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Keywords = nucleotide analogues

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16 pages, 1485 KiB  
Article
Mode of Action of Toxin 6-Hydroxydopamine in SH-SY5Y Using NMR Metabolomics
by Roktima Tamuli, George D. Mellick, Horst Joachim Schirra and Yunjiang Feng
Molecules 2025, 30(16), 3352; https://doi.org/10.3390/molecules30163352 - 12 Aug 2025
Viewed by 294
Abstract
This study used NMR-based metabolomics to investigate the mode of action (MoA) of 6-hydroxydopamine (6-OHDA) toxicity in the SH-SY5Y neuroblastoma cell model. 6-OHDA, a structural analogue of dopamine, has been used to create a Parkinson’s disease model since 1968. Its selective uptake via [...] Read more.
This study used NMR-based metabolomics to investigate the mode of action (MoA) of 6-hydroxydopamine (6-OHDA) toxicity in the SH-SY5Y neuroblastoma cell model. 6-OHDA, a structural analogue of dopamine, has been used to create a Parkinson’s disease model since 1968. Its selective uptake via catecholaminergic transporters leads to intracellular oxidative stress and mitochondrial dysfunction. SH-SY5Y cells were treated with 6-OHDA at its IC50 concentration of 60 μM, and samples of treated and untreated groups were collected after 24 h. The endo metabolome was extracted using a methanol–water mixture, while the exo metabolome was represented by the culture media. Further, endo- and exo metabolomes of treated and untreated cells were analysed for metabolic changes. Our results demonstrated significantly high levels of glutathione, acetate, propionate, and NAD+, which are oxidative stress markers, enhanced due to ROS production in the system. In addition, alteration of myoinositol, taurine, and o-phosphocholine could be due to oxidative stress-induced membrane potential disturbance. Mitochondrial complex I inhibition causes electron transport chain (ETC) dysfunction. Changes in key metabolites of glycolysis and energy metabolism, such as glucose, pyruvate, lactate, creatine, creatine phosphate, glycine, and methionine, respectively, demonstrated ETC dysfunction. We also identified changes in amino acids such as glutamine, glutamate, and proline, followed by nucleotide metabolism such as uridine and uridine monophosphate levels, which were decreased in the treated group. Full article
(This article belongs to the Section Chemical Biology)
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27 pages, 2123 KiB  
Article
Exploring Cloned Disease Resistance Gene Homologues and Resistance Gene Analogues in Brassica nigra, Sinapis arvensis, and Sinapis alba: Identification, Characterisation, Distribution, and Evolution
by Aria Dolatabadian, Junrey C. Amas, William J. W. Thomas, Mohammad Sayari, Hawlader Abdullah Al-Mamun, David Edwards and Jacqueline Batley
Genes 2025, 16(8), 849; https://doi.org/10.3390/genes16080849 - 22 Jul 2025
Viewed by 345
Abstract
This study identifies and classifies resistance gene analogues (RGAs) in the genomes of Brassica nigra, Sinapis arvensis and Sinapis alba using the RGAugury pipeline. RGAs were categorised into four main classes: receptor-like kinases (RLKs), receptor-like proteins (RLPs), nucleotide-binding leucine-rich repeat (NLR) proteins [...] Read more.
This study identifies and classifies resistance gene analogues (RGAs) in the genomes of Brassica nigra, Sinapis arvensis and Sinapis alba using the RGAugury pipeline. RGAs were categorised into four main classes: receptor-like kinases (RLKs), receptor-like proteins (RLPs), nucleotide-binding leucine-rich repeat (NLR) proteins and transmembrane-coiled-coil (TM-CC) genes. A total of 4499 candidate RGAs were detected, with species-specific proportions. RLKs were the most abundant across all genomes, followed by TM-CCs and RLPs. The sub-classification of RLKs and RLPs identified LRR-RLKs, LRR-RLPs, LysM-RLKs, and LysM-RLPs. Atypical NLRs were more frequent than typical ones in all species. Atypical NLRs were more frequent than typical ones in all species. We explored the relationship between chromosome size and RGA count using regression analysis. In B. nigra and S. arvensis, larger chromosomes generally harboured more RGAs, while S. alba displayed the opposite trend. Exceptions were observed in all species, where some larger chromosomes contained fewer RGAs in B. nigra and S. arvensis, or more RGAs in S. alba. The distribution and density of RGAs across chromosomes were examined. RGA distribution was skewed towards chromosomal ends, with patterns differing across RGA types. Sequence hierarchical pairwise similarity analysis revealed distinct gene clusters, suggesting evolutionary relationships. The study also identified homologous genes among RGAs and non-RGAs in each species, providing insights into disease resistance mechanisms. Finally, RLKs and RLPs were co-localised with reported disease resistance loci in Brassica, indicating significant associations. Phylogenetic analysis of cloned RGAs and QTL-mapped RLKs and RLPs identified distinct clusters, enhancing our understanding of their evolutionary trajectories. These findings provide a comprehensive view of RGA diversity and genomics in these Brassicaceae species, providing valuable insights for future research in plant disease resistance and crop improvement. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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15 pages, 758 KiB  
Article
Novel Micro-LC-MS/MS Method for the Quantification of Tenofovir and Its Active Metabolite Tenofovir-Diphosphate in Biological Matrices for Therapeutic Drug Monitoring
by Isabela Tarcomnicu, Simona Iacob, Valentina Anuta, Emil Neaga and Dan Otelea
Pharmaceuticals 2025, 18(6), 899; https://doi.org/10.3390/ph18060899 - 16 Jun 2025
Viewed by 768
Abstract
Background/Objectives: Sustained drug exposure is a key factor in the treatment of patients infected with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) in order to achieve the intended virological response. Although influenced also by other parameters, adherence to the treatment [...] Read more.
Background/Objectives: Sustained drug exposure is a key factor in the treatment of patients infected with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) in order to achieve the intended virological response. Although influenced also by other parameters, adherence to the treatment scheme is the most important for adequate drug exposure. This can be assessed by therapeutic drug monitoring (TDM). Tenofovir (TFV) is a nucleotide analogue used in the treatment of both HIV and HBV. Although various analytical methods for the quantification of tenofovir prodrugs have been published, there is limited literature on methods for simultaneous TFV and its active metabolite, tenofovir diphosphate (TFVDP) direct determination. Methods: In this study, we describe a novel micro-liquid-chromatography-mass spectrometry (micro-LC-MS/MS) method for TDM of TFV and TFVDP in biological matrices (whole blood, plasma). The challenging separation of the high-polarity analytes was resolved on an amino stationary phase, eluted in HILIC (hydrophilic interaction liquid chromatography) mode. The sample preparation included a clean-up step with hexane for the removal of lipophilic compounds and then protein precipitation with organic solvent. Results: The achieved low limits of quantification in blood were 0.25 ng/mL for TFV, and 0.5 ng/mL for TFVDP. Linearity, accuracy (91.63–109.18%), precision (2.48–14.08), and stability were validated for whole blood matrix, meeting the guidelines performance criteria. Samples collected from treated patients were analyzed, with results being in accordance with the reported pharmacokinetics. Conclusions: The new method is adequate for analyzing samples in a clinical set-up. The measurement of both TFV and TFVDP improves clinical decision by an in-depth evaluation of long-term adherence, and together with viral load and resistance data helps guiding the treatment towards the intended virological suppression. Full article
(This article belongs to the Section Pharmaceutical Technology)
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40 pages, 2483 KiB  
Review
Biological and Biosimilar Medicines in Contemporary Pharmacotherapy for Metabolic Syndrome
by Wiktoria Górecka, Daria Berezovska, Monika Mrozińska, Grażyna Nowicka and Monika E. Czerwińska
Pharmaceutics 2025, 17(6), 768; https://doi.org/10.3390/pharmaceutics17060768 - 11 Jun 2025
Viewed by 1507
Abstract
The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly [...] Read more.
The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly being supplemented by biological and biosimilar agents. This trend is particularly evident in the development and advancement of anti-diabetic and hypolipemic therapies. This review explores advances in the treatment of hypercholesterolemia and hypertriglyceridemia, elevated lipoprotein(a) [Lp(a)], diabetes, and obesity associated with metabolic syndrome. It focuses mainly on biopharmaceuticals such as proteins and nucleotide-based drugs (antisense oligonucleotides, small interfering RNA), but also on dipeptidyl peptidase-4 (DPP-4) inhibitors classified as incretin drugs along with glucagon-like peptide-1 (GLP-1) analogues. Due to the substantial role of SGLT-2 (sodium/glucose cotransporter 2) inhibitors in novel diabetes therapies, especially for managing cardiovascular risk, this group of compounds was also included in this review. Many clinical data in the field of effectiveness of biopharmaceuticals in metabolic disorders are provided. Therefore, in this review, we mainly include a brief history of drug development and approval, first synthesis and structure modifications, which relevantly influence pharmacokinetics, and safety. We provide only brief comparison of biological drugs with metformin and sulphonylureas derivatives. Databases such as PubMed, Scopus, and Google Scholar are searched for the period between 2000 and 2024. Full article
(This article belongs to the Section Biologics and Biosimilars)
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13 pages, 1451 KiB  
Article
Effects of 5-Methyl-2′-Deoxycytidine in G-Quadruplex Forming Aptamers d(G3C)4 and d[GCG2(CG3)3C]: Investigating the Key Role of the Loops
by Veronica Esposito, Daniela Benigno, Carla Aliberti, Camilla Esposito, Elisabetta Panza, Antonella Virgilio and Aldo Galeone
Biomolecules 2025, 15(6), 753; https://doi.org/10.3390/biom15060753 - 23 May 2025
Viewed by 821
Abstract
T40214 (STAT) and its recently investigated analogue STATB are G-quadruplex (G4) forming aptamers characterized by an unusually high percentage of C. The therapeutic potential of T40214 relies on its ability to inhibit the signalling pathway of STAT3, a protein frequently overexpressed in tumor [...] Read more.
T40214 (STAT) and its recently investigated analogue STATB are G-quadruplex (G4) forming aptamers characterized by an unusually high percentage of C. The therapeutic potential of T40214 relies on its ability to inhibit the signalling pathway of STAT3, a protein frequently overexpressed in tumor cells. STAT adopts a dimeric 5′-5′ end-stacked quadruplex structure, characterized by parallel strands, three G-tetrads and three propeller-shaped loops formed by a cytidine residue. STATB folds in a very similar structure, apart from an additional cytidine bulge loop. Many studies suggest that thermal stability and topology of G4 can be significantly affected by C methylation, thus resulting in altered interaction of G4-binding proteins with these structures. Considering this, two series of STAT and STATB analogues containing a single 5-methyl-2′-deoxycytidine (mC) residue instead of canonical C nucleotide in the loop have been prepared and investigated by a combination of spectroscopic and electrophoretic techniques. CD, NMR and PAGE data clearly indicate that all derivatives adopt dimeric G4 strictly similar to that assumed by parent aptamers, but with higher stabilities. Furthermore, the resistance to nucleases and the antiproliferative activity of these mC-containing derivatives against HCT116 (human colorectal carcinoma) and T24 (human bladder carcinoma) cell lines have been evaluated. In most of the cases, STAT and STATB derivatives inhibit cell proliferation to different extents, although to a lesser degree than the unmodified parent sequences. All the data highlight the key role of the loops and indicate mC as a useful tool to contribute favorably to the stability of G4-forming aptamers without alteration of their topology, required for the biological activity. Full article
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24 pages, 7199 KiB  
Article
Choice of ATP Analogues for Biophysical Studies—A Systematic NMR-Based Investigation for the AAA Enzyme p97
by Maxim A. Droemer, Mikhail Shein and Anne K. Schütz
Biophysica 2025, 5(1), 9; https://doi.org/10.3390/biophysica5010009 - 10 Mar 2025
Viewed by 1656
Abstract
ATP analogues are essential tools in enzymology and structural biology, but the structural and functional implications of their chemical modifications on nucleotide-binding proteins are often underappreciated. To address this, we evaluated a panel of ATP analogues, focusing on thiosubstituted and fluorinated molecules, using [...] Read more.
ATP analogues are essential tools in enzymology and structural biology, but the structural and functional implications of their chemical modifications on nucleotide-binding proteins are often underappreciated. To address this, we evaluated a panel of ATP analogues, focusing on thiosubstituted and fluorinated molecules, using the AAA+ ATPase p97 as a benchmark system. Hydrolysis stability and impact on protein conformation, binding modes, and kinetics of enzymatic catalysis were assessed by protein-detected methyl NMR and ligand-detected 19F NMR in solution, as well as 31P solid-state NMR of nucleotides within protein sediments. ATPγS and AMP-PNP emerged as the most suitable analogues for preserving pre-hydrolysis states over extended periods, despite undergoing gradual hydrolysis. In contrast, both AMP-PCP and α/β-thiosubstituted analogues failed to induce native protein conformations in p97. Notably, we demonstrate a novel real-time NMR setup to explore the effect of nucleotide mixtures on cooperativity and the regulation of enzymes. Additionally, aromatic fluorine TROSY-based 19F NMR shows promise for direct ligand detection in solution, even in the context of large macromolecular complexes. These findings provide critical guidance for selecting ATP analogues in functional and structural studies of nucleotide-binding proteins. Full article
(This article belongs to the Collection Feature Papers in Biophysics)
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18 pages, 1542 KiB  
Article
Pharmacogenetic Influences on Individual Responses to Ocular Hypotensive Agents in Glaucoma Patients
by Sara Labay-Tejado, Virginia Fortuna, Néstor Ventura-Abreu, Mar Hernaez, Valeria Opazo-Toro, Alba Garcia-Humanes, Mercè Brunet and Elena Milla
Pharmaceutics 2025, 17(3), 325; https://doi.org/10.3390/pharmaceutics17030325 - 2 Mar 2025
Viewed by 1134
Abstract
Background/Objectives: To analyze the genotype that predicts the phenotypic characteristics of a cohort of patients with glaucoma and ocular hypertension (OHT) and explore their influence on the response to ocular hypotensive treatment. Methods: This was a prospective study that included 193 [...] Read more.
Background/Objectives: To analyze the genotype that predicts the phenotypic characteristics of a cohort of patients with glaucoma and ocular hypertension (OHT) and explore their influence on the response to ocular hypotensive treatment. Methods: This was a prospective study that included 193 eyes of 109 patients with glaucoma or OHT under monotherapy with beta-blockers, prostaglandin, or prostamide analogues (BBs, PGAs, PDs). Eight single-nucleotide polymorphisms were genotyped using real-time PCR assays: prostaglandin-F2α receptor (PTGFR) (rs3766355, rs3753380); beta-2-adrenergic receptor (ADRB2) (rs1042714); and cytochrome P450 2D6 (CYP2D6) (*2 rs16947; *35 rs769258; *4 rs3892097; *9 rs5030656, and *41 rs28371725). The main variables studied were baseline (bIOP), treated (tIOP), and rate of variation in intraocular pressure (vIOP), and mean deviation of the visual field (MD). The metabolizer phenotype and the CYP2D6 copy number variation were also evaluated. Results: In total, 112 eyes were treated with PGAs (58.0%), 59 with BBs (30.6%), and 22 with PDs (11.4%). For PTGFR (rs3753380), statistically significant differences were observed in vIOP in the PGA group (p = 0.032). Differences were also observed for ADRB2 (rs1042714) in MD (p < 0.001) and vIOP (p = 0.017). For CYP2D6, ultrarapid metabolizers exhibited higher tIOP (p = 0.010) and lower vIOP (p = 0.046) compared to the intermediate and poor metabolizers of the BB group. Additionally, systemic treatment metabolized by CYP2D6 showed a significant influence on vIOP (p = 0.019) in this group. Conclusions: These preliminary findings suggest the future potential of pharmacogenetic-based treatments in glaucoma to achieve personalized treatment for each patient, and thus optimal clinical management. Full article
(This article belongs to the Special Issue Advances in Pharmacokinetics and Drug Interactions)
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17 pages, 4309 KiB  
Article
Metabolomics Analysis Reveals Characteristic Functional Components in Pigeon Eggs
by Rui Zhang, Lingling Chang, Xinyue Shen, Qingping Tang, Chunyu Mu, Shengyong Fu and Zhu Bu
Metabolites 2025, 15(2), 122; https://doi.org/10.3390/metabo15020122 - 12 Feb 2025
Cited by 1 | Viewed by 1135
Abstract
We aimed to identify the characteristic functional components of pigeon eggs and the differences among pigeon, chicken, and quail eggs. We analyzed the metabolite profiles of three kinds of eggs using an untargeted metabolomics-based approach to better understand the differences in metabolites among [...] Read more.
We aimed to identify the characteristic functional components of pigeon eggs and the differences among pigeon, chicken, and quail eggs. We analyzed the metabolite profiles of three kinds of eggs using an untargeted metabolomics-based approach to better understand the differences in metabolites among pigeon, chicken, and quail eggs. Then, we quantitatively validated the differences in abundance of partial metabolites through a targeted metabolomics-based approach. A total of 692 metabolites were identified in the three types of eggs. A total of 263 significantly differentially abundant metabolites were found between pigeon eggs and chicken eggs, and 263 significantly differentially abundant metabolites were found between pigeon eggs and quail eggs. The metabolites that were significantly more abundant in pigeon eggs than in other eggs were mainly lipids, lipid-like molecules, nucleosides, nucleotides, and their analogues. We identified the eight metabolites that were significantly greater in abundance in pigeon eggs than in chicken eggs and quail eggs and quantitatively validated the differences in abundance of these metabolites. Our study demonstrates that there are more functional components in pigeon eggs than chicken eggs and quail eggs, especially for the prevention and treatment of various disordered glucose and lipid metabolism-related diseases. The discovery of these differentially abundant metabolites paves the way for further research on the unique nutritional functions of pigeon eggs and the further utilization of pigeon egg products. Full article
(This article belongs to the Section Food Metabolomics)
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13 pages, 824 KiB  
Article
Assessment of Response and Safety of Bulevirtide Treatment in Patients with Chronic Delta Virus Infection: The ARISTOTLE Pilot Observational Study
by Luca Rinaldi, Mauro Viganò, Alessia Ciancio, Alfredo Caturano, Vincenzo Messina, Grazia Anna Niro, Nicolina Capoluongo, Alessandro Loglio, Letizia Marinaro, Aldo Marrone, Ernesto Claar, Maurizio Russello, Emanuela Ciracì, Umberto Vespasiani Gentilucci, Valeria Pace Palitti, Carlo Acierno, Clelia Cosentino, Andrea Mormone, Rosa Cotugno, Francesca Terracciani, Paolo Gallo, Maria Rita Cannavò, Valerio Rosato, Ferdinando Carlo Sasso, Chiara Petrucciello, Giulio Petronio Petronio, Giovanni Villone, Francesco Benanti, Giuseppe Cariti, Elisabetta Falbo, Marco Distefano, Rodolfo Sacco, Alessandro Perrella and Antonio Izziadd Show full author list remove Hide full author list
Viruses 2025, 17(2), 251; https://doi.org/10.3390/v17020251 - 12 Feb 2025
Viewed by 1693
Abstract
Introduction: Hepatitis D virus (HDV) infection remains a significant global health challenge due to its severity and high risk of progression to cirrhosis and hepatocellular carcinoma (HCC). Bulevirtide, a novel HDV entry inhibitor, has shown promise in managing chronic hepatitis D by blocking [...] Read more.
Introduction: Hepatitis D virus (HDV) infection remains a significant global health challenge due to its severity and high risk of progression to cirrhosis and hepatocellular carcinoma (HCC). Bulevirtide, a novel HDV entry inhibitor, has shown promise in managing chronic hepatitis D by blocking viral entry into hepatocytes. This study evaluated the efficacy and safety of bulevirtide in reducing HDV RNA levels and improving liver function in a real-life cohort of Italian patients with HDV infection. Methods: This multicenter prospective trial enrolled 108 consecutive patients with chronic HDV infection, from June 2023 to June 2024, who received 2 mg/day of bulevirtide in combination with a nucleoside/nucleotide analogue for hepatitis B virus (HBV) infection. Patients with any stage of liver fibrosis or compensated cirrhosis were included. Data collected included demographic and clinical characteristics, liver function tests, HDV RNA levels, and adverse events at baseline and 6 months. Results: The virological response was achieved in 54.6% of patients (n = 59), with 36 demonstrating undetectable HDV RNA levels. Among responders, ALT levels decreased significantly from 67.0 U/mL [IQR 44.0–116.3] to 31.5 U/mL [IQR 24.0–36.5, p = 0.001], and AST levels from 66.0 U/mL [IQR 46.5–91.0] to 32.5 U/mL [IQR 28.0–38.0, p = 0.021]. Median HDV RNA dropped from 29,800 IU/mL [IQR 3100–375,000] to 0 IU/mL [IQR 0–291, p < 0.001]. No significant predictors of response emerged. Mild adverse events, including pruritus (5.6%) and injection-site reactions (1.9%) and flu-like syndrome (0.9) were reported, with no treatment discontinuation. Conclusions: Bulevirtide effectively reduces HDV RNA levels and improves liver function with a favorable safety profile, offering a promising therapeutic option for chronic hepatitis D. Further large-scale studies are needed to confirm these findings and explore long-term outcomes. Full article
(This article belongs to the Collection Efficacy and Safety of Antiviral Therapy)
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27 pages, 5467 KiB  
Article
GWAS Identifies SNP Markers and Candidate Genes for Off-Flavours and Protein Content in Faba Bean (Vicia faba L.)
by Antonio Lippolis, Boudewijn Hollebrands, Valentina Acierno, Catrienus de Jong, Laurice Pouvreau, João Paulo, Salvador A. Gezan and Luisa M. Trindade
Plants 2025, 14(2), 193; https://doi.org/10.3390/plants14020193 - 11 Jan 2025
Cited by 1 | Viewed by 1816
Abstract
Faba bean (Vicia faba L.) is a valuable ingredient in plant-based foods such as meat and dairy analogues. However, its typical taste and aroma are considered off-flavours in these food applications, representing a bottleneck during processing. Breeding is needed to develop varieties [...] Read more.
Faba bean (Vicia faba L.) is a valuable ingredient in plant-based foods such as meat and dairy analogues. However, its typical taste and aroma are considered off-flavours in these food applications, representing a bottleneck during processing. Breeding is needed to develop varieties with minimal off-flavours and high protein content. The genetic regulation of these traits is underexplored. To dissect their genetic architecture, we performed a genome-wide association study (GWAS). A total of 245 faba bean accessions (the CGN population) were genotyped using the 90K-SPET targeted assay. These accessions were phenotyped in 2021 and 2022 in the Netherlands for protein, oil, fatty acids, lipid-derived products, phenolic acids, flavonoids, and tannins. The CGN population showed large phenotypic variation and moderate-to-high narrow-sense heritability for most traits. The growing environment significantly affected all traits, with trait-specific genotype-by-year (GxY) interactions. Condensed tannins and fatty acids were the most stable across the two years and had the highest heritability estimates (h2 > 0.6). GWAS identified a total of 148 single nucleotide polymorphisms (SNPs) loci in 2021 and 167 in 2022. Key candidate regulators included genes involved in lipid biosynthesis (ATS2, KAS, LPP), amino acid transport (CAT4) for protein storage, zero tannins locus-1 (zt-1), and regulators of the phenylpropanoid pathway, such as a shikimate kinase gene and transcription factors bHLH137-like and MYB. These results pave the way for validation studies and biotechnological applications to improve the quality of faba bean-based foods. Full article
(This article belongs to the Section Plant Genetics, Genomics and Biotechnology)
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14 pages, 3007 KiB  
Article
Production of Value-Added Arabinofuranosyl Nucleotide Analogues from Nucleoside by an In Vitro Enzymatic Synthetic Biosystem
by Yuxue Liu, Xiaojing Zhang, Erchu Yang, Xiaobei Liu, Weiwei Su, Zhenyu Wang and Hailei Wang
Biomolecules 2024, 14(11), 1440; https://doi.org/10.3390/biom14111440 - 13 Nov 2024
Viewed by 1318
Abstract
Arabinofuranosyl nucleotide analogue (arabinoside) and the derived compounds, a family of nucleoside analogues, exhibit diverse, typically biological activities and are widely used as antibacterial, antiviral, anti-inflammatory, and antitumor drugs in both clinical and preclinical trials. Despite their long and rich history in medicinal [...] Read more.
Arabinofuranosyl nucleotide analogue (arabinoside) and the derived compounds, a family of nucleoside analogues, exhibit diverse, typically biological activities and are widely used as antibacterial, antiviral, anti-inflammatory, and antitumor drugs in both clinical and preclinical trials. Despite their long and rich history in medicinal chemistry, the biosynthesis of arabinoside has only been sporadically designed and studied and has remained a challenging task. In this study, an in vitro synthetic enzymatic biosystem was designed and constructed for the production of arabinoside from low-cost nucleoside, based on a phosphorolysis -isomerization-dephosphorylation enzymatic cascade conversion routes. The enzymatic system achieves the biosynthesis of arabinoside by isomerizing the ribose part of nucleoside to arabinose. The reaction conditions affecting the yield of arabinoside were investigated and optimized, including meticulous enzyme selection, key enzyme dosage, the concentration of orthophosphate, and reaction time. Under the optimized conditions, we achieved the production of 0.12 mM of arabinofuranosylguanine from 0.5 mM of guanosine, representing 24% of the theoretical yield. Furthermore, this biosystem also demonstrated the capability to produce other arabinosides, such as vidarabine, spongouridine, and hypoxanthine arabinofuranoside from corresponding nucleosides. Overall, our biosynthesis approach provides a pathway for the biosynthesis of arabinoside. Full article
(This article belongs to the Section Synthetic Biology and Bioengineering)
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16 pages, 3210 KiB  
Article
Widely Targeted Metabolomics Method Reveals Differences in Volatile and Nonvolatile Metabolites in Three Different Varieties of Raw Peanut by GC–MS and HPLC–MS
by Jiantao Fu, Yuxing An, Dao Yao, Lijun Chen, Liwen Zhou, Dachun Shen, Sixing Dai, Yinglin Lu and Donglei Sun
Molecules 2024, 29(22), 5230; https://doi.org/10.3390/molecules29225230 - 5 Nov 2024
Viewed by 1297
Abstract
The aim of the present study was to comprehensively analyze and identify the metabolites of different varieties of raw peanut, as well as provide a reference for the utilization of different varieties of peanuts. In this study, three varieties of peanuts, namely ZKH1H, [...] Read more.
The aim of the present study was to comprehensively analyze and identify the metabolites of different varieties of raw peanut, as well as provide a reference for the utilization of different varieties of peanuts. In this study, three varieties of peanuts, namely ZKH1H, ZKH13H, and CFD, were investigated via ultrahigh-performance liquid chromatography (UPLC) and widely targeted metabolomics methods based on tandem mass spectrometry (MS) and solid-phase microextraction-gas chromatography–mass spectrometry (SPME-GC–MS). In total, 417 nonvolatile and 55 volatile substances were detected. The nonvolatile substances were classified into the following 10 categories: organic acids and derivatives (28.9%); organic oxygen compounds (21.9%); lipids and lipid-like molecules (12.6%); organoheterocyclic compounds (9.9%); nucleosides, nucleotides, and analogues (9.4%); benzenoids (7.8%); phenylpropanoids and polyketides (6.1%); organic nitrogen compounds (2.7%); lignans, neolignans, and related compounds (0.5%); and alkaloids and their derivatives (0.3%). The volatile compounds (VOCs) were classified into the following eight categories: organic oxygen compounds (24.1%); organic cyclic compounds (20.4%); organic nitrogen compounds (13%); organic acids and their derivatives (13%); lipids and lipid-like molecules (11.2%); benzenoids (11.1%); hydrocarbons (3.7%); and homogeneous non-metallic compounds (3.7%). Differentially abundant metabolites among the different peanut varieties (ZKH13H vs. CFD, ZKH1H vs. CFD, and ZKH1H vs. ZKH13H) were investigated via multivariate statistical analyses, which identified 213, 204, and 157 nonvolatile differentially abundant metabolites, respectively, and 12, 11, and 10 volatile differentially abundant metabolites, respectively. KEGG metabolic pathway analyses of the differential non-VOCs revealed that the most significant metabolic pathways among ZKH13H vs. CFD, ZKH1H vs. CFD, and ZKH1H vs. ZKH13H were galactose metabolism, purine metabolism, and aminoacyl-tRNA, while the nitrogen metabolism pathway was identified as a significant metabolic pathway for the VOCs. The present findings provide a theoretical foundation for the development and utilization of these three peanut species, as well as for the breeding of new peanut varieties. Full article
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18 pages, 3269 KiB  
Article
Exploring the Mutated Kinases for Chemoenzymatic Synthesis of N4-Modified Cytidine Monophosphates
by Martyna Koplūnaitė, Kamilė Butkutė, Jonita Stankevičiūtė and Rolandas Meškys
Molecules 2024, 29(16), 3767; https://doi.org/10.3390/molecules29163767 - 9 Aug 2024
Viewed by 1353
Abstract
Nucleosides, nucleotides, and their analogues are an important class of molecules that are used as substrates in research of enzymes and nucleic acid, or as antiviral and antineoplastic agents. Nucleoside phosphorylation is usually achieved with chemical methods; however, enzymatic phosphorylation is a viable [...] Read more.
Nucleosides, nucleotides, and their analogues are an important class of molecules that are used as substrates in research of enzymes and nucleic acid, or as antiviral and antineoplastic agents. Nucleoside phosphorylation is usually achieved with chemical methods; however, enzymatic phosphorylation is a viable alternative. Here, we present a chemoenzymatic synthesis of modified cytidine monophosphates, where a chemical synthesis of novel N4-modified cytidines is followed by an enzymatic phosphorylation of the nucleosides by nucleoside kinases. To enlarge the substrate scope, multiple mutant variants of Drosophila melanogaster deoxynucleoside kinase (DmdNK) (EC:2.7.1.145) and Bacillus subtilis deoxycytidine kinase (BsdCK) (EC:2.7.1.74) have been created and tested. It has been determined that certain point mutations in the active sites of the kinases alter their substrate specificities noticeably and allow phosphorylation of compounds that had been otherwise not phosphorylated by the wild-type DmdNK or BsdCK. Full article
(This article belongs to the Special Issue Exploring Bioactive Organic Compounds for Drug Discovery, 2nd Edition)
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14 pages, 2788 KiB  
Article
The Synergistic Effect of N2 and N7 Modifications on the Inhibitory Efficacy of mRNA Cap Analogues
by Karol Kurpiejewski, Karolina Piecyk, Maciej Lukaszewicz, Karol Kamel, Kazimierz Chmurski, Sebastian Kmiecik and Marzena Jankowska-Anyszka
Pharmaceuticals 2024, 17(5), 632; https://doi.org/10.3390/ph17050632 - 14 May 2024
Cited by 3 | Viewed by 2142
Abstract
In the fight against cancer, researchers have turned their attention to the eukaryotic initiation factor eIF4E, a protein whose increased level is strongly correlated with the development and progression of various types of cancer. Among the numerous strategies devised to tackle eIF4E overexpression, [...] Read more.
In the fight against cancer, researchers have turned their attention to the eukaryotic initiation factor eIF4E, a protein whose increased level is strongly correlated with the development and progression of various types of cancer. Among the numerous strategies devised to tackle eIF4E overexpression, the use of 5′ end mRNA cap analogues has emerged as a promising approach. Here, we present new candidates as potent m7GMP analogues for inhibiting translation and interfacing with eIF4E. By employing an appropriate strategy, we synthesized doubly modified mono- and dinucleotide cap analogues, introducing simultaneous substituents at both the N7 and N2 positions of the guanine ring. This approach was identified as an effective and promising combination. Our findings reveal that these dual modifications increase the potency of the dinucleotide analogue, marking a significant advancement in the development of cancer therapeutics targeting the eIF4E pathway. Full article
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12 pages, 704 KiB  
Article
Reduced Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Receiving Long-Term Besifovir Therapy
by Hyung Joon Yim, Seong Hee Kang, Young Kul Jung, Sang Hoon Ahn, Won Kim, Jin Mo Yang, Jae Young Jang, Yong Oh Kweon, Yong Kyun Cho, Yoon Jun Kim, Gun Young Hong, Dong Joon Kim, Joo Hyun Sohn, Jin Woo Lee, Sung Jae Park, Sun Young Yim, Jin Kyung Park and Soon Ho Um
Cancers 2024, 16(5), 887; https://doi.org/10.3390/cancers16050887 - 22 Feb 2024
Cited by 2 | Viewed by 2056
Abstract
No information is available regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study evaluated the reduced risk of HCC in patients undergoing BSV treatment. A total [...] Read more.
No information is available regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study evaluated the reduced risk of HCC in patients undergoing BSV treatment. A total of 188 patients with CHB were treated with BSV for up to 8 years. We prospectively assessed the incidence of HCC compared with the risk from prediction models. During the follow-up, 5 patients developed HCC: 1 of 139 patients with non-cirrhotic CHB, and 4 of 49 patients with liver cirrhosis. We compared the HCC incidence in non-cirrhotic and cirrhotic patients with the predicted number derived from the REACH-B (risk estimation for HCC in CHB) model and GAG-HCC (guide with age, gender, HBV DNA, core promotor mutation, and cirrhosis) model, respectively. The standardized incidence ratio (SIR) was 0.128 (p = 0.039) at 7 years in non-cirrhotic CHB patients, and the SIR was 0.371 (p = 0.047) at 7.5 years in cirrhotic patients, suggesting a significantly decreased HCC incidence in both groups. HCC prediction was available for BSV-treated patients using existing models. In conclusion, BSV decreased the risk of HCC in patients with CHB, and prediction models were applicable. Clinical trial registry website and trial number: ClinicalTrials.gov no: NCT01937806. Full article
(This article belongs to the Section Cancer Epidemiology and Prevention)
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