Biomolecules

15 pages, 4089 KB

Open AccessEditor’s ChoiceArticle

Increased [¹⁸F]DPA-714 Uptake in the Skeletal Muscle of SOD1^G93A Mice: A New Potential of Translocator Protein 18 kDa Imaging in Amyotrophic Lateral Sclerosis

by Cecilia Marini, Mattia Riondato, Edoardo Dighero, Alessia Democrito, Serena Losacco, Laura Emionite, Lucilla Nobbio, Irene Di Patrizi, Mattia Camera, Chiara Ghersi, Maddalena Ghelardoni, Francesco Lanfranchi, Francesca Vitale, Sonia Carta, Sabrina Chiesa, Carola Torazza, Marco Milanese, Matteo Bauckneht, Mehrnaz Hamedani, Federico Zaottini, Angelo Schenone, Carlo Martinoli, Federica Grillo and Gianmario Sambuceti Show full author list Hide full author list

Biomolecules 2025, 15(6), 799; https://doi.org/10.3390/biom15060799 - 31 May 2025

Cited by 1 | Viewed by 1550

Abstract

Purpose: The skeletal muscle has been proposed to contribute to the progressive loss of motor neurons typical of amyotrophic lateral sclerosis (ALS). However, this mechanism has not yet been clarified due to the lack of suitable imaging tools. Here, we aimed to verify [...] Read more.

Purpose: The skeletal muscle has been proposed to contribute to the progressive loss of motor neurons typical of amyotrophic lateral sclerosis (ALS). However, this mechanism has not yet been clarified due to the lack of suitable imaging tools. Here, we aimed to verify whether PET imaging of the translocator protein 18 kDa (TSPO) can detect a muscular abnormality in an experimental model of ALS. Methods: In vivo biodistribution and kinetics of [¹⁸F]DPA-714 were analyzed in skeletal muscle and brain of SOD1^G93A transgenic mice and in wildtype (WT) littermates. Both cohorts were divided into three groups (n = 6 each) to be studied at 60, 90 and 120 days. After microPET imaging, animals were sacrificed to evaluate inflammatory infiltrates by hematoxylin/eosin staining and TSPO expression by immunohistochemistry and Western blot in both quadriceps and brain. Results: [¹⁸F]DPA-714 uptake was higher in the skeletal muscles of SOD1^G93A than in WT mice in the preclinical phase (60 and 90 days) and further increased up to the symptomatic late stage (120 days). Inflammatory cells were absent in the quadriceps of SOD1^G93A mice whose myocytes, instead, showed a progressive increase in TSPO expression with advancing age. By contrast, brain tracer uptake and TSPO expression were comparably low in both groups, regardless of age and genotype. Conclusion: Upregulation of TSPO expression is characteristic of skeletal muscle, but not the brain, in the experimental SOD1^G93A mouse model of ALS. Tracers targeting this pathway have been mostly proposed for the evaluation of inflammatory processes within the central nervous system. Nevertheless, the ubiquitous nature of TSPO expression and its responsiveness to various signals may broaden the diagnostic potential of these tracers to include disease conditions beyond inflammation. Full article

(This article belongs to the Section Molecular Medicine)

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14 pages, 1004 KB

Open AccessEditor’s ChoiceArticle

Designing New Chimeric Proline-Rich Antimicrobial Peptides to Enhance Efficacy Toward the ESKAPE+E: Beyond Sequence Extension

by Adriana Di Stasi, Luigi de Pascale, Martino Morici, Daniel N. Wilson, Marco Scocchi and Mario Mardirossian

Biomolecules 2025, 15(6), 776; https://doi.org/10.3390/biom15060776 - 27 May 2025

Cited by 3 | Viewed by 1615

Abstract

Proline-rich antimicrobial peptides (PrAMPs) primarily exert their antimicrobial effects intracellularly, inhibiting protein synthesis. B7-005, a synthetic 16-amino acid PrAMP, has a broader antimicrobial spectrum compared to native counterparts, despite shorter PrAMPs typically exhibiting reduced activity. This study aimed to enhance B7-005’s potency by [...] Read more.

Proline-rich antimicrobial peptides (PrAMPs) primarily exert their antimicrobial effects intracellularly, inhibiting protein synthesis. B7-005, a synthetic 16-amino acid PrAMP, has a broader antimicrobial spectrum compared to native counterparts, despite shorter PrAMPs typically exhibiting reduced activity. This study aimed to enhance B7-005’s potency by extending it with 6 or 11 amino acids derived from the C-terminal sequences of cetacean Tur1A and Lip1 PrAMPs, as well as bovine Bac7(1-35). Six chimeric derivatives were evaluated for antimicrobial and bactericidal potency, cytotoxicity, bacterial membrane permeabilization, and in vitro inhibition of protein synthesis. Extending B7-005 with sequences from other PrAMPs increased its activity against most ESKAPE+E pathogens, reducing minimum inhibitory concentration (MIC) values by 2- to 8-fold, with notable differences among bacterial species, without increasing cytotoxicity toward the A549 cell line. All chimeras retained the ability to inhibit protein synthesis in Escherichia coli and to modestly perturb the E. coli membranes like B7-005. These novel chimeric PrAMPs, particularly the 22-mer derivatives, hold promise for developing new antimicrobial agents. The study also highlights variability in bacterial responses to PrAMPs and underscores how minor sequence differences can significantly impact efficacy against specific microorganisms. PrAMPs thus represent a valuable scaffold to rationally design derivatives targeting high-priority pathogens. Full article

(This article belongs to the Special Issue State of the Art and Perspectives in Antimicrobial Peptides)

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16 pages, 4031 KB

Open AccessEditor’s ChoiceArticle

Oxidative DNA Damage and Repair Dynamics in Multiple Sclerosis: Insights from Comet Assay Kinetics, Base Excision Repair Gene Expression, and Genotype Analysis

by Beata Filipek, Anna Macieja, Aleksandra Binda, Rafal Szelenberger, Leslaw Gorniak, Elzbieta Miller, Mariola Swiderek-Matysiak, Mariusz Stasiolek, Ireneusz Majsterek and Tomasz Poplawski

Biomolecules 2025, 15(6), 756; https://doi.org/10.3390/biom15060756 - 24 May 2025

Cited by 4 | Viewed by 1523

Abstract

Multiple sclerosis (MS) is a neuroinflammatory disease where oxidative stress and DNA damage may influence disease progression. We investigated whether defects in base excision repair (BER) pathways contribute to MS by combining functional DNA repair assays, gene expression profiling, and genotype analysis. We [...] Read more.

Multiple sclerosis (MS) is a neuroinflammatory disease where oxidative stress and DNA damage may influence disease progression. We investigated whether defects in base excision repair (BER) pathways contribute to MS by combining functional DNA repair assays, gene expression profiling, and genotype analysis. We collected peripheral blood mononuclear cells from 70 MS patients and 61 healthy controls. These cells were subjected to tert-butyl hydroperoxide (TBH)-induced oxidative stress, and comet assay kinetics were measured over a period of 60 min. Additionally, we quantified the mRNA expression of nine key BER genes and genotyped selected polymorphisms related to DNA repair capacity. Samples from MS patients exhibited significantly higher levels of TBH-induced DNA lesions and displayed a distinct repair trajectory over time, as indicated by area-under-the-curve (AUC) analyses (p < 0.001). The transcripts of MBD4 and NTHL1 were notably reduced in MS patients compared to those in the controls (p < 0.0001). A logistic regression analysis revealed an association between the specific BER-related single nucleotide polymorphisms (SNPs) rs3087404, rs4135054, and rs1052133 and ineffective DNA repair. Subset analyses of B cells, CD4⁺ cells, and CD8⁺ cells further supported the presence of altered repair kinetics in MS, even though some subsets exhibited similar baseline lesion levels. Our findings suggest that impaired oxidative DNA repair is present in MS, likely driven by functional deficits in repair kinetics and alterations in the expression of BER genes and polymorphisms. This integrated approach highlights DNA repair pathways as potential therapeutic or prognostic targets in MS. Full article

(This article belongs to the Special Issue DNA Damage, Mutagenesis, and Repair Mechanisms)

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28 pages, 3773 KB

Open AccessEditor’s ChoiceReview

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

Cited by 2 | Viewed by 2233

Abstract

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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15 pages, 1975 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 1 | Viewed by 1093

Abstract

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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39 pages, 9047 KB

Open AccessEditor’s ChoiceArticle

Silver Nanoparticles (AgNPs) from Lysinibacillus sp. Culture Broths: Antibacterial Activity, Mechanism Insights, and Synergy with Classical Antibiotics

by Carlos Pernas-Pleite, Amparo M. Conejo-Martínez, Irma Marín and José P. Abad

Biomolecules 2025, 15(5), 731; https://doi.org/10.3390/biom15050731 - 16 May 2025

Cited by 5 | Viewed by 1854

Abstract

Antibiotic-resistant bacteria pose problems for infection prevention and treatment, so developing new procedures or substances against infection is mandatory. Silver nanomaterials are among the more promising antibacterial agents. Herein, we describe the biogenic synthesis of silver nanoparticles (AgNPs) using culture broths from an [...] Read more.

Antibiotic-resistant bacteria pose problems for infection prevention and treatment, so developing new procedures or substances against infection is mandatory. Silver nanomaterials are among the more promising antibacterial agents. Herein, we describe the biogenic synthesis of silver nanoparticles (AgNPs) using culture broths from an undescribed species of Lysinibacillus. Culture broths with or without NaCl and from the exponential and stationary growth phases produced four AgNP types. Nanoparticles’ shapes were quasi-spherical, with core sizes of 7.5–14.7 nm and hydrodynamic diameters of 48.5–80.2 nm. All the AgNPs contained Ag⁰ crystals and some AgCl ones. Moreover, their coronas presented different proportions of carbohydrates, proteins, and aliphatic compounds. The AgNPs were good antibacterial agents against six bacterial species, three Gram-positive and three Gram-negative, with MICs of 0.3–9.0 µg/mL. Their activity was higher against the Gram-negative bacteria and particularly against Pseudomonas aeruginosa. These AgNPs acted synergistically with several of the fifteen tested antibiotics. Interestingly, AgNP combinations with some of these inhibited the growth of antibiotic-resistant bacteria, as in the case of S. epidermidis for streptomycin and S. aureus for colistin. The ROS production by E. coli and S. aureus when treated with most AgNPs suggested different mechanisms for bacterial killing depending on the AgNP. Full article

(This article belongs to the Section Bio-Engineered Materials)

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13 pages, 5029 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Crystal Structure of the Multidomain Pectin Methylesterase PmeC5 from Butyrivibrio fibrisolvens D1^T

by Vincenzo Carbone, Kerri Reilly, Carrie Sang, Linley R. Schofield, William J. Kelly, Ron S. Ronimus, Graeme T. Attwood and Nikola Palevich

Biomolecules 2025, 15(5), 720; https://doi.org/10.3390/biom15050720 - 14 May 2025

Cited by 1 | Viewed by 1033

Abstract

Pectin is a dynamic and complex polysaccharide that forms a substantial proportion of the primary plant cell wall and middle lamella of forage ingested by grazing ruminants. Pectin methylesterases (PMEs) are enzymes that belongs to the carbohydrate esterase family 8 (CE8) and catalyze [...] Read more.

Pectin is a dynamic and complex polysaccharide that forms a substantial proportion of the primary plant cell wall and middle lamella of forage ingested by grazing ruminants. Pectin methylesterases (PMEs) are enzymes that belongs to the carbohydrate esterase family 8 (CE8) and catalyze the demethylesterification of pectin, a key polysaccharide in cell walls. Here we present the crystal structure of the catalytic domain of PmeC5 that is associated with a gene from Butyrivibrio fibrisolvens D1^T that encodes a large secreted pectinesterase family protein (2089 aa) determined to a resolution of 1.33 Å. Protein in silico modelling of the secreted pectinesterase confirmed the presence of an additional pectate lyase (PL9) and adhesin-like domains. The structure of PmeC5 was the characteristic right-handed parallel β-helical topology and active site residues of Asp231, Asp253, and Arg326 typical of the enzyme class. PmeC5 is a large modular enzyme that is characteristic of rumen B. fibrisolvens megaplasmids and plays a central role in degrading plant cell wall components and releasing methanol in the rumen environment. Such secreted PMEs are significant contributors to plant fiber digestion and methane production, making them attractive targets for both methane mitigation strategies and livestock productivity enhancement. Full article

(This article belongs to the Topic Design, Synthesis and Biological Evaluation of Novel Small Molecules as Multi-target Enzyme Inhibitors)

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13 pages, 467 KB

Open AccessEditor’s ChoiceReview

OX40–OX40L Axis in Cutaneous T-Cell Lymphomas: Pathogenic, Prognostic, and Potential Therapeutic Perspectives

by Alba Guglielmo, Alessandro Borghi, Corrado Zengarini, Bianca Maria Piraccini, Monica Corazza and Alessandro Pileri

Biomolecules 2025, 15(5), 715; https://doi.org/10.3390/biom15050715 - 13 May 2025

Cited by 4 | Viewed by 1698

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent forms of cutaneous T-cell lymphoma (CTCL) and are characterized by the proliferation of CD4⁺ T-helper cells. The pathogenesis of CTCLs involves a critical interaction between neoplastic cells and the tumor microenvironment. [...] Read more.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most prevalent forms of cutaneous T-cell lymphoma (CTCL) and are characterized by the proliferation of CD4⁺ T-helper cells. The pathogenesis of CTCLs involves a critical interaction between neoplastic cells and the tumor microenvironment. This interaction is driven not only by cytokines but also by surface proteins that mediate cell–cell contact. One such protein, OX40 (also known as CD134), is a member of the TNF receptor superfamily and serves as an induced costimulatory molecule that facilitates the interaction between T-cells and antigen-presenting cells. In this narrative review, we explore the literature surrounding the OX40–OX40L interaction in CTCLs, highlighting its pathogenic and prognostic significance. Additionally, we compare the expression and function of OX40–OX40L in chronic inflammatory skin diseases, such as atopic dermatitis and psoriasis, with their role in CTCLs. Finally, we provide an overview of the current state of therapeutic research, discussing the potential of targeting the OX40–OX40L axis in CTCL treatment. Full article

(This article belongs to the Section Molecular Biomarkers)

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22 pages, 683 KB

Open AccessFeature PaperEditor’s ChoiceReview

Interplay Between Vascular Dysfunction and Neurodegenerative Pathology: New Insights into Molecular Mechanisms and Management

by Avanthika Mekala and Hongyu Qiu

Biomolecules 2025, 15(5), 712; https://doi.org/10.3390/biom15050712 - 13 May 2025

Cited by 13 | Viewed by 2824

Abstract

Vascular dysfunction frequently coexists with neurodegenerative disorders such as dementia and Alzheimer’s disease (AD) in older individuals; however, the cause-and-effect relationship remains unclear. While AD is primarily characterized by neural tissue degeneration, emerging evidence suggests that aging-induced vascular dysfunction contributes to both the [...] Read more.

Vascular dysfunction frequently coexists with neurodegenerative disorders such as dementia and Alzheimer’s disease (AD) in older individuals; however, the cause-and-effect relationship remains unclear. While AD is primarily characterized by neural tissue degeneration, emerging evidence suggests that aging-induced vascular dysfunction contributes to both the onset and progression of cognitive impairment and dementia by decreasing cerebral blood flow (CBF) and disrupting the blood–brain barrier (BBB). This challenges the traditional notion and underscores vascular dysfunction as an early pathogenic stimulus; thus, targeting vascular pathologies could be a promising strategy to slow dementia progression and potentially prevent AD. Conversely, aging-related neurodegeneration exacerbates vascular dysfunction, accelerating dementia pathology through oxidative stress and inflammation as well as deposition of neurotoxic substances such as beta-amyloid (Aβ) and tau in vascular walls. This bidirectional interaction creates a vicious cycle that worsens cognitive decline, underscoring the complexity of these diseases. This review aims to highlight recent advances in research on the mechanisms of aging-related vascular dysfunction in neurodegenerative diseases, focusing on vascular contributions to cognitive impairment and dementia (VCID) and AD. Additionally, we will explore the reciprocal effects and intricate relationship between vascular dysfunction and neurodegenerative pathologies, enhancing our understanding of relative disease pathogenesis and guiding the development of innovative prevention and treatment strategies. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment (2nd Edition))

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12 pages, 1743 KB

Open AccessEditor’s ChoiceArticle

Cell-Penetrating Peptide Based on Myosin Phosphatase Target Subunit Sequence Mediates Myosin Phosphatase Activity

by Andrea Kiss, Mohamad Mahfood, Zsófia Bodogán, Zoltán Kónya, Bálint Bécsi and Ferenc Erdődi

Biomolecules 2025, 15(5), 705; https://doi.org/10.3390/biom15050705 - 12 May 2025

Cited by 1 | Viewed by 1080

Abstract

Myosin phosphatase (MP) holoenzyme consists of protein phosphatase-1 (PP1) catalytic subunit (PP1c) associated with myosin phosphatase target subunit-1 (MYPT1) and it plays an important role in mediating the phosphorylation of the 20 kDa light chain (MLC20) of myosin, thereby regulating cell contractility. The [...] Read more.

Myosin phosphatase (MP) holoenzyme consists of protein phosphatase-1 (PP1) catalytic subunit (PP1c) associated with myosin phosphatase target subunit-1 (MYPT1) and it plays an important role in mediating the phosphorylation of the 20 kDa light chain (MLC20) of myosin, thereby regulating cell contractility. The association of MYPT1 with PP1c increases the phosphatase activity toward myosin; therefore, disrupting/dissociating this interaction may result in inhibition of the dephosphorylation of myosin. In this study, we probed how MYPT1^32–58 peptide including major PP1c interactive regions coupled with biotin and cell-penetrating TAT sequence (biotin-TAT-MYPT1) may influence MP activity. Biotin-TAT-MYPT1 inhibited the activity of MP holoenzyme and affinity chromatography as well as surface plasmon resonance (SPR) binding studies established its stable association with PP1c. Biotin-TAT-MYPT1 competed for binding to PP1c with immobilized GST-MYPT1 in SPR assays and it partially relieved PP1c inhibition by thiophosphorylated (on Thr696 and Thr853) MYPT1. Moreover, biotin-TAT-MYPT1 dissociated PP1c from immunoprecipitated PP1c-MYPT1 complex implying its holoenzyme disrupting ability. Biotin-TAT-MYPT1 penetrated into A7r5 smooth muscle cells localized in the cytoplasm and nucleus and exerted inhibition on MP with a parallel increase in MLC20 phosphorylation. Our results imply that the biotin-TAT-MYPT1 peptide may serve as a specific MP regulatory cell-penetrating peptide as well as possibly being applicable to further development for pharmacological interventions. Full article

(This article belongs to the Section Enzymology)

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15 pages, 800 KB

Open AccessEditor’s ChoiceArticle

Melatonin Secretion and Impacts of Training and Match Schedules on Sleep Quality, Recovery, and Circadian Rhythms in Young Professional Football Players

by Antonio Almendros-Ruiz, Javier Conde-Pipó, Paula Aranda-Martínez, Jesús Olivares-Jabalera, Darío Acuña-Castroviejo, Bernardo Requena, José Fernández-Martínez and Miguel Mariscal-Arcas

Biomolecules 2025, 15(5), 700; https://doi.org/10.3390/biom15050700 - 11 May 2025

Cited by 2 | Viewed by 5585

Abstract

Modern elite football is becoming increasingly physically demanding, often requiring training and matches to be played at night. This schedule may disrupt circadian rhythms and melatonin secretion, thereby impairing sleep and recovery. This study investigated the effects of training time on melatonin secretion, [...] Read more.

Modern elite football is becoming increasingly physically demanding, often requiring training and matches to be played at night. This schedule may disrupt circadian rhythms and melatonin secretion, thereby impairing sleep and recovery. This study investigated the effects of training time on melatonin secretion, circadian phase markers, and sleep parameters in elite youth soccer players. Forty male players (aged 16–18 years) from an elite Spanish youth football club were studied. Two groups followed the same training program but trained either in the morning (MT) or in the evening (ET). Salivary melatonin was measured at six time points to determine the mean levels, dim light melatonin onset (DLMO), amplitude, and acrophase. Chronotype, sleep quality (PSQI), and daytime sleepiness (ESS) were assessed using validated questionnaires. Dietary intake and anthropometric variables were also recorded. The MT group had higher mean melatonin levels (p = 0.026) and earlier DLMO (p = 0.023) compared to the ET group. Sleep quality was significantly better in the MT group (p < 0.001), despite shorter sleep duration (p = 0.014). No major differences in diet or anthropometry were observed. The chronotype had a secondary effect on the circadian markers. Evening training is associated with alterations in melatonin rhythms and reduced sleep quality, possibly due to light-induced chronodisruption. These findings highlight the importance of training timing as a modifiable factor in the chronobiology and recovery of athletes. Incorporating circadian principles into training schedules may optimize resting time and thus performance and long-term health in athletes. Full article

(This article belongs to the Special Issue Melatonin in Normal Physiology and Disease, 2nd Edition)

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26 pages, 1958 KB

Open AccessEditor’s ChoiceReview

Molecular and Biophysical Perspectives on Dormancy Breaking: Lessons from Yeast Spore

by Keiichiro Sakai, Yohei Kondo, Kazuhiro Aoki and Yuhei Goto

Biomolecules 2025, 15(5), 701; https://doi.org/10.3390/biom15050701 - 11 May 2025

Cited by 2 | Viewed by 3222

Abstract

Dormancy is a physiological state that enables cells to survive under adverse conditions by halting their proliferation while retaining the capacity to resume growth when conditions become favorable. This remarkable transition between dormant and proliferative states occurs across a wide range of species, [...] Read more.

Dormancy is a physiological state that enables cells to survive under adverse conditions by halting their proliferation while retaining the capacity to resume growth when conditions become favorable. This remarkable transition between dormant and proliferative states occurs across a wide range of species, including bacteria, fungi, plants, and tardigrades. Among these organisms, yeast cells have emerged as powerful model systems for elucidating the molecular and biophysical principles governing dormancy and dormancy breaking. In this review, we provide a comprehensive summary of current knowledge on the molecular mechanisms underlying cellular dormancy, with particular focus on the two major model yeasts: Saccharomyces cerevisiae and Schizosaccharomyces pombe. Recent advances in multifaceted approaches—such as single-cell RNA-seq, proteomic analysis, and live-cell imaging—have revealed dynamic changes in gene expression, proteome composition, and viability. Furthermore, insights into the biophysical properties of the cytoplasm have offered new understanding of dormant cell regulation through changes in cytoplasmic fluidity. These properties contribute to both the remarkable stability of dormant cells and their capacity to exit dormancy upon environmental cues, deepening our understanding of fundamental cellular survival strategies across diverse species. Full article

(This article belongs to the Special Issue Cellular Quiescence and Dormancy)

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15 pages, 14165 KB

Open AccessEditor’s ChoiceArticle

LIFR-Mediated ERBB2 Signaling Is Essential for Successful Embryo Implantation in Mice

by Jumpei Terakawa, Sakura Nakamura, Mana Ohtomo, Saki Uehara, Yui Kawata, Shunsuke Takarabe, Hibiki Sugita, Takafumi Namiki, Atsuko Kageyama, Michiko Noguchi, Hironobu Murakami, Naomi Kashiwazaki and Junya Ito

Biomolecules 2025, 15(5), 698; https://doi.org/10.3390/biom15050698 - 10 May 2025

Cited by 3 | Viewed by 1907

Abstract

In eutherian mammals, embryo implantation is a critical process for a successful pregnancy. In mice, the activation of the leukemia inhibitory factor (LIF) receptor–STAT3 signaling axis induces embryo adhesion and decidualization. The LIF receptor is believed to function as a heterodimer composed of [...] Read more.

In eutherian mammals, embryo implantation is a critical process for a successful pregnancy. In mice, the activation of the leukemia inhibitory factor (LIF) receptor–STAT3 signaling axis induces embryo adhesion and decidualization. The LIF receptor is believed to function as a heterodimer composed of LIFR (encoded by Lifr) and GP130 (encoded by Il6st); however, their distinct expression patterns in the uterine epithelium immediately prior to implantation suggest divergent functional roles. In this study, we generated uterine epithelium-specific Lifr knockout (Lifr eKO) mice and conducted a comprehensive gene expression analysis of the endometrium before implantation. We compared these results with those from uterine epithelium-specific Gp130 knockout (Gp130 eKO) mice. Similarly to Gp130 eKO mice, Lifr eKO mice were completely infertile. We identified 299 genes with expression changes greater than twofold following gene deletion; among these, 31 genes were downregulated and 57 genes were upregulated in both eKO models. Many of the downregulated genes were previously implicated in uterine function. Hub gene analysis identified Erbb2 and c-Fos as key regulators in both models. Further experiments using an ERBB2 inhibitor suggested that LIFR–ERBB2-mediated signaling plays a crucial role in embryo implantation. Full article

(This article belongs to the Special Issue Properties and Functions of Endometrial Stromal Cells)

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18 pages, 674 KB

Open AccessEditor’s ChoiceReview

Celebrating Ulrik Ringborg: Multi-Omics-Based Patient Stratification for Precision Cancer Treatment

by Maria-Veronica Teleanu, Annika Schneider, Claudia R. Ball, Mathias Felix Leber, Christoph Stange, Eva Krieghoff-Henning, Katja Beck, Christoph E. Heilig, Simon Kreutzfeldt, Bernhard Kuster, Daniel B. Lipka and Stefan Fröhling

Biomolecules 2025, 15(5), 693; https://doi.org/10.3390/biom15050693 - 10 May 2025

Cited by 2 | Viewed by 1873

Abstract

Precision oncology is becoming a mainstay in the standard of care for cancer patients. Recent technological advancements have significantly lowered the cost of various tumor profiling approaches, broadening the reach of molecular diagnostics and improving patient access to precision oncology. In parallel, drug [...] Read more.

Precision oncology is becoming a mainstay in the standard of care for cancer patients. Recent technological advancements have significantly lowered the cost of various tumor profiling approaches, broadening the reach of molecular diagnostics and improving patient access to precision oncology. In parallel, drug development and discovery pipelines continue to evolve, driving targeted therapeutic options forward. Yet, not all patients harboring actionable molecular alterations respond to these interventions, and existing therapies do not cover the entire spectrum of potential molecular targets. In this review, we examine the current suite of omics technologies employed in clinical settings and underscore their roles in deepening our understanding of tumor biology and optimizing patient stratification for targeted treatments. We also highlight relevant precision oncology trials and share our own experiences using multi-omics data within a molecular tumor board framework. Finally, we discuss areas for future exploration aimed at propelling precision oncology to new heights. Full article

(This article belongs to the Special Issue The Development of Translational Cancer Research: In Honor of a Pioneering Professor, Ulrik Ringborg)

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16 pages, 738 KB

Open AccessEditor’s ChoiceReview

Nav1.8 and Chronic Pain: From Laboratory Animals to Clinical Patients

by Yu-Feng Xie

Biomolecules 2025, 15(5), 694; https://doi.org/10.3390/biom15050694 - 10 May 2025

Cited by 8 | Viewed by 7289

Abstract

As a subtype of voltage-gated sodium channel and predominantly expressed in the sensory neurons located in the dorsal root ganglion (DRG), the Nav1.8 channel encoded by the SCN10A gene is found to have different variants in patients suffering chronic pain or insensitivity to [...] Read more.

As a subtype of voltage-gated sodium channel and predominantly expressed in the sensory neurons located in the dorsal root ganglion (DRG), the Nav1.8 channel encoded by the SCN10A gene is found to have different variants in patients suffering chronic pain or insensitivity to pain due to the gain-of-function or loss-of-function of Nav1.8 channels. In animal models of chronic pain, Nav1.8 is also verified to be involved, suggesting that Nav1.8 may be a potential target for treatment of chronic pain. Another voltage-gated sodium channel, Nav1.7, is also proposed to be a target for chronic pain, supported by clinical findings in patients and laboratory animal models; however, there is no Nav1.7-specific drug that has passed clinical trials, although they demonstrated satisfactory effects in laboratory animals. This discrepancy between clinical and preclinical studies may be related to the differences between humans and laboratory animals or due to the degeneracy in different sodium channels governing the DRG neuronal excitability, which is thought of as the underlying machinery of chronic pain and mostly studied. This review summarizes recent findings of Nav1.8 in chronic pain from clinics and laboratories and discusses the difference, which may be helpful for future investigation of Nav1.8 in chronic pain, considering the dilemma of the Nav1.7 channel in chronic pain. Full article

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

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24 pages, 11315 KB

Open AccessEditor’s ChoiceArticle

Enhancing Ferroptosis in Lung Adenocarcinoma Cells via the Synergistic Action of Nonthermal Biocompatible Plasma and a Bioactive Phenolic Compound

by Sabnaj Khanam, Young June Hong, Youngsun Kim, Eun Ha Choi and Ihn Han

Biomolecules 2025, 15(5), 691; https://doi.org/10.3390/biom15050691 - 9 May 2025

Cited by 1 | Viewed by 2309

Abstract

Para-coumaric acid (p-CA) is a phenolic compound that has antioxidant, anti-inflammatory, and anticancer properties which make it potential for cancer treatment. However, its effectiveness has been limited by poor solubility, rapid metabolism, and poor absorptivity. Nonthermal biocompatible pressure plasma (NBP) has gained attention [...] Read more.

Para-coumaric acid (p-CA) is a phenolic compound that has antioxidant, anti-inflammatory, and anticancer properties which make it potential for cancer treatment. However, its effectiveness has been limited by poor solubility, rapid metabolism, and poor absorptivity. Nonthermal biocompatible pressure plasma (NBP) has gained attention as a cancer treatment due to its ability to generate reactive oxygen and nitrogen species (RONS), inducing oxidative stress that damages cancer cells. This study aimed to investigate the combined effect of NBP and p-CA on the induction of ferroptosis in lung adenocarcinoma via the GPX4, xCT, and NRF2 pathways. H460 and A549 lung adenocarcinoma cells as well as normal lung cells (MRC5) were treated with p-CA, NBP, and their combination. Cell movement, intracellular RONS levels, and lipid peroxidation, along with apoptosis and ferroptosis-related gene expression, were evaluated by co-treatment. Co-treatment also significantly elevated NO₂⁻, NO₃⁻, and H₂O₂ levels and reduced cancer cell (H460, A549) viability (26, 31%) without affecting normal cells MRC5 (7%). Elevated MDA levels and changed expression of ferroptotic proteins indicated mitochondrial dysfunction, oxidative damage, lipid peroxidation, and DNA damage, which resulted in the induction of ferroptosis. These findings reveal a novel ferroptosis mechanism, emphasizing co-treatment for delivering bioavailable natural anticancer drugs. Full article

(This article belongs to the Special Issue Signaling Pathways as Therapeutic Targets for Cancer)

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20 pages, 16630 KB

Open AccessEditor’s ChoiceArticle

MECP2 mRNA Profile in Brain Tissues from a Rett Syndrome Patient and Three Human Controls: Mutated Allele Preferential Transcription and In Situ RNA Mapping

by Martina Mietto, Silvia Montanari, Maria Sofia Falzarano, Elisa Manzati, Paola Rimessi, Marina Fabris, Rita Selvatici, Francesca Gualandi, Marcella Neri, Fernanda Fortunato, Miryam Rosa Stella Foti, Stefania Bigoni, Marco Gessi, Marcella Vacca, Silvia Torelli, Joussef Hayek and Alessandra Ferlini

Biomolecules 2025, 15(5), 687; https://doi.org/10.3390/biom15050687 - 8 May 2025

Cited by 2 | Viewed by 2676

Abstract

Rett syndrome (RTT) is a rare X-linked dominant neurodevelopmental disorder caused by pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a methyl-CpG-binding protein (MeCP2) that acts as a repressor of gene expression, crucial in neurons. Dysfunction of MeCP2 [...] Read more.

Rett syndrome (RTT) is a rare X-linked dominant neurodevelopmental disorder caused by pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene, which encodes a methyl-CpG-binding protein (MeCP2) that acts as a repressor of gene expression, crucial in neurons. Dysfunction of MeCP2 due to its pathogenic variants explains the clinical features of RTT. Here, we performed histological and RNA analyses on a post-mortem brain sample from an RTT patient carrying the p.Arg106Trp missense mutation. This patient is part of a cohort of 56 genetically and clinically characterized RTT patients, for whom we provide an overview of the mutation landscape. In the RTT brain specimen, RT-PCR analysis detected preferential transcription of the mutated mRNA. X-inactivation studies revealed a skewed X-chromosome inactivation ratio (95:5), supporting the transcriptional findings. We also mapped the MECP2 transcript in control human brain regions (temporal cortex and cerebellum) using the RNAscope assay, confirming its high expression. This study reports the MECP2 transcript representation in a post-mortem RTT brain and, for the first time, the in situ MECP2 transcript localization in a human control brain, offering insights into how specific MECP2 mutations may differentially impact neuronal functions. We suggest these findings are crucial for developing RNA-based therapies for Rett syndrome. Full article

(This article belongs to the Special Issue Molecular Advances in Rett Syndrome and Other Chromatin Related Disorders)

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19 pages, 5482 KB

Open AccessEditor’s ChoiceArticle

The α5-α6-α7-Pba3-Pba4 Complex: A Starting Unit in Proteasome Core Particle Assembly

by Ana C. Matias, Margarida N. Tiago, Jessica Zimmermann, R. Jürgen Dohmen and Paula C. Ramos

Biomolecules 2025, 15(5), 683; https://doi.org/10.3390/biom15050683 - 8 May 2025

Cited by 1 | Viewed by 1474

Abstract

A complex composed of Pba3-Pba4 and subunits α5, α6, and α7 is identified as an early intermediate in proteasome core particle assembly in wild-type Saccharomyces cerevisiae cells. The same complex can be reconstituted from recombinantly produced components in vitro. Assembly of [...] Read more.

A complex composed of Pba3-Pba4 and subunits α5, α6, and α7 is identified as an early intermediate in proteasome core particle assembly in wild-type Saccharomyces cerevisiae cells. The same complex can be reconstituted from recombinantly produced components in vitro. Assembly of α6 and α7 with Pba3-Pba4 depends on the presence of the α5 subunit, the binding of which apparently initiates the formation of this intermediate. Our data suggest the following order of events: first, Pba3-Pba4 binds α5, then α6 is incorporated, and at the end α7. In the absence of the chaperones Pba1-Pba2 or Ump1, alternative Pba4-containing complexes are detected, the formation of which depends on the Blm10/PA200 protein. Overexpression of Pba1-Pba2 abolishes the formation of these complexes containing Pba4 and Blm10, suggesting that Blm10 may replace Pba1-Pba2 as an alternative assembly factor. Full article

(This article belongs to the Special Issue Mechanisms, Biology and Regulation of Proteasomes—in Memory of Professor Alfred L. Goldberg (1942–2023))

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23 pages, 2272 KB

Open AccessFeature PaperEditor’s ChoiceReview

Bio-Based Polyurethane Foams: Feedstocks, Synthesis, and Applications

by Marta Santos, Marcos Mariz, Igor Tiago, Susana Alarico and Paula Ferreira

Biomolecules 2025, 15(5), 680; https://doi.org/10.3390/biom15050680 - 7 May 2025

Cited by 6 | Viewed by 5671

Abstract

Polyurethanes (PUs) are extremely versatile materials used across different industries. Traditionally, they are synthesized by reacting polyols and isocyanates, both of which are petroleum-derived reagents. In response to the demand for more eco-friendly materials, research has increasingly focused on developing new routes for [...] Read more.

Polyurethanes (PUs) are extremely versatile materials used across different industries. Traditionally, they are synthesized by reacting polyols and isocyanates, both of which are petroleum-derived reagents. In response to the demand for more eco-friendly materials, research has increasingly focused on developing new routes for PU synthesis using renewable feedstocks. While substituting isocyanates remains a greater challenge, replacing fossil-based polyols with bio-based alternatives is now a promising strategy. This review explores the main natural sources and their transformations into bio-polyols, the incorporation of bio-fillers into PU formulations, and the production of non-isocyanate polyurethanes (NIPUs). Additionally, the study summarizes the growing body of research that has reported successful outcomes using bio-polyols in PU foams for distinct applications. Full article

(This article belongs to the Special Issue Applications of Biomaterials in Medicine and Healthcare)

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18 pages, 1361 KB

Open AccessEditor’s ChoiceReview

Inflammasome-Mediated Neuroinflammation: A Key Driver in Alzheimer’s Disease Pathogenesis

by Julie McGroarty, Shelbi Salinas, Hayden Evans, Bryan Jimenez, Vincent Tran, Samuel Kadavakollu, Arti Vashist and Venkata Atluri

Biomolecules 2025, 15(5), 676; https://doi.org/10.3390/biom15050676 - 7 May 2025

Cited by 9 | Viewed by 5217

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly, characterized by memory loss, cognitive decline, and functional impairment. While hallmark pathological features include extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence points [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder predominantly affecting the elderly, characterized by memory loss, cognitive decline, and functional impairment. While hallmark pathological features include extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein, increasing evidence points to chronic neuroinflammation as a key driver of disease progression. Among inflammatory mechanisms, the activation of the NLRP3 (nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome in microglia plays a pivotal role by amplifying neuroinflammatory cascades, exacerbating synaptic dysfunction, and accelerating neuronal loss. This review examines the molecular underpinnings of AD with a focus on NLRP3 inflammasome-mediated neuroinflammation, detailing the crosstalk between Aβ, tau pathology, and innate immune responses. Finally, we highlight emerging therapeutic strategies targeting NLRP3 inflammasome activation as promising avenues for mitigating neuroinflammation and slowing AD progression. Full article

(This article belongs to the Special Issue Pathogenesis and Neuropathology of Alzheimer's Disease)

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26 pages, 1243 KB

Open AccessEditor’s ChoiceReview

The Critical Balance Between Quiescence and Reactivation of Neural Stem Cells

by Adam M. Elkin, Sarah Robbins, Claudia S. Barros and Torsten Bossing

Biomolecules 2025, 15(5), 672; https://doi.org/10.3390/biom15050672 - 6 May 2025

Cited by 2 | Viewed by 4996

Abstract

Neural stem cells (NSC) are multipotent, self-renewing cells that give rise to all neural cell types within the central nervous system. During adulthood, most NSCs exist in a quiescent state which can be reactivated in response to metabolic and signalling changes, allowing for [...] Read more.

Neural stem cells (NSC) are multipotent, self-renewing cells that give rise to all neural cell types within the central nervous system. During adulthood, most NSCs exist in a quiescent state which can be reactivated in response to metabolic and signalling changes, allowing for long-term continuous neurogenesis and response to injury. Ensuring a critical balance between quiescence and reactivation is required to maintain the limited NSC reservoir and neural replenishment throughout lifetime. The precise mechanisms and signalling pathways behind this balance are at the focus of current research. In this review, we highlight and discuss recent studies using Drosophila, mammalian and zebrafish models contributing to the understanding of molecular mechanisms underlying quiescence and reactivation of NSCs. Full article

(This article belongs to the Special Issue Cellular Quiescence and Dormancy)

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17 pages, 1315 KB

Open AccessEditor’s ChoiceArticle

Biological Activities of Essential Oils and Hydrolates from Different Parts of Croatian Sea Fennel (Crithmum maritimum L.)

by Livia Slišković, Nikolina Režić Mužinić, Olivera Politeo, Petra Brzović, Josip Tomaš, Ivana Generalić Mekinić and Marijana Popović

Biomolecules 2025, 15(5), 666; https://doi.org/10.3390/biom15050666 - 4 May 2025

Cited by 2 | Viewed by 1515

Abstract

The traditional nutritional use of sea fennel (Crithmum maritimum L.) has been rediscovered and reestablished, making this halophyte plant a prominent ingredient in coastal cuisine and a subject of interest in various scientific disciplines, including pharmacy and medicine. The first objective of [...] Read more.

The traditional nutritional use of sea fennel (Crithmum maritimum L.) has been rediscovered and reestablished, making this halophyte plant a prominent ingredient in coastal cuisine and a subject of interest in various scientific disciplines, including pharmacy and medicine. The first objective of this study was to identify the volatile profiles of essential oils (EOs) and hydrolates derived from the leaves, flowers, and fruits of sea fennel using gas chromatography–mass spectrometry. A total of 25 different volatiles were identified in the EOs and 63 were identified in the hydrolates. Limonene was the most abundant component in the EOs (74.85%, 74.30%, and 67.41%, respectively), while in the hydrolates, it was terpinen-4-ol in the leaves (27.8%) and the flowers (36.7%) and (Z)-carveol in the fruits (11.4%). The second objective was to investigate the biological activities of the samples. The antioxidant and choline inhibitory activities of hydrolates were generally low, with the flower hydrolate providing the inhibition of both enzymes and the leaf hydrolate with the highest antiradical activity. The cytotoxic activities of the EOs and hydrolates were also investigated. The human breast adenocarcinoma cell line MDA-MB-23 was the most sensitive against EOs from the flowers and fruits, reaching the IC₅₀ after 48 and 72 h, respectively. The leaf hydrolate exhibited cytotoxic activity after 72 h, while the flower hydrolate was effective after 48 h. The MCF-7 cell line was sensitive to the flower and fruit EOs, and the IC₅₀ was reached at all the tested periods. Overall, the results highlight sea fennel as a rich source of bioactive compounds that have significant potential for greater utilization in the nutraceutical and pharmaceutical industries. Full article

(This article belongs to the Special Issue Natural Bioactives as Leading Molecules for Drug Development)

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20 pages, 337 KB

Open AccessEditor’s ChoiceReview

Prebiotics and Probiotics Supplementation in Pigs as a Model for Human Gut Health and Disease

by Raffaella Rossi and Edda Mainardi

Biomolecules 2025, 15(5), 665; https://doi.org/10.3390/biom15050665 - 3 May 2025

Cited by 7 | Viewed by 2854

Abstract

Animal models are an essential part of translational research for the purpose of improving human health. The pig is a potential human research model that can be used to assess the effects of dietary interventions, pathologies, and drugs on gut health and the [...] Read more.

Animal models are an essential part of translational research for the purpose of improving human health. The pig is a potential human research model that can be used to assess the effects of dietary interventions, pathologies, and drugs on gut health and the microbiome, due to its anatomical and physiological similarity to humans. It is recognised that a healthy gut is closely linked to the prevention of several chronic diseases, including obesity, diabetes, gastrointestinal inflammation, as well as neurological and cardiovascular diseases. The use of prebiotics and probiotics plays an important role in maintaining a healthy digestive system, which is responsible for modulating all other body functions. The present review focuses on the applications of prebiotics and probiotics in the pig as an animal model in healthy and diseased conditions, in order to highlight the efficacy of these molecules in the perspective of human health outcomes. The data support the use of prebiotics to improve intestinal health in both healthy and diseased states. In addition, the use of human microbiota-associated (HMA) gnotobiotic pigs provided a good model to study the intestinal and systemic immune response and microbiota composition following probiotic supplementation after a vaccine or virus challenge. Full article

(This article belongs to the Special Issue Prebiotics and Probiotics in Health and Disease: Looking at the Future)

18 pages, 4193 KB

Open AccessFeature PaperEditor’s ChoiceArticle

Distinct Clinical Phenotypes in KIF1A-Associated Neurological Disorders Result from Different Amino Acid Substitutions at the Same Residue in KIF1A

by Lu Rao, Wenxing Li, Yufeng Shen, Wendy K. Chung and Arne Gennerich

Biomolecules 2025, 15(5), 656; https://doi.org/10.3390/biom15050656 - 2 May 2025

Cited by 3 | Viewed by 1941

Abstract

KIF1A is a neuron-specific kinesin motor responsible for intracellular transport along axons. Pathogenic KIF1A mutations cause KIF1A-associated neurological disorders (KAND), a spectrum of severe neurodevelopmental and neurodegenerative conditions. While individual KIF1A mutations have been studied, how different substitutions at the same residue affect [...] Read more.

KIF1A is a neuron-specific kinesin motor responsible for intracellular transport along axons. Pathogenic KIF1A mutations cause KIF1A-associated neurological disorders (KAND), a spectrum of severe neurodevelopmental and neurodegenerative conditions. While individual KIF1A mutations have been studied, how different substitutions at the same residue affect motor function and disease progression remains unclear. Here, we systematically examine the molecular and clinical consequences of mutations at three key motor domain residues—R216, R254, and R307—using single-molecule motility assays and genotype–phenotype associations. We find that different substitutions at the same residue produce distinct molecular phenotypes, and that homodimeric mutant motor properties correlate with developmental outcomes. In addition, we present the first analysis of heterodimeric KIF1A motors—mimicking the heterozygous context in patients—and demonstrate that while heterodimers retain substantial motility, their properties are less predictive of clinical severity than homodimers. These results highlight the finely tuned mechanochemical properties of KIF1A and suggest that dysfunctional homodimers may disproportionately drive the diverse clinical phenotypes observed in KAND. By establishing residue-specific genotype–phenotype relationships, this work provides fundamental insights into KAND pathogenesis and informs targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in the Structure and Function of Microtubule-Associated Motor Proteins)

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13 pages, 551 KB

Open AccessEditor’s ChoiceReview

Drosophila as a Genetic Model System to Study Organismal Energy Metabolism

by Arely V. Diaz, Izel Tekin and Tânia Reis

Biomolecules 2025, 15(5), 652; https://doi.org/10.3390/biom15050652 - 1 May 2025

Cited by 2 | Viewed by 2379

Abstract

Metabolism is the essential process by which an organism converts nutrients into energy to fuel growth, development, and repair. Metabolism at the level of a multicellular, multi-organ animal is inherently more complex than metabolism at the single-cell level. Indeed, each organ also must [...] Read more.

Metabolism is the essential process by which an organism converts nutrients into energy to fuel growth, development, and repair. Metabolism at the level of a multicellular, multi-organ animal is inherently more complex than metabolism at the single-cell level. Indeed, each organ also must maintain its own homeostasis to function. At all three scales, homeostasis is a defining feature: as energy sources and energetic demands wax and wane, the system must be robust. While disruption of organismal energy homeostasis can be manifested in different ways in humans, obesity (defined as excess body fat) is an increasingly common outcome of metabolic imbalance. Here we will discuss the genetic basis of metabolic dysfunction that underlies obesity. We focus on what we are learning from Drosophila melanogaster as a model organism to explore and dissect genetic causes of metabolic dysfunction in the context of a whole organism. Full article

(This article belongs to the Special Issue Drosophila as a Model System to Study Metabolism)

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23 pages, 714 KB

Open AccessEditor’s ChoiceReview

Bispecific Antibodies, Nanobodies and Extracellular Vesicles: Present and Future to Cancer Target Therapy

by Asier Lizama-Muñoz and Julio Plaza-Diaz

Biomolecules 2025, 15(5), 639; https://doi.org/10.3390/biom15050639 - 29 Apr 2025

Cited by 5 | Viewed by 4177

Abstract

Cancer remains one of the leading causes of mortality worldwide, with a growing need for precise and effective treatments. Traditional therapies such as chemotherapy and radiotherapy have limitations, including off-target effects and drug resistance. In recent years, targeted therapies have emerged as promising [...] Read more.

Cancer remains one of the leading causes of mortality worldwide, with a growing need for precise and effective treatments. Traditional therapies such as chemotherapy and radiotherapy have limitations, including off-target effects and drug resistance. In recent years, targeted therapies have emerged as promising alternatives, aiming to improve treatment specificity and reduce systemic toxicity. Among the most innovative approaches, bispecific antibodies, nanobodies, and extracellular vesicles offer distinct and complementary mechanisms for cancer therapy. Bispecific antibodies enhance immune responses and enable dual-targeting of cancer cells, nanobodies provide superior tumor penetration due to their small size, and extracellular vesicles present a novel platform for drug and RNA delivery. This work aims to review and analyze these three approaches, assessing their current applications, advantages, challenges, and future perspectives. 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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12 pages, 2016 KB

Open AccessEditor’s ChoiceArticle

Ionic Strength Investigation on the Interaction Between miR-155 and a PNA-Based Probe by Atomic Force Spectroscopy

by Davide Atzei, Francesco Lavecchia di Tocco and Anna Rita Bizzarri

Biomolecules 2025, 15(5), 634; https://doi.org/10.3390/biom15050634 - 28 Apr 2025

Cited by 2 | Viewed by 1070

Abstract

Peptide nucleic acids (PNAs) are synthetic analogues of DNA/RNA characterized by the absence of negative phosphate groups, which confer a low sensitivity to ionic strength for hybridization with respect to the canonical counterpart. PNAs are a suitable probe for miRNAs, as well as [...] Read more.

Peptide nucleic acids (PNAs) are synthetic analogues of DNA/RNA characterized by the absence of negative phosphate groups, which confer a low sensitivity to ionic strength for hybridization with respect to the canonical counterpart. PNAs are a suitable probe for miRNAs, as well as endogenous molecules of single-strand non-coding RNA whose dysregulation is often linked to several diseases. The interaction forces between PNA and microRNA-155 (miR-155), a multifunctional microRNA overexpressed in a variety of tumors, were investigated by Atomic Force Spectroscopy (AFS) in fluid under different conditions. We found that the unbinding forces acquired at the ionic strength of 150 mM for a rather wide range of loading rates (ΔF/Δt) can be described using the Bell–Evans model. This allows us to extract information on the kinetics and thermodynamic properties of the miR-155/PNA duplex. Additionally, we probed the unbinding forces and the target recognition times between miR-155 and PNA in the 50–300 mM ionic strength range. Our results indicate that both of these parameters are practically independent from the ionic strength in the analyzed range. The results provide information that is useful for a wider use of PNA in biosensors for diagnostics and therapeutics, even in situ. Full article

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

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32 pages, 3209 KB

Open AccessEditor’s ChoiceReview

CD99: A Key Regulator in Immune Response and Tumor Microenvironment

by Maria Cristina Manara, Valentina Fiori, Angelo Sparti and Katia Scotlandi

Biomolecules 2025, 15(5), 632; https://doi.org/10.3390/biom15050632 - 28 Apr 2025

Cited by 8 | Viewed by 4226

Abstract

CD99 is a membrane protein critical for various immunological functions, including T-cell activation, protein trafficking, cell apoptosis, and leukocyte movement. It is also highly expressed in certain malignant tumors, contributing to the development, invasion, immune evasion, and adaptation of tumor cells to stress [...] Read more.

CD99 is a membrane protein critical for various immunological functions, including T-cell activation, protein trafficking, cell apoptosis, and leukocyte movement. It is also highly expressed in certain malignant tumors, contributing to the development, invasion, immune evasion, and adaptation of tumor cells to stress stimuli, including drug resistance. CD99 is crucial at the intersection of normal biological processes and pathological conditions like cancer. While research indicates that CD99 may interact homotypically, there is evidence of some heterotypic ligands that align with its roles. The development of multiple anti-CD99 antibodies has shed light on its functions, particularly regarding interactions between tumor cells that overexpress CD99 and immune cells expressing the same protein within the microenvironment. Anti-CD99 antibodies effectively eliminate tumors and attract immune cells to the tumor area. Additionally, CD99 influences the expression of specific immune checkpoint molecules, such as CD47, paving the way for potential combinations of anti-CD99 with immune checkpoint inhibitors. This review explores CD99’s role in normal physiology and cancer biology, focusing on how monoclonal antibodies affect CD99 expression and activity, thereby influencing cancer cells’ interactions with their microenvironment. It summarizes key findings about how these changes impact cancer cell behavior and the effectiveness of treatments. Full article

(This article belongs to the Section Biological Factors)

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42 pages, 3927 KB

Open AccessEditor’s ChoiceReview

Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers

by Whi-An Kwon and Jae Young Joung

Biomolecules 2025, 15(5), 625; https://doi.org/10.3390/biom15050625 - 27 Apr 2025

Cited by 6 | Viewed by 4257

Abstract

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite [...] Read more.

Metastatic prostate cancer (mPCa) remains a significant cause of cancer-related mortality in men. Advances in molecular profiling have demonstrated that the androgen receptor (AR) axis, DNA damage repair pathways, and the PI3K/AKT/mTOR pathway are critical drivers of disease progression and therapeutic resistance. Despite the established benefits of hormone therapy, chemotherapy, and bone-targeting agents, mPCa commonly becomes treatment-resistant. Recent breakthroughs have highlighted the importance of identifying actionable genetic alterations, such as BRCA2 or ATM defects, that render tumors sensitive to poly-ADP ribose polymerase (PARP) inhibitors. Parallel efforts have refined imaging—particularly prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography—to detect and localize metastatic lesions with high sensitivity, thereby guiding patient selection for PSMA-targeted radioligand therapies. Multi-omics innovations, including liquid biopsy technologies, enable the real-time tracking of emergent AR splice variants or reversion mutations, supporting adaptive therapy paradigms. Nonetheless, the complexity of mPCa necessitates combination strategies, such as pairing AR inhibition with PI3K/AKT blockade or PARP inhibitors, to inhibit tumor plasticity. Immuno-oncological approaches remain challenging for unselected patients; however, subsets with mismatch repair deficiency or neuroendocrine phenotypes may benefit from immune checkpoint blockade or targeted epigenetic interventions. We present these pivotal advances, and discuss how biomarker-guided integrative treatments can improve mPCa management. Full article

(This article belongs to the Special Issue Prostate Cancer Biomarkers and Therapeutics)

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15 pages, 2903 KB

Open AccessEditor’s ChoiceArticle

Field-Effect Transistor Based on Nanocrystalline Graphite for DNA Immobilization

by Bianca Adiaconita, Eugen Chiriac, Tiberiu Burinaru, Catalin Marculescu, Cristina Pachiu, Oana Brincoveanu, Octavian Simionescu and Marioara Avram

Biomolecules 2025, 15(5), 619; https://doi.org/10.3390/biom15050619 - 25 Apr 2025

Cited by 3 | Viewed by 2073

Abstract

In recent years, field-effect transistors (FETs) based on graphene have attracted significant interest due to their unique electrical properties and their potential for biosensing and molecular detection applications. This study uses FETs with a nanocrystalline graphite (NCG) channel to detect DNA nucleobases. The [...] Read more.

In recent years, field-effect transistors (FETs) based on graphene have attracted significant interest due to their unique electrical properties and their potential for biosensing and molecular detection applications. This study uses FETs with a nanocrystalline graphite (NCG) channel to detect DNA nucleobases. The exceptional electronic properties of NCG, and its high surface area, enable strong π–π stacking interactions with DNA nucleobases, promoting efficient adsorption and stabilization of the biomolecules. The direct attachment of nucleobases to the NCG channel leads to substantial changes in the device’s electrical characteristics, which can be measured in real time to assess DNA binding and sequence recognition. This method enables highly sensitive, label-free DNA detection, opening up new possibilities for rapid genetic analysis and diagnostics. Understanding the interactions between DNA nucleobases and graphene-based materials is crucial for advancing genetic research and biotechnology, paving the way for more accurate and efficient diagnostic tools. Full article

(This article belongs to the Special Issue Biomolecules and Materials Based Approaches in Biomedical Field: 2nd Edition)

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14 pages, 2726 KB

Open AccessEditor’s ChoiceArticle

Pancreatic MicroRNAs in Ictidomys tridecemlineatus Associated with Metabolic Diseases: Nature’s Insights into Important Biomarkers

by Olawale O. Taiwo, Saif Rehman and Kenneth B. Storey

Biomolecules 2025, 15(5), 616; https://doi.org/10.3390/biom15050616 - 23 Apr 2025

Cited by 1 | Viewed by 1063

Abstract

Hibernation involves a profound metabolic rate depression (MRD) that enables certain species to survive prolonged periods of low energy availability. The thirteen-lined ground squirrel uses MRD to arrange cellular and biochemical pathways which suppress nonvital genetic and cellular pathways to conserve internal energy [...] Read more.

Hibernation involves a profound metabolic rate depression (MRD) that enables certain species to survive prolonged periods of low energy availability. The thirteen-lined ground squirrel uses MRD to arrange cellular and biochemical pathways which suppress nonvital genetic and cellular pathways to conserve internal energy while preserving all essential processes. This study investigates the role of microRNAs (miRNAs) in controlling key signaling pathways and cellular processes in pancreatic tissue during hibernation. Using next-generation sequencing and broad genomic analysis, we analyzed and identified seven differentially expressed miRNAs (miR-29a-3p, miR-22-3p, miR-125-5p, miR-200a-3p, miR-328-3p, miR-21-5p, and miR-148-3p) in the pancreas of hibernating 13-lined ground squirrels (Ictidomys tridecemlineatus). Our findings reveal that these miRNAs regulate pathways involved in glucose homeostasis, including insulin secretion and metabolic regulation, contributing to the unique adaptations of hibernation. These insights advance our understanding of the molecular adaptations underlying hibernation and may have implications for therapeutic strategies targeting metabolic disorders such as diabetes. Full article

(This article belongs to the Section Molecular Biology)

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38 pages, 2476 KB

Open AccessEditor’s ChoiceReview

Understanding the Role of Adipokines in Cardiometabolic Dysfunction: A Review of Current Knowledge

by Sayantap Datta, Saisudha Koka and Krishna M. Boini

Biomolecules 2025, 15(5), 612; https://doi.org/10.3390/biom15050612 - 23 Apr 2025

Cited by 11 | Viewed by 6214

Abstract

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and [...] Read more.

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and progression of cardiometabolic disorders remain poorly understood. Adipokines are adipocyte-specific cytokines that are central to deleterious cardiometabolic alterations. They exhibit both pro-inflammatory and anti-inflammatory effects, complicating their association with cardiometabolic disturbances. Thus, understanding the cardiometabolic association of adipokines from a molecular and signaling perspective assumes great importance. This review presents a comprehensive outline of the most prominent adipokines exhibiting pro-inflammatory and/or anti-inflammatory functions in cardiometabolic dysfunction. The review also presents an insight into the pathophysiological implications of such adipokines in different cardiometabolic dysfunction conditions, the status of adipokine druggability, and future studies that can be undertaken to address the existing scientific gap. A clear understanding of the functional and mechanistic role of adipokines can potentially improve our understanding of cardiovascular disease pathophysiology and enhance our current therapeutic regimen in the years to come. Full article

(This article belongs to the Special Issue Insights from the Editorial Board Members)

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35 pages, 3801 KB

Open AccessEditor’s ChoiceReview

Targeting the Electron Transport System for Enhanced Longevity

by Marko Radovic, Lucas P. Gartzke, Simon E. Wink, Joris A. van der Kleij, Frouwkje A. Politiek and Guido Krenning

Biomolecules 2025, 15(5), 614; https://doi.org/10.3390/biom15050614 - 23 Apr 2025

Cited by 7 | Viewed by 5835

Abstract

Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. [...] Read more.

Damage to mitochondrial DNA (mtDNA) results in defective electron transport system (ETS) complexes, initiating a cycle of impaired oxidative phosphorylation (OXPHOS), increased reactive oxygen species (ROS) production, and chronic low-grade inflammation (inflammaging). This culminates in energy failure, cellular senescence, and progressive tissue degeneration. Rapamycin and metformin are the most extensively studied longevity drugs. Rapamycin inhibits mTORC1, promoting mitophagy, enhancing mitochondrial biogenesis, and reducing inflammation. Metformin partially inhibits Complex I, lowering reverse electron transfer (RET)-induced ROS formation and activating AMPK to stimulate autophagy and mitochondrial turnover. Both compounds mimic caloric restriction, shift metabolism toward a catabolic state, and confer preclinical—and, in the case of metformin, clinical—longevity benefits. More recently, small molecules directly targeting mitochondrial membranes and ETS components have emerged. Compounds such as Elamipretide, Sonlicromanol, SUL-138, and others modulate metabolism and mitochondrial function while exhibiting similarities to metformin and rapamycin, highlighting their potential in promoting longevity. The key question moving forward is whether these interventions should be applied chronically to sustain mitochondrial health or intermittently during episodes of stress. A pragmatic strategy may combine chronic metformin use with targeted mitochondrial therapies during acute physiological stress. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Life-Extending Biomolecules and Interventions with Medical and Technological Implications)

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21 pages, 3207 KB

Open AccessEditor’s ChoiceArticle

Integrating Biochemical and Computational Approaches Reveal Structural Insights in Trastuzumab scFv-Fc Antibody Engineering

by Olga Bednova, Jessica Pougoue Ketchemen, Hazem Mslati, Mark Barok, Heikki Joensuu, Natalie Zeytuni, Francesco Gentile, Leon Sanche, Humphrey Fonge and Jeffrey Victor Leyton

Biomolecules 2025, 15(5), 606; https://doi.org/10.3390/biom15050606 - 22 Apr 2025

Cited by 2 | Viewed by 2953

Abstract

Antibody-based agents have become a preferred treatment for various diseases, including cancer, due to significant advances in antibody engineering. The use of single-chain Fv-Fcs (scFv-Fcs) has been a promising engineering approach for therapeutic design. The concept is that the Fc provides increased stability [...] Read more.

Antibody-based agents have become a preferred treatment for various diseases, including cancer, due to significant advances in antibody engineering. The use of single-chain Fv-Fcs (scFv-Fcs) has been a promising engineering approach for therapeutic design. The concept is that the Fc provides increased stability and target binding and ultimately improves performance. However, the structural and dynamic relationship between the variable and Fc domains, which are fused in close proximity, and the impact on stability and target binding are not well understood. This study evaluated trastuzumab-derived scFv-Fc antibodies, focusing on the impact of their design on important biopharmaceutical parameters. Computational modelling and molecular dynamics, alongside experimental studies, were used to ascertain their dynamics, expression and purification, stabilities, and binding potencies. The results showed that the scFv subunits exhibited stochastic interplays that lead to diverse shapes and were associated with functional performance. This new understanding of scFv-Fc antibodies and their structural and functional nuances provides important details to further guide the design of more effective and less toxic therapeutics. Full article

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

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15 pages, 3023 KB

Open AccessEditor’s ChoiceArticle

Link N Directly Targets IL-1β to Suppress Inflammation and Regulate Sensory Pain in Intervertebral Disc Degeneration

by Michael P. Grant, Muskan Alad, Fajer Yousef, Laura M. Epure, John Antoniou and Fackson Mwale

Biomolecules 2025, 15(4), 603; https://doi.org/10.3390/biom15040603 - 19 Apr 2025

Cited by 4 | Viewed by 1630

Abstract

Intervertebral disc (IVD) disease is typically characterized by the degradation of IVD tissue, secretion of inflammatory and painful factors, and hyperinnervation of the disc. The pro-inflammatory cytokine interleukin-1β (IL-1β) has been regarded as a principal factor in orchestrating disc degeneration. Link N (LN) [...] Read more.

Intervertebral disc (IVD) disease is typically characterized by the degradation of IVD tissue, secretion of inflammatory and painful factors, and hyperinnervation of the disc. The pro-inflammatory cytokine interleukin-1β (IL-1β) has been regarded as a principal factor in orchestrating disc degeneration. Link N (LN) is a peptide derived from the link protein that has been shown to promote extracellular disc regeneration even in an inflammatory milieu; however, no mechanism(s) has been described for their behaviour to date. Building on prior studies on LN, we hypothesize that LN directly inhibits IL-1β. IVD degeneration was experimentally induced in New Zealand white rabbits, followed by the injection of either sLN or saline as the vehicle control. To determine the expression of markers of pain, histology was performed. Cultured human Nucleus Pulposus disc cells (hNP) were used to determine the effects of LN on IL-1β-induced changes in gene expression, including the effects on IL-1β, TNFα, and IL6 signalling. Isolated murine dorsal root ganglia (DRG) neurons were used to assess the effect of LN on IL-1β-induced neuronal hyperactivity. LN significantly reduced IL-1β-induced NF-κB activation in a dose-dependent manner in disc cells and was further able to modulate IL-1β-induced gene expression, inflammatory mediators, and neurotrophic factors. Peptide docking simulations revealed that LN could interact with IL-1β. A direct interaction of LN and IL-1β was revealed through co-immunoprecipitation experiments. Although IL-1β was able to hypersensitize DRG neurons following a seven-day exposure, as demonstrated by Ca²⁺ imaging, this effect was significantly blunted when co-treated with LN. LN demonstrates a novel mechanism of action by directly inhibiting IL-1β, in addition to mitigating IL-1β-induced hypersensitivity in DRG neurons. These data suggest a potential role for LN in reducing discogenic pain. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 7835 KB

Open AccessEditor’s ChoiceArticle

Identification of TSSK1 and TSSK2 as Novel Targets for Male Contraception

by Saman Nayyab, Marıá Gracia Gervasi, Darya A. Tourzani, Yeva Shamailova, Hiroki Akizawa, Mahboubeh Taghavi, Wei Cui, Rafael Fissore, Ana Maria Salicioni, Gunda I. Georg, Elizabeth Snyder and Pablo E. Visconti

Biomolecules 2025, 15(4), 601; https://doi.org/10.3390/biom15040601 - 18 Apr 2025

Cited by 3 | Viewed by 1313

Abstract

The testis-specific serine kinases (TSSKs) are post-meiotically expressed in testicular germ cells. Their testis-specific expression, together with their putative role in phosphorylation pathways, suggests that TSSKs have relevant roles in spermiogenesis, sperm function, or both. Independent Tssk3 and Tssk6 knockout mice, as well [...] Read more.

The testis-specific serine kinases (TSSKs) are post-meiotically expressed in testicular germ cells. Their testis-specific expression, together with their putative role in phosphorylation pathways, suggests that TSSKs have relevant roles in spermiogenesis, sperm function, or both. Independent Tssk3 and Tssk6 knockout mice, as well as the double Tssk1/Tssk2 KO males, are sterile. However, the double KO results are silent regarding the individual roles of TSSK1 and TSSK2. The aim of this study was to develop independent mutant mouse models of Tssk1 and Tssk2, using CRISPR/Cas9, to evaluate their independent roles in reproduction. Male heterozygous pups were used to establish one Tssk1 and two independent Tssk2 mutant lines. Natural mating mutant Tssk1 and Tssk2 homozygous males but not females were found to be sterile. Additionally, homozygous males have lower sperm numbers and decreased motility, and were infertile in vitro. Anti-TSSK2 antibodies were validated against Tssk2 mutants and used in Western blot and immunofluorescence experiments. TSSK2 is localized to the sperm head; importantly, it is present in the testes and sperm from Tssk1 mutant mice, confirming individual mutation. Our results indicate that both TSSK1 and TSSK2 are individually essential for male reproduction and support both kinases as suitable nonhormonal male contraceptive targets. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

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19 pages, 2854 KB

Open AccessEditor’s ChoiceArticle

Sex-Specific Inflammatory Profiles Affect Neuropsychiatric Issues in COVID-19 Survivors

by Mariagrazia Palladini, Mario Gennaro Mazza, Beatrice Bravi, Margherita Bessi, Maria Cristina Lorenzi, Sara Spadini, Rebecca De Lorenzo, Patrizia Rovere-Querini, Roberto Furlan and Francesco Benedetti

Biomolecules 2025, 15(4), 600; https://doi.org/10.3390/biom15040600 - 18 Apr 2025

Cited by 2 | Viewed by 1487

Abstract

Post-COVID syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analyzed the interplay of a one-month 48-biomarker inflammatory panel, with three-months of [...] Read more.

Post-COVID syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analyzed the interplay of a one-month 48-biomarker inflammatory panel, with three-months of depressive symptoms and cognitive performance. The findings indicate that cognitive impairment is influenced by both inflammation and depression in the overall cohort. However, prominent sex-specific differences emerged. In females, a lingering imbalance between pro- and anti-inflammatory responses—likely reflecting the long-lasting immune alterations triggered by COVID-19—significantly affects cognitive functioning and shows a marginal, though not statistically significant, association with depressive symptoms. This suggests that a mixed inflammatory profile may contribute to these outcomes. Conversely, in males, inflammation was inversely associated with depression severity, with protective effects from regulatory mediators (IL-2, IL-4, IL-6, IL-15, LIF, TNF-α, β-NGF) against depression. In males, cognitive impairment appeared to be driven mainly by depressive symptoms, with minimal influence from inflammatory markers. These results highlight distinct sex-specific pathways in immune and inflammatory responses post-COVID-19, potentially shaped by endocrine mechanisms. The findings suggest that persistent inflammation may foster long-term neuropsychiatric sequelae, possibly through its effects on the brain, and underscore the need for sex-tailored therapeutic strategies to address the lasting impact of COVID-19. Full article

(This article belongs to the Section Biological Factors)

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17 pages, 3557 KB

Open AccessEditor’s ChoiceArticle

The Role of Antigen Carbohydrate 125 in Modulating Soluble ST2: Prognostic-Related Effects in Acute Heart Failure

by Arancha Martí-Martínez, Julio Núñez, Herminio López-Escribano, Elena Revuelta-López, Anna Mollar, Marta Peiró, Juan Sanchis, Antoni Bayés-Genís, Arturo Carratala, Òscar Miró, Pere Llorens and Pablo Herrero-Puente

Biomolecules 2025, 15(4), 602; https://doi.org/10.3390/biom15040602 - 18 Apr 2025

Cited by 1 | Viewed by 1016

Abstract

Background: Acute heart failure (AHF) is a complex syndrome associated with high mortality and hospital readmissions, characterized by volume overload and inflammation. Soluble ST2 (sST2) and antigen carbohydrate 125 (CA125) are emerging biomarkers that reflect these processes and may interact to influence long-term [...] Read more.

Background: Acute heart failure (AHF) is a complex syndrome associated with high mortality and hospital readmissions, characterized by volume overload and inflammation. Soluble ST2 (sST2) and antigen carbohydrate 125 (CA125) are emerging biomarkers that reflect these processes and may interact to influence long-term outcomes in AHF patients. This study aims to examine the prognostic relationship between sST2 and CA125 in predicting mortality and heart failure (HF)-related hospitalizations in patients with decompensated heart failure. Methods: In a cohort of 635 patients with AHF, we investigated whether the prognostic value of sST2 varies according to CA125 levels (≤35 vs. >35 U/mL). The endpoints were: (a) time to all-cause death, and (b) the combination of time to death or new HF admission. Results: This study of EAHFE registry data shows that the association between sST2 and long-term adverse outcomes (mortality and HF hospitalizations) in patients with AHF was differentially influenced by CA125 concentrations (p-value for interactions = 0.031 and 0.029, respectively). Higher sST2 was associated with the risk of death and the combined risk of death/HF readmission when CA125 was >35 U/mL [HR = 1.02 (CI 95%: 1.01–1.04), p = 0.006 and 1.02 (CI 95%: 1.01–1.03); p = 0.013 per increase in 10 ng/mL, respectively], but not when CA125 was ≤35 U/mL. Conclusions: This study highlights the prognostic interaction between sST2 and CA125 in AHF. Elevated sST2 predicts poor outcomes mainly in patients with high CA125 levels (>35 U/mL), suggesting CA125’s role in modulating inflammatory activity in HF. Further research is needed. Full article

(This article belongs to the Special Issue Chronic Heart Failure: From Molecular Mechanisms to Therapies Strategies)

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14 pages, 1928 KB

Open AccessEditor’s ChoiceArticle

Diagnostic Utility of Bronchoalveolar Lavage Flow Cytometric Leukocyte Profiling in Interstitial Lung Disease and Infection

by Erika M. Novoa-Bolivar, José A. Ros, Sonia Pérez-Fernández, José A. Campillo, Ruth López-Hernández, Rosana González-López, Inmaculada Ruiz-Lorente, Almudena Otálora-Alcaraz, Cristina Ortuño-Hernández, Lourdes Gimeno, Diana Ceballos-Francisco, Manuel Muro, Elena Solana-Martínez, Pablo Martínez-Camblor and Alfredo Minguela

Biomolecules 2025, 15(4), 597; https://doi.org/10.3390/biom15040597 - 17 Apr 2025

Cited by 1 | Viewed by 3058

Abstract

Interstitial lung diseases (ILD) represent a diverse group of disorders that primarily affect the pulmonary interstitium and, less commonly, involve the alveolar and vascular epithelium. Overlapping clinical, radiological and histopathological features make proper classification difficult, requiring multiple complementary methodologies, including flow cytometry of [...] Read more.

Interstitial lung diseases (ILD) represent a diverse group of disorders that primarily affect the pulmonary interstitium and, less commonly, involve the alveolar and vascular epithelium. Overlapping clinical, radiological and histopathological features make proper classification difficult, requiring multiple complementary methodologies, including flow cytometry of bronchoalveolar lavages (BAL). This retrospective study analyzed BAL flow cytometry data from 1074 real-life patients, quantifying alveolar macrophages, CD4/CD8 lymphocytes, neutrophils, eosinophils, and CD1a+ Langerhans cells, with the aim of evaluating its diagnostic utility in ILD and pulmonary infection. Clustering and logistic regression analyses identified seven distinct leukocyte profiles: lymphocytic (associated with hypersensitivity pneumonitis, cryptogenic organizing pneumonia, and lymphocytic interstitial pneumonia), sarcoidosis, macrophagic (including nonspecific interstitial pneumonia, desquamative interstitial pneumonitis, pneumoconiosis, and unclassifiable ILD), neutrophilic (including usual interstitial pneumonia, respiratory bronchiolitis ILD, and acute interstitial pneumonia), infectious diseases, eosinophilic ILD, and Langerhans cell histiocytosis. The estimated leukocyte profiles were associated with different overall survival (OS) outcomes. Neutrophilic profiles, both infectious and non-infectious, correlated with poorer OS, particularly in patients without pulmonary fibrosis. Furthermore, corticosteroids and other immunosuppressive therapies did not show significant OS differences across leukocyte profiles. Although the gold standard in BAL cytology continues to be cytopathology, these results support BAL flow cytometry as a rapid and reliable complementary tool to aid in the classification of interstitial lung diseases based on immune cell profiles, providing valuable predictive information and contributing to personalized therapeutic approaches. Full article

(This article belongs to the Special Issue Immune-Related Biomarkers: 2nd Edition)

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16 pages, 3419 KB

Open AccessEditor’s ChoiceArticle

[¹⁸F]Mefway: Imaging Serotonin 5HT_1A Receptors in Human Postmortem Alzheimer’s and Parkinson’s Disease Anterior Cingulate. Potential Applications to Human Positron Emission Tomography Studies

by Noresa L. Gonzaga, Fariha Karim, Christopher Liang and Jogeshwar Mukherjee

Biomolecules 2025, 15(4), 592; https://doi.org/10.3390/biom15040592 - 16 Apr 2025

Cited by 2 | Viewed by 1187

Abstract

Serotonin 5HT_1A receptors may be affected in neurodegeneration, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using the selective 5HT_1A receptor positron emission tomography (PET) imaging agent, [¹⁸F]mefway, autoradiographic studies from postmortem human brains of AD, PD, and [...] Read more.

Serotonin 5HT_1A receptors may be affected in neurodegeneration, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Using the selective 5HT_1A receptor positron emission tomography (PET) imaging agent, [¹⁸F]mefway, autoradiographic studies from postmortem human brains of AD, PD, and cognitively normal (CN) subjects were carried out. Levels of [¹⁸F]mefway binding were compared with monoamine oxidase A (MAO-A) measured using [¹⁸F]FAZIN3 binding and dopamine D2/D3 receptors measured using [¹⁸F]fallypride binding in the same subjects. Autoradiograms of brain sections of the anterior cingulate and corpus callosum from CN, PD, and AD subjects (n = 6 in each group) were analyzed. Significant increased binding of [¹⁸F]mefway was found in the AD (+30%) and PD (+11%) brains compared to CN brains. This increase positively correlated to increased [¹⁸F]FAZIN3 binding, suggesting greater 5HT_1A receptor availability when MAO-A levels are higher. Differences in [¹⁸F]fallypride binding in the three groups were not significant. Our results support the finding that the availability of 5HT_1A receptors in AD and PD is elevated in the anterior cingulate cortex and is negatively correlated with MAO-A. This upregulation may potentially be a response to lower serotonin levels due to the increased levels of MAO-A activity in this brain region or other neuroinflammatory changes. Thus, 5HT_1A receptors may be a potential target for diagnostic and therapeutic approaches for AD and PD. Full article

(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration—2nd Edition)

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16 pages, 1222 KB

Open AccessEditor’s ChoiceArticle

A Pangenomic Approach to Improve Population Genetics Analysis and Reference Bias in Underrepresented Middle Eastern and Horn of Africa Populations

by Adrien Oliva, Rachel Foare, Peter Campbell, Natalie A. Twine, Denis C. Bauer and Angad Singh Johar

Biomolecules 2025, 15(4), 582; https://doi.org/10.3390/biom15040582 - 15 Apr 2025

Cited by 2 | Viewed by 4764

Abstract

Genomics plays a crucial role in addressing health disparities, yet most studies rely on the hg38 linear reference genome, limiting the potential of pangenomic approaches, particularly for underrepresented populations. In this study, we focus on characterising East African populations, particularly Somalis, by constructing [...] Read more.

Genomics plays a crucial role in addressing health disparities, yet most studies rely on the hg38 linear reference genome, limiting the potential of pangenomic approaches, particularly for underrepresented populations. In this study, we focus on characterising East African populations, particularly Somalis, by constructing a variation graph using Mozabites from the Human Genome Diversity Project (HGDP) given their ancestral affinity with Somalis. We evaluated the effectiveness of this graph-based reference in estimating effective population sizes (Ne) in Bedouins compared to the hg38 reference and examined its impact on allele frequencies and genome-wide association studies (GWAS). Applying a coalescent model to the graph-based reference produced a Ne estimate of approximately 17 for the Bedouin population, which was significantly lower than the estimate from the hg38 reference (approximately 79,000). Only the graph-based estimate fell within the 95% confidence interval in simulations, indicating improved accuracy. Moreover, graph variants exhibited significantly lower allele frequencies (p-value < 2.2 × 10⁻¹⁶), suggesting potential effects on the interpretation and power of GWAS. Notably, GWAS variants specific to Bedouins derived from the graph showed lower frequencies (p = 0.023) than those obtained from the linear reference. These findings suggest that a pangenomic approach, informed by populations with ancestral affinities such as the Mozabites, provides more accurate estimates of Ne and allele frequencies. This highlights the importance of pangenomic strategies to better capture genetic diversity in underrepresented populations, a critical step towards improving population genetics studies, personalised medicine, and equitable healthcare. Full article

(This article belongs to the Special Issue The Genomics Era: From Reference Genomes to Pan-Genomic Approach, 2nd Edition)

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34 pages, 3038 KB

Open AccessEditor’s ChoiceReview

Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease

by Varshini V. Suresh, Sathish Sivaprakasam, Yangzom D. Bhutia, Puttur D. Prasad, Muthusamy Thangaraju and Vadivel Ganapathy

Biomolecules 2025, 15(4), 580; https://doi.org/10.3390/biom15040580 - 14 Apr 2025

Cited by 8 | Viewed by 9439

Abstract

Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal [...] Read more.

Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease. Full article

(This article belongs to the Special Issue Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders)

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14 pages, 1489 KB

Open AccessEditor’s ChoiceReview

Epigenetic Biomarkers in Thoracic Aortic Aneurysm, Dissection, and Bicuspid Aortopathy: A Comprehensive Review

by Dimitrios E. Magouliotis, Serge Sicouri, Noah Sicouri, Massimo Baudo, Francesco Cabrucci, Yoshiyuki Yamashita and Basel Ramlawi

Biomolecules 2025, 15(4), 568; https://doi.org/10.3390/biom15040568 - 11 Apr 2025

Cited by 6 | Viewed by 2456

Abstract

Thoracic aortic disease (TAD) encompasses a spectrum of life-threatening conditions, including thoracic aortic aneurysm (TAA), acute type A aortic dissection (ATAAD), and bicuspid aortic valve (BAV)-associated aortopathy. While genetic mutations are well-documented contributors, emerging evidence highlights epigenetic mechanisms as critical regulators of TAD [...] Read more.

Thoracic aortic disease (TAD) encompasses a spectrum of life-threatening conditions, including thoracic aortic aneurysm (TAA), acute type A aortic dissection (ATAAD), and bicuspid aortic valve (BAV)-associated aortopathy. While genetic mutations are well-documented contributors, emerging evidence highlights epigenetic mechanisms as critical regulators of TAD pathogenesis. This comprehensive review explores the role of epigenetic modifications—DNA methylation, histone modifications, and microRNA (miRNA) regulation—in vascular remodeling, extracellular matrix degradation, and endothelial dysfunction. Aberrant DNA methylation patterns have been implicated in TAA and ATAAD, influencing genes responsible for vascular integrity and inflammation. Histone modifications modulate smooth muscle cell phenotype switching, impacting aneurysm progression. Additionally, dysregulated miRNA expression contributes to endothelial barrier disruption and extracellular matrix remodeling, presenting novel avenues for biomarker discovery. The reversibility of epigenetic modifications offers a promising therapeutic target, with pharmacological agents such as histone deacetylase inhibitors and miRNA-based therapies showing potential in preclinical models. This review underscores the translational potential of epigenetic biomarkers for early disease detection, risk stratification, and precision medicine approaches. Further research is needed to integrate these findings into clinical practice, paving the way for innovative diagnostic and therapeutic strategies in TAD management. Full article

(This article belongs to the Section Molecular Biomarkers)

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18 pages, 3299 KB

Open AccessEditor’s ChoiceArticle

Endometriotic Follicular Fluid Affects Granulosa Cells’ Morphology and Increases Duplication Rate and Connexin-43 Expression

by Loris Marin, Chiara Sabbadin, Giovanni Faggin, Claudia Maria Radu, Decio Armanini, Michele Paccagnella, Cristiano Salata, Luciana Bordin, Eugenio Ragazzi, Guido Ambrosini and Alessandra Andrisani

Biomolecules 2025, 15(4), 561; https://doi.org/10.3390/biom15040561 - 10 Apr 2025

Cited by 1 | Viewed by 1383

Abstract

Endometriosis is a complicated condition characterized by inflammation, low oocyte quality, and decreased uterus receptivity, associated with fertility issues. This study aims to better understand the reduced pregnancy outcome in endometriosis by analyzing both the granulosa cells (GCs) and the follicular fluids (FFs) [...] Read more.

Endometriosis is a complicated condition characterized by inflammation, low oocyte quality, and decreased uterus receptivity, associated with fertility issues. This study aims to better understand the reduced pregnancy outcome in endometriosis by analyzing both the granulosa cells (GCs) and the follicular fluids (FFs) obtained during the assisted reproductive technology (ART)-related oocyte pick-up. Seventy patients, approaching our ART Center with the diagnosis of infertility for Age-Idiopathic Factor (AIF) (n = 36), endometriosis (ENDO) (n = 23), or male factor (MF) (n = 11), were enrolled in this study. GCs from each group were separately analyzed for morphology, replication, and expression of Connexin-43 and Follicle-Stimulating Hormone Receptor (FSHR) by microscopy, flow cytometry, and immunocytochemistry. Results show that FF in a culture medium allowed GCs to survive and replicate. Upon culturing GCs from each group with ENDO follicular fluid, increases were observed in both population doublings and in the development of fibroblast-like and muscle-like morphologies. Despite undergoing morphological changes, GCs consistently expressed FSHR. However, exposure to ENDO follicular fluid led to an upregulation of Connexin-43 expression across all GC groups. These findings suggest that in endometriosis, FF contains unidentified factors that can induce aberrant replication, morphological differentiation, and overexpression of Connexin-43, potentially contributing to follicular dysfunction. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Endometriosis)

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29 pages, 3410 KB

Open AccessEditor’s ChoiceReview

HOXA10 and HOXA11 in Human Endometrial Benign Disorders: Unraveling Molecular Pathways and Their Impact on Reproduction

by Lorin-Manuel Pîrlog, Andrada-Adelaida Pătrășcanu, Mara-Diana Ona, Andreea Cătană and Ioana Cristina Rotar

Biomolecules 2025, 15(4), 563; https://doi.org/10.3390/biom15040563 - 10 Apr 2025

Cited by 12 | Viewed by 4544

Abstract

HOX genes, a family of conserved transcription factors, are critical for reproductive tract development and endometrial functionality. This review highlights the molecular underpinnings of HOXA10/HOXA11 in reproductive health and their dysregulation in benign pathologies associated with infertility, such as endometriosis, adenomyosis, and endometrial [...] Read more.

HOX genes, a family of conserved transcription factors, are critical for reproductive tract development and endometrial functionality. This review highlights the molecular underpinnings of HOXA10/HOXA11 in reproductive health and their dysregulation in benign pathologies associated with infertility, such as endometriosis, adenomyosis, and endometrial polyps. These genes are dynamically regulated by estrogen and progesterone, with peak expression during the secretory phase of the menstrual cycle when implantation takes place. The molecular mechanisms underlying their action include the modulation of extracellular matrix (ECM) remodeling via metalloproteinases, cytokines like leukemia inhibitory factor, and cell adhesion molecules such as β3-integrin, all of which are essential for the differentiation of epithelial and stromal cells, as well as for trophoblast invasion. Aberrant HOX gene expression, driven by DNA hypermethylation or altered histone acetylation, compromises endometrial receptivity and implantation. For instance, reduced HOXA10 expression in endometriosis stems from hypermethylation and chronic inflammation, disrupting immune modulation and cytokine signaling. Similarly, adenomyosis alters HOXA11-regulated ECM remodeling and β3-integrin expression, impairing embryo attachment. Furthermore, regulatory pathways involving vitamin D and retinoic acid offer promising therapeutic avenues pathways, as they enhance HOXA10/HOXA11 expression and endometrial receptivity. This review underscores the critical molecular roles of HOXA10/HOXA11 genes as biomarkers and therapeutic targets to optimize fertility outcomes and address reproductive pathologies. Full article

(This article belongs to the Special Issue Embryo Implantation: New Molecular Insights in Endometrial Receptivity, Trophoblast Invasion and Signaling)

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14 pages, 484 KB

Open AccessEditor’s ChoiceArticle

The Quantification of Vitamin D in Humans: A Promising, Non-Invasive and Cost-Effective Method to Measure 25-Hydroxyvitamin D

by Giulia Squillacioti, Samar El Sherbiny, Veronica Lettico, Federica Ghelli, Marco Panizzolo, Giacomo Scaioli, Manuela Martella, Selene Limoncelli, Giulio Mengozzi and Roberto Bono

Biomolecules 2025, 15(4), 560; https://doi.org/10.3390/biom15040560 - 10 Apr 2025

Cited by 3 | Viewed by 3920

Abstract

Background: Vitamin D intake and synthesis are essential. Vitamin D deficiency is increasing across all age groups, raising concerns regarding public health. Serum 25(OH)D is measured to define vitamin D deficiency. However, its quantification in non-invasively collected biological matrices is still poorly studied. [...] Read more.

Background: Vitamin D intake and synthesis are essential. Vitamin D deficiency is increasing across all age groups, raising concerns regarding public health. Serum 25(OH)D is measured to define vitamin D deficiency. However, its quantification in non-invasively collected biological matrices is still poorly studied. This study aimed to assess 25(OH)D levels in unconventional matrices using cost-effective analytical methods. Methods: Serum, urine, and saliva were collected from 62 healthy, non-smoking volunteers, 25–44 years of age. Biological samples were analysed using the Enzyme-Linked Immunosorbent Assay (ELISA). The serum was additionally analysed via the chemiluminescent microparticle immunoassay (CMIA), which was used as a benchmark. Results: We observed a linear correlation (Pearson r = 0.44; p = 0.05) between the benchmark and ELISA-measured 25(OH)D urinary levels. After stratification by sex, the correlation was stronger and significant only in females (Pearson r = 0.62; p = 0.04). Salivary 25(OH)D levels did not correlate with serum levels for both ELISA and CMIA measures. Subjects with a CMIA serum-based deficiency showed lower urinary 25(OH)D levels (p = 0.04). Conclusion: Our study opens up the possibility of using urinary 25(OH)D levels as a proxy measurement of vitamin D. Such an approach may allow future investigations on the association between environmental factors and vitamin D assessed in non-invasively collected biological matrices via cost-effective analytical methods. Full article

(This article belongs to the Section Biological Factors)

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18 pages, 3620 KB

Open AccessEditor’s ChoiceArticle

Fecal Calprotectin as a Prognostic Biomarker for Mortality and Renal Outcomes in Chronic Kidney Disease

by So Young Lee, Kyungdo Han, Hyuk-Sang Kwon, Eun Sil Koh and Sungjin Chung

Biomolecules 2025, 15(4), 557; https://doi.org/10.3390/biom15040557 - 10 Apr 2025

Cited by 1 | Viewed by 1816

Abstract

Background/Objectives: Fecal calprotectin (FC) is a biomarker of intestinal inflammation widely used in the assessment of gastrointestinal disorders. However, its role in chronic kidney disease (CKD) remains unclear. Given the growing recognition of the gut–kidney axis in CKD pathophysiology, this study aimed to [...] Read more.

Background/Objectives: Fecal calprotectin (FC) is a biomarker of intestinal inflammation widely used in the assessment of gastrointestinal disorders. However, its role in chronic kidney disease (CKD) remains unclear. Given the growing recognition of the gut–kidney axis in CKD pathophysiology, this study aimed to investigate the association between FC levels, systemic inflammation, renal outcomes, and mortality in CKD patients. Methods: We enrolled a total of 515 CKD patients who underwent fecal calprotectin measurement between 2016 and 2023. After applying the exclusion criteria (inflammatory bowel disease, ongoing renal replacement therapy, or incomplete laboratory data), 260 patients were included in the final analysis and stratified into low-FC (<102 μg/g, n = 130) and high-FC (≥102 μg/g, n = 130) groups based on the median FC value. Factors associated with kidney disease progression and patient survival were analyzed. Results: Patients in the high-FC group (≥102 μg/g) were significantly older (72.8 ± 14.63 vs. 64.02 ± 18.15 years, p < 0.0001) and had a higher prevalence of diabetes mellitus (55.38% vs. 42.31%, p = 0.0349), heart failure (21.54% vs. 7.69%, p = 0.0016), and history of acute kidney injury (33.85% vs. 18.46%, p = 0.0048). Elevated FC was independently associated with increased mortality risk (hazards ratio [HR] 1.658, 95% confidence interval [CI] 1.034–2.658, p = 0.0357) with higher mortality rates (48.36 vs. 18.46 per 100,000 person-years). Subgroup analyses revealed stronger associations between FC and mortality in males (HR 2.160, 95% CI 1.046–4.463, p = 0.0375), elderly patients (≥75 years) (HR 2.122, 95% CI 1.209–3.725, p = 0.0088), and non-diabetic patients (HR 2.487, 95% CI 1.141–5.421, p = 0.0219). While FC was not significantly associated with end-stage kidney disease (ESKD) progression (odds ratio [OR] 1.289, 95% CI 0.455–3.650, p = 0.6323), higher FC levels paradoxically predicted slower estimated glomerular filtration rate (eGFR) decline (OR 2.763, 95% CI 1.139–6.699, p = 0.0245). Combined analysis revealed patients with both elevated FC and high-sensitivity C-reactive protein (hs-CRP) had the highest mortality risk (HR 3.504, 95% CI 1.163–10.554, p < 0.0001) compared to those with low levels of both markers. Conclusions: FC is a potential prognostic biomarker for mortality in CKD patients, independently of traditional inflammatory markers. Further research is warranted to elucidate the mechanisms underlying its paradoxical relationship with renal outcomes and its potential role in risk stratification and therapeutic targeting in CKD. Full article

(This article belongs to the Special Issue The Biomarkers in Renal Diseases)

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33 pages, 1662 KB

Open AccessEditor’s ChoiceReview

Oxidant-Based Cytotoxic Agents During Aging: From Disturbed Energy Metabolism to Chronic Inflammation and Disease Progression

by Jürgen Arnhold

Biomolecules 2025, 15(4), 547; https://doi.org/10.3390/biom15040547 - 9 Apr 2025

Cited by 4 | Viewed by 2502

Abstract

In humans, aging is an inevitable consequence of diminished growth processes after reaching maturity. The high order of biomolecules in cells and tissues is continuously disturbed by numerous physical and chemical destructive impacts. Host-derived oxidant-based cytotoxic agents (reactive species, transition free metal ions, [...] Read more.

In humans, aging is an inevitable consequence of diminished growth processes after reaching maturity. The high order of biomolecules in cells and tissues is continuously disturbed by numerous physical and chemical destructive impacts. Host-derived oxidant-based cytotoxic agents (reactive species, transition free metal ions, and free heme) contribute considerably to this damage. These agents are under the control of immediately acting antagonizing principles, which are important to ensure cell and tissue homeostasis. In this review, I apply the concept of host-derived cytotoxic agents and their interplay with antagonizing principles to the aging process. During aging, energy metabolism and the supply of tissues with dioxygen and nutrients are increasingly disturbed. In addition, a chronic inflammatory state develops, a condition known as inflammaging. The balance between oxidant-based cytotoxic agents and protective mechanisms is analyzed depending on age-based physiological alterations in ATP production. Disturbances in this balance are associated with the development of age-related diseases and comorbidities. An enhanced production of reactive species from dysfunctional mitochondria, alterations in cellular redox homeostasis, and adaptations to hypoxia are highlighted. Examples of how disturbances between oxidant-based cytotoxic agents and antagonizing principles contribute to the pathogenesis of diseases in persons of advanced age are given. Full article

(This article belongs to the Special Issue Advances in Host-Derived Cytotoxic Agents)

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23 pages, 2065 KB

Open AccessEditor’s ChoiceReview

Comparative Insights on IL-5 Targeting with Mepolizumab and Benralizumab: Enhancing EGPA Treatment Strategies

by Mayu Shiomi, Ryu Watanabe, Ryuhei Ishihara, Sayaka Tanaka, Takashi Nakazawa and Motomu Hashimoto

Biomolecules 2025, 15(4), 544; https://doi.org/10.3390/biom15040544 - 8 Apr 2025

Cited by 5 | Viewed by 6780

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis characterized by extravascular granulomas and eosinophilia in both blood and tissues. Eosinophils, which play a critical role in the pathophysiology of EGPA, require interleukin (IL)-5 for maturation in the bone marrow and migration to [...] Read more.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis characterized by extravascular granulomas and eosinophilia in both blood and tissues. Eosinophils, which play a critical role in the pathophysiology of EGPA, require interleukin (IL)-5 for maturation in the bone marrow and migration to tissues. Glucocorticoids and immunosuppressants have been the cornerstone of treatment; however, their side effects have imposed a significant burden on many patients. Mepolizumab, an antibody that binds to and neutralizes IL-5, demonstrated efficacy in controlling disease activity in EGPA in the MIRRA trial conducted in 2017. In 2024, benralizumab, an IL-5 receptor alpha antagonist, was shown to be non-inferior to mepolizumab in efficacy against EGPA in the MANDARA trial. Both drugs were originally used for severe asthma and have benefited EGPA by reducing eosinophil counts. Due to differences in pharmacological structure and pharmacokinetics, the degree of eosinophil suppression varies between the two agents, and recent studies suggest that they may also affect inflammatory and homeostatic eosinophils differently. This review summarizes the latest insights into the pathophysiology of EGPA, highlights the similarities and differences between the two drugs, and discusses future treatment strategies for EGPA based on current clinical unmet needs, including drug selection. Full article

(This article belongs to the Section Molecular Medicine)

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39 pages, 4341 KB

Open AccessEditor’s ChoiceArticle

Synergistic Effects of UVB and Ionizing Radiation on Human Non-Malignant Cells: Implications for Ozone Depletion and Secondary Cosmic Radiation Exposure

by Angeliki Gkikoudi, Gina Manda, Christina Beinke, Ulrich Giesen, Amer Al-Qaaod, Elena-Mihaela Dragnea, Maria Dobre, Ionela Victoria Neagoe, Traimate Sangsuwan, Siamak Haghdoost, Spyridon N. Vasilopoulos, Sotiria Triantopoulou, Anna Georgakopoulou, Ioanna Tremi, Paraskevi N. Koutsoudaki, Sophia Havaki, Vassilis G. Gorgoulis, Michael Kokkoris, Faton Krasniqi, Georgia I. Terzoudi and Alexandros G. Georgakilas Show full author list Hide full author list

Biomolecules 2025, 15(4), 536; https://doi.org/10.3390/biom15040536 - 6 Apr 2025

Cited by 6 | Viewed by 4191

Abstract

The ozone layer in the Earth’s atmosphere filters solar radiation and limits the unwanted effects on humans. A depletion of this ozone shield would permit hazardous levels of UV solar radiation, especially in the UVB range, to bombard Earth’s surface, resulting in potentially [...] Read more.

The ozone layer in the Earth’s atmosphere filters solar radiation and limits the unwanted effects on humans. A depletion of this ozone shield would permit hazardous levels of UV solar radiation, especially in the UVB range, to bombard Earth’s surface, resulting in potentially significant effects on human health. The concern for these adverse effects intensifies if we consider that the UVB solar radiation is combined with secondary cosmic radiation (SCR) components, such as protons and muons, as well as terrestrial gamma rays. This research aims to delve into the intricate interplay between cosmic and solar radiation on earth at the cellular level, focusing on their synergistic effects on human cell biology. Through a multidisciplinary approach integrating radiobiology and physics, we aim to explore key aspects of biological responses, including cell viability, DNA damage, stress gene expression, and finally, genomic instability. To assess the impact of the combined exposure, normal i.e., non-malignant human cells (skin fibroblasts, keratinocytes, monocytes, and lymphocytes) were exposed to high-energy protons or gamma rays in combination with UVB. Cellular molecular and cytogenetic biomarkers of radiation exposure, such as DNA damage (γH2AΧ histone protein and dicentric chromosomes), as well as the expression pattern of various stress genes, were analyzed. In parallel, the MTS reduction and lactate dehydrogenase assays were used as indicators of cell viability, proliferation, and cytotoxicity. Results reveal remaining DNA damage for the co-exposed samples compared to samples exposed to only one type of radiation in all types of cells, accompanied by increased genomic instability and distinct stress gene expression patterns detected at 24–48 h post-exposure. Understanding the impact of combined radiation exposures is crucial for assessing the health risks posed to humans if the ozone layer is partially depleted, with structural and functional damages inflicted by combined cosmic and UVB exposure. Full article

(This article belongs to the Special Issue Molecular Mechanisms in DNA and RNA Damage and Repair)

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