequent exacerbation of the clinical symptoms of chronic respiratory diseases. In our work, we analyzed the pathogenetic and prognostic involvement of IL-33 during the main respiratory viral infections, with particular interest in the recent SARS-CoV-2virus pandemic and the aim of determining a possible connection point on which to act with a targeted therapy that is able to improve the clinical outcome of patients. Full article
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15 pages, 2549 KiB  
Article
Periodontal Disease Augments Cardiovascular Disease Risk Biomarkers in Rheumatoid Arthritis
by Jeneen Panezai, Ambereen Ghaffar, Mohammad Altamash, Mikael Åberg, Thomas E. Van Dyke, Anders Larsson and Per-Erik Engström
Biomedicines 2022, 10(3), 714; https://doi.org/10.3390/biomedicines10030714 - 19 Mar 2022
Cited by 4 | Viewed by 3342
Abstract
Objectives: Periodontal disease (PD) and rheumatoid arthritis (RA) are known chronic conditions with sustained inflammation leading to osteolysis. Cardiovascular diseases (CVD) are frequent comorbidities that may arise from sustained inflammation associated with both PD and RA. In order to determine CVD risk, alterations [...] Read more.
Objectives: Periodontal disease (PD) and rheumatoid arthritis (RA) are known chronic conditions with sustained inflammation leading to osteolysis. Cardiovascular diseases (CVD) are frequent comorbidities that may arise from sustained inflammation associated with both PD and RA. In order to determine CVD risk, alterations at the molecular level need to be identified. The objective of this study, therefore, was to assess the relationship of CVD associated biomarkers in RA patients and how it is influenced by PD. Methods: The study consisted of patient (26 RA with PD, 21 RA without PD, 51 patients with PD only) and systemically and periodontally healthy control (n = 20) groups. Periodontal parameters bleeding on probing, probing pocket depth, and marginal bone loss were determined to characterize the patient groups. Proteomic analysis of 92 CVD-related protein biomarkers was performed using a multiplex proximity extension assay. Biomarkers were clustered using the search tool for retrieval of interacting genes (STRING) to determine protein–protein interaction (PPI) networks. Results: RA patients with PD had higher detection levels for 47% of the measured markers (ANGPT1, BOC, CCL17, CCL3, CD4, CD84, CTRC, FGF-21, FGF-23, GLO1, HAOX1, HB-EGF, hOSCAR, HSP 27, IL16, IL-17D, IL18, IL-27, IL6, LEP, LPL, MERTK, MMP12, MMP7, NEMO, PAPPA, PAR-1, PARP-1, PD-L2, PGF, PIgR, PRELP, RAGE, SCF, SLAMF7, SRC, THBS2, THPO, TNFRSF13B, TRAIL-R2, VEGFD, VSIG2, and XCL1) as compared to RA without PD. Furthermore, a strong biological network was identified amongst these proteins (clustering coefficient = 0.52, PPI enrichment p-value < 0.0001). Coefficients for protein clusters involved in CVD (0.59), metabolic (0.53), and skeletal (0.51) diseases were strongest in the PD group. Conclusion: Periodontal disease augments CVD-related biomarkers in RA through shared pathological clusters, concurrently enhancing metabolic and skeletal disease protein interactions, independent of autoimmune status. Full article
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20 pages, 1472 KiB  
Review
Natural Compounds Targeting Cancer-Associated Fibroblasts against Digestive System Tumor Progression: Therapeutic Insights
by Kuan-Jung Chiu, Hsin-Ying Clair Chiou, Chi-Han Huang, Pin-Chun Lu, Hui-Ru Kuo, Jiunn-Wei Wang and Ming-Hong Lin
Biomedicines 2022, 10(3), 713; https://doi.org/10.3390/biomedicines10030713 - 19 Mar 2022
Cited by 14 | Viewed by 3201
Abstract
Cancer-associated fibroblasts (CAFs) are critical for cancer occurrence and progression in the tumor microenvironment (TME), due to their versatile roles in extracellular matrix remodeling, tumor–stroma crosstalk, immunomodulation, and angiogenesis. CAFs are the most abundant stromal component in the TME and undergo epigenetic modification [...] Read more.
Cancer-associated fibroblasts (CAFs) are critical for cancer occurrence and progression in the tumor microenvironment (TME), due to their versatile roles in extracellular matrix remodeling, tumor–stroma crosstalk, immunomodulation, and angiogenesis. CAFs are the most abundant stromal component in the TME and undergo epigenetic modification and abnormal signaling cascade activation, such as transforming growth factor-β (TGF-β) and Wnt pathways that maintain the distinct phenotype of CAFs, which differs from normal fibroblasts. CAFs have been considered therapeutic targets due to their putative oncogenic functions. Current digestive system cancer treatment strategies often result in lower survival outcomes and fail to prevent cancer progression; therefore, comprehensive characterization of the tumor-promoting and -restraining CAF activities might facilitate the design of new therapeutic approaches. In this review, we summarize the enormous literature on natural compounds that mediate the crosstalk of CAFs with digestive system cancer cells, discuss how the biology and the multifaceted functions of CAFs contribute to cancer progression, and finally, pave the way for CAF-related antitumor therapies. Full article
(This article belongs to the Special Issue Tumor Microenvironment Regulation and Anti-cancer Natural Products)
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16 pages, 5666 KiB  
Article
LSEA Evaluation of Lipid Mediators of Inflammation in Lung and Cortex of Mice Exposed to Diesel Air Pollution
by Luca Massimino, Alessandra Bulbarelli, Paola Antonia Corsetto, Chiara Milani, Laura Botto, Francesca Farina, Luigi Antonio Lamparelli, Elena Lonati, Federica Ungaro, Krishna Rao Maddipati, Paola Palestini and Angela Maria Rizzo
Biomedicines 2022, 10(3), 712; https://doi.org/10.3390/biomedicines10030712 - 19 Mar 2022
Cited by 1 | Viewed by 2367
Abstract
Airborne ultrafine particle (UFP) exposure is a great concern as they have been correlated to increased cardiovascular mortality, neurodegenerative diseases and morbidity in occupational and environmental settings. The ultrafine components of diesel exhaust particles (DEPs) represent about 25% of the emission mass; these [...] Read more.
Airborne ultrafine particle (UFP) exposure is a great concern as they have been correlated to increased cardiovascular mortality, neurodegenerative diseases and morbidity in occupational and environmental settings. The ultrafine components of diesel exhaust particles (DEPs) represent about 25% of the emission mass; these particles have a great surface area and consequently high capacity to adsorb toxic molecules, then transported throughout the body. Previous in-vivo studies indicated that DEP exposure increases pro- and antioxidant protein levels and activates inflammatory response both in respiratory and cardiovascular systems. In cells, DEPs can cause additional reactive oxygen species (ROS) production, which attacks surrounding molecules, such as lipids. The cell membrane provides lipid mediators (LMs) that modulate cell-cell communication, inflammation, and resolution processes, suggesting the importance of understanding lipid modifications induced by DEPs. In this study, with a lipidomic approach, we evaluated in the mouse lung and cortex how DEP acute and subacute treatments impact polyunsaturated fatty acid-derived LMs. To analyze the data, we designed an ad hoc bioinformatic pipeline to evaluate the functional enrichment of lipid sets belonging to the specific biological processes (Lipid Set Enrichment Analysis-LSEA). Moreover, the data obtained correlate tissue LMs and proteins associated with inflammatory process (COX-2, MPO), oxidative stress (HO-1, iNOS, and Hsp70), involved in the activation of many xenobiotics as well as PAH metabolism (Cyp1B1), suggesting a crucial role of lipids in the process of DEP-induced tissue damage. Full article
(This article belongs to the Special Issue The Lipid Metabolism in Health and Diseases)
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10 pages, 512 KiB  
Review
Stathmins and Motor Neuron Diseases: Pathophysiology and Therapeutic Targets
by Delia Gagliardi, Elisa Pagliari, Megi Meneri, Valentina Melzi, Federica Rizzo, Giacomo Pietro Comi, Stefania Corti, Michela Taiana and Monica Nizzardo
Biomedicines 2022, 10(3), 711; https://doi.org/10.3390/biomedicines10030711 - 19 Mar 2022
Cited by 9 | Viewed by 3648
Abstract
Motor neuron diseases (MNDs) are a group of fatal, neurodegenerative disorders with different etiology, clinical course and presentation, caused by the loss of upper and lower motor neurons (MNs). MNs are highly specialized cells equipped with long, axonal processes; axonal defects are some [...] Read more.
Motor neuron diseases (MNDs) are a group of fatal, neurodegenerative disorders with different etiology, clinical course and presentation, caused by the loss of upper and lower motor neurons (MNs). MNs are highly specialized cells equipped with long, axonal processes; axonal defects are some of the main players underlying the pathogenesis of these disorders. Microtubules are key components of the neuronal cytoskeleton characterized by dynamic instability, switching between rapid polymerization and shrinkage. Proteins of the stathmin family affect microtubule dynamics regulating the assembly and the dismantling of tubulin. Stathmin-2 (STMN2) is one of the most abundantly expressed genes in MNs. Following axonal injury, STMN2 expression is upregulated, and the protein is transported toward the growth cones of regenerating axons. STMN2 has a critical role in axonal maintenance, and its dysregulation plays an important role in neurodegenerative processes. Stathmin-1 (STMN1) is a ubiquitous protein that is highly expressed during the development of the nervous system, and its phosphorylation controls microtubule dynamics. In the present review, we summarize what is currently known about the involvement of stathmin alterations in MNDs and the potential therapeutic effect of their modulation, with a specific focus on the most common forms of MND, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Full article
(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)
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20 pages, 3176 KiB  
Article
Prognosis Value of Immunoregulatory Molecules in Oral Cancer Microenvironment: An Immunohistochemical Study
by Juan Francisco Peña-Cardelles, José Juan Pozo-Kreilinger, Giovanna Roncador, Jesús Esteban-Hernández, José Ernesto Moro-Rodríguez, Ana Sastre-Perona, Beatriz Castelo-Fernández and José Luis Cebrián-Carretero
Biomedicines 2022, 10(3), 710; https://doi.org/10.3390/biomedicines10030710 - 19 Mar 2022
Cited by 1 | Viewed by 1979
Abstract
Objectives: To evaluate the relationship of the immune-checkpoint PD-1/PD-L1 with the clinical evolution of OSCC; to assess survival in OSCC based on the characteristics of TME and histologic risk score; to evaluate the clinical and histopathological relationship of OSCC with immunological TME. Material [...] Read more.
Objectives: To evaluate the relationship of the immune-checkpoint PD-1/PD-L1 with the clinical evolution of OSCC; to assess survival in OSCC based on the characteristics of TME and histologic risk score; to evaluate the clinical and histopathological relationship of OSCC with immunological TME. Material and Methods: A retrospective study was carried out on 65 samples from patients with OSCC on the floor of the mouth or tongue. Clinicopathological variables and the expression of the biomarkers PD-1, PD-L1, FoxP3, CD4, CD8, CSF1R, and p16 were recorded. The relationship of the clinical and histological variables with the expression of the biomarkers and survival was studied. Results: The univariate and multivariate analysis indicated that positive PD-1 expression was an independent protective factor for survival (overall, disease-free, disease-specific survival) and that high PD-L1 also improved survival. Poorly differentiated histological grades and metastasis were associated with a worse prognosis. Conclusions: PD-1 is a protective survival factor that is maintained independently of PD-L1 expression. High values of PD-L1 expression also improve survival. Higher expression of PD-1 is observed in smaller tumors, and higher expression of PD-L1 is more likely in women. No relationship between the tumor microenvironment and histologic risk score was found to influence the survival patterns studied in the OSCC. There is no evidence of a relationship between the histopathological features and the studied markers, although the positive PD-1 and PD-L1 cases have a lower risk of a high WPOI score, and positive PD-1 expression was associated with a lower DOI. Full article
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16 pages, 2321 KiB  
Article
Thioredoxin Domain Containing 5 Suppression Elicits Serum Amyloid A-Containing High-Density Lipoproteins
by Javier Sánchez-Marco, Roberto Martínez-Beamonte, Alicia De Diego, Tania Herrero-Continente, Cristina Barranquero, Carmen Arnal, Joaquín Surra, María A. Navarro and Jesús Osada
Biomedicines 2022, 10(3), 709; https://doi.org/10.3390/biomedicines10030709 - 18 Mar 2022
Cited by 3 | Viewed by 1863
Abstract
Thioredoxin domain containing 5 (TXNDC5) is a protein disulfide isomerase involved in several diseases related to oxidative stress, energy metabolism and cellular inflammation. In a previous manuscript, a negative association between fatty liver development and hepatic Txndc5 expression was observed. To study the [...] Read more.
Thioredoxin domain containing 5 (TXNDC5) is a protein disulfide isomerase involved in several diseases related to oxidative stress, energy metabolism and cellular inflammation. In a previous manuscript, a negative association between fatty liver development and hepatic Txndc5 expression was observed. To study the role of TXNDC5 in the liver, we generated Txndc5-deficient mice. The absence of the protein caused an increased metabolic need to gain weight along with a bigger and fatter liver. RNAseq was performed to elucidate the putative mechanisms, showing a substantial liver overexpression of serum amyloid genes (Saa1, Saa2) with no changes in hepatic protein, but discrete plasma augmentation by the gene inactivation. Higher levels of malonyldialdehyde, apolipoprotein A1 and platelet activating factor-aryl esterase activity were also found in serum from Txndc5-deficient mice. However, no difference in the distribution of high-density lipoproteins (HDL)-mayor components and SAA was found between groups, and even the reactive oxygen species decreased in HDL coming from Txndc5-deficient mice. These results confirm the relation of this gene with hepatic steatosis and with a fasting metabolic derive remedying an acute phase response. Likewise, they pose a new role in modulating the nature of HDL particles, and SAA-containing HDL particles are not particularly oxidized. Full article
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11 pages, 1042 KiB  
Article
Calculated Tumor-Associated Neutrophils Are Associated with the Tumor—Stroma Ratio and Predict a Poor Prognosis in Advanced Gastric Cancer
by Eun Young Kim, Jamshid Abdul-Ghafar, Yosep Chong and Kwangil Yim
Biomedicines 2022, 10(3), 708; https://doi.org/10.3390/biomedicines10030708 - 18 Mar 2022
Cited by 10 | Viewed by 2140
Abstract
The tumor-associated neutrophils (TANs) value and tumor—stroma ratio (TSR) are promising prognostic parameters in the tumor microenvironment. We aimed to evaluate the prognostic role and relationship of TANs and TSR in gastric cancer. Our study comprised 157 patients who underwent gastrectomy for advanced [...] Read more.
The tumor-associated neutrophils (TANs) value and tumor—stroma ratio (TSR) are promising prognostic parameters in the tumor microenvironment. We aimed to evaluate the prognostic role and relationship of TANs and TSR in gastric cancer. Our study comprised 157 patients who underwent gastrectomy for advanced gastric cancer. TANs were assessed by immunohistochemical staining (CD15 and CD66b) and were analyzed with an image analyzer. TANs have been known to have different functional subpopulations of N1 (anti-tumor) and N2 (pro-tumor). We developed “calculated TANs with pro-tumor function (cN2; CD15 minus CD66b)”. The TSR was evaluated using hematoxylin and eosin staining. High-grade CD15-positive, cN2 in the tumor center, and TSR were significantly related to poor disease-free survival (DFS). TSR and cN2 were independent prognostic factors for DFS (hazard ratio (HR) = 2.614; p = 0.001, HR = 3.976; p = 0.002) and cN2 in the tumor center showed a positive correlation with TSR (R = 0.179, p = 0.025). While CD66b stained both N1 and N2, CD15 detected most of N2. Combining both markers revealed a novel cN2, which was an independent marker of poor prognosis. The transformation from N1 to N2 predominantly occurred in the tumor center, and was associated with TSR. Full article
(This article belongs to the Special Issue Gastric Cancer: From Mechanisms to Therapeutic Approaches)
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17 pages, 8381 KiB  
Review
ER-phagy in the Occurrence and Development of Cancer
by Huimin Zhou, Kexin Wang, Mengyan Wang, Wenxia Zhao, Conghui Zhang, Meilian Cai, Yuhan Qiu, Tianshu Zhang, Rongguang Shao and Wuli Zhao
Biomedicines 2022, 10(3), 707; https://doi.org/10.3390/biomedicines10030707 - 18 Mar 2022
Cited by 6 | Viewed by 2572
Abstract
As an organelle, the endoplasmic reticulum (ER) is closely related to protein synthesis and modification. When physiological or pathological stimuli induce disorders of ER function, misfolded proteins trigger ER-phagy, which is beneficial for restoring cell homeostasis or promoting cell apoptosis. As a double-edged [...] Read more.
As an organelle, the endoplasmic reticulum (ER) is closely related to protein synthesis and modification. When physiological or pathological stimuli induce disorders of ER function, misfolded proteins trigger ER-phagy, which is beneficial for restoring cell homeostasis or promoting cell apoptosis. As a double-edged sword, ER-phagy actively participates in various stages of development and progression in tumor cells, regulating tumorigenesis and maintaining tumor cell homeostasis. Through the unfolded protein response (UPR), the B cell lymphoma 2 (BCL-2) protein family, the Caspase signaling pathway, and others, ER-phagy plays an initiating role in tumor occurrence, migration, stemness, and proliferation. At the same time, many vital proteins strongly associated with ER-phagy, such as family with sequence similarity 134 member B (FAM134B), translocation protein SEC62 (SEC62), and C/EBP-homologous protein (CHOP), can produce a marked effect in many complex environments, which ultimately lead to entirely different tumor fates. Our article comprehensively focused on introducing the relationship and interaction between ER-phagy and cancers, as well as their molecular mechanism and regulatory pathways. Via these analyses, we tried to clarify the possibility of ER-phagy as a potential target for cancer therapy and provide ideas for further research. Full article
(This article belongs to the Special Issue Autophagy in Inflammation-Associated Damage and Diseases)
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21 pages, 8685 KiB  
Article
Biofunctionalization of Xenogeneic Collagen Membranes with Autologous Platelet Concentrate—Influence on Rehydration Protocol and Angiogenesis
by Sebastian Blatt, Saskia-Vanessa Schröger, Andreas Pabst, Peer W. Kämmerer, Keyvan Sagheb and Bilal Al-Nawas
Biomedicines 2022, 10(3), 706; https://doi.org/10.3390/biomedicines10030706 - 18 Mar 2022
Cited by 4 | Viewed by 1836
Abstract
Background: The aim of this study was to analyze possible interactions of different xenogeneic collagen membranes (CM) and platelet-rich fibrin (PRF). PH values were evaluated in the CM rehydration process with PRF, and their influence on angiogenesis was analyzed in vivo. Materials and [...] Read more.
Background: The aim of this study was to analyze possible interactions of different xenogeneic collagen membranes (CM) and platelet-rich fibrin (PRF). PH values were evaluated in the CM rehydration process with PRF, and their influence on angiogenesis was analyzed in vivo. Materials and Methods: Porcine (Bio-Gide®, Geistlich)- and bovine-derived collagen membranes (Symbios®, Dentsply Sirona) were biofunctionalized with PRF by plotting process. PRF in comparison to blood, saline and a puffer pH7 solution was analysed for pH-value changes in CM rehydration process in vitro. The yolk sac membrane (YSM) model was used to investigate pro-angiogenic effects of the combination of PRF and the respective CM in comparison to native pendant by vessel in-growth and branching points after 24, 48 and 72 h evaluated light-microscopically and by immunohistochemical staining (CD105, αSMA) in vivo. Results: Significantly higher pH values were found at all points in time in PRF alone and its combined variants with Bio-Gide® and Symbios® compared with pure native saline solution and pH 7 solution, as well as saline with Symbios® and Bio-Gide® (each p < 0.01). In the YSM, vessel number and branching points showed no significant differences at 24 and 48 h between all groups (each p > 0.05). For PRF alone, a significantly increased vessel number and branching points between 24 and 48 h (each p < 0.05) and between 24 and 72 h (each p < 0.05) was shown. After 72 h, CM in combination with PRF induced a statistically significant addition to vessels and branching points in comparison with native YSM (p < 0.01) but not vs. its native pendants (p > 0.05). Summary: PRF represents a promising alternative for CM rehydration to enhance CM vascularization. Full article
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19 pages, 2615 KiB  
Review
Klotho an Autophagy Stimulator as a Potential Therapeutic Target for Alzheimer’s Disease: A Review
by Tsz Yan Fung, Ashok Iyaswamy, Sravan G. Sreenivasmurthy, Senthilkumar Krishnamoorthi, Xin-Jie Guan, Zhou Zhu, Cheng-Fu Su, Jia Liu, Yuxuan Kan, Yuan Zhang, Hoi Leong Xavier Wong and Min Li
Biomedicines 2022, 10(3), 705; https://doi.org/10.3390/biomedicines10030705 - 18 Mar 2022
Cited by 14 | Viewed by 4152
Abstract
Alzheimer’s disease (AD) is an age-associated neurodegenerative disease; it is the most common cause of senile dementia. Klotho, a single-pass transmembrane protein primarily generated in the brain and kidney, is active in a variety of metabolic pathways involved in controlling neurodegeneration and ageing. [...] Read more.
Alzheimer’s disease (AD) is an age-associated neurodegenerative disease; it is the most common cause of senile dementia. Klotho, a single-pass transmembrane protein primarily generated in the brain and kidney, is active in a variety of metabolic pathways involved in controlling neurodegeneration and ageing. Recently, many studies have found that the upregulation of Klotho can improve pathological cognitive deficits in an AD mice model and have demonstrated that Klotho plays a role in the induction of autophagy, a major contributing factor for AD. Despite the close association between Klotho and neurodegenerative diseases, such as AD, the underlying mechanism by which Klotho contributes to AD remains poorly understood. In this paper, we will introduce the expression, location and structure of Klotho and its biological functions. Specifically, this review is devoted to the correlation of Klotho protein and the AD phenotype, such as the effect of Klotho in upregulating the amyloid-beta clearance and in inducing autophagy for the clearance of toxic proteins, by regulating the autophagy lysosomal pathway (ALP). In summary, the results of multiple studies point out that targeting Klotho would be a potential therapeutic strategy in AD treatment. Full article
(This article belongs to the Special Issue Autophagy in Inflammation-Associated Damage and Diseases)
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24 pages, 3562 KiB  
Article
CD5 Deficiency Alters Helper T Cell Metabolic Function and Shifts the Systemic Metabolome
by Kiara V. Whitley, Claudia M. Tellez Freitas, Carlos Moreno, Christopher Haynie, Joshua Bennett, John C. Hancock, Tyler D. Cox, Brett E. Pickett and K. Scott Weber
Biomedicines 2022, 10(3), 704; https://doi.org/10.3390/biomedicines10030704 - 18 Mar 2022
Cited by 1 | Viewed by 2359
Abstract
Metabolic function plays a key role in immune cell activation, destruction of foreign pathogens, and memory cell generation. As T cells are activated, their metabolic profile is significantly changed due to signaling cascades mediated by the T cell receptor (TCR) and co-receptors found [...] Read more.
Metabolic function plays a key role in immune cell activation, destruction of foreign pathogens, and memory cell generation. As T cells are activated, their metabolic profile is significantly changed due to signaling cascades mediated by the T cell receptor (TCR) and co-receptors found on their surface. CD5 is a T cell co-receptor that regulates thymocyte selection and peripheral T cell activation. The removal of CD5 enhances T cell activation and proliferation, but how this is accomplished is not well understood. We examined how CD5 specifically affects CD4+ T cell metabolic function and systemic metabolome by analyzing serum and T cell metabolites from CD5WT and CD5KO mice. We found that CD5 removal depletes certain serum metabolites, and CD5KO T cells have higher levels of several metabolites. Transcriptomic analysis identified several upregulated metabolic genes in CD5KO T cells. Bioinformatic analysis identified glycolysis and the TCA cycle as metabolic pathways promoted by CD5 removal. Functional metabolic analysis demonstrated that CD5KO T cells have higher oxygen consumption rates (OCR) and higher extracellular acidification rates (ECAR). Together, these findings suggest that the loss of CD5 is linked to CD4+ T cell metabolism changes in metabolic gene expression and metabolite concentration. Full article
(This article belongs to the Special Issue Omics Data Analysis and Integration in Complex Diseases)
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18 pages, 2813 KiB  
Article
The Importance of Lipid Conjugation on Anti-Fusion Peptides against Nipah Virus
by Marta C. Marques, Diana Lousa, Patrícia M. Silva, André F. Faustino, Cláudio M. Soares and Nuno C. Santos
Biomedicines 2022, 10(3), 703; https://doi.org/10.3390/biomedicines10030703 - 18 Mar 2022
Cited by 2 | Viewed by 2126
Abstract
Nipah virus (NiV) is a recently emerging zoonotic virus that belongs to the Paramyxoviridae family and the Henipavirus genus. It causes a range of conditions, from asymptomatic infection to acute respiratory illness and fatal encephalitis. The high mortality rate of 40 to 90% [...] Read more.
Nipah virus (NiV) is a recently emerging zoonotic virus that belongs to the Paramyxoviridae family and the Henipavirus genus. It causes a range of conditions, from asymptomatic infection to acute respiratory illness and fatal encephalitis. The high mortality rate of 40 to 90% ranks these viruses among the deadliest viruses known to infect humans. Currently, there is no antiviral drug available for Nipah virus disease and treatment is only supportive. Thus, there is an urgent demand for efficient antiviral therapies. NiV F protein, which catalyzes fusion between the viral and host membranes, is a potential target for antiviral drugs, as it is a key protein in the initial stages of infection. Fusion inhibitor peptides derived from the HRC-domain of the F protein are known to bind to their complementary domain in the protein’s transient intermediate state, preventing the formation of a six-helix bundle (6HB) thought to be responsible for driving the fusion of the viral and cell membranes. Here, we evaluated the biophysical and structural properties of four different C-terminal lipid-tagged peptides. Different compositions of the lipid tags were tested to search for properties that might promote efficacy and broad-spectrum activity. Fluorescence spectroscopy was used to study the interaction of the peptides with biomembrane model systems and human blood cells. In order to understand the structural properties of the peptides, circular dichroism measurements and molecular dynamics simulations were performed. Our results indicate a peptide preference for cholesterol-enriched membranes and a lipid conjugation-driven stabilization of the peptide α-helical secondary structure. This work may contribute for the development of highly effective viral fusion against NiV inhibitors. Full article
(This article belongs to the Special Issue Conformational Dynamics of Viral Proteins)
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23 pages, 2692 KiB  
Review
Association between COVID-19 Diagnosis and Coronary Artery Thrombosis: A Narrative Review
by Francesco Nappi, Omar Giacinto, Omar Ellouze, Antonio Nenna, Sanjeet Singh Avtaar Singh, Massimo Chello, Assine Bouzguenda and Xavier Copie
Biomedicines 2022, 10(3), 702; https://doi.org/10.3390/biomedicines10030702 - 18 Mar 2022
Cited by 13 | Viewed by 2807
Abstract
Coronavirus disease 2019 is characterized by its severe respiratory effects. Data early on indicated an increased risk of mortality in patients with cardiovascular comorbidities. Early reports highlighted the multisystem inflammatory syndrome, cytokine storm, and thromboembolic events as part of the disease processes. The [...] Read more.
Coronavirus disease 2019 is characterized by its severe respiratory effects. Data early on indicated an increased risk of mortality in patients with cardiovascular comorbidities. Early reports highlighted the multisystem inflammatory syndrome, cytokine storm, and thromboembolic events as part of the disease processes. The aim of this review is to assess the association between COVID-19 and its thrombotic complications, specifically related to the cardiovascular system. The role of neutrophil extracellular traps (NETs) is explored in the pathogenesis of the disease. The structure and anatomy of the virus are pivotal to its virulence in comparison to other α and β Coronaviridae (HCoV-229E, HCoV-OC43, HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1). In particular, the host interaction and response may explain the variability of severity in patients. Angio tensin-converting enzyme 2 (ACE2) activation may be implicated in the cardiovascular and throm bogenic potential of the disease. The virus may also have direct effects on the endothelial lining affecting hemostasis and resulting in thrombosis through several mechanisms. Dipyridamole may have a therapeutic benefit in NET suppression. Therapeutic avenues should be concentrated on the different pathophysiological steps involving the virus and the host. Full article
(This article belongs to the Special Issue Molecular Researches in Pro-thrombotic Disorders)
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19 pages, 819 KiB  
Review
Bacterial and Viral Infection and Sepsis in Kidney Transplanted Patients
by Alberto Mella, Filippo Mariano, Caterina Dolla, Ester Gallo, Ana Maria Manzione, Maria Cristina Di Vico, Rossana Cavallo, Francesco Giuseppe De Rosa, Cristina Costa and Luigi Biancone
Biomedicines 2022, 10(3), 701; https://doi.org/10.3390/biomedicines10030701 - 18 Mar 2022
Cited by 8 | Viewed by 3341
Abstract
Kidney transplanted patients are a unique population with intrinsic susceptibility to viral and bacterial infections, mainly (but not exclusively) due to continuous immunosuppression. In this setting, infectious episodes remain among the most important causes of death, with different risks according to the degree [...] Read more.
Kidney transplanted patients are a unique population with intrinsic susceptibility to viral and bacterial infections, mainly (but not exclusively) due to continuous immunosuppression. In this setting, infectious episodes remain among the most important causes of death, with different risks according to the degree of immunosuppression, time after transplantation, type of infection, and patient conditions. Prevention, early diagnosis, and appropriate therapy are the goals of infective management, taking into account that some specific characteristics of transplanted patients may cause a delay (the absence of fever or inflammatory symptoms, the negativity of serological tests commonly adopted for the general population, or the atypical anatomical presentation depending on the surgical site and graft implantation). This review considers the recent available findings of the most common viral and bacterial infection in kidney transplanted patients and explores risk factors and outcomes in septic evolution. Full article
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