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 1310

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

Cited by 1 | Viewed by 2909

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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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 1637

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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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 15 | Viewed by 5545

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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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 2 | Viewed by 2162

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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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 1418

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 1468

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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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 1658

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, 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

Cited by 1 | Viewed by 1493

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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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 1950

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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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 1279

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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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 1395

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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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 1366

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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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 2262

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 4 | Viewed by 4298

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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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 3528

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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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 7 | Viewed by 1744

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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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 7 | Viewed by 6316

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 2677

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 1585

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 2832

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 1517

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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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 1585

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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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 7 | Viewed by 3640

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 1576

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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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 10 | Viewed by 5710

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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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 4824

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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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 2126

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 1426

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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24 pages, 2944 KB

Open AccessEditor’s ChoiceArticle

Oral Pharmacokinetic Evaluation of a Microemulsion-Based Delivery System for Novel A190 Prodrugs

by Sagun Poudel, Chaolong Qin, Rudra Pangeni, Ziwei Hu, Grant Berkbigler, Madeline Gunawardena, Adam S. Duerfeldt and Qingguo Xu

Biomolecules 2025, 15(8), 1101; https://doi.org/10.3390/biom15081101 - 30 Jul 2025

Viewed by 1898

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that [...] Read more.

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. Full article

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

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23 pages, 4653 KB

Open AccessEditor’s ChoiceArticle

Zinc-Induced Folding and Solution Structure of the Eponymous Novel Zinc Finger from the ZC4H2 Protein

by Rilee E. Harris, Antonio J. Rua and Andrei T. Alexandrescu

Biomolecules 2025, 15(8), 1091; https://doi.org/10.3390/biom15081091 - 28 Jul 2025

Cited by 1 | Viewed by 1736

Abstract

The ZC4H2 gene is the site of congenital mutations linked to neurodevelopmental and musculoskeletal pathologies collectively termed ZARD (ZC4H2-Associated Rare Disorders). ZC4H2 consists of a coiled coil and a single novel zinc finger with four cysteines and two histidines, from which the protein [...] Read more.

The ZC4H2 gene is the site of congenital mutations linked to neurodevelopmental and musculoskeletal pathologies collectively termed ZARD (ZC4H2-Associated Rare Disorders). ZC4H2 consists of a coiled coil and a single novel zinc finger with four cysteines and two histidines, from which the protein obtains its name. Alpha Fold 3 confidently predicts a structure for the zinc finger but also for similarly sized random sequences, providing equivocal information on its folding status. We show using synthetic peptide fragments that the zinc finger of ZC4H2 is genuine and folds upon binding a zinc ion with picomolar affinity. NMR pH titration of histidines and UV–Vis of a cobalt complex of the peptide indicate its four cysteines coordinate zinc, while two histidines do not participate in binding. The experimental NMR structure of the zinc finger has a novel structural motif similar to RANBP2 zinc fingers, in which two orthogonal hairpins each contribute two cysteines to coordinate zinc. Most of the nine ZARD mutations that occur in the ZC4H2 zinc finger are likely to perturb this structure. While the ZC4H2 zinc finger shares the folding motif and cysteine-ligand spacing of the RANBP2 family, it is missing key substrate-binding residues. Unlike the NZF branch of the RANBP2 family, the ZC4H2 zinc finger does not bind ubiquitin. Since the ZC4H2 zinc finger occurs in a single copy, it is also unlikely to bind DNA. Based on sequence homology to the VAB-23 protein, the ZC4H2 zinc finger may bind RNA of a currently undetermined sequence or have alternative functions. Full article

(This article belongs to the Special Issue Functional Peptides and Their Interactions (3rd Edition))

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22 pages, 1822 KB

Open AccessEditor’s ChoiceArticle

Increased Concentration of Anti-Egg Albumin Antibodies in Cerebrospinal Fluid and Serum of Patients with Alzheimer’s Disease—Discussion on Human Serpins’ Similarity and Probable Involvement in the Disease Mechanism

by Dionysia Amanatidou, Magdalini Tsolaki, Vasileios Fouskas, Ioannis Gavriilidis, Maria Myriouni, Anna Anastasiou, Efthimia Papageorgiou, Diona Porfyriadou, Zoi Parcharidi, Eleftheria Papasavva, Maria Fili and Phaedra Eleftheriou

Biomolecules 2025, 15(8), 1085; https://doi.org/10.3390/biom15081085 - 27 Jul 2025

Viewed by 1917

Abstract

Alzheimer’s Disease (AD) is a multifactorial process. Amyloid plaque formation constitutes the main characteristic of the disease. Despite the identification of numerous factors associated with AD, the mechanism remains unclear in several aspects. Disturbances in intestinal and blood–brain barrier (BBB) penetration, observed in [...] Read more.

Alzheimer’s Disease (AD) is a multifactorial process. Amyloid plaque formation constitutes the main characteristic of the disease. Despite the identification of numerous factors associated with AD, the mechanism remains unclear in several aspects. Disturbances in intestinal and blood–brain barrier (BBB) penetration, observed in AD, may facilitate immunologic response to food-derived antigens. In the present study, antibodies against egg albumin, bovine-casein, and N-Glycolyl-Neuraminic acid (Neu5Gc) were measured in the cerebrospinal fluid (CSF) and serum of the patients using an enzyme-linked immunosorbent assay (ELISA). Zero anti-Neu5Gc and low concentrations of anti-casein antibodies were detected. Increased anti-native egg albumin antibodies were present in the serum of patients of all stages with 65% positivity (p < 0.001) in mild disease and a higher percentage in females (81.9%, p < 0.001). Lower serum positivity to anti-denatured egg albumin antibodies was observed, showing a gradual increase with severity and higher prevalence also in females. In the CSF, anti-native and anti-denatured egg albumin antibodies were mainly observed in severely ill patients with accumulative positivity to either antigen, reaching 61.8% in severe vs. 15% in mild disease (p < 0.001). Increased values were mainly observed in males. Anti-egg albumin antibodies may be implicated in the disease mechanism through sequence/structural similarity with human proteins, mainly serpins, and it would be worth consideration in further investigations and therapeutic strategies. Full article

(This article belongs to the Special Issue Food, Microbe, Viral and Parasite-Derived Antibodies in Autoimmune and Chronic Diseases)

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18 pages, 1330 KB

Open AccessEditor’s ChoiceReview

Metallothionein and Other Factors Influencing Cadmium-Induced Kidney Dysfunction: Review and Commentary

by Gunnar F. Nordberg and Monica Nordberg

Biomolecules 2025, 15(8), 1083; https://doi.org/10.3390/biom15081083 - 26 Jul 2025

Cited by 7 | Viewed by 2691

Abstract

Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals. Kidney dysfunction occurs at very low exposures and is often considered as the most sensitive or critical effect. Cadmium [...] Read more.

Cadmium is widely recognized as an important environmental toxicant that may give rise to kidney dysfunction, bone disease, and cancer in humans and animals. Kidney dysfunction occurs at very low exposures and is often considered as the most sensitive or critical effect. Cadmium exposures of concern occur in many countries. In low- and middle-income countries with small-scale mining, excessive exposure to cadmium and other metals occurs in occupational and environmental settings. This is of particular importance in view of the growing demand for metals in global climate change mitigation. Since the 1970s, the present authors have contributed evidence concerning the role of metallothionein and other factors in influencing the toxicokinetics and toxicity of cadmium, particularly as it relates to the development of adverse effects on kidneys in humans and animals. The findings gave a background to the development of biomarkers employed in epidemiological studies, demonstrating the important role of metallothionein in protection against cadmium-induced kidney dysfunction in humans. Studies in cadmium-exposed population groups demonstrated how biomarkers of kidney dysfunction changed during 8 years after drastic lowering of environmental cadmium exposure. Other epidemiological studies showed the impact of a good zinc status in lowering the prevalence of cadmium-related kidney dysfunction. Increased susceptibility to Cd-induced kidney dysfunction was shown in a population with high exposure to inorganic arsenic when compared with a group with low such exposure. Several national and international organizations have used part of the reviewed information, but the metallothionein-related biomarkers and the interaction effects have not been fully considered. We hope that these data sets will also be included and improve risk assessments and preventive measures. Full article

(This article belongs to the Special Issue Current Advances of Metal Complexes for Biomedical Applications)

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20 pages, 17373 KB

Open AccessEditor’s ChoiceArticle

The Memory Gene, Murashka, Is a Regulator of Notch Signalling and Controls the Size of the Drosophila Germline Stem Cell Niche

by Thifeen Deen, Hideyuki Shimizu, Marian B. Wilkin and Martin Baron

Biomolecules 2025, 15(8), 1082; https://doi.org/10.3390/biom15081082 - 26 Jul 2025

Viewed by 1178

Abstract

We identified Murashka, a RING finger protein, in an oogenesis screen as a regulator of Drosophila ovary germline stem cell niche development. Mutant alleles of murashka exhibited an enlarged niche phenotype reminiscent of increased Notch signalling and displayed genetic interactions with Notch alleles, [...] Read more.

We identified Murashka, a RING finger protein, in an oogenesis screen as a regulator of Drosophila ovary germline stem cell niche development. Mutant alleles of murashka exhibited an enlarged niche phenotype reminiscent of increased Notch signalling and displayed genetic interactions with Notch alleles, and with polychaetoid, a regulator of Notch during niche development. These interactions uncovered both positive and negative impacts on Notch in different genetic backgrounds. In S2 cells, Murashka formed a complex with Notch and colocalised with Notch in the secretory pathway. Murashka expression in S2 cells down-regulated Notch signalling levels but could result in increased fold induction due to the proportionally greater decrease in basal ligand-independent activity. In vivo Murashka expression had different outcomes on different Notch target genes. We observed a decrease in the expression of vestigial along the anterior/posterior boundary of the wing imaginal disc, but not of wingless at the dorsal/ventral boundary. Instead, weak ectopic wingless was observed, which was synergistically increased by the coexpression of Deltex, a positive regulator of ligand-independent signalling. Our results identify a novel developmental role for murashka, a gene previously only associated with a function in long-term memory, and indicate a regulatory role for Murashka through a physical interaction with Notch that has context-dependent outcomes. Murashka adds to a growing number of ubiquitin ligase regulators which interact with Notch at different locations within its secretory and endocytic trafficking pathways. Full article

(This article belongs to the Special Issue Notch and Its Regulation in Health and Disease)

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17 pages, 13173 KB

Open AccessEditor’s ChoiceArticle

High-Resolution Imaging and Interpretation of Three-Dimensional RPE Sheet Structure

by Kevin J. Donaldson, Micah A. Chrenek, Jeffrey H. Boatright and John M. Nickerson

Biomolecules 2025, 15(8), 1084; https://doi.org/10.3390/biom15081084 - 26 Jul 2025

Viewed by 1380

Abstract

The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), [...] Read more.

The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell-to-cell contact and barrier function, as well as conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers. We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (α-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misidentifying multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO₃ oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes. Full article

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

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20 pages, 547 KB

Open AccessEditor’s ChoiceArticle

Empirical Assessment of Sequence-Based Predictions of Intrinsically Disordered Regions Involved in Phase Separation

by Xuantai Wu, Kui Wang, Gang Hu and Lukasz Kurgan

Biomolecules 2025, 15(8), 1079; https://doi.org/10.3390/biom15081079 - 25 Jul 2025

Viewed by 1807

Abstract

Phase separation processes facilitate the formation of membrane-less organelles and involve interactions within structured domains and intrinsically disordered regions (IDRs) in protein sequences. The literature suggests that the involvement of proteins in phase separation can be predicted from their sequences, leading to the [...] Read more.

Phase separation processes facilitate the formation of membrane-less organelles and involve interactions within structured domains and intrinsically disordered regions (IDRs) in protein sequences. The literature suggests that the involvement of proteins in phase separation can be predicted from their sequences, leading to the development of over 30 computational predictors. We focused on intrinsic disorder due to its fundamental role in related diseases, and because recent analysis has shown that phase separation can be accurately predicted for structured proteins. We evaluated eight representative amino acid-level predictors of phase separation, capable of identifying phase-separating IDRs, using a well-annotated, low-similarity test dataset under two complementary evaluation scenarios. Several methods generate accurate predictions in the easier scenario that includes both structured and disordered sequences. However, we demonstrate that modern disorder predictors perform equally well in this scenario by effectively differentiating phase-separating IDRs from structured regions. In the second, more challenging scenario—considering only predictions in disordered regions—disorder predictors underperform, and most phase separation predictors produce only modestly accurate results. Moreover, some predictors are broadly biased to classify disordered residues as phase-separating, which results in low predictive performance in this scenario. Finally, we recommend PSPHunter as the most accurate tool for identifying phase-separating IDRs in both scenarios. Full article

(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)

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15 pages, 8667 KB

Open AccessEditor’s ChoiceArticle

A Novel Synthetic Tag Induces Palmitoylation and Directs the Subcellular Localization of Target Proteins

by Jun Ka, Gwanyeob Lee, Seunghyun Han, Haekwan Jeong and Suk-Won Jin

Biomolecules 2025, 15(8), 1076; https://doi.org/10.3390/biom15081076 - 25 Jul 2025

Viewed by 1796

Abstract

Proper subcellular localization is essential to exert the designated function of a protein, not only for endogenous proteins but also transgene-encoded proteins. Post-translational modification is a frequently used method to regulate the subcellular localization of a specific protein. While there are a number [...] Read more.

Proper subcellular localization is essential to exert the designated function of a protein, not only for endogenous proteins but also transgene-encoded proteins. Post-translational modification is a frequently used method to regulate the subcellular localization of a specific protein. While there are a number of tags that are widely used to direct the target protein to a specific location within a cell, these tags often fail to emulate the dynamics of protein trafficking, necessitating an alternative approach to the direct subcellular localization of transgene-encoded proteins. Here, we report the development of a new synthetic polypeptide protein tag comprised of ten amino acids, which promotes membrane localization of a target protein. This short synthetic peptide tag, named “Palmito-Tag”, induces ectopic palmitoylation on the cysteine residue within the tag, thereby promoting membrane localization of the target proteins without affecting their innate function. We show that the target proteins with the Palmito-Tag are incorporated into the membranous organelles within the cells, including the endosomes, as well as extracellular vesicles. Given the reversible nature of palmitoylation, the Palmito-Tag may allow us to shift the subcellular localization of the target protein in a context-dependent manner. With the advent of therapeutic applications of exosomes and other extracellular vesicles, we believe that the ability to reversibly modify a target protein and direct its deposition to the specific subcellular milieu will help us explore more effective venues to harness the potential of extracellular vesicle-based therapies. Full article

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

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23 pages, 36719 KB

Open AccessEditor’s ChoiceArticle

The Impact of Hybrid Bionanomaterials Based on Gold Nanoparticles on Liver Injury in an Experimental Model of Thioacetamide-Induced Hepatopathy

by Mara Filip, Simona Valeria Clichici, Mara Muntean, Luminița David, Bianca Moldovan, Vlad Alexandru Toma, Cezar Login and Şoimița Mihaela Suciu

Biomolecules 2025, 15(8), 1068; https://doi.org/10.3390/biom15081068 - 24 Jul 2025

Cited by 1 | Viewed by 1165

Abstract

The present study aimed to evaluate the therapeutic benefits of a hybrid material based on gold nanoparticles and natural extracts on an experimental model of thioacetamide-induced (TAA) liver injury in rats. The nanomaterials were synthesized using a green method, with Cornus sanguinea L. [...] Read more.

The present study aimed to evaluate the therapeutic benefits of a hybrid material based on gold nanoparticles and natural extracts on an experimental model of thioacetamide-induced (TAA) liver injury in rats. The nanomaterials were synthesized using a green method, with Cornus sanguinea L. extract as a reducing and capping agent (NPCS), and were then mixed with Vaccinium myrtillus L. (VL) extract in order to achieve a final mixture with enhanced properties (NPCS-VL). NPCSs were characterized using UV–vis spectrophotometry and transmission electron microscopy (TEM), which demonstrated the formation of spherical, stable gold nanoparticles with an average diameter of 20 nm. NPCS-VL’s hepatoprotective effects were evaluated through an analysis of oxidative stress, inflammation, hepatic cytolysis, histology assays, and TEM in comparison to silymarin on an animal model of thioacetamide (TAA)-induced toxic hepatitis. TAA administration determined hepatotoxicity, as it triggered redox imbalance, increased proinflammatory cytokine levels and alanine aminotransferase (ALAT) activity, and induced morphological and ultrastructural changes characteristic of liver fibrosis. In rats treated with NPCS-VL, all these pathological processes were attenuated, suggesting a potential antifibrotic effect of this hybrid bionanomaterial. Full article

(This article belongs to the Special Issue Bionanomaterials: Synthesis, Characterization, Toxicity and Biomedical Applications, 3rd Edition)

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16 pages, 2130 KB

Open AccessEditor’s ChoiceArticle

A Distinct miRNA Profile in Intimal Hyperplasia of Failed Arteriovenous Fistulas Reveals Key Pathogenic Pathways

by Carmen Ciavarella, Francesco Vasuri, Alessio Degiovanni, Lena Christ, Raffaella Mauro, Mauro Gargiulo and Gianandrea Pasquinelli

Biomolecules 2025, 15(8), 1064; https://doi.org/10.3390/biom15081064 - 23 Jul 2025

Viewed by 1272

Abstract

Intimal hyperplasia (IH) compromises the patency of arteriovenous fistula (AVF) vascular access in patients with end-stage kidney disease. Uncontrolled cell proliferation and migration, driven by inflammation, shear stress and surgery, are well-known triggers in IH. Recently, microRNAs (miRNAs) have emerged as regulators of [...] Read more.

Intimal hyperplasia (IH) compromises the patency of arteriovenous fistula (AVF) vascular access in patients with end-stage kidney disease. Uncontrolled cell proliferation and migration, driven by inflammation, shear stress and surgery, are well-known triggers in IH. Recently, microRNAs (miRNAs) have emerged as regulators of core mechanisms in cardiovascular diseases and as potential markers of IH. This study was aimed at identifying a specific miRNA panel in failed AVFs and clarifying the miRNA involvement in IH. miRNA profiling performed in tissues from patients with IH (AVFs) and normal veins (NVs) highlighted a subset of four miRNAs significantly deregulated (hsa-miR-155-5p, hsa-miR-449a-5p, hsa-miR-29c-3p, hsa-miR-194-5p) between the two groups. These miRNAs were analyzed in tissue-derived cells (NVCs and AVFCs), human aortic smooth muscle cells (HAOSMCs) and human umbilical vein endothelial cells (HUVECs). The panel of hsa-miR-449a-5p, hsa-miR-155-5p, hsa-miR-29c-3p and hsa-miR-194-5p was up-regulated in AVFCs, HAOSMCs and HUVEC under inflammatory stimuli. Notably, overexpression of hsa-miR-449a-5p exacerbated the proliferative, migratory and inflammatory features of AVFCs. In vitro pharmacological modulation of these miRNAs with pioglitazone, particularly the down-regulation of hsa-miR-155-5p and hsa-miR-29c-3p, suggested their involvement in IH pathogenesis and a potential translational application. Overall, these findings provide new insights into the pathogenesis of AVF failure, reinforcing the miRNA contribution to IH detection and prevention. Full article

(This article belongs to the Section Molecular Biology)

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13 pages, 1988 KB

Open AccessEditor’s ChoiceArticle

Genetic Diversity in the Suppressyn Gene Sequence: From Polymorphisms to Loss-of-Function Mutations

by Jun Sugimoto, Danny J. Schust, Takeshi Nagamatsu, Yoshihiro Jinno and Yoshiki Kudo

Biomolecules 2025, 15(7), 1051; https://doi.org/10.3390/biom15071051 - 21 Jul 2025

Cited by 1 | Viewed by 1302

Abstract

The suppressive regulator of cell fusion, suppressyn, is specifically expressed in the human placenta and is thought to play a crucial role in trophoblast fusion or syncytialization. Previous studies have suggested that alterations in its expression are associated with aberrant placental development, [...] Read more.

The suppressive regulator of cell fusion, suppressyn, is specifically expressed in the human placenta and is thought to play a crucial role in trophoblast fusion or syncytialization. Previous studies have suggested that alterations in its expression are associated with aberrant placental development, such as the immature placental morphology observed in Down syndrome, and may contribute to the pathogenesis of fetal growth restriction. While syncytialization in trophoblasts is an essential process for normal placental development, the precise molecular causes of its dysregulation remain poorly understood. In the present study, we aimed to elucidate the potential contribution of genomic variation to the loss of suppressyn function, extending previous analyses of expression abnormalities in perinatal disorders. Through sequence analysis, (1) we identified six polymorphisms within the coding region of the suppressyn gene, and (2) discovered that certain deletions and specific amino acid substitutions result in a complete loss of suppressyn-mediated inhibition of cell fusion. Although these mutations have not yet been reported in disease-associated genomic databases, our findings suggest that comprehensive genomic studies of perinatal and other disorders may reveal pathogenic variants of suppressyn, thereby uncovering novel genetic contributions to placental dysfunction. It is also anticipated that these findings might direct the development of therapeutic strategies targeting loss-of-function mutations. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond 2025)

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17 pages, 1772 KB

Open AccessEditor’s ChoiceArticle

Exploration of the Possible Relationships Between Gut and Hypothalamic Inflammation and Allopregnanolone: Preclinical Findings in a Post-Finasteride Rat Model

by Silvia Diviccaro, Roberto Oleari, Federica Amoruso, Fabrizio Fontana, Lucia Cioffi, Gabriela Chrostek, Vera Abenante, Jacopo Troisi, Anna Cariboni, Silvia Giatti and Roberto Cosimo Melcangi

Biomolecules 2025, 15(7), 1044; https://doi.org/10.3390/biom15071044 - 18 Jul 2025

Cited by 2 | Viewed by 6731

Abstract

Background: Finasteride, a 5α-reductase inhibitor commonly prescribed for androgenetic alopecia, has been linked to persistent adverse effects after discontinuation, known as post-finasteride syndrome (PFS). Symptoms include neurological, psychiatric, sexual, and gastrointestinal disturbances. Emerging evidence suggests that PFS may involve disruption of sex steroid [...] Read more.

Background: Finasteride, a 5α-reductase inhibitor commonly prescribed for androgenetic alopecia, has been linked to persistent adverse effects after discontinuation, known as post-finasteride syndrome (PFS). Symptoms include neurological, psychiatric, sexual, and gastrointestinal disturbances. Emerging evidence suggests that PFS may involve disruption of sex steroid homeostasis, neuroactive steroid deficiency (notably allopregnanolone, ALLO), and gut–brain axis alterations. Objective: This study aimed to investigate the effects of finasteride withdrawal (FW) in a rat model and evaluate the potential protective effects of ALLO on gut and hypothalamic inflammation. Methods: Adult male Sprague Dawley rats were treated with finasteride for 20 days, followed by one month of drug withdrawal. A subgroup received ALLO treatment during the withdrawal. Histological, molecular, and biochemical analyses were performed on the colon and hypothalamus. Gut microbiota-derived metabolites and markers of neuroinflammation and blood–brain barrier (BBB) integrity were also assessed. Results: At FW, rats exhibited significant colonic inflammation, including a 4.3-fold increase in Mφ1 levels (p < 0.001), a 2.31-fold decrease in butyrate concentration (p < 0.01), and elevated hypothalamic GFAP and Iba-1 protein expression (+360%, p < 0.01 and +100%, p < 0.01, respectively). ALLO treatment rescued these parameters in both the colon and hypothalamus but only partially restored mucosal and BBB structural integrity, as well as the NF-κB/PPARγ pathway. Conclusions: This preclinical study shows that FW causes inflammation in both the gut and hypothalamus in rats. ALLO treatment helped reduce several of these effects. These results suggest ALLO could have a protective role and have potential as a treatment for PFS patients. Full article

(This article belongs to the Section Molecular Medicine)

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28 pages, 1119 KB

Open AccessEditor’s ChoiceReview

β-Catenin: A Key Molecule in Osteoblast Differentiation

by Edyta Wróbel, Piotr Wojdasiewicz, Agnieszka Mikulska and Dariusz Szukiewicz

Biomolecules 2025, 15(7), 1043; https://doi.org/10.3390/biom15071043 - 18 Jul 2025

Cited by 11 | Viewed by 3986

Abstract

β-catenin is a key regulator of osteoblast differentiation, proliferation, and bone homeostasis. Through its interaction with transcription factors such as TCF/LEF, Runx2, and Osx, it coordinates gene expression essential for osteogenesis. The aim of this review is to demonstrate how β-catenin signaling is [...] Read more.

β-catenin is a key regulator of osteoblast differentiation, proliferation, and bone homeostasis. Through its interaction with transcription factors such as TCF/LEF, Runx2, and Osx, it coordinates gene expression essential for osteogenesis. The aim of this review is to demonstrate how β-catenin signaling is modulated by various physiological and pathological factors, including mechanical loading, oxidative stress, HIV-1 gp120, fluoride, implant topography, and microRNAs. These factors influence Wnt/β-catenin signaling through different mechanisms, often exerting opposing effects on osteoblast function. By integrating these modulators, we provide a comprehensive view of the dynamic regulation of β-catenin in bone biology. Understanding this complexity may provide insight into novel therapeutic strategies targeting β-catenin in bone regeneration, metabolic bone diseases, and pathologies such as HIV-associated bone loss or osteosarcoma. Full article

(This article belongs to the Section Molecular Biology)

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18 pages, 7149 KB

Open AccessEditor’s ChoiceArticle

Co-Inhibition of PARP and STAT3 as a Promising Approach for Triple-Negative Breast Cancer

by Changyou Shi, Li Pan, Satomi Amano, Mei-Yi Wu, Chenglong Li and Jiayuh Lin

Biomolecules 2025, 15(7), 1035; https://doi.org/10.3390/biom15071035 - 17 Jul 2025

Cited by 2 | Viewed by 1812

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk [...] Read more.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk early-stage settings. However, acquired resistance to PARP inhibitors and their limited applicability in non-BRCA TNBCs are now two major growing clinical problems. Activation of the IL-6/STAT3 signaling cascade has been implicated in therapeutic resistance. In this study, we evaluated the combined effects of the PARP inhibitor olaparib and the STAT3 inhibitor LLL12B in human TNBC cell lines with both BRCA mutations and wild-type BRCA status. Our results demonstrate that the PARP inhibitor olaparib can induce increased interleukin-6 (IL-6) in TNBC cells, with ELISA showing a 2- to 39-fold increase across five cell lines. MTT assays revealed that knocking down or inhibiting STAT3, a key downstream effector of the IL-6/GP130 pathway, sensitizes TNBC cells to olaparib. Treatment with either olaparib or LLL12B alone reduced TNBC cell viability, migration, and invasion. Notably, their combined administration produced a markedly enhanced inhibitory effect compared to individual treatments, regardless of BRCA mutation status. These findings highlight the potential of dual PARP and STAT3 inhibition as a novel targeted therapeutic strategy for both BRCA-mutant and BRCA-proficient TNBC. Full article

(This article belongs to the Special Issue PARPs in Cell Death and PARP Inhibitors in Cancers: 2nd Edition)

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27 pages, 7011 KB

Open AccessEditor’s ChoiceReview

Conceptus Elongation, Implantation, and Early Placental Development in Species with Central Implantation: Pigs, Sheep, and Cows

by Gregory A. Johnson, Thainá Minela, Heewon Seo, Fuller W. Bazer, Robert C. Burghardt, Guoyao Wu, Ky G. Pohler, Claire Stenhouse, Joe W. Cain, Zachary K. Seekford and Dallas R. Soffa

Biomolecules 2025, 15(7), 1037; https://doi.org/10.3390/biom15071037 - 17 Jul 2025

Cited by 6 | Viewed by 3833

Abstract

Species have different strategies for implantation and placentation. Much can be learned about general molecular and cellular biology through the examination and comparison of these differences. To varying degrees, implantation in all species includes alterations in epithelial polarity, the transformation of the endometrial [...] Read more.

Species have different strategies for implantation and placentation. Much can be learned about general molecular and cellular biology through the examination and comparison of these differences. To varying degrees, implantation in all species includes alterations in epithelial polarity, the transformation of the endometrial stroma, the differentiation of the trophoblast, cell-to-cell and tissue-to-tissue signaling through hormones, cytokines, and extracellular vesicles, and the alteration of the maternal immune system. This review focuses on implantation in pigs, sheep, and cows. These species share with mice/rats and humans/primates the key events of early embryonic development, pregnancy recognition, and the establishment of functional placentation. However, there are differences between the pregnancies of livestock and other species that make livestock unique biomedical models for the study of pregnancy and cell biology in general. Pig, sheep, and cow conceptuses (embryo/fetus and associated placental membranes) elongate prior to implantation, displaying central implantation, extended periods of conceptus attachment to the uterus, and epitheliochorial (pigs) and synepitheliochorial (sheep and cows) placentation. This review will discuss what is understood about how the trophoblast and extraembryonic endoderm of pig, sheep, and cow conceptuses elongate, and how a major goal of current in vitro models is to achieve conceptus elongation. It will then examine the adhesion cascade for conceptus implantation that initiates early placental development in pigs, sheep, and cows. Finally, it will conclude with a brief overview of early placental development in pigs, sheep, and cows, with a listing of some important “omics” studies that have been published. Full article

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

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30 pages, 1106 KB

Open AccessEditor’s ChoiceReview

Transcription-Coupled Nucleotide Excision Repair: A Faster Solution or the Only Option?

by Andriy Khobta and Leen Sarmini

Biomolecules 2025, 15(7), 1026; https://doi.org/10.3390/biom15071026 - 16 Jul 2025

Cited by 6 | Viewed by 3145

Abstract

A branch of the nucleotide excision repair (NER) pathway, transcription-coupled repair (TCR or TC-NER) specifically operates on the template DNA strand of actively transcribed genes. Initiated by stalling of elongating RNA polymerase complexes at damaged sites, TC-NER has historically been viewed as “accelerated [...] Read more.

A branch of the nucleotide excision repair (NER) pathway, transcription-coupled repair (TCR or TC-NER) specifically operates on the template DNA strand of actively transcribed genes. Initiated by stalling of elongating RNA polymerase complexes at damaged sites, TC-NER has historically been viewed as “accelerated repair”, arguably necessary for the maintenance of vital transcription function. Conversely, the conventional “global genome” (GG-NER) mechanism, operating throughout the genome, is usually regarded as a much slower process, even though it has long been found that differences in repair kinetics between transcribed DNA and the rest of the genome are not manifested for all structural types of DNA damage. Considering that damage detection is the rate-limiting step of overall repair reactions in most cases and that the mechanisms of the initial recognition of modified DNA structure are fundamentally different between TC-NER and GG-NER, it is suggestive to attribute the observed kinetic differences to different damage spectra recognized by the two pathways. This review summarizes current knowledge on the differential requirements of TC-NER and GG-NER towards specific damage types, based on their structural rather than spatial characteristics, and highlights some common features of DNA modifications repaired preferentially or exclusively by TC-NER, while evading other repair mechanisms. Full article

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

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53 pages, 2310 KB

Open AccessEditor’s ChoiceReview

Metabolic Reprogramming in Respiratory Viral Infections: A Focus on SARS-CoV-2, Influenza, and Respiratory Syncytial Virus

by Jordi Camps, Simona Iftimie, Andrea Jiménez-Franco, Antoni Castro and Jorge Joven

Biomolecules 2025, 15(7), 1027; https://doi.org/10.3390/biom15071027 - 16 Jul 2025

Cited by 8 | Viewed by 5295

Abstract

Respiratory infections caused by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus pose significant global health challenges, leading to high morbidity and mortality, particularly in vulnerable populations. Despite their distinct virological characteristics, these viruses exploit host cellular metabolism to [...] Read more.

Respiratory infections caused by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus pose significant global health challenges, leading to high morbidity and mortality, particularly in vulnerable populations. Despite their distinct virological characteristics, these viruses exploit host cellular metabolism to support replication, modulate immune responses, and promote disease progression. Emerging evidence shows that they induce metabolic reprogramming, shifting cellular energy production toward glycolysis to meet the bioenergetic demands of viral replication. Additionally, alterations in lipid metabolism, including enhanced fatty acid synthesis and disrupted cholesterol homeostasis, facilitate viral entry, replication, and immune evasion. The dysregulation of mitochondrial function and oxidative stress pathways also contributes to disease severity and long-term complications, such as persistent inflammation and immune exhaustion. Understanding these metabolic shifts is crucial for identifying new therapeutic targets and novel biomarkers for early disease detection, prognosis, and patient stratification. This review provides an overview of the metabolic alterations induced by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus, highlighting shared and virus-specific mechanisms and potential therapeutic interventions. Full article

(This article belongs to the Special Issue Metabolic Pathways, COVID-19 and Other Viral Acute Respiratory Infections: Mechanisms and Clinical Implications: 2nd Edition)

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21 pages, 3177 KB

Open AccessEditor’s ChoiceReview

Galectin-3: Integrator of Signaling via Hexosamine Flux

by Mana Mohan Mukherjee, Devin Biesbrock and John Allan Hanover

Biomolecules 2025, 15(7), 1028; https://doi.org/10.3390/biom15071028 - 16 Jul 2025

Cited by 6 | Viewed by 2591

Abstract

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a prognostic indicator for multiple clinically important disorders, including cardiovascular disease. Gal-3 binds to cell surface glycans to form lattices that modulate [...] Read more.

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a prognostic indicator for multiple clinically important disorders, including cardiovascular disease. Gal-3 binds to cell surface glycans to form lattices that modulate surface receptor signaling and internalization. However, the tissue-specific regulation of Gal-3 surface expression remains poorly understood. Here, we review evidence for the involvement of Gal-3 in cell surface signaling, intranuclear events, and intracellular trafficking. Our focus will be on the O-GlcNAc modification as a regulator of Gal-3 biosynthesis, non-canonical secretion, and recycling. We argue that the nutrient-driven cytoplasmic hexosamine biosynthetic pathway (HBP) and endomembrane transport mechanisms generate unique pools of nucleotide sugars. The differing levels of nucleotide sugars in the cytosol, endoplasmic reticulum (ER), and Golgi apparatus generate differential thresholds for the responsiveness of O-GlcNAc cycling, N- and O-linked glycan synthesis/branching, and glycolipid synthesis. By regulating Gal-3 synthesis and non-canonical secretion, O-GlcNAc cycling may serve as a nexus constraining Gal-3 cell surface expression and lattice formation. This homeostatic feedback mechanism would be critical under conditions where extensive glycan synthesis and branching in the endomembrane system and on the cell surface are maintained by elevated hexosamine synthesis. Thus, O-GlcNAc cycling and Gal-3 synergize to regulate Gal-3 secretion and influence cellular signaling. In humans, Gal-3 serves as an early-stage prognostic indicator for heart disease, kidney disease, viral infection, autoimmune disease, and neurodegenerative disorders. Since O-GlcNAc cycling has also been linked to these pathologic states, exploring the interconnections between O-GlcNAc cycling and Gal-3 expression and synthesis is likely to emerge as an exciting area of research. Full article

(This article belongs to the Special Issue Cell Biology and Biomedical Application of Galectins)

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19 pages, 1237 KB

Open AccessEditor’s ChoiceReview

Circadian Biomarkers in Humans: Methodological Insights into the Detection of Melatonin and Cortisol

by Cene Skubic, Urša Zevnik, Katarina Nahtigal, Leja Dolenc Grošelj and Damjana Rozman

Biomolecules 2025, 15(7), 1006; https://doi.org/10.3390/biom15071006 - 14 Jul 2025

Cited by 12 | Viewed by 8772

Abstract

Circadian rhythms are intrinsic, with roughly 24 h oscillations that coordinate many physiological functions and are increasingly recognized as key determinants of human health. When these rhythms become misaligned, there is an increased risk for neurodegenerative and psychiatric disorders, metabolic syndrome, sleep disturbances, [...] Read more.

Circadian rhythms are intrinsic, with roughly 24 h oscillations that coordinate many physiological functions and are increasingly recognized as key determinants of human health. When these rhythms become misaligned, there is an increased risk for neurodegenerative and psychiatric disorders, metabolic syndrome, sleep disturbances, and even certain cancers. The hormones, melatonin that rises in the evening and cortisol that peaks shortly after awakening, represent crucial biochemical markers of the circadian phase. This review systematically evaluates contemporary techniques for quantifying melatonin and cortisol, comparing biological matrices (blood, saliva, urine) alongside analytical platforms. Special focus is placed on two clinically informative markers: Dim Light Melatonin Onset (DLMO) and the Cortisol Awakening Response (CAR). We compared immunoassays with liquid chromatography tandem mass spectrometry (LC MS/MS), highlighting differences in sensitivity, specificity, and laboratory feasibility. Potential confounders, including ambient light, body posture, and exact sampling times—are discussed in detail, to show the capacity of providing the most reliable results. By emphasizing the need for standardized protocols and controlled sampling conditions, this review provides essential guidance for researchers and clinicians aiming to assess the circadian biomarkers melatonin and cortisol with precision since they can be used in clinical practice as diagnostic and prognostic tools for assessing numerous pathologies. Full article

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

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28 pages, 1513 KB

Open AccessEditor’s ChoiceReview

The Impact of the Microbiota on the Immune Response Modulation in Colorectal Cancer

by Ana Iulia Neagu, Marinela Bostan, Vlad Alexandru Ionescu, Gina Gheorghe, Camelia Mia Hotnog, Viviana Roman, Mirela Mihaila, Simona Isabelle Stoica, Camelia Cristina Diaconu, Carmen Cristina Diaconu, Simona Maria Ruta and Coralia Bleotu

Biomolecules 2025, 15(7), 1005; https://doi.org/10.3390/biom15071005 - 14 Jul 2025

Cited by 6 | Viewed by 3695

Abstract

Colorectal cancer (CRC) is a multifactorial disease increasingly recognized for its complex interplay with the gut microbiota. The disruption of microbial homeostasis—dysbiosis—has profound implications for intestinal barrier integrity and host immune function. Pathogenic bacterial species such as Fusobacterium nucleatum, Escherichia coli harboring polyketide [...] Read more.

Colorectal cancer (CRC) is a multifactorial disease increasingly recognized for its complex interplay with the gut microbiota. The disruption of microbial homeostasis—dysbiosis—has profound implications for intestinal barrier integrity and host immune function. Pathogenic bacterial species such as Fusobacterium nucleatum, Escherichia coli harboring polyketide synthase (pks) island, and enterotoxigenic Bacteroides fragilis are implicated in CRC through mechanisms involving mucosal inflammation, epithelial barrier disruption, and immune evasion. These pathogens promote pro-tumorigenic inflammation, enhance DNA damage, and suppress effective anti-tumor immunity. Conversely, commensal and probiotic bacteria, notably Lactobacillus and Bifidobacterium species, exert protective effects by preserving epithelial barrier function and priming host immune responses. These beneficial microbes can promote the maturation of dendritic cells, stimulate CD8⁺ T cell cytotoxicity, and modulate regulatory T cell populations, thereby enhancing anti-tumor immunity. The dichotomous role of the microbiota underscores its potential as both a biomarker and a therapeutic target in CRC. Recent advances in studies have explored microbiota-modulating strategies—ranging from dietary interventions and prebiotics to fecal microbiota transplantation (FMT) and microbial consortia—as adjuncts to conventional therapies. Moreover, the composition of the gut microbiome has been shown to influence the responses to immunotherapy and chemotherapy, raising the possibility of microbiome-informed precision oncology therapy. This review synthesizes the current findings on the pathogenic and protective roles of bacteria in CRC and evaluates the translational potential of microbiome-based interventions in shaping future therapeutic paradigms. Full article

(This article belongs to the Special Issue Colorectal and Gastric Cancers: Molecular Mechanisms and Potential Biomarkers)

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30 pages, 2678 KB

Open AccessEditor’s ChoiceReview

Therapeutic Plasma Exchange: Current and Emerging Applications to Mitigate Cellular Signaling in Disease

by R. M. Imtiaz Karim Rony, Alireza Shokrani, Naseeb Kaur Malhi, Deborah Hussey, Rachael Mooney, Zhen Bouman Chen, Tristan Scott, Haiyong Han, Jaeger Moore, Jiahui Liu, Wendong Huang, Adolfo Garcia-Ocaña, Maria B. Grant, Karen Aboody, Daniel Von Hoff, Rama Natarajan and Joshua D. Tompkins

Biomolecules 2025, 15(7), 1000; https://doi.org/10.3390/biom15071000 - 12 Jul 2025

Cited by 6 | Viewed by 11350

Abstract

Therapeutic plasma exchange (TPE) is a blood purification technique which functions to remove pathological plasma constituents such as autoantibodies, inflammatory cytokines, immune complexes, and extracellular vesicles (EVs) that contribute to a range of disease states. In this review, we examine current and emerging [...] Read more.

Therapeutic plasma exchange (TPE) is a blood purification technique which functions to remove pathological plasma constituents such as autoantibodies, inflammatory cytokines, immune complexes, and extracellular vesicles (EVs) that contribute to a range of disease states. In this review, we examine current and emerging indications for TPE across cardiovascular, metabolic, neurological, inflammatory, and oncological diseases. We cover emerging preclinical animal models and new applications, emphasizing the roles of cellular signaling and EV biology in mediating plasma functions, and discuss unique therapeutic “windows of opportunity” offered by TPE. We conclude that TPE is underutilized in both preventative and precision medicine, and that next generation TPE therapies will involve personalized plasma biomarker and modulation feedback, with synergistic plasma infusion therapies to mitigate age associated disease and promote tissue rejuvenation. Full article

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

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