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Biomolecules, Volume 11, Issue 3 (March 2021) – 146 articles

Cover Story (view full-size image): Circadian rhythm and the molecules involved in it, such as melanopsin and melatonin, play a key role in the eye to regulate homeostasis and even to treat some ocular conditions. As a result, many ocular pathologies, such as dry eye, corneal wound healing, cataracts, myopia, retinal diseases and glaucoma, are affected by this cycle. This review summarizes the current scientific literature about the influence of circadian patterns on the eye, focusing on its relationship with increased intraocular pressure and glaucoma. Further study is required on whether these treatments could improve their effect when posology is established in function of circadian patterns, as well as on if new drugs such as melatonin or its analogs, which are related to the circadian rhythm, not only could be used as the main treatment but as coadjutant, improving the circadian pattern or its antioxidant and [...] Read more.

 

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Open AccessArticle
Neisseria gonorrhoeae Multivalent Maxibody with a Broad Spectrum of Strain Specificity and Sensitivity for Gonorrhea Diagnosis
Biomolecules 2021, 11(3), 484; https://doi.org/10.3390/biom11030484 - 23 Mar 2021
Viewed by 420
Abstract
Gonorrhea is one of the most common, but still hidden and insidious, sexually transmitted diseases caused by Neisseria gonorrhoeae (gonococci). However, the diagnosis and treatment of gonorrhea are hampered by antigenic variability among gonococci, the lack of acquired immunity, and [...] Read more.
Gonorrhea is one of the most common, but still hidden and insidious, sexually transmitted diseases caused by Neisseria gonorrhoeae (gonococci). However, the diagnosis and treatment of gonorrhea are hampered by antigenic variability among gonococci, the lack of acquired immunity, and antimicrobial resistance. Further, strains resistant to cephalosporins, including ceftriaxone, the last line of defense, represent a growing threat, which prompted us to develop gonococci-specific diagnostic antibodies with broad-spectrum binding to gonococci strains to generate gonorrhea-detecting reagents. This study reports the identification of gonococci antibodies via bio-panning on gonococci cells using scFv-phage libraries. Reformatting the lead scFv-phage Clones 1 and 4 to a multivalent scFv1-Fc-scFv4 maxibody increased the sensitivity by up to 20-fold compared to the single scFv-Fc (maxibody) alone. Moreover, the multivalent maxibody showed broader cross-reactivity with clinical isolates and the ceftriaxone antibiotic-resistant World Health Organization (WHO) reference strain L. In contrast, the selected antibodies in the scFv-phage, maxibody, and multivalent maxibody did not bind to N. sicca, N. meningitides, and N. lactamica, suggesting the clinical and pharmaceutical diagnostic value of these selected antibodies for gonorrheal infections. The present study illustrates the advantages and potential application of multivalent maxibodies to develop rapid and sensitive diagnostic reagents for infectious diseases and cancer. Full article
(This article belongs to the Section Molecular Pathology)
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Open AccessReview
Multifaceted Functions of Protein Kinase D in Pathological Processes and Human Diseases
Biomolecules 2021, 11(3), 483; https://doi.org/10.3390/biom11030483 - 23 Mar 2021
Viewed by 442
Abstract
Protein kinase D (PKD) is a family of serine/threonine protein kinases operating in the signaling network of the second messenger diacylglycerol. The three family members, PKD1, PKD2, and PKD3, are activated by a variety of extracellular stimuli and transduce cell signals affecting many [...] Read more.
Protein kinase D (PKD) is a family of serine/threonine protein kinases operating in the signaling network of the second messenger diacylglycerol. The three family members, PKD1, PKD2, and PKD3, are activated by a variety of extracellular stimuli and transduce cell signals affecting many aspects of basic cell functions including secretion, migration, proliferation, survival, angiogenesis, and immune response. Dysregulation of PKD in expression and activity has been detected in many human diseases. Further loss- or gain-of-function studies at cellular levels and in animal models provide strong support for crucial roles of PKD in many pathological conditions, including cancer, metabolic disorders, cardiac diseases, central nervous system disorders, inflammatory diseases, and immune dysregulation. Complexity in enzymatic regulation and function is evident as PKD isoforms may act differently in different biological systems and disease models, and understanding the molecular mechanisms underlying these differences and their biological significance in vivo is essential for the development of safer and more effective PKD-targeted therapies. In this review, to provide a global understanding of PKD function, we present an overview of the PKD family in several major human diseases with more focus on cancer-associated biological processes. Full article
(This article belongs to the Special Issue Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways)
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Open AccessArticle
Inhibiting Neddylation with MLN4924 Suppresses Growth and Delays Multicellular Development in Dictyostelium discoideum
Biomolecules 2021, 11(3), 482; https://doi.org/10.3390/biom11030482 - 23 Mar 2021
Viewed by 435
Abstract
Neddylation is a post-translational modification that is essential for a variety of cellular processes and is linked to many human diseases including cancer, neurodegeneration, and autoimmune disorders. Neddylation involves the conjugation of the ubiquitin-like modifier neural precursor cell expressed developmentally downregulated protein 8 [...] Read more.
Neddylation is a post-translational modification that is essential for a variety of cellular processes and is linked to many human diseases including cancer, neurodegeneration, and autoimmune disorders. Neddylation involves the conjugation of the ubiquitin-like modifier neural precursor cell expressed developmentally downregulated protein 8 (NEDD8) to target proteins, and has been studied extensively in various eukaryotes including fungi, plants, and metazoans. Here, we examine the biological processes influenced by neddylation in the social amoeba, Dictyostelium discoideum, using a well-established inhibitor of neddylation, MLN4924 (pevonedistat). NEDD8, and the target of MLN4924 inhibition, NEDD8-activating enzyme E1 (NAE1), are highly conserved in D. discoideum (Nedd8 and Nae1, respectively). Treatment of D. discoideum cells with MLN4924 increased the amount of free Nedd8, suggesting that MLN4924 inhibited neddylation. During growth, MLN4924 suppressed cell proliferation and folic acid-mediated chemotaxis. During multicellular development, MLN4924 inhibited cyclic adenosine monophosphate (cAMP)-mediated chemotaxis, delayed aggregation, and suppressed fruiting body formation. Together, these findings indicate that neddylation plays an important role in regulating cellular and developmental events during the D. discoideum life cycle and that this organism can be used as a model system to better understand the essential roles of neddylation in eukaryotes, and consequently, its involvement in human disease. Full article
(This article belongs to the Special Issue Looking Back and Ahead: Emerging Concepts in Ubiquitin and UBLs)
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Open AccessArticle
MRAP2 Interaction with Melanocortin-4 Receptor in SnakeHead (Channa argus)
Biomolecules 2021, 11(3), 481; https://doi.org/10.3390/biom11030481 - 23 Mar 2021
Viewed by 406
Abstract
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure. Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of MC4R. The Northern snakehead (Channa argus) is an economically important freshwater [...] Read more.
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of food intake and energy expenditure. Melanocortin-2 receptor accessory protein 2 (MRAP2) modulates trafficking, ligand binding, and signaling of MC4R. The Northern snakehead (Channa argus) is an economically important freshwater fish native to East Asia. To explore potential interaction between snakehead MC4R and MRAP2, herein we cloned snakehead mc4r and mrap2. The snakehead mc4r consisted of a 984 bp open reading frame encoding a protein of 327 amino acids, while snakehead mrap2 contained a 693 bp open reading frame encoding a protein of 230 amino acids. Synteny analysis indicated that mc4r was highly conserved with similar gene arrangement, while mrap2 contained two isoforms in teleost with different gene orders. Snakehead mc4r was primarily expressed in the brain, whereas mrap2 was expressed in the brain and intestine. Snakehead mc4r and mrap2 expression was modulated by fasting and refeeding. Further pharmacological experiments showed that the cloned snakehead MC4R was functional, capable of binding to peptide agonists and increasing intracellular cAMP production in a dose-dependent manner. Snakehead MC4R exhibited high constitutive activity. MRAP2 significantly decreased basal and agonist-stimulated cAMP signaling. These findings suggest that snakehead MC4R might be involved in energy balance regulation by interacting with MRAP2. Further studies are needed to elucidate MC4R in regulating diverse physiological processes in snakehead. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
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Open AccessArticle
Zebrafish mafbb Mutants Display Osteoclast Over-Activation and Bone Deformity Resembling Osteolysis in MCTO Patients
Biomolecules 2021, 11(3), 480; https://doi.org/10.3390/biom11030480 - 23 Mar 2021
Viewed by 385
Abstract
Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia with osteolysis at the carpal and tarsal bones. Heterozygous missense mutations in the transcription factor MAFB are found in patients with MCTO. MAFB is reported to negatively regulate osteoclastogenesis in vitro. However, the in [...] Read more.
Multicentric carpotarsal osteolysis (MCTO) is a rare skeletal dysplasia with osteolysis at the carpal and tarsal bones. Heterozygous missense mutations in the transcription factor MAFB are found in patients with MCTO. MAFB is reported to negatively regulate osteoclastogenesis in vitro. However, the in vivo function of MAFB and its relation to MCTO remains unknown. In this study, we generated zebrafish MAFB homolog mafbb mutant utilizing CRISPR/Cas9 technology. Mafbb deficient zebrafish demonstrated enhanced osteoclast cell differentiation and abnormal cartilage and bone development resembling MCTO patients. It is known that osteoclasts are hematopoietic cells derived from macrophages. Loss of mafbb caused selective expansion of definitive macrophages and myeloid cells, supporting that mafbb restricts myeloid differentiation in vivo. We also demonstrate that MAFB MCTO mutations failed to rescue the defective osteoclastogenesis in mafbb−/− embryos, but did not affect osteoclast cells in wild type embryos. The mechanism of MCTO mutations is likely haploinsufficiency. Zebrafish mafbb mutant provides a useful model to study the function of MAFB in osteoclastogenesis and the related MCTO disease. Full article
(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)
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Open AccessArticle
Insight into Inhibitory Mechanism of PDE4D by Dietary Polyphenols Using Molecular Dynamics Simulations and Free Energy Calculations
Biomolecules 2021, 11(3), 479; https://doi.org/10.3390/biom11030479 - 23 Mar 2021
Viewed by 528
Abstract
Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective [...] Read more.
Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective therapeutic strategy for the treatment of neurological disorders. PDE4D constitutes a high-interest therapeutic target primarily for the treatment of Alzheimer’s disease, as it is highly involved in neuroinflammation, learning ability, and memory dysfunctions. In the present study, a thorough computational investigation consisting of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on the linear response approximation (LRA) method was performed to study dietary polyphenols as potential PDE4D inhibitors. The obtained results revealed that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential PDE4D inhibitors; however, the predicted binding free energies of 6-gingerol, capsaicin, and resveratrol were less negative than in the case of curcumin, which exhibited the highest inhibitory potency in comparison with a positive control rolipram. Our results also revealed that the electrostatic component through hydrogen bonding represents the main driving force for the binding and inhibitory activity of curcumin, 6-gingerol, and resveratrol, while the van der Waals component through shape complementarity plays the most important role in capsaicin’s inhibitory activity. All investigated compounds form hydrophobic interactions with residues Gln376 and Asn602 as well as hydrogen bonds with nearby residues Asp438, Met439, and Ser440. The binding mode of the studied natural compounds is consequently very similar; however, it significantly differs from the binding of known PDE4 inhibitors. The uncovered molecular inhibitory mechanisms of four investigated natural polyphenols, curcumin, 6-gingerol, capsaicin, and resveratrol, form the basis for the design of novel PDE4D inhibitors for the treatment of Alzheimer’s disease with a potentially wider therapeutic window and fewer adverse side effects. Full article
(This article belongs to the Special Issue Natural and Synthetic Compounds in Neurodegenerative Disorders)
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Open AccessArticle
Selective Fatty Acid Retention and Turnover in the Freshwater Amphipod Pallaseopsis quadrispinosa
Biomolecules 2021, 11(3), 478; https://doi.org/10.3390/biom11030478 - 23 Mar 2021
Viewed by 604
Abstract
Gammarid amphipods are a crucial link connecting primary producers with secondary consumers, but little is known about their nutritional ecology. Here we asked how starvation and subsequent feeding on different nutritional quality algae influences fatty acid retention, compound-specific isotopic carbon fractionation, and biosynthesis [...] Read more.
Gammarid amphipods are a crucial link connecting primary producers with secondary consumers, but little is known about their nutritional ecology. Here we asked how starvation and subsequent feeding on different nutritional quality algae influences fatty acid retention, compound-specific isotopic carbon fractionation, and biosynthesis of ω-3 and ω-6 polyunsaturated fatty acids (PUFA) in the relict gammarid amphipod Pallaseopsis quadrispinosa. The fatty acid profiles of P. quadrispinosa closely matched with those of the dietary green algae after only seven days of refeeding, whereas fatty acid patterns of P. quadrispinosa were less consistent with those of the diatom diet. This was mainly due to P. quadrispinosa suffering energy limitation in the diatom treatment which initiated the metabolization of 16:1ω7 and partly 18:1ω9 for energy, but retained high levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) similar to those found in wild-caught organisms. Moreover, α-linolenic acid (ALA) from green algae was mainly stored and not allocated to membranes at high levels nor biosynthesized to EPA. The arachidonic acid (ARA) content in membrane was much lower than EPA and P. quadrispinosa was able to biosynthesize long-chain ω-6 PUFA from linoleic acid (LA). Our experiment revealed that diet quality has a great impact on fatty acid biosynthesis, retention and turnover in this consumer. Full article
(This article belongs to the Special Issue Fatty Acids in Natural Ecosystems and Human Nutrition 2021)
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Open AccessArticle
A Novel Graph Neural Network Methodology to Investigate Dihydroorotate Dehydrogenase Inhibitors in Small Cell Lung Cancer
Biomolecules 2021, 11(3), 477; https://doi.org/10.3390/biom11030477 - 23 Mar 2021
Viewed by 521
Abstract
Small cell lung cancer (SCLC) is a particularly aggressive tumor subtype, and dihydroorotate dehydrogenase (DHODH) has been demonstrated to be a therapeutic target for SCLC. Network pharmacology analysis and virtual screening were utilized to find out related proteins and investigate candidates with high [...] Read more.
Small cell lung cancer (SCLC) is a particularly aggressive tumor subtype, and dihydroorotate dehydrogenase (DHODH) has been demonstrated to be a therapeutic target for SCLC. Network pharmacology analysis and virtual screening were utilized to find out related proteins and investigate candidates with high docking capacity to multiple targets. Graph neural networks (GNNs) and machine learning were used to build reliable predicted models. We proposed a novel concept of multi-GNNs, and then built three multi-GNN models called GIAN, GIAT, and SGCA, which achieved satisfactory results in our dataset containing 532 molecules with all R^2 values greater than 0.92 on the training set and higher than 0.8 on the test set. Compared with machine learning algorithms, random forest (RF), and support vector regression (SVR), multi-GNNs had a better modeling effect and higher precision. Furthermore, the long-time 300 ns molecular dynamics simulation verified the stability of the protein–ligand complexes. The result showed that ZINC8577218, ZINC95618747, and ZINC4261765 might be the potentially potent inhibitors for DHODH. Multi-GNNs show great performance in practice, making them a promising field for future research. We therefore suggest that this novel concept of multi-GNNs is a promising protocol for drug discovery. Full article
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Open AccessArticle
Metabolic Changes of Cholangiocarcinoma Cells in Response to Coniferyl Alcohol Treatment
Biomolecules 2021, 11(3), 476; https://doi.org/10.3390/biom11030476 - 22 Mar 2021
Viewed by 745
Abstract
Cholangiocarcinoma (CCA) is a major cause of mortality in Northeast Thailand with about 14,000 deaths each year. There is an urgent necessity for novel drug discovery to increase effective treatment possibilities. A recent study reported that lignin derived from Scoparia dulcis can cause [...] Read more.
Cholangiocarcinoma (CCA) is a major cause of mortality in Northeast Thailand with about 14,000 deaths each year. There is an urgent necessity for novel drug discovery to increase effective treatment possibilities. A recent study reported that lignin derived from Scoparia dulcis can cause CCA cell inhibition. However, there is no evidence on the inhibitory effect of coniferyl alcohol (CA), which is recognized as a major monolignol-monomer forming a very complex structure of lignin. Therefore, we aimed to investigate the effect of CA on CCA cell apoptosis. We demonstrated that a half-inhibitory concentration of CA on KKU-100 cells at 48 h and 72 h was 361.87 ± 30.58 and 268.27 ± 18.61 μg/mL, respectively, and on KKU-213 cells 184.37 ± 11.15 and 151.03 ± 24.99 μg/mL, respectively. Furthermore, CA induced CCA cell apoptosis as demonstrated by annexin V/PI staining in correspondence with an increase in the BAX/Bcl-2 ratio. A metabonomic study indicated that CA significantly decreased the intracellular concentrations of glutathione and succinate in KKU-213 cells and increased dihydrogen acetone phosphate levels in KKU-100 cells treated with 200 µg/mL of CA compared to the control group. In conclusion, CA induced cellular metabolic changes which are involved in the antioxidant defense mechanism, glycerophospholipid metabolism and the tricarboxylic acid cycle. CA may serve as a potent anticancer agent for CCA treatment by inducing CCA cellular apoptosis. Full article
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Open AccessArticle
In Vitro Preformed Biofilms of Bacillus safensis Inhibit the Adhesion and Subsequent Development of Listeria monocytogenes on Stainless-Steel Surfaces
Biomolecules 2021, 11(3), 475; https://doi.org/10.3390/biom11030475 - 22 Mar 2021
Viewed by 438
Abstract
Listeria monocytogenes continues to be one of the most important public health challenges for the meat sector. Many attempts have been made to establish the most efficient cleaning and disinfection protocols, but there is still the need for the sector to develop plans [...] Read more.
Listeria monocytogenes continues to be one of the most important public health challenges for the meat sector. Many attempts have been made to establish the most efficient cleaning and disinfection protocols, but there is still the need for the sector to develop plans with different lines of action. In this regard, an interesting strategy could be based on the control of this type of foodborne pathogen through the resident microbiota naturally established on the surfaces. A potential inhibitor, Bacillus safensis, was found in a previous study that screened the interaction between the resident microbiota and L. monocytogenes in an Iberian pig processing plant. The aim of the present study was to evaluate the effect of preformed biofilms of Bacillus safensis on the adhesion and implantation of 22 strains of L. monocytogenes. Mature preformed B. safensis biofilms can inhibit adhesion and the biofilm formation of multiple L. monocytogenes strains, eliminating the pathogen by a currently unidentified mechanism. Due to the non-enterotoxigenic properties of B. safensis, its presence on certain meat industry surfaces should be favored and it could represent a new way to fight against the persistence of L. monocytogenes in accordance with other bacterial inhibitors and hygiene operations. Full article
(This article belongs to the Special Issue Recent Advance of Listeria)
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Open AccessReview
Antiviral Cyanometabolites—A Review
Biomolecules 2021, 11(3), 474; https://doi.org/10.3390/biom11030474 - 22 Mar 2021
Viewed by 525
Abstract
Global processes, such as climate change, frequent and distant travelling and population growth, increase the risk of viral infection spread. Unfortunately, the number of effective and accessible medicines for the prevention and treatment of these infections is limited. Therefore, in recent years, efforts [...] Read more.
Global processes, such as climate change, frequent and distant travelling and population growth, increase the risk of viral infection spread. Unfortunately, the number of effective and accessible medicines for the prevention and treatment of these infections is limited. Therefore, in recent years, efforts have been intensified to develop new antiviral medicines or vaccines. In this review article, the structure and activity of the most promising antiviral cyanobacterial products are presented. The antiviral cyanometabolites are mainly active against the human immunodeficiency virus (HIV) and other enveloped viruses such as herpes simplex virus (HSV), Ebola or the influenza viruses. The majority of the metabolites are classified as lectins, monomeric or dimeric proteins with unique amino acid sequences. They all show activity at the nanomolar range but differ in carbohydrate specificity and recognize a different epitope on high mannose oligosaccharides. The cyanobacterial lectins include cyanovirin-N (CV-N), scytovirin (SVN), microvirin (MVN), Microcystisviridis lectin (MVL), and Oscillatoria agardhii agglutinin (OAA). Cyanobacterial polysaccharides, peptides, and other metabolites also have potential to be used as antiviral drugs. The sulfated polysaccharide, calcium spirulan (CA-SP), inhibited infection by enveloped viruses, stimulated the immune system’s response, and showed antitumor activity. Microginins, the linear peptides, inhibit angiotensin-converting enzyme (ACE), therefore, their use in the treatment of COVID-19 patients with injury of the ACE2 expressing organs is considered. In addition, many cyanobacterial extracts were revealed to have antiviral activities, but the active agents have not been identified. This fact provides a good basis for further studies on the therapeutic potential of these microorganisms. Full article
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Open AccessFeature PaperReview
Coupling Machine Learning and Lipidomics as a Tool to Investigate Metabolic Dysfunction-Associated Fatty Liver Disease. A General Overview
Biomolecules 2021, 11(3), 473; https://doi.org/10.3390/biom11030473 - 22 Mar 2021
Viewed by 651
Abstract
Hepatic biopsy is the gold standard for staging nonalcoholic fatty liver disease (NAFLD). Unfortunately, accessing the liver is invasive, requires a multidisciplinary team and is too expensive to be conducted on large segments of the population. NAFLD starts quietly and can progress until [...] Read more.
Hepatic biopsy is the gold standard for staging nonalcoholic fatty liver disease (NAFLD). Unfortunately, accessing the liver is invasive, requires a multidisciplinary team and is too expensive to be conducted on large segments of the population. NAFLD starts quietly and can progress until liver damage is irreversible. Given this complex situation, the search for noninvasive alternatives is clinically important. A hallmark of NAFLD progression is the dysregulation in lipid metabolism. In this context, recent advances in the area of machine learning have increased the interest in evaluating whether multi-omics data analysis performed on peripheral blood can enhance human interpretation. In the present review, we show how the use of machine learning can identify sets of lipids as predictive biomarkers of NAFLD progression. This approach could potentially help clinicians to improve the diagnosis accuracy and predict the future risk of the disease. While NAFLD has no effective treatment yet, the key to slowing the progression of the disease may lie in predictive robust biomarkers. Hence, to detect this disease as soon as possible, the use of computational science can help us to make a more accurate and reliable diagnosis. We aimed to provide a general overview for all readers interested in implementing these methods. Full article
(This article belongs to the Special Issue Metabolomics and Integrated Multi-Omics in Health and Disease)
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Open AccessArticle
Differential MicroRNA Expression Involved in Endometrial Receptivity of Goats
Biomolecules 2021, 11(3), 472; https://doi.org/10.3390/biom11030472 - 22 Mar 2021
Viewed by 417
Abstract
Endometrial receptivity represents one of the leading factors affecting the successful implantation of embryos during early pregnancy. However, the mechanism of microRNAs (miRNAs) to establish goat endometrial receptivity remains unclear. This study was intended to identify potential miRNAs and regulatory mechanisms associated with [...] Read more.
Endometrial receptivity represents one of the leading factors affecting the successful implantation of embryos during early pregnancy. However, the mechanism of microRNAs (miRNAs) to establish goat endometrial receptivity remains unclear. This study was intended to identify potential miRNAs and regulatory mechanisms associated with establishing endometrial receptivity through integrating bioinformatics analysis and experimental verification. MiRNA expression profiles were obtained by high-throughput sequencing, resulting in the detection of 33 differentially expressed miRNAs (DEMs), followed by their validation through quantitative RT-PCR. Furthermore, 10 potential transcription factors (TFs) and 1316 target genes of these DEMs were obtained, and the TF–miRNA and miRNA–mRNA interaction networks were constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these miRNAs were significantly linked to establishing endometrial receptivity. Moreover, the fluorescence in situ hybridization (FISH) analysis, dual-luciferase report assay, and immunohistochemistry (IHC) analysis corroborated that chi-miR-483 could directly bind to deltex E3 ubiquitin ligase 3L (DTX3L) to reduce its expression level. In conclusion, our findings contribute to a better understanding of molecular mechanisms regulating the endometrial receptivity of goats, and they provide a reference for improving embryo implantation efficiency. Full article
(This article belongs to the Special Issue Molecular Genetics of Reproductive Health)
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Open AccessArticle
Deep Learning for Novel Antimicrobial Peptide Design
Biomolecules 2021, 11(3), 471; https://doi.org/10.3390/biom11030471 - 22 Mar 2021
Viewed by 501
Abstract
Antimicrobial resistance is an increasing issue in healthcare as the overuse of antibacterial agents rises during the COVID-19 pandemic. The need for new antibiotics is high, while the arsenal of available agents is decreasing, especially for the treatment of infections by Gram-negative bacteria [...] Read more.
Antimicrobial resistance is an increasing issue in healthcare as the overuse of antibacterial agents rises during the COVID-19 pandemic. The need for new antibiotics is high, while the arsenal of available agents is decreasing, especially for the treatment of infections by Gram-negative bacteria like Escherichia coli. Antimicrobial peptides (AMPs) are offering a promising route for novel antibiotic development and deep learning techniques can be utilised for successful AMP design. In this study, a long short-term memory (LSTM) generative model and a bidirectional LSTM classification model were constructed to design short novel AMP sequences with potential antibacterial activity against E. coli. Two versions of the generative model and six versions of the classification model were trained and optimised using Bayesian hyperparameter optimisation. These models were used to generate sets of short novel sequences that were classified as antimicrobial or non-antimicrobial. The validation accuracies of the classification models were 81.6–88.9% and the novel AMPs were classified as antimicrobial with accuracies of 70.6–91.7%. Predicted three-dimensional conformations of selected short AMPs exhibited the alpha-helical structure with amphipathic surfaces. This demonstrates that LSTMs are effective tools for generating novel AMPs against targeted bacteria and could be utilised in the search for new antibiotics leads. Full article
(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)
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Open AccessArticle
The Antimicrobial, Antioxidant, and Anticancer Activity of Greenly Synthesized Selenium and Zinc Composite Nanoparticles Using Ephedra aphylla Extract
Biomolecules 2021, 11(3), 470; https://doi.org/10.3390/biom11030470 - 22 Mar 2021
Viewed by 447
Abstract
The current work aimed to synthesize selenium and zinc nanoparticles using the aqueous extract of Ephedra aphylla as a valuable medicinal plant. The prepared nanoparticles were characterized by TEM, zeta potential, and changes in the phytochemical constituents. Hence, the phenolic, flavonoid, and tannin [...] Read more.
The current work aimed to synthesize selenium and zinc nanoparticles using the aqueous extract of Ephedra aphylla as a valuable medicinal plant. The prepared nanoparticles were characterized by TEM, zeta potential, and changes in the phytochemical constituents. Hence, the phenolic, flavonoid, and tannin contents were reduced in the case of the prepared samples of nanoparticles than the original values in the aqueous extract. The prepared extract of Ephedra aphylla and its selenium and zinc nanoparticles showed high potency as antioxidant agents as a result of the DPPH assay. The samples were assessed as anticancer agents against six tumor cells and a normal lung fibroblast (WI-38) cell line. The selenium nanoparticles of Ephedra aphylla extract revealed very strong cytotoxicity against HePG-2 cells (inhibitory concentration (IC50) = 7.56 ± 0.6 µg/mL), HCT-116 cells (IC50 = 10.02 ± 0.9 µg/mL), and HeLa cells (IC50 = 9.23 ± 0.8 µg/mL). The samples were evaluated as antimicrobial agents against bacterial and fungal strains. Thus, selenium nanoparticles showed potent activities against Gram-negative strains (Salmonella typhimurium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli), Gram-positive strains (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus, and Staphylococcus epidermidis), and the fungal strain Candida albicans. In conclusion, the preparation of nanoparticles of either selenium or zinc is crucial for improved biological characteristics. Full article
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Open AccessReview
The Cys Sense: Thiol Redox Switches Mediate Life Cycles of Cellular Proteins
Biomolecules 2021, 11(3), 469; https://doi.org/10.3390/biom11030469 - 22 Mar 2021
Viewed by 477
Abstract
Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, [...] Read more.
Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, cell damage, and death. This merges together the processes of protein homeostasis and redox regulation. At the heart of this process are redox-regulated proteins or thiol-based switches, which carefully mediate various steps of protein homeostasis across folding, localization, quality control, and degradation pathways. In this review, we discuss the “redox code” of the proteostasis network, which shapes protein health during cell growth and aging. We describe the sources and types of thiol modifications and elaborate on diverse strategies of evolving antioxidant proteins in proteostasis networks during oxidative stress conditions. We also highlight the involvement of cysteines in protein degradation across varying levels, showcasing the importance of cysteine thiols in proteostasis at large. The individual examples and mechanisms raised open the door for extensive future research exploring the interplay between the redox and protein homeostasis systems. Understanding this interplay will enable us to re-write the redox code of cells and use it for biotechnological and therapeutic purposes. Full article
(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)
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Open AccessArticle
Cerrena unicolor Laccases, Genes Expression and Regulation of Activity
Biomolecules 2021, 11(3), 468; https://doi.org/10.3390/biom11030468 - 22 Mar 2021
Viewed by 339
Abstract
A white rot fungus Cerrena unicolor has been identified as an important source of laccase, unfortunately regulation of this enzyme genes expression is poorly understood. Using 1D and 2D PAGE and LC-MS/MS, laccase isoenzymes were investigated in the liquid filtrate of C. unicolor [...] Read more.
A white rot fungus Cerrena unicolor has been identified as an important source of laccase, unfortunately regulation of this enzyme genes expression is poorly understood. Using 1D and 2D PAGE and LC-MS/MS, laccase isoenzymes were investigated in the liquid filtrate of C. unicolor culture. The level of expression of laccase genes was measured using qPCR. The elevated concentrations of copper and manganese in the medium caused greatest change in genes expression and three laccase transcripts were significantly affected after culture temperature was decreased from 28 to 4 °C or increased to 40 °C. The small differences in the PAGE band intensities of individual laccase proteins were also observed, indicating that given compound affect particular laccase’s transcript. Analyses of laccase-specific activity, at all tested conditions, showed the increased activities as compared to the control, suggesting that enzyme is regulated at the post-translational stage. We observed that the aspartic protease purified from C. unicolor, significantly stimulate laccase activity. Moreover, electrochemical analysis of protease-treated laccase sample had 5 times higher redox peaks. The obtained results indicate that laccases released by C. unicolor are regulated at transcriptional, translational, and at the post-translational steps of gene expression helping fungus adapt to the environmental changes. Full article
(This article belongs to the Special Issue Fungal Metabolism - Enzymes and Bioactive Compounds)
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Open AccessArticle
Chemoinformatic Screening for the Selection of Potential Senolytic Compounds from Natural Products
Biomolecules 2021, 11(3), 467; https://doi.org/10.3390/biom11030467 - 22 Mar 2021
Viewed by 501
Abstract
Cellular senescence is a cellular condition that involves significant changes in gene expression and the arrest of cell proliferation. Recently, it has been suggested in experimental models that the elimination of senescent cells with pharmacological methods delays, prevents, and improves multiple adverse outcomes [...] Read more.
Cellular senescence is a cellular condition that involves significant changes in gene expression and the arrest of cell proliferation. Recently, it has been suggested in experimental models that the elimination of senescent cells with pharmacological methods delays, prevents, and improves multiple adverse outcomes related to age. In this sense, the so-called senoylitic compounds are a class of drugs that selectively eliminates senescent cells (SCs) and that could be used in order to delay such adverse outcomes. Interestingly, the first senolytic drug (navitoclax) was discovered by using chemoinformatic and network analyses. Thus, in the present study, we searched for novel senolytic compounds through the use of chemoinformatic tools (fingerprinting and network pharmacology) over different chemical databases (InflamNat and BIOFACQUIM) coming from natural products (NPs) that have proven to be quite remarkable for drug development. As a result of screening, we obtained three molecules (hinokitiol, preussomerin C, and tanshinone I) that could be considered senolytic compound candidates since they share similarities in structure with senolytic leads (tunicamycin, ginsenoside Rb1, ABT 737, rapamycin, navitoclax, timosaponin A-III, digoxin, roxithromycin, and azithromycin) and targets involved in senescence pathways with potential use in the treatment of age-related diseases. Full article
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Open AccessReview
Neuropathology of Animal Prion Diseases
Biomolecules 2021, 11(3), 466; https://doi.org/10.3390/biom11030466 - 21 Mar 2021
Viewed by 538
Abstract
Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrPC) into a misfolded pathological isoform (PrPSc or [...] Read more.
Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrPC) into a misfolded pathological isoform (PrPSc or prion- proteinaceous infectious particle) that self-propagates by conformational conversion of PrPC. Yet by an unknown mechanism, PrPC can fold into different PrPSc conformers that may result in different prion strains that display specific disease phenotype (incubation time, clinical signs and lesion profile). Although the pathways for neurodegeneration as well as the involvement of brain inflammation in these diseases are not well understood, the spongiform changes, neuronal loss, gliosis and accumulation of PrPSc are the characteristic neuropathological lesions. Scrapie affecting small ruminants was the first identified TSE and has been considered the archetype of prion diseases, though atypical and new animal prion diseases continue to emerge highlighting the importance to investigate the lesion profile in naturally affected animals. In this report, we review the neuropathology and the neuroinflammation of animal prion diseases in natural hosts from scrapie, going through the zoonotic bovine spongiform encephalopathy (BSE), the chronic wasting disease (CWD) to the newly identified camel prion disease (CPD). Full article
(This article belongs to the Special Issue Prion Diseases: A Natural Model for Neurodegenerative Disorders)
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Open AccessArticle
Silymarin-Enriched Biostimulant Foliar Application Minimizes the Toxicity of Cadmium in Maize by Suppressing Oxidative Stress and Elevating Antioxidant Gene Expression
Biomolecules 2021, 11(3), 465; https://doi.org/10.3390/biom11030465 - 21 Mar 2021
Viewed by 467
Abstract
For maize, the potential preventive role of foliar spraying with an extract derived from maize grain (MEg, 2%), silymarin (Sm, 0.5 mM), or silymarin-enriched MEg (MEg-Sm) in attenuating the stress effects of cadmium (Cd, 0.5 mM) was examined using a completely randomized design [...] Read more.
For maize, the potential preventive role of foliar spraying with an extract derived from maize grain (MEg, 2%), silymarin (Sm, 0.5 mM), or silymarin-enriched MEg (MEg-Sm) in attenuating the stress effects of cadmium (Cd, 0.5 mM) was examined using a completely randomized design layout. Under normal conditions, foliar spraying with MEg, Sm, or MEg-Sm was beneficial (with MEg-Sm preferred) for maize plants, whereas the benefit was more pronounced under Cd stress. The use of Cd through irrigation water decreased plant growth traits, photosynthetic efficiency, including instantaneous carboxylation efficiency, Fv/Fm, and pigment contents, and hormonal contents (e.g., auxin, gibberellins, cytokinins including trans-zeatin, and salicylic acid). These undesired findings were due to an increase in Cd content, leading to increased levels of oxidative stress (O2 and H2O2), ionic leakage, and lipid peroxidation. Therefore, this damage resulted in an increase in the activities of nonenzymatic antioxidants, Sm, antioxidative enzymes, and enzyme gene expression. However, under Cd stress, although foliar spray with MEg or Sm had better findings than control, MEg-Sm had better findings than MEg or Sm. Application of MEg-Sm greatly increased photosynthesis efficiency, restored hormonal homeostasis, and further increased the activities of various antioxidants, Sm, antioxidative enzymes, and enzyme gene expression. These desired findings were due to the suppression of the Cd content, and thus the levels of O2, H2O2, ionic leakage, and lipid peroxidation, which were positively reflected in the growth and accumulation of dry matter in maize plants. The data obtained in this study recommend applying silymarin-enriched maize grain extract (MEg-Sm at 0.24 g Sm L−1 of MEg) as a spray solution to maize plants when exposed to excess Cd in soil or irrigation water. Full article
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Open AccessArticle
The Effect of Cultivation Passaging on the Relative Telomere Length and Proliferation Capacity of Dental Pulp Stem Cells
Biomolecules 2021, 11(3), 464; https://doi.org/10.3390/biom11030464 - 20 Mar 2021
Viewed by 493
Abstract
Telomeres are repetitive nucleoprotein DNA sequences that shorten with each cell division. The stem cells activate telomerase to compensate for the telomere loss. This study aimed to evaluate the effect of cultivation passaging on the relative telomere length and proliferation capacity of dental [...] Read more.
Telomeres are repetitive nucleoprotein DNA sequences that shorten with each cell division. The stem cells activate telomerase to compensate for the telomere loss. This study aimed to evaluate the effect of cultivation passaging on the relative telomere length and proliferation capacity of dental pulp stem cells. We used ten dental pulp stem cell (DPSC) lineages stored for 12 months using uncontrolled-rate freezing to reach the study’s goal. We analyzed their proliferation rate, phenotype using flow cytometry, multipotency, and relative telomere length using a qPCR analysis. We determined the relative telomere length in the added study by performing analysis after one, two, and three weeks of cultivation with no passaging. We documented the telomere attrition with increasing passaging. The shorter the relative telomere length, the lower reached population doublings, and longer population doubling time were observed at the end of the cultivation. We observed the telomere prolongation in DPSCs cultivated for two weeks with no passaging in the added subsequent study. We concluded that excessive proliferation demands on DPSCs during in vitro cultivation result in telomere attrition. We opened the theory that the telomerase might be more efficient during cell cultivation with no passaging. This observation could help in preserving the telomere length during ex vivo DPSC expansion. Full article
(This article belongs to the Special Issue Oral Regenerative Medicine: Current and Future)
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Open AccessArticle
Dilignans with a Chromanol Motif Discovered by Molecular Networking from the Stem Barks of Magnolia obovata and Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activity
Biomolecules 2021, 11(3), 463; https://doi.org/10.3390/biom11030463 - 19 Mar 2021
Viewed by 355
Abstract
Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool [...] Read more.
Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool is expected to expedite the dereplication of secondary metabolites. In this study, using this tool, two new dilignans with a 2-phenyl-3-chromanol motif, obovatolins A (1) and B (2), were discovered from the stem barks of Magnolia obovata Thunb. along with six known compounds (38), expanding chemical diversity of lignan skeletons in this natural source. Their structures and configurations were elucidated using spectroscopic data. All isolates were evaluated for their PCSK9 mRNA expression inhibitory activity. Obovatolins A (1) and B (2), and magnolol (3) showed potent lipid controlling activities. To identify transcriptionally controlled genes by 1 along with downregulation of PCSK9, using small set of genes (42 genes) related to lipid metabolism selected from the database, focused bioinformatic analysis was carried out. As a result, it showed the correlations between gene expression under presence of 1, which led to detailed insight of the lipid metabolism caused by 1. Full article
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Open AccessArticle
Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives
Biomolecules 2021, 11(3), 462; https://doi.org/10.3390/biom11030462 - 19 Mar 2021
Viewed by 395
Abstract
Phenylketonuria (PKU) is a genetic disease caused by deficient activity of human phenylalanine hydroxylase (hPAH) that, when untreated, can lead to severe psychomotor impairment. Protein misfolding is recognized as the main underlying pathogenic mechanism of PKU. Therefore, the use of stabilizers of protein [...] Read more.
Phenylketonuria (PKU) is a genetic disease caused by deficient activity of human phenylalanine hydroxylase (hPAH) that, when untreated, can lead to severe psychomotor impairment. Protein misfolding is recognized as the main underlying pathogenic mechanism of PKU. Therefore, the use of stabilizers of protein structure and/or activity is an attractive therapeutic strategy for this condition. Here, we report that 3-hydroxyquinolin-2(1H)-one derivatives can act as protectors of hPAH enzyme activity. Electron paramagnetic resonance spectroscopy demonstrated that the 3-hydroxyquinolin-2(1H)-one compounds affect the coordination of the non-heme ferric center at the enzyme active-site. Moreover, surface plasmon resonance studies showed that these stabilizing compounds can be outcompeted by the natural substrate l-phenylalanine. Two of the designed compounds functionally stabilized hPAH by maintaining protein activity. This effect was observed on the recombinant purified protein and in a cellular model. Besides interacting with the catalytic iron, one of the compounds also binds to the N-terminal regulatory domain, although to a different location from the allosteric l-Phe binding site, as supported by the solution structures obtained by small-angle X-ray scattering. Full article
(This article belongs to the Section Natural and Bio-inspired Molecules)
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Open AccessArticle
A Biorefinery Approach to the Biomass of the Seaweed Undaria pinnatifida (Harvey Suringar, 1873): Obtaining Phlorotannins-Enriched Extracts for Wound Healing
Biomolecules 2021, 11(3), 461; https://doi.org/10.3390/biom11030461 - 19 Mar 2021
Viewed by 418
Abstract
Brown seaweeds are recognized sources of compounds with a wide range of properties and applications. Within these compounds, phlorotannins are known to possess several bioactivities (e.g., antioxidant, anti-inflammatory, and antimicrobial) with potential to improve wound healing. To obtain phlorotannins enriched extracts from Undaria [...] Read more.
Brown seaweeds are recognized sources of compounds with a wide range of properties and applications. Within these compounds, phlorotannins are known to possess several bioactivities (e.g., antioxidant, anti-inflammatory, and antimicrobial) with potential to improve wound healing. To obtain phlorotannins enriched extracts from Undaria pinnatifida, a biorefinery was set using low-cost industry-friendly methodologies, such as sequential solid–liquid extraction and liquid–liquid extraction. The obtained extracts were screened for their antioxidant and antimicrobial activity against five common wound pathogens and for their anti-inflammatory potential. The ethanolic wash fraction (wE100) had the highest antioxidant activity (114.61 ± 10.04 mmol·mg−1 extract by Diphenyl-1-picrylhydrazyl (DPPH) and 6.56 ± 1.13 mM eq. Fe II·mg−1 extract by and Ferric Reducing Antioxidant Power (FRAP)), acting efficiently against Gram-negative (Pseudomonas aeruginosa) and Gram-positive (Staphylococcus aureus) bacteria, and showing a nitric oxide production inhibition over 47% when used at 0.01 µg·mL−1. NMR and FTIR chemical characterization suggested that phlorotannins are present. Obtained fraction wE100 proved to be a promising candidate for further inclusion as wound healing agents, while the remaining fractions analyzed are potential sources for other biotechnological applications, giving emphasis to a biorefinery and circular economy framework to add value to this seaweed and the industry. Full article
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Open AccessArticle
Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)
Biomolecules 2021, 11(3), 460; https://doi.org/10.3390/biom11030460 - 19 Mar 2021
Viewed by 792
Abstract
The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine [...] Read more.
The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = −8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = −6.49 kcal/mol), and nsp10 (ΔG = −9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = −7.99 kcal/mol), spike glycoproteins (ΔG = −6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = −8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2. Full article
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Open AccessArticle
QSAR-Based Virtual Screening of Natural Products Database for Identification of Potent Antimalarial Hits
Biomolecules 2021, 11(3), 459; https://doi.org/10.3390/biom11030459 - 19 Mar 2021
Viewed by 411
Abstract
With about 400,000 annual deaths worldwide, malaria remains a public health burden in tropical and subtropical areas, especially in low-income countries. Selection of drug-resistant Plasmodium strains has driven the need to explore novel antimalarial compounds with diverse modes of action. In this context, [...] Read more.
With about 400,000 annual deaths worldwide, malaria remains a public health burden in tropical and subtropical areas, especially in low-income countries. Selection of drug-resistant Plasmodium strains has driven the need to explore novel antimalarial compounds with diverse modes of action. In this context, biodiversity has been widely exploited as a resourceful channel of biologically active compounds, as exemplified by antimalarial drugs such as quinine and artemisinin, derived from natural products. Thus, combining a natural product library and quantitative structure–activity relationship (QSAR)-based virtual screening, we have prioritized genuine and derivative natural compounds with potential antimalarial activity prior to in vitro testing. Experimental validation against cultured chloroquine-sensitive and multi-drug-resistant P. falciparum strains confirmed the potent and selective activity of two sesquiterpene lactones (LDT-597 and LDT-598) identified in silico. Quantitative structure–property relationship (QSPR) models predicted absorption, distribution, metabolism, and excretion (ADME) and physiologically based pharmacokinetic (PBPK) parameters for the most promising compound, showing that it presents good physiologically based pharmacokinetic properties both in rats and humans. Altogether, the in vitro parasite growth inhibition results obtained from in silico screened compounds encourage the use of virtual screening campaigns for identification of promising natural compound-based antimalarial molecules. Full article
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Open AccessArticle
A Molecular Modeling Approach to Identify Potential Antileishmanial Compounds Against the Cell Division Cycle (cdc)-2-Related Kinase 12 (CRK12) Receptor of Leishmania donovani
Biomolecules 2021, 11(3), 458; https://doi.org/10.3390/biom11030458 - 18 Mar 2021
Viewed by 709
Abstract
The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial [...] Read more.
The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial drugs has made the eradication of the disease difficult to achieve, thus warranting the search for new drug targets. We report here studies that used computational methods to identify inhibitors of receptors from natural products. The cell division cycle-2-related kinase 12 (CRK12) receptor is a plausible drug target against Leishmania donovani. This study modelled the 3D molecular structure of the L. donovani CRK12 (LdCRK12) and screened for small molecules with potential inhibitory activity from African flora. An integrated library of 7722 African natural product-derived compounds and known inhibitors were screened against the LdCRK12 using AutoDock Vina after performing energy minimization with GROMACS 2018. Four natural products, namely sesamin (NANPDB1649), methyl ellagic acid (NANPDB1406), stylopine (NANPDB2581), and sennecicannabine (NANPDB6446) were found to be potential LdCRK12 inhibitory molecules. The molecular docking studies revealed two compounds NANPDB1406 and NANPDB2581 with binding affinities of −9.5 and −9.2 kcal/mol, respectively, against LdCRK12 which were higher than those of the known inhibitors and drugs, including GSK3186899, amphotericin B, miltefosine, and paromomycin. All the four compounds were predicted to have inhibitory constant (Ki) values ranging from 0.108 to 0.587 μM. NANPDB2581, NANPDB1649 and NANPDB1406 were also predicted as antileishmanial with Pa and Pi values of 0.415 and 0.043, 0.391 and 0.052, and 0.351 and 0.071, respectively. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations reinforced their good binding mechanisms. Most compounds were observed to bind in the ATP binding pocket of the kinase domain. Lys488 was predicted as a key residue critical for ligand binding in the ATP binding pocket of the LdCRK12. The molecules were pharmacologically profiled as druglike with inconsequential toxicity. The identified molecules have scaffolds that could form the backbone for fragment-based drug design of novel leishmanicides but warrant further studies to evaluate their therapeutic potential. Full article
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Open AccessArticle
The In Vitro Interaction of 12-Oxophytodienoic Acid and Related Conjugated Carbonyl Compounds with Thiol Antioxidants
Biomolecules 2021, 11(3), 457; https://doi.org/10.3390/biom11030457 - 18 Mar 2021
Viewed by 409
Abstract
α,β-unsaturated carbonyls interfere with numerous plant physiological processes. One mechanism of action is their reactivity toward thiols of metabolites like cysteine and glutathione (GSH). This work aimed at better understanding these interactions. Both 12-oxophytodienoic acid (12-OPDA) and abscisic acid (ABA) conjugated with cysteine. [...] Read more.
α,β-unsaturated carbonyls interfere with numerous plant physiological processes. One mechanism of action is their reactivity toward thiols of metabolites like cysteine and glutathione (GSH). This work aimed at better understanding these interactions. Both 12-oxophytodienoic acid (12-OPDA) and abscisic acid (ABA) conjugated with cysteine. It was found that the reactivity of α,β-unsaturated carbonyls with GSH followed the sequence trans-2-hexenal < 12-OPDA ≈ 12-OPDA-ethylester < 2-cyclopentenone << methyl vinylketone (MVK). Interestingly, GSH, but not ascorbate (vitamin C), supplementation ameliorated the phytotoxic potential of MVK. In addition, 12-OPDA and 12-OPDA-related conjugated carbonyl compounds interacted with proteins, e.g., with members of the thioredoxin (TRX)-fold family. 12-OPDA modified two cysteinyl residues of chloroplast TRX-f1. The OPDAylated TRX-f1 lost its activity to activate the Calvin–Benson-cycle enzyme fructose-1,6-bisphosphatase (FBPase). Finally, we show that 12-OPDA interacts with cyclophilin 20-3 (Cyp20-3) non-covalently and affects its peptidyl-prolyl-cis/trans isomerase activity. The results demonstrate the high potential of 12-OPDA as a diverse interactor and cellular regulator and suggest that OPDAylation may occur in plant cells and should be investigated as novel regulatory mechanism. Full article
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Open AccessArticle
Plasma Catestatin Levels and Advanced Glycation End Products in Patients on Hemodialysis
Biomolecules 2021, 11(3), 456; https://doi.org/10.3390/biom11030456 - 18 Mar 2021
Viewed by 291
Abstract
Catestatin (CST) is a pleiotropic peptide involved in cardiovascular protection with its antihypertensive and angiogenic effects. Considering that patients with end-stage renal disease (ESRD) who are undergoing hemodialysis (HD) are associated with higher cardiovascular risk, the aim of this study was to investigate [...] Read more.
Catestatin (CST) is a pleiotropic peptide involved in cardiovascular protection with its antihypertensive and angiogenic effects. Considering that patients with end-stage renal disease (ESRD) who are undergoing hemodialysis (HD) are associated with higher cardiovascular risk, the aim of this study was to investigate plasma CST levels in HD patients, compare them to healthy controls and evaluate possible CST associations with advanced glycation end products (AGEs) and laboratory, anthropometric and clinical parameters. The study included 91 patients on HD and 70 healthy controls. Plasma CST levels were determined by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit, while AGEs were determined using skin autofluorescence. Plasma CST levels were significantly higher in the HD group compared to the controls (32.85 ± 20.18 vs. 5.39 ± 1.24 ng/mL, p < 0.001) and there was a significant positive correlation between CST and AGEs (r = 0.492, p < 0.001). Furthermore, there was a significant positive correlation between plasma CST levels with both the Dialysis Malnutrition Score (r = 0.295, p = 0.004) and Malnutrition-Inflammation Score (r = 0.290, p = 0.005). These results suggest that CST could be playing a role in the complex pathophysiology of ESRD/HD and that it could affect the higher cardiovascular risk of patients on HD. Full article
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Open AccessReview
The Biological Significance of Targeting Acetylation-Mediated Gene Regulation for Designing New Mechanistic Tools and Potential Therapeutics
Biomolecules 2021, 11(3), 455; https://doi.org/10.3390/biom11030455 - 18 Mar 2021
Viewed by 396
Abstract
The molecular interplay between nucleosomal packaging and the chromatin landscape regulates the transcriptional programming and biological outcomes of downstream genes. An array of epigenetic modifications plays a pivotal role in shaping the chromatin architecture, which controls DNA access to the transcriptional machinery. Acetylation [...] Read more.
The molecular interplay between nucleosomal packaging and the chromatin landscape regulates the transcriptional programming and biological outcomes of downstream genes. An array of epigenetic modifications plays a pivotal role in shaping the chromatin architecture, which controls DNA access to the transcriptional machinery. Acetylation of the amino acid lysine is a widespread epigenetic modification that serves as a marker for gene activation, which intertwines the maintenance of cellular homeostasis and the regulation of signaling during stress. The biochemical horizon of acetylation ranges from orchestrating the stability and cellular localization of proteins that engage in the cell cycle to DNA repair and metabolism. Furthermore, lysine acetyltransferases (KATs) modulate the functions of transcription factors that govern cellular response to microbial infections, genotoxic stress, and inflammation. Due to their central role in many biological processes, mutations in KATs cause developmental and intellectual challenges and metabolic disorders. Despite the availability of tools for detecting acetylation, the mechanistic knowledge of acetylation-mediated cellular processes remains limited. This review aims to integrate molecular and structural bases of KAT functions, which would help design highly selective tools for understanding the biology of KATs toward developing new disease treatments. Full article
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