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Biomolecules
Volume 11
Issue 8
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Biomolecules, Volume 11, Issue 8 (August 2021) – 193 articles

Cover Story (view full-size image): The small size, antigen specificity, plasticity, and potential to recognize unique conformational epitopes of single-domain antibodies (sdAb) represent a diagnostic and therapeutic opportunity for many central nervous system (CNS) pathologies. However, the blood–brain barrier (BBB) poses a challenge for their delivery into the brain parenchyma. This review analyzes different strategies and methods to transport sdAB through the BBB to fulfill their therapeutic, diagnostic, and theragnostic promises for the benefit of patients suffering from CNS pathologies. View this paper
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12 pages, 275 KiB  
Communication
Chronic Pain in the Elderly: Mechanisms and Distinctive Features
by Andrea Tinnirello, Silvia Mazzoleni and Carola Santi
Biomolecules 2021, 11(8), 1256; https://doi.org/10.3390/biom11081256 - 23 Aug 2021
Cited by 37 | Viewed by 8232
Abstract
Background: Chronic pain is a major issue affecting more than 50% of the older population and up to 80% of nursing homes residents. Research on pain in the elderly focuses mainly on the development of clinical tools to assess pain in patients with [...] Read more.
Background: Chronic pain is a major issue affecting more than 50% of the older population and up to 80% of nursing homes residents. Research on pain in the elderly focuses mainly on the development of clinical tools to assess pain in patients with dementia and cognitive impairment or on the efficacy and tolerability of medications. In this review, we searched for evidence of specific pain mechanisms or modifications in pain signals processing either at the cellular level or in the central nervous system. Methods: Narrative review. Results: Investigation on pain sensitivity led to conflicting results, with some studies indicating a modest decrease in age-related pain sensitivity, while other researchers found a reduced pain threshold for pressure stimuli. Areas of the brain involved in pain perception and analgesia are susceptible to pathological changes such as gliosis and neuronal death and the effectiveness of descending pain inhibitory mechanisms, particularly their endogenous opioid component, also appears to deteriorate with advancing age. Hyperalgesia is more common at older age and recovery from peripheral nerve injury appears to be delayed. In addition, peripheral nociceptors may contribute minimally to pain sensation at either acute or chronic time points in aged populations. Conclusions: Elderly subjects appear to be more susceptible to prolonged pain development, and medications acting on peripheral sensitization are less efficient. Pathologic changes in the central nervous system are responsible for different pain processing and response to treatment. Specific guidelines focusing on specific pathophysiological changes in the elderly are needed to ensure adequate treatment of chronic pain conditions. Full article
(This article belongs to the Special Issue State-of-the-Art of the New Pharmacological Targets for Treating Chronic Neuropsychiatric Disorders in Italy)
21 pages, 3693 KiB  
Article
Degraded Sericin Significantly Regulates Blood Glucose Levels and Improves Impaired Liver Function in T2D Rats by Reducing Oxidative Stress
by Heng-Da Wang, Zhi-Hao Zhong, Yu-Jie Weng, Zhen-Zhen Wei and Yu-Qing Zhang
Biomolecules 2021, 11(8), 1255; https://doi.org/10.3390/biom11081255 - 23 Aug 2021
Cited by 16 | Viewed by 2456
Abstract
Sericin could be degraded well into low-molecular-weight sericin (SS) through a novel and environmentally friendly recycling process using an ultrasonically degumming method in Ca(OH)2 aqueous solution. The oral administration of the SS has an evidently hypoglycemic effect on STZ-induced T2D rats. At [...] Read more.
Sericin could be degraded well into low-molecular-weight sericin (SS) through a novel and environmentally friendly recycling process using an ultrasonically degumming method in Ca(OH)2 aqueous solution. The oral administration of the SS has an evidently hypoglycemic effect on STZ-induced T2D rats. At oral doses of 2.5 and 5% SS for four weeks, the fasting blood glucose decreased by over 60% compared with that in the untreated model group. Oral glucose tolerance and insulin tolerance were ameliorated by the peptide treatment. The serum insulin level was reduced by approximately 35%, the insulin resistance index was reduced by more than 66%. The 8-hydroxy-2 deoxyguanosine level showed a large reduction of 20%, and the total antioxidant activities significantly increased. Hematoxylin-eosin staining and fluorescent immunostaining sections showed that liver and pancreas damage was partly recovered in T2D rats. In summary, oral SS demonstrated evidently hypoglycemic effects mainly related to reducing oxidative stress in the damaged liver and pancreas of T2D rats. Therefore, these results have suggested that the degraded sericin has a potential use in SS-based healthy functional food or hypoglycemic drugs as a waste recovered from sericulture resources. Full article
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28 pages, 2282 KiB  
Review
Anticoronavirus and Immunomodulatory Phenolic Compounds: Opportunities and Pharmacotherapeutic Perspectives
by Naiara Naiana Dejani, Hatem A. Elshabrawy, Carlos da Silva Maia Bezerra Filho and Damião Pergentino de Sousa
Biomolecules 2021, 11(8), 1254; https://doi.org/10.3390/biom11081254 - 23 Aug 2021
Cited by 14 | Viewed by 3851
Abstract
In 2019, COVID-19 emerged as a severe respiratory disease that is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The disease has been associated with high mortality rate, especially in patients with comorbidities such as diabetes, cardiovascular and kidney diseases. [...] Read more.
In 2019, COVID-19 emerged as a severe respiratory disease that is caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The disease has been associated with high mortality rate, especially in patients with comorbidities such as diabetes, cardiovascular and kidney diseases. This could be attributed to dysregulated immune responses and severe systemic inflammation in COVID-19 patients. The use of effective antiviral drugs against SARS-CoV-2 and modulation of the immune responses could be a potential therapeutic strategy for COVID-19. Studies have shown that natural phenolic compounds have several pharmacological properties, including anticoronavirus and immunomodulatory activities. Therefore, this review discusses the dual action of these natural products from the perspective of applicability at COVID-19. Full article
(This article belongs to the Special Issue Bioactive Natural Compounds against Animal and Human Pathogens)
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19 pages, 4899 KiB  
Article
Transcriptional Regulation of MECP2E1-E2 Isoforms and BDNF by Metformin and Simvastatin through Analyzing Nascent RNA Synthesis in a Human Brain Cell Line
by Marjorie Buist, David Fuss and Mojgan Rastegar
Biomolecules 2021, 11(8), 1253; https://doi.org/10.3390/biom11081253 - 22 Aug 2021
Cited by 11 | Viewed by 3071
Abstract
Methyl CpG binding protein 2 (MeCP2) is the main DNA methyl-binding protein in the brain that binds to 5-methylcytosine and 5-hydroxymethyl cytosine. MECP2 gene mutations are the main origin of Rett Syndrome (RTT), a neurodevelopmental disorder in young females. The disease has no [...] Read more.
Methyl CpG binding protein 2 (MeCP2) is the main DNA methyl-binding protein in the brain that binds to 5-methylcytosine and 5-hydroxymethyl cytosine. MECP2 gene mutations are the main origin of Rett Syndrome (RTT), a neurodevelopmental disorder in young females. The disease has no existing cure, however, metabolic drugs such as metformin and statins have recently emerged as potential therapeutic candidates. In addition, induced MECP2-BDNF homeostasis regulation has been suggested as a therapy avenue. Here, we analyzed nascent RNA synthesis versus steady state total cellular RNA to study the transcriptional effects of metformin (an anti-diabetic drug) on MECP2 isoforms (E1 and E2) and BNDF in a human brain cell line. Additionally, we investigated the impact of simvastatin (a cholesterol lowering drug) on transcriptional regulation of MECP2E1/E2-BDNF. Metformin was capable of post-transcriptionally inducing BDNF and/or MECP2E1, while transcriptionally inhibiting MECP2E2. In contrast simvastatin significantly inhibited BDNF transcription without significantly impacting MECP2E2 transcripts. Further analysis of ribosomal RNA transcripts confirmed that the drug neither individually nor in combination affected these fundamentally important transcripts. Experimental analysis was completed in conditions of the presence or absence of serum starvation that showed minimal impact for serum deprival, although significant inhibition of steady state MECP2E1 by simvastatin was only detected in non-serum starved cells. Taken together, our results suggest that metformin controls MECP2E1/E2-BDNF transcriptionally and/or post-transcriptionally, and that simvastatin is a potent transcriptional inhibitor of BDNF. The transcriptional effect of these drugs on MECP2E1/E2-BDNF were not additive under these tested conditions, however, either drug may have potential application for related disorders. Full article
(This article belongs to the Collection DNA Methylation Dynamics in Health and Disease)
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11 pages, 1633 KiB  
Article
Benefits of Metformin Combined with Pemetrexed-Based Platinum Doublets as a First-Line Therapy for Advanced Lung Adenocarcinoma Patients with Diabetes
by Jiun-Long Wang, Yi-Ting Tsai, Ching-Heng Lin, Abdulkadir Cidem, Theresa Staniczek, Gary Ro-Lin Chang, Chih-Ching Yen, Wei Chen, Kowit-Yu Chong and Chuan-Mu Chen
Biomolecules 2021, 11(8), 1252; https://doi.org/10.3390/biom11081252 - 21 Aug 2021
Cited by 5 | Viewed by 2728
Abstract
Lung cancer remains a challenge in daily practice. Chemotherapy is first considered for advanced lung adenocarcinoma bearing no active driver mutations. Maintaining drug efficacy and overcoming drug resistance are essential. This study aimed to explore the real-world use of anti-diabetic agent metformin in [...] Read more.
Lung cancer remains a challenge in daily practice. Chemotherapy is first considered for advanced lung adenocarcinoma bearing no active driver mutations. Maintaining drug efficacy and overcoming drug resistance are essential. This study aimed to explore the real-world use of anti-diabetic agent metformin in combination with pemetrexed-based platinum doublets in a first-line setting. We retrospectively collected data during 2004~2013 from TaiwaN′s National Health Insurance Research Database to access the survival benefit of metformin combined with pemetrexed-based platinum doublets as a first-line therapy for diabetic patients with advanced lung adenocarcinoma. Demographic data and information regarding platinum reagents, diabetes medications, and metformin doses were gathered, and overall survival status regarding metformin use was analyzed. Overall survival status based on the daily dose and the calculated cumulative defined daily dose (DDD) of metformin prescribed during the first 3 months after lung cancer was diagnosed was also assessed. A total of 495 patients were enrolled with a mean age of 67 years old, and the majority of the patients were male. After adjusting for age, sex, diabetes medication, and platinum reagents used, the adjusted hazard ratio (HR) for the metformin-user group was 0.61 (95% confidence interval (CI); 0.46~0.79; p < 0.001). The metformin-user group had a survival benefit (log-rank p < 0.001). We analyzed metformin dosing during the first 3 months after lung cancer diagnosis, and for a daily dose ≥ 1500 mg, the adjusted hazard ratio (aHR) was 0.42 (95% CI; 0.27~0.65; p < 0.001). Regarding the cumulative DDD of metformin, a DDD equal to or exceeding 21 resulted in aHR of 0.48 (95% CI; 0.34~0.69; p < 0.001). In this study, we found that the combination of metformin and pemetrexed-based platinum doublets provides a robust survival benefit as a first-line therapy for diabetic patients with advanced lung adenocarcinoma. It is worth conducting a large and randomized clinical trial to further investigate the antitumor effects of metformin on advanced lung adenocarcinoma when used as a first-ling therapy, including in non-diabetic patients. Full article
(This article belongs to the Special Issue Metformin and Cancer)
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15 pages, 3075 KiB  
Article
Computational Insights into the Structural Dynamics of MDA5 Variants Associated with Aicardi–Goutières Syndrome and Singleton–Merten Syndrome
by Vijayakumar Gosu, Santanu Sasidharan, Prakash Saudagar, Hak-Kyo Lee and Donghyun Shin
Biomolecules 2021, 11(8), 1251; https://doi.org/10.3390/biom11081251 - 21 Aug 2021
Cited by 14 | Viewed by 2704
Abstract
Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by IFIH1 in humans. Single nucleotide polymorphisms in the IFIH1 results in fatal genetic disorders such as Aicardi–Goutières syndrome and Singleton–Merten syndrome, and in increased risk of type I [...] Read more.
Melanoma differentiation-associated protein 5 (MDA5) is a crucial RIG-I-like receptor RNA helicase enzyme encoded by IFIH1 in humans. Single nucleotide polymorphisms in the IFIH1 results in fatal genetic disorders such as Aicardi–Goutières syndrome and Singleton–Merten syndrome, and in increased risk of type I diabetes in humans. In this study, we chose four different amino acid substitutions of the MDA5 protein responsible for genetic disorders: MDA5L372F, MDA5A452T, MDA5R779H, and MDA5R822Q and analyzed their structural and functional relationships using molecular dynamic simulations. Our results suggest that the mutated complexes are relatively more stable than the wild-type MDA5. The radius of gyration, interaction energies, and intra-hydrogen bond analysis indicated the stability of mutated complexes over the wild type, especially MDA5L372F and MDA5R822Q. The dominant motions exhibited by the wild-type and mutant complexes varied significantly. Moreover, the betweenness centrality of the wild-type and mutant complexes showed shared residues for intra-signal propagation. The observed results indicate that the mutations lead to a gain of function, as reported in previous studies, due to increased interaction energies and stability between RNA and MDA5 in mutated complexes. These findings are expected to deepen our understanding of MDA5 variants and may assist in the development of relevant therapeutics against the disorders. Full article
(This article belongs to the Collection Biomolecules In Silico: Contemporary Advances in Computational Approaches to Investigating the Molecular Dynamics of Biological Systems)
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15 pages, 15351 KiB  
Article
3D Bioprinting Mesenchymal Stem Cell-Derived Neural Tissues Using a Fibrin-Based Bioink
by Milena Restan Perez, Ruchi Sharma, Nadia Zeina Masri and Stephanie Michelle Willerth
Biomolecules 2021, 11(8), 1250; https://doi.org/10.3390/biom11081250 - 21 Aug 2021
Cited by 16 | Viewed by 4930
Abstract
Current treatments for neurodegenerative diseases aim to alleviate the symptoms experienced by patients; however, these treatments do not cure the disease nor prevent further degeneration. Improvements in current disease-modeling and drug-development practices could accelerate effective treatments for neurological diseases. To that end, 3D [...] Read more.
Current treatments for neurodegenerative diseases aim to alleviate the symptoms experienced by patients; however, these treatments do not cure the disease nor prevent further degeneration. Improvements in current disease-modeling and drug-development practices could accelerate effective treatments for neurological diseases. To that end, 3D bioprinting has gained significant attention for engineering tissues in a rapid and reproducible fashion. Additionally, using patient-derived stem cells, which can be reprogrammed to neural-like cells, could generate personalized neural tissues. Here, adipose tissue-derived mesenchymal stem cells (MSCs) were bioprinted using a fibrin-based bioink and the microfluidic RX1 bioprinter. These tissues were cultured for 12 days in the presence of SB431542 (SB), LDN-193189 (LDN), purmorphamine (puro), fibroblast growth factor 8 (FGF8), fibroblast growth factor-basic (bFGF), and brain-derived neurotrophic factor (BDNF) to induce differentiation to dopaminergic neurons (DN). The constructs were analyzed for expression of neural markers, dopamine release, and electrophysiological activity. The cells expressed DN-specific and early neuronal markers (tyrosine hydroxylase (TH) and class III beta-tubulin (TUJ1), respectively) after 12 days of differentiation. Additionally, the tissues exhibited immature electrical signaling after treatment with potassium chloride (KCl). Overall, this work shows the potential of bioprinting engineered neural tissues from patient-derived MSCs, which could serve as an important tool for personalized disease models and drug-screening. Full article
(This article belongs to the Special Issue Extracellular Matrix-Based Bioinks for 3D Bioprinting Applications)
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19 pages, 601 KiB  
Review
Transcription-Replication Collisions—A Series of Unfortunate Events
by Commodore St Germain, Hongchang Zhao and Jacqueline H. Barlow
Biomolecules 2021, 11(8), 1249; https://doi.org/10.3390/biom11081249 - 21 Aug 2021
Cited by 9 | Viewed by 4030
Abstract
Transcription-replication interactions occur when DNA replication encounters genomic regions undergoing transcription. Both replication and transcription are essential for life and use the same DNA template making conflicts unavoidable. R-loops, DNA supercoiling, DNA secondary structure, and chromatin-binding proteins are all potential obstacles for processive [...] Read more.
Transcription-replication interactions occur when DNA replication encounters genomic regions undergoing transcription. Both replication and transcription are essential for life and use the same DNA template making conflicts unavoidable. R-loops, DNA supercoiling, DNA secondary structure, and chromatin-binding proteins are all potential obstacles for processive replication or transcription and pose an even more potent threat to genome integrity when these processes co-occur. It is critical to maintaining high fidelity and processivity of transcription and replication while navigating through a complex chromatin environment, highlighting the importance of defining cellular pathways regulating transcription-replication interaction formation, evasion, and resolution. Here we discuss how transcription influences replication fork stability, and the safeguards that have evolved to navigate transcription-replication interactions and maintain genome integrity in mammalian cells. Full article
(This article belongs to the Section Molecular Genetics)
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31 pages, 2226 KiB  
Review
The Role of Methionine Residues in the Regulation of Liquid-Liquid Phase Separation
by Juan Carlos Aledo
Biomolecules 2021, 11(8), 1248; https://doi.org/10.3390/biom11081248 - 21 Aug 2021
Cited by 5 | Viewed by 3658
Abstract
Membraneless organelles are non-stoichiometric supramolecular structures in the micron scale. These structures can be quickly assembled/disassembled in a regulated fashion in response to specific stimuli. Membraneless organelles contribute to the spatiotemporal compartmentalization of the cell, and they are involved in diverse cellular processes [...] Read more.
Membraneless organelles are non-stoichiometric supramolecular structures in the micron scale. These structures can be quickly assembled/disassembled in a regulated fashion in response to specific stimuli. Membraneless organelles contribute to the spatiotemporal compartmentalization of the cell, and they are involved in diverse cellular processes often, but not exclusively, related to RNA metabolism. Liquid-liquid phase separation, a reversible event involving demixing into two distinct liquid phases, provides a physical framework to gain insights concerning the molecular forces underlying the process and how they can be tuned according to the cellular needs. Proteins able to undergo phase separation usually present a modular architecture, which favors a multivalency-driven demixing. We discuss the role of low complexity regions in establishing networks of intra- and intermolecular interactions that collectively control the phase regime. Post-translational modifications of the residues present in these domains provide a convenient strategy to reshape the residue–residue interaction networks that determine the dynamics of phase separation. Focus will be placed on those proteins with low complexity domains exhibiting a biased composition towards the amino acid methionine and the prominent role that reversible methionine sulfoxidation plays in the assembly/disassembly of biomolecular condensates. Full article
(This article belongs to the Section Cellular Biochemistry)
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17 pages, 12178 KiB  
Article
Gastroprotection against Rat Ulcers by Nephthea Sterol Derivative
by Tarik A. Mohamed, Abdelsamed I. Elshamy, Mahmoud A. A. Ibrahim, Mohamed A. M. Atia, Rania F. Ahmed, Sherin K. Ali, Karam A. Mahdy, Shifaa O. Alshammari, Ahmed M. Al-Abd, Mahmoud F. Moustafa, Abdel Razik H. Farrag and Mohamed-Elamir F. Hegazy
Biomolecules 2021, 11(8), 1247; https://doi.org/10.3390/biom11081247 - 21 Aug 2021
Cited by 6 | Viewed by 2733
Abstract
Different species belonging to the genus Nephthea (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine [...] Read more.
Different species belonging to the genus Nephthea (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine the anti-ulcer activity of 4α,24-dimethyl-5α-cholest-8β,18-dihydroxy,22E-en-3β-ol (ST-1) isolated from samples of a Nephthea species. This in vivo study was supported by in silico molecular docking and protein–protein interaction techniques. Oral administration of ST-1 reduced rat stomach ulcers with a concurrent increase in gastric mucosa. Molecular docking calculations against the H+/K+-ATPase transporter showed a higher binding affinity of ST-1, with a docking score value of −9.9 kcal/mol and a pKi value of 59.7 nM, compared to ranitidine (a commercial proton pump inhibitor, which gave values of −6.2 kcal/mol and 27.9 µM, respectively). The combined PEA-reactome analysis results revealed promising evidence of ST-1 potency as an anti-ulcer compound through significant modulation of the gene set controlling the PI3K signaling pathway, which subsequently plays a crucial role in signaling regarding epithelialization and tissue regeneration, tissue repairing and tissue remodeling. These results indicate a probable protective role for ST-1 against ethanol-induced gastric ulcers. Full article
(This article belongs to the Topic Compounds with Medicinal Value)
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23 pages, 985 KiB  
Review
Circulating Biomarkers in Neuromuscular Disorders: What Is Known, What Is New
by Andrea Barp, Amanda Ferrero, Silvia Casagrande, Roberta Morini and Riccardo Zuccarino
Biomolecules 2021, 11(8), 1246; https://doi.org/10.3390/biom11081246 - 20 Aug 2021
Cited by 8 | Viewed by 3731
Abstract
The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: [...] Read more.
The urgent need for new therapies for some devastating neuromuscular diseases (NMDs), such as Duchenne muscular dystrophy or amyotrophic lateral sclerosis, has led to an intense search for new potential biomarkers. Biomarkers can be classified based on their clinical value into different categories: diagnostic biomarkers confirm the presence of a specific disease, prognostic biomarkers provide information about disease course, and therapeutic biomarkers are designed to predict or measure treatment response. Circulating biomarkers, as opposed to instrumental/invasive ones (e.g., muscle MRI or nerve ultrasound, muscle or nerve biopsy), are generally easier to access and less “time-consuming”. In addition to well-known creatine kinase, other promising molecules seem to be candidate biomarkers to improve the diagnosis, prognosis and prediction of therapeutic response, such as antibodies, neurofilaments, and microRNAs. However, there are some criticalities that can complicate their application: variability during the day, stability, and reliable performance metrics (e.g., accuracy, precision and reproducibility) across laboratories. In the present review, we discuss the application of biochemical biomarkers (both validated and emerging) in the most common NMDs with a focus on their diagnostic, prognostic/predictive and therapeutic application, and finally, we address the critical issues in the introduction of new biomarkers. Full article
(This article belongs to the Special Issue Molecular Basis of Neuromuscular Diseases)
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41 pages, 593 KiB  
Review
Biomolecule and Bioentity Interaction Databases in Systems Biology: A Comprehensive Review
by Fotis A. Baltoumas, Sofia Zafeiropoulou, Evangelos Karatzas, Mikaela Koutrouli, Foteini Thanati, Kleanthi Voutsadaki, Maria Gkonta, Joana Hotova, Ioannis Kasionis, Pantelis Hatzis and Georgios A. Pavlopoulos
Biomolecules 2021, 11(8), 1245; https://doi.org/10.3390/biom11081245 - 20 Aug 2021
Cited by 14 | Viewed by 5035
Abstract
Technological advances in high-throughput techniques have resulted in tremendous growth of complex biological datasets providing evidence regarding various biomolecular interactions. To cope with this data flood, computational approaches, web services, and databases have been implemented to deal with issues such as data integration, [...] Read more.
Technological advances in high-throughput techniques have resulted in tremendous growth of complex biological datasets providing evidence regarding various biomolecular interactions. To cope with this data flood, computational approaches, web services, and databases have been implemented to deal with issues such as data integration, visualization, exploration, organization, scalability, and complexity. Nevertheless, as the number of such sets increases, it is becoming more and more difficult for an end user to know what the scope and focus of each repository is and how redundant the information between them is. Several repositories have a more general scope, while others focus on specialized aspects, such as specific organisms or biological systems. Unfortunately, many of these databases are self-contained or poorly documented and maintained. For a clearer view, in this article we provide a comprehensive categorization, comparison and evaluation of such repositories for different bioentity interaction types. We discuss most of the publicly available services based on their content, sources of information, data representation methods, user-friendliness, scope and interconnectivity, and we comment on their strengths and weaknesses. We aim for this review to reach a broad readership varying from biomedical beginners to experts and serve as a reference article in the field of Network Biology. Full article
(This article belongs to the Special Issue Computational Approaches for the Study of Biomolecular Networks)
10 pages, 2461 KiB  
Article
Molecular Dynamics Simulation Study of the Interaction between Human Angiotensin Converting Enzyme 2 and Spike Protein Receptor Binding Domain of the SARS-CoV-2 B.1.617 Variant
by Priya Antony and Ranjit Vijayan
Biomolecules 2021, 11(8), 1244; https://doi.org/10.3390/biom11081244 - 20 Aug 2021
Cited by 17 | Viewed by 3216
Abstract
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a significant impact on people’s daily lives. The rapidly spreading B.1.617 lineage harbors two key mutations—L452R and E484Q—in the receptor binding domain (RBD) of its spike (S) protein. To understand the impact and [...] Read more.
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a significant impact on people’s daily lives. The rapidly spreading B.1.617 lineage harbors two key mutations—L452R and E484Q—in the receptor binding domain (RBD) of its spike (S) protein. To understand the impact and structural dynamics of the variations in the interface of S protein and its host factor, the human angiotensin-converting enzyme 2 (hACE2), triplicate 500 ns molecular dynamics simulations were performed using single (E484Q or L452R) and double (E484Q + L452R) mutant structures and compared to wild type simulations. Our results indicate that the E484Q mutation disrupts the conserved salt bridge formed between Lys31 of hACE2 and Glu484 of S protein. Additionally, E484Q, which could favor the up conformation of the RBD, may help in enhanced hACE2 binding and immune escape. L452R introduces a charged patch near the binding surface that permits increased electrostatic attraction between the proteins. An improved network of intramolecular interactions observed is likely to increase the stability of the S protein and conformational changes may prevent the binding of neutralizing antibodies. The results obtained from the molecular dynamics simulations suggest that structural and dynamic changes introduced by these variations enhance the affinity of the viral S protein to hACE2 and could form the basis for further studies. Full article
(This article belongs to the Special Issue Unveiling Protein Functions, Dynamics and Interactions in Health and Disease Using Experimental and Theoretical Approaches)
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11 pages, 1658 KiB  
Article
Diagnosis of Wilson Disease and Its Phenotypes by Using Artificial Intelligence
by Valentina Medici, Anna Czlonkowska, Tomasz Litwin and Cecilia Giulivi
Biomolecules 2021, 11(8), 1243; https://doi.org/10.3390/biom11081243 - 20 Aug 2021
Cited by 6 | Viewed by 3156
Abstract
WD is caused by ATP7B variants disrupting copper efflux resulting in excessive copper accumulation mainly in liver and brain. The diagnosis of WD is challenged by its variable clinical course, onset, morbidity, and ATP7B variant type. Currently it is diagnosed by a combination [...] Read more.
WD is caused by ATP7B variants disrupting copper efflux resulting in excessive copper accumulation mainly in liver and brain. The diagnosis of WD is challenged by its variable clinical course, onset, morbidity, and ATP7B variant type. Currently it is diagnosed by a combination of clinical symptoms/signs, aberrant copper metabolism parameters (e.g., low ceruloplasmin serum levels and high urinary and hepatic copper concentrations), and genetic evidence of ATP7B mutations when available. As early diagnosis and treatment are key to favorable outcomes, it is critical to identify subjects before the onset of overtly detrimental clinical manifestations. To this end, we sought to improve WD diagnosis using artificial neural network algorithms (part of artificial intelligence) by integrating available clinical and molecular parameters. Surprisingly, WD diagnosis was based on plasma levels of glutamate, asparagine, taurine, and Fischer’s ratio. As these amino acids are linked to the urea–Krebs’ cycles, our study not only underscores the central role of hepatic mitochondria in WD pathology but also that most WD patients have underlying hepatic dysfunction. Our study provides novel evidence that artificial intelligence utilized for integrated analysis for WD may result in earlier diagnosis and mechanistically relevant treatments for patients with WD. Full article
(This article belongs to the Special Issue Mechanisms of Nonalcoholic Liver Diseases)
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16 pages, 3780 KiB  
Article
Cytokines Induced by Edwardsiella tarda: Profile and Role in Antibacterial Immunity
by Huili Li, Boguang Sun, Shuai Jiang and Li Sun
Biomolecules 2021, 11(8), 1242; https://doi.org/10.3390/biom11081242 - 19 Aug 2021
Cited by 6 | Viewed by 2294
Abstract
Edwardsiella tarda is a Gram-negative bacterial pathogen with a broad range of hosts, including fish and mammals. In the present study, we used an advanced antibody array technology to identify the expression pattern of cytokines induced by E. tarda in a mouse infection [...] Read more.
Edwardsiella tarda is a Gram-negative bacterial pathogen with a broad range of hosts, including fish and mammals. In the present study, we used an advanced antibody array technology to identify the expression pattern of cytokines induced by E. tarda in a mouse infection model. In total, 31 and 24 differentially expressed cytokines (DECs) were identified in the plasma at 6 h and 24 h post-infection (hpi), respectively. The DECs were markedly enriched in the Gene Ontology (GO) terms associated with cell migration and response to chemokine and in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with immunity, diseases, and infection. Ten key DECs, including IL6 and TNF-α, were found to form extensive protein-protein interaction networks. IL6 was demonstrated to inhibit E. tarda infection and be required for E. tarda-induced inflammatory response. TNF-α also exerted an inhibitory effect on E. tarda infection, and knockdown of fish (Japanese flounder) TNF-α promoted E. tarda invasion in host cells. Together, the results of this study revealed a comprehensive profile of cytokines induced by E. tarda, thus adding new insights into the role of cytokine-associated immunity against bacterial infection and also providing the potential plasma biomarkers of E. tarda infection for future studies. Full article
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16 pages, 4124 KiB  
Article
Postprandial Bioactivity of a Spread Cheese Enriched with Mountain Tea and Orange Peel Extract in Plasma Oxidative Stress Status, Serum Lipids and Glucose Levels: An Interventional Study in Healthy Adults
by Olga Papagianni, Konstantina Argyri, Thomas Loukas, Athanasios Magkoutis, Theodora Biagki, Dimitrios Skalkos, Dimitrios Kafetzopoulos, Charalampia Dimou, Haralampos C. Karantonis and Antonios E. Koutelidakis
Biomolecules 2021, 11(8), 1241; https://doi.org/10.3390/biom11081241 - 19 Aug 2021
Cited by 10 | Viewed by 2704
Abstract
Postprandial lipemia, glycemia and oxidative stress may affect the occurrence of cardiovascular disease. The purpose of the present intervention study was to investigate the effect of a spread cheese enriched with mountain tea (Sideritis sp.) and orange peel (Citrus sinensis) [...] Read more.
Postprandial lipemia, glycemia and oxidative stress may affect the occurrence of cardiovascular disease. The purpose of the present intervention study was to investigate the effect of a spread cheese enriched with mountain tea (Sideritis sp.) and orange peel (Citrus sinensis) extract on postprandial metabolic biomarkers in healthy volunteers. In a cross-over design, 14 healthy subjects 20–30 years old were consumed either a meal rich in fat and carbohydrates (80 g white bread, 40 g butter and 30 g full fat spread cheese) or a meal with the spread cheese enriched with 6% mountain tea–orange peel extract. Differences in postprandial total plasma antioxidant capacity, resistance of plasma to oxidation, serum lipids, glucose and uric acid levels were evaluated at 0, 1.5 and 3 h after consumption. Plasma total antioxidant capacity was significantly increased 3 h after the consumption of the meal in the presence of the extract-enriched cheese, compared to the conventional cheese (p = 0.05). Plasma resistance to oxidation was increased at 30 min in the Functional meal compared with the Control meal. A tendency to decrease the postprandial rise in glucose and triglyceride levels, 1.5 h and 3 h, respectively, after the intake of the meal with the extract-enriched cheese was observed (p = 0.062). No significant changes in the concentrations of the remaining biomarkers studied were observed (p > 0.05). Further studies with a larger sample are needed in both healthy adults and patients with cardiovascular disease to draw safer conclusions about the postprandial effect of the extracts on metabolic biomarkers that predict cardiovascular risk. Full article
(This article belongs to the Special Issue Potential Mechanism of Natural-Based Biomolecules for Disease Treatment)
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15 pages, 5107 KiB  
Article
Pinocembrin Ameliorates Skin Fibrosis via Inhibiting TGF-β1 Signaling Pathway
by Xiaohe Li, Yunqian Zhai, Buri Xi, Wei Ma, Jianwei Zhang, Xiaoyang Ma, Yang Miao, Yongjian Zhao, Wen Ning, Honggang Zhou and Cheng Yang
Biomolecules 2021, 11(8), 1240; https://doi.org/10.3390/biom11081240 - 19 Aug 2021
Cited by 18 | Viewed by 3524
Abstract
Skin fibrotic diseases, such as keloids, are mainly caused by pathologic scarring of wounds during healing and characterized by benign cutaneous overgrowths of dermal fibroblasts. Current surgical and therapeutic modalities of skin fibrosis are unsatisfactory. Pinocembrin, a natural flavonoid, has been shown to [...] Read more.
Skin fibrotic diseases, such as keloids, are mainly caused by pathologic scarring of wounds during healing and characterized by benign cutaneous overgrowths of dermal fibroblasts. Current surgical and therapeutic modalities of skin fibrosis are unsatisfactory. Pinocembrin, a natural flavonoid, has been shown to possess a vast range of pharmacological activities including antimicrobial, antioxidant, anti-inflammatory, and anti-tumor activities. In this study we explored the potential effect and mechanisms of pinocembrin on skin fibrosis in vitro and in vivo. In vitro studies indicated that pinocembrin dose-dependently suppressed proliferation, migration, and invasion of keloid fibroblasts and mouse primary dermal fibroblasts. The in vivo studies showed that pinocembrin could effectively alleviate bleomycin (BLM)-induced skin fibrosis and reduce the gross weight and fibrosis-related protein expression of keloid tissues in xenograft mice. Further mechanism studies indicated that pinocembrin could suppress TGF-β1/Smad signaling and attenuate TGF-β1-induced activation of skin fibroblasts. In conclusion, our results demonstrate the therapeutic potential of pinocembrin for skin fibrosis. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)
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14 pages, 910 KiB  
Review
Targeting the NLRP3 Inflammasome in Glaucoma
by Sophie Coyle, Mohammed Naeem Khan, Melody Chemaly, Breedge Callaghan, Chelsey Doyle, Colin E. Willoughby, Sarah D. Atkinson, Meredith Gregory-Ksander and Victoria McGilligan
Biomolecules 2021, 11(8), 1239; https://doi.org/10.3390/biom11081239 - 19 Aug 2021
Cited by 26 | Viewed by 4587
Abstract
Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological [...] Read more.
Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological risk factors in glaucoma, and is currently the only modifiable risk factor. However, 30–40% of glaucoma patients do not present with elevated IOP and still proceed to lose vision. The pathophysiology of glaucoma is therefore not completely understood, and there is a need for the development of IOP-independent neuroprotective therapies to preserve vision. Neuroinflammation has been shown to play a key role in glaucoma and, specifically, the NLRP3 inflammasome, a key driver of inflammation, has recently been implicated. The NLRP3 inflammasome is expressed in the eye and its activation is reported in pre-clinical studies of glaucoma. Activation of the NLRP3 inflammasome results in IL-1β processing. This pro inflammatory cytokine is elevated in the blood of glaucoma patients and is believed to drive neurotoxic inflammation, resulting in axon degeneration and the death of retinal ganglion cells (RGCs). This review discusses glaucoma as an inflammatory disease and evaluates targeting the NLRP3 inflammasome as a therapeutic strategy. A hypothetical mechanism for the action of the NLRP3 inflammasome in glaucoma is presented. Full article
(This article belongs to the Special Issue Cellular Therapies for Glaucoma)
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10 pages, 290 KiB  
Article
Assessment of Cardiovascular Risk in Women with Periodontal Diseases According to C-reactive Protein Levels
by Claudia Da Venezia, Nayib Hussein, Marcela Hernández, Johanna Contreras, Alicia Morales, Macarena Valdés, Francisca Rojas, Loreto Matamala and Patricia Hernández-Ríos
Biomolecules 2021, 11(8), 1238; https://doi.org/10.3390/biom11081238 - 19 Aug 2021
Cited by 6 | Viewed by 2312
Abstract
Cardiovascular diseases (CVD) are highly prevalent non-communicable diseases worldwide. Periodontitis may act as a non-traditional cardiovascular risk (CVR) factor, linked by a low-grade systemic inflammation mediated by C-reactive protein (CRP). Patients with periodontitis reported higher serum CRP levels; however, a CRP systemic and [...] Read more.
Cardiovascular diseases (CVD) are highly prevalent non-communicable diseases worldwide. Periodontitis may act as a non-traditional cardiovascular risk (CVR) factor, linked by a low-grade systemic inflammation mediated by C-reactive protein (CRP). Patients with periodontitis reported higher serum CRP levels; however, a CRP systemic and periodontal correlation in gingival crevicular fluid (GCF) and its CVR impact have been barely studied. We aimed to assess the association between periodontal diseases and CVR in a group of adult women, based on serum high-sensitivity CRP (hs-CRP) levels; and secondly, to determine the association between serum and GCF CRP levels. Gingival crevicular fluid and blood samples were obtained from women with periodontitis, gingivitis, and healthy controls. Serum and GCF CRP were determined by turbidimetric method and Luminex technology, respectively. Data were analyzed and adjusted by CVR factors. All women presented moderate CVR, without an evident association between serum hs-CRP levels and periodontal diseases. While serum hs-CRP concentrations did not significantly differ between groups, patients with gingivitis and periodontitis showed higher CRP levels in GCF, which positively correlated to CRP detection in serum. Full article
(This article belongs to the Special Issue Biomolecules and Cardiovascular Disease in Women)
27 pages, 1250 KiB  
Systematic Review
Neuropathic and Psychogenic Components of Burning Mouth Syndrome: A Systematic Review
by Marie Orliaguet and Laurent Misery
Biomolecules 2021, 11(8), 1237; https://doi.org/10.3390/biom11081237 - 18 Aug 2021
Cited by 28 | Viewed by 6889
Abstract
The pathophysiology of primary burning mouth syndrome (BMS) has been extensively debated but is poorly understood despite a large number of hypotheses attempting to explain its etiopathogenic mechanisms. The aim of the present work was to systematically review papers that could provide arguments [...] Read more.
The pathophysiology of primary burning mouth syndrome (BMS) has been extensively debated but is poorly understood despite a large number of hypotheses attempting to explain its etiopathogenic mechanisms. The aim of the present work was to systematically review papers that could provide arguments in favour of the neuropathic and psychogenic components of primary BMS for a better understanding of the disease. This systematic review (SR) was registered in PROSPERO (CRD42021224160). The search was limited to articles in English or French from 1990 to 01 December 2020. A total of 113 articles were considered for data extraction. We divided them into four subgroups: pharmacological and nonpharmacological management studies (n = 23); neurophysiological studies (n = 35); biohistopathological studies (n = 25); and questionnaire-based studies (n = 30). Several of these studies have shown neuropathic involvement at various levels of the neuraxis in BMS with the contribution of quantitative sensory testing (QST), functional brain imaging, and biohistopathological or pharmacologic studies. On the other hand, the role of psychological factors in BMS has also been the focus of several studies and has shown a link with psychiatric disorders such as anxiety and/or depression symptoms. Depending on the patient, the neuropathic and psychogenic components may exist simultaneously, with a preponderance of one or the other, or exist individually. These two components cannot be dissociated to define BMS. Consequently, BMS may be considered nociplastic pain. Full article
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23 pages, 4675 KiB  
Article
Impact of a Single Nucleotide Change or Non-Nucleoside Modifications in G-Rich Region on the Quadruplex–Duplex Hybrid Formation
by Dorota Gudanis, Karolina Zielińska, Daniel Baranowski, Ryszard Kierzek, Piotr Kozłowski and Zofia Gdaniec
Biomolecules 2021, 11(8), 1236; https://doi.org/10.3390/biom11081236 - 18 Aug 2021
Viewed by 2586
Abstract
In this paper, a method to discriminate between two target RNA sequences that differ by one nucleotide only is presented. The method relies on the formation of alternative structures, i.e., quadruplex–duplex hybrid (QDH) and duplex with dangling ends (Dss), after hybridization of DNA [...] Read more.
In this paper, a method to discriminate between two target RNA sequences that differ by one nucleotide only is presented. The method relies on the formation of alternative structures, i.e., quadruplex–duplex hybrid (QDH) and duplex with dangling ends (Dss), after hybridization of DNA or RNA G-rich oligonucleotides with target sequences containing 5′–GGGCUGG–3′ or 5′–GGGCGGG–3′ fragments. Using biophysical methods, we studied the effect of oligonucleotide types (DNA, RNA), non-nucleotide modifications (aliphatic linkers or abasic), and covalently attached G4 ligand on the ability of G-rich oligonucleotides to assemble a G-quadruplex motif. We demonstrated that all examined non-nucleotide modifications could mimic the external loops in the G-quadruplex domain of QDH structures without affecting their stability. Additionally, some modifications, in particular the presence of two abasic residues in the G-rich oligonucleotide, can induce the formation of non-canonical QDH instead of the Dss structure upon hybridization to a target sequence containing the GGGCUGG motif. Our results offer new insight into the sequential requirements for the formation of G-quadruplexes and provide important data on the effects of non-nucleotide modifications on G-quadruplex formation. Full article
(This article belongs to the Special Issue Principles and Molecular Mechanisms of DNA and RNA G-Quadruplexes in Gene Regulation)
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24 pages, 2434 KiB  
Review
Perineuronal Nets and Metal Cation Concentrations in the Microenvironments of Fast-Spiking, Parvalbumin-Expressing GABAergic Interneurons: Relevance to Neurodevelopment and Neurodevelopmental Disorders
by Jessica A. Burket, Jason D. Webb and Stephen I. Deutsch
Biomolecules 2021, 11(8), 1235; https://doi.org/10.3390/biom11081235 - 18 Aug 2021
Cited by 14 | Viewed by 5389
Abstract
Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local [...] Read more.
Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range. Full article
(This article belongs to the Special Issue Clinical Phenotype of Autism Spectrum Disorder: Development and Delivery of Therapeutic Biomolecules to the CNS)
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10 pages, 704 KiB  
Review
Immunologic Roles of Hyaluronan in Dermal Wound Healing
by Aditya Kaul, Walker D. Short, Sundeep G. Keswani and Xinyi Wang
Biomolecules 2021, 11(8), 1234; https://doi.org/10.3390/biom11081234 - 18 Aug 2021
Cited by 14 | Viewed by 3587
Abstract
Hyaluronic acid (HA), a glycosaminoglycan ubiquitous in the skin, has come into the limelight in recent years for its role in facilitating dermal wound healing. Specifically, HA’s length of linearly repeating disaccharides—in other words, its molecular weight (MW)—determines its effects. High molecular weight [...] Read more.
Hyaluronic acid (HA), a glycosaminoglycan ubiquitous in the skin, has come into the limelight in recent years for its role in facilitating dermal wound healing. Specifically, HA’s length of linearly repeating disaccharides—in other words, its molecular weight (MW)—determines its effects. High molecular weight (HMW)-HA serves an immunosuppressive and anti-inflammatory role, whereas low molecular weight (LMW)-HA contributes to immunostimulation and thus inflammation. During the inflammatory stage of tissue repair, direct and indirect interactions between HA and the innate and adaptive immune systems are of particular interest for their long-lasting impact on wound repair. This review seeks to synthesize the literature on wound healing with a focus on HA’s involvement in the immune subsystems. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)
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16 pages, 4678 KiB  
Article
Comparative Transcriptomic Analysis Reveals the Effects of Drought on the Biosynthesis of Methyleugenol in Asarum sieboldii Miq.
by Fawang Liu, Tahir Ali and Zhong Liu
Biomolecules 2021, 11(8), 1233; https://doi.org/10.3390/biom11081233 - 18 Aug 2021
Cited by 8 | Viewed by 2324
Abstract
Asarum sieboldii Miq., a perennial herb in the family Aristolochiaceae, is widely used to treat colds, fever, headache and toothache in China. However, little is known about the drought-tolerance characteristics of A. sieboldii. In this study, to elucidate the molecular–genetic mechanisms [...] Read more.
Asarum sieboldii Miq., a perennial herb in the family Aristolochiaceae, is widely used to treat colds, fever, headache and toothache in China. However, little is known about the drought-tolerance characteristics of A. sieboldii. In this study, to elucidate the molecular–genetic mechanisms of drought-stress tolerance of A. sieboldii, RNA-seq was conducted. In total, 53,344 unigenes were assembled, and 28,715 unigenes were annotated. A total of 6444 differential-expression unigenes (DEGs) were found, which were mainly enriched in phenylpropanoid, starch and sucrose metabolic pathways. Drought stress revealed significant up-regulation of the unigenes encoding PAL, C4H, HCT, C3H, CCR and IGS in the methyleugenol-biosynthesis pathway. Under the condition of maintaining drought for 15 days and 30 days, drought stress reduced the biosynthesis of volatile oil by 24% and 38%, respectively, while the production of key medicinal ingredients (such as methyl eugenol) was increased. These results provide valuable information about the diverse mechanisms of drought resistance in the A. sieboldii, and the changes in the expression of the genes involved in methyleugenol biosynthesis in response to drought stress. Full article
(This article belongs to the Special Issue Molecular-Genetic Bases of Plant Breeding)
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26 pages, 1588 KiB  
Review
Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets
by Phuong Linh Nguyen and Jungsook Cho
Biomolecules 2021, 11(8), 1232; https://doi.org/10.3390/biom11081232 - 18 Aug 2021
Cited by 19 | Viewed by 9365
Abstract
High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine [...] Read more.
High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings. Full article
(This article belongs to the Special Issue New Developments in Histamine Research)
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10 pages, 801 KiB  
Review
Metformin and Cancer Glucose Metabolism: At the Bench or at the Bedside?
by Cecilia Marini, Vanessa Cossu, Matteo Bauckneht, Francesco Lanfranchi, Stefano Raffa, Anna Maria Orengo, Silvia Ravera, Silvia Bruno and Gianmario Sambuceti
Biomolecules 2021, 11(8), 1231; https://doi.org/10.3390/biom11081231 - 18 Aug 2021
Cited by 9 | Viewed by 3886
Abstract
Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This [...] Read more.
Several studies reported that metformin, the most widely used drug for type 2 diabetes, might affect cancer aggressiveness. The biguanide seems to directly impair cancer energy asset, with the consequent phosphorylation of AMP-activated protein kinase (AMPK) inhibiting cell proliferation and tumor growth. This action is most often attributed to a well-documented blockage of oxidative phosphorylation (OXPHOS) caused by a direct interference of metformin on Complex I function. Nevertheless, several other pleiotropic actions seem to contribute to the anticancer potential of this biguanide. In particular, in vitro and in vivo experimental studies recently documented that metformin selectively inhibits the uptake of 2-[18F]-Fluoro-2-Deoxy-D-Glucose (FDG), via an impaired catalytic function of the enzyme hexose-6P-dehydrogenase (H6PD). H6PD triggers a still largely uncharacterized pentose-phosphate pathway (PPP) within the endoplasmic reticulum (ER) that has been found to play a pivotal role in feeding the NADPH reductive power for both cellular proliferation and antioxidant responses. Regardless of its exploitability in the clinical setting, this metformin action might configure the ER metabolism as a potential target for innovative therapeutic strategies in patients with solid cancers and potentially modifies the current interpretative model of FDG uptake, attributing PET/CT capability to predict cancer aggressiveness to the activation of H6PD catalytic function. Full article
(This article belongs to the Special Issue Metformin and Cancer)
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15 pages, 2716 KiB  
Article
Epithelial Cell Line Derived from Endometriotic Lesion Mimics Macrophage Nervous Mechanism of Pain Generation on Proteome and Metabolome Levels
by Benjamin Neuditschko, Marlene Leibetseder, Julia Brunmair, Gerhard Hagn, Lukas Skos, Marlene C. Gerner, Samuel M. Meier-Menches, Iveta Yotova and Christopher Gerner
Biomolecules 2021, 11(8), 1230; https://doi.org/10.3390/biom11081230 - 17 Aug 2021
Cited by 4 | Viewed by 3972
Abstract
Endometriosis is a benign disease affecting one in ten women of reproductive age worldwide. Although the pain level is not correlated to the extent of the disease, it is still one of the cardinal symptoms strongly affecting the patients’ quality of life. Yet, [...] Read more.
Endometriosis is a benign disease affecting one in ten women of reproductive age worldwide. Although the pain level is not correlated to the extent of the disease, it is still one of the cardinal symptoms strongly affecting the patients’ quality of life. Yet, a molecular mechanism of this pathology, including the formation of pain, remains to be defined. Recent studies have indicated a close interaction between newly generated nerve cells and macrophages, leading to neurogenic inflammation in the pelvic area. In this context, the responsiveness of an endometriotic cell culture model was characterized upon inflammatory stimulation by employing a multi-omics approach, including proteomics, metabolomics and eicosanoid analysis. Differential proteomic profiling of the 12-Z endometriotic cell line treated with TNFα and IL1β unexpectedly showed that the inflammatory stimulation was able to induce a protein signature associated with neuroangiogenesis, specifically including neuropilins (NRP1/2). Untargeted metabolomic profiling in the same setup further revealed that the endometriotic cells were capable of the autonomous production of 7,8-dihydrobiopterin (BH2), 7,8-dihydroneopterin, normetanephrine and epinephrine. These metabolites are related to the development of neuropathic pain and the former three were found up-regulated upon inflammatory stimulation. Additionally, 12-Z cells were found to secrete the mono-oxygenated oxylipin 16-HETE, a known inhibitor of neutrophil aggregation and adhesion. Thus, inflammatory stimulation of endometriotic 12-Z cells led to specific protein and metabolite expression changes suggesting a direct involvement of these epithelial-like cells in endometriosis pain development. Full article
(This article belongs to the Special Issue Integrative Multi-Omics in Biomedical Research)
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16 pages, 3275 KiB  
Article
Engineering of Thermal Stability in a Cold-Active Oligo-1,6-Glucosidase from Exiguobacterium sibiricum with Unusual Amino Acid Content
by Yana Y. Berlina, Lada E. Petrovskaya, Elena A. Kryukova, Lyudmila N. Shingarova, Sultan Sh. Gapizov, Mariya V. Kryukova, Elizaveta M. Rivkina, Mikhail P. Kirpichnikov and Dmitry A. Dolgikh
Biomolecules 2021, 11(8), 1229; https://doi.org/10.3390/biom11081229 - 17 Aug 2021
Cited by 8 | Viewed by 2258
Abstract
A gene coding for a novel putative amylase, oligo-1,6-glucosidase from a psychrotrophic bacterium Exiguobacterium sibiricum from Siberian permafrost soil was cloned and expressed in Escherichia coli. The amino acid sequence of the predicted protein EsOgl and its 3D model displayed several features [...] Read more.
A gene coding for a novel putative amylase, oligo-1,6-glucosidase from a psychrotrophic bacterium Exiguobacterium sibiricum from Siberian permafrost soil was cloned and expressed in Escherichia coli. The amino acid sequence of the predicted protein EsOgl and its 3D model displayed several features characteristic for the cold-active enzymes while possessing an unusually high number of proline residues in the loops—a typical feature of thermophilic enzymes. The activity of the purified recombinant protein was tested with p-nitrophenyl α-D-glucopyranoside as a substrate. The enzyme displayed a plateau-shaped temperature-activity profile with the optimum at 25 °C and a pronounced activity at low temperatures (50% of maximum activity at 5 °C). To improve the thermal stability at temperatures above 40 °C, we have introduced proline residues into four positions of EsOgl by site-directed mutagenesis according to “the proline rule”. Two of the mutants, S130P and A109P demonstrated a three- and two-fold increased half-life at 45 °C. Moreover, S130P mutation led to a 60% increase in the catalytic rate constant. Combining the mutations resulted in a further increase in stability transforming the temperature-activity profile to a typical mesophilic pattern. In the most thermostable variant A109P/S130P/E176P, the half-life at 45 °C was increased from 11 min (wild-type) to 129 min. Full article
(This article belongs to the Special Issue State-of-Art in Protein Engineering)
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11 pages, 1135 KiB  
Article
Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients
by Katalin Koczok, László Horváth, Zeljka Korade, Zoltán András Mezei, Gabriella P. Szabó, Ned A. Porter, Eszter Kovács, Károly Mirnics and István Balogh
Biomolecules 2021, 11(8), 1228; https://doi.org/10.3390/biom11081228 - 17 Aug 2021
Cited by 3 | Viewed by 2686
Abstract
Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated [...] Read more.
Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography–tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low–normal plasma vitamin E concentrations (7.19–15.68 μmol/L), while vitamin A concentrations were found to be normal or high (1.26–2.68 μmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2–0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial. Full article
(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)
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18 pages, 4670 KiB  
Article
Identification of Reference Genes for Circadian Studies on Brain Microvessels and Choroid Plexus Samples Isolated from Rats
by Aleksandra Szczepkowska, András Harazin, Lilla Barna, Mária A. Deli and Janina Skipor
Biomolecules 2021, 11(8), 1227; https://doi.org/10.3390/biom11081227 - 17 Aug 2021
Cited by 6 | Viewed by 2592
Abstract
Delivery of putative compounds of therapeutic value to the brain is limited by brain barriers: the blood–brain barrier located in the endothelium of the brain microvessels (BrMVs) and the blood–cerebrospinal fluid barrier located in the epithelium of the choroid plexus (ChP). Understanding their [...] Read more.
Delivery of putative compounds of therapeutic value to the brain is limited by brain barriers: the blood–brain barrier located in the endothelium of the brain microvessels (BrMVs) and the blood–cerebrospinal fluid barrier located in the epithelium of the choroid plexus (ChP). Understanding their function and modulation by the circadian clock may enhance the efficacy of brain-targeting therapies. The aim of the present study was to evaluate the stability of 10 reference genes in the BrMV and ChP, isolated from male and female rats at six time points (ZT1, 5, 9, 13, 17, and 21). Gene evaluations were performed by qPCR, analyzed by RefFinder tool, and verified by analyzing the expression of the brain and muscle ARNT-like 1 (Bmal1) using the qPCR and digital PCR methods. We identified as the most stable genes for circadian studies tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (Ywhaz) and apolipoprotein E (Apoe) for BrMV, and beta actin (Actb) and hypoxanthine-guanine phosphoribosyltransferase (Hprt1) for ChP. After verification, ribosomal protein (Rps18) was also included as a sufficient reference gene. Additionally, the observed gender difference in the Bmal1 oscillations in both BrMV and ChP suggests that separate studies for each gender are recommended. Full article
(This article belongs to the Special Issue Therapeutic Aspects of Circadian Rhythms)
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