Biomolecules

24 pages, 1214 KiB

Open AccessArticle

Identification of Potential New Genes Related to the SREBP Pathway in Xanthophyllomyces dendrorhous

by Maximiliano Venegas, Alejandro Durán, Sebastián Campusano, Salvador Barahona, Dionisia Sepúlveda, Marcelo Baeza, Víctor Cifuentes and Jennifer Alcaíno

Biomolecules 2024, 14(7), 778; https://doi.org/10.3390/biom14070778 (registering DOI) - 29 Jun 2024

Abstract

The sterol regulatory element-binding protein (SREBP) pathway is an integral cellular mechanism that regulates lipid homeostasis, in which transcriptional activator SREBPs regulate the expression of various genes. In the carotenogenic yeast Xanthophyllomyces dendrorhous, Sre1 (the yeast SREBP homolog) regulates lipid biosynthesis and [...] Read more.

The sterol regulatory element-binding protein (SREBP) pathway is an integral cellular mechanism that regulates lipid homeostasis, in which transcriptional activator SREBPs regulate the expression of various genes. In the carotenogenic yeast Xanthophyllomyces dendrorhous, Sre1 (the yeast SREBP homolog) regulates lipid biosynthesis and carotenogenesis, among other processes. Despite the characterization of several components of the SREBP pathway across various eukaryotes, the specific elements of this pathway in X. dendrorhous remain largely unknown. This study aimed to explore the potential regulatory mechanisms of the SREBP pathway in X. dendrorhous using the strain CBS.cyp61^- as a model, which is known to have Sre1 in its active state under standard culture conditions, resulting in a carotenoid-overproducing phenotype. This strain was subjected to random mutagenesis with N-methyl-N’-nitro-N-nitrosoguanidine (NTG), followed by a screening methodology that focused on identifying mutants with altered Sre1 activation phenotypes. Single-nucleotide polymorphism (SNP) analysis of 20 selected mutants detected 5439 single-nucleotide variants (SNVs), narrowing them down to 1327 SNPs of interest after a series of filters. Classification based on SNP impact identified 116 candidate genes, including 49 genes with high impact and 68 genes with deleterious moderate-impact mutations. BLAST, InterProScan, and gene ontology enrichment analyses highlighted 25 genes as potential participants in regulating Sre1 in X. dendrorhous. The key findings of this study include the identification of genes potentially encoding proteins involved in protein import/export to the nucleus, sterol biosynthesis, the ubiquitin–proteasome system, protein regulatory activities such as deacetylases, a subset of kinases and proteases, as well as transcription factors that could be influential in SREBP regulation. These findings are expected to significantly contribute to the current understanding of the intricate regulation of the transcription factor Sre1 in X. dendrorhous, providing valuable groundwork for future research and potential biotechnological applications. Full article

(This article belongs to the Special Issue Sterol Biosynthesis and Function in Organisms)

20 pages, 2006 KiB

Open AccessArticle

Skin Rejuvenation Efficacy and Safety Evaluation of Kaempferia parviflora Standardized Extract (BG100) in Human 3D Skin Models and Clinical Trial

by Wannita Klinngam, Phetploy Rungkamoltip, Ratjika Wongwanakul, Jaruwan Joothamongkhon, Sakkarin Du-a-man, Mattaka Khongkow, Udom Asawapirom, Tawin Iempridee and Uracha Ruktanonchai

Biomolecules 2024, 14(7), 776; https://doi.org/10.3390/biom14070776 (registering DOI) - 29 Jun 2024

Abstract

Polymethoxyflavones from Kaempferia parviflora rhizomes have been shown to effectively combat aging in skin cells and tissues by inhibiting senescence, reducing oxidative stress, and enhancing skin structure and function. This study assessed the anti-aging effects and safety of standardized K. parviflora extract (BG100), [...] Read more.

Polymethoxyflavones from Kaempferia parviflora rhizomes have been shown to effectively combat aging in skin cells and tissues by inhibiting senescence, reducing oxidative stress, and enhancing skin structure and function. This study assessed the anti-aging effects and safety of standardized K. parviflora extract (BG100), enriched with polymethoxyflavones including 5,7-dimethoxyflavone, 5,7,4’-trimethoxyflavone, 3,5,7,3’,4’-pentamethoxyflavone, 3,5,7-trimethoxyflavone, and 3,5,7,4ʹ-tetramethoxyflavone. We evaluated BG100’s impact on skin rejuvenation and antioxidant properties using photoaged human 3D full-thickness skin models. The potential for skin irritation and sensitization was also assessed through studies on reconstructed human epidermis and clinical trials. Additionally, in vitro genotoxicity testing was performed following OECD guidelines. Results indicate that BG100 promotes collagen and hyaluronic acid production, reduces oxidative stress, and minimizes DNA damage in photoaged full-thickness 3D skin models. Furthermore, it exhibited non-irritating and non-sensitizing properties, as supported by tests on reconstructed human epidermis and clinical settings. BG100 also passed in vitro genotoxicity tests, adhering to OECD guidelines. These results underscore BG100′s potential as a highly effective and safe, natural anti-aging agent, suitable for inclusion in cosmeceutical and nutraceutical products aimed at promoting skin rejuvenation. Full article

(This article belongs to the Section Natural and Bio-inspired Molecules)

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32 pages, 14477 KiB

Open AccessArticle

De Novo Design of Inhibitors of DNA Methyltransferase 1: A Critical Comparison of Ligand- and Structure-Based Approaches

by Diana L. Prado-Romero, Fernanda I. Saldívar-González, Iván López-Mata, Pedro A. Laurel-García, Adrián Durán-Vargas, Enrique García-Hernández, Norberto Sánchez-Cruz and José L. Medina-Franco

Biomolecules 2024, 14(7), 775; https://doi.org/10.3390/biom14070775 (registering DOI) - 28 Jun 2024

Abstract

Designing and developing inhibitors against the epigenetic target DNA methyltransferase (DNMT) is an attractive strategy in epigenetic drug discovery. DNMT1 is one of the epigenetic enzymes with significant clinical relevance. Structure-based de novo design is a drug discovery strategy that was used in [...] Read more.

Designing and developing inhibitors against the epigenetic target DNA methyltransferase (DNMT) is an attractive strategy in epigenetic drug discovery. DNMT1 is one of the epigenetic enzymes with significant clinical relevance. Structure-based de novo design is a drug discovery strategy that was used in combination with similarity searching to identify a novel DNMT inhibitor with a novel chemical scaffold and warrants further exploration. This study aimed to continue exploring the potential of de novo design to build epigenetic-focused libraries targeted toward DNMT1. Herein, we report the results of an in-depth and critical comparison of ligand- and structure-based de novo design of screening libraries focused on DNMT1. The newly designed chemical libraries focused on DNMT1 are freely available on GitHub. Full article

(This article belongs to the Special Issue Chemoinformatics and Molecular Modeling of Pharmacologically Active Biomolecules: A Themed Issue in Honor of Prof. José L. Medina-Franco)

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21 pages, 7608 KiB

Open AccessArticle

Oligomer Formation by Physiologically Relevant C-Terminal Isoforms of Amyloid β-Protein

by Rachit Pandey and Brigita Urbanc

Biomolecules 2024, 14(7), 774; https://doi.org/10.3390/biom14070774 (registering DOI) - 28 Jun 2024

Abstract

Alzheimer’s disease (AD) is a neurological disorder associated with amyloid

β

-protein (A

β

) assembly into toxic oligomers. In addition to the two predominant alloforms, A

β_{1 - 40}

and A

β_{1 - 42}

, other C-terminally truncated A

β

[...] Read more.

Alzheimer’s disease (AD) is a neurological disorder associated with amyloid

β

-protein (A

β

) assembly into toxic oligomers. In addition to the two predominant alloforms, A

β_{1 - 40}

and A

β_{1 - 42}

, other C-terminally truncated A

β

peptides, including A

β_{1 - 38}

and A

β_{1 - 43}

, are produced in the brain. Here, we use discrete molecular dynamics (DMD) and a four-bead protein model with amino acid-specific hydropathic interactions, DMD4B-HYDRA, to examine oligomer formation of A

β_{1 - 38}

, A

β_{1 - 40}

, A

β_{1 - 42}

, and A

β_{1 - 43}

. Self-assembly of 32 unstructured monomer peptides into oligomers is examined using 32 replica DMD trajectories for each of the four peptides. In a quasi-steady state, A

β_{1 - 38}

and A

β_{1 - 40}

adopt similar unimodal oligomer size distributions with a maximum at trimers, whereas A

β_{1 - 42}

and A

β_{1 - 43}

oligomer size distributions are multimodal with the dominant maximum at trimers or tetramers, and additional maxima at hexamers and unidecamers (for A

β_{1 - 42}

) or octamers and pentadecamers (for A

β_{1 - 43}

). The free energy landscapes reveal isoform- and oligomer-order specific structural and morphological features of oligomer ensembles. Our results show that oligomers of each of the four isoforms have unique features, with A

β_{1 - 42}

alone resulting in oligomers with disordered and solvent-exposed N-termini. Our findings help unravel the structure–function paradigm governing oligomers formed by various A

β

isoforms. Full article

(This article belongs to the Special Issue New Insights into Protein Aggregation in Condensed and Amyloid States)

16 pages, 1770 KiB

Open AccessReview

Zinc, Copper, and Calcium: A Triangle in the Synapse for the Pathogenesis of Vascular-Type Senile Dementia

by Masahiro Kawahara, Ken-ichiro Tanaka and Midori Kato-Negishi

Biomolecules 2024, 14(7), 773; https://doi.org/10.3390/biom14070773 (registering DOI) - 28 Jun 2024

Viewed by 8

Abstract

Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, [...] Read more.

Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, in pathological conditions such as transient global ischemia, excess Zn is secreted to synaptic clefts, which causes neuronal death and can eventually trigger the pathogenesis of a vascular type of senile dementia. We have previously investigated the characteristics of Zn-induced neurotoxicity and have demonstrated that low concentrations of Cu can exacerbate Zn neurotoxicity. Furthermore, during our pharmacological approaches to clarify the molecular pathways of Cu-enhanced Zn-induced neurotoxicity, we have revealed the involvement of Ca homeostasis disruption. In the present review, we discuss the roles of Zn and Cu in the synapse, as well as the crosstalk between Zn, Cu, and Ca, which our study along with other recent studies suggest may underlie the pathogenesis of vascular-type senile dementia. Full article

(This article belongs to the Special Issue Zinc in Health and Disease Conditions II)

18 pages, 1663 KiB

Open AccessArticle

Helicobacter pylori-Induced Decrease in Membrane Expression of Na,K-ATPase Leads to Gastric Injury

by Olga Vagin, Elmira Tokhtaeva, Muriel Larauche, Joshua Davood and Elizabeth A. Marcus

Biomolecules 2024, 14(7), 772; https://doi.org/10.3390/biom14070772 (registering DOI) - 28 Jun 2024

Viewed by 14

Abstract

Helicobacter pylori is a highly prevalent human gastric pathogen that causes gastritis, ulcer disease, and gastric cancer. It is not yet fully understood how H. pylori injures the gastric epithelium. The Na,K-ATPase, an essential transporter found in virtually all mammalian cells, has been [...] Read more.

Helicobacter pylori is a highly prevalent human gastric pathogen that causes gastritis, ulcer disease, and gastric cancer. It is not yet fully understood how H. pylori injures the gastric epithelium. The Na,K-ATPase, an essential transporter found in virtually all mammalian cells, has been shown to be important for maintaining the barrier function of lung and kidney epithelia. H. pylori decreases levels of Na,K-ATPase in the plasma membrane of gastric epithelial cells, and the aim of this study was to demonstrate that this reduction led to gastric injury by impairing the epithelial barrier. Similar to H. pylori infection, the inhibition of Na,K-ATPase with ouabain decreased transepithelial electrical resistance and increased paracellular permeability in cell monolayers of human gastric cultured cells, 2D human gastric organoids, and gastric epithelium isolated from gerbils. Similar effects were caused by a partial shRNA silencing of Na,K-ATPase in human gastric organoids. Both H. pylori infection and ouabain exposure disrupted organization of adherens junctions in human gastric epithelia as demonstrated by E-cadherin immunofluorescence. Functional and structural impairment of epithelial integrity with a decrease in Na,K-ATPase amount or activity provides evidence that the H. pylori-induced downregulation of Na,K-ATPase plays a role in the complex mechanism of gastric disease induced by the bacteria. Full article

(This article belongs to the Special Issue The Role of P-type ATPases in Health and Diseases)

26 pages, 1671 KiB

Open AccessArticle

Functional Characterization of the Lysosomal Peptide/Histidine Transporter PHT1 (SLC15A4) by Solid Supported Membrane Electrophysiology (SSME)

by Jonai Pujol-Giménez, Sven P. Baumann, Tin Manh Ho, Bartlomiej Augustynek and Matthias A. Hediger

Biomolecules 2024, 14(7), 771; https://doi.org/10.3390/biom14070771 (registering DOI) - 28 Jun 2024

Viewed by 106

Abstract

The peptide/histidine transporter PHT1 (SLC15A4) is expressed in the lysosomal membranes of immune cells where it plays an important role in metabolic and inflammatory signaling. PHT1 is an H⁺-coupled/histidine symporter that can transport a wide range of oligopeptides, including [...] Read more.

The peptide/histidine transporter PHT1 (SLC15A4) is expressed in the lysosomal membranes of immune cells where it plays an important role in metabolic and inflammatory signaling. PHT1 is an H⁺-coupled/histidine symporter that can transport a wide range of oligopeptides, including a variety of bacterial-derived peptides. Moreover, it enables the scaffolding of various metabolic signaling molecules and interacts with key regulatory elements of the immune response. Not surprisingly, PHT1 has been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Unfortunately, the pharmacological development of PHT1 modulators has been hampered by the lack of suitable transport assays. To address this shortcoming, a novel transport assay based on solid-supported membrane-based electrophysiology (SSME) is presented. Key findings of the present SSME studies include the first recordings of electrophysiological properties, a pH dependence analysis, an assessment of PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates. In contrast to previous work, PHT1 is studied in its native lysosomal environment. Moreover, observed substrate selectivity is validated by molecular docking. Overall, this new SSME-based assay is expected to contribute to unlocking the pharmacological potential of PHT1 and to deepen the understanding of its functional properties. Full article

(This article belongs to the Section Cellular Biochemistry)

16 pages, 850 KiB

Open AccessReview

The Sweet Relationship between the Endometrium and Protein Glycosylation

by Linyu Zhang, Ying Feng, Yue Zhang, Xinrui Sun, Qianhong Ma and Fang Ma

Biomolecules 2024, 14(7), 770; https://doi.org/10.3390/biom14070770 - 27 Jun 2024

Viewed by 212

Abstract

The endometrium is an important part of women’s bodies for menstruation and pregnancy. Various proteins are widely expressed on the surface of endometrial cells, and glycosylation is an important post-translational modification of proteins. Glycosylation modification is closely related not only to endometrial receptivity [...] Read more.

The endometrium is an important part of women’s bodies for menstruation and pregnancy. Various proteins are widely expressed on the surface of endometrial cells, and glycosylation is an important post-translational modification of proteins. Glycosylation modification is closely related not only to endometrial receptivity but also to common diseases related to endometrial receptivity. Glycosylation can improve endometrial receptivity, promote embryo localization and trophoblast cell adhesion and invasion, and contribute to successful implantation. Two diseases related to endometrial receptivity include endometriosis and endometrial cancer. As a common benign disease in women, endometriosis is often accompanied by an increased menstrual volume, prolonged menstrual periods, progressive and aggravated dysmenorrhea, and may be accompanied by infertility. Protein glycosylation modification of the endometrial surface indicates the severity of the disease and may be an important pathogenesis of endometriosis. In cancer, glycosylation modifications on the surface of tumor cells can be a marker to distinguish the type and severity of endometrial cancer. This review highlights the role of protein glycosylation in embryo–maternal endometrial dialogue and explores its potential mechanisms in diseases related to endometrial receptivity, which could provide a new clinical approach for their diagnosis and treatment. Full article

(This article belongs to the Collection Feature Papers in Molecular Reproduction)

16 pages, 2180 KiB

Open AccessArticle

Phloridzin Docosahexaenoate, an Omega-3 Fatty Acid Ester of a Flavonoid Precursor, Inhibits Angiogenesis by Suppressing Endothelial Cell Proliferation, Migration, and Differentiation

by Wasundara Fernando, Emma MacLean, Susan Monro, Melanie R. Power Coombs, Paola Marcato, H. P. Vasantha Rupasinghe and David W. Hoskin

Biomolecules 2024, 14(7), 769; https://doi.org/10.3390/biom14070769 - 27 Jun 2024

Viewed by 192

Abstract

Angiogenesis is a normal physiological process that also contributes to diabetic retinopathy-related complications and facilitates tumor metastasis by promoting the hematogenic dissemination of malignant cells from solid tumors. Here, we investigated the in vitro, ex vivo, and in vivo anti-angiogenic activity of phloridzin [...] Read more.

Angiogenesis is a normal physiological process that also contributes to diabetic retinopathy-related complications and facilitates tumor metastasis by promoting the hematogenic dissemination of malignant cells from solid tumors. Here, we investigated the in vitro, ex vivo, and in vivo anti-angiogenic activity of phloridzin docosahexaenoate (PZ-DHA), a novel ω-3 fatty acid ester of a flavonoid precursor. Human umbilical vein endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) treated with a sub-cytotoxic concentration of PZ-DHA to assess in vitro anti-angiogenic activity showed impaired tubule formation on a Matrigel matrix. Ex vivo angiogenesis was measured using rat thoracic aortas, which exhibited reduced vessel sprouting and tubule formation in the presence of PZ-DHA. Female BALB/c mice bearing VEGF₁₆₅- and basic fibroblast growth factor-containing Matrigel plugs showed a significant reduction in blood vessel development following PZ-DHA treatment. PZ-DHA inhibited HUVEC and HMVEC proliferation, as well as the migration of HUVECs in gap closure and trans-well cell migration assays. PZ-DHA inhibited upstream and downstream components of the Akt pathway and vascular endothelial growth factor (VEGF₁₆₅)-induced overexpression of small molecular Rho GTPases in HUVECs, suggesting a decrease in actin cytoskeletal-mediated stress fiber formation and migration. Taken together, these findings reveal the potential of combined food biomolecules in PZ-DHA to inhibit angiogenesis. Full article

(This article belongs to the Special Issue The Value of Natural Compounds as Therapeutic Agents)

20 pages, 640 KiB

Open AccessArticle

Concentrations of Glypican-4, Irisin and Total Antioxidant Status in Women with Metabolic Syndrome: Influence of Physical Activity

by Teresa Grzelak, Marcelina Sperling, Marta Pelczyńska, Aniceta Ada Mikulska-Sauermann, Paweł Bogdański, Krystyna Czyżewska and Edyta Mądry

Biomolecules 2024, 14(7), 768; https://doi.org/10.3390/biom14070768 - 27 Jun 2024

Viewed by 180

Abstract

Glypican-4 belongs to a group of poorly understood adipokines, with potential importance in people with metabolic syndrome, especially in groups of patients with glucose metabolism disorder. This study aimed to assess the effect of physical activity on serum glypican-4 and irisin levels and [...] Read more.

Glypican-4 belongs to a group of poorly understood adipokines, with potential importance in people with metabolic syndrome, especially in groups of patients with glucose metabolism disorder. This study aimed to assess the effect of physical activity on serum glypican-4 and irisin levels and total antioxidant status (TAS) in plasma and saliva in women with metabolic syndrome (MetS). Seventy-two Caucasian women aged 25–60 were included in the study (36 women with MetS and 36 women without MetS (control group, CONTR)). The glypican-4 and irisin concentrations, total antioxidant status, glycemia, lipid profile, anthropometric parameters, and blood pressure were analyzed before and after 28 days of controlled physical activity. Serum glypican-4 and plasma TAS levels were higher (p = 0.006 and p = 0.043, respectively) on the 28th day than on the first day of the study only in the CONTR group. In the MetS group, 28 days of physical activity caused a reduction in body fat mass (p = 0.049) without changes in glypican-4, irisin, or TAS levels. In both groups, glypican-4 levels correlated positively with irisin levels and negatively with Waist-Hip Ratio (WHR), while irisin levels correlated positively with High-Density Lipoprotein Cholesterol (HDL-C) levels and negatively with waist circumference (WC) and WHR values on the 28th day of the study. To summarize, a 28-day moderate training, accompanied by a reduction in body fat mass, stabilized glypican-4 levels and TAS in female patients with MetS. Full article

(This article belongs to the Special Issue Advances in Cardiometabolic Health)

12 pages, 1307 KiB

Open AccessArticle

mRCat: A Novel CatBoost Predictor for the Binary Classification of mRNA Subcellular Localization by Fusing Large Language Model Representation and Sequence Features

by Xiao Wang, Lixiang Yang and Rong Wang

Biomolecules 2024, 14(7), 767; https://doi.org/10.3390/biom14070767 - 27 Jun 2024

Viewed by 230

Abstract

The subcellular localization of messenger RNAs (mRNAs) is a pivotal aspect of biomolecules, tightly linked to gene regulation and protein synthesis, and offers innovative insights into disease diagnosis and drug development in the field of biomedicine. Several computational methods have been proposed to [...] Read more.

The subcellular localization of messenger RNAs (mRNAs) is a pivotal aspect of biomolecules, tightly linked to gene regulation and protein synthesis, and offers innovative insights into disease diagnosis and drug development in the field of biomedicine. Several computational methods have been proposed to predict the subcellular localization of mRNAs within cells. However, there remains a deficiency in the accuracy of these predictions. In this study, we propose an mRCat predictor based on the gradient boosting tree algorithm specifically to predict whether mRNAs are localized in the nucleus or in the cytoplasm. This predictor firstly uses large language models to thoroughly explore hidden information within sequences and then integrates traditional sequence features to collectively characterize mRNA gene sequences. Finally, it employs CatBoost as the base classifier for predicting the subcellular localization of mRNAs. The experimental validation on an independent test set demonstrates that mRCat obtained accuracy of 0.761, F1 score of 0.710, MCC of 0.511, and AUROC of 0.751. The results indicate that our method has higher accuracy and robustness compared to other state-of-the-art methods. It is anticipated to offer deep insights for biomolecular research. Full article

(This article belongs to the Special Issue Artificial Intelligence (AI) in Biomedicine)

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18 pages, 1492 KiB

Open AccessArticle

DeepIMAGER: Deeply Analyzing Gene Regulatory Networks from scRNA-seq Data

by Xiguo Zhou, Jingyi Pan, Liang Chen, Shaoqiang Zhang and Yong Chen

Biomolecules 2024, 14(7), 766; https://doi.org/10.3390/biom14070766 - 27 Jun 2024

Viewed by 180

Abstract

Understanding the dynamics of gene regulatory networks (GRNs) across diverse cell types poses a challenge yet holds immense value in unraveling the molecular mechanisms governing cellular processes. Current computational methods, which rely solely on expression changes from bulk RNA-seq and/or scRNA-seq data, often [...] Read more.

Understanding the dynamics of gene regulatory networks (GRNs) across diverse cell types poses a challenge yet holds immense value in unraveling the molecular mechanisms governing cellular processes. Current computational methods, which rely solely on expression changes from bulk RNA-seq and/or scRNA-seq data, often result in high rates of false positives and low precision. Here, we introduce an advanced computational tool, DeepIMAGER, for inferring cell-specific GRNs through deep learning and data integration. DeepIMAGER employs a supervised approach that transforms the co-expression patterns of gene pairs into image-like representations and leverages transcription factor (TF) binding information for model training. It is trained using comprehensive datasets that encompass scRNA-seq profiles and ChIP-seq data, capturing TF-gene pair information across various cell types. Comprehensive validations on six cell lines show DeepIMAGER exhibits superior performance in ten popular GRN inference tools and has remarkable robustness against dropout-zero events. DeepIMAGER was applied to scRNA-seq datasets of multiple myeloma (MM) and detected potential GRNs for TFs of RORC, MITF, and FOXD2 in MM dendritic cells. This technical innovation, combined with its capability to accurately decode GRNs from scRNA-seq, establishes DeepIMAGER as a valuable tool for unraveling complex regulatory networks in various cell types. Full article

22 pages, 2918 KiB

Open AccessArticle

Biochemical and Functional Profiling of Thioredoxin-Dependent Cytosolic GPX-like Proteins in Euglena gracilis

by Md Topu Raihan and Takahiro Ishikawa

Biomolecules 2024, 14(7), 765; https://doi.org/10.3390/biom14070765 - 27 Jun 2024

Viewed by 194

Abstract

Unlike plants and animals, the phytoflagellate Euglena gracilis lacks catalase and contains a non-selenocysteine glutathione peroxidase-like protein (EgGPXL), two peroxiredoxins (EgPrx1 and EgPrx4), and one ascorbate peroxidase in the cytosol to maintain reactive oxygen species (ROS) homeostasis. In the present study, the full-length [...] Read more.

Unlike plants and animals, the phytoflagellate Euglena gracilis lacks catalase and contains a non-selenocysteine glutathione peroxidase-like protein (EgGPXL), two peroxiredoxins (EgPrx1 and EgPrx4), and one ascorbate peroxidase in the cytosol to maintain reactive oxygen species (ROS) homeostasis. In the present study, the full-length cDNA of three cytosolic EgGPXLs was obtained and further characterized biochemically and functionally. These EgGPXLs used thioredoxin instead of glutathione as an electron donor to reduce the levels of H₂O₂ and t-BOOH. The specific peroxidase activities of these enzymes for H₂O₂ and t-BOOH were 1.3 to 4.9 and 0.79 to 3.5 µmol/min/mg protein, respectively. Cytosolic EgGPXLs and EgPrx1/EgPrx4 were silenced simultaneously to investigate the synergistic effects of these genes on the physiological function of E. gracilis. The suppression of cytosolic EgGPXL genes was unable to induce any critical phenomena in Euglena under normal (100 μmol photons m⁻² s⁻¹) and high-light conditions (350 μmol photons m⁻² s⁻¹) at both autotrophic and heterotrophic states. Unexpectedly, the suppression of EgGPXL genes was able to rescue the EgPrx1/EgPrx4-silenced cell line from a critical situation. This study explored the potential resilience of Euglena to ROS, even with restriction of the cytosolic antioxidant system, indicating the involvement of some compensatory mechanisms. Full article

(This article belongs to the Section Enzymology)

18 pages, 6202 KiB

Open AccessArticle

The Evaluation of Drugs as Potential Modulators of the Trafficking and Maturation of ACE2, the SARS-CoV-2 Receptor

by Nesreen F. Alkhofash and Bassam R. Ali

Biomolecules 2024, 14(7), 764; https://doi.org/10.3390/biom14070764 - 27 Jun 2024

Viewed by 242

Abstract

ACE2, part of the angiotensin-converting enzyme family and the renin–angiotensin–aldosterone system (RAAS), plays vital roles in cardiovascular and renal functions. It is also the primary receptor for SARS-CoV-2, enabling its entry into cells. This project aimed to study ACE2’s cellular trafficking and maturation [...] Read more.

ACE2, part of the angiotensin-converting enzyme family and the renin–angiotensin–aldosterone system (RAAS), plays vital roles in cardiovascular and renal functions. It is also the primary receptor for SARS-CoV-2, enabling its entry into cells. This project aimed to study ACE2’s cellular trafficking and maturation to the cell surface and assess the impact of various drugs and compounds on these processes. We used cellular and biochemical analyses to evaluate these compounds as potential leads for COVID-19 therapeutics. Our screening assay focused on ACE2 maturation levels and subcellular localization with and without drug treatments. Results showed that ACE2 maturation is generally fast and robust, with certain drugs having a mild impact. Out of twenty-three tested compounds, eight significantly reduced ACE2 maturation levels, and three caused approximately 20% decreases. Screening trafficking inhibitors revealed significant effects from most molecular modulators of protein trafficking, mild effects from most proposed COVID-19 drugs, and no effects from statins. This study noted that manipulating ACE2 levels could be beneficial or harmful, depending on the context. Thus, using this approach to uncover leads for COVID-19 therapeutics requires a thorough understanding ACE2’s biogenesis and biology. Full article

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21 pages, 2122 KiB

Open AccessArticle

Effect of Health Status and Heat-Induced Inactivation on the Proteomic Profile of Plasma Rich in Growth Factors Obtained from Donors with Chronic Inflammatory Skin Conditions

by Eduardo Anitua, Roberto Tierno, Mikel Azkargorta, Félix Elortza and Mohammad H. Alkhraisat

Biomolecules 2024, 14(7), 763; https://doi.org/10.3390/biom14070763 - 26 Jun 2024

Viewed by 189

Abstract

Atopic dermatitis, psoriasis and lichen sclerosus are among the most challenging conditions treated by dermatologists worldwide, with potentially significant physical, social and psychological impacts. Emerging evidence suggests that autologous-platelet-rich plasma could be used to manage skin inflammation. However, the presence of soluble autoimmune [...] Read more.

Atopic dermatitis, psoriasis and lichen sclerosus are among the most challenging conditions treated by dermatologists worldwide, with potentially significant physical, social and psychological impacts. Emerging evidence suggests that autologous-platelet-rich plasma could be used to manage skin inflammation. However, the presence of soluble autoimmune components could hinder their therapeutic potential. The aim of this study was to analyze the proteomic profile of plasma rich in growth factors (PRGFs) obtained from donors with inflammatory skin conditions to evaluate the impact of skin health status on the composition and bioactivity of PRGF-based treatments. Venous blood from healthy volunteers and patients with psoriasis, lichen sclerosus and atopic dermatitis was processed to produce PRGF supernatant. Half of the samples were subjected to an additional thermal treatment (56 °C) to inactivate inflammatory and immune molecules. Proteomic analysis was performed to assess the protein profile of PRGFs from healthy and non-healthy patients and the effect of Immunosafe treatment. Differential abundance patterns of several proteins related to key biological processes have been identified, including complement activation, blood coagulation, and glycolysis- and gluconeogenesis-related genes. These results also demonstrate that the thermal treatment (Immunosafe) contributes to the inactivation of the complement system and, as a consequence, reduction in the immunogenic potential of PRGF products. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

25 pages, 888 KiB

Open AccessReview

Agro-Industrial By-Products of Plant Origin: Therapeutic Uses as well as Antimicrobial and Antioxidant Activity

by Yessica Enciso-Martínez, B. Shain Zuñiga-Martínez, Jesús Fernando Ayala-Zavala, J. Abraham Domínguez-Avila, Gustavo A. González-Aguilar and Manuel Viuda-Martos

Biomolecules 2024, 14(7), 762; https://doi.org/10.3390/biom14070762 - 26 Jun 2024

Viewed by 158

Abstract

The importance of bioactive compounds in agro-industrial by-products of plant origin lies in their direct impacts on human health. These compounds have been shown to possess antioxidant, anti-inflammatory, and antimicrobial properties, contributing to disease prevention and strengthening the immune system. In particular, the [...] Read more.

The importance of bioactive compounds in agro-industrial by-products of plant origin lies in their direct impacts on human health. These compounds have been shown to possess antioxidant, anti-inflammatory, and antimicrobial properties, contributing to disease prevention and strengthening the immune system. In particular, the antimicrobial action of these compounds emerges as an important tool in food preservation, providing natural alternatives to synthetic preservatives and contributing to combating antimicrobial resistance. Using agro-industrial by-products of plant origin not only addresses the need to reduce waste and promote sustainability but also inaugurates a new era in the formulation of functional foods. From fruit peels to pulps and seeds, these by-products are emerging as essential ingredients in the creation of products that can promote health. Continued research in this area will unveil new applications and properties of these by-products and open doors to a food paradigm in which health and sustainability converge, paving the way to a healthier and more equitable future. The present review presents an overview of our knowledge of agro-industrial by-products and some of their more relevant health-promoting bioactivities. Full article

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24 pages, 2090 KiB

Open AccessReview

Histamine H₃ Receptor Isoforms: Insights from Alternative Splicing to Functional Complexity

by Meichun Gao, Jasper F. Ooms, Rob Leurs and Henry F. Vischer

Biomolecules 2024, 14(7), 761; https://doi.org/10.3390/biom14070761 - 26 Jun 2024

Viewed by 180

Abstract

Alternative splicing significantly enhances the diversity of the G protein-coupled receptor (GPCR) family, including the histamine H₃ receptor (H₃R). This post-transcriptional modification generates multiple H₃R isoforms with potentially distinct pharmacological and physiological profiles. H₃R is primarily [...] Read more.

Alternative splicing significantly enhances the diversity of the G protein-coupled receptor (GPCR) family, including the histamine H₃ receptor (H₃R). This post-transcriptional modification generates multiple H₃R isoforms with potentially distinct pharmacological and physiological profiles. H₃R is primarily involved in the presynaptic inhibition of neurotransmitter release in the central nervous system. Despite the approval of pitolisant for narcolepsy (Wakix^®) and daytime sleepiness in adults with obstructive sleep apnea (Ozawade^®) and ongoing clinical trials for other H₃R antagonists/inverse agonists, the functional significance of the numerous H₃R isoforms remains largely enigmatic. Recent publicly available RNA sequencing data have confirmed the expression of multiple H₃R isoforms in the brain, with some isoforms exhibiting unique tissue-specific distribution patterns hinting at isoform-specific functions and interactions within neural circuits. In this review, we discuss the complexity of H₃R isoforms with a focus on their potential roles in central nervous system (CNS) function. Comparative analysis across species highlights evolutionary conservation and divergence in H₃R splicing, suggesting species-specific regulatory mechanisms. Understanding the functionality of H₃R isoforms is crucial for the development of targeted therapeutics. This knowledge will inform the design of more precise pharmacological interventions, potentially enhancing therapeutic efficacy and reducing adverse effects in the treatment of neurological and psychiatric disorders. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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18 pages, 844 KiB

Open AccessReview

Electroceuticals and Magnetoceuticals in Gastroenterology

by Gengqing Song, Roberta Sclocco, Sharma Amol, Ingrid Guerrero-López and Braden Kuo

Biomolecules 2024, 14(7), 760; https://doi.org/10.3390/biom14070760 - 26 Jun 2024

Viewed by 149

Abstract

In the realm of gastroenterology, the inadequacy of current medical treatments for gastrointestinal (GI) motility disorders and inflammatory bowel disease (IBD), coupled with their potential side effects, necessitates novel therapeutic approaches. Neuromodulation, targeting the nervous system’s control of GI functions, emerges as a [...] Read more.

In the realm of gastroenterology, the inadequacy of current medical treatments for gastrointestinal (GI) motility disorders and inflammatory bowel disease (IBD), coupled with their potential side effects, necessitates novel therapeutic approaches. Neuromodulation, targeting the nervous system’s control of GI functions, emerges as a promising alternative. This review explores the promising effects of vagal nerve stimulation (VNS), magnetic neuromodulation, and acupuncture in managing these challenging conditions. VNS offers targeted modulation of GI motility and inflammation, presenting a potential solution for patients not fully relieved from traditional medications. Magnetic neuromodulation, through non-invasive means, aims to enhance neurophysiological processes, showing promise in improving GI function and reducing inflammation. Acupuncture and electroacupuncture, grounded in traditional medicine yet validated by modern science, exert comprehensive effects on GI physiology via neuro-immune-endocrine mechanisms, offering relief from motility and inflammatory symptoms. This review highlights the need for further research to refine these interventions, emphasizing their prospective role in advancing patient-specific management strategies for GI motility disorders and IBD, thus paving the way for a new therapeutic paradigm. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

25 pages, 27588 KiB

Open AccessArticle

Structural Analysis of the Drosophila melanogaster GSTome

by Nicolas Petiot, Mathieu Schwartz, Patrice Delarue, Patrick Senet, Fabrice Neiers and Adrien Nicolaï

Biomolecules 2024, 14(7), 759; https://doi.org/10.3390/biom14070759 - 26 Jun 2024

Viewed by 114

Abstract

Glutathione transferase (GST) is a superfamily of ubiquitous enzymes, multigenic in numerous organisms and which generally present homodimeric structures. GSTs are involved in numerous biological functions such as chemical detoxification as well as chemoperception in mammals and insects. GSTs catalyze the conjugation of [...] Read more.

Glutathione transferase (GST) is a superfamily of ubiquitous enzymes, multigenic in numerous organisms and which generally present homodimeric structures. GSTs are involved in numerous biological functions such as chemical detoxification as well as chemoperception in mammals and insects. GSTs catalyze the conjugation of their cofactor, reduced glutathione (GSH), to xenobiotic electrophilic centers. To achieve this catalytic function, GSTs are comprised of a ligand binding site and a GSH binding site per subunit, which is very specific and highly conserved; the hydrophobic substrate binding site enables the binding of diverse substrates. In this work, we focus our interest in a model organism, the fruit fly Drosophila melanogaster (D. mel), which comprises 42 GST sequences distributed in six classes and composing its GSTome. The goal of this study is to describe the complete structural GSTome of D. mel to determine how changes in the amino acid sequence modify the structural characteristics of GST, particularly in the GSH binding sites and in the dimerization interface. First, we predicted the 3D atomic structures of each GST using the AlphaFold (AF) program and compared them with X-ray crystallography structures, when they exist. We also characterized and compared their global and local folds. Second, we used multiple sequence alignment coupled with AF-predicted structures to characterize the relationship between the conservation of amino acids in the sequence and their structural features. Finally, we applied normal mode analysis to estimate thermal B-factors of all GST structures of D. mel. Particularly, we extracted flexibility profiles of GST and identify key residues and motifs that are systematically involved in the ligand binding/dimerization processes and thus playing a crucial role in the catalytic function. This methodology will be extended to guide the in silico design of synthetic GST with new/optimal catalytic properties for detoxification applications. Full article

(This article belongs to the Special Issue The Multiple Roles of Glutathione-Dependent Enzymes: A Themed Issue in Honor of Prof. Bengt Mannervik)

16 pages, 3381 KiB

Open AccessArticle

Structural and Thermodynamic Insights into Dimerization Interfaces of Drosophila Glutathione Transferases

by Mathieu Schwartz, Nicolas Petiot, Jeanne Chaloyard, Véronique Senty-Segault, Frédéric Lirussi, Patrick Senet, Adrien Nicolai, Jean-Marie Heydel, Francis Canon, Sanjiv Sonkaria, Varsha Khare, Claude Didierjean and Fabrice Neiers

Biomolecules 2024, 14(7), 758; https://doi.org/10.3390/biom14070758 - 26 Jun 2024

Viewed by 360

Abstract

This study presents a comprehensive analysis of the dimerization interfaces of fly GSTs through sequence alignment. Our investigation revealed GSTE1 as a particularly intriguing target, providing valuable insights into the variations within Delta and Epsilon GST interfaces. The X-ray structure of GSTE1 was [...] Read more.

This study presents a comprehensive analysis of the dimerization interfaces of fly GSTs through sequence alignment. Our investigation revealed GSTE1 as a particularly intriguing target, providing valuable insights into the variations within Delta and Epsilon GST interfaces. The X-ray structure of GSTE1 was determined, unveiling remarkable thermal stability and a distinctive dimerization interface. Utilizing circular dichroism, we assessed the thermal stability of GSTE1 and other Drosophila GSTs with resolved X-ray structures. The subsequent examination of GST dimer stability correlated with the dimerization interface supported by findings from X-ray structural analysis and thermal stability measurements. Our discussion extends to the broader context of GST dimer interfaces, offering a generalized perspective on their stability. This research enhances our understanding of the structural and thermodynamic aspects of GST dimerization, contributing valuable insights to the field. Full article

(This article belongs to the Special Issue The Multiple Roles of Glutathione-Dependent Enzymes: A Themed Issue in Honor of Prof. Bengt Mannervik)

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15 pages, 1441 KiB

Open AccessArticle

Extracellular Vesicle-Mediated Modulation of Stem-like Phenotype in Breast Cancer Cells under Fluid Shear Stress

by Spenser R. Brown, Margaret E. Radcliffe, Joseph T. Danner, Wilmer J. Andújar Cruz, Kimberly H. Lackey, Han-A Park, Steven T. Weinman and Yonghyun Kim

Biomolecules 2024, 14(7), 757; https://doi.org/10.3390/biom14070757 - 25 Jun 2024

Viewed by 395

Abstract

Circulating tumor cells (CTCs) are some of the key culprits that cause cancer metastasis and metastasis-related deaths. These cells exist in a dynamic microenvironment where they experience fluid shear stress (FSS), and the CTCs that survive FSS are considered to be highly metastatic [...] Read more.

Circulating tumor cells (CTCs) are some of the key culprits that cause cancer metastasis and metastasis-related deaths. These cells exist in a dynamic microenvironment where they experience fluid shear stress (FSS), and the CTCs that survive FSS are considered to be highly metastatic and stem cell-like. Biophysical stresses such as FSS are also known to cause the production of extracellular vesicles (EVs) that can facilitate cell–cell communication by carrying biomolecular cargos such as microRNAs. Here, we hypothesized that physiological FSS will impact the yield of EV production, and that these EVs will have biomolecules that transform the recipient cells. The EVs were isolated using direct flow filtration with and without FSS from the MDA-MB-231 cancer cell line, and the expression of key stemness-related genes and microRNAs was characterized. There was a significantly increased yield of EVs under FSS. These EVs also contained significantly increased levels of miR-21, which was previously implicated to promote metastatic progression and chemotherapeutic resistance. When these EVs from FSS were introduced to MCF-7 cancer cells, the recipient cells had a significant increase in their stem-like gene expression and CD44⁺/CD24⁻ cancer stem cell-like subpopulation. There was also a correlated increased proliferation along with an increased ATP production. Together, these findings indicate that the presence of physiological FSS can directly influence the EVs’ production and their contents, and that the EV-mediated transfer of miR-21 can have an important role in FSS-existing contexts, such as in cancer metastasis. Full article

(This article belongs to the Special Issue Advances in Nano-Based Drug Delivery: Unveiling the Next Frontier)

16 pages, 1339 KiB

Open AccessArticle

Evaluation of the Effect of β-Wrapin AS69 in a Mouse Model Based on Alpha-Synuclein Overexpression

by Lennart Höfs, David Geißler-Lösch, Kristof M. Wunderlich, Eva M. Szegö, Chris Van den Haute, Veerle Baekelandt, Wolfgang Hoyer and Björn H. Falkenburger

Biomolecules 2024, 14(7), 756; https://doi.org/10.3390/biom14070756 - 25 Jun 2024

Viewed by 353

Abstract

Aggregation of the protein α-Synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple systems atrophy, and alleviating the extent of αSyn pathology is an attractive strategy against neurodegeneration. The engineered binding protein β-wrapin AS69 binds monomeric [...] Read more.

Aggregation of the protein α-Synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple systems atrophy, and alleviating the extent of αSyn pathology is an attractive strategy against neurodegeneration. The engineered binding protein β-wrapin AS69 binds monomeric αSyn. AS69 reduces primary and secondary nucleation as well as fibril elongation in vitro. It also mitigates aSyn pathology in a mouse model based on intrastriatal injection of aSyn pre-formed fibrils (PFFs). Since the PFF-based model does not represent all aspects of PD, we tested here whether AS69 can reduce neurodegeneration resulting from αSyn overexpression. Human A53T-αSyn was overexpressed in the mouse Substantia nigra (SN) by using recombinant adeno-associated viral vector (rAAV). AS69 was also expressed by rAAV transduction. Behavioral tests and immunofluorescence staining were used as outcomes. Transduction with rAAV-αSyn resulted in αSyn pathology as reported by phospho-αSyn staining and caused degeneration of dopaminergic neurons in the SN. The co-expression of rAAV-AS69 did not reduce αSyn pathology or the degeneration of dopaminergic neurons. We conclude that αSyn monomer binding by rAAV-AS69 was insufficient to protect from aSyn pathology resulting from αSyn overexpression. Full article

(This article belongs to the Special Issue Synuclein Proteins II)

12 pages, 20671 KiB

Open AccessArticle

In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease

by Yuri Alves de Oliveira Só, Katyanna Sales Bezzera, Ricardo Gargano, Fabio L. L. Mendonça, Janeusa Trindade Souto, Umberto L. Fulco, Marcelo Lopes Pereira Junior and Luiz Antônio Ribeiro Junior

Biomolecules 2024, 14(7), 755; https://doi.org/10.3390/biom14070755 - 25 Jun 2024

Viewed by 573

Abstract

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 M^pro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness [...] Read more.

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 M^pro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 M^pro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized M^pro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19. Full article

(This article belongs to the Section Chemical Biology)

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16 pages, 1118 KiB

Open AccessReview

FLASH Radiotherapy: Mechanisms of Biological Effects and the Therapeutic Potential in Cancer

by Ouying Yan, Shang Wang, Qiaoli Wang and Xin Wang

Biomolecules 2024, 14(7), 754; https://doi.org/10.3390/biom14070754 - 25 Jun 2024

Viewed by 373

Abstract

Radiotherapy is an important treatment for many unresectable advanced malignant tumors, and radiotherapy-associated inflammatory reactions to radiation and other toxic side effects are significant reasons which reduce the quality of life and survival of patients. FLASH-radiotherapy (FLASH-RT), a prominent topic in recent radiation [...] Read more.

Radiotherapy is an important treatment for many unresectable advanced malignant tumors, and radiotherapy-associated inflammatory reactions to radiation and other toxic side effects are significant reasons which reduce the quality of life and survival of patients. FLASH-radiotherapy (FLASH-RT), a prominent topic in recent radiation therapy research, is an ultra-high dose rate treatment known for significantly reducing therapy time while effectively targeting tumors. This approach minimizes radiation side effects on at-risk organs and maximally protects surrounding healthy tissues. Despite decades of preclinical exploration and some notable achievements, the mechanisms behind FLASH effects remain debated. Standardization is still required for the type of FLASH-RT rays and dose patterns. This review addresses the current state of FLASH-RT research, summarizing the biological mechanisms behind the FLASH effect. Additionally, it examines the impact of FLASH-RT on immune cells, cytokines, and the tumor immune microenvironment. Lastly, this review will discuss beam characteristics, potential clinical applications, and the relevance and applicability of FLASH-RT in treating advanced cancers. Full article

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17 pages, 4069 KiB

Open AccessReview

The Role of Hyperuricemia in Cardiac Diseases: Evidence, Controversies, and Therapeutic Strategies

by Yue Zheng, Zhirui Chen, Jinya Yang, Jing Zheng, Xiaorong Shui, Yiguang Yan, Shian Huang, Zheng Liang, Wei Lei and Yuan He

Biomolecules 2024, 14(7), 753; https://doi.org/10.3390/biom14070753 - 25 Jun 2024

Viewed by 180

Abstract

dial infarction, arrhythmias, and heart failure. We also combined recent findings from basic research to analyze potential mechanisms linking HUA with myocardial injury. In different pathological models (such as direct action of high uric acid on myocardial cells or combined with myocardial ischemia-reperfusion [...] Read more.

dial infarction, arrhythmias, and heart failure. We also combined recent findings from basic research to analyze potential mechanisms linking HUA with myocardial injury. In different pathological models (such as direct action of high uric acid on myocardial cells or combined with myocardial ischemia-reperfusion model), HUA may cause damage by activating the NOD-like receptor protein 3 inflammasome-induced inflammatory response, interfering with cardiac cell energy metabolism, affecting antioxidant defense systems, and stimulating reactive oxygen species production to enhance the oxidative stress response, ultimately resulting in decreased cardiac function. Additionally, we discuss the impact of lowering uric acid intervention therapy and potential safety issues that may arise. However, as the mechanism underlying HUA-induced myocardial injury is poorly defined, further research is warranted to aid in the development novel therapeutic strategies for HUA-related cardiovascular diseases. Full article

(This article belongs to the Special Issue New Insights into Cardiometabolic Diseases)

21 pages, 2236 KiB

Open AccessArticle

Enhanced ε-Poly-L-Lysine Production in Streptomyces albulus through Multi-Omics-Guided Metabolic Engineering

by Liang Wang, Hao Yang, Mengping Wu, Hongjian Zhang, Jianhua Zhang and Xusheng Chen

Biomolecules 2024, 14(7), 752; https://doi.org/10.3390/biom14070752 - 25 Jun 2024

Viewed by 184

Abstract

Safe and eco-friendly preservatives are crucial to preventing food spoilage and illnesses, as foodborne diseases caused by pathogens result in approximately 600 million cases of illness and 420,000 deaths annually. ε-Poly-L-lysine (ε-PL) is a novel food preservative widely used in many countries. However, [...] Read more.

Safe and eco-friendly preservatives are crucial to preventing food spoilage and illnesses, as foodborne diseases caused by pathogens result in approximately 600 million cases of illness and 420,000 deaths annually. ε-Poly-L-lysine (ε-PL) is a novel food preservative widely used in many countries. However, its commercial application has been hindered by high costs and low production. In this study, ε-PL’s biosynthetic capacity was enhanced in Streptomyces albulus WG608 through metabolic engineering guided by multi-omics techniques. Based on transcriptome and metabolome data, differentially expressed genes (fold change >2 or <0.5; p < 0.05) and differentially expressed metabolites (fold change >1.2 or <0.8) were separately subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The integrative analysis of transcriptome, metabolome, and overexpression revealed the essential roles of isocitrate lyase, succinate dehydrogenase, flavoprotein subunit, diaminopimelate dehydrogenase, polyphosphate kinase, and polyP:AMP phosphotransferase in ε-PL biosynthesis. Subsequently, a strain with enhanced ATP supply, L-lysine supply, and ε-PL synthetase expression was constructed to improve its production. Finally, the resulting strain, S. albulus WME10, achieved an ε-PL production rate of 77.16 g/L in a 5 L bioreactor, which is the highest reported ɛ-PL production to date. These results suggest that the integrative analysis of the transcriptome and metabolome can facilitate the identification of key pathways and genetic elements affecting ε-PL synthesis, guiding further metabolic engineering and thus significantly enhancing ε-PL production. The method presented in this study could be applicable to other valuable natural antibacterial agents. Full article

3 pages, 1532 KiB

Open AccessCorrection

Correction: Firoozi et al. A Cell-Free SDKP-Conjugated Self-Assembling Peptide Hydrogel Sufficient for Improvement of Myocardial Infarction. Biomolecules 2020, 10, 205

by Saman Firoozi, Sara Pahlavan, Mohammad-Hossein Ghanian, Shahram Rabbani, Shima Tavakol, Maryam Barekat, Saeed Yakhkeshi, Elena Mahmoudi, Mansoureh Soleymani and Hossein Baharvand

Biomolecules 2024, 14(7), 751; https://doi.org/10.3390/biom14070751 - 25 Jun 2024

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Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Special Issue Self-Assembling Peptides)

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24 pages, 4494 KiB

Open AccessArticle

Synthesis of Chiral Acyclic Pyrimidine Nucleoside Analogues from DHAP-Dependent Aldolases

by Mariano Nigro, Israél Sánchez-Moreno, Raúl Benito-Arenas, Ana L. Valino, Adolfo M. Iribarren, Nicolás Veiga, Eduardo García-Junceda and Elizabeth S. Lewkowicz

Biomolecules 2024, 14(7), 750; https://doi.org/10.3390/biom14070750 - 25 Jun 2024

Viewed by 203

Abstract

Dihydroxyacetone phosphate (DHAP)-dependent aldolases catalyze the aldol addition of DHAP to a variety of aldehydes and generate compounds with two stereocenters. This reaction is useful to synthesize chiral acyclic nucleosides, which constitute a well-known class of antiviral drugs currently used. In such compounds, [...] Read more.

Dihydroxyacetone phosphate (DHAP)-dependent aldolases catalyze the aldol addition of DHAP to a variety of aldehydes and generate compounds with two stereocenters. This reaction is useful to synthesize chiral acyclic nucleosides, which constitute a well-known class of antiviral drugs currently used. In such compounds, the chirality of the aliphatic chain, which mimics the open pentose residue, is crucial for activity. In this work, three DHAP-dependent aldolases: fructose-1,6-biphosphate aldolase from rabbit muscle, rhanmulose-1-phosphate aldolase from Thermotoga maritima, and fuculose-1-phosphate aldolase from Escherichia coli, were used as biocatalysts. Aldehyde derivatives of thymine and cytosine were used as acceptor substrates, generating new acyclic nucleoside analogues containing two new stereocenters with conversion yields between 70% and 90%. Moreover, structural analyses by molecular docking were carried out to gain insights into the diasteromeric excess observed. Full article

(This article belongs to the Special Issue Biotechnological and Biomedical Applications of Enzymes Involved in the Synthesis of Nucleosides and Nucleotides—2nd Edition)

15 pages, 2999 KiB

Open AccessArticle

TFTF: An R-Based Integrative Tool for Decoding Human Transcription Factor–Target Interactions

by Jin Wang

Biomolecules 2024, 14(7), 749; https://doi.org/10.3390/biom14070749 - 24 Jun 2024

Viewed by 385

Abstract

Transcription factors (TFs) are crucial in modulating gene expression and sculpting cellular and organismal phenotypes. The identification of TF–target gene interactions is pivotal for comprehending molecular pathways and disease etiologies but has been hindered by the demanding nature of traditional experimental approaches. This [...] Read more.

Transcription factors (TFs) are crucial in modulating gene expression and sculpting cellular and organismal phenotypes. The identification of TF–target gene interactions is pivotal for comprehending molecular pathways and disease etiologies but has been hindered by the demanding nature of traditional experimental approaches. This paper introduces a novel web application and package utilizing the R program, which predicts TF–target gene relationships and vice versa. Our application integrates the predictive power of various bioinformatic tools, leveraging their combined strengths to provide robust predictions. It merges databases for enhanced precision, incorporates gene expression correlation for accuracy, and employs pan-tissue correlation analysis for context-specific insights. The application also enables the integration of user data with established resources to analyze TF–target gene networks. Despite its current limitation to human data, it provides a platform to explore gene regulatory mechanisms comprehensively. This integrated, systematic approach offers researchers an invaluable tool for dissecting the complexities of gene regulation, with the potential for future expansions to include a broader range of species. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

13 pages, 3477 KiB

Open AccessReview

Molecular Mechanisms and Potential Antiviral Strategies of Liquid–Liquid Phase Separation during Coronavirus Infection

by Ying Wang, Liying Zhou, Xiaohan Wu, Shixing Yang, Xiaochun Wang, Quan Shen, Yuwei Liu, Wen Zhang and Likai Ji

Biomolecules 2024, 14(7), 748; https://doi.org/10.3390/biom14070748 - 24 Jun 2024

Viewed by 380

Abstract

Highly pathogenic coronaviruses have caused significant outbreaks in humans and animals, posing a serious threat to public health. The rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in millions of infections and deaths. However, the mechanisms through which coronaviruses [...] Read more.

Highly pathogenic coronaviruses have caused significant outbreaks in humans and animals, posing a serious threat to public health. The rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in millions of infections and deaths. However, the mechanisms through which coronaviruses evade a host’s antiviral immune system are not well understood. Liquid–liquid phase separation (LLPS) is a recently discovered mechanism that can selectively isolate cellular components to regulate biological processes, including host antiviral innate immune signal transduction pathways. This review focuses on the mechanism of coronavirus-induced LLPS and strategies for utilizing LLPS to evade the host antiviral innate immune response, along with potential antiviral therapeutic drugs and methods. It aims to provide a more comprehensive understanding and novel insights for researchers studying LLPS induced by pandemic viruses. Full article

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