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Biomolecules, Volume 10, Issue 12 (December 2020) – 112 articles

Cover Story (view full-size image): Cannabinoid receptor interacting protein 1a (CRIP1a) can (left to right): attenuate CB1 receptor-mediated inhibition of adenylyl cyclase, alter the activated Gi subtype, and reduce beta-arrestin binding to the CB1 receptor. CRIP1a expression thereby increases intracellular cAMP production but decreases CB1 receptor internalization and ERK phosphorylation. This suggests that CRIP1a can regulate physiology in healthy tissues, and that genetic or epigenetic changes can be associated with disease states. Physiological and pathophysiological implications of CRIP1a expression have been reported in embryonic development, seizures, schizophrenia, visual and auditory sensory systems, and cancer. View this paper
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64 pages, 4254 KiB  
Review
Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants
by Clémence Rives, Anne Fougerat, Sandrine Ellero-Simatos, Nicolas Loiseau, Hervé Guillou, Laurence Gamet-Payrastre and Walter Wahli
Biomolecules 2020, 10(12), 1702; https://doi.org/10.3390/biom10121702 - 21 Dec 2020
Cited by 83 | Viewed by 11341
Abstract
Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis. Full article
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18 pages, 1208 KiB  
Review
Nanobodies Right in the Middle: Intrabodies as Toolbox to Visualize and Modulate Antigens in the Living Cell
by Teresa R. Wagner and Ulrich Rothbauer
Biomolecules 2020, 10(12), 1701; https://doi.org/10.3390/biom10121701 - 21 Dec 2020
Cited by 22 | Viewed by 5128
Abstract
In biomedical research, there is an ongoing demand for new technologies to elucidate disease mechanisms and develop novel therapeutics. This requires comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, post-translational modifications and dynamic interactions of cellular [...] Read more.
In biomedical research, there is an ongoing demand for new technologies to elucidate disease mechanisms and develop novel therapeutics. This requires comprehensive understanding of cellular processes and their pathophysiology based on reliable information on abundance, localization, post-translational modifications and dynamic interactions of cellular components. Traceable intracellular binding molecules provide new opportunities for real-time cellular diagnostics. Most prominently, intrabodies derived from antibody fragments of heavy-chain only antibodies of camelids (nanobodies) have emerged as highly versatile and attractive probes to study and manipulate antigens within the context of living cells. In this review, we provide an overview on the selection, delivery and usage of intrabodies to visualize and monitor cellular antigens in living cells and organisms. Additionally, we summarize recent advances in the development of intrabodies as cellular biosensors and their application to manipulate disease-related cellular processes. Finally, we highlight switchable intrabodies, which open entirely new possibilities for real-time cell-based diagnostics including live-cell imaging, target validation and generation of precisely controllable binding reagents for future therapeutic applications. Full article
(This article belongs to the Special Issue The Therapeutic and Diagnostic Potential of Nanobodies)
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14 pages, 3949 KiB  
Article
Molecular Dynamics Simulations Predict that rSNP Located in the HNF-1α Gene Promotor Region Linked with MODY3 and Hepatocellular Carcinoma Promotes Stronger Binding of the HNF-4α Transcription Factor
by Eva Španinger, Uroš Potočnik and Urban Bren
Biomolecules 2020, 10(12), 1700; https://doi.org/10.3390/biom10121700 - 21 Dec 2020
Cited by 5 | Viewed by 2418
Abstract
Our study aims to investigate the impact of the Maturity-onset diabetes of the young 3 disease-linked rSNP rs35126805 located in the HNF-1α gene promotor on the binding of the transcription factor HNF-4α and consequently on the regulation of HNF-1α gene expression. Our focus [...] Read more.
Our study aims to investigate the impact of the Maturity-onset diabetes of the young 3 disease-linked rSNP rs35126805 located in the HNF-1α gene promotor on the binding of the transcription factor HNF-4α and consequently on the regulation of HNF-1α gene expression. Our focus is to calculate the change in the binding affinity of the transcription factor HNF-4α to the DNA, caused by the regulatory single nucleotide polymorphism (rSNP) through molecular dynamics simulations and thermodynamic analysis of acquired results. Both root-mean-square difference (RMSD) and the relative binding free energy ΔΔGbind reveal that the HNF-4α binds slightly more strongly to the DNA containing the mutation (rSNP) making the complex more stable/rigid, and thereby influencing the expression of the HNF-1α gene. The resulting disruption of the HNF-4α/HNF-1α pathway is also linked to hepatocellular carcinoma metastasis and enhanced apoptosis in pancreatic cancer cells. To the best of our knowledge, this represents the first study where thermodynamic analysis of the results obtained from molecular dynamics simulations is performed to uncover the influence of rSNP on the protein binding to DNA. Therefore, our approach can be generally applied for studying the impact of regulatory single nucleotide polymorphisms on the binding of transcription factors to the DNA. Full article
(This article belongs to the Special Issue Computational Approaches for the Study of Biomolecular Networks)
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32 pages, 1134 KiB  
Review
The Regulation of Fat Metabolism during Aerobic Exercise
by Antonella Muscella, Erika Stefàno, Paola Lunetti, Loredana Capobianco and Santo Marsigliante
Biomolecules 2020, 10(12), 1699; https://doi.org/10.3390/biom10121699 - 21 Dec 2020
Cited by 66 | Viewed by 21298
Abstract
Since the lipid profile is altered by physical activity, the study of lipid metabolism is a remarkable element in understanding if and how physical activity affects the health of both professional athletes and sedentary subjects. Although not fully defined, it has become clear [...] Read more.
Since the lipid profile is altered by physical activity, the study of lipid metabolism is a remarkable element in understanding if and how physical activity affects the health of both professional athletes and sedentary subjects. Although not fully defined, it has become clear that resistance exercise uses fat as an energy source. The fatty acid oxidation rate is the result of the following processes: (a) triglycerides lipolysis, most abundant in fat adipocytes and intramuscular triacylglycerol (IMTG) stores, (b) fatty acid transport from blood plasma to muscle sarcoplasm, (c) availability and hydrolysis rate of intramuscular triglycerides, and (d) transport of fatty acids through the mitochondrial membrane. In this review, we report some studies concerning the relationship between exercise and the aforementioned processes also in light of hormonal controls and molecular regulations within fat and skeletal muscle cells. Full article
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3 pages, 164 KiB  
Editorial
Bioactive Lipids in Health and Disease
by Monica Bari, Tiziana Bisogno and Natalia Battista
Biomolecules 2020, 10(12), 1698; https://doi.org/10.3390/biom10121698 - 21 Dec 2020
Cited by 6 | Viewed by 2383
Abstract
Although the primordial concept of lipids is associated with the role they play as key components of the cell membrane, growing research in the field of bioactive lipids and lipidomic technologies proves the prominent role of these molecules in other biological functions [...] [...] Read more.
Although the primordial concept of lipids is associated with the role they play as key components of the cell membrane, growing research in the field of bioactive lipids and lipidomic technologies proves the prominent role of these molecules in other biological functions [...] Full article
12 pages, 696 KiB  
Article
Measurement of Serum Testosterone in Nondiabetic Young Obese Men: Comparison of Direct Immunoassay to Liquid Chromatography-Tandem Mass Spectrometry
by Ana Martínez-Escribano, Julia Maroto-García, Maximiliano Ruiz-Galdón, Rocío Barrios-Rodríguez, Juan J. Álvarez-Millán, Pablo Cabezas-Sánchez, Isaac Plaza-Andrades, María Molina-Vega, Francisco J. Tinahones, María Isabel Queipo-Ortuño and José Carlos Fernández-García
Biomolecules 2020, 10(12), 1697; https://doi.org/10.3390/biom10121697 - 19 Dec 2020
Cited by 5 | Viewed by 2489
Abstract
Hypoandrogenemia, a frequent finding in men with obesity, is defined by low concentrations of serum testosterone. Although immunoassay (IA) is the most used method for the determination of this steroid in clinical practice, liquid chromatography-mass spectrometry (LC-MS/MS) is considered a more reliable method. [...] Read more.
Hypoandrogenemia, a frequent finding in men with obesity, is defined by low concentrations of serum testosterone. Although immunoassay (IA) is the most used method for the determination of this steroid in clinical practice, liquid chromatography-mass spectrometry (LC-MS/MS) is considered a more reliable method. In this study, we aimed to compare IA versus LC-MS/MS measurement for the diagnosis of hypoandrogenemia in a cohort of 273 nondiabetic young obese men. Mean total testosterone (TT) levels were 3.20 ± 1.24 ng/mL for IA and 3.78 ± 1.4 ng/mL for LC-MS/MS. 53.7% and 26.3% of patients were classified as presenting hypoandrogenemia with IA and LC-MS/MS, respectively. Considering LC-MS/MS as the reference method, sensitivity and specificity of IA were 91.4% (95% CI 82.3–96.8) and 61.1% (95% CI 54.0–67.8), respectively. IA presented an AUC of 0.879 (95% CI 0.83–0.928). Multivariate regression analysis indicated that sex hormone-binding globulin (SHBG) concentrations (p = 0.002) and insulin resistance (p = 0.008) were factors associated with discrepant IA values. In conclusion, the determination of TT by IA in nondiabetic young men with obesity yields lower concentrations of TT than LC-MS/MS, resulting in an equivocal increased diagnosis of hypoandrogenemia, which could lead to inaccurate diagnosis and unnecessary treatment. Full article
(This article belongs to the Section Cellular Biochemistry)
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18 pages, 5647 KiB  
Article
Electrical Stimulation of Adipose-Derived Stem Cells in 3D Nanofibrillar Cellulose Increases Their Osteogenic Potential
by Mesude Bicer, Jonathan Sheard, Donata Iandolo, Samuel Y. Boateng, Graeme S. Cottrell and Darius Widera
Biomolecules 2020, 10(12), 1696; https://doi.org/10.3390/biom10121696 - 18 Dec 2020
Cited by 16 | Viewed by 4387
Abstract
Due to the ageing population, there is a steadily increasing incidence of osteoporosis and osteoporotic fractures. As conventional pharmacological therapy options for osteoporosis are often associated with severe side effects, bone grafts are still considered the clinical gold standard. However, the availability of [...] Read more.
Due to the ageing population, there is a steadily increasing incidence of osteoporosis and osteoporotic fractures. As conventional pharmacological therapy options for osteoporosis are often associated with severe side effects, bone grafts are still considered the clinical gold standard. However, the availability of viable, autologous bone grafts is limited making alternative cell-based strategies a promising therapeutic alternative. Adipose-derived stem cells (ASCs) are a readily available population of mesenchymal stem/stromal cells (MSCs) that can be isolated within minimally invasive surgery. This ease of availability and their ability to undergo osteogenic differentiation makes ASCs promising candidates for cell-based therapies for bone fractures. Recent studies have suggested that both exposure to electrical fields and cultivation in 3D can positively affect osteogenic potential of MSCs. To elucidate the osteoinductive potential of a combination of these biophysical cues on ASCs, cells were embedded within anionic nanofibrillar cellulose (aNFC) hydrogels and exposed to electrical stimulation (ES) for up to 21 days. ES was applied to ASCs in 2D and 3D at a voltage of 0.1 V/cm with a duration of 0.04 ms, and a frequency of 10 Hz for 30 min per day. Exposure of ASCs to ES in 3D resulted in high alkaline phosphatase (ALP) activity and in an increased mineralisation evidenced by Alizarin Red S staining. Moreover, ES in 3D aNFC led to an increased expression of the osteogenic markers osteopontin and osteocalcin and a rearrangement and alignment of the actin cytoskeleton. Taken together, our data suggest that a combination of ES with 3D cell culture can increase the osteogenic potential of ASCs. Thus, exposure of ASCs to these biophysical cues might improve the clinical outcomes of regenerative therapies in treatment of osteoporotic fractures. Full article
(This article belongs to the Special Issue Recent Advances in Translational Adipose-Derived Stem Cell Biology)
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24 pages, 1931 KiB  
Review
Nanobodies as Versatile Tool for Multiscale Imaging Modalities
by Marco Erreni, Tilo Schorn, Francesca D’Autilia and Andrea Doni
Biomolecules 2020, 10(12), 1695; https://doi.org/10.3390/biom10121695 - 18 Dec 2020
Cited by 17 | Viewed by 3405
Abstract
Molecular imaging is constantly growing in different areas of preclinical biomedical research. Several imaging methods have been developed and are continuously updated for both in vivo and in vitro applications, in order to increase the information about the structure, localization and function of [...] Read more.
Molecular imaging is constantly growing in different areas of preclinical biomedical research. Several imaging methods have been developed and are continuously updated for both in vivo and in vitro applications, in order to increase the information about the structure, localization and function of molecules involved in physiology and disease. Along with these progresses, there is a continuous need for improving labeling strategies. In the last decades, the single domain antigen-binding fragments nanobodies (Nbs) emerged as important molecular imaging probes. Indeed, their small size (~15 kDa), high stability, affinity and modularity represent desirable features for imaging applications, providing higher tissue penetration, rapid targeting, increased spatial resolution and fast clearance. Accordingly, several Nb-based probes have been generated and applied to a variety of imaging modalities, ranging from in vivo and in vitro preclinical imaging to super-resolution microscopy. In this review, we will provide an overview of the state-of-the-art regarding the use of Nbs in several imaging modalities, underlining their extreme versatility and their enormous potential in targeting molecules and cells of interest in both preclinical and clinical studies. Full article
(This article belongs to the Special Issue The Therapeutic and Diagnostic Potential of Nanobodies)
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23 pages, 1401 KiB  
Review
Yersinia Outer Membrane Vesicles as Potential Vaccine Candidates in Protecting against Plague
by Andrey A. Byvalov, Ilya V. Konyshev, Vladimir N. Uversky, Svetlana V. Dentovskaya and Andrey P. Anisimov
Biomolecules 2020, 10(12), 1694; https://doi.org/10.3390/biom10121694 - 18 Dec 2020
Cited by 7 | Viewed by 3366
Abstract
Despite the relatively low incidence of plague, its etiological agent, Yersinia pestis, is an exceptional epidemic danger due to the high infectivity and mortality of this infectious disease. Reports on the isolation of drug-resistant Y. pestis strains indicate the advisability of using [...] Read more.
Despite the relatively low incidence of plague, its etiological agent, Yersinia pestis, is an exceptional epidemic danger due to the high infectivity and mortality of this infectious disease. Reports on the isolation of drug-resistant Y. pestis strains indicate the advisability of using asymmetric responses, such as phage therapy and vaccine prophylaxis in the fight against this problem. The current relatively effective live plague vaccine is not approved for use in most countries because of its ability to cause heavy local and system reactions and even a generalized infectious process in people with a repressed immune status or metabolic disorders, as well as lethal infection in some species of nonhuman primates. Therefore, developing alternative vaccines is of high priority and importance. However, until now, work on the development of plague vaccines has mainly focused on screening for the potential immunogens. Several investigators have identified the protective potency of bacterial outer membrane vesicles (OMVs) as a promising basis for bacterial vaccine candidates. This review is aimed at presenting these candidates of plague vaccine and the results of their analysis in animal models. Full article
(This article belongs to the Collection Yersinia pestis Biomolecules)
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27 pages, 3617 KiB  
Article
Role of Ferrous Sulfate (FeSO4) in Resistance to Cadmium Stress in Two Rice (Oryza sativa L.) Genotypes
by Javaria Afzal, Muhammad Hamzah Saleem, Fatima Batool, Ali Mohamed Elyamine, Muhammad Shoaib Rana, Asma Shaheen, Mohamed A. El-Esawi, Muhammad Tariq Javed, Qasim Ali, Muhammad Arslan Ashraf, Ghulam Sabir Hussain and Chengxiao Hu
Biomolecules 2020, 10(12), 1693; https://doi.org/10.3390/biom10121693 - 18 Dec 2020
Cited by 53 | Viewed by 5398
Abstract
The impact of heavy metal, i.e., cadmium (Cd), on the growth, photosynthetic pigments, gas exchange characteristics, oxidative stress biomarkers, and antioxidants machinery (enzymatic and non-enzymatic antioxidants), ions uptake, organic acids exudation, and ultra-structure of membranous bounded organelles of two rice (Oryza sativa [...] Read more.
The impact of heavy metal, i.e., cadmium (Cd), on the growth, photosynthetic pigments, gas exchange characteristics, oxidative stress biomarkers, and antioxidants machinery (enzymatic and non-enzymatic antioxidants), ions uptake, organic acids exudation, and ultra-structure of membranous bounded organelles of two rice (Oryza sativa L.) genotypes (Shan 63 and Lu 9803) were investigated with and without the exogenous application of ferrous sulfate (FeSO4). Two O. sativa genotypes were grown under different levels of CdCl2 [0 (no Cd), 50 and 100 µM] and then treated with exogenously supplemented ferrous sulfate (FeSO4) [0 (no Fe), 50 and 100 µM] for 21 days. The results revealed that Cd stress significantly (p < 0.05) affected plant growth and biomass, photosynthetic pigments, gas exchange characteristics, affected antioxidant machinery, sugar contents, and ions uptake/accumulation, and destroy the ultra-structure of many membranous bounded organelles. The findings also showed that Cd toxicity induces oxidative stress biomarkers, i.e., malondialdehyde (MDA) contents, hydrogen peroxide (H2O2) initiation, and electrolyte leakage (%), which was also manifested by increasing the enzymatic antioxidants, i.e., superoxidase dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX) and non-enzymatic antioxidant compounds (phenolics, flavonoids, ascorbic acid, and anthocyanin) and organic acids exudation pattern in both O. sativa genotypes. At the same time, the results also elucidated that the O. sativa genotypes Lu 9803 are more tolerant to Cd stress than Shan 63. Although, results also illustrated that the exogenous application of ferrous sulfate (FeSO4) also decreased Cd toxicity in both O. sativa genotypes by increasing antioxidant capacity and thus improved the plant growth and biomass, photosynthetic pigments, gas exchange characteristics, and decrease oxidative stress in the roots and shoots of O. sativa genotypes. Here, we conclude that the exogenous supplementation of FeSO4 under short-term exposure of Cd stress significantly improved plant growth and biomass, photosynthetic pigments, gas exchange characteristics, regulate antioxidant defense system, and essential nutrients uptake and maintained the ultra-structure of membranous bounded organelles in O. sativa genotypes. Full article
(This article belongs to the Section Natural and Bio-inspired Molecules)
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26 pages, 6433 KiB  
Article
Role of Hydrogen Sulfide and 3-Mercaptopyruvate Sulfurtransferase in the Regulation of the Endoplasmic Reticulum Stress Response in Hepatocytes
by Theodora Panagaki, Elisa B. Randi and Csaba Szabo
Biomolecules 2020, 10(12), 1692; https://doi.org/10.3390/biom10121692 - 18 Dec 2020
Cited by 11 | Viewed by 2999
Abstract
It is estimated that over 1.5 billion people suffer from various forms of chronic liver disease worldwide. The emerging prevalence of metabolic syndromes and alcohol misuse, along with the lack of disease-modifying agents for the therapy of many severe liver conditions predicts that [...] Read more.
It is estimated that over 1.5 billion people suffer from various forms of chronic liver disease worldwide. The emerging prevalence of metabolic syndromes and alcohol misuse, along with the lack of disease-modifying agents for the therapy of many severe liver conditions predicts that chronic liver disease will continue to be a major problem in the future. Better understanding of the underlying pathogenetic mechanisms and identification of potential therapeutic targets remains a priority. Herein, we explored the potential role of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide (H2S) system in the regulation of the endoplasmic reticulum (ER) stress and of its downstream processes in the immortalized hepatic cell line HepG2 in vitro. ER stress suppressed endogenous H2S levels and pharmacological supplementation of H2S with sodium hydrogen sulfide (NaHS) mitigated many aspects of ER stress, culminating in improved cellular bioenergetics and prevention of autophagic arrest, thereby switching cells’ fate towards survival. Genetic silencing of 3-MST or pharmacological inhibition of the key enzymes involved in hepatocyte H2S biosynthesis exacerbated many readouts related to ER-stress or its downstream functional responses. Our findings implicate the 3-MST/H2S system in the intracellular network that governs proteostasis and ER-stress adaptability in hepatocytes and reinforce the therapeutic potential of pharmacological H2S supplementation. Full article
(This article belongs to the Special Issue 2020 Feature Papers by Biomolecules’ Editorial Board Members)
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16 pages, 4480 KiB  
Article
Model-Agnostic Method for Thoracic Wall Segmentation in Fetal Ultrasound Videos
by Kanto Shozu, Masaaki Komatsu, Akira Sakai, Reina Komatsu, Ai Dozen, Hidenori Machino, Suguru Yasutomi, Tatsuya Arakaki, Ken Asada, Syuzo Kaneko, Ryu Matsuoka, Akitoshi Nakashima, Akihiko Sekizawa and Ryuji Hamamoto
Biomolecules 2020, 10(12), 1691; https://doi.org/10.3390/biom10121691 - 17 Dec 2020
Cited by 30 | Viewed by 3806
Abstract
The application of segmentation methods to medical imaging has the potential to create novel diagnostic support models. With respect to fetal ultrasound, the thoracic wall is a key structure on the assessment of the chest region for examiners to recognize the relative orientation [...] Read more.
The application of segmentation methods to medical imaging has the potential to create novel diagnostic support models. With respect to fetal ultrasound, the thoracic wall is a key structure on the assessment of the chest region for examiners to recognize the relative orientation and size of structures inside the thorax, which are critical components in neonatal prognosis. In this study, to improve the segmentation performance of the thoracic wall in fetal ultrasound videos, we proposed a novel model-agnostic method using deep learning techniques: the Multi-Frame + Cylinder method (MFCY). The Multi-frame method (MF) uses time-series information of ultrasound videos, and the Cylinder method (CY) utilizes the shape of the thoracic wall. To evaluate the achieved improvement, we performed segmentation using five-fold cross-validation on 538 ultrasound frames in the four-chamber view (4CV) of 256 normal cases using U-net and DeepLabv3+. MFCY increased the mean values of the intersection over union (IoU) of thoracic wall segmentation from 0.448 to 0.493 for U-net and from 0.417 to 0.470 for DeepLabv3+. These results demonstrated that MFCY improved the segmentation performance of the thoracic wall in fetal ultrasound videos without altering the network structure. MFCY is expected to facilitate the development of diagnostic support models in fetal ultrasound by providing further accurate segmentation of the thoracic wall. Full article
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25 pages, 1146 KiB  
Review
A Comparative View on the Oviductal Environment during the Periconception Period
by Leopoldo González-Brusi, Blanca Algarra, Carla Moros-Nicolás, Mª José Izquierdo-Rico, Manuel Avilés and Maria Jiménez-Movilla
Biomolecules 2020, 10(12), 1690; https://doi.org/10.3390/biom10121690 - 17 Dec 2020
Cited by 15 | Viewed by 3170
Abstract
The oviduct plays important roles in reproductive events: sperm reservoir formation, final gamete maturation, fertilization and early embryo development. It is well known that the oviductal environment affects gametes and embryos and, ultimately, the health of offspring, so that in vivo embryos are [...] Read more.
The oviduct plays important roles in reproductive events: sperm reservoir formation, final gamete maturation, fertilization and early embryo development. It is well known that the oviductal environment affects gametes and embryos and, ultimately, the health of offspring, so that in vivo embryos are better in terms of morphology, cryotolerance, pregnancy rates or epigenetic profile than those obtained in vitro. The deciphering of embryo–maternal interaction in the oviduct may provide a better understanding of the embryo needs during the periconception period to improve reproductive efficiency. Here, we perform a comparative analysis among species of oviductal gene expression related to embryonic development during its journey through the oviduct, as described to date. Cross-talk communication between the oviduct environment and embryo will be studied by analyses of the secreted or exosomal proteins of the oviduct and the presence of receptors in the membrane of the embryo blastomeres. Finally, we review the data that are available to date on the expression and characterization of the most abundant protein in the oviduct, oviductin (OVGP1), highlighting its fundamental role in fertilization and embryonic development. Full article
(This article belongs to the Special Issue Biomolecules in Maternal–Embryo Communication in Implantation)
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17 pages, 3173 KiB  
Article
Determination of Major Endogenous FAHFAs in Healthy Human Circulation: The Correlations with Several Circulating Cardiovascular-Related Biomarkers and Anti-Inflammatory Effects on RAW 264.7 Cells
by Rachmad Anres Dongoran, Tsung-Jen Lin, Akhsholphan Byekyet, Sheau-Chung Tang, Jen-Hung Yang and Chin-Hung Liu
Biomolecules 2020, 10(12), 1689; https://doi.org/10.3390/biom10121689 - 17 Dec 2020
Cited by 20 | Viewed by 3276
Abstract
Fatty acid esters of hydroxy fatty acids (FAHFAs) are newly discovered long-chain fatty acids. However, the major endogenous FAHFAs in healthy human circulation, their correlation with cardiovascular (CV) biomarkers, and their anti-inflammatory effects have not been investigated and remain unclear. In the present [...] Read more.
Fatty acid esters of hydroxy fatty acids (FAHFAs) are newly discovered long-chain fatty acids. However, the major endogenous FAHFAs in healthy human circulation, their correlation with cardiovascular (CV) biomarkers, and their anti-inflammatory effects have not been investigated and remain unclear. In the present study, a total of 57 healthy subjects were recruited. Liquid chromatography–mass spectrometry (LC-MS) was developed for the simultaneous determination of seven FAHFAs, four long-chain fatty acids, and four non-traditional circulating CV-related biomarkers. We found two major types of FAHFAs in healthy human circulation, palmitoleic acid ester of 9-hydroxystearic acid (9-POHSA), and oleic acid ester of 9-hydroxystearic acid (9-OAHSA). Both 9-POHSA and 9-OAHSA had a strong positive correlation with each other and were negatively correlated with fasting blood glucose, S-adenosyl-l-homocysteine (SAH), and trimethylamine N-oxide (TMAO), but not with l-homocysteine. 9-POHSA was also positively correlated with l-carnitine. Moreover, we confirmed that both 9-POHSA and 9-OAHSA exhibited an anti-inflammatory effect by suppressing LPS stimulated cytokines, including IL-1β and IL-6 in RAW 264.7 cells. In addition, palmitoleic acid also had a positive correlation with 9-POHSA and 9-OAHSA. As far as we know, this is the first report showing the major endogenous FAHFAs in healthy subjects and their CV protection potential which might be correlated with SAH and TMAO reduction, l-Carnitine elevation, and their anti-inflammatory effects. Full article
(This article belongs to the Section Biological Factors)
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22 pages, 1545 KiB  
Review
Nrf2—A Molecular Target for Sepsis Patients in Critical Care
by Sandra Gunne, Ulrike Heinicke, Michael J. Parnham, Volker Laux, Kai Zacharowski and Andreas von Knethen
Biomolecules 2020, 10(12), 1688; https://doi.org/10.3390/biom10121688 - 17 Dec 2020
Cited by 16 | Viewed by 3303
Abstract
The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with [...] Read more.
The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with this, data obtained in cell culture experiments and preclinical settings have shown that Nrf2 is important in regulating target genes that are necessary to ensure cellular redox balance. Additionally, Nrf2 is involved in the induction of phase II drug metabolizing enzymes, which are important both in degrading and converting drugs into active forms, and into putative carcinogens. Therefore, Nrf2 has also been implicated in tumorigenesis. This must be kept in mind when new therapy approaches are planned for the treatment of sepsis. Therefore, this review highlights the function of Nrf2 in sepsis with a special focus on the translation of rodent-based results into sepsis patients in the intensive care unit (ICU). Full article
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23 pages, 2528 KiB  
Article
On the Liquid Chemistry of the Reactive Nitrogen Species Peroxynitrite and Nitrogen Dioxide Generated by Physical Plasmas
by Giuliana Bruno, Sebastian Wenske, Jan-Wilm Lackmann, Michael Lalk, Thomas von Woedtke and Kristian Wende
Biomolecules 2020, 10(12), 1687; https://doi.org/10.3390/biom10121687 - 16 Dec 2020
Cited by 21 | Viewed by 3144
Abstract
Cold physical plasmas modulate cellular redox signaling processes, leading to the evolution of a number of clinical applications in recent years. They are a source of small reactive species, including reactive nitrogen species (RNS). Wound healing is a major application and, as its [...] Read more.
Cold physical plasmas modulate cellular redox signaling processes, leading to the evolution of a number of clinical applications in recent years. They are a source of small reactive species, including reactive nitrogen species (RNS). Wound healing is a major application and, as its physiology involves RNS signaling, a correlation between clinical effectiveness and the activity of plasma-derived RNS seems evident. To investigate the type and reactivity of plasma-derived RNS in aqueous systems, a model with tyrosine as a tracer was utilized. By high-resolution mass spectrometry, 26 different tyrosine derivatives including the physiologic nitrotyrosine were identified. The product pattern was distinctive in terms of plasma parameters, especially gas phase composition. By scavenger experiments and isotopic labelling, gaseous nitric dioxide radicals and liquid phase peroxynitrite ions were determined as dominant RNS. The presence of water molecules in the active plasma favored the generation of peroxynitrite. A pilot study, identifying RNS driven post-translational modifications of proteins in healing human wounds after the treatment with cold plasma (kINPen), demonstrated the presence of in vitro determined chemical pathways. The plasma-driven nitration and nitrosylation of tyrosine allows the conclusion that covalent modification of biomolecules by RNS contributes to the clinically observed impact of cold plasmas. Full article
(This article belongs to the Section Chemical Biology)
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12 pages, 4116 KiB  
Article
Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer
by Miku Wada, Asako Kukita, Kenbun Sone, Ryuji Hamamoto, Syuzo Kaneko, Masaaki Komatsu, Yu Takahashi, Futaba Inoue, Machiko Kojima, Harunori Honjoh, Ayumi Taguchi, Tomoko Kashiyama, Yuichiro Miyamoto, Michihiro Tanikawa, Tetsushi Tsuruga, Mayuyo Mori-Uchino, Osamu Wada-Hiraike, Yutaka Osuga and Tomoyuki Fujii
Biomolecules 2020, 10(12), 1686; https://doi.org/10.3390/biom10121686 - 16 Dec 2020
Cited by 13 | Viewed by 3024
Abstract
The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still [...] Read more.
The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still unknown. The purpose of this study was to investigate the role of SETD8 in HGSOC. We performed quantitative real-time PCR and immunohistochemistry to detect the expression of SETD8 in HGSOC samples and normal ovarian specimens. Then, we assessed the effect of the inhibition of SETD8 expression using small interfering RNA (siRNA) and a selective inhibitor (UNC0379) on cell proliferation and apoptosis in HGSOC cells. The expression of SETD8 was significantly upregulated in clinical ovarian cancer specimens compared to that in the corresponding normal ovary. In addition, suppression of SETD8 expression in HGSOC cells with either siRNA or UNC0379 resulted in reduced levels of H4K20 monomethylation, inhibition of cell proliferation, and induction of apoptosis. Furthermore, UNC0379 showed a long-term antitumor effect against HGSOC cells, as demonstrated by colony-formation assays. SETD8 thus constitutes a promising therapeutic target for HGSOC, warranting further functional studies. Full article
(This article belongs to the Special Issue Epigenetics in Cancer)
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14 pages, 490 KiB  
Review
The Potential Role of Hydrogen Sulfide in the Regulation of Cerebrovascular Tone
by Eleni Dongó and Levente Kiss
Biomolecules 2020, 10(12), 1685; https://doi.org/10.3390/biom10121685 - 16 Dec 2020
Cited by 10 | Viewed by 2089
Abstract
A better understanding of the regulation of cerebrovascular circulation is of great importance because stroke and other cerebrovascular diseases represent a major concern in healthcare leading to millions of deaths yearly. The circulation of the central nervous system is regulated in a highly [...] Read more.
A better understanding of the regulation of cerebrovascular circulation is of great importance because stroke and other cerebrovascular diseases represent a major concern in healthcare leading to millions of deaths yearly. The circulation of the central nervous system is regulated in a highly complex manner involving many local factors and hydrogen sulfide (H2S) is emerging as one such possible factor. Several lines of evidence support that H2S takes part in the regulation of vascular tone. Examinations using either exogenous treatment with H2S donor molecules or alterations to the enzymes that are endogenously producing this molecule revealed numerous important findings about its physiological and pathophysiological role. The great majority of these studies were performed on vessel segments derived from the systemic circulation but there are important observations made using cerebral vessels as well. The findings of these experimental works indicate that H2S is having a complex, pleiotropic effect on the vascular wall not only in the systemic circulation but in the cerebrovascular region as well. In this review, we summarize the most important experimental findings related to the potential role of H2S in the cerebral circulation. Full article
(This article belongs to the Special Issue Gaseous Transmitters and Cardiovascular System)
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14 pages, 3565 KiB  
Article
Furan-Conjugated Tripeptides as Potent Antitumor Drugs
by Hunain Ali, Almas Jabeen, Rukesh Maharjan, Muhammad Nadeem-ul-Haque, Husena Aamra, Salma Nazir, Serab Khan, Hamza Olleik, Marc Maresca and Farzana Shaheen
Biomolecules 2020, 10(12), 1684; https://doi.org/10.3390/biom10121684 - 16 Dec 2020
Cited by 14 | Viewed by 3865
Abstract
Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate [...] Read more.
Cervical cancer is among the leading causes of death in women. Chemotherapy options available for cervical cancer include highly cytotoxic drugs such as taxol, cisplatin, 5-florouracil, and doxorubicin, which are not specific. In the current study, we have identified a new peptide conjugate (Fur4-2-Nal3-Ala2-Phe1-CONH2) (conjugate 4), from screening of a small library of tripeptide-conjugates of furan, as highly potent anticancer compound against human cervical cancer cells (HeLa cells) (IC50 = 0.15 ± 0.05 µg/mL or 0.28 +/− 0.09 µM). Peptides were constructed on Rink amide resin from C- to N-terminus followed by capping by α-furoic acid moiety. The synthesized peptides were purified by recycling RP-HPLC, and structures of all the peptides were confirmed by using FABMS/ESIMS, 1H- NMR, 13C-NMR, and HR-FABMS. Conjugate 4 was furthermore found to be specifically active against human cervical cancer cells since it did not inhibit the proliferation of other human normal cells (HUVEC (human umbilical vein endothelial cells) and IMR-90 (normal human fibroblasts)), and cancer cells tested (HUVEC, MCF-7, and MDA-MB-231 cells), as well as in mice 3T3 cells (normal fibroblasts). This study revealed a good structure activity relationship of various peptide conjugates. Conjugate 4 in branched forms (4a and 4b) were also synthesized and evaluated against HeLa cells, and results revealed that both were inactive. Atomic force microscopy (AFM) studies and staining with rhodamine 123 and propidium iodide (PI) revealed that conjugate 4 possesses a membranolytic effect and causes the loss of mitochondrial membrane potential. Full article
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23 pages, 1839 KiB  
Review
GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer
by Octavio Silva-García, Ricarda Cortés-Vieyra, Francisco N. Mendoza-Ambrosio, Guillermo Ramírez-Galicia and Víctor M. Baizabal-Aguirre
Biomolecules 2020, 10(12), 1683; https://doi.org/10.3390/biom10121683 - 16 Dec 2020
Cited by 9 | Viewed by 3566
Abstract
The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3β, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders [...] Read more.
The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3β, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer’s disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3β kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways)
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14 pages, 3834 KiB  
Review
S-adenosyl-l-homocysteine Hydrolase: A Structural Perspective on the Enzyme with Two Rossmann-Fold Domains
by Krzysztof Brzezinski
Biomolecules 2020, 10(12), 1682; https://doi.org/10.3390/biom10121682 - 16 Dec 2020
Cited by 11 | Viewed by 3320
Abstract
S-adenosyl-l-homocysteine hydrolase (SAHase) is a major regulator of cellular methylation reactions that occur in eukaryotic and prokaryotic organisms. SAHase activity is also a significant source of l-homocysteine and adenosine, two compounds involved in numerous vital, as well as pathological [...] Read more.
S-adenosyl-l-homocysteine hydrolase (SAHase) is a major regulator of cellular methylation reactions that occur in eukaryotic and prokaryotic organisms. SAHase activity is also a significant source of l-homocysteine and adenosine, two compounds involved in numerous vital, as well as pathological processes. Therefore, apart from cellular methylation, the enzyme may also influence other processes important for the physiology of particular organisms. Herein, presented is the structural characterization and comparison of SAHases of eukaryotic and prokaryotic origin, with an emphasis on the two principal domains of SAHase subunit based on the Rossmann motif. The first domain is involved in the binding of a substrate, e.g., S-adenosyl-l-homocysteine or adenosine and the second domain binds the NAD+ cofactor. Despite their structural similarity, the molecular interactions between an adenosine-based ligand molecule and macromolecular environment are different in each domain. As a consequence, significant differences in the conformation of d-ribofuranose rings of nucleoside and nucleotide ligands, especially those attached to adenosine moiety, are observed. On the other hand, the chemical nature of adenine ring recognition, as well as an orientation of the adenine ring around the N-glycosidic bond are of high similarity for the ligands bound in the substrate- and cofactor-binding domains. Full article
(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)
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20 pages, 694 KiB  
Review
Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside
by Gabriel Brawerman and Peter J. Thompson
Biomolecules 2020, 10(12), 1681; https://doi.org/10.3390/biom10121681 - 16 Dec 2020
Cited by 17 | Viewed by 5310
Abstract
Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta [...] Read more.
Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta cell stress responses are also important contributors to disease onset. Here we review the pathways driving different kinds of beta cell dysfunction and their respective therapeutic targets in the prevention of T1D. We discuss opportunities and important open questions around the effectiveness of beta cell therapies and challenges for clinical utility. We further evaluate ways in which beta cell drug therapy could be combined with immunotherapy for preventing T1D in light of our growing appreciation of disease heterogeneity and patient endotypes. Ultimately, the emergence of pharmacologic beta cell therapies for T1D have armed us with new tools and closing the knowledge gaps in T1D etiology will be essential for maximizing the potential of these approaches. Full article
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21 pages, 5769 KiB  
Article
DNA Repair Biosensor-Identified DNA Damage Activities of Endophyte Extracts from Garcinia cowa
by Tassanee Lerksuthirat, Rakkreat Wikiniyadhanee, Sermsiri Chitphuk, Wasana Stitchantrakul, Somponnat Sampattavanich, Siwanon Jirawatnotai, Juangjun Jumpathong and Donniphat Dejsuphong
Biomolecules 2020, 10(12), 1680; https://doi.org/10.3390/biom10121680 - 16 Dec 2020
Viewed by 2936
Abstract
Recent developments in chemotherapy focus on target-specific mechanisms, which occur only in cancer cells and minimize the effects on normal cells. DNA damage and repair pathways are a promising target in the treatment of cancer. In order to identify novel compounds targeting DNA [...] Read more.
Recent developments in chemotherapy focus on target-specific mechanisms, which occur only in cancer cells and minimize the effects on normal cells. DNA damage and repair pathways are a promising target in the treatment of cancer. In order to identify novel compounds targeting DNA repair pathways, two key proteins, 53BP1 and RAD54L, were tagged with fluorescent proteins as indicators for two major double strand break (DSB) repair pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). The engineered biosensor cells exhibited the same DNA repair properties as the wild type. The biosensor cells were further used to investigate the DNA repair activities of natural biological compounds. An extract from Phyllosticta sp., the endophyte isolated from the medicinal plant Garcinia cowa Roxb. ex Choisy, was tested. The results showed that the crude extract induced DSB, as demonstrated by the increase in the DNA DSB marker γH2AX. The damaged DNA appeared to be repaired through NHEJ, as the 53BP1 focus formation in the treated fraction was higher than in the control group. In conclusion, DNA repair-based biosensors are useful for the preliminary screening of crude extracts and biological compounds for the identification of potential targeted therapeutic drugs. Full article
(This article belongs to the Section Natural and Bio-inspired Molecules)
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21 pages, 4252 KiB  
Article
Diosgenin Loaded Polymeric Nanoparticles with Potential Anticancer Efficacy
by Nikita Sharma, Monisha Singhal, R. Mankamna Kumari, Nidhi Gupta, Romila Manchanda, Asad Syed, Ali H. Bahkali and Surendra Nimesh
Biomolecules 2020, 10(12), 1679; https://doi.org/10.3390/biom10121679 - 16 Dec 2020
Cited by 14 | Viewed by 3028
Abstract
This study aims to determine the anticancer efficacy of diosgenin encapsulated poly-glycerol malate co-dodecanedioate (PGMD) nanoparticles. Diosgenin loaded PGMD nanoparticles (variants 7:3 and 6:4) were synthesized by the nanoprecipitation method. The synthesis of PGMD nanoparticles was systematically optimized employing the Box-Behnken design and [...] Read more.
This study aims to determine the anticancer efficacy of diosgenin encapsulated poly-glycerol malate co-dodecanedioate (PGMD) nanoparticles. Diosgenin loaded PGMD nanoparticles (variants 7:3 and 6:4) were synthesized by the nanoprecipitation method. The synthesis of PGMD nanoparticles was systematically optimized employing the Box-Behnken design and taking into account the influence of various independent variables such as concentrations of each PGMD, diosgenin and PF-68 on the responses such as size and PDI of the particles. Mathematical modeling was done using the Quadratic second order modeling method and response surface analysis was undertaken to elucidate the factor-response relationship. The obtained size of PGMD 7:3 and PGMD 6:4 nanoparticles were 133.6 nm and 121.4 nm, respectively, as measured through dynamic light scattering (DLS). The entrapment efficiency was in the range of 77–83%. The in vitro drug release studies showed diffusion and dissolution controlled drug release pattern following Korsmeyer–Peppas kinetic model. Furthermore, in vitro morphological and cytotoxic studies were performed to evaluate the toxicity of synthesized drug loaded nanoparticles in model cell lines. The IC50 after 48 h was observed to be 27.14 µM, 15.15 µM and 13.91 µM for free diosgenin, PGMD 7:3 and PGMD 6:4 nanoparticles, respectively, when administered in A549 lung carcinoma cell lines. Full article
(This article belongs to the Section Biological and Bio- Materials)
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21 pages, 2405 KiB  
Article
Peritoneal Dialysis Fluid Supplementation with Alanyl-Glutamine Attenuates Conventional Dialysis Fluid-Mediated Endothelial Cell Injury by Restoring Perturbed Cytoprotective Responses
by Rebecca Herzog, Maria Bartosova, Silvia Tarantino, Anja Wagner, Markus Unterwurzacher, Juan Manuel Sacnun, Anton M. Lichtenauer, Lilian Kuster, Betti Schaefer, Seth L. Alper, Christoph Aufricht, Claus Peter Schmitt and Klaus Kratochwill
Biomolecules 2020, 10(12), 1678; https://doi.org/10.3390/biom10121678 - 15 Dec 2020
Cited by 19 | Viewed by 2924
Abstract
Long-term clinical outcome of peritoneal dialysis (PD) depends on adequate removal of small solutes and water. The peritoneal endothelium represents the key barrier and peritoneal transport dysfunction is associated with vascular changes. Alanyl-glutamine (AlaGln) has been shown to counteract PD-induced deteriorations but the [...] Read more.
Long-term clinical outcome of peritoneal dialysis (PD) depends on adequate removal of small solutes and water. The peritoneal endothelium represents the key barrier and peritoneal transport dysfunction is associated with vascular changes. Alanyl-glutamine (AlaGln) has been shown to counteract PD-induced deteriorations but the effect on vascular changes has not yet been elucidated. Using multiplexed proteomic and bioinformatic analyses we investigated the molecular mechanisms of vascular pathology in-vitro (primary human umbilical vein endothelial cells, HUVEC) and ex-vivo (arterioles of patients undergoing PD) following exposure to PD-fluid. An overlap of 1813 proteins (40%) of over 3100 proteins was identified in both sample types. PD-fluid treatment significantly altered 378 in endothelial cells and 192 in arterioles. The HUVEC proteome resembles the arteriolar proteome with expected sample specific differences of mainly immune system processes only present in arterioles and extracellular region proteins primarily found in HUVEC. AlaGln-addition to PD-fluid revealed 359 differentially abundant proteins and restored the molecular process landscape altered by PD fluid. This study provides evidence on validity and inherent limitations of studying endothelial pathomechanisms in-vitro compared to vascular ex-vivo findings. AlaGln could reduce PD-associated vasculopathy by reducing endothelial cellular damage, restoring perturbed abundances of pathologically important proteins and enriching protective processes. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Peritoneal Membrane Pathophysiology)
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23 pages, 1846 KiB  
Review
Cell-Free DNA-Methylation-Based Methods and Applications in Oncology
by Francesca Galardi, Francesca De Luca, Dario Romagnoli, Chiara Biagioni, Erica Moretti, Laura Biganzoli, Angelo Di Leo, Ilenia Migliaccio, Luca Malorni and Matteo Benelli
Biomolecules 2020, 10(12), 1677; https://doi.org/10.3390/biom10121677 - 15 Dec 2020
Cited by 33 | Viewed by 8345
Abstract
Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm [...] Read more.
Liquid biopsy based on cell-free DNA (cfDNA) enables non-invasive dynamic assessment of disease status in patients with cancer, both in the early and advanced settings. The analysis of DNA-methylation (DNAm) from cfDNA samples holds great promise due to the intrinsic characteristics of DNAm being more prevalent, pervasive, and cell- and tumor-type specific than genomics, for which established cfDNA assays already exist. Herein, we report on recent advances on experimental strategies for the analysis of DNAm in cfDNA samples. We describe the main steps of DNAm-based analysis workflows, including pre-analytics of cfDNA samples, DNA treatment, assays for DNAm evaluation, and methods for data analysis. We report on protocols, biomolecular techniques, and computational strategies enabling DNAm evaluation in the context of cfDNA analysis, along with practical considerations on input sample requirements and costs. We provide an overview on existing studies exploiting cell-free DNAm biomarkers for the detection and monitoring of cancer in early and advanced settings, for the evaluation of drug resistance, and for the identification of the cell-of-origin of tumors. Finally, we report on DNAm-based tests approved for clinical use and summarize their performance in the context of liquid biopsy. Full article
(This article belongs to the Special Issue Epigenetics in Cancer)
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29 pages, 3378 KiB  
Review
New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin
by Monserrat Olea-Flores, Juan C. Juárez-Cruz, Miriam D. Zuñiga-Eulogio, Erika Acosta, Eduardo García-Rodríguez, Ana E. Zacapala-Gomez, Miguel A. Mendoza-Catalán, Julio Ortiz-Ortiz, Carlos Ortuño-Pineda and Napoleón Navarro-Tito
Biomolecules 2020, 10(12), 1676; https://doi.org/10.3390/biom10121676 - 15 Dec 2020
Cited by 23 | Viewed by 4958
Abstract
Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal [...] Read more.
Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer. Full article
(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)
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19 pages, 3628 KiB  
Article
Actinomycetes Enrich Soil Rhizosphere and Improve Seed Quality as well as Productivity of Legumes by Boosting Nitrogen Availability and Metabolism
by Hamada AbdElgawad, Walid Abuelsoud, Mahmoud M. Y. Madany, Samy Selim, Gaurav Zinta, Ahmed S. M. Mousa and Wael N. Hozzein
Biomolecules 2020, 10(12), 1675; https://doi.org/10.3390/biom10121675 - 15 Dec 2020
Cited by 58 | Viewed by 7542
Abstract
The use of actinomycetes for improving soil fertility and plant production is an attractive strategy for developing sustainable agricultural systems due to their effectiveness, eco-friendliness, and low production cost. Out of 17 species isolated from the soil rhizosphere of legume crops, 4 bioactive [...] Read more.
The use of actinomycetes for improving soil fertility and plant production is an attractive strategy for developing sustainable agricultural systems due to their effectiveness, eco-friendliness, and low production cost. Out of 17 species isolated from the soil rhizosphere of legume crops, 4 bioactive isolates were selected and their impact on 5 legumes: soybean, kidney bean, chickpea, lentil, and pea were evaluated. According to the morphological and molecular identification, these isolates belong to the genus Streptomyces. Here, we showed that these isolates increased soil nutrients and organic matter content and improved soil microbial populations. At the plant level, soil enrichment with actinomycetes increased photosynthetic reactions and eventually increased legume yield. Actinomycetes also increased nitrogen availability in soil and legume tissue and seeds, which induced the activity of key nitrogen metabolizing enzymes, e.g., glutamine synthetase, glutamate synthase, and nitrate reductase. In addition to increased nitrogen-containing amino acids levels, we also report high sugar, organic acids, and fatty acids as well as antioxidant phenolics, mineral, and vitamins levels in actinomycete treated legume seeds, which in turn improved their seed quality. Overall, this study shed the light on the impact of actinomycetes on enhancing the quality and productivity of legume crops by boosting the bioactive primary and secondary metabolites. Moreover, our findings emphasize the positive role of actinomycetes in improving the soil by enriching its microbial population. Therefore, our data reinforce the usage of actinomycetes as biofertilizers to provide sustainable food production and achieve biosafety. Full article
(This article belongs to the Special Issue Recent Advance of Actinomycetes)
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3 pages, 167 KiB  
Editorial
Novel Natural-based Biomolecules Discovery for Tackling Chronic Diseases
by Hang Fai Kwok
Biomolecules 2020, 10(12), 1674; https://doi.org/10.3390/biom10121674 - 15 Dec 2020
Viewed by 1741
Abstract
In the last decade, natural-derived/-based biomolecules have continuously played an important role in novel drug discovery (as a prototype drug template) for potential chronic disease treatment [...] Full article
25 pages, 2374 KiB  
Review
Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy
by Faheem Shaik, Gary A. Cuthbert, Shervanthi Homer-Vanniasinkam, Stephen P. Muench, Sreenivasan Ponnambalam and Michael A. Harrison
Biomolecules 2020, 10(12), 1673; https://doi.org/10.3390/biom10121673 - 15 Dec 2020
Cited by 42 | Viewed by 6327
Abstract
Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in [...] Read more.
Vascular endothelial growth factors (VEGFs) bind to membrane receptors on a wide variety of cells to regulate diverse biological responses. The VEGF-A family member promotes vasculogenesis and angiogenesis, processes which are essential for vascular development and physiology. As angiogenesis can be subverted in many disease states, including tumour development and progression, there is much interest in understanding the mechanistic basis for how VEGF-A regulates cell and tissue function. VEGF-A binds with high affinity to two VEGF receptor tyrosine kinases (VEGFR1, VEGFR2) and with lower affinity to co-receptors called neuropilin-1 and neuropilin-2 (NRP1, NRP2). Here, we use a structural viewpoint to summarise our current knowledge of VEGF-VEGFR activation and signal transduction. As targeting VEGF-VEGFR activation holds much therapeutic promise, we examine the structural basis for anti-angiogenic therapy using small-molecule compounds such as tyrosine kinase inhibitors that block VEGFR activation and downstream signalling. This review provides a rational basis towards reconciling VEGF and VEGFR structure and function in developing new therapeutics for a diverse range of ailments. Full article
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