Biomolecules

19 pages, 576 KB

Open AccessArticle

Molecular Drivers of Vascular Adaptation in Young Athletes: An Integrative Analysis of Endothelial, Metabolic and Lipoprotein Biomarkers

by Jonas Haferanke, Lisa Baumgartner, Maximilian Dettenhofer, Stefanie Huber, Frauke Mühlbauer, Tobias Engl, Paulina Wasserfurth, Karsten Köhler, Renate Oberhoffer, Thorsten Schulz and Sebastian Freilinger

Biomolecules 2025, 15(12), 1726; https://doi.org/10.3390/biom15121726 - 11 Dec 2025

Abstract

Adolescence is a critical window for cardiovascular (CV) development, yet the molecular drivers of vascular adaptation to regular exercise in youth remain poorly understood. This cross-sectional study assessed vascular structure and function alongside endothelial, metabolic, and lipoprotein biomarkers in 203 healthy young athletes [...] Read more.

Adolescence is a critical window for cardiovascular (CV) development, yet the molecular drivers of vascular adaptation to regular exercise in youth remain poorly understood. This cross-sectional study assessed vascular structure and function alongside endothelial, metabolic, and lipoprotein biomarkers in 203 healthy young athletes (aged 10–16). Vascular phenotyping included carotid intima-media thickness (IMT), pulse wave velocity, and carotid deformation indices (strain, strain rate). Circulating nitric oxide (NO), endothelin-1, free triiodothyronine (fT3), leptin, low-density lipoprotein, and high-density lipoprotein were analyzed. Associations were examined using hierarchically adjusted multivariable linear regression, mediation and moderation were tested and sex-stratified/matched analyses were conducted. While training volume was not associated with endothelial markers, leptin was correlated positively with NO and negatively with diastolic strain rate, suggesting dual vascular actions. fT3 was inversely associated with IMT, indicating a potential protective role in vascular remodeling. Lipoprotein profiles showed no independent associations with vascular parameters. Hemodynamic load, particularly systolic blood pressure, emerged as the dominant determinant of arterial stiffness. Sex-specific differences across biomarkers and vascular indices support a multifactorial model: in active youth, vascular phenotype reflects hemodynamics, body composition, and endocrine–metabolic signals more than training; longitudinal mechanistic studies should clarify causal pathways and guide individualized cardiovascular risk profiling. Full article

(This article belongs to the Special Issue Biomolecular Sciences and Precision Medicine in Vascular Disease)

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18 pages, 8274 KB

Open AccessArticle

The Adaptable Binding Cleft of RmuAP1, a Pepsin-like Peptidase from Rhodotorula mucilaginosa, Enables the Enzyme to Degrade Immunogenic Peptides Derived from Gluten

by Yu-Han Zhang, Chia-Liang Lin and Menghsiao Meng

Biomolecules 2025, 15(12), 1725; https://doi.org/10.3390/biom15121725 - 11 Dec 2025

Abstract

Celiac disease (CD) is an autoimmune disorder triggered by pepsin-resistant, gluten-derived immunogenic peptides (GIPs) in genetically predisposed individuals. Enzyme therapy targeting GIPs has been suggested as a complementary practice to a gluten-free diet to help reduce the symptoms of CD. Here, we present [...] Read more.

Celiac disease (CD) is an autoimmune disorder triggered by pepsin-resistant, gluten-derived immunogenic peptides (GIPs) in genetically predisposed individuals. Enzyme therapy targeting GIPs has been suggested as a complementary practice to a gluten-free diet to help reduce the symptoms of CD. Here, we present the crystal structure of RmuAP1, a pepsin-like aspartic protease from Rhodotorula mucilaginosa, which effectively degrades the toxic 33-mer and 26-mer GIPs under postprandial gastric conditions (pH 3.0–6.0). RmuAP1 has a canonical fold characteristic of the aspartic protease subfamily A1; however, it features a distinct flap and a flexible loop structure. Compared to pepsin, RmuAP1 accommodates the tetrapeptides PQQP and PQPQ, motifs frequently repeated on GIPs, via an adaptable binding cleft. Molecular dynamics (MD) simulations have shown that RmuAP1 stably engages these ligands, maintaining both the catalytic water in position and a closed flap conformation, primarily through ligand-induced remodeling of the S1′ pocket. In contrast, pepsin neither binds these ligands effectively nor achieves a catalytically competent conformation. Structural comparisons and dihedral analysis further support an induced-fit mechanism underlying RmuAP1’s pocket remodeling. Together, this study clarifies the structural basis for RmuAP1 to hydrolyze GIPs, emphasizing the potential of RmuAP1 as a platform for developing enhanced oral peptidase for CD patients through protein engineering approaches. Full article

(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)

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25 pages, 2269 KB

Open AccessReview

Complexes Formed by the K63-Specific Deubiquitinating Enzyme BRCC36: New Promising Therapeutic Targets in Human Disease

by Xinyu Zhang, Xiaodong Pang, Yili Chen, Yue Liu, Jian-An Huang and Yuanyuan Zeng

Biomolecules 2025, 15(12), 1724; https://doi.org/10.3390/biom15121724 - 11 Dec 2025

Abstract

BRCC36, a member of the JAB1/MPN/Mov34 metalloenzymes family, exhibits distinct biochemical characteristics compared to other monomeric deubiquitinating enzymes. To function as a deubiquitinating enzyme, BRCC36 must assemble into a complex with other subunits that specifically cleaves K63-linked polyubiquitin chains. In the cytoplasm, BRCC36 [...] Read more.

BRCC36, a member of the JAB1/MPN/Mov34 metalloenzymes family, exhibits distinct biochemical characteristics compared to other monomeric deubiquitinating enzymes. To function as a deubiquitinating enzyme, BRCC36 must assemble into a complex with other subunits that specifically cleaves K63-linked polyubiquitin chains. In the cytoplasm, BRCC36 forms the BRISC complex, which plays a crucial role in regulating various signaling pathways through modulating the K63-linked ubiquitination of substrate proteins. The BRISC complex can interact with the cytoplasmic SHMT2, thereby influencing diverse biological processes, including inflammation, mitosis, and hematopoiesis. Within the nucleolus, BRCC36 forms the BRCA1-A complex, which contributes to DNA damage repair. Growing evidence underscores the importance of the ubiquitin system, particularly deubiquitinating enzymes, in the initiation and progression of various diseases. In this review, we first provide a comprehensive overview of the localization, assembly, mutations, and functions of BRCC36 and its associated complexes. We then discuss recent advances in research on BRCC36 across various diseases and explore its potential as a therapeutic target. Full article

(This article belongs to the Section Molecular Biology)

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20 pages, 5876 KB

Open AccessReview

Molecular Portrait of Autoantigens in Type 1 Diabetes

by Ilya Kandinov, Anastasia Knyazeva, Elizaveta Lander, Dmitry Gryadunov and Elena Savvateeva

Biomolecules 2025, 15(12), 1723; https://doi.org/10.3390/biom15121723 - 11 Dec 2025

Abstract

This review focuses on the molecular pathogenesis of Type 1 diabetes (T1D), specifically on the key autoantigens targeted by the autoimmune response and the clinical implications of their epitope specificity. T1D is characterized by the destruction of insulin-producing pancreatic β-cells. The autoimmune attack [...] Read more.

This review focuses on the molecular pathogenesis of Type 1 diabetes (T1D), specifically on the key autoantigens targeted by the autoimmune response and the clinical implications of their epitope specificity. T1D is characterized by the destruction of insulin-producing pancreatic β-cells. The autoimmune attack is directed against a defined set of autoantigens, primarily insulin, glutamic acid decarboxylase 65, tyrosine phosphatase-like protein, zinc transporter 8, as well as several minor autoantigens. A critical advancement in understanding the disease has been the analysis of epitope specificity, revealing that immunodominant epitopes are conformational and often localized to C-terminal protein regions, exposed during β-cell degradation. The introduction of sensitive multiplex assays for the simultaneous detection of T1D-associated autoantibodies represents a major diagnostic breakthrough. These platforms enable early diagnosis, risk stratification, and the identification of a “therapeutic window” for intervention. At this preclinical stage, antigen-specific immunotherapies aimed at restoring immune tolerance show significant promise. Ultimately, the combination of personalized diagnostic profiles, epitope mapping, and targeted therapies forms the basis for a new T1D management paradigm focused on halting the autoimmune process itself and preserving functional β-cell mass. Full article

(This article belongs to the Special Issue Immune Responses in Type 1 Diabetes)

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15 pages, 1073 KB

Open AccessArticle

In Vitro Digestibility, Structural and Functional Properties of Millettia speciosa Champ. Seed Protein

by Qing Yang, Shuxian Ding, Qinglong Wang, Li Xu, Xiaoxia Yan, Huan Tang, Langxing Yuan, Xiaoyan Chen, Zhunian Wang and Maoyuan Wang

Biomolecules 2025, 15(12), 1722; https://doi.org/10.3390/biom15121722 - 11 Dec 2025

Abstract

As an underutilized industrial byproduct generated during bioactive compound extraction from Millettia speciosa Champ. seeds, the residual protein fraction represents a promising sustainable resource for valorization. Millettia speciosa Champ. seed protein (MP) was extracted, and its fundamental physicochemical and functional properties were evaluated [...] Read more.

As an underutilized industrial byproduct generated during bioactive compound extraction from Millettia speciosa Champ. seeds, the residual protein fraction represents a promising sustainable resource for valorization. Millettia speciosa Champ. seed protein (MP) was extracted, and its fundamental physicochemical and functional properties were evaluated for potential applications in the food industry. Structural characterization revealed that MP had a molecular weight distribution with major components at 14.0 kDa and 116.0 kDa, with respective denaturation temperatures of 79.75 °C and 91.77 °C. The main structure of MP included different proportions of intramolecular α-helices and random coils in different pH microenvironments, based on circular dichroism spectroscopy. The MP displayed similar solubility profiles to the soy protein isolate (SP), but with lower solubility at slightly acidic pH, low solubility at pH 5.0, and comparable solubility above pH 8.0. Functional assessments showed that MP possessed emulsifying, foaming, water-binding, and fat-absorption capacities comparable to those of SPI, although the in vitro digestibility was relatively lower. These findings indicate that MP may serve as a safe and nutritious functional ingredient for health-oriented food products. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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18 pages, 2437 KB

Open AccessArticle

Investigation of the Jasmonate ZIM-Domain Family Reveals PavJAZ8 Regulates Fruit Aroma Traits in Sweet Cherry (Prunus avium L.)

by Wei Wang, Tianle Shi, Zhengrong Dai, Xiaoming Zhang, Jing Wang, Chuanbao Wu, Chen Feng, Guohua Yan, Kaichun Zhang, Yuan Yang and Xuwei Duan

Biomolecules 2025, 15(12), 1721; https://doi.org/10.3390/biom15121721 - 11 Dec 2025

Abstract

Jasmonate ZIM-domain (JAZ) family genes, which belong to TIFY family, are plant-specific transcriptional repressors. As key regulators of the jasmonic acid signaling pathway, JAZ proteins play crucial roles in various aspects of plant biology. However, the identification and functional characterization of JAZ genes [...] Read more.

Jasmonate ZIM-domain (JAZ) family genes, which belong to TIFY family, are plant-specific transcriptional repressors. As key regulators of the jasmonic acid signaling pathway, JAZ proteins play crucial roles in various aspects of plant biology. However, the identification and functional characterization of JAZ genes in sweet cherry (Prunus avium L.) fruit remain unknown. In the present study, we identified nine JAZ members in the sweet cherry genome. We systematically analyzed the gene structures, protein domains, evolutionary relationships, and physicochemical properties of these members and also evaluated their expression levels across different fruit developmental stages, as well as under methyl jasmonate (MeJA) treatment. Among these members, our results revealed a previously uncharacterized JAZ member, PavJAZ8, as a crucial regulator of fruit aroma traits. Specifically, RT-qPCR analysis showed that PavJAZ8 overexpression modulates the expression of genes involved in the biosynthesis of aroma volatiles, such as PavLOX2, PavLOX3, PavHPL1, PavADH1.1, PavADH1.2, and PavADH7, which are involved in the synthesis of aldehydes and alcohols. Consistent with the gene expression data, analysis of volatile metabolites revealed that PavJAZ8 overexpression significantly inhibited the accumulation of several related aldehydes and alcohols, including hexanal, geraniol, and benzyl alcohol. Furthermore, PavJAZ8 expression was highly responsive to phytohormone treatments, such as abscisic acid (ABA) and MeJA. Further analysis showed that PavJAZ8 interacts with PavMYC2, thereby mediating JA signal transduction. Our results highlight PavJAZ8 as a novel regulator of fruit aroma quality, offering a valuable genetic target for sweet cherry improvement. Full article

(This article belongs to the Special Issue Molecular Advances in Stress Response, Growth, Development, and Breeding of Horticultural Crops)

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2 pages, 136 KB

Open AccessCorrection

Correction: Meli et al. Ngn2-Induced Differentiation of the NG108-15 Cell Line Enhances Motor Neuronal Differentiation and Neuromuscular Junction Formation. Biomolecules 2025, 15, 637

by Madeline Meli, Kristy Swiderski, Jinchao Gu, Ben Rollo, Ben Bartlett, Marissa K. Caldow, Gordon S. Lynch, Patrick Kwan, Huseyin Sumer and Brett A. Cromer

Biomolecules 2025, 15(12), 1720; https://doi.org/10.3390/biom15121720 - 11 Dec 2025

Abstract

There was an error in the original publication [...] Full article

1 pages, 133 KB

Open AccessCorrection

Correction: Ávila et al. The Metabolism of Creatinine and Its Usefulness to Evaluate Kidney Function and Body Composition in Clinical Practice. Biomolecules 2025, 15, 41

by Marcela Ávila, Mariana G. Mora Sánchez, Alma Sofía Bernal Amador and Ramón Paniagua

Biomolecules 2025, 15(12), 1719; https://doi.org/10.3390/biom15121719 - 11 Dec 2025

Abstract

In the original publication [...] Full article

34 pages, 8108 KB

Open AccessArticle

Tuning Scaffold Properties of New 1,4-Substituted Pyrrolo[3,2-c]quinoline Derivatives Endowed with Anticancer Potential, New Biological and In Silico Insights

by Francesco Mingoia, Caterina Di Sano, Claudia D’Anna, Marco Fazzari, Alessia Bono, Gabriele La Monica, Annamaria Martorana and Antonino Lauria

Biomolecules 2025, 15(12), 1718; https://doi.org/10.3390/biom15121718 - 10 Dec 2025

Abstract

A new series of angular tricyclic pyrrolo[3,2-c]quinoline derivatives (PQs) was designed and synthesized to further explore the previously promising antiproliferative activity exhibited by the 4-benzodioxole-substituted hit 7d. Accordingly, several structural modifications mainly focused on the benzodioxole moiety were introduced, allowing us to [...] Read more.

A new series of angular tricyclic pyrrolo[3,2-c]quinoline derivatives (PQs) was designed and synthesized to further explore the previously promising antiproliferative activity exhibited by the 4-benzodioxole-substituted hit 7d. Accordingly, several structural modifications mainly focused on the benzodioxole moiety were introduced, allowing us to gain new insights into the activity and biological profile. NCI antiproliferative screening (SRB colorimetric assay), together with MTS-based assay against six other tumour cell lines, enabled us a deeper understanding of the selectivity and potency patterns. This led to the identification of a new promising hit, compound 7p, which exhibited cytotoxic activity in the low micromolar range against MCF-7 and HeLa cells. Further biological evaluations, including apoptosis induction, clonogenic, and scratch tests, provided additional biological insights into the anticancer potential of these compounds, supporting the subsequent lead optimization process for more potent anticancer activity. The integrated in silico docking results evidenced a clear multi-target profile, as testified by the broad anticancer activity, and suggest a good potential for rational polypharmacology. Full article

(This article belongs to the Section Chemical Biology)

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19 pages, 3511 KB

Open AccessArticle

Enhancing CD8⁺ T Cells Infiltration Through the Protein Arginine Methyltransferase 5 (PRMT5)/CXCL10 Axis Restricts Cervical Cancer Progression

by Yongshuai Jiang, Yingying Wei, Ziyang Li, Zhenghang Huang, Junsheng Dong, Weijuan Gong and Li Qian

Biomolecules 2025, 15(12), 1717; https://doi.org/10.3390/biom15121717 - 10 Dec 2025

Abstract

PRMT5, a type II methyltransferase catalyzing symmetric dimethylation of arginine residues, has emerged as a promising therapeutic target in various cancers. However, the precise mechanism by which PRMT5 mediated the tumor immune microenvironment, particularly CD8⁺ T cell recruitment in cervical cancer remains [...] Read more.

PRMT5, a type II methyltransferase catalyzing symmetric dimethylation of arginine residues, has emerged as a promising therapeutic target in various cancers. However, the precise mechanism by which PRMT5 mediated the tumor immune microenvironment, particularly CD8⁺ T cell recruitment in cervical cancer remains elusive. Analysis of data from The Cancer Genome Atlas (TCGA) revealed elevated PRMT5 mRNA levels in cervical cancer tissues, which correlated with reduced immune cell infiltration and poorer patient prognosis. To further investigate the role of PRMT5 in tumor development, a CD8 knockout (KO) mouse tumor model was utilized. Significant inhibition of tumor growth was observed in cervical cancer using a mouse model lacking PRMT5. Notably, this antitumor effect was attenuated in CD8 KO mice lacking functional CD8⁺ T cells. Mechanistically, RNA sequencing (RNA-seq) analysis was conducted to explore how PRMT5 regulates immune cell recruitment. Disruption of PRMT5 was found to increase the secretion of chemokine CXCL10 by tumor cells. CXCL10 binds to its receptor CXCR3, thereby recruiting T cells to the tumor. Furthermore, in CXCR3 KO mice, PRMT5 knockdown failed to enhance T cell infiltration into tumors. These findings indicate that PRMT5 knockdown promotes CD8⁺ T cell recruitment to the tumor microenvironment via CXCL10 signaling. Furthermore, the therapeutic efficacy of the selective PRMT5 inhibitor EPZ015666 was evaluated in a cervical cancer xenograft mouse model. Treatment with EPZ015666 effectively suppressed tumor growth. In summary, these findings elucidate a novel mechanism whereby PRMT5 depletion in cervical cancer cells triggers a CXCL10-mediated chemotactic response, enhancing CD8⁺ T cell infiltration and restricting tumor progression. Thus, our study provides compelling evidence supporting the potential targeting of PRMT5 as a viable immunotherapeutic strategy for cervical cancer. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 354 KB

Open AccessArticle

Investigating the Eye as a Biomarker of Gulf War Illness: Sphingolipid and Eicosanoid Composition in Tears and Plasma

by Laura Beatriz Paule Jimenez, Amanda Prislovsky, Loralei Ann Parchejo, Kim Cabrera, Andrew J. Nafziger, Daniel J. Stephenson, Charles E. Chalfant, Kristina Aenlle, Nancy Klimas, Fei Tang, Nawajes Mandal and Anat Galor

Biomolecules 2025, 15(12), 1716; https://doi.org/10.3390/biom15121716 - 10 Dec 2025

Abstract

Gulf War Illness (GWI) is a chronic multi-symptom condition affecting veterans of the 1990–1991 Gulf War, with ocular discomfort increasingly recognized among its manifestations. This pilot study evaluated whether lipid alterations in tears and plasma could serve as potential biomarkers of GWI. Participants [...] Read more.

Gulf War Illness (GWI) is a chronic multi-symptom condition affecting veterans of the 1990–1991 Gulf War, with ocular discomfort increasingly recognized among its manifestations. This pilot study evaluated whether lipid alterations in tears and plasma could serve as potential biomarkers of GWI. Participants included Gulf War-era veterans seen in the Miami Veterans Affairs Hospital eye clinic from 2018–2022. Cases met GWI criteria, while controls were non-deployed, age- and gender-matched veterans without GWI. Participants completed systemic and ocular symptom questionnaires, and lipidomic profiling of tears and plasma quantified sphingolipids and eicosanoids. Compared to controls (n = 21), GWI cases (n = 19) reported greater ocular symptom burden, while ocular signs were similar between groups. Lipidomic analyses revealed increased tear eicosanoids ((±)14(15)-EET and (±)8(9)-EET), elevated plasma sphingomyelins (SM C16:0 DH, SM C20:0, SM C22:0), and reduced plasma monohexosylceramide (MHC C16:0) and sphingomyelin (SM C14:0) in cases. Logistic regression and random forest models identified plasma SM C16:0 DH and SM C20:0 as top predictors distinguishing GWI cases from controls, with an area under the receiver operating characteristic curve (AUC) of 0.89. These findings suggest lipid dysregulation in ocular and systemic compartments and support further investigation of tears as a minimally invasive source for biomarker discovery. Full article

(This article belongs to the Special Issue Ocular Surface and Corneal Diseases: From Cellular and Molecular Biology to Therapeutic Strategies)

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20 pages, 3951 KB

Open AccessArticle

Molecular Evolution of the NLR Gene Family Reveals Diverse Innate Immune Strategies in Bats

by Gang Liu, Fujie Han, Xinya Guo, Liya Yang, Nishan Du, Xue Zhao, Chen Zhang, Jie Peng, Kangkang Zhang, Jiang Feng and Ying Liu

Biomolecules 2025, 15(12), 1715; https://doi.org/10.3390/biom15121715 - 10 Dec 2025

Abstract

Bats, as the world’s second-largest mammalian order, have garnered significant attention for their ability to harbor numerous viruses without exhibiting disease symptoms. Nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) are crucial components of the immune system. This study conducted an evolutionary analysis of [...] Read more.

Bats, as the world’s second-largest mammalian order, have garnered significant attention for their ability to harbor numerous viruses without exhibiting disease symptoms. Nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) are crucial components of the immune system. This study conducted an evolutionary analysis of the NLR gene family across 26 bat species to investigate the molecular mechanisms underlying their role in viral resistance under high viral load pressure. We identified gene duplication events in multiple genes. The NLR gene family exhibited high conservation throughout evolution, which may contribute to the occurrence of gene duplication. This conserved genomic structure also ensures functional stability, safeguarding bats’ antiviral resistance. Most NLR genes primarily function within the type I interferon (IFN) signaling pathway and the NF-κB signaling pathway. The NLR gene family enhances the innate immune capacity of bats through the adaptive evolution of some genes, combining enhanced gene functionality with the maintenance of gene conservation at a low evolutionary rate. Moreover, bats employ diverse innate immune strategies, where multiple immune pathways collectively establish the innate immune barrier. The molecular evolution of this gene family provides new insights into the molecular mechanisms and functional pathways involved in the innate immune response of bats. Full article

(This article belongs to the Section Molecular Genetics)

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17 pages, 1916 KB

Open AccessArticle

The Impact of Sex Hormones on Transcranial Magnetic Stimulation Against the Oxidative Stress in the Pathogenesis of Multiple Sclerosis

by Begoña M. Escribano, Manuel E. Valdevira, Ana Muñoz-Jurado, Montse Feijóo, Eduardo Agüera, Javier Caballero-Villarraso, Manuel LaTorre, Ana I. Giraldo, Abel Santamaría and Isaac Túnez

Biomolecules 2025, 15(12), 1714; https://doi.org/10.3390/biom15121714 - 10 Dec 2025

Abstract

Background: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease with a higher prevalence in women. While puberty appears to act as a trigger for MS, menopause has no clear effects on disease progression. Many studies have shown that transcranial magnetic stimulation (TMS) is [...] Read more.

Background: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease with a higher prevalence in women. While puberty appears to act as a trigger for MS, menopause has no clear effects on disease progression. Many studies have shown that transcranial magnetic stimulation (TMS) is a potential antioxidant treatment for MS, but the sexual hormones have been identified as a potential factor affecting TMS response by affecting cortical excitability and possibly clinical outcomes. Methods: The aim of this study was to test the effect of estrogen, progesterone, and testosterone hormonal supplementation as adjuvants to TMS treatment of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. The effects of the three hormones were also tested as replacement therapy in ovariectomized rats treated with TMS. Clinical signs of the disease, as well as disease-induced oxidative stress and antioxidant defenses of the glutathione system, were evaluated. Results: TMS alone, without supplements or replacement therapies, is effective against oxidative stress caused by EAE. Estrogen and progesterone replacement therapy is useful to enhance the role of TMS in ovariectomized rats, activating antioxidant defenses and improving clinical signs of the disease. Conclusions: TMS is effective in the treatment of MS, but its role could be enhanced, using hormone replacement therapy with estrogens and/or progesterone. Full article

(This article belongs to the Section Molecular Medicine)

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6 pages, 184 KB

Open AccessCorrection

Correction: Chaves et al. Voltage-Gated Proton Channels in the Tree of Life. Biomolecules 2023, 13, 1035

by Gustavo Chaves, Christophe Jardin, Christian Derst and Boris Musset

Biomolecules 2025, 15(12), 1713; https://doi.org/10.3390/biom15121713 - 9 Dec 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)

15 pages, 1691 KB

Open AccessPerspective

Use of the Split Luciferase Complementation Assay to Identify Novel Small Molecules That Disrupt Essential Protein–Protein Interactions of Viruses

by Tisa Biswas and Richard E. Sutton

Biomolecules 2025, 15(12), 1712; https://doi.org/10.3390/biom15121712 - 9 Dec 2025

Abstract

Protein–protein interactions (PPIs) are fundamental to viral replication, regulating transcription, assembly, and genome packaging. Despite their biological importance, few FDA-approved therapeutics directly target these complexes. The split luciferase complementation assay (SLCA) is a quantitative bioluminescence system to measure protein–protein interactions in vitro after [...] Read more.

Protein–protein interactions (PPIs) are fundamental to viral replication, regulating transcription, assembly, and genome packaging. Despite their biological importance, few FDA-approved therapeutics directly target these complexes. The split luciferase complementation assay (SLCA) is a quantitative bioluminescence system to measure protein–protein interactions in vitro after the proteins in question have been fused in-frame to N and C luciferase fragments. The SLCA can be performed both in vitro using purified protein components and in live cells, as the luciferase substrate luciferin is cell-permeable, allowing detection of protein interactions in intact cells. Assay performance, however, depends on the expression level and stability of the fusion proteins used. SLCA has been successfully applied to target Rev–Rev interactions in human immunodeficiency virus type 1 (HIV-1) for high-throughput small-molecule screening, establishing a proof-of-concept to target other parts of the viral life cycle. The system can be extended to other pathogens that currently do not have specific antiviral therapies such as HIV-1 Tat–cyclin T1, Capsid dimerization in Dengue virus, capsid interactions in equine encephalitis viruses, capsid assembly in Epstein–Barr virus, and nucleoprotein oligomerization in rabies virus. These applications demonstrate how the assay’s ability to quantify multimeric structural interactions is essential to viral replication, providing an avenue to identify small-molecule inhibitors that prevent viral replication and spread. Although there are challenges to protein stability and assay optimization, the sensitivity and adaptability of the SLCA has broader implications in virology to accelerate antiviral drug development. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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34 pages, 1268 KB

Open AccessReview

Boron Bioavailability Revisited: From Plasma-Accessible Species to Microbiota-Accessible Complexes—Implications for Nutritional Essentiality

by Andrei Biţă, Ion Romulus Scorei, Marvin A. Soriano-Ursúa, Cătălina Gabriela Pisoschi, Cristina Elena Biţă, Laura Dincă, Simona Ştefănescu, Maria-Victoria Racu, Iurie Pinzaru, Cristina Florescu, Diana-Ruxandra Hădăreanu, Cristian Adrian Siloşi, Johny Neamţu, Dan Ionuţ Gheonea, George Dan Mogoşanu and Marian Valentin Zorilă

Biomolecules 2025, 15(12), 1711; https://doi.org/10.3390/biom15121711 - 8 Dec 2025

Abstract

Boron (B) remains one of the least understood trace elements in human nutrition. Traditionally regarded as non-essential, its biological role has been reevaluated in light of emerging microbiome research. We provide a narrative synthesis of mechanistic, preclinical, and clinical studies to assess whether [...] Read more.

Boron (B) remains one of the least understood trace elements in human nutrition. Traditionally regarded as non-essential, its biological role has been reevaluated in light of emerging microbiome research. We provide a narrative synthesis of mechanistic, preclinical, and clinical studies to assess whether the colonic actions of B meet accepted criteria for nutritional essentiality. This review revisits B bioavailability through a dual-pathway framework distinguishing plasma-accessible boron (PAB)—small, fully absorbable species with transient systemic effects—from microbiota-accessible boron complexes (MABCs)—indigestible conjugates that reach the colon intact. Evidence indicates that PAB exerts short-term metabolic modulation, whereas MABCs act as prebiotic cofactors that stabilize microbial quorum sensing (autoinducer-2–borate; AI-2B), reinforce the colonic mucus barrier through borate–diol crosslinking, and support host–microbiota symbiosis. Deficiency or low intake of MABCs leads to dysbiosis, barrier fragility, and low-grade inflammation along gut–organ axes—effects reversible by MABC-rich diets. Analytical and clinical tools are proposed to discriminate between PAB and MABC pathways, including fecal B/speciation, AI-2B assays, and mucus-penetration markers. Recognizing B’s essentiality as a microbiota-dependent nutrient reframes its nutritional assessment, guiding future dietary guidelines and prebiotic design toward the microbiome–mucus interface. Full article

(This article belongs to the Section Chemical Biology)

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16 pages, 2057 KB

Open AccessArticle

Cloning and Characterization of the Novel Endoglucanase Identified in Deep Subsurface Thermal Well of Biragzang (North Ossetia) by Metagenomic Analysis

by Natalia V. Trachtmann, Stepan V. Toshchakov, Anna O. Izotova, Aleksei A. Korzhenkov, Martha A. Evteeva, Gennady S. Kachmazov, Esperant E. Agboigba and Shamil Z. Validov

Biomolecules 2025, 15(12), 1710; https://doi.org/10.3390/biom15121710 - 7 Dec 2025

Abstract

The phylum Armatimonadota represents one of the least characterized bacterial lineages, with only three formally described species despite its widespread distribution in various environments. Deep subsurface thermal environments harbor significant microbial diversity and represent promising sources for novel enzyme discovery through metagenomic approaches. [...] Read more.

The phylum Armatimonadota represents one of the least characterized bacterial lineages, with only three formally described species despite its widespread distribution in various environments. Deep subsurface thermal environments harbor significant microbial diversity and represent promising sources for novel enzyme discovery through metagenomic approaches. This study reports the identification, cloning, and biochemical characterization of Cel7465, a novel endoglucanase from an uncultured GBS-DC family within the order Fimbriimonadales. The enzyme was identified through metagenomic analysis of microbial mats from the Biragzang deep thermal well (North Ossetia, Russia, 48 °C) and successfully expressed in cells of Escherichia coli strain ArcticExpress (DE3). Phylogenetic analysis assigned Cel7465 to glycoside hydrolase family 5 subfamily 36. The purified recombinant enzyme exhibited optimal activity at 55 °C and pH 8.0, with high specific activity of 4347 U/mg. The enzyme demonstrated broad pH tolerance (50% activity retained from pH 4.0 to 10.0) and notable thermal stability, retaining 60% activity after one hour at 80 °C and 20% after four hours. Remarkably, the presence of Mn²⁺ ions enhanced enzyme activity more than 7-fold, while Mg²⁺ and Ca²⁺ ions provided moderate activation. Cel7465 represents the first biochemically characterized glycoside hydrolase from the order Fimbriimonadales, expanding our understanding of enzymatic capabilities within the understudied phylum Armatimonadota and demonstrating the continued potential of extreme environments as sources of novel industrial biocatalysts. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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29 pages, 11796 KB

Open AccessArticle

Vitamin B12-Loaded Chitosan Nanoparticles Promote Skeletal Muscle Injury Repair in Aged Rats via Amelioration of Aging-Suppressed Efferocytosis

by Walaa Bayoumie El Gazzar, Amina A. Farag, Heba Bayoumi, Shaimaa E. Radwaan, Lina Abdelhady Mohammed, Hend Elsayed Nasr, Nashwa E. Ahmed, Reham M. Ibrahim, Mahmoud Mostafa, Shimaa K. Mohamed, Dania Abdelhady, Eman E. Elwakeel, Amira M. Badr and Sahar Soliman

Biomolecules 2025, 15(12), 1709; https://doi.org/10.3390/biom15121709 - 7 Dec 2025

Abstract

Muscle gradually loses its regenerative capacity with aging. Recent evidence highlights age-related immune dysregulation as a key driver of satellite cell dysfunction and reduced muscle regeneration. Timely elimination of apoptotic cells by phagocytes through efferocytosis is essential for tissue repair. Therefore, exploring age-related [...] Read more.

Muscle gradually loses its regenerative capacity with aging. Recent evidence highlights age-related immune dysregulation as a key driver of satellite cell dysfunction and reduced muscle regeneration. Timely elimination of apoptotic cells by phagocytes through efferocytosis is essential for tissue repair. Therefore, exploring age-related alterations in the molecular machinery of efferocytosis and their impact on muscle regeneration is of great relevance. This study examined the efferocytic machinery in the gastrocnemius muscle tissue of young and aged rats after doxorubicin-induced acute myotoxicity and assessed the potential of Vitamin B12-loaded chitosan nanoparticles (B12 CS NPS) to enhance efferocytosis and promote skeletal muscle injury repair in aged rats. Aged rats exhibited impaired efferocytosis with a significant reduction in MerTK, PPARγ, and miR-124 expression, and increased ADAM17 expression. B12 CS NPS administration significantly improved efferocytosis and reduced necrotic tissue areas, accompanied by increased MerTK, PPARγ, and miR-124, and reduced ADAM17 expression. Supplementation with B12 CS NPS significantly enhanced satellite cell proliferation and differentiation, which was indicated by upregulated expression of Pax7, Myog, and MyoD. These findings reveal that age-related alterations in regulatory molecules impair efferocytosis in aged muscle and demonstrate the potential of B12 CS NPs to enhance efferocytosis and improve skeletal muscle repair. Full article

(This article belongs to the Section Molecular Medicine)

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Open AccessReview

Integrative Regulatory Networks of MicroRNA-483: Unveiling Its Systematic Role in Human Diseases and Clinical Implications

by Jiatong Xu, Shupeng Luxu, Hsi-Yuan Huang, Yang-Chi-Dung Lin and Hsien-Da Huang

Biomolecules 2025, 15(12), 1707; https://doi.org/10.3390/biom15121707 - 7 Dec 2025

Abstract

MicroRNA-483 regulates multiple human disease categories, spanning oncology, cardiopulmonary, metabolic, immune, neurological, and musculoskeletal pathologies. We integrate experimentally validated interactions from 146 studies to construct a comprehensive regulatory network, encompassing transcription factors, long non-coding RNAs, circular RNAs, and messenger RNA targets. Our analysis [...] Read more.

MicroRNA-483 regulates multiple human disease categories, spanning oncology, cardiopulmonary, metabolic, immune, neurological, and musculoskeletal pathologies. We integrate experimentally validated interactions from 146 studies to construct a comprehensive regulatory network, encompassing transcription factors, long non-coding RNAs, circular RNAs, and messenger RNA targets. Our analysis reveals that miR-483 promotes tumorigenesis by suppressing tumor-suppressive checkpoints, yet it protects cardiopulmonary, metabolic, and neurological tissues from pathological injury. This functional duality arises from tissue-specific modulation of shared signaling pathways, particularly TGF-β and MAPK cascades, which function as the core hubs driving its context-dependent activity across six disease categories. By mapping miR-483 regulatory circuits across multiple diseases, we define the molecular determinants of its context-dependent activity. These findings establish miR-483 as both a diagnostic biomarker and a therapeutic target whose function is dictated by cellular context. Full article

(This article belongs to the Special Issue The Role of Non-Coding RNAs in Health and Disease)

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