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“One Pot” Enzymatic Synthesis of Caffeic Acid Phenethyl Ester in Deep Eutectic Solvent
Carnitine O-Acetyltransferase as a Central Player in Lipid and Branched-Chain Amino Acid Metabolism, Epigenetics, Cell Plasticity, and Organelle Function
Integrin and Its Associated Proteins as a Mediator for Mechano-Signal Transduction
Deletion of Murine APP Aggravates Tau and Amyloid Pathologies in the 5xFADXTg30 Alzheimer’s Disease Model
Integrated Clinomics and Molecular Dynamics Simulation Approaches Reveal the SAA1.1 Allele as a Biomarker in Alkaptonuria Disease Severity

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 and Molecular Biology) / CiteScore - Q1 (Biochemistry)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 18.4 days after submission; acceptance to publication is undertaken in 2.7 days (median values for papers published in this journal in the second half of 2024).
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 15 topical sections.
Testimonials: See what our editors and authors say about Biomolecules.
Companion journal: Receptors.

Impact Factor: 4.8 (2023); 5-Year Impact Factor: 5.4 (2023)

Imprint Information Journal Flyer Open Access ISSN: 2218-273X

Latest Articles

23 pages, 6905 KiB

Open AccessArticle

Separation-of-Function Alleles of smc-5 Reveal Domain-Specific Defects and a Conserved Residue Critical for Genome Maintenance

by Haiyan Yuan, Arome Solomon Odiba, Guiyan Liao, Ziteng Zhou, Wenxia Fang, Cheng Jin, Shaojun Li, Xihui Liu and Bin Wang

Biomolecules 2025, 15(6), 755; https://doi.org/10.3390/biom15060755 - 23 May 2025

The SMC-5/6 complex safeguards genome stability through the coordinated action of its core SMC proteins and associated NSE subunits. NSE-1 is a key component of the complex and is essential for DNA repair, yet it remains poorly characterized in Caenorhabditis elegans. To [...] Read more.

The SMC-5/6 complex safeguards genome stability through the coordinated action of its core SMC proteins and associated NSE subunits. NSE-1 is a key component of the complex and is essential for DNA repair, yet it remains poorly characterized in Caenorhabditis elegans. To further elucidate the functional mechanisms of NSE-1, we performed an EMS-based forward genetic screen in an nse-1::gfp(wsh1) reporter strain to identify mutants with defective NSE-1 expression or nuclear localization. We isolated three mutants; smc-5(wsh31), smc-5(wsh32), and smc-5(wsh33), that display impaired NSE-1::GFP nuclear localization. SNP mapping and whole-genome sequencing revealed three novel smc-5 alleles: two truncations, alleles smc-5(wsh31) (C587*) and smc-5(wsh32) (Q655*), and one missense variant, smc-5(wsh33) (Y975D), each altering a highly conserved residue in the SMC domain. All three mutants exhibited significantly reduced brood size, progeny viability, and slightly elevated male percentages. Phenotypic characterization revealed that the truncations completely abrogate NSE-1::GFP nuclear localization, whereas the missense allele causes stage-dependent, partial mislocalization. Functional assays further demonstrated allele-specific and developmental stage-dependent hypersensitivities to DNA-damaging agents (MMS, HU, and cisplatin). These separation-of-function smc-5 alleles underscore the importance of domains and conserved residues in complex integrity and genome maintenance, and provide powerful genetic tools to dissect SMC-5/6 functions in vivo. Full article

(This article belongs to the Section Molecular Genetics)

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28 pages, 3773 KiB

Open AccessReview

Hostile Environments: Modifying Surfaces to Block Microbial Adhesion and Biofilm Formation

by Derek Wilkinson, Libuše Váchová and Zdena Palková

Biomolecules 2025, 15(6), 754; https://doi.org/10.3390/biom15060754 - 23 May 2025

Since the first observations of biofilm formation by microorganisms on various surfaces more than 50 years ago, it has been shown that most “unicellular” microorganisms prefer to grow in multicellular communities that often adhere to surfaces. The microbes in these communities adhere to [...] Read more.

Since the first observations of biofilm formation by microorganisms on various surfaces more than 50 years ago, it has been shown that most “unicellular” microorganisms prefer to grow in multicellular communities that often adhere to surfaces. The microbes in these communities adhere to each other, produce an extracellular matrix (ECM) that protects them from drugs, toxins and the host’s immune system, and they coordinate their development and differentiate into different forms via signaling molecules and nutrient gradients. Biofilms are a serious problem in industry, agriculture, the marine environment and human and animal health. Many researchers are therefore investigating ways to disrupt biofilm formation by killing microbes or disrupting adhesion to a surface, quorum sensing or ECM production. This review provides an overview of approaches to altering various surfaces through physical, chemical or biological modifications to reduce/prevent microbial cell adhesion and biofilm development and maintenance. It also discusses the advantages and disadvantages of each approach and the challenges faced by researchers in this field. Full article

(This article belongs to the Section Biological Factors)

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13 pages, 1451 KiB

Open AccessArticle

Effects of 5-Methyl-2′-Deoxycytidine in G-Quadruplex Forming Aptamers d(G₃C)₄ and d[GCG₂(CG₃)₃C]: Investigating the Key Role of the Loops

by Veronica Esposito, Daniela Benigno, Carla Aliberti, Camilla Esposito, Elisabetta Panza, Antonella Virgilio and Aldo Galeone

Biomolecules 2025, 15(6), 753; https://doi.org/10.3390/biom15060753 - 23 May 2025

T40214 (STAT) and its recently investigated analogue STATB are G-quadruplex (G4) forming aptamers characterized by an unusually high percentage of C. The therapeutic potential of T40214 relies on its ability to inhibit the signalling pathway of STAT3, a protein frequently overexpressed in tumor [...] Read more.

T40214 (STAT) and its recently investigated analogue STATB are G-quadruplex (G4) forming aptamers characterized by an unusually high percentage of C. The therapeutic potential of T40214 relies on its ability to inhibit the signalling pathway of STAT3, a protein frequently overexpressed in tumor cells. STAT adopts a dimeric 5′-5′ end-stacked quadruplex structure, characterized by parallel strands, three G-tetrads and three propeller-shaped loops formed by a cytidine residue. STATB folds in a very similar structure, apart from an additional cytidine bulge loop. Many studies suggest that thermal stability and topology of G4 can be significantly affected by C methylation, thus resulting in altered interaction of G4-binding proteins with these structures. Considering this, two series of STAT and STATB analogues containing a single 5-methyl-2′-deoxycytidine (mC) residue instead of canonical C nucleotide in the loop have been prepared and investigated by a combination of spectroscopic and electrophoretic techniques. CD, NMR and PAGE data clearly indicate that all derivatives adopt dimeric G4 strictly similar to that assumed by parent aptamers, but with higher stabilities. Furthermore, the resistance to nucleases and the antiproliferative activity of these mC-containing derivatives against HCT116 (human colorectal carcinoma) and T24 (human bladder carcinoma) cell lines have been evaluated. In most of the cases, STAT and STATB derivatives inhibit cell proliferation to different extents, although to a lesser degree than the unmodified parent sequences. All the data highlight the key role of the loops and indicate mC as a useful tool to contribute favorably to the stability of G4-forming aptamers without alteration of their topology, required for the biological activity. Full article

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11 pages, 2387 KiB

Open AccessArticle

A Convenient Fluorogenic Detection Strategy for Phosphorothioate Modification of DNA Through Photocatalytic Oligonucleotide-Templated Reaction

by Nannan Jing, Yantian Qin, Xinli Fan, Qian Wang, Jing Wang, Fuping You and Xinjing Tang

Biomolecules 2025, 15(6), 752; https://doi.org/10.3390/biom15060752 - 23 May 2025

DNA phosphorothioate (PT) modifications, characterized by the replacement of a non-bridging phosphate oxygen atom with a sulfur atom, are widely observed in bacterial genomes. Sensitive detection of phosphorothioate is crucial for elucidating their biological roles and functions. Herein, we developed an innovative method [...] Read more.

DNA phosphorothioate (PT) modifications, characterized by the replacement of a non-bridging phosphate oxygen atom with a sulfur atom, are widely observed in bacterial genomes. Sensitive detection of phosphorothioate is crucial for elucidating their biological roles and functions. Herein, we developed an innovative method that leverages oligonucleotide-templated reactions (OTRs) and fluorogenic oligonucleotide probes. By optimizing temperature, probe sequence length, and the relative distance between PT position and the fluorophore probe, we achieved sensitive detection for DNA PT modifications through fluorogenic signal amplification, which provides an efficient and cost-effective approach for sensitive detection of phosphorothioate-modified DNA. Full article

(This article belongs to the Section Chemical Biology)

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26 pages, 2285 KiB

Open AccessReview

Immune Checkpoint Inhibitor Therapy for Prostate Cancer: Present and Future Prospectives

by Vikrant Rai

Biomolecules 2025, 15(6), 751; https://doi.org/10.3390/biom15060751 - 22 May 2025

Prostate cancer, a slow-growing tumor, develops through the over-proliferation of malignant cells in the prostate and is one of the most common types of cancer. Active surveillance, radical prostatectomy, external beam radiation, brachytherapy, cryotherapy, stereotactic body radiation therapy, hormone therapy, and chemotherapy are [...] Read more.

Prostate cancer, a slow-growing tumor, develops through the over-proliferation of malignant cells in the prostate and is one of the most common types of cancer. Active surveillance, radical prostatectomy, external beam radiation, brachytherapy, cryotherapy, stereotactic body radiation therapy, hormone therapy, and chemotherapy are common treatment strategies for prostate cancer. However, resistance to treatment in advanced prostate cancer is a concerning issue in the use of these therapies. Immune checkpoint inhibitor (ICI) therapy for prostate cancer is an emerging strategy for the treatment of advanced prostate cancers but the resistance and limited efficacy to ICIs observed in metastatic castration-resistant prostate cancer (mCRPC) raises concerns. The ongoing clinical trials for combination therapies for mCRPC have provided some hope. This review concisely discusses the molecular and cellular mechanisms, immunotherapy, the limitations of ICIs, combination therapies, and the prospects of developing novel therapeutics for prostate cancer. Full article

(This article belongs to the Special Issue Advances in Cellular and Molecular Mechanisms in Immuno-Oncology and Onco-Hematology)

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23 pages, 2903 KiB

Open AccessArticle

A Mechanistic Insight into the Anti-Staphylococcal Mode of Action of (+)-Usnic Acid and Its Synergy with Norfloxacin Against Methicillin-Resistant Staphylococcus aureus

by Bhavana Gangwar, Santosh Kumar, Parmanand Kumar, Anirban Pal and Mahendra P. Darokar

Biomolecules 2025, 15(6), 750; https://doi.org/10.3390/biom15060750 - 22 May 2025

In this study, a global response analysis was performed to explore the mechanism of action of Usnic acid and its synergy with Norfloxacin, a well-known quinolone antibiotic to which MRSA clinical isolates showed resistance (MIC, 500 µg/mL). A microdilution assay, a growth kinetics [...] Read more.

In this study, a global response analysis was performed to explore the mechanism of action of Usnic acid and its synergy with Norfloxacin, a well-known quinolone antibiotic to which MRSA clinical isolates showed resistance (MIC, 500 µg/mL). A microdilution assay, a growth kinetics analysis, a microscopic analysis, and cell-based assays consistently showed that Usnic acid possesses strong anti-staphylococcal activity (MIC, 7.8 µg/mL), causes cell leakage, modulates efflux pump activity, and synergizes with Norfloxacin against the multi-drug-resistant clinical isolate MRSA 2071. Whole-cell proteome profiling using gel-free proteomics-based nano-LC-ESI-QTOF-MS/MS revealed several proteins whose expression was significantly modulated by Usnic acid and Norfloxacin alone or in combination. Usnic acid downregulated the abundance of RNA polymerase subunits (RpoB and RpoC), carbamoyl phosphate synthase large subunit (PyrAB), chaperone (GroEL), and adenylosuccinate synthetase (PurA). Interestingly, proteins found to be upregulated in the presence of Usnic acid and Norfloxacin included oxidative-stress-related proteins such as peroxidase (Tpx), alkyl hydroperoxide reductase (AphC), and general stress protein (UspA). This study clearly shows that Usnic acid affects numerous cellular targets and can potentiate the action of Norfloxacin. Furthermore, an in vivo study showed that UA at low concentrations prevents body weight gain, but changes in other tested toxicological parameters were found to be within normal limits. Thus, UA at low doses appears to be a promising candidate for repurposing old antibiotics through combination therapy against MRSA infections. Full article

(This article belongs to the Special Issue Key Molecules in Traditional Medicine: From Molecular Mechanisms to Therapies Strategies)

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15 pages, 5633 KiB

Open AccessArticle

Mechanistic Insights into the Mechanism of Allosteric Inhibition of Ubiquitin-Specific Protease 7 (USP7)

by Xuebin Wang, Ning Liu, Nuan Li, Shaoyong Lu and Zongtao Chai

Biomolecules 2025, 15(6), 749; https://doi.org/10.3390/biom15060749 - 22 May 2025

Ubiquitin-specific protease 7 (USP7), a deubiquitinase enzyme responsible for removing ubiquitin (Ub) from target proteins, plays a crucial role in oncogenic pathways and has been implicated in various human diseases. X-ray crystallography has revealed distinct conformations of USP7, including apo (ligand-free), allosteric inhibitor-, [...] Read more.

Ubiquitin-specific protease 7 (USP7), a deubiquitinase enzyme responsible for removing ubiquitin (Ub) from target proteins, plays a crucial role in oncogenic pathways and has been implicated in various human diseases. X-ray crystallography has revealed distinct conformations of USP7, including apo (ligand-free), allosteric inhibitor-, and Ub-bound states. However, the dynamic mechanisms underlying the allosteric inhibition of USP7 remain unclear. This study investigates the effect of allosteric inhibitor binding on the dynamics of USP7 through multiple replica molecular dynamics simulations. Our results demonstrate that Ub binding stabilizes the USP7 conformation, while allosteric inhibitor binding increases flexibility and variability in the fingers and palm domains of USP7. Furthermore, our analysis of USP7 local regions reveals that allosteric inhibitor binding not only restrains the dynamics of the C-terminal Ub binding site, thereby impeding the accessibility of Ub to USP7, but also disrupts the proper alignment of the catalytic triad (Cys223-His464-Asp481) in USP7. Additionally, community network analysis indicates that intra-domain communications within the fingers domain in USP7 are significantly enhanced upon allosteric inhibitor binding. This study reveals that the binding of an allosteric inhibitor induces a dynamic shift in enzyme’s conformational equilibrium, effectively disrupting its catalytic activity through allosteric modulation. Full article

(This article belongs to the Special Issue Computational Analysis and Conformational Modeling for Protein Structure and Interaction)

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26 pages, 9830 KiB

Open AccessArticle

Neuronal Plasticity-Dependent Paradigm and Young Plasma Treatment Prevent Synaptic and Motor Deficit in a Rett Syndrome Mouse Model

by Sofía Espinoza, Camila Navia, Rodrigo F. Torres, Nuria Llontop, Verónica Valladares, Cristina Silva, Ariel Vivero, Exequiel Novoa-Padilla, Jessica Soto-Covasich, Jessica Mella, Ricardo Kouro, Sharin Valdivia, Marco Pérez-Bustamante, Patricia Ojeda-Provoste, Nancy Pineda, Sonja Buvinic, Dasfne Lee-Liu, Juan Pablo Henríquez and Bredford Kerr

Biomolecules 2025, 15(5), 748; https://doi.org/10.3390/biom15050748 - 21 May 2025

Classical Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene, resulting in a devastating phenotype associated with a lack of gene expression control. Mouse models lacking Mecp2 expression with an RTT-like phenotype have been developed to advance therapeutic [...] Read more.

Classical Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene, resulting in a devastating phenotype associated with a lack of gene expression control. Mouse models lacking Mecp2 expression with an RTT-like phenotype have been developed to advance therapeutic alternatives. Environmental enrichment (EE) attenuates RTT symptoms in patients and mouse models. However, the mechanisms underlying the effects of EE on RTT have not been fully elucidated. We housed male hemizygous Mecp2-null (Mecp2^-/y) and wild-type mice in specially conditioned cages to enhance sensory, cognitive, social, and motor stimulation. EE attenuated the progression of the RTT phenotype by preserving neuronal cytoarchitecture and neural plasticity markers. Furthermore, EE ameliorated defects in neuromuscular junction organization and restored the motor deficit of Mecp2^-/y mice. Treatment with plasma from young WT mice was used to assess whether the increased activity could modify plasma components, mimicking the benefits of EE in Mecp2^-/y. Plasma treatment attenuated the RTT phenotype by improving neurological markers, suggesting that peripheral signals of mice with normal motor function have the potential to reactivate dormant neurodevelopment in RTT mice. These findings demonstrate how EE and treatment with young plasma ameliorate RTT-like phenotype in mice, opening new therapeutical approaches for RTT patients. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)

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21 pages, 703 KiB

Open AccessReview

Functional Thyroid Organoids—Powerful Stem Cell-Derived Models in Basic and Translational Research

by Meghna Parakkal Shankar, Alessandra Boggian, Daniela Aparicio-Quiñonez, Sami Djerbib, Eduardo Rios-Morris, Sabine Costagliola and Mírian Romitti

Biomolecules 2025, 15(5), 747; https://doi.org/10.3390/biom15050747 - 21 May 2025

Thyroid organoids, three-dimensional in vitro models derived from stem cells, have emerged as a powerful tool for studying thyroid development, function, and disease mechanisms. These organoids recapitulate the key aspects of the thyroid gland, including the follicular structure, hormone production, and response to [...] Read more.

Thyroid organoids, three-dimensional in vitro models derived from stem cells, have emerged as a powerful tool for studying thyroid development, function, and disease mechanisms. These organoids recapitulate the key aspects of the thyroid gland, including the follicular structure, hormone production, and response to stimuli such as to the thyroid-stimulating hormone (TSH). Recent advances in thyroid organoid technology have established the basis for the modeling of development and thyroid diseases, including congenital hypothyroidism (CH), autoimmune conditions like Graves’ disease and Hashimoto’s thyroiditis, and other thyroid-related disorders. By utilizing pluripotent stem cells (PSCs) and adult tissue, researchers have generated organoid models suitable for dissecting the mechanisms associated with thyroid development while mimicking the genetic, functional, and inflammatory characteristics of thyroid diseases. Additionally, thyroid organoids offer the potential for personalized medicine by providing a platform to test therapies in a more clinically relevant context. This review highlights the recent progress in thyroid organoid generation, discusses their applications in dissecting the thyroid development mechanisms and disease modeling, and explores their potential for advancing our understanding of the thyroid physiology and pathology. Furthermore, we address the challenges and future directions in the optimization and use of thyroid organoids in translational research. Full article

(This article belongs to the Special Issue Biosynthesis and Function of Thyroid Hormones)

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22 pages, 3143 KiB

Open AccessArticle

Multiomics-Based Profiling of the Fecal Microbiome Reveals Potential Disease-Specific Signatures in Pediatric IBD (PIBD)

by Anita H. DeSantis, Kristina Buss, Keaton M. Coker, Brad A. Pasternak, Jinhua Chi, Jeffrey S. Patterson, Haiwei Gu, Peter W. Jurutka and Todd R. Sandrin

Biomolecules 2025, 15(5), 746; https://doi.org/10.3390/biom15050746 - 21 May 2025

Inflammatory bowel disease (IBD), which includes Crohn’s Disease (CD) and Ulcerative Colitis (UC), is a chronic gastrointestinal (GI) disorder affecting 1 in 100 people in the United States. Pediatric IBD (PIBD) is estimated to impact 15 per 100,000 children in North America. Factors [...] Read more.

Inflammatory bowel disease (IBD), which includes Crohn’s Disease (CD) and Ulcerative Colitis (UC), is a chronic gastrointestinal (GI) disorder affecting 1 in 100 people in the United States. Pediatric IBD (PIBD) is estimated to impact 15 per 100,000 children in North America. Factors such as the gut microbiome (GM), genetic predisposition to the disease, and certain environmental factors are thought to be involved in pathogenesis. However, the pathophysiology of IBD is incompletely understood, and diagnostic biomarkers and effective treatments, particularly for PIBD, are limited. Recent work suggests that these factors may interact to influence disease development, and multiomic approaches have emerged as promising tools to elucidate the pathophysiology. We employed metagenomics, metabolomics- and metatranscriptomics-based approaches to examine the microbiome, its genetic potential, and its activity to identify factors associated with PIBD. Metagenomics-based analyses revealed pathways such as octane oxidation and glycolysis that were differentially expressed in UC patients. Additionally, metatranscriptomics-based analyses suggested enrichment of glycan degradation and two component systems in UC samples as well as protein processing in the endoplasmic reticulum, ribosome, and protein export in CD and UC samples. In addition, metabolomics-based approaches revealed patterns of differentially abundant metabolites between healthy and PIBD individuals. Interestingly, overall microbiome community composition (as measured by alpha and beta diversity indices) did not appear to be associated with PIBD. However, we observed a small number of differentially abundant taxa in UC versus healthy controls, including members of the Classes Gammaproteobacteria and Clostridia as well as members of the Family Rikenellaceae. Accordingly, when identifying potential biomarkers for PIBD, our results suggest that multiomics-based approaches afford enhanced potential to detect putative biomarkers for PIBD compared to microbiome community composition sequence data alone. Full article

(This article belongs to the Special Issue Integrating Genetics, Immune Dysregulation, and the Gut Microbiome: Advances in Elucidating IBD Pathophysiology and Emerging Therapeutic Strategies)

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17 pages, 1115 KiB

Open AccessArticle

Real-World Analysis of HRD Assay Variability in High-Grade Serous Ovarian Cancer: Impacts of BRCA1/2 Mutation Subtypes on HRD Assessment

by Giovanni Luca Scaglione, Valentina Lombardo, Maurizio Polano, Giuseppa Scandurra, Angela Pettinato, Corrado Giunta, Rosario Iemmolo, Paolo Scollo and Ettore D. Capoluongo

Biomolecules 2025, 15(5), 745; https://doi.org/10.3390/biom15050745 - 21 May 2025

The HRD (Homologous Recombination Deficiency) test is considered a genomic alteration useful for guiding therapeutic decisions in patients with ovarian cancer. Some commercial and in house alternative “academic” tests are available. Recent findings indicate that not all BRCA1/2 mutations determine the magnitude of [...] Read more.

The HRD (Homologous Recombination Deficiency) test is considered a genomic alteration useful for guiding therapeutic decisions in patients with ovarian cancer. Some commercial and in house alternative “academic” tests are available. Recent findings indicate that not all BRCA1/2 mutations determine the magnitude of HRD and that some patients carrying BRCA1/2 mutations may exhibit indeterminate or even negative HRD scores. Furthermore, certain therapies (e.g., olaparib and bevacizumab) offer particularly pronounced benefits for high-grade serous ovarian cancer (HGSOC) patients harboring mutations in the DNA-binding domain (DBD) of BRCA1/2. The aim of the present study is to investigate the relationship between the HRD scores and BRCA1/2 status of 51 HGSOC patients (50 BRCA1/2 mutated and 1 wild type). The HRD status was assessed by means of shallow whole-genome sequencing and BRCA1/2 status by the NGS pipeline. We did not find a correlation between the HRD status and type of BRCA1/2 alterations. A strong correlation between the HRD score and age was found. Our paper underlines the need to introduce other biological factors within the algorithms of the HRD evaluation in order to better tailor the HRD status, harmonize the metrics of the HRD assessment, and personalize therapies. Full article

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

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17 pages, 2157 KiB

Open AccessArticle

Modulation of Kv Channel Gating by Light-Controlled Membrane Thickness

by Rohit Yadav, Juergen Pfeffermann, Nikolaus Goessweiner-Mohr, Toma Glasnov, Sergey A. Akimov and Peter Pohl

Biomolecules 2025, 15(5), 744; https://doi.org/10.3390/biom15050744 - 21 May 2025

Voltage-gated potassium (Kv) channels are e ssential for shaping action potentials and rely on anionic lipids for proper gating, yet the mechanistic basis of lipid–channel interactions remains unclear. Cryo-electron microscopy studies suggest that, in the down state, arginine residues of the voltage sensor [...] Read more.

Voltage-gated potassium (Kv) channels are e ssential for shaping action potentials and rely on anionic lipids for proper gating, yet the mechanistic basis of lipid–channel interactions remains unclear. Cryo-electron microscopy studies suggest that, in the down state, arginine residues of the voltage sensor draw lipid phosphates upward, leading to a local membrane thinning of ~5 Å—an effect absent in the open state. To test whether membrane thickness directly affects voltage sensor function, we reconstituted Kv channels from Aeropyrum pernix (KvAP) into planar lipid bilayers containing photoswitchable lipids. Upon blue light illumination, the membrane thickened, and KvAP activity increased; UV light reversed both effects. Our findings indicate that membrane thickening weakens the interaction between lipid phosphates and voltage-sensing arginines in the down state, lowering the energy barrier for the transition to the up state and thereby promoting channel opening. This non-genetic, membrane-mediated approach provides a new strategy to control ion channel activity using light and establishes a direct, reversible link between membrane mechanics and voltage sensing, with potential applications in the remote control of neuronal excitability. Full article

(This article belongs to the Special Issue Light as a Tool to Manipulate the Structure and Function of Membranes and Membrane Proteins)

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15 pages, 1975 KiB

Open AccessArticle

Cathepsin B Levels Correlate with the Severity of Canine Myositis

by Valeria De Pasquale, Emanuela Vaccaro, Federica Rossin, Mariangela Ciampa, Melania Scarcella, Orlando Paciello and Simona Tafuri

Biomolecules 2025, 15(5), 743; https://doi.org/10.3390/biom15050743 - 21 May 2025

Cathepsins are protease enzymes vital for normal physiological functions, such as digestion, coagulation, hormone secretion, bone resorption, apoptosis, autophagy, and both innate and adaptive immunity. Their altered expression and/or activity is associated with various pathological conditions, including inflammatory processes. In this study, we [...] Read more.

Cathepsins are protease enzymes vital for normal physiological functions, such as digestion, coagulation, hormone secretion, bone resorption, apoptosis, autophagy, and both innate and adaptive immunity. Their altered expression and/or activity is associated with various pathological conditions, including inflammatory processes. In this study, we investigated the expression levels of cathepsins in muscle specimens collected from dogs affected by inflammatory myopathy (IM) of variable severity established through histopathological analysis. Samples collected from dogs affected by IM at mild, moderate, and severe stages and from healthy (control) dogs were analyzed for the expression profile of 35 proteases using a proteome profiler array. Among the other proteases, cathepsin B was upregulated to an extent depending on disease progression. By exploring the molecular mechanisms underlying the impact of cathepsin B on the disease, we found that the upregulation of cathepsin B in diseased tissues correlates with increased TGFβ-1 expression levels and elevated phosphorylation levels of the TGFβ-1 signaling mediator SMAD2/3. These results suggest that cathepsin B might be involved in the onset and progression of fibrosis commonly occurring in IM diseased dogs. Overall, our findings reveal that modulating cathepsin B activity may hold therapeutic potential for IM. Full article

(This article belongs to the Section Biological Factors)

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31 pages, 14267 KiB

Open AccessArticle

Iron Replacement Attenuates Hypoxic Pulmonary Hypertension by Remodeling Energy Metabolism via Regulating the HIF2α/Mitochondrial Complex I, III/ROS Axis

by Yumei Geng, Huijie Wang, Zhenzhong Bai and Rili Ge

Biomolecules 2025, 15(5), 742; https://doi.org/10.3390/biom15050742 - 21 May 2025

Iron deficiency is highly prevalent in patients with idiopathic pulmonary hypertension; nevertheless, its role and clinical significance in hypoxic pulmonary hypertension (HPH) remain elusive. Therefore, this study aims to clarify the role and molecular mechanisms of iron in HPH. By means of a [...] Read more.

Iron deficiency is highly prevalent in patients with idiopathic pulmonary hypertension; nevertheless, its role and clinical significance in hypoxic pulmonary hypertension (HPH) remain elusive. Therefore, this study aims to clarify the role and molecular mechanisms of iron in HPH. By means of a retrospective analysis of clinical data from HPH patients and examinations of HPH animal models, we discovered that both HPH patients and animal models exhibit significant iron deficiency, characterized by reduced hepatic iron storage and elevated hepcidin expression. To further explore iron’s role in HPH, we modulated iron metabolism through pharmacological and dietary interventions in chronic hypoxic animal models. The results showed that iron deficiency exacerbated chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy, while iron supplementation alleviated these conditions. Further investigations revealed that iron regulates HIF2α expression in pulmonary arterial endothelial cells (PAECs) under chronic hypoxia. Therefore, through in vivo and in vitro experiments, we demonstrated that HIF2α inhibition attenuates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Mechanistically, chronic hypoxia-mediated iron deficiency enhances HIF2α activation, subsequently suppressing iron/sulfur cluster assembly enzyme (ISCU) expression. This leads to decreased mitochondrial complexes I and III activity, increased reactive oxygen species (ROS) production, and inhibited oxidative phosphorylation. Consequently, metabolic reprogramming in PAECs results in a proliferation/apoptosis imbalance, ultimately exacerbating hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Collectively, our findings demonstrate that iron supplementation mitigates HPH progression by modulating HIF2α-mediated metabolic reprogramming in PAECs, revealing multiple therapeutic targets for HPH. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 2946 KiB

Open AccessArticle

The Novel Imiqualine EAPB02303 Is a Potent Drug for Treating Acute Myeloid Leukemia

by Perla Makhoul, Rita Hleihel, Shaymaa Itani, Maguy Hamie, Stephanie Pagniagua-Gayraud, Cindy Patinote, Myriam Richaud, Raghida Abou Merhi, Marwan El-Sabban, Simon Galas, Carine Deleuze-Masquefa, Pierre-Antoine Bonnet and Hiba El Hajj

Biomolecules 2025, 15(5), 741; https://doi.org/10.3390/biom15050741 - 20 May 2025

Although 60% of AML patients respond well to standard chemotherapy, most patients eventually relapse, develop chemoresistance, and do not survive more than five years. Targeted therapies, including analogs of imiquimod belonging to the family of imiqualines, emerged as promising agents against AML. Notably, [...] Read more.

Although 60% of AML patients respond well to standard chemotherapy, most patients eventually relapse, develop chemoresistance, and do not survive more than five years. Targeted therapies, including analogs of imiquimod belonging to the family of imiqualines, emerged as promising agents against AML. Notably, the first-generation imiqualine EAPB0503 proved selective potency against nucleophosmin-1-mutant (NPM1c) AML. Recently, chemical modifications of EAPB0503 led to the development of the lead compound from the second generation, EAPB02303. Here, we demonstrate that EAPB02303 displays 200-fold greater potency, broader activity across AML subtypes, and, importantly, a distinct mechanistic profile when compared to EAPB0503. Unlike EAPB0503, which primarily targeted NPM1c AML cells, EAPB02303 exhibits broad-spectrum activity across various AML subtypes. Remarkably, EAPB02303 anti-leukemic activity was attributed to the inhibition of PI3K/AKT/mTOR signaling activity. Nevertheless, NPM1c AML cells were more sensitive to EAPB02303, likely due to its ability to promote NPM1c protein degradation. In vivo, EAPB02303 potently reduced the leukemic burden and improved organ tumor infiltration in both wt-NPM1 and NPM1c AML xenograft mice. Yet, the significant prolonged survival was exclusive to NPM1c AML xenografts, likely due to superior response conferred by NPM1c degradation. Overall, these findings highlight the potential of EAPB02303 as a powerful therapeutic agent for a range of AML subtypes, supporting its further development for broader clinical use. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 3623 KiB

Open AccessArticle

LPS2336, a New TREK-1 Channel Activator Identified by High Throughput Screening

by Romane Boyer, Romane Bony, Maxence Maugis, Julien Schopp, Marion Leroux, Clément Michelin, Laurie Gonthier, Quentin Grzeskiewicz, Alexandre Jouannet, Youssef Aissouni, Bruno Didier, Mihaela Gulea, Nicolas Girard, Jean-Christophe Cintrat, Antoine Dumeige, Jérôme Busserolles, Sylvie Ducki and Stéphane Lolignier

Biomolecules 2025, 15(5), 740; https://doi.org/10.3390/biom15050740 - 20 May 2025

TWIK-related K+ (TREK-1) channels are involved in pain perception and their pharmacological activation has potential for pain relief. The development of new pharmacological tools to study these channels and enrich our knowledge of structure–activity relationships is therefore important. We optimized a high throughput [...] Read more.

TWIK-related K+ (TREK-1) channels are involved in pain perception and their pharmacological activation has potential for pain relief. The development of new pharmacological tools to study these channels and enrich our knowledge of structure–activity relationships is therefore important. We optimized a high throughput screening method based on thallium flux monitoring for the detection of TREK-1 activators in chemical libraries. We screened 1040 compounds from the French National Essential Chemical Library and identified LPS2336 as a potent TREK-1 activator with an EC₅₀ of 11.76 µM. Thirty-three LPS2336 analogs were subsequently tested but none of them retained activity on TREK-1. In vivo, LPS2336 produces antinociceptive activity when administered systemically and, to a lesser extent, intracerebroventricularly, but not intrathecally, showing that targeting peripheral TREK-1 channels may be important to produce pain relief, with the interest of reducing potential central adverse effects. LPS2336 was shown to produce sedation and hypothermia with a narrow therapeutic window. As these adverse effects are also observed in TREK-1 knock-out mice, they are likely mediated by off-targets. Our work provides key optimization steps for thallium-based assays and a new pharmacological tool for the study of TREK-1 channels. It also raises the importance of investigating adverse effects in vivo at early stages of drug discovery. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 809 KiB

Open AccessArticle

Supplementation with Bioactive Compounds Improves Health and Rejuvenates Biological Age in Postmenopausal Women

by Estefanía Díaz-Del Cerro, Judith Félix, Mª Carmen Martínez-Poyato and Mónica De la Fuente

Biomolecules 2025, 15(5), 739; https://doi.org/10.3390/biom15050739 - 20 May 2025

Aging involves immune system deterioration (immunosenescence) and increased oxidative stress, both associated with morbidity and mortality. Menopause accelerates aging, highlighting the need for strategies to mitigate its effects in postmenopausal women. This study assessed the impact of daily oral supplementation for one month [...] Read more.

Aging involves immune system deterioration (immunosenescence) and increased oxidative stress, both associated with morbidity and mortality. Menopause accelerates aging, highlighting the need for strategies to mitigate its effects in postmenopausal women. This study assessed the impact of daily oral supplementation for one month with 39 bioactive compounds (UNAMINA)—including amino acids, vitamins, and antioxidants—on immune function, redox parameters, stress-related hormones, and biological age in healthy postmenopausal women. Peripheral blood samples were collected before and after supplementation to analyze lymphocyte and neutrophil functions (adherence, chemotaxis, natural killer cell antitumor capacity, and lymphoproliferative response to mitogens), oxidative stress markers (antioxidant defenses such as glutathione peroxidase (GPx) and reductase activities, reduced glutathione (GSH) concentrations, as well as oxidants such as oxidized glutathione (GSSG), and lipid peroxidative damage) in blood cells, and stress-related hormones (dehydroepiandrosterone (DHEA) and cortisol) in plasma. Supplementation improved all immune cell functions and decreased oxidative stress (increasing antioxidants defenses such as GPx activity and GSH concentration and decreasing GSSG amount) and cortisol concentrations, whereas those of DHEA increased. The biological age also decreased. The results suggest that these bioactive compounds may be a beneficial strategy for promoting healthier aging in postmenopausal women by enhancing immune function, reducing biological age, improving redox balance, and regulating stress hormones. Full article

(This article belongs to the Special Issue Diet and Immune Response)

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15 pages, 1833 KiB

Open AccessArticle

Sex- and Tissue-Specific Effects of Leukemia Inhibitory Factor on Mitochondrial Bioenergetics Following Ischemic Stroke

by Hemendra J. Vekaria, Sarah J. Shelley, Sarah J. Messmer, Prashant D. Kunjadia, Christopher J. McLouth, Patrick G. Sullivan, Justin F. Fraser, Keith R. Pennypacker and Chirayu D. Pandya

Biomolecules 2025, 15(5), 738; https://doi.org/10.3390/biom15050738 - 20 May 2025

Oxidative stress due to increased reactive oxygen species (ROS) formation and/or inflammation is considered to play an important role in ischemic stroke injury. Leukemia inhibitory factor (LIF) has been shown to protect both oligodendrocytes and neurons from ischemia by upregulating endogenous anti-oxidants, though [...] Read more.

Oxidative stress due to increased reactive oxygen species (ROS) formation and/or inflammation is considered to play an important role in ischemic stroke injury. Leukemia inhibitory factor (LIF) has been shown to protect both oligodendrocytes and neurons from ischemia by upregulating endogenous anti-oxidants, though the effect of ischemia and the protective role of LIF treatment in mitochondrial function have not been studied. The goal of this study was to determine whether LIF protects ischemia-induced altered mitochondrial bioenergetics in reproductively senescent aged rats of both sexes (≥18 months old), approximately equivalent to the average age of human stroke patients. Animals were euthanized at 3 days after permanent middle cerebral artery occlusion (MCAO) surgery. We found that MCAO surgery significantly reduced mitochondrial oxidative phosphorylation in both the ipsilateral striatum and prefrontal cortex in male aged rats compared to their respective contralateral regions of the brain. MCAO injury showed mitochondrial bioenergetic dysfunction only in the striatum in female rats; however, the prefrontal cortex remained unaffected to the injury. LIF-treated rats significantly prevented mitochondrial dysfunction in the striatum in male rats compared to their vehicle-treated counterparts. Collectively, MCAO-induced mitochondrial dysfunction and LIF’s potential as a therapeutic biomolecule exhibited sex- and tissue-specific effects, varying between the striatum and prefrontal cortex in male and female rats. Full article

(This article belongs to the Special Issue Bioactive Molecules against Aging: Organism-, Cell-, and Mitochondria-Based Approaches)

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27 pages, 1697 KiB

Open AccessReview

Multimodal Function of Mesenchymal Stem Cells in Psoriasis Treatment

by Jiaxin Ou, Ziqing Li, Danni Yao, Chuanjian Lu and Xiang Zeng

Biomolecules 2025, 15(5), 737; https://doi.org/10.3390/biom15050737 - 19 May 2025

Psoriasis is a chronic inflammatory disease mediated by the innate and adaptive immune systems, and its pathogenesis involves multiple aspects, including abnormal interleukin (IL)-23–Th17 axis, dysfunction of Tregs and other immune cells, and a complex relationship between keratinocytes and the vascular endothelium. Dysfunction [...] Read more.

Psoriasis is a chronic inflammatory disease mediated by the innate and adaptive immune systems, and its pathogenesis involves multiple aspects, including abnormal interleukin (IL)-23–Th17 axis, dysfunction of Tregs and other immune cells, and a complex relationship between keratinocytes and the vascular endothelium. Dysfunction of mesenchymal stem cells in psoriatic skin may also be the main reason for the dysregulated inflammatory response. Mesenchymal stem cells, a type of adult stem cells with multidifferentiation potential, are involved in the regulation of multiple links and targets in the pathogenesis of psoriasis. Thus, a detailed exploration of these mechanisms may lead to the development of new therapeutic strategies for the treatment of psoriasis. In this paper, the role of mesenchymal stem cells in skin homeostasis, the pathogenesis of psoriasis, and the multimodal function of using mesenchymal stem cells in the treatment of psoriasis are reviewed. Full article

(This article belongs to the Section Cellular Biochemistry)

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18 pages, 1521 KiB

Open AccessArticle

Chemical Composition, Antioxidant, and Enzyme Inhibitory Activities of Artemisia schmidtiana Maxim. Essential Oil

by Xinyu Zhu and Xu Liu

Biomolecules 2025, 15(5), 736; https://doi.org/10.3390/biom15050736 - 19 May 2025

Artemisia schmidtiana Maxim., a plant belonging to the Asteraceae family, is renowned for its extensive ethnomedicinal applications and distinctive aromatic qualities. This study evaluated the chemical composition, antioxidant capacity, and inhibitory effects on acetylcholinesterase (AChE), α-glucosidase, and β-lactamase of its essential oil (EO). [...] Read more.

Artemisia schmidtiana Maxim., a plant belonging to the Asteraceae family, is renowned for its extensive ethnomedicinal applications and distinctive aromatic qualities. This study evaluated the chemical composition, antioxidant capacity, and inhibitory effects on acetylcholinesterase (AChE), α-glucosidase, and β-lactamase of its essential oil (EO). The major constituents of the EO were identified as germacrene D (16.29%), falcarinol (11.02%), β-caryophyllene (9.43%), α-zingiberene (7.93%), phytol (6.06%), and α-humulene (4.04%). The EO demonstrated radical scavenging activity against DPPH (44.9% at 5 mg/mL) and ABTS (IC₅₀ = 0.72 ± 0.02 mg/mL) radicals, with a FRAP antioxidant capacity of 126.61 ± 0.59 μmol·g⁻¹. Additionally, the EO exhibited modest AChE inhibition (16.7% at 250 μg/mL) and significant inhibition of α-glucosidase and β-lactamase, with IC₅₀ values of 178.80 ± 17.02 μg/mL and 40.06 ± 8.22 μg/mL, respectively. Molecular docking revealed favorable interactions between the major EO compounds and the tested enzymes, providing a theoretical foundation for future drug development. These findings suggest that A. schmidtiana EO holds potential for applications in the food and pharmaceutical industries, warranting further investigation. Full article

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

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