Biomolecules

15 pages, 919 KB

Open AccessEditor’s ChoiceArticle

Modulating Effect of Carbohydrate Antigen 125 on the Prognostic Value of High-Sensitivity C-Reactive Protein in Heart Failure

by Enrique Santas, Arancha Martí-Martínez, Elena Revuelta-López, Sandra Villar, Rafael de la Espriella, Patricia Palau, Pau Llàcer, Gema Miñana, Enrique Rodriguez-Borja, Arturo Carratalá, Arantxa Gonzalez, Antoni Bayés-Genís, Juan Sanchis and Julio Núñez

Biomolecules 2025, 15(9), 1260; https://doi.org/10.3390/biom15091260 - 30 Aug 2025

Cited by 1 | Viewed by 1280

Abstract

Inflammation and congestion are key pathophysiological processes in heart failure (HF). Our aim was to evaluate the potential modulatory effect of carbohydrate antigen 125 (CA125) on inflammation, assessed by high-sensitivity C-reactive protein (hs-CRP). We analyzed a cohort of 4043 consecutive patients in whom [...] Read more.

Inflammation and congestion are key pathophysiological processes in heart failure (HF). Our aim was to evaluate the potential modulatory effect of carbohydrate antigen 125 (CA125) on inflammation, assessed by high-sensitivity C-reactive protein (hs-CRP). We analyzed a cohort of 4043 consecutive patients in whom hs-CRP and CA125 levels were measured during a hospitalization for acute HF. Multivariate Cox regression models were applied to assess the association between the biomarkers and all-cause mortality and death/HF rehospitalization at 6 months. In multivariable analysis, a significant interaction between hs-CRP and CA125 was observed for both outcomes (p-value for interaction = 0.036 and <0.001, respectively). hs-CRP was significantly associated with an increased risk of death (HR = 1.27; 95% CI 1.16–1.41; p < 0.001) and death/HF rehospitalization (HR = 1.18; 95% CI 1.09–1.28; p < 0.001) if CA125 > 35 U/mL. In contrast, hs-CRP was not predictive of events when CA125 ≤ 35 U/mL. In conclusion, in patients with acute HF, the association between hs-CRP and clinical outcomes was modulated by CA125 levels. hs-CRP was associated with a higher risk of events only in patients with elevated CA125. These findings support a potential modulatory and amplifying role for CA125 in the inflammatory response in HF. Full article

(This article belongs to the Special Issue Biomolecules in Myocarditis and Inflammatory Heart Disease)

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21 pages, 2229 KB

Open AccessEditor’s ChoiceArticle

A Multi-Ingredient Supplement Improves Body Re-Composition, Ovarian Aging Markers, and Reproductive Success in Young and Middle-Aged Female Mice

by Alessandra Chiarot, Mahek Minhas, Nicoletta M. de Maat, Jenny Doan, Mats I. Nilsson, Bart P. Hettinga, Mehrnoosh Faghih, Michael S. Neal, Joshua P. Nederveen and Mark A. Tarnopolsky

Biomolecules 2025, 15(9), 1258; https://doi.org/10.3390/biom15091258 - 30 Aug 2025

Viewed by 2825

Abstract

Ovarian aging is characterized by mitochondrial dysfunction, oxidative stress, and inflammation. The development of adjunctive treatments that mitigate age-related subfertility is warranted. We examined the benefits of nutraceutical supplementation (FE; Fertility Enhancer) with mitochondrial antioxidants, anti-inflammatory agents, metabolic activators, vitamins and minerals, and [...] Read more.

Ovarian aging is characterized by mitochondrial dysfunction, oxidative stress, and inflammation. The development of adjunctive treatments that mitigate age-related subfertility is warranted. We examined the benefits of nutraceutical supplementation (FE; Fertility Enhancer) with mitochondrial antioxidants, anti-inflammatory agents, metabolic activators, vitamins and minerals, and amino acids on ovarian aging, metabolic activity, and reproductive success in young (Y; 6-month-old) and middle-aged (O; 11-month-old) female C57BL/6J mice. The mice were fed calorie- and macronutrient-matched diets w/wo the FE supplement for three months and harem mated twice. Daily FE supplementation promoted significant body re-composition, including loss of white adipose tissue (gWAT: −36% vs. CON, p < 0.001), gain of skeletal muscle (SkM: +67% vs. CON, p < 0.001), and improved SkM/gWAT ratio (+185% vs. CON, p < 0.001). Metabolic testing showed enhanced fat oxidation (+38%, p < 0.01) and energy expenditure (+7%, p = 0.051) in FE mice. Breeding and immunoblotting data demonstrated improved reproductive success (Y-CON: 44%, Y-FE: 89%, O-CON: 0%, O-FE: 18%) and a modest attenuation of ovarian aging markers in both FE groups. We surmise that a multi-ingredient supplement, such as the Fertility Enhancer, may improve body re-composition, metabolic activity, and markers of ovarian aging, thus enhancing reproductive health and fertility in females. Full article

(This article belongs to the Special Issue Molecular Aspects of Female Infertility)

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21 pages, 1190 KB

Open AccessEditor’s ChoiceReview

Glycerol Kinase 2 as a Metabolic Sentinel for Human Sperm Motility and Male Fertility

by João S. Oliveira, Rúben J. Moreira, Ana D. Martins, Marco G. Alves and Pedro F. Oliveira

Biomolecules 2025, 15(9), 1249; https://doi.org/10.3390/biom15091249 - 29 Aug 2025

Cited by 1 | Viewed by 2080

Abstract

Male infertility affects 8–12% of couples worldwide and is solely responsible in up to 30% of cases. Assisted Reproductive Technologies (ARTs) provide potential solutions, particularly in conditions where spermatozoa display structural abnormalities or impaired motility, such as asthenozoospermia. Sperm metabolism demonstrates remarkable flexibility, [...] Read more.

Male infertility affects 8–12% of couples worldwide and is solely responsible in up to 30% of cases. Assisted Reproductive Technologies (ARTs) provide potential solutions, particularly in conditions where spermatozoa display structural abnormalities or impaired motility, such as asthenozoospermia. Sperm metabolism demonstrates remarkable flexibility, shifting between glycolysis and oxidative phosphorylation to produce ATP required for motility. Glycerol kinase 2 (GK2) phosphorylates glycerol in the sperm midpiece, generating glycerol-3-phosphate, a key intermediate in glycolysis, lipid metabolism, and oxidative phosphorylation. The localization of GK2 suggests not only a regulatory role in sperm metabolism but also a possible association with VDAC proteins, contributing to ADP-ATP exchange between the cytosol and mitochondria. Elucidating the role of GK2 in spermatozoa is of particular relevance, as this enzyme not only contributes to key metabolic pathways but may also interact with VDAC proteins, influencing mitochondrial function and energy exchange. Such interactions could play a pivotal role in regulating sperm motility. A deeper understanding of these mechanisms could position GK2 as a valuable biomarker: in scenarios where GK2–VDAC interactions are confirmed, it may guide optimized sperm selection methods in ARTs, whereas the absence or impairment of such interactions could serve as a diagnostic indicator in asthenozoospermic men. Full article

(This article belongs to the Special Issue Advances in Metabolomics in Health and Disease)

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32 pages, 1220 KB

Open AccessEditor’s ChoiceReview

Mitochondrial Aging in the CNS: Unravelling Implications for Neurological Health and Disease

by Davide Steffan, Camilla Pezzini, Martina Esposito and Anais Franco-Romero

Biomolecules 2025, 15(9), 1252; https://doi.org/10.3390/biom15091252 - 29 Aug 2025

Cited by 11 | Viewed by 5334

Abstract

Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. [...] Read more.

Mitochondrial aging plays a central role in the functional decline of the central nervous system (CNS), with profound consequences for neurological health. As the brain is one of the most energy-demanding organs, neurons are particularly susceptible to mitochondrial dysfunction that arises with aging. Key features of mitochondrial aging include impaired mitochondrial dynamics, reduced mitophagy, increased production of reactive oxygen species (ROS), and accumulation of mitochondrial DNA (mtDNA) mutations. These alterations dramatically compromise neuronal bioenergetics, disrupt synaptic integrity, and promote oxidative stress and neuroinflammation, paving the path for the development of neurodegenerative diseases. This review also examines the complex mechanisms driving mitochondrial aging in the central nervous system (CNS), including the disruption of mitochondrial-organelle communication, and explores how mitochondrial dysfunction contributes to neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. By synthesizing current evidence and identifying key knowledge gaps, we emphasize the urgent need for targeted strategies to restore mitochondrial function, maintain cognitive health, and delay or prevent age-related neurodegeneration. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders: 3rd Edition)

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27 pages, 9028 KB

Open AccessEditor’s ChoiceArticle

Neuromuscular Defects in a Drosophila Model of the Congenital Disorder of Glycosylation SLC35A2-CDG

by Kazuyoshi Itoh, Masaki Kurogochi, Tadashi Kaname, Jun-ichi Furukawa and Shoko Nishihara

Biomolecules 2025, 15(9), 1256; https://doi.org/10.3390/biom15091256 - 29 Aug 2025

Viewed by 1571

Abstract

SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the SLC35A2 gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired [...] Read more.

SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the SLC35A2 gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired galactose-containing glycans and various neurological symptoms, although the underlying mechanisms remain largely unknown. We identified a novel SLC35A2-CDG patient carrying a pathogenic variant (c.617_620del, p.(Gln206ArgfsTer45)) who exhibited neurological abnormalities including bilateral ventriculomegaly. To investigate the disease mechanism, we established the first Drosophila model of SLC35A2-CDG. Knockout of Ugalt, the fly ortholog of SLC35A2, resulted in embryonic lethality, indicating its essential role. Knockdown of Ugalt reduced mucin-type O-glycans on muscles and neuromuscular junctions (NMJs), without affecting N-glycans. Ugalt knockdown larvae exhibited mislocalized NMJ boutons accompanied by a deficiency in basement membrane components on muscles. This phenotype resembles that of mutants of dC1GalT1 and dGlcAT-P, both involved in mucin-type O-glycosylation. Genetic interaction between Ugalt and dC1GalT1 was confirmed through double knockdown and double heterozygous analyses. Given that Drosophila NMJs are widely used as a model for mammalian central synapses, our findings suggest that Ugalt regulates NMJ architecture via mucin-type O-glycosylation and provide insights into the molecular basis of neurological abnormalities in SLC35A2-CDG. Full article

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

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17 pages, 3302 KB

Open AccessEditor’s ChoiceArticle

Consequences of Adhesion Molecule Close Homolog of L1 Deficiency for Neurons and Glial Cells in the Mouse Spinal Cord After Injury

by Igor Jakovcevski, Ayse Acar, Benjamin Schwindenhammer, Mohammad I. K. Hamad, Gebhard Reiss, Eckart Förster and Melitta Schachner

Biomolecules 2025, 15(9), 1247; https://doi.org/10.3390/biom15091247 - 28 Aug 2025

Viewed by 1358

Abstract

After spinal cord injury, pathological changes predominantly proceed caudal to the site of injury. To what extent these changes contribute to abnormalities during regeneration is poorly understood. Here, we addressed this question with a low-thoracic compression injury mouse model. The total numbers of [...] Read more.

After spinal cord injury, pathological changes predominantly proceed caudal to the site of injury. To what extent these changes contribute to abnormalities during regeneration is poorly understood. Here, we addressed this question with a low-thoracic compression injury mouse model. The total numbers of immunohistochemically stained neuronal and glial cell types in the lumbar spinal cord were stereologically determined 6 weeks after injury. We also investigated injured mice deficient in close homolog of L1 (CHL1), which had been reported to recover better after injury than their wild-type littermates. We here report that there were no differences between genotypes in uninjured animals. In both injured CHL1-deficient and wild-type littermates, gray and white matter volumes were decreased as compared with uninjured mice. Numbers of motoneurons and parvalbumin-expressing interneurons were also reduced in both genotypes. Numbers of interneurons in injured mutant mice were lower than in wild-type littermates. Whereas injury did not affect numbers of astrocytes and oligodendrocytes in the gray matter, numbers of microglia/macrophages were increased. In the mutant white matter, numbers of oligodendrocytes were reduced, with no changes in numbers of astrocytes and microglia. A loss of motoneurons and interneurons was observed in both genotypes, but loss of interneurons was more prominent in the absence of CHL1. We propose that, after injury, CHL1 deficiency causes deficits in structural outcome not seen after injury of wild-type mice. Full article

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

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23 pages, 4058 KB

Open AccessEditor’s ChoiceArticle

Inhibition of Astrocyte Reactivity by Mdivi-1 After Status Epilepticus in Rats Exacerbates Microglia-Mediated Neuroinflammation and Impairs Limbic–Cortical Glucose Metabolism

by Francisca Gómez-Oliver, Rubén Fernández de la Rosa, Mirjam Brackhan, Pablo Bascuñana, Miguel Ángel Pozo and Luis García-García

Biomolecules 2025, 15(9), 1242; https://doi.org/10.3390/biom15091242 - 27 Aug 2025

Cited by 2 | Viewed by 1385

Abstract

The lithium–pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a [...] Read more.

The lithium–pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp1, for its ability to modulate astrocytic mitochondrial dynamics and for its reported preventive neuroprotective properties. Mdivi-1 was administered shortly after SE onset, and we assessed brain glucose metabolism using [¹⁸F]FDG PET, alongside histological markers of neurodegeneration, astrocyte reactivity, and microglial activation, at 3 days post-SE. As expected, SE induced widespread brain hypometabolism measured by a VOI analysis, hippocampal neurodegeneration, and glial activation. Post-SE Mdivi-1 administration reduced hippocampal astrogliosis but neither conferred neuroprotection nor rescued glucose metabolism. On the contrary, Mdivi-1 exacerbated limbic–cortical hypometabolism when evaluated by SPM and normalized to whole brain tracer uptake and microglia-mediated neuroinflammation. These findings challenge the assumption that early astrocyte inhibition confers neuroprotection. Furthermore, early suppression of astrocyte reactivity after the damage has occurred may shift the neuroinflammatory response toward maladaptive microglial activation. Thus, while Mdivi-1 holds promise as a preventive neuroprotective agent, its use post-SE may have unintended adverse effects on the brain’s response to SE. Full article

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

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17 pages, 2356 KB

Open AccessEditor’s ChoiceArticle

Obesity Risk Factors Promote Metabolic Reprogramming and Viral Infection in Airways with Type 1 High Inflammation

by Paige Hartsoe, Niccolette Schaunaman, Taylor Nichols, Diana Cervantes, Stephanie Dawrs, Fernando Holguin and Hong Wei Chu

Biomolecules 2025, 15(9), 1229; https://doi.org/10.3390/biom15091229 - 26 Aug 2025

Viewed by 1314

Abstract

Obesity is a significant health issue, as it is related to human diseases such as asthma and respiratory viral infections. Asthma patients with obesity have more severe diseases, which can be presented with type 1 (e.g., IFN-γ) high inflammation. The interactions of obesity [...] Read more.

Obesity is a significant health issue, as it is related to human diseases such as asthma and respiratory viral infections. Asthma patients with obesity have more severe diseases, which can be presented with type 1 (e.g., IFN-γ) high inflammation. The interactions of obesity or saturated fatty acids (e.g., palmitic acid, PA) with IFN-γ in airway viral infections have not been clear. In this study, we determined the role of obesity risk factors high-fat diet (HFD) and PA in rhinovirus infection in the context of IFN-γ stimulation in mice and cultured human tracheobronchial epithelial cells. We further examined the therapeutic effect of a glycolytic inhibitor on metabolic reprogramming and viral infection in our experimental models. In mice, HFD in combination with IFN-γ significantly increased lung rhinovirus levels as well as neutrophilic inflammation. Similarly, PA and IFN-γ combination increased viral infection in mice, but HFD or PA alone had a minimal effect on viral infection. Mouse model data were confirmed in cultured primary healthy human airway epithelial cells where PA and IFN-γ together increased viral load. Mechanistically, HFD or PA in combination with IFN-γ up-regulated the glycolytic pathway and generated metabolites favoring viral replication. Inhibition of glycolysis by 2-DG effectively reduced viral infection in human airway epithelial cells. Our data suggest that hosts with obesity along with type 1 high inflammation may be at an increased risk of respiratory viral infections. Intervention of the glycolytic pathway or its metabolites may reduce the severity of viral infection. Full article

(This article belongs to the Section Molecular Medicine)

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19 pages, 6650 KB

Open AccessEditor’s ChoiceArticle

Protective Effect of Low 2-O, 3-O Desulfated Heparin (ODSH) Against LPS-Induced Acute Lung Injury in Mice

by Joyce Gonzales, Rahul S. Patil, Thomas P. Kennedy, Nagavedi S. Umapathy, Rudolf Lucas and Alexander D. Verin

Biomolecules 2025, 15(9), 1232; https://doi.org/10.3390/biom15091232 - 26 Aug 2025

Viewed by 1575

Abstract

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are critical conditions lacking effective pharmacologic therapies. Lipopolysaccharide (LPS), a bacterial endotoxin, is a well-established trigger of ALI. Emerging evidence suggests that heparin derivatives may attenuate lung injury, but [...] Read more.

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are critical conditions lacking effective pharmacologic therapies. Lipopolysaccharide (LPS), a bacterial endotoxin, is a well-established trigger of ALI. Emerging evidence suggests that heparin derivatives may attenuate lung injury, but their mechanisms remain unclear. Methods: This study evaluated the protective effects of 2-O, 3-O desulfated heparin (ODSH) in a murine model of LPS-induced ALI. Mice received LPS intratracheally with or without ODSH pre-treatment. Lung injury was assessed by bronchoalveolar lavage fluid (BALF) analysis, Evans blue dye albumin EBDA) extravasation, and histopathology. Results: ODSH treatment significantly reduced BALF protein concentration, inflammatory cell infiltration, and EBDA leakage. ODSH preserved endothelial barrier function in vitro, as evidenced by transendothelial electrical resistance (TER) measurements in human lung microvascular endothelial cell (HLMVEC) monolayers. Histological assessment (H&E staining) and myeloperoxidase (MPO) staining demonstrated reduced lung injury and neutrophil infiltration in the ODSH group. ODSH also downregulated pro-inflammatory mediators (NF-κB, IL-6, p38 MAPK) and upregulated the anti-inflammatory cytokine IL-10. Conclusions: ODSH mitigates LPS-induced ALI by reducing vascular permeability, neutrophilic inflammation, and pro-inflammatory signaling while enhancing IL-10 expression. These findings suggest ODSH may offer a novel therapeutic approach for treating ALI. Full article

(This article belongs to the Special Issue Lung Disease: From Molecular Mechanism to Therapeutic Opportunities)

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14 pages, 1711 KB

Open AccessEditor’s ChoiceArticle

A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy

by Alessia Nasca, Alessia Catania, Andrea Legati, Rossella Izzo, Carola D’onofrio, Teresa Ciavattini, Eleonora Lamantea, Costanza Lamperti and Daniele Ghezzi

Biomolecules 2025, 15(9), 1230; https://doi.org/10.3390/biom15091230 - 26 Aug 2025

Viewed by 1356

Abstract

Mitochondrial network dynamics, encompassing processes like fission, fusion, and mitophagy, are crucial for mitochondrial function and overall cellular health. Dysregulation of these processes has been linked to various human diseases. Particularly, pathogenic variants in the gene DNM1L can lead to a broad range [...] Read more.

Mitochondrial network dynamics, encompassing processes like fission, fusion, and mitophagy, are crucial for mitochondrial function and overall cellular health. Dysregulation of these processes has been linked to various human diseases. Particularly, pathogenic variants in the gene DNM1L can lead to a broad range of clinical phenotypes, ranging from isolated optic atrophy to severe neurological conditions. DNM1L encodes DRP1 (dynamin-1-like protein), which is a key player in mitochondrial and peroxisomal fission. This study describes two twin sisters with a de novo heterozygous variant in DNM1L, due to possible paternal germline mosaicism identified through clinical exome sequencing. The two twins showed a variable clinical presentation, including paraparesis and optic neuropathy. Functional studies of patient-derived fibroblasts revealed altered mitochondrial and peroxisomal morphology, along with dysregulated DNM1L transcript levels, indicating the deleterious effect of the variant. These findings allowed us to reclassify the identified variant from a variant of uncertain significance to a likely pathogenic variant. Our report provides insight into the phenotypic spectrum of DNM1L-related disorders and highlights the need to combine genetic and functional analyses to accurately diagnose rare mitochondrial diseases. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders: 3rd Edition)

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21 pages, 4387 KB

Open AccessEditor’s ChoiceArticle

Comparative Analysis of Aggregation of β- and γ-Synucleins in Vertebrates

by Maria Carmela Bonaccorsi di Patti, Martina Meoni and Mattia Toni

Biomolecules 2025, 15(9), 1231; https://doi.org/10.3390/biom15091231 - 26 Aug 2025

Cited by 1 | Viewed by 1237

Abstract

This study explores the structural transitions and aggregation behaviour of recombinant β- and γ-synucleins from five vertebrate species—Cyprinus carpio, Danio rerio, Xenopus laevis, Anolis carolinensis, and Homo sapiens—using thioflavin T fluorescence and circular dichroism spectroscopy, with and without [...] Read more.

This study explores the structural transitions and aggregation behaviour of recombinant β- and γ-synucleins from five vertebrate species—Cyprinus carpio, Danio rerio, Xenopus laevis, Anolis carolinensis, and Homo sapiens—using thioflavin T fluorescence and circular dichroism spectroscopy, with and without copper ions. Although synucleins are well-conserved proteins among vertebrates, species-specific differences in amino acid composition and predicted secondary structures were observed, particularly within β-strand-forming regions. During a six-day incubation, human β-synuclein exhibited a time-dependent increase in β-sheet-rich structures, while non-mammalian β-synucleins showed limited variation. In contrast, γ-synucleins from all species displayed greater aggregation propensity, with variations in kinetics and magnitude. The presence of copper reduced the rate of aggregation in human β-synuclein, likely due to high-affinity metal-binding sites, whereas γ-synuclein aggregation was only mildly affected. Notably, copper enhanced late-phase aggregation in A. carolinensis β-synuclein. These findings suggest that sequence divergence among synuclein isoforms may underlie species-specific aggregation mechanisms and metal sensitivity. The differential aggregation behaviour observed across taxa may reflect evolutionary adaptations in synuclein function and folding propensity, with implications for understanding the molecular basis of synucleinopathies and their potential modulation by metal ions. Full article

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

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19 pages, 3290 KB

Open AccessEditor’s ChoiceArticle

From Corncob By-Product to Functional Lignins: Comparative Analysis of Alkaline and Organosolv Extraction Followed by Laccase Treatment

by Elise Martin, Swarnima Agnihotri, Fabrice Audonnet, Eric Record, Pascal Dubessay, Mohammad J. Taherzadeh and Philippe Michaud

Biomolecules 2025, 15(9), 1226; https://doi.org/10.3390/biom15091226 - 26 Aug 2025

Cited by 1 | Viewed by 1865

Abstract

Corncobs, produced globally at over 200 million tons annually with 11–18% lignin content, represent an abundant and underexploited lignocellulosic resource for sustainable lignin valorization. In this study, two distinct extraction methodologies, alkaline treatment using sodium hydroxide and an organosolv process with a 50:50 [...] Read more.

Corncobs, produced globally at over 200 million tons annually with 11–18% lignin content, represent an abundant and underexploited lignocellulosic resource for sustainable lignin valorization. In this study, two distinct extraction methodologies, alkaline treatment using sodium hydroxide and an organosolv process with a 50:50 ethanol/water mixture, were systematically compared for their efficiency in isolating lignin from corncobs. Both protocols achieved high yields, up to 82% for alkaline and 84% for organosolv extraction under optimized conditions. The resulting lignins displayed notable differences in chemical structure and physical properties, as revealed by spectroscopic and thermal analyses, highlighting their divergent potential for downstream applications. To evaluate the suitability of these lignins to biocatalytic upgrading, post-extraction enzymatic treatment was performed using Pycnoporus cinnabarinus laccase (EC 1.10.3.2). Significant structural modifications were observed in alkaline-extracted lignin, as determined by FTIR spectroscopy, while organosolv lignin remained largely unaltered, a difference attributed to its lower aqueous solubility at the enzyme’s optimal pH. These results demonstrate the critical impact of extraction conditions on lignin reactivity and suitability for enzymatic tailoring. This work underscores the potential for holistic corncob valorization within integrated biorefinery frameworks. Selective extraction and targeted enzymatic modification not only facilitate efficient by-product utilization but also expand the prospects for producing versatile bio-based materials, thereby advancing the transition toward a sustainable, circular bioeconomy. Full article

(This article belongs to the Special Issue Recent Advances in Laccases and Laccase-Based Bioproducts: 2nd Edition)

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14 pages, 668 KB

Open AccessEditor’s ChoiceArticle

Serum Growth Differentiation Factor 15 (GDF15) Levels Reflect Ischemic Etiology in Heart Failure Patients with Iron Deficiency: A Cross-Sectional Study

by Marta Tajes, Maria del Mar Ras-Jiménez, Josefa Girona, Raúl Ramos-Polo, Montse Guardiola, José Manuel García-Pinilla, Josep Ribalta, Marta Cobo-Marcos, Lluís Masana, Javier de Juan-Bagudá, Cândida Fonseca, Cristina Enjuanes, Manuel Vázquez-Carrera, Josep Comin-Colet and Ricardo Rodríguez-Calvo

Biomolecules 2025, 15(9), 1234; https://doi.org/10.3390/biom15091234 - 26 Aug 2025

Viewed by 1408

Abstract

Heart failure (HF), particularly of an ischemic etiology, is steadily increasing worldwide. Non-anemic iron deficiency (ID) is highly prevalent among HF patients, and it has been related to worse outcomes. Growth differentiation factor 15 (GDF15) has been related to atherosclerotic cardiovascular (CV) disease, [...] Read more.

Heart failure (HF), particularly of an ischemic etiology, is steadily increasing worldwide. Non-anemic iron deficiency (ID) is highly prevalent among HF patients, and it has been related to worse outcomes. Growth differentiation factor 15 (GDF15) has been related to atherosclerotic cardiovascular (CV) disease, HF and iron pathophysiology. Nevertheless, the specific potential role of GDF15 in HF patients with ID has not been fully explored. In this cross-sectional study we determined serum GDF15 levels in 60 HF patients with ID from the IRON-PATH II study. The discriminative capacity of GDF15 in logistic regression models for classifying these patients according to ischemic etiology was defined as the primary endpoint. Additionally, relationships between GDF15 levels and impaired right ventricle function, impaired functional capacity and HF were included as secondary endpoints. GDF15 was inversely related to tricuspid annular plane systolic excursion (TAPSE) and the six-minute walking test (6MWT), and positively related to hallmarks of HF [i.e., N-terminal prohormone of brain natriuretic peptide (NT-proBNP)] and other molecules influenced by HF progression [i.e., creatinine and ferritin]. Moreover, GDF15 was inversely related to hemoglobin, suggesting a potential link to iron homeostasis. Furthermore, GDF15 showed good classification capacity and improved the accuracy of a logistic regression model for ischemic HF classification in patients with ID. Overall, the findings of this study propose serum GDF15 levels as a potential tool for the classification of HF patients with ID according to the ischemic etiology. Full article

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

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14 pages, 2001 KB

Open AccessEditor’s ChoiceArticle

Icatibant Acts as a Balanced Ligand of MRGPRX2 in Human Skin Mast Cells

by Zhuoran Li, Jean Schneikert, Gürkan Bal, Torsten Zuberbier and Magda Babina

Biomolecules 2025, 15(9), 1224; https://doi.org/10.3390/biom15091224 - 25 Aug 2025

Cited by 2 | Viewed by 2194

Abstract

MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces [...] Read more.

MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces injection-site reactions in most patients and is used experimentally to probe MRGPRX2 function in skin tests. While reported to be G-protein-biased, it is unknown how skin MCs respond to icatibant, although these are the primary target cells during therapy. We therefore compared responses to icatibant with those induced by the balanced agonist substance P (SP) in skin MCs. Degranulation and desensitization were assessed via β-hexosaminidase release, receptor internalization by flow cytometry, and downstream signaling by immunoblotting. Skin MCs degranulated in response to SP and icatibant, relying on Gi proteins and calcium channels; Gq and PI3K (Phosphoinositide 3-kinase) contributed more strongly to exocytosis following icatibant, while JNK (c-Jun n-terminal kinase) was more relevant for SP. Both agonists activated ERK, PI3K/AKT, and (weakly) p38. Surprisingly, and in contrast to the LAD2 (Laboratory of Allergic Diseases 2 mast cell line) MC line, icatibant was at least as potent as SP in eliciting MRGPRX2 internalization and (cross-)desensitization in skin MCs. These findings suggest that icatibant functions differently in primary versus transformed MCs, acting as a fully balanced ligand in the former by triggering not only degranulation but also receptor internalization and desensitization. Therefore, not only the ligand but also the MRGPRX2-expressing cell plays a decisive role in whether a ligand is balanced or biased. These findings are relevant to our understanding of icatibant’s clinical effects on edema and itch. Full article

(This article belongs to the Special Issue Molecular Basis of Mast Cells Activation and Medical Implications)

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56 pages, 1727 KB

Open AccessEditor’s ChoiceReview

From Natriuretic Peptides to microRNAs: Multi-Analyte Liquid Biopsy Horizons in Heart Failure

by Evelina Charidemou, Kyriacos Felekkis and Christos Papaneophytou

Biomolecules 2025, 15(8), 1189; https://doi.org/10.3390/biom15081189 - 19 Aug 2025

Cited by 3 | Viewed by 4163

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, underscoring the need for improved diagnostic, prognostic, and therapeutic strategies. Circulating microRNAs (c-miRNAs) have emerged as promising non-invasive biomarkers due to their stability, tissue specificity, and regulatory roles in cardiac pathophysiology. [...] Read more.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, underscoring the need for improved diagnostic, prognostic, and therapeutic strategies. Circulating microRNAs (c-miRNAs) have emerged as promising non-invasive biomarkers due to their stability, tissue specificity, and regulatory roles in cardiac pathophysiology. This review highlights the potential of c-miRNAs in enhancing HF diagnosis, risk stratification, and therapeutic monitoring, particularly when integrated with conventional biomarkers such as natriuretic peptides, galectin-3, soluble ST2, and high-sensitivity troponins. We explore the roles of key miRNAs in HF pathogenesis—including cardiac hypertrophy, fibrosis, inflammation, apoptosis, and vascular remodeling—and discuss their diagnostic and prognostic significance. The potential of multi-analyte liquid biopsy approaches that combine c-miRNAs with protein biomarkers is also examined within the context of precision medicine. Despite promising data, challenges related to standardization, assay variability, and clinical validation remain. Addressing these gaps through harmonized protocols and large-scale studies will be essential for translating c-miRNAs into routine HF management. Full article

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

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17 pages, 4158 KB

Open AccessEditor’s ChoiceArticle

Exploring the Role of Ferroptosis in the Pathophysiology and Circadian Regulation of Restless Legs Syndrome

by Maria Paola Mogavero, Giovanna Marchese, Giovanna Maria Ventola, Giuseppe Lanza, Oliviero Bruni, Luigi Ferini-Strambi and Raffaele Ferri

Biomolecules 2025, 15(8), 1184; https://doi.org/10.3390/biom15081184 - 18 Aug 2025

Cited by 6 | Viewed by 1656

Abstract

The study objectives were to investigate the role of ferroptosis, the mechanism linking iron accumulation, oxidative stress, and dopaminergic dysfunction, in restless legs syndrome (RLS), and to explore its connection with circadian regulation, a key feature of RLS and a known modulator of [...] Read more.

The study objectives were to investigate the role of ferroptosis, the mechanism linking iron accumulation, oxidative stress, and dopaminergic dysfunction, in restless legs syndrome (RLS), and to explore its connection with circadian regulation, a key feature of RLS and a known modulator of ferroptosis. We conducted pathway and gene expression analyses in 17 RLS patients and 39 controls, focusing on pathways related to ferroptosis, oxidative stress, iron metabolism, dopaminergic signaling, circadian rhythms, and immune responses. Enrichment analysis, differential gene expression, and cross-pathway gene overlaps were assessed. Ferroptosis and efferocytosis pathways were significantly upregulated in RLS, while oxidative phosphorylation, phosphatidylinositol signaling, PI3K-Akt, FoxO, and adipocytokine pathways were downregulated. The circadian rhythm pathway was markedly suppressed, with 12 circadian genes downregulated, suggesting that circadian disruption may drive ferroptosis activation. Decreased expression of protective pathways, including antioxidant responses and autophagy, was associated with increased iron accumulation, oxidative stress, and inflammation. Dopaminergic synapse genes were upregulated, possibly as a compensatory response to neuronal damage. Several genes overlapped across ferroptosis, circadian, and dopaminergic pathways, indicating a shared pathogenic mechanism. Our findings support a model in which circadian disruption promotes ferroptosis in RLS, contributing to iron overload, oxidative damage, and dopaminergic dysfunction. This pathogenic cascade may also enhance immune activation and inflammation. Circadian regulation and ferroptosis emerge as promising therapeutic targets in RLS. Further studies in larger cohorts are warranted to validate these mechanistic insights. Full article

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

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18 pages, 969 KB

Open AccessEditor’s ChoiceReview

Obesity-Mediated Inflammation and Its Influence on Inflammatory Bowel Disease: Pathophysiology, Clinical Impact, and Therapeutic Implications

by Diego Casas-Deza, Santiago García-López, Vanesa Bernal-Monterde, Cristina Polo-Cuadro, Carmen Yagüe-Caballero and José M. Arbones-Mainar

Biomolecules 2025, 15(8), 1185; https://doi.org/10.3390/biom15081185 - 18 Aug 2025

Cited by 5 | Viewed by 3393

Abstract

Obesity and inflammatory bowel disease (IBD) are two chronic conditions whose prevalence continues to rise globally. Emerging evidence suggests a bidirectional interplay between them, mediated by shared pathophysiological pathways. This narrative review explores the mechanisms Ilinking obesity to IBD development and progression, focusing [...] Read more.

Obesity and inflammatory bowel disease (IBD) are two chronic conditions whose prevalence continues to rise globally. Emerging evidence suggests a bidirectional interplay between them, mediated by shared pathophysiological pathways. This narrative review explores the mechanisms Ilinking obesity to IBD development and progression, focusing on the role of adipose tissue dysfunction. Both diseases exhibit intestinal dysbiosis, low-grade systemic inflammation, and impaired epithelial barrier integrity, contributing to immune activation. Visceral adiposity, particularly mesenteric fat, acts as an immunometabolic organ producing cytokines and adipokines that may exacerbate intestinal inflammation. In Crohn’s disease, mesenteric fat expansion, or “creeping fat”, is associated with transmural inflammation, fibrosis, and luminal narrowing. Epidemiological data on obesity as a risk factor for IBD remain inconsistent due to methodological heterogeneity and confounders. Similarly, the impact of obesity on IBD outcomes, including disease activity, phenotype, and the need for surgery, is debated. While mesenteric surgical approaches like Kono-S anastomosis showed initial promise in reducing recurrence, recent randomized trials offer conflicting results. Finally, metabolic drugs such as statins, metformin, and GLP-1 receptor agonists have demonstrated anti-inflammatory properties with potential utility in IBD management. Prospective studies are warranted to elucidate the clinical significance of obesity and metabolic dysfunction in IBD and evaluate targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Metabolic Inflammation and Insulin Resistance in Obesity)

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26 pages, 1161 KB

Open AccessEditor’s ChoiceReview

The Multifaceted Functions of Lactoferrin in Antimicrobial Defense and Inflammation

by Jung Won Kim, Ji Seok Lee, Yu Jung Choi and Chaekyun Kim

Biomolecules 2025, 15(8), 1174; https://doi.org/10.3390/biom15081174 - 16 Aug 2025

Cited by 5 | Viewed by 6040

Abstract

Lactoferrin (Lf) is a multifunctional iron-binding glycoprotein of the transferrin family that plays a central role in host defense, particularly in protection against infection and tissue injury. Abundantly present in colostrum, secretory fluids, and neutrophil granules, Lf exerts broad-spectrum antimicrobial activity against bacteria, [...] Read more.

Lactoferrin (Lf) is a multifunctional iron-binding glycoprotein of the transferrin family that plays a central role in host defense, particularly in protection against infection and tissue injury. Abundantly present in colostrum, secretory fluids, and neutrophil granules, Lf exerts broad-spectrum antimicrobial activity against bacteria, viruses, fungi, and parasites. These effects are mediated by iron sequestration, disruption of microbial membranes, inhibition of microbial adhesion, and interference with host–pathogen interactions. Beyond its antimicrobial functions, Lf regulates pro- and anti-inflammatory mediators and mitigates excessive inflammation. Additionally, Lf alleviates oxidative stress by scavenging reactive oxygen species and enhancing antioxidant enzyme activity. This review summarizes the current understanding of Lf’s biological functions, with a particular focus on its roles in microbial infections, immune modulation, oxidative stress regulation, and inflammation. These insights underscore the therapeutic promise of Lf as a natural, multifunctional agent for managing infectious and inflammatory diseases and lay the groundwork for its clinical application in immune-related disorders. Full article

(This article belongs to the Special Issue Feature Papers in Cellular Biochemistry)

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31 pages, 4259 KB

Open AccessEditor’s ChoiceArticle

Neuronal Count, Brain Injury, and Sustained Cognitive Function in 5×FAD Alzheimer’s Disease Mice Fed DHA-Enriched Diets

by Cristina de Mello-Sampayo, Mafalda Soares Pádua, Maria Rosário Silva, Maria Lourenço, Rui M. A. Pinto, Sandra Carvalho, Jorge Correia, Cátia F. Martins, Romina Gomes, Ana Gomes-Bispo, Cláudia Afonso, Carlos Cardoso, Narcisa Bandarra and Paula A. Lopes

Biomolecules 2025, 15(8), 1164; https://doi.org/10.3390/biom15081164 - 14 Aug 2025

Cited by 2 | Viewed by 2588

Abstract

Alzheimer’s disease (AD) is the most common form of dementia, affecting over 50 million people globally. Since 1906, efforts to understand this neurodegenerative disease and to develop effective treatments have continued to this day. Recognizing docosahexaenoic acid (DHA, 22:6n-3) as a safe, inexpensive [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia, affecting over 50 million people globally. Since 1906, efforts to understand this neurodegenerative disease and to develop effective treatments have continued to this day. Recognizing docosahexaenoic acid (DHA, 22:6n-3) as a safe, inexpensive and vital nutrient for brain health and cognitive protection due to its key role in brain development and function, this study explores novel, sustainable non-fish sources as potential dietary supplements to prevent or mitigate AD, within a blue biotechnology framework. Forty 5×FAD male mice, five weeks old, were allocated to five body weight-matched dietary groups (n = 8) and fed isocaloric diets based on AIN-93M standard chow for 6 months. Each diet, except the control feed (non-supplemented group), enclosed a modified lipid fraction supplemented with 2% of the following: (1) linseed oil (LSO, rich in alpha-linolenic acid (ALA,18:3n-3)); (2) cod liver oil (fish oil, FO, rich in both DHA and eicosapentaenoic acid (EPA, 20:5n-3)); (3) Schizochytrium sp. microalga oil (Schizo) with 40% of DHA; and (4) commercial DHASCO oil (DHASCO) with 70% of DHA. The different diets did not affect (p > 0.05) growth performance criteria (e.g., final body weight, daily feed intake, and body weight gain) suggesting no effect on the overall caloric balance or mice growth, but n-3 long-chain polyunsaturated-fatty acid (n-3 LCPUFA) supplementation significantly reduced total cholesterol (p < 0.001) and total lipids (p < 0.001). No systemic inflammation was detected in 5×FAD mice. In parallel, a beneficial modulation of lipid metabolism by DHA-enriched diets was observed, with polyunsaturated fatty acid incorporation, particularly DHA, across key metabolic tissues, such as the liver (p < 0.001) and the brain (p < 0.001). No behavioural variations were detected using an open-field test after 6 months of diet (p > 0.05). While mice fed a standard diet or LSO diet showed cognitive deficit, the incorporation of FO, Schizo or DHASCO oils into dietary routine showed promising protective effects on the working memory (p < 0.05) and the last two diets also on the recognition memory (p < 0.05) Increased neuronal count (p < 0.05), reflecting neuronal survival, was clearly observed with the fish oil diet. In turn, the number of TAU-positive cells (p < 0.05) was reduced in the Schizo diet, while β-amyloid deposition (p < 0.01) and the neuroinflammatory marker, IBA1 (p < 0.05), were decreased across all DHA-enriched diets. These promising findings open new avenues for further studies focused on the protective effects of DHA derived from sustainable and underexploited Schizochytrium sp. microalga in the prevention of AD. Full article

(This article belongs to the Section Cellular Biochemistry)

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20 pages, 4584 KB

Open AccessEditor’s ChoiceArticle

Systemic Lonp1 Haploinsufficiency Mitigates Cardiac Mitochondrial Dysfunction Induced by Cardiomyocyte-Specific Lonp1 Haploinsufficiency via Potential Inter-Organ Crosstalk

by Sakthijothi Muthu, Zinnia Tran, Ramasamy Saminathan, Pratikshya Shrestha and Sundararajan Venkatesh

Biomolecules 2025, 15(8), 1159; https://doi.org/10.3390/biom15081159 - 13 Aug 2025

Cited by 1 | Viewed by 1517

Abstract

Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether [...] Read more.

Efficient mitochondrial matrix protein quality control (mPQC), regulated by the mitochondrial matrix protease LONP1, is essential for preserving cardiac bioenergetics, particularly in post-mitotic cardiomyocytes, which are highly susceptible to mitochondrial dysfunction. While cardiac mPQC defects could impair heart function, it remains unclear whether such defects can be mitigated through inter-organ crosstalk by modulating mPQC in extra-cardiac tissues, a potentially valuable strategy given the challenges of directly targeting the heart. To investigate this, we examined two mouse models of Lonp1 haploinsufficiency at young adulthood: a cardiomyocyte-specific heterozygous knockout (Lonp1^CKO-HET) and a whole-body heterozygous knockout (Lonp1^GKO-HET). Despite similar reductions in Lonp1 mRNA expression in the hearts, Lonp1^GKO-HET mice exhibited no cardiac dysfunction, whereas Lonp1^CKO-HET mice showed mild cardiac dysfunction accompanied by activation of the mitochondrial stress response, including induction of genes such as Clpx, Spg7, Hspa9, and Hspd1, increased mitochondrial dynamics (Pink1, Dnm1l), reduced mitochondrial biogenesis, and compensatory upregulation of the mtDNA transcriptional regulator Tfam, all occurring without overt structural remodeling. These alterations were absent in Lonp1^GKO-HET hearts. Our findings reveal a novel adaptive mechanism in which systemic mPQC deficiency can buffer mitochondrial dysfunction in the heart through inter-organ communication that is lost with cardiomyocyte-specific mPQC disruption. This study identifies systemic modulation of Lonp1-mediated mitochondrial stress pathways as a promising strategy to promote cardiac resilience through protective inter-organ signaling. Full article

(This article belongs to the Special Issue Mitochondrial Proteins: From Import and Biogenesis to Complex Functional Network)

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17 pages, 8538 KB

Open AccessEditor’s ChoiceArticle

Thermodynamic and Kinetic Aspects of Calcium Oxalate Crystallization and Renal Lithiasis

by Jaume Dietrich, Antònia Costa-Bauza and Félix Grases

Biomolecules 2025, 15(8), 1141; https://doi.org/10.3390/biom15081141 - 7 Aug 2025

Cited by 2 | Viewed by 2736

Abstract

Thermodynamic factors (supersaturation of substances that form crystals) and kinetic factors (heterogeneous nucleants and crystallization inhibitors) affect the formation of crystals and stones in the urinary tract. We studied the effect of five different polyhydroxycarboxylic acids and phytate on the formation of calcium [...] Read more.

Thermodynamic factors (supersaturation of substances that form crystals) and kinetic factors (heterogeneous nucleants and crystallization inhibitors) affect the formation of crystals and stones in the urinary tract. We studied the effect of five different polyhydroxycarboxylic acids and phytate on the formation of calcium oxalate crystals in artificial urine. All tested molecules are known to inhibit the crystallization of this calcium salt, and to also form complexes with calcium ions. Considering the typical concentration of polyhydroxycarboxylic acids in urine (similar to that of the calcium ion) and their ability to inhibit crystallization, their most important effect is the capacity to complex calcium—a thermodynamic effect. For phytate and its metabolites, which are present in concentrations much lower than that of the calcium ion, the most important effect is as a crystallization inhibitor—a kinetic effect. Among the five polyhydroxycarboxylic acids examined here, hydroxycitrate had the strongest complexing capacity, and the addition of phytate to hydroxycitrate led to greater inhibition of crystallization. Therefore, because oral consumption of hydroxycitrate does not increase the urinary pH, it is likely that the combined consumption of hydroxycitrate and phytate can provide certain benefits for patients with increased risk of developing calcium oxalate stones. We also discussed the effects of these different molecules on the different calcium oxalate stones, including papillary calcium oxalate monohydrate stones, cavity calcium oxalate monohydrate stones, calcium oxalate dihydrate stones, and mixed calcium oxalate dihydrate/hydroxyapatite stones. Full article

(This article belongs to the Section Molecular Medicine)

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20 pages, 3219 KB

Open AccessEditor’s ChoiceReview

Tauopathies: Calmodulin Regulates Tau Hyperphosphorylation and Its Transformation into Disease-Specific Aggregates

by Danton H. O’Day

Biomolecules 2025, 15(8), 1133; https://doi.org/10.3390/biom15081133 - 6 Aug 2025

Cited by 4 | Viewed by 1445

Abstract

Tauopathies are a diverse group of neurodegenerative diseases characterized by the presence of Tau inclusions in neurons and glia. Rather than the classic steps in the transformation of Tau into neurofibrillary tangles, as first studied in Alzheimer’s disease, studies on tauopathies reveal the [...] Read more.

Tauopathies are a diverse group of neurodegenerative diseases characterized by the presence of Tau inclusions in neurons and glia. Rather than the classic steps in the transformation of Tau into neurofibrillary tangles, as first studied in Alzheimer’s disease, studies on tauopathies reveal the presence of diverse Tau aggregates that appear to be disease-specific. Regardless, the phosphorylation and hyperphosphorylation of Tau, involving various kinases and phosphatases, appear to be central to all tauopathies. As in other neurodegenerative diseases, calcium dysregulation is an early event in multiple tauopathies, where it activates calmodulin to effect downstream events. Here, the events of Tau phosphorylation and hyperphosphorylation, which involve several CaM-dependent kinases and a single CaM-regulated phosphatase, are covered. In addition, CaM has been linked to other events, including Tau aggregation. As a central player in tauopathies, CaM offers several alternative therapeutic routes that are worth investigating. For example, evidence is presented here that supports targeting specific binding motifs of key CaM-regulated Tau kinases as a novel therapeutic approach. Full article

(This article belongs to the Section Molecular Biomarkers)

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23 pages, 890 KB

Open AccessEditor’s ChoiceReview

Relationship of S100 Proteins with Neuroinflammation

by Mario García-Domínguez

Biomolecules 2025, 15(8), 1125; https://doi.org/10.3390/biom15081125 - 4 Aug 2025

Cited by 5 | Viewed by 3496

Abstract

S100 proteins, a family of Ca²⁺-binding proteins, play numerous roles in cellular processes such as proliferation, differentiation, and apoptosis. Recent evidence has highlighted their critical involvement in neuroinflammation, a pathological hallmark of various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and [...] Read more.

S100 proteins, a family of Ca²⁺-binding proteins, play numerous roles in cellular processes such as proliferation, differentiation, and apoptosis. Recent evidence has highlighted their critical involvement in neuroinflammation, a pathological hallmark of various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Among these proteins, S100B and S100A8/A9 are particularly implicated in modulating inflammatory responses in the CNS. Acting as DAMPs, they interact with pattern recognition receptors like RAGE and TLRs, triggering pro-inflammatory signaling cascades and glial activation. While low concentrations of S100 proteins may support neuroprotective functions, increased levels are often associated with exacerbated inflammation and neuronal damage. This review explores the dualistic nature of S100 proteins in neuroinflammatory processes, their molecular interactions, and their potential as biomarkers and therapeutic targets in neurodegenerative disease management. Full article

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24 pages, 2279 KB

Open AccessEditor’s ChoiceArticle

Dual Oxytocin Signals in Striatal Astrocytes

by Elisa Farsetti, Sarah Amato, Monica Averna, Diego Guidolin, Marco Pedrazzi, Guido Maura, Luigi Francesco Agnati, Chiara Cervetto and Manuela Marcoli

Biomolecules 2025, 15(8), 1122; https://doi.org/10.3390/biom15081122 - 4 Aug 2025

Cited by 1 | Viewed by 1522

Abstract

The ability of the neuropeptide oxytocin to affect glial cell function is receiving increasing attention. We previously reported that oxytocin at a low nanomolar concentration could inhibit both astrocytic Ca²⁺ signals and glutamate release. Here, we investigate the ability of oxytocin receptors [...] Read more.

The ability of the neuropeptide oxytocin to affect glial cell function is receiving increasing attention. We previously reported that oxytocin at a low nanomolar concentration could inhibit both astrocytic Ca²⁺ signals and glutamate release. Here, we investigate the ability of oxytocin receptors to couple both inhibitory and stimulatory pathways in astrocytes, as already reported in neurons. We assessed the effects of oxytocin at concentrations ranging from low to high in the nanomolar range on intracellular Ca²⁺ signals and on the glutamate release in astrocyte processes freshly prepared from the striatum of adult rats. Our main findings are as follows: oxytocin could induce dual responses in astrocyte processes, namely the inhibition and facilitation of both Ca²⁺ signals and glutamate release; the inhibitory and the facilitatory response appeared dependent on activation of the G_i and the G_q pathway, respectively; both inhibitory and facilitatory responses were evoked at the same nanomolar oxytocin concentrations; and the biased agonists atosiban and carbetocin could duplicate oxytocin’s inhibitory and facilitatory response, respectively. In conclusion, due to the coupling of striatal astrocytic oxytocin receptors to different transduction pathways and the dual effects on Ca²⁺ signals and glutamate release, oxytocin could also play a crucial role in neuron–astrocyte bi-directional communication through a subtle regulation of striatal glutamatergic synapses. Therefore, astrocytic oxytocin receptors may offer pharmacological targets to regulate glutamatergic striatal transmission, which is potentially useful in neuropsychiatric disorders and in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Neuron–Astrocyte Interactions in Neurological Function and Disease)

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16 pages, 1318 KB

Open AccessEditor’s ChoiceArticle

Aptamer-Coated PLGA Nanoparticles Selectively Internalize into Epithelial Ovarian Cancer Cells In Vitro and In Vivo

by Gregory Benedetto, Anthony Fowler, Dan Langdon, Maya Raine, Molly Lynne White, Joshua Ogle, Corey Garmon, Craig Ogle and Christine Richardson

Biomolecules 2025, 15(8), 1123; https://doi.org/10.3390/biom15081123 - 4 Aug 2025

Cited by 3 | Viewed by 1524

Abstract

Ovarian cancer is a deadly gynecological malignancy that will affect about 21,000 women and result in almost 153,000 deaths in the United States in 2025. New clinical tools that facilitate early diagnosis and treatment of ovarian malignancies will significantly help reduce mortality and [...] Read more.

Ovarian cancer is a deadly gynecological malignancy that will affect about 21,000 women and result in almost 153,000 deaths in the United States in 2025. New clinical tools that facilitate early diagnosis and treatment of ovarian malignancies will significantly help reduce mortality and improve current long-term survival rates. We utilized a previously identified single-strand DNA aptamer RLA01 that binds and internalizes into target epithelial ovarian cancer cells to label PLGA-based nanoparticles and determine their ability to selectively target EOC cells and deliver payloads for cellular internalization. Nanoparticles labeled with RLA01 significantly enhanced cellular uptake 20–85% by receptor-mediated endocytosis into target EOC Caov-3 cells and inhibited cellular uptake in non-target HOSE 6-3 cells. Further, labeling of paclitaxel-loaded nanoparticles with RLA01 significantly decreased cell proliferation and induced apoptosis. A preliminary pilot study looking at the in vivo stability of aptamers demonstrated their ability to promote retention and honing of nanoparticles at tumors. These data demonstrate the effective combinatorial use of aptamer RLA01 and nanoparticle technologies for the direct targeting of tumor cell populations both in vitro and in vivo. Full article

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

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29 pages, 2132 KB

Open AccessEditor’s ChoiceReview

Polyphenol-Based Therapeutic Strategies for Mitochondrial Dysfunction in Aging

by Tamara Maksimović, Carmen Gădău, Gabriela Antal, Mihaela Čoban, Oana Eșanu, Elisabeta Atyim, Alexandra Mioc and Codruța Șoica

Biomolecules 2025, 15(8), 1116; https://doi.org/10.3390/biom15081116 - 3 Aug 2025

Cited by 11 | Viewed by 4249

Abstract

Aging, a progressive and time-dependent decline in physiological functions, is driven by interconnected hallmarks, among which mitochondrial dysfunction plays a central role. Mitochondria not only regulate energy production but also play key roles in other cellular processes, including ROS generation, apoptosis, and metabolic [...] Read more.

Aging, a progressive and time-dependent decline in physiological functions, is driven by interconnected hallmarks, among which mitochondrial dysfunction plays a central role. Mitochondria not only regulate energy production but also play key roles in other cellular processes, including ROS generation, apoptosis, and metabolic signaling—all of which decline with aging. Polyphenols are a diverse group of natural compounds found in fruits, vegetables, tea, and wine; they emerged as promising anti-aging agents due to their ability to modulate several hallmarks of aging, particularly mitochondrial dysfunction. This review explores how various polyphenolic classes influence mitochondrial function and mitigate aging-related decline. These natural compounds have been shown to reduce oxidative stress, increase energy production, and help maintain normal mitochondrial structure. Moreover, in vitro and in vivo studies suggest that polyphenols can delay signs of aging and improve physical and cognitive functions. Overall, polyphenols show great potential to promote healthy aging and even delay the decline in physiological functions by protecting and enhancing mitochondrial health. Full article

(This article belongs to the Special Issue Bioactive Compounds as Modifiers of Mitochondrial Function)

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33 pages, 938 KB

Open AccessEditor’s ChoiceReview

Exploring the Antioxidant Roles of Cysteine and Selenocysteine in Cellular Aging and Redox Regulation

by Marta Pace, Chiara Giorgi, Giorgia Lombardozzi, Annamaria Cimini, Vanessa Castelli and Michele d’Angelo

Biomolecules 2025, 15(8), 1115; https://doi.org/10.3390/biom15081115 - 3 Aug 2025

Cited by 7 | Viewed by 5469

Abstract

Aging is a complex, universal biological process characterized by the progressive and irreversible decline of physiological functions across multiple organ systems. This deterioration is primarily driven by cumulative cellular damage arising from both intrinsic and extrinsic stressors. The free radical theory of aging, [...] Read more.

Aging is a complex, universal biological process characterized by the progressive and irreversible decline of physiological functions across multiple organ systems. This deterioration is primarily driven by cumulative cellular damage arising from both intrinsic and extrinsic stressors. The free radical theory of aging, first proposed by Denham Harman in 1956, highlights the role of reactive oxygen species (ROS), byproducts of normal metabolism, in driving oxidative stress and age-related degeneration. Emerging evidence emphasizes the importance of redox imbalance in the onset of neurodegenerative diseases and aging. Among the critical cellular defenses against oxidative stress are sulfur-containing amino acids, namely cysteine (Cys) and selenocysteine (Sec). Cysteine serves as a precursor for glutathione (GSH), a central intracellular antioxidant, while selenocysteine is incorporated into key antioxidant enzymes such as glutathione peroxidases (GPx) and thioredoxin reductases (TrxR). These molecules play pivotal roles in neutralizing ROS and maintaining redox homeostasis. This review aims to provide an updated and critical overview of the role of thiol-containing amino acids, specifically cysteine and selenocysteine, in the regulation of redox homeostasis during aging. Full article

(This article belongs to the Special Issue Cysteine and Selenocysteine in Antioxidant Defense, Protein Synthesis and Signaling Pathways)

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32 pages, 20583 KB

Open AccessEditor’s ChoiceArticle

Application of Prodigiosin Extracts in Textile Dyeing and Novel Printing Processes for Halochromic and Antimicrobial Wound Dressings

by Cátia Alves, Pedro Soares-Castro, Rui D. V. Fernandes, Adriana Pereira, Rui Rodrigues, Ana Rita Fonseca, Nuno C. Santos and Andrea Zille

Biomolecules 2025, 15(8), 1113; https://doi.org/10.3390/biom15081113 - 1 Aug 2025

Cited by 2 | Viewed by 1995

Abstract

The textile industry’s reliance on synthetic dyes contributes significantly to pollution, highlighting the need for sustainable alternatives like biopigments. This study investigates the production and application of the biopigment prodigiosin, which was produced by Pseudomonas putida with a yield of 1.85 g/L. Prodigiosin [...] Read more.

The textile industry’s reliance on synthetic dyes contributes significantly to pollution, highlighting the need for sustainable alternatives like biopigments. This study investigates the production and application of the biopigment prodigiosin, which was produced by Pseudomonas putida with a yield of 1.85 g/L. Prodigiosin was prepared under acidic, neutral, and alkaline conditions, resulting in varying protonation states that influenced its affinity for cotton and polyester fibers. Three surfactants (anionic, cationic, non-ionic) were tested, with non-ionic Tween 80 yielding a promising color strength (above 4) and fastness results with neutral prodigiosin at 1.3 g/L. Cotton and polyester demonstrated good washing (color difference up to 14 for cotton, 5 for polyester) and light fastness (up to 15 for cotton, 16 for polyester). Cellulose acetate, used in the conventional printing process as a thickener, produced superior color properties compared to commercial thickeners. Neutral prodigiosin achieved higher color strength, and cotton fabrics displayed halochromic properties, distinguishing them from polyester, which showed excellent fastness. Prodigiosin-printed samples also exhibited strong antimicrobial activity against Pseudomonas aeruginosa and retained halochromic properties over 10 pH cycles. These findings suggest prodigiosin as a sustainable dye alternative and pH sensor, with potential applications in biomedical materials, such as antimicrobial and pH-responsive wound dressings. Full article

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

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16 pages, 2742 KB

Open AccessEditor’s ChoiceArticle

miRNA408 from Camellia japonica L. Mediates Cross-Kingdom Regulation in Human Skin Recovery

by Soll Jin, Jae-Goo Kim, Hye Jin Kim, Ji Young Kim, Sang Hoon Kim, Hee Cheol Kang and Mi Jung Kim

Biomolecules 2025, 15(8), 1108; https://doi.org/10.3390/biom15081108 - 1 Aug 2025

Cited by 4 | Viewed by 1356

Abstract

Wound healing is a complex and dynamic process involving several stages of tissue repair. This study has shown that extracellular vesicles (EVs) derived from the callus of Camellia japonica L. and their associated microRNAs (miRNAs) possess significant wound healing activities. In human fibroblasts, [...] Read more.

Wound healing is a complex and dynamic process involving several stages of tissue repair. This study has shown that extracellular vesicles (EVs) derived from the callus of Camellia japonica L. and their associated microRNAs (miRNAs) possess significant wound healing activities. In human fibroblasts, EVs from C. japonica L. stimulated wound healing and upregulated collagen gene expression. The EVs also decreased inflammation levels in human keratinocytes, supporting wound healing. Among the miRNAs identified, miR408, one of the abundant miRNAs in the EVs, also showed similar wound healing efficacy. These findings suggest that both EVs and miR408 from the callus of C. japonica L. play a pivotal role in promoting wound healing. Additionally, this study shows that the regulation of miRNAs between different kingdoms can be achieved and suggests a new direction for the utilization of plant-derived components. Full article

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

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15 pages, 4150 KB

Open AccessEditor’s ChoiceArticle

PRMT5 Identified as a Viable Target for Combination Therapy in Preclinical Models of Pancreatic Cancer

by Xiaolong Wei, William J. Kane, Sara J. Adair, Sarbajeet Nagdas, Denis Liu and Todd W. Bauer

Biomolecules 2025, 15(7), 948; https://doi.org/10.3390/biom15070948 - 30 Jun 2025

Cited by 1 | Viewed by 1819

Abstract

Pancreatic cancer is the third leading cause of cancer-related death in the US. First-line chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC) include FOLFIRINOX or gemcitabine (Gem) with or without paclitaxel (Ptx); however, 5-year survival with these regimens remains poor. Previous work has demonstrated [...] Read more.

Pancreatic cancer is the third leading cause of cancer-related death in the US. First-line chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC) include FOLFIRINOX or gemcitabine (Gem) with or without paclitaxel (Ptx); however, 5-year survival with these regimens remains poor. Previous work has demonstrated protein arginine methyltransferase 5 (PRMT5) to be a promising therapeutic target in combination with Gem for the treatment of PDAC; however, these findings have yet to be confirmed in relevant preclinical models of PDAC. To test the possibility of PRMT5 as a viable therapeutic target, clinically relevant orthotopic and metastatic patient-derived xenograft (PDX) mouse models of PDAC growth were utilized to evaluate the effect of PRMT5 knockout (KO) or pharmacologic inhibition on treatment with Gem alone or Gem with Ptx. Primary endpoints included tumor volume, tumor weight, or metastatic tumor burden as appropriate. The results showed that Gem-treated PRMT5 KO tumors exhibited decreased growth and were smaller in size compared to Gem-treated wild-type (WT) tumors. Similarly, the Gem-treated PRMT5 KO metastatic burden was lower than the Gem-treated WT metastatic burden. The addition of a PRMT5 pharmacologic inhibitor to Gem and Ptx therapy resulted in a lower final tumor weight and fewer metastatic tumors. The depletion of PRMT5 results in increased DNA damage in response to Gem and Ptx treatment. Thus, PRMT5 genetic depletion or inhibition in combination with Gem-based therapy improved the response in primary and metastatic PDAC in clinically relevant mouse models, suggesting that PRMT5 is a viable therapeutic target for combination therapy in PDAC. Full article

(This article belongs to the Special Issue Advancing Innovations in Biomedical Research for Translational Applications)

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13 pages, 25033 KB

Open AccessEditor’s ChoiceArticle

Ultrastructural Aspects of Physiological Mineralization: A Comparative Study in Different Hard Tissues

by Marina Borgese, Mario Raspanti, Marina Protasoni, Piero Antonio Zecca, Fulvia Ortolani and Marcella Reguzzoni

Biomolecules 2025, 15(7), 932; https://doi.org/10.3390/biom15070932 - 26 Jun 2025

Cited by 1 | Viewed by 1062

Abstract

The calcified tissues of vertebrates are essentially represented by bone, cartilage, dentin and calcified tendons. In all these tissues a major hallmark of mineralization is the deposition of the inorganic phase on a pre-existing collagen template, but evident differences exist among these materials [...] Read more.

The calcified tissues of vertebrates are essentially represented by bone, cartilage, dentin and calcified tendons. In all these tissues a major hallmark of mineralization is the deposition of the inorganic phase on a pre-existing collagen template, but evident differences exist among these materials and the molecular details of the process are still incompletely understood. In this study, the ultrastructural aspects of the mineral phase of these tissues were investigated by means of high-resolution scanning electron microscopy (HR-SEM) after low-temperature thermal deproteination, a technique allowing a direct, unrestricted visualization of the mineral component. Each tissue showed distinctive features. In most cases, calcification proceeds in a discontinuous way through the formation of clumps or clusters of mineralized tissue; in all cases, except cartilage, the mineral phase shows an evident relationship with the layout and/or the D-period of the collagen fibrils. Our results highlight the peculiar aspect of the mineralization process in the cartilage with respect to the other tissues, all of them containing collagen type I instead of type II, and suggest that a different molecular mechanism may be at work. It is still unclear whether and how this may be related to the content, exclusive of cartilage, of collagen type II. The identification of the tissue-specific features exhibited by cartilage versus those shared by all the other three tissues, although from different species, requires further research on physiological calcification. Full article

(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)

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29 pages, 1506 KB

Open AccessEditor’s ChoiceReview

The Link Between Endoplasmic Reticulum Stress and Lysosomal Dysfunction Under Oxidative Stress in Cancer Cells

by Mariapia Vietri, Maria Rosaria Miranda, Giuseppina Amodio, Tania Ciaglia, Alessia Bertamino, Pietro Campiglia, Paolo Remondelli, Vincenzo Vestuto and Ornella Moltedo

Biomolecules 2025, 15(7), 930; https://doi.org/10.3390/biom15070930 - 25 Jun 2025

Cited by 9 | Viewed by 4175

Abstract

Lysosomal dysfunction and endoplasmic reticulum (ER) stress play essential roles in cancer cell survival, growth, and stress adaptation. Among the various stressors in the tumor microenvironment, oxidative stress (OS) is a central driver that exacerbates both lysosomal and ER dysfunction. In healthy cells, [...] Read more.

Lysosomal dysfunction and endoplasmic reticulum (ER) stress play essential roles in cancer cell survival, growth, and stress adaptation. Among the various stressors in the tumor microenvironment, oxidative stress (OS) is a central driver that exacerbates both lysosomal and ER dysfunction. In healthy cells, the ER manages protein folding and redox balance, while lysosomes regulate autophagy and degradation. Cancer cells, however, are frequently exposed to elevated levels of reactive oxygen species (ROS), which disrupt protein folding in the ER and damage lysosomal membranes and enzymes, promoting dysfunction. Persistent OS activates the unfolded protein response (UPR) and contributes to lysosomal membrane permeabilization (LMP), leading to pro-survival autophagy or cell death depending on the context and on the modulation of pathways like PERK, IRE1, and ATF6. Cancer cells exploit these pathways by enhancing their tolerance to OS and shifting UPR signaling toward survival. Moreover, lysosomal impairment due to ROS accumulation compromises autophagy, resulting in the buildup of damaged organelles and further amplifying oxidative damage. This vicious cycle of ROS-induced ER stress and lysosomal dysfunction contributes to tumor progression, therapy resistance, and metabolic adaptation. Thus, targeting lysosomal and ER stress responses offers potential as cancer therapy, particularly in increasing oxidative stress and promoting apoptosis. This review explores the interconnected roles of lysosomal dysfunction, ER stress, and OS in cancer, focusing on the mechanisms driving their crosstalk and its implications for tumor progression and therapeutic resistance. Full article

(This article belongs to the Section Cellular Biochemistry)

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14 pages, 1717 KB

Open AccessEditor’s ChoiceArticle

Impact of Long-Term Plasma Storage on Cell-Free DNA Epigenetic Biomarker Studies

by Jianming Shao, Thao Nguyen and Zejuan Li

Biomolecules 2025, 15(7), 927; https://doi.org/10.3390/biom15070927 - 25 Jun 2025

Viewed by 2429

Abstract

Impact of long-term plasma storage on biomarker analysis is critical for ensuring data reliability. Cell-free DNA (cfDNA) epigenetic markers, including 5-hydroxymethylcytosine (5hmC), have emerged for disease detection, prognosis, and treatment response. However, the effects of prolonged storage on 5hmC analysis remain unclear. We [...] Read more.

Impact of long-term plasma storage on biomarker analysis is critical for ensuring data reliability. Cell-free DNA (cfDNA) epigenetic markers, including 5-hydroxymethylcytosine (5hmC), have emerged for disease detection, prognosis, and treatment response. However, the effects of prolonged storage on 5hmC analysis remain unclear. We evaluated the quantity and quality of cfDNA and 5hmC sequencing analyses in 1070 plasma samples stored for up to 14 years from patients with solid tumors and acute myeloid leukemia (AML) and non-cancer individuals. In long-term stored plasma samples, cfDNA yield remained largely stable; however, uniquely mapped reads (UMRs) from 5hmC sequencing were significantly reduced in solid tumor and control samples. Notably, prolonged plasma storage independently contributed to increased genomic DNA (gDNA) contamination in solid tumor and AML samples and significantly correlated with decreased UMRs in control samples. Across all groups, samples with gDNA contamination exhibited significantly reduced UMRs. Furthermore, gDNA contamination independently compromised cfDNA fragment integrity, decreased sequencing library success in solid tumors, and reduced 5hmC sequencing UMRs across all groups. Therefore, extended plasma storage contributes to increased gDNA contamination, compromising cfDNA and 5hmC sequencing quality. Implementing measures to minimize gDNA contamination in long-term plasma storage is crucial for improving downstream cfDNA analysis reliability. Full article

(This article belongs to the Special Issue Genetic and Genomic Biomarkers in Cancer Diagnosis, Prognosis, and Treatment Prediction)

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15 pages, 524 KB

Open AccessEditor’s ChoiceArticle

Inflammatory Drug-Resistant Epilepsy Index (IDREI) as a Molecular Compound Biomarker in Focal Epilepsies

by Maria José Aguilar-Castillo, Guillermo Estivill-Torrús, Guillermina García-Martín, Pablo Cabezudo-García, Yolanda López-Moreno, Jesús Ortega-Pinazo, Teresa Ramírez-García, Nicolas Lundahl Ciano-Petersen and Pedro Jesus Serrano-Castro

Biomolecules 2025, 15(7), 914; https://doi.org/10.3390/biom15070914 - 22 Jun 2025

Viewed by 3137

Abstract

Background: There is growing evidence that neuroinflammation is involved in epileptogenesis. Identifying its biomarkers can be important for distinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from drug-resistant epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved [...] Read more.

Background: There is growing evidence that neuroinflammation is involved in epileptogenesis. Identifying its biomarkers can be important for distinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from drug-resistant epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved epilepsy patients divided into three groups: healthy controls (HC), seizure-free epilepsy (SFE), and DRE. Demographic and clinical data and plasmatic and/or CSF levels of 24 different inflammation-related molecules were collected for each patient and were analyzed through univariate and multivariate analysis. Results: The study included 68 patients: 38 in the DRE group, 14 in the SFE group, and 16 in the HC group. A new Inflammatory Drug-Resistant Epilepsy Index (IDREI) was created using key variables with significant or trending significance. This index combined pro-inflammatory mediators (ICAM-1 and NfL) and anti-inflammatory factors (IL-10 and IL-4), showing statistical significance (p = 0.002). ROC curve analysis for the IDREI gave an AUC of 0.731 (95% CI: 0.608–0.854). A multivariate logistic regression model’s ROC analysis resulted in a higher AUC of 0.891 (95% CI: 0.791–0.991). Conclusions: The IDREI molecular index shows promise in predicting epilepsy and drug-resistant epilepsy (DRE). Additional prospective studies are required to assess its clinical utility. Full article

(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)

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15 pages, 2142 KB

Open AccessEditor’s ChoiceArticle

DNA Damage Response Regulation Alleviates Neuroinflammation in a Mouse Model of α-Synucleinopathy

by Sazzad Khan, Himanshi Singh, Jianfeng Xiao and Mohammad Moshahid Khan

Biomolecules 2025, 15(7), 907; https://doi.org/10.3390/biom15070907 - 20 Jun 2025

Cited by 2 | Viewed by 1877

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression [...] Read more.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach. Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks. In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapeutic Approaches of Neurodegenerative Diseases)

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25 pages, 1445 KB

Open AccessEditor’s ChoiceReview

The Role of Astrocytes in Synaptic Dysfunction and Memory Deficits in Alzheimer’s Disease

by Cristina A. Muñoz de León-López, Irene Navarro-Lobato and Zafar U. Khan

Biomolecules 2025, 15(7), 910; https://doi.org/10.3390/biom15070910 - 20 Jun 2025

Cited by 4 | Viewed by 4858

Abstract

Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes [...] Read more.

Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes express various receptors, transporters, gliotransmitters, and other molecules that enable them to sense and respond to external signals. They are also implicated in amyloid-β clearance. In Alzheimer’s disease, excessive accumulation of amyloid-β induces the polarization of astrocytes into the A1 phenotype, promoting the release of inflammatory cytokines and mitochondrial reactive oxygen species, leading to alterations in astrocytic functions. Under such conditions, gliotransmitter release, glutamate neurotransmission, AMPA receptor trafficking, and both Hebbian and non-Hebbian forms of synaptic plasticity—biological activities essential for synaptic functions—are compromised. Moreover, astrocytes are essential for learning, memory, and synaptic plasticity, and alterations in their function are associated with memory deficits in Alzheimer’s disease. This review provides an overview of the current understanding of the defects in astrocytes that lead to altered synaptic functions, neuronal structural plasticity, and memory deficits in Alzheimer’s disease. Full article

(This article belongs to the Special Issue The Role of Astrocytes in Neurodegenerative Diseases)

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21 pages, 842 KB

Open AccessEditor’s ChoiceReview

Advances in Local Drug Delivery for Periodontal Treatment: Present Strategies and Future Directions

by Mayuka Nakajima, Mayuko Yanagawa, Honoka Takikawa, Truong Tran Thien, Lorena Zegarra-Caceres, Chunyang Yan and Koichi Tabeta

Biomolecules 2025, 15(6), 903; https://doi.org/10.3390/biom15060903 - 19 Jun 2025

Cited by 8 | Viewed by 6785

Abstract

Periodontitis is a highly prevalent, irreversible inflammatory disease characterized by the destruction of tooth-supporting tissues, eventually leading to tooth loss. Conventional treatment involves the mechanical removal of the subgingival biofilm, which is a major cause of gingival inflammation. However, the inaccessibility of deep-seated [...] Read more.

Periodontitis is a highly prevalent, irreversible inflammatory disease characterized by the destruction of tooth-supporting tissues, eventually leading to tooth loss. Conventional treatment involves the mechanical removal of the subgingival biofilm, which is a major cause of gingival inflammation. However, the inaccessibility of deep-seated polymicrobial biofilms limits its effectiveness. Despite the adjunct use of systemic antimicrobials, their low site-specific bioavailability and systemic side effects remain concerns. Local drug administration offers a targeted alternative. However, the dynamic oral environment, which is characterized by continuous salivary and gingival crevicular fluid flow, poses challenges in maintaining therapeutic drug levels. Drug delivery systems (DDSs) provide technical solutions to overcome these limitations. With advancements in materials science and nanotechnology, diverse local DDS (LDDS) formulations tailored for periodontal applications have been developed. While traditionally focused on infection control, the application of LDDSs has expanded beyond antimicrobial therapy. Increasing attention has been paid to LDDS-based regenerative strategies, which aim to overcome the limitations of conventional regenerative therapies. This review aims to provide a comprehensive overview of the current and emerging DDS strategies in periodontal therapy, focusing on their applications in infection management and bone regeneration and discussing their limitations and prospects for clinical translation. Full article

(This article belongs to the Special Issue Biologics and Biomaterials for Periodontal Treatment: Current and Future Challenges)

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13 pages, 1444 KB

Open AccessEditor’s ChoiceArticle

Cycloadditions as a Sweet Route to ‘Double C-Glycosylation’

by Kevin P. P. Mahoney, Rosemary Lynch, Rhea T. Bown, Sunil V. Sharma, Piyasiri Chueakwon, G. Richard Stephenson, David B. Cordes, Alexandra M. Z. Slawin and Rebecca J. M. Goss

Biomolecules 2025, 15(6), 905; https://doi.org/10.3390/biom15060905 - 19 Jun 2025

Viewed by 1516

Abstract

Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and, in natural products, glycosylation [...] Read more.

Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and, in natural products, glycosylation often confers improved bioactivity and bioavailability. Whilst a single C-glycoside link between a sugar moiety and its aglycone core is a common feature in natural products isolated to date, only a small number, including the antibiotics granaticin and sarubicin, are covalently bonded twice to a single sugar moiety. The way in which this “double C-glycosylation” is naturally mediated is not yet known, yet has been speculated on. Here, we report the exploration and development of a potentially biomimetic procedure that utilises intermolecular cycloaddition chemistry to access new “double C-glycosylated” products and enables the creation of bridged polycyclic ethers from a common maltol-derived oxidopyrylium salt precursor. Full article

(This article belongs to the Section Chemical Biology)

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19 pages, 947 KB

Open AccessEditor’s ChoiceArticle

Early-Life Adversity and Epigenetic Aging: Findings from a 17-Year Longitudinal Study

by Emily Barr, Maude Comtois-Cabana, Andressa Coope, Sylvana M. Coté, Michael S. Kobor, Chaini Konwar, Sonia Lupien, Marie-Claude Geoffroy, Michel Boivin, Nadine Provençal, Nicole L. A. Catherine, Jessica K. Dennis and Isabelle Ouellet-Morin

Biomolecules 2025, 15(6), 887; https://doi.org/10.3390/biom15060887 - 18 Jun 2025

Viewed by 3297

Abstract

Youth exposed to early-life adversity (ELA) are at greater risk for poorer physical and mental health outcomes in adolescence and adulthood. Although the biological mechanisms underlying these associations remain elusive, DNA methylation (DNAm) has emerged as a potential pathway. DNAm-based measures of epigenetic [...] Read more.

Youth exposed to early-life adversity (ELA) are at greater risk for poorer physical and mental health outcomes in adolescence and adulthood. Although the biological mechanisms underlying these associations remain elusive, DNA methylation (DNAm) has emerged as a potential pathway. DNAm-based measures of epigenetic age have been associated with ELA, indicating accelerated aging. According to the stress sensitization hypothesis, prenatal adversity may further heighten sensitivity to subsequent stressors in childhood and adolescence. This study examined the associations between ELA and six epigenetic aging measures, considering both the timing of adversity and the participant’s sex. Data were drawn from the Quebec Longitudinal Study of Child Development, with two cumulative indices of ELA derived from prospectively collected data: the Perinatal Adversity and the Child and Adolescent Adversity indices. Higher Perinatal Adversity scores were associated with accelerated DunedinPACE scores. No significant associations were found between ELA and the other epigenetic clocks, nor did we find support for the stress sensitization hypothesis—though a sex-specific trend emerged among girls. The findings suggest that DunedinPACE may be more sensitive to variations in ELA than other clocks. Future research should systematically investigate sex-dimorphic associations between ELA and epigenetic aging, with particular attention to the impact of perinatal adversity. Full article

(This article belongs to the Special Issue Molecular Advances in Mechanism and Regulation of Lifespan and Aging)

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12 pages, 925 KB

Open AccessEditor’s ChoiceArticle

Pre-Amplification of Cell-Free DNA: Balancing Amplification Errors with Enhanced Sensitivity

by Wei Yen Chan, Ashleigh Stewart, Russell J. Diefenbach, Elin S. Gray, Jenny H. Lee, Richard A. Scolyer, Georgina V. Long and Helen Rizos

Biomolecules 2025, 15(6), 883; https://doi.org/10.3390/biom15060883 - 17 Jun 2025

Viewed by 1455

Abstract

Circulating tumour DNA (ctDNA) is a promising biomarker for personalised oncology. However, its clinical utility is limited by detection sensitivity, particularly in early-stage disease. T-Oligo Primed Polymerase Chain Reaction (TOP-PCR) is a commercial amplification approach utilising an efficient “half-adapter” ligation design and a [...] Read more.

Circulating tumour DNA (ctDNA) is a promising biomarker for personalised oncology. However, its clinical utility is limited by detection sensitivity, particularly in early-stage disease. T-Oligo Primed Polymerase Chain Reaction (TOP-PCR) is a commercial amplification approach utilising an efficient “half-adapter” ligation design and a single-primer-based PCR strategy. This study evaluated the clinical value and application of cell-free DNA (cfDNA) pre-amplification. cfDNA amplification with TOP-PCR preserved DNA size profiles and resulted in a 22 bp size increase due to the half-adaptor ligation. Gene target amplification rates varied, showing lower efficiency for the GC-rich TERT promoter amplicon and higher efficiency for the BRAF and TP53 amplicons. Optimised pre-amplification (20 ng cfDNA input and 5–7 cycles of PCR) enhanced ctDNA detection sensitivity and expanded sample availability for the detection of multiple tumour-informed mutations. Importantly, PCR errors emerged in pre-amplified cfDNA samples, underscoring the necessity for negative controls and the establishment of stringent mutation positivity thresholds. Full article

(This article belongs to the Special Issue Tumor Genomics and Liquid Biopsy in Cancer Biology)

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21 pages, 13615 KB

Open AccessEditor’s ChoiceArticle

Real-Time SPR Biosensing to Detect and Characterize Fast Dissociation Rate Binding Interactions Missed by Endpoint Detection and Implications for Off-Target Toxicity Screening

by William Martelly, Rebecca L. Cook, Chidozie Victor Agu, Lydia R. Gushgari, Salvador Moreno, Sailaja Kesiraju, Mukilan Mohan and Bharath Takulapalli

Biomolecules 2025, 15(6), 882; https://doi.org/10.3390/biom15060882 - 17 Jun 2025

Cited by 2 | Viewed by 2428

Abstract

Accurate detection of biomolecular interactions is essential in many areas, from the detection of the presence of biomarkers in the clinic to the development of therapeutic drugs and biologics in biopharma to the understanding of various biological processes in basic research. Traditional endpoint [...] Read more.

Accurate detection of biomolecular interactions is essential in many areas, from the detection of the presence of biomarkers in the clinic to the development of therapeutic drugs and biologics in biopharma to the understanding of various biological processes in basic research. Traditional endpoint approaches can suffer from false-negative results for biomolecular interactions with fast kinetics. By contrast, real-time detection techniques like surface plasmon resonance (SPR) monitor interactions as they form and disassemble, reducing the risk of false-negative results. By leveraging cell-free expressed proteins captured on either glass or SPR biosensors and using two different commercial antibodies with variable off-rates that both target HaloTag antigens as a model, we compare and contrast results from a fluorescence endpoint assay versus real-time sensor-integrated proteome on chip (SPOC^®) SPR-based detection. In this study, we illustrate the limitations of the representative immunofluorescent endpoint assay when investigating transient interactions characterized by fast dissociation rates. We highlight the importance of choosing reagents well suited to the selected assay, as well as the importance of considering binding kinetics and protein ligand conformational states when interpreting results from binding assays, especially for applications as critical as the off-target screening of therapeutics. Full article

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

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17 pages, 989 KB

Open AccessEditor’s ChoiceArticle

Age Trajectories of O₂ Saturation and Levels of Serum Bicarbonate or End-Tidal CO₂ Across the Life Course of Women and Men: Insights from EHR and PSG Data

by Leping Li, Min Shi, David M. Umbach and Zheng Fan

Biomolecules 2025, 15(6), 884; https://doi.org/10.3390/biom15060884 - 17 Jun 2025

Cited by 4 | Viewed by 1030

Abstract

To elucidate the changes in gas exchange across the life course, we estimated the age trajectories of O₂ saturation, CO₂ (as either end-tidal or serum bicarbonate), resting heart rate, and resting respiratory rate from age 2 yr onward in female and [...] Read more.

To elucidate the changes in gas exchange across the life course, we estimated the age trajectories of O₂ saturation, CO₂ (as either end-tidal or serum bicarbonate), resting heart rate, and resting respiratory rate from age 2 yr onward in female and male patients separately. We utilized two sources’ data: electronic health records (EHR) representing ambulatory visits of approximately 53,000 individuals and sleep clinic polysomnogram (PSG) records representing an additional ~21,000. We used linear regression to estimate age-group-specific mean response levels for women and men. We compared estimated female–male differences between pre- and post-pubertal children and between pre- and post-menopausal periods among adults. Women between 15 and 45 years had higher O₂ saturation and lower serum bicarbonate levels or end-tidal CO₂ levels than men of similar ages. For O₂ saturation and for both measures of CO₂, the female–male difference was larger on average among adults at pre-menopausal ages than those at post-menopausal ages. Women had higher O₂ saturation throughout their lives than men; however, the difference disappeared in the elderly. Women between menarche and menopause had significantly lower end-tidal CO₂ and serum bicarbonate than men of similar ages. After menopause, however, women appeared to have higher mean levels of both end-tidal CO₂ and serum bicarbonate than men. Full article

(This article belongs to the Section Biological Factors)

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26 pages, 2956 KB

Open AccessFeature PaperEditor’s ChoiceReview

Unraveling Osteoarthritis: Mechanistic Insights and Emerging Therapies Targeting Pain and Inflammation

by Muskan Alad, Fajer Yousef, Laura M. Epure, Angelina Lui, Michael P. Grant, Geraldine Merle, Nicoletta Eliopoulos, Jake Barralet, John Antoniou and Fackson Mwale

Biomolecules 2025, 15(6), 874; https://doi.org/10.3390/biom15060874 - 16 Jun 2025

Cited by 7 | Viewed by 8530

Abstract

Osteoarthritis (OA) is now widely recognized not merely as a cartilage-centric disease but as a multifactorial disorder affecting the entire joint as an organ, including the articular cartilage, subchondral bone, synovium, ligaments, menisci, and the innervating neural elements. This review explores the complex [...] Read more.

Osteoarthritis (OA) is now widely recognized not merely as a cartilage-centric disease but as a multifactorial disorder affecting the entire joint as an organ, including the articular cartilage, subchondral bone, synovium, ligaments, menisci, and the innervating neural elements. This review explores the complex pathophysiology of OA with a focus on the emerging mechanisms of pain and inflammation that extend beyond articular cartilage degradation. Joint inflammation driven by immune activation in response to cellular stress signals promotes the release of pro-inflammatory mediators and catabolic enzymes. Key signaling pathways such as NF-κB, MAPKs, and JAK/STAT amplify these responses, and pain is sustained through peripheral and central sensitization, contributing to exacerbating symptoms even in the absence of visible joint damage. This review also integrates molecular and cellular mechanisms to highlight innovative therapies aimed at modifying both the structural damage and neurosensory drivers of pain. These approaches offer the potential to not only alleviate symptoms but also alter disease progression, signaling a move toward personalized, mechanism-based treatments. Given the intricate interactions among joint tissues, immune activation, and sensory processing, a comprehensive strategy that targets both structural degeneration and neuroinflammation is essential for the future of OA management. Emphasizing the joint as an integrated organ, we advocate for translational research linking molecular pathology with clinically meaningful outcomes. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 7793 KB

Open AccessEditor’s ChoiceArticle

Targeting Cellular Senescence to Enhance Human Endometrial Stromal Cell Decidualization and Inhibit Their Migration

by Julia Delenko, Nathaniel Hyman, Prodyot K. Chatterjee, Polona Safaric Tepes, Andrew J. Shih, Xiangying Xue, Jane Gurney, Andrew G. Baker, Cheng Wei, Daniel Munoz Espin, Ljiljana Fruk, Peter K. Gregersen and Christine N. Metz

Biomolecules 2025, 15(6), 873; https://doi.org/10.3390/biom15060873 - 16 Jun 2025

Cited by 3 | Viewed by 3156

Abstract

Cellular senescence leads to stable cell cycle arrest and an inflammatory senescence-associated secretory phenotype that varies with stressor and cell type. To mitigate these effects and improve health, senotherapeutics (e.g., senolytics and senomorphics) have been developed. Senescent-like endometrial stromal cells (eSCs) lining the [...] Read more.

Cellular senescence leads to stable cell cycle arrest and an inflammatory senescence-associated secretory phenotype that varies with stressor and cell type. To mitigate these effects and improve health, senotherapeutics (e.g., senolytics and senomorphics) have been developed. Senescent-like endometrial stromal cells (eSCs) lining the uterus of patients with endometriosis and infertility are proposed to impair decidualization, a differentiation process required for uterine receptivity in humans. Quercetin, a natural flavonoid senolytic, dramatically improves decidualization and reduces endometriosis in rodent models. However, little is known about the comparative effects of various senotherapeutics on eSCs. Using menstrual effluent-derived eSCs, we evaluated the effects of flavonoid and non-flavonoid compounds on eSC functions associated with endometriosis, aiming to identify optimal senotherapeutics for future clinical trials. Among flavonoids tested, all senolytics (quercetin, fisetin, and luteolin) and kaempferol, a senomorphic, significantly improved decidualization without cytotoxicity. Although non-flavonoids exhibited notable cytotoxicity, dasatinib, but neither ABT-737 nor navitoclax, enhanced decidualization. Flavonoid senotherapeutics and dasatinib significantly inhibited eSC migration. Mechanistic studies revealed that all flavonoids and dasatinib suppressed AKT phosphorylation and upregulated p53 expression. Notably, only quercetin and fisetin reduced ERK1/2 phosphorylation. Furthermore, flavonoid-senolytics and dasatinib consistently eliminated senescent eSCs. These findings support future studies to assess the therapeutic potential of in vivo supplementation with flavonoid senolytics on eSC function using menstrual effluent. Full article

(This article belongs to the Section Molecular Reproduction)

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36 pages, 6162 KB

Open AccessEditor’s ChoiceReview

Biomolecule-Based Coacervation: Mechanisms, Applications, and Future Perspectives in Biomedical and Biotechnological Fields

by Dong Hyun Kim, Mi-Ran Ki, Da Yeon Chung and Seung Pil Pack

Biomolecules 2025, 15(6), 861; https://doi.org/10.3390/biom15060861 - 13 Jun 2025

Cited by 6 | Viewed by 6539

Abstract

Coacervate is a form of liquid–liquid phase separation (LLPS) in which a solution containing one or more charged components spontaneously separates into two immiscible liquid phases. Due to their ability to mimic membraneless cellular environments and their high biocompatibility, coacervates have found broad [...] Read more.

Coacervate is a form of liquid–liquid phase separation (LLPS) in which a solution containing one or more charged components spontaneously separates into two immiscible liquid phases. Due to their ability to mimic membraneless cellular environments and their high biocompatibility, coacervates have found broad applications across various fields of life sciences. This review provides a comprehensive overview of recent advances in biomolecule-based coacervation for biotechnological and biomedical applications. Encapsulation via biomolecule-based coacervation enables high encapsulation efficiency, enhanced stability, and the sustained release of cargos. In the field of tissue engineering, coacervates not only support cell adhesion and proliferation but also serve as printable bioinks with tunable rheological properties for 3D bioprinting. Moreover, biomolecule-based coacervates have been utilized to mimic membraneless organelles, serving as experimental models to understand the origin of life or investigate the mechanisms of biochemical compartmentalization. This review discusses the mechanisms of coacervation induced by various types of biomolecules, evaluates their respective advantages and limitations in applied contexts, and outlines future research directions. Given their modularity and biocompatibility, biomolecule-based coacervates are expected to play a pivotal role in next-generation therapeutic development and the construction of controlled tissue microenvironments, especially when integrated with emerging technologies. Full article

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

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38 pages, 5974 KB

Open AccessEditor’s ChoiceReview

Mechanobiology in Action: Biomaterials, Devices, and the Cellular Machinery of Force Sensing

by Miriam Lucariello, Maria Luisa Valicenti, Samuele Giannoni, Leonardo Donati, Ilaria Armentano, Francesco Morena and Sabata Martino

Biomolecules 2025, 15(6), 848; https://doi.org/10.3390/biom15060848 - 10 Jun 2025

Cited by 5 | Viewed by 6144

Abstract

Mechanical forces are increasingly recognised as fundamental regulators of cellular function, complementing classical biochemical cues to direct development, tissue homeostasis, and disease progression. Cells detect external and internal forces via mechanosensor proteins and adapt their cytoskeletal architecture, leading to changes in cell behaviour. [...] Read more.

Mechanical forces are increasingly recognised as fundamental regulators of cellular function, complementing classical biochemical cues to direct development, tissue homeostasis, and disease progression. Cells detect external and internal forces via mechanosensor proteins and adapt their cytoskeletal architecture, leading to changes in cell behaviour. Biomaterials and biodevices come to the aid of tailoring biomaterials’ properties in terms of chemical/physical properties and, by emulating dynamical forces, e.g., shear stress and cell swelling, they may enlighten mechanobiological processes. Additionally, emerging technologies expand the experimental toolkit for probing mechanobiological phenomena in complex, customisable settings. Central to these processes are mechanotransducer proteins and membrane–organelle networks that convert mechanical deformation into biochemical signals, orchestrating downstream transcriptional and post-translational modifications. This review highlights how through bridging material engineering and cellular mechanics, mechanobiology provides a unified framework to understand how physical forces shape tissues and drive pathologies. The continued integration of advanced biomaterials, dynamic biodevices, and multiscale analytical methods promises to uncover new mechanistic insights and inform the development of mechanotherapeutic strategies. Full article

(This article belongs to the Special Issue The Role of Mechanotransduction in Cellular Biology)

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Graphical abstract

30 pages, 5870 KB

Open AccessFeature PaperEditor’s ChoiceReview

Diagnosis of Inherited Platelet Disorders: Clinical Evaluation and Functional and Molecular Assays

by Ana Sánchez-Fuentes, Juliana Pérez-Botero, José M. Bastida and José Rivera

Biomolecules 2025, 15(6), 846; https://doi.org/10.3390/biom15060846 - 10 Jun 2025

Cited by 5 | Viewed by 5089

Abstract

Inherited platelet disorders (IPDs) are a group of rare conditions affecting platelet number, function, or both. Clinical manifestations vary widely, from asymptomatic cases to patients with severe bleeding, syndromic features, or early-onset blood cancers. Some are diagnosed due to family history. Early and [...] Read more.

Inherited platelet disorders (IPDs) are a group of rare conditions affecting platelet number, function, or both. Clinical manifestations vary widely, from asymptomatic cases to patients with severe bleeding, syndromic features, or early-onset blood cancers. Some are diagnosed due to family history. Early and accurate diagnosis—through both clinical and molecular evaluation—is essential for effective patient management and to avoid inappropriate treatments due to misdiagnosis. Genetic confirmation aids in prognosis, follow-up planning, family screening, genetic counseling, and donor selection for stem cell transplantation if required. However, diagnosing IPD is still challenging due to the disorders’ complexity and the limitations of current lab tests. This review outlines the diagnostic process for IPD and provides evidence-based, practical recommendations informed by scientific literature and clinical experience. Full article

(This article belongs to the Special Issue Molecular Advances in Platelet Disease, Thrombosis and Hemostasis)

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20 pages, 8532 KB

Open AccessEditor’s ChoiceArticle

Synergistic Effect of Stauntonia hexaphylla (Thunb.) Decne Fruit and Leaf on RAW 264.7 Osteoclast and MC3T3-E1 Osteoblast Differentiation

by Reshmi Akter, Muhammad Awais, Md Niaj Morshed, Jong Hak Kim, Byoung Man Kong, Dong Wook Lee, Sung Keun Choi, Chang Soon Lee, Jong Chan Ahn and Deok Chun Yang

Biomolecules 2025, 15(6), 844; https://doi.org/10.3390/biom15060844 - 10 Jun 2025

Cited by 1 | Viewed by 1617

Abstract

Stauntonia hexaphylla (Thunb.) Decne (SH) is known for its anti-inflammatory, analgesic, antioxidant, and anti-osteoporotic properties. This study investigated the composition of SH leaves and fruits and assessed their individual and combined effects in an in vitro osteoporosis model. Extracts with varying leaf-to-fruit ratios [...] Read more.

Stauntonia hexaphylla (Thunb.) Decne (SH) is known for its anti-inflammatory, analgesic, antioxidant, and anti-osteoporotic properties. This study investigated the composition of SH leaves and fruits and assessed their individual and combined effects in an in vitro osteoporosis model. Extracts with varying leaf-to-fruit ratios (SH82, SH55, SH28) were evaluated in MC3T3-E1 and RAW264.7 cells to examine osteogenesis and bone resorption biomarkers. SH leaves were rich in chlorogenic acids (CGAs) and flavonoids, while fruits contained phenolic acids with minimal flavonoids. Leaf extracts exhibited superior antioxidant activity and ROS suppression. Both leaf and fruit extracts enhanced ALP activity, calcium deposition, and collagen formation in MC3T3-E1 cells, with leaf extracts demonstrating greater efficacy. Additionally, osteoblastogenesis-related genes were upregulated, while TRAP activity and osteoclast-related gene expression were significantly inhibited. The combined extract exerted a synergistic effect, with SH28 showing the most pronounced osteogenic enhancement and TRAP inhibition. Key components, including neo-CGA, CGA, rutin, and luteolin-7-O-glucoside, positively influenced ALP and TRAP activities. These findings highlight the potential of SH, particularly at a high leaf-to-fruit ratio, as a promising natural agent for osteoporosis prevention. Full article

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23 pages, 4360 KB

Open AccessEditor’s ChoiceArticle

Conditioned Generative Modeling of Molecular Glues: A Realistic AI Approach for Synthesizable Drug-like Molecules

by Naeyma N. Islam and Thomas R. Caulfield

Biomolecules 2025, 15(6), 849; https://doi.org/10.3390/biom15060849 - 10 Jun 2025

Cited by 4 | Viewed by 3621

Abstract

Alzheimer’s disease (AD) is marked by the pathological accumulation of amyloid beta-42 (Aβ42), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular Aβ42 as an early and toxic driver of disease progression. In this study, we [...] Read more.

Alzheimer’s disease (AD) is marked by the pathological accumulation of amyloid beta-42 (Aβ42), contributing to synaptic dysfunction and neurodegeneration. While extracellular amyloid plaques are well-studied, increasing evidence highlights intracellular Aβ42 as an early and toxic driver of disease progression. In this study, we present a novel, Generative AI–based drug design approach to promote targeted degradation of Aβ42 via the ubiquitin–proteasome system (UPS), using E3 ligase–directed molecular glues. We systematically evaluated the ternary complex formation potential of Aβ42 with three E3 ligases (CRBN, VHL, and MDM2) through structure-based modeling, ADMET screening, and docking. We then developed a Ligase-Conditioned Junction Tree Variational Autoencoder (LC-JT-VAE) to generate ligase-specific small molecules, incorporating protein sequence embeddings and torsional angle-aware molecular graphs. Our results demonstrate that this generative model can produce chemically valid, novel, and target-specific molecular glues capable of facilitating Aβ42 degradation. This integrated approach offers a promising framework for designing UPS-targeted therapies for neurodegenerative diseases. Full article

(This article belongs to the Special Issue In Silico Drug Design and Discovery: Big Data for Small Molecule Design 2nd Edition)

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20 pages, 3355 KB

Open AccessEditor’s ChoiceArticle

FmocFF Peptide Hydrogel Is a Promising Matrix for Encapsulation and Controlled Release of the Anticancer Peptide Drug Bortezomib

by Peter Divanach, Antzela Noti, Panagiotis Vouvopoulos, Thanasis Athanasiou, Nikos Kountourakis, Vagelis Harmandaris, Anastassia N. Rissanou and Anna Mitraki

Biomolecules 2025, 15(6), 839; https://doi.org/10.3390/biom15060839 - 8 Jun 2025

Cited by 5 | Viewed by 1974

Abstract

One major public health issue is cancer chemotherapy; despite constant progress in the area, administration of anticancer drugs to patients is often associated with serious side effects. It is therefore imperative to develop vehicles for encapsulation and controlled delivery of such drugs. Anticancer [...] Read more.

One major public health issue is cancer chemotherapy; despite constant progress in the area, administration of anticancer drugs to patients is often associated with serious side effects. It is therefore imperative to develop vehicles for encapsulation and controlled delivery of such drugs. Anticancer drugs include small peptide drugs, such as Bortezomib (BTZ). Self-assembling peptides have been recently reported as promising drug delivery agents. The research reported here proposes the encapsulation of BTZ into peptide hydrogels formed by the self-assembling FmocFF dipeptide as delivery vehicle. We selected FmocFF as an encapsulation vehicle based on our previous simulation study on the complexation propensity of Bortezomib (BTZ) with various peptide gelators. Herein we undertook additional computational studies that highlight the benefits of FmocFF as a potential effective nanocarrier for BTZ combined with experiments of encapsulation and evaluation of BTZ release. Based on these computational and experimental results, we propose the Fmoc-FF dipeptide hydrogel as a promising matrix for the controlled delivery of BTZ. Full article

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

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