Journal Description
Biomolecules
Biomolecules
is a peer-reviewed, open access journal on structures and functions of bioactive and biogenic substances, molecular mechanisms with biological and medical implications as well as biomaterials and their applications. Biomolecules is published monthly online by MDPI. The Spanish Society for Biochemistry and Molecular Biology (SEBBM) is affiliated with Biomolecules and their members receive discounts on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Biochemistry & Molecular Biology) / CiteScore - Q1 (Biochemistry)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16.9 days after submission; acceptance to publication is undertaken in 2.9 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Sections: published in 19 topical sections.
- Testimonials: See what our editors and authors say about Biomolecules.
- Companion journal: Receptors.
Impact Factor:
5.5 (2022);
5-Year Impact Factor:
5.8 (2022)
Latest Articles
Promising Application, Efficient Production, and Genetic Basis of Mannosylerythritol Lipids
Biomolecules 2024, 14(5), 557; https://doi.org/10.3390/biom14050557 (registering DOI) - 05 May 2024
Abstract
Mannosylerythritol lipids (MELs) are a class of glycolipids that have been receiving increasing attention in recent years due to their diverse biological activities. MELs are produced by certain fungi and display a range of bioactivities, making them attractive candidates for various applications in
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Mannosylerythritol lipids (MELs) are a class of glycolipids that have been receiving increasing attention in recent years due to their diverse biological activities. MELs are produced by certain fungi and display a range of bioactivities, making them attractive candidates for various applications in medicine, agriculture, and biotechnology. Despite their remarkable qualities, industrial-scale production of MELs remains a challenge for fungal strains. Excellent fungal strains and fermentation processes are essential for the efficient production of MELs, so efforts have been made to improve the fermentation yield by screening high-yielding strains, optimizing fermentation conditions, and improving product purification processes. The availability of the genome sequence is pivotal for elucidating the genetic basis of fungal MEL biosynthesis. This review aims to shed light on the applications of MELs and provide insights into the genetic basis for efficient MEL production. Additionally, this review offers new perspectives on optimizing MEL production, contributing to the advancement of sustainable biosurfactant technologies.
Full article
(This article belongs to the Section Biomacromolecules: Lipids)
Open AccessReview
Bone and Extracellular Signal-Related Kinase 5 (ERK5)
by
Lei Wen, Zirui Liu, Libo Zhou, Zhongcheng Liu, Qingda Li, Bin Geng and Yayi Xia
Biomolecules 2024, 14(5), 556; https://doi.org/10.3390/biom14050556 (registering DOI) - 04 May 2024
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Bones are vital for anchoring muscles, tendons, and ligaments, serving as a fundamental element of the human skeletal structure. However, our understanding of bone development mechanisms and the maintenance of bone homeostasis is still limited. Extracellular signal-related kinase 5 (ERK5), a recently identified
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Bones are vital for anchoring muscles, tendons, and ligaments, serving as a fundamental element of the human skeletal structure. However, our understanding of bone development mechanisms and the maintenance of bone homeostasis is still limited. Extracellular signal-related kinase 5 (ERK5), a recently identified member of the mitogen-activated protein kinase (MAPK) family, plays a critical role in the pathogenesis and progression of various diseases, especially neoplasms. Recent studies have highlighted ERK5’s significant role in both bone development and bone-associated pathologies. This review offers a detailed examination of the latest research on ERK5 in different tissues and diseases, with a particular focus on its implications for bone health. It also examines therapeutic strategies and future research avenues targeting ERK5.
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Open AccessArticle
Defining a Water-Soluble Formulation of Arachidonic Acid as a Novel Ferroptosis Inducer in Cancer Cells
by
Zoe I. Day, Alyce J. Mayfosh, Amy A. Baxter, Scott A. Williams, Joanne M. Hildebrand, Thomas F. Rau, Ivan K. H. Poon and Mark D. Hulett
Biomolecules 2024, 14(5), 555; https://doi.org/10.3390/biom14050555 (registering DOI) - 04 May 2024
Abstract
Here, we describe GS-9, a novel water-soluble fatty acid-based formulation comprising L-lysine and arachidonic acid, that we have shown to induce ferroptosis. GS-9 forms vesicle-like structures in solution and mediates lipid peroxidation, as evidenced by increased C11-BODIPY fluorescence and an accumulation of toxic
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Here, we describe GS-9, a novel water-soluble fatty acid-based formulation comprising L-lysine and arachidonic acid, that we have shown to induce ferroptosis. GS-9 forms vesicle-like structures in solution and mediates lipid peroxidation, as evidenced by increased C11-BODIPY fluorescence and an accumulation of toxic malondialdehyde, a downstream product of lipid peroxidation. Ferroptosis inhibitors counteracted GS-9-induced cell death, whereas caspase 3 and 7 or MLKL knock-out cell lines are resistant to GS-9-induced cell death, eliminating other cell death processes such as apoptosis and necroptosis as the mechanism of action of GS-9. We also demonstrate that through their role of sequestering fatty acids, lipid droplets play a protective role against GS-9-induced ferroptosis, as inhibition of lipid droplet biogenesis enhanced GS-9 cytotoxicity. In addition, Fatty Acid Transport Protein 2 was implicated in GS-9 uptake. Overall, this study identifies and characterises the mechanism of GS-9 as a ferroptosis inducer. This formulation of arachidonic acid offers a novel tool for investigating and manipulating ferroptosis in various cellular and anti-cancer contexts.
Full article
(This article belongs to the Topic Advances in Natural Products and Phytochemicals in Cancer Prevention and Therapeutics)
Open AccessReview
Proteomic Insights into Osteoporosis: Unraveling Diagnostic Markers of and Therapeutic Targets for the Metabolic Bone Disease
by
Jihan Wang, Mengju Xue, Ya Hu, Jingwen Li, Zhenzhen Li and Yangyang Wang
Biomolecules 2024, 14(5), 554; https://doi.org/10.3390/biom14050554 (registering DOI) - 04 May 2024
Abstract
Osteoporosis (OP), a prevalent skeletal disorder characterized by compromised bone strength and increased susceptibility to fractures, poses a significant public health concern. This review aims to provide a comprehensive analysis of the current state of research in the field, focusing on the application
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Osteoporosis (OP), a prevalent skeletal disorder characterized by compromised bone strength and increased susceptibility to fractures, poses a significant public health concern. This review aims to provide a comprehensive analysis of the current state of research in the field, focusing on the application of proteomic techniques to elucidate diagnostic markers and therapeutic targets for OP. The integration of cutting-edge proteomic technologies has enabled the identification and quantification of proteins associated with bone metabolism, leading to a deeper understanding of the molecular mechanisms underlying OP. In this review, we systematically examine recent advancements in proteomic studies related to OP, emphasizing the identification of potential biomarkers for OP diagnosis and the discovery of novel therapeutic targets. Additionally, we discuss the challenges and future directions in the field, highlighting the potential impact of proteomic research in transforming the landscape of OP diagnosis and treatment.
Full article
(This article belongs to the Special Issue Biomarkers in Metabolic Diseases)
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Open AccessReview
LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond
by
Hyun-Min Kim and Zifei Liu
Biomolecules 2024, 14(5), 553; https://doi.org/10.3390/biom14050553 - 03 May 2024
Abstract
Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with
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Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with cancer. However, while LSD1 has received significant attention, LSD2 has not been recognized to the same extent. In this study, we conduct a comprehensive comparison between LSD2 and LSD1, with a focus on exploring LSD2’s implications. While both share structural similarities, LSD2 possesses unique features as well. Functionally, LSD2 shows diverse roles, particularly in cancer, with tissue-dependent roles. Additionally, LSD2 extends beyond histone demethylation, impacting DNA methylation, cancer cell reprogramming, E3 ubiquitin ligase activity and DNA damage repair pathways. This study underscores the distinct roles of LSD2, providing insights into their contributions to cancer and other cellular processes.
Full article
(This article belongs to the Special Issue Histone Modifications in Health and Diseases)
Open AccessReview
Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update
by
Michele Correale, Lucia Tricarico, Ester Maria Lucia Bevere, Francesco Chirivì, Francesca Croella, Paolo Severino, Valentina Mercurio, Damiano Magrì, Frank Dini, Roberto Licordari, Matteo Beltrami, Giuseppe Dattilo, Andrea Salzano and Alberto Palazzuoli
Biomolecules 2024, 14(5), 552; https://doi.org/10.3390/biom14050552 - 03 May 2024
Abstract
Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis,
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Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.
Full article
(This article belongs to the Special Issue Molecular Biomarkers In Cardiology 2022–2023)
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Open AccessArticle
4-Hydroxy-1α,25-Dihydroxyvitamin D3: Synthesis and Structure–Function Study
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Carole Peluso-Iltis, Noé Pierrat, Daniela Rovito, Judit Osz, Daisuke Sawada, Atsushi Kittaka, Gilles Laverny and Natacha Rochel
Biomolecules 2024, 14(5), 551; https://doi.org/10.3390/biom14050551 - 03 May 2024
Abstract
The active vitamin D metabolites, 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), are produced by successive hydroxylation steps and play key roles in several cellular processes. However, alternative metabolic pathways exist, and among them, the 4-hydroxylation of
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The active vitamin D metabolites, 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), are produced by successive hydroxylation steps and play key roles in several cellular processes. However, alternative metabolic pathways exist, and among them, the 4-hydroxylation of 25D3 is a major one. This study aims to investigate the structure–activity relationships of 4-hydroxy derivatives of 1,25D3. Structural analysis indicates that 1,4α,25(OH)3D3 and 1,4β,25(OH)3D3 maintain the anchoring hydrogen bonds of 1,25D3 and form additional interactions, stabilizing the active conformation of VDR. In addition, 1,4α,25D3 and 1,4β,25D3 are as potent as 1,25D3 in regulating the expression of VDR target genes in rat intestinal epithelial cells and in the mouse kidney. Moreover, these two 4-hydroxy derivatives promote hypercalcemia in mice at a dose similar to that of the parent compound.
Full article
(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)
Open AccessArticle
Molecular Evolution of RAMOSA1 (RA1) in Land Plants
by
Carolina Bellino, Fernando E. Herrera, Daniel Rodrigues, A. Sergio Garay, Sofía V. Huck and Renata Reinheimer
Biomolecules 2024, 14(5), 550; https://doi.org/10.3390/biom14050550 - 03 May 2024
Abstract
RAMOSA1 (RA1) is a Cys2-His2-type (C2H2) zinc finger transcription factor that controls plant meristem fate and identity and has played an important role in maize domestication. Despite its importance, the origin of RA1 is unknown, and the evolution in plants is only partially
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RAMOSA1 (RA1) is a Cys2-His2-type (C2H2) zinc finger transcription factor that controls plant meristem fate and identity and has played an important role in maize domestication. Despite its importance, the origin of RA1 is unknown, and the evolution in plants is only partially understood. In this paper, we present a well-resolved phylogeny based on 73 amino acid sequences from 48 embryophyte species. The recovered tree topology indicates that, during grass evolution, RA1 arose from two consecutive SUPERMAN duplications, resulting in three distinct grass sequence lineages: RA1-like A, RA1-like B, and RA1; however, most of these copies have unknown functions. Our findings indicate that RA1 and RA1-like play roles in the nucleus despite lacking a traditional nuclear localization signal. Here, we report that copies diversified their coding region and, with it, their protein structure, suggesting different patterns of DNA binding and protein–protein interaction. In addition, each of the retained copies diversified regulatory elements along their promoter regions, indicating differences in their upstream regulation. Taken together, the evidence indicates that the RA1 and RA1-like gene families in grasses underwent subfunctionalization and neofunctionalization enabled by gene duplication.
Full article
(This article belongs to the Special Issue Molecular Plant Reproduction: From Cells to Nature)
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Open AccessReview
Is Neonatal Uterine Bleeding Involved in Early-Onset Endometriosis?
by
Marwan Habiba, Sun-Wei Guo and Giuseppe Benagiano
Biomolecules 2024, 14(5), 549; https://doi.org/10.3390/biom14050549 - 03 May 2024
Abstract
Background: There has been considerable progress in our understanding of endometriosis, but its pathophysiology remains uncertain. Uncovering the underlying mechanism of the rare instances of endometriosis reported in early postmenarcheal years and in girls before menarche can have wide implications. Methods: We conducted
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Background: There has been considerable progress in our understanding of endometriosis, but its pathophysiology remains uncertain. Uncovering the underlying mechanism of the rare instances of endometriosis reported in early postmenarcheal years and in girls before menarche can have wide implications. Methods: We conducted a literature review of all relevant articles on Medline. Results: In the review, we explore the pathogenetic theories of premenarcheal endometriosis, the role of retrograde menstruation in the adult and its potential role in early-onset disease, as well as the factors that argue against the existence of a link between early-onset endometriosis (EOE) and neonatal uterine bleeding (NUB). Conclusions: As with endometriosis in adult women, the pathogenesis of early-onset disease remains unclear. A link between NUB and EOE is plausible, but there are considerable challenges to collating supporting evidence. The state of our understanding of early uterine development and of the pathophysiology of NUB leaves many unknowns that need exploration. These include proof of the existence of viable endometrial cells or endometrial mesenchymal stem cells in NUB, their passage to the pelvic cavity, their possible response to steroids, and whether they can reside within the pelvic cavity and remain dormant till menarche.
Full article
(This article belongs to the Section Molecular Medicine)
Open AccessReview
Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis
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Elan May Shellard, Shraddha S. Rane, Stephen Eyre and Richard B. Warren
Biomolecules 2024, 14(5), 548; https://doi.org/10.3390/biom14050548 - 03 May 2024
Abstract
Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1–3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS)
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Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1–3% of the world’s population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS) studies showing that many psoriasis risk genes lie along the IL-23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. This review is focused on the IL-23/Th17 axis, providing an insight into key cell types, cytokines, and intracellular signaling pathways involved. This includes examination of currently available biological treatments, time to relapse post drug withdrawal, and rates of primary/secondary drug failure, showing the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely to reduce the burden of disease for the longest period possible.
Full article
(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)
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Open AccessArticle
SNP-Associated Substitutions of Amino Acid Residues in the dNTP Selection Subdomain Decrease Polβ Polymerase Activity
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Olga A. Kladova, Timofey E. Tyugashev, Aleksandr A. Miroshnikov, Daria S. Novopashina, Nikita A. Kuznetsov and Aleksandra A. Kuznetsova
Biomolecules 2024, 14(5), 547; https://doi.org/10.3390/biom14050547 - 02 May 2024
Abstract
In the cell, DNA polymerase β (Polβ) is involved in many processes aimed at maintaining genome stability and is considered the main repair DNA polymerase participating in base excision repair (BER). Polβ can fill DNA gaps formed by other DNA repair enzymes. Single-nucleotide
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In the cell, DNA polymerase β (Polβ) is involved in many processes aimed at maintaining genome stability and is considered the main repair DNA polymerase participating in base excision repair (BER). Polβ can fill DNA gaps formed by other DNA repair enzymes. Single-nucleotide polymorphisms (SNPs) in the POLB gene can affect the enzymatic properties of the resulting protein, owing to possible amino acid substitutions. For many SNP-associated Polβ variants, an association with cancer, owing to changes in polymerase activity and fidelity, has been shown. In this work, kinetic analyses and molecular dynamics simulations were used to examine the activity of naturally occurring polymorphic variants G274R, G290C, and R333W. Previously, the amino acid substitutions at these positions have been found in various types of tumors, implying a specific role of Gly-274, Gly-290, and Arg-333 in Polβ functioning. All three polymorphic variants had reduced polymerase activity. Two substitutions—G274R and R333W—led to the almost complete disappearance of gap-filling and primer elongation activities, a decrease in the deoxynucleotide triphosphate–binding ability, and a lower polymerization constant, due to alterations of local contacts near the replaced amino acid residues. Thus, variants G274R, G290C, and R333W may be implicated in an elevated level of unrepaired DNA damage.
Full article
(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)
Open AccessReview
The Possible Roles of IL-4/IL-13 in the Development of Eosinophil-Predominant Severe Asthma
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Kazuyuki Nakagome and Makoto Nagata
Biomolecules 2024, 14(5), 546; https://doi.org/10.3390/biom14050546 - 02 May 2024
Abstract
Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play
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Bronchial asthma is characterized by airway inflammation, airway hyperresponsiveness, and reversible airway obstruction. Eosinophils contribute to the pathogenesis of airway disease mainly by releasing eosinophil-specific granules, lipid mediators, superoxide anions, and their DNA. Type-2 cytokines such as interleukin (IL)-4 and IL-13 also play roles in the development of bronchial asthma. Among these cytokines, IL-4 is involved in T-cell differentiation, B-cell activation, B-cell differentiation into plasma cells, and the production of immunoglobulin E. Although IL-13 has similar effects to IL-4, IL-13 mainly affects structural cells, such as epithelial cells, smooth muscle cells, and fibroblasts. IL-13 induces the differentiation of goblet cells that produce mucus and induces the airway remodeling, including smooth muscle hypertrophy. IL-4 and IL-13 do not directly activate the effector functions of eosinophils; however, they can induce eosinophilic airway inflammation by upregulating the expression of vascular cell adhesion molecule-1 (for adhesion) and CC chemokine receptor 3 ligands (for migration). Dupilumab, a human anti-IL-4 receptor α monoclonal antibody that inhibits IL-4 and IL-13 signaling, decreases asthma exacerbations and mucus plugs and increases lung function in moderate to severe asthma. In addition, dupilumab is effective for chronic rhinosinusitis with nasal polyps and for atopic dermatitis, and IL-4/IL-13 blocking is expected to suppress allergen sensitization, including transcutaneous sensitization and atopic march.
Full article
(This article belongs to the Special Issue Eosinophils in Allergy and Related Diseases—Selected Papers from “The Workshop on Eosinophils in Allergy and Related Diseases 2022”)
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Open AccessArticle
Scorpion Venom Antimicrobial Peptide Derivative BmKn2-T5 Inhibits Enterovirus 71 in the Early Stages of the Viral Life Cycle In Vitro
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Zhiqiang Xia, Huijuan Wang, Weilie Chen, Aili Wang and Zhijian Cao
Biomolecules 2024, 14(5), 545; https://doi.org/10.3390/biom14050545 - 01 May 2024
Abstract
Enterovirus 71 (EV71), a typical representative of unenveloped RNA viruses, is the main pathogenic factor responsible for hand, foot, and mouth disease (HFMD) in infants. This disease seriously threatens the health and lives of humans worldwide, especially in the Asia–Pacific region. Numerous animal
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Enterovirus 71 (EV71), a typical representative of unenveloped RNA viruses, is the main pathogenic factor responsible for hand, foot, and mouth disease (HFMD) in infants. This disease seriously threatens the health and lives of humans worldwide, especially in the Asia–Pacific region. Numerous animal antimicrobial peptides have been found with protective functions against viruses, bacteria, fungi, parasites, and other pathogens, but there are few studies on the use of scorpion-derived antimicrobial peptides against unenveloped viruses. Here, we investigated the antiviral activities of scorpion venom antimicrobial peptide BmKn2 and five derivatives, finding that BmKn2 and its derivative BmKn2-T5 exhibit a significant inhibitory effect on EV71. Although both peptides exhibit characteristics typical of amphiphilic α-helices in terms of their secondary structure, BmKn2-T5 displayed lower cellular cytotoxicity than BmKn2. BmKn2-T5 was further found to inhibit EV71 in a dose-dependent manner in vitro. Moreover, time-of-drug-addition experiments showed that BmKn2-T5 mainly restricts EV71, but not its virion or replication, at the early stages of the viral cycle. Interestingly, BmKn2-T5 was also found to suppress the replication of the enveloped viruses DENV, ZIKV, and HSV-1 in the early stages of the viral cycle, which suggests they may share a common early infection step with EV71. Together, the results of our study identified that the scorpion-derived antimicrobial peptide BmKn2-T5 showed valuable antiviral properties against EV71 in vitro, but also against other enveloped viruses, making it a potential new candidate therapeutic molecule.
Full article
(This article belongs to the Section Natural and Bio-inspired Molecules)
Open AccessArticle
Virtual Screening of Small Molecules Targeting BCL-2 with Machine Learning, Molecular Docking, and MD Simulation
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Abtin Tondar, Sergio Sánchez-Herrero, Asim Kumar Bepari, Amir Bahmani, Laura Calvet Liñán and David Hervás-Marín
Biomolecules 2024, 14(5), 544; https://doi.org/10.3390/biom14050544 - 01 May 2024
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This study aimed to identify potential BCL-2 small molecule inhibitors using deep neural networks (DNN) and random forest (RF) algorithms as well as molecular docking and molecular dynamics (MD) simulations to screen a library of small molecules. The RF model classified 61% (2355/3867)
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This study aimed to identify potential BCL-2 small molecule inhibitors using deep neural networks (DNN) and random forest (RF) algorithms as well as molecular docking and molecular dynamics (MD) simulations to screen a library of small molecules. The RF model classified 61% (2355/3867) of molecules as ‘Active’. Further analysis through molecular docking with Vina identified CHEMBL3940231, CHEMBL3938023, and CHEMBL3947358 as top-scored small molecules with docking scores of −11, −10.9, and 10.8 kcal/mol, respectively. MD simulations validated these compounds’ stability and binding affinity to the BCL-2 protein.
Full article
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Open AccessArticle
Interplay between Energy Supply and Glutamate Toxicity in the Primary Cortical Culture
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Annette Vaglio-Garro, Andrea Halasz, Ema Nováková, Andreas Sebastian Gasser, Sergejs Zavadskis, Adelheid Weidinger and Andrey V. Kozlov
Biomolecules 2024, 14(5), 543; https://doi.org/10.3390/biom14050543 - 30 Apr 2024
Abstract
Limited substrate availability because of the blood–brain barrier (BBB) has made the brain develop specific molecular mechanisms to survive, using lactate synthesized by astrocytes as a source of energy in neurons. To understand if lactate improves cellular viability and susceptibility to glutamate toxicity,
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Limited substrate availability because of the blood–brain barrier (BBB) has made the brain develop specific molecular mechanisms to survive, using lactate synthesized by astrocytes as a source of energy in neurons. To understand if lactate improves cellular viability and susceptibility to glutamate toxicity, primary cortical cells were incubated in glucose- or lactate-containing media and toxic concentrations of glutamate for 24 h. Cell death was determined by immunostaining and lactate dehydrogenase (LDH) release. Mitochondrial membrane potential and nitric oxide (NO) levels were measured using Tetramethylrhodamine, methyl ester (TMRM) and 4-Amino-5-Methylamino-2′,7′-Difluorofluorescein Diacetate (DAF-FM) live staining, respectively. LDH activity was quantified in single cells in the presence of lactate (LDH substrate) and oxamate (LDH inhibitor). Nuclei of cells were stained with DAPI and neurons with MAP2. Based on the distance between neurons and glial cells, they were classified as linked (<10 µm) and non-linked (>10 µm) neurons. Lactate increased cell death rate and the mean value of endogenous NO levels compared to glucose incubations. Mitochondrial membrane potential was lower in the cells cultured with lactate, but this effect was reversed when glutamate was added to the lactate medium. LDH activity was higher in linked neurons compared to non-linked neurons, supporting the hypothesis of the existence of the lactate shuttle between astrocytes and at least a portion of neurons. In conclusion, glucose or lactate can equally preserve primary cortical neurons, but those neurons having a low level of LDH activity and incubated with lactate cannot cover high energetic demand solely with lactate and become more susceptible to glutamate toxicity.
Full article
Open AccessArticle
Synthesis of a Side Chain Alkyne Analogue of Sitosterol as a Chemical Probe for Imaging in Plant Cells
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Miriam Hollweck, David Jordan and Franz Bracher
Biomolecules 2024, 14(5), 542; https://doi.org/10.3390/biom14050542 - 30 Apr 2024
Abstract
Clickable chemical tools are essential for studying the localization and role of biomolecules in living cells. For this purpose, alkyne-based close analogs of the respective biomolecules are of outstanding interest. Here, in the field of phytosterols, we present the first alkyne derivative of
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Clickable chemical tools are essential for studying the localization and role of biomolecules in living cells. For this purpose, alkyne-based close analogs of the respective biomolecules are of outstanding interest. Here, in the field of phytosterols, we present the first alkyne derivative of sitosterol, which fulfills the crucial requirements for such a chemical tool as follows: very similar in size and lipophilicity to the plant phytosterols, and correct absolute configuration at C-24. The alkyne sitosterol FB-DJ-1 was synthesized, starting from stigmasterol, which comprised nine steps, utilizing a novel alkyne activation method, a Johnson–Claisen rearrangement for the stereoselective construction of a branched sterol side chain, and a Bestmann–Ohira reaction for the generation of the alkyne moiety.
Full article
(This article belongs to the Special Issue Sterol Biosynthesis and Function in Organisms)
Open AccessArticle
A Tiny Viral Protein, SARS-CoV-2-ORF7b: Functional Molecular Mechanisms
by
Gelsomina Mansueto, Giovanna Fusco and Giovanni Colonna
Biomolecules 2024, 14(5), 541; https://doi.org/10.3390/biom14050541 - 30 Apr 2024
Abstract
This study presents the interaction with the human host metabolism of SARS-CoV-2 ORF7b protein (43 aa), using a protein–protein interaction network analysis. After pruning, we selected from BioGRID the 51 most significant proteins among 2753 proven interactions and 1708 interactors specific to ORF7b.
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This study presents the interaction with the human host metabolism of SARS-CoV-2 ORF7b protein (43 aa), using a protein–protein interaction network analysis. After pruning, we selected from BioGRID the 51 most significant proteins among 2753 proven interactions and 1708 interactors specific to ORF7b. We used these proteins as functional seeds, and we obtained a significant network of 551 nodes via STRING. We performed topological analysis and calculated topological distributions by Cytoscape. By following a hub-and-spoke network architectural model, we were able to identify seven proteins that ranked high as hubs and an additional seven as bottlenecks. Through this interaction model, we identified significant GO-processes (5057 terms in 15 categories) induced in human metabolism by ORF7b. We discovered high statistical significance processes of dysregulated molecular cell mechanisms caused by acting ORF7b. We detected disease-related human proteins and their involvement in metabolic roles, how they relate in a distorted way to signaling and/or functional systems, in particular intra- and inter-cellular signaling systems, and the molecular mechanisms that supervise programmed cell death, with mechanisms similar to that of cancer metastasis diffusion. A cluster analysis showed 10 compact and significant functional clusters, where two of them overlap in a Giant Connected Component core of 206 total nodes. These two clusters contain most of the high-rank nodes. ORF7b acts through these two clusters, inducing most of the metabolic dysregulation. We conducted a co-regulation and transcriptional analysis by hub and bottleneck proteins. This analysis allowed us to define the transcription factors and miRNAs that control the high-ranking proteins and the dysregulated processes within the limits of the poor knowledge that these sectors still impose.
Full article
(This article belongs to the Section Biomacromolecules: Proteins)
Open AccessReview
Therapeutic Potential of Hydrogen Sulfide in Reproductive System Disorders
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Xutao Sun, Caiyun Mao, Ying Xie, Qing Zhong, Rong Zhang, Deyou Jiang and Yunjia Song
Biomolecules 2024, 14(5), 540; https://doi.org/10.3390/biom14050540 - 30 Apr 2024
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Hydrogen sulfide (H2S), previously regarded as a toxic exhaust and atmospheric pollutant, has emerged as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO). Recent research has revealed significant biological effects of H2S in a
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Hydrogen sulfide (H2S), previously regarded as a toxic exhaust and atmospheric pollutant, has emerged as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO). Recent research has revealed significant biological effects of H2S in a variety of systems, such as the nervous, cardiovascular, and digestive systems. Additionally, H2S has been found to impact reproductive system function and may have therapeutic implications for reproductive disorders. This paper explores the relationship between H2S and male reproductive disorders, specifically erectile dysfunction, prostate cancer, male infertility, and testicular damage. Additionally, it examines the impact of H2S regulation on the pathophysiology of the female reproductive system, including improvements in preterm birth, endometriosis, pre-eclampsia, fetal growth restriction, unexplained recurrent spontaneous abortion, placental oxidative damage, embryo implantation, recovery of myometrium post-delivery, and ovulation. The study delves into the regulatory functions of H2S within the reproductive systems of both genders, including its impact on the NO/cGMP pathway, the activation of K+ channels, and the relaxation mechanism of the spongy smooth muscle through the ROCK pathway, aiming to broaden the scope of potential therapeutic strategies for treating reproductive system disorders in clinical settings.
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Open AccessReview
Brain-Derived Neurotrophic Factor, Nociception, and Pain
by
Adalberto Merighi
Biomolecules 2024, 14(5), 539; https://doi.org/10.3390/biom14050539 - 30 Apr 2024
Abstract
This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of
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This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of synaptic transmission. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF’s involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.
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(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor in Health and Diseases)
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Open AccessReview
MSC-Based Cell Therapy in Neurological Diseases: A Concise Review of the Literature in Pre-Clinical and Clinical Research
by
Xiaorui Zhang, Qihong Kuang, Jianguang Xu, Qing Lin, Haoming Chi and Daojin Yu
Biomolecules 2024, 14(5), 538; https://doi.org/10.3390/biom14050538 - 30 Apr 2024
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to self-renew and multi-directional differentiation potential. Exogenously administered MSCs can migrate to damaged tissue sites and participate in the repair of damaged tissues. A large number of pre-clinical studies and clinical trials
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Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to self-renew and multi-directional differentiation potential. Exogenously administered MSCs can migrate to damaged tissue sites and participate in the repair of damaged tissues. A large number of pre-clinical studies and clinical trials have demonstrated that MSCs have the potential to treat the abnormalities of congenital nervous system and neurodegenerative diseases. Therefore, MSCs hold great promise in the treatment of neurological diseases. Here, we summarize and highlight current progress in the understanding of the underlying mechanisms and strategies of MSC application in neurological diseases.
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