Biomolecules

26 pages, 9830 KiB

Open AccessArticle

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

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

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

Viewed by 534

Abstract

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

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

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

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21 pages, 703 KiB

Open AccessReview

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

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

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

Viewed by 816

Abstract

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

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

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

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22 pages, 3123 KiB

Open AccessArticle

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

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

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

Viewed by 787

Abstract

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

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

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

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17 pages, 1115 KiB

Open AccessArticle

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

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

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

Viewed by 776

Abstract

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

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

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

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17 pages, 2157 KiB

Open AccessArticle

Modulation of Kv Channel Gating by Light-Controlled Membrane Thickness

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

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

Viewed by 552

Abstract

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

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

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

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15 pages, 1975 KiB

Open AccessArticle

Cathepsin B Levels Correlate with the Severity of Canine Myositis

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

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

Viewed by 493

Abstract

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

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

(This article belongs to the Section Biological Factors)

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31 pages, 14267 KiB

Open AccessArticle

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

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

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

Viewed by 917

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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19 pages, 2946 KiB

Open AccessArticle

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

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

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

Cited by 1 | Viewed by 474

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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22 pages, 3623 KiB

Open AccessArticle

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

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

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

Viewed by 589

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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19 pages, 809 KiB

Open AccessArticle

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

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

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

Viewed by 810

Abstract

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

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

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

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15 pages, 1833 KiB

Open AccessArticle

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

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

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

Viewed by 486

Abstract

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

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

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

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27 pages, 1697 KiB

Open AccessReview

Multimodal Function of Mesenchymal Stem Cells in Psoriasis Treatment

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

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

Viewed by 748

Abstract

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

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

(This article belongs to the Section Cellular Biochemistry)

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18 pages, 1521 KiB

Open AccessArticle

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

by Xinyu Zhu and Xu Liu

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

Viewed by 466

Abstract

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

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

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

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11 pages, 1386 KiB

Open AccessArticle

An Exogenous NO Donor Provokes Mechanical Alternans in Normal Rat Atria and Impairs Sarcomere Contractility in Right Atrial Cardiomyocytes in Atrial Fibrillation

by Xenia Butova, Tatiana Myachina, Polina Mikhryakova, Raisa Simonova, Daniil Shchepkin and Anastasia Khokhlova

Biomolecules 2025, 15(5), 735; https://doi.org/10.3390/biom15050735 - 17 May 2025

Viewed by 338

Abstract

Atrial fibrillation (AF) is the most common arrhythmia worldwide. AF is associated with a deficiency in nitric oxide (NO) production, which contributes to disturbances in the electrical and mechanical function of the atrial myocardium. NO donors are considered promising for the treatment and [...] Read more.

Atrial fibrillation (AF) is the most common arrhythmia worldwide. AF is associated with a deficiency in nitric oxide (NO) production, which contributes to disturbances in the electrical and mechanical function of the atrial myocardium. NO donors are considered promising for the treatment and prevention of AF, but their effects on atrial contractility are unclear. This study examines the direct impact of a low-molecular-weight NO donor, spermine-NONOate (NOC-22), on the contractile function of atrial cardiomyocytes in paroxysmal AF. To study whether an NO donor-induced increase in NO level causes chamber-specific changes in atrial contractility, we measured sarcomere length (SL) dynamics in contracting single cardiomyocytes from the rat left and right atria (LA, RA) using a 7-day acetylcholine-CaCl₂-induced AF model. We showed that in control rats NOC-22 provoked alternans of sarcomere shortening in both LA and RA cardiomyocytes. In AF, NOC-22 decreased the sarcomere-shortening amplitudes and velocities of sarcomere shortening–relengthening and increased the magnitude of sarcomere-shortening alternans only in RA cardiomyocytes. The negative effects of NO donors on RA contractility warrant careful consideration of their use in AF treatment. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 3018 KiB

Open AccessArticle

Uncovering a Novel Role of ROR1 in the Epigenetic Regulation of Tumor Suppressor Gene CREB3L1 in Triple-Negative Breast Cancer Cells

by Victoria L. Reed, Eric Lalu, Leena Yoon, Norman Fultang and Bela Peethambaran

Biomolecules 2025, 15(5), 734; https://doi.org/10.3390/biom15050734 - 16 May 2025

Viewed by 495

Abstract

A characteristic of triple-negative breast cancer (TNBC) is the epigenetic regulation of tumor suppressor genes, leading to TNBC heterogeneity and treatment resistance in patients. TNBC exhibits high methylation rates, leading to the silencing of numerous tumor suppressor genes. DNA methyltransferase inhibitors (DNMTis) have [...] Read more.

A characteristic of triple-negative breast cancer (TNBC) is the epigenetic regulation of tumor suppressor genes, leading to TNBC heterogeneity and treatment resistance in patients. TNBC exhibits high methylation rates, leading to the silencing of numerous tumor suppressor genes. DNA methyltransferase inhibitors (DNMTis) have shown limited clinical efficacy in TNBC treatment. This study aims to uncover a target that could be used to reverse the epigenetic silencing of tumor suppressor genes in TNBC. The Western blot analysis demonstrated that ROR1 knockdown, an oncofetal gene, reduced DNMT3A and DNMT3B protein expression in the TNBC cell lines MDA-MB-231 and HCC1806, as well as a non-malignant breast cell line, MCF10A. The reduced representation bisulfite sequencing (RRBS) analysis identified differential methylation of CREB3L1 when ROR1 is knocked down in TNBC cell lines. CREB3L1 is a transcription factor that plays tumor-suppressive roles in TNBC and is commonly epigenetically silenced in patients. This study shows that ROR1 requires pSTAT3 activation to upregulate DNMT3A and DNMT3B expression to induce CREB3L1 epigenetic silencing in TNBC. ROR1 knockdown resulted in the re-expression of CREB3L1 in TNBC cells. The data provide evidence that ROR1 inhibition, in combination with DNMTis, could enhance patient outcomes as a therapeutic approach for TNBC. Full article

(This article belongs to the Special Issue Tumour Suppressor Genes: The Guardians of Cell Integrity)

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8 pages, 1487 KiB

Open AccessCommentary

Ossification in Normal and Pathological Contexts: The Key Role of Static Osteogenesis vs. Dynamic Osteogenesis in the Etiopathology of Some Skeletal Alterations

by Carla Palumbo, Francesca Paganelli and Marzia Ferretti

Biomolecules 2025, 15(5), 733; https://doi.org/10.3390/biom15050733 - 16 May 2025

Viewed by 338

Abstract

This Commentary is intended to start a discussion in the field of calcification/ossification related to osteogenesis. It highlights that two types of bone formation, static osteogenesis (SO) and dynamic osteogenesis (DO), are temporally followed by each other in bone histogenesis and bone lesion [...] Read more.

This Commentary is intended to start a discussion in the field of calcification/ossification related to osteogenesis. It highlights that two types of bone formation, static osteogenesis (SO) and dynamic osteogenesis (DO), are temporally followed by each other in bone histogenesis and bone lesion repair. Moreover, they also represent the common denominator in the pathological processes of both calcification and peculiar ossifications, such as heterotopic ossification and the formation of supernumerary skeletal segments. The final objective is to propose a different interpretation of certain bone alterations/pathologies, attributable to the two peculiar osteogenesis patterns (SO and DO), occurring in both physiological and pathological conditions. From these reflections, new approaches in the definition of diagnosis and therapies of certain alterations could be derived. Full article

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

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23 pages, 3352 KiB

Open AccessArticle

Neurologic Deficit Score at 4–5 Days Post-eCPR Predicts Long-Term Brain Dysfunction in Rats Following Cardiac Arrest

by Wolfgang Weihs, Alexandra-Maria Stommel, Andrea Müllebner, Alexander Franz Szinovatz, Matthias Müller, Ingrid Magnet, Michael Holzer, Andrey V. Kozlov, Sandra Högler and J. Catharina Duvigneau

Biomolecules 2025, 15(5), 732; https://doi.org/10.3390/biom15050732 - 16 May 2025

Viewed by 779

Abstract

Cardiac arrest (CA) survivors often develop long-term neurological deficits, but its long-term impact on vulnerable brain regions and neurological outcomes remains unclear. In a previous CA model with conventional cardiopulmonary resuscitation, we found reduced heme oxygenase (HO) activity in the hippocampus and cortex [...] Read more.

Cardiac arrest (CA) survivors often develop long-term neurological deficits, but its long-term impact on vulnerable brain regions and neurological outcomes remains unclear. In a previous CA model with conventional cardiopulmonary resuscitation, we found reduced heme oxygenase (HO) activity in the hippocampus and cortex 14 days post-CA, suggesting its potential as a functional outcome marker. Here, we used a rat model with 6 or 8 min of CA followed by extracorporeal cardiopulmonary resuscitation. While in the 6 min-CA group, 67% survived to day 14, increased mortality within 4 days resulted in only 33% survival in the 8 min group post-ROSC. All animals displayed neurological impairment assessed by daily neurologic deficit scoring (NDS). While deficits declined within the first 3–4 days in the 6 min-CA animals, the 8 min-CA group showed significantly worse neurological outcomes until day 14. Two weeks post-CA, neuroinflammatory and neurodegenerative markers (HO-1, TNF-R1, Iba1, and GFAP) were elevated in the hippocampus, while HO and 2-oxoglutarate dehydrogenase complex activities were reduced in all rats, indicating a decrease in anti-oxidative capacity and mitochondrial capacity for metabolizing glutamate. NDS at day 4–5 strongly correlated with the delayed CA-mediated enzymatic dysfunction determined in the hippocampus. This finding highlights this time point for identifying at-risk individuals and suggests a prolonged therapeutic intervention lasting at least until 4 days post-CA. Full article

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

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39 pages, 9047 KiB

Open AccessArticle

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

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

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

Viewed by 636

Abstract

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

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

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

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18 pages, 2856 KiB

Open AccessArticle

The Influence of Topiramate on Morphine Dependence in Mice

by Adrian Pysiewicz, Antonina Mazur, Jolanta Kotlińska, Irena Baranowska-Bosiacka, Krzysztof Fronc, Małgorzata Łupina, Marta Kruk-Słomka and Joanna Listos

Biomolecules 2025, 15(5), 730; https://doi.org/10.3390/biom15050730 - 16 May 2025

Viewed by 534

Abstract

Topiramate evokes pharmacological activity via a blockade of voltage-dependent sodium channels, reduction in glutamate release, inhibition of AMPA receptors and kainate receptors, and potentiation of GABAergic neurotransmission. Therefore, it is used not only as an antiseizure drug but is also effective in migraine [...] Read more.

Topiramate evokes pharmacological activity via a blockade of voltage-dependent sodium channels, reduction in glutamate release, inhibition of AMPA receptors and kainate receptors, and potentiation of GABAergic neurotransmission. Therefore, it is used not only as an antiseizure drug but is also effective in migraine prophylaxis, cluster headaches, neuropathic pain, and alcohol dependence. The aim of this study was to investigate the effect of topiramate in morphine dependence in mice, particularly in terms of morphine tolerance, morphine withdrawal signs, and morphine sensitization. In these experiments, topiramate was administered both acutely and chronically. Topiramate significantly reduced the morphine tolerance in the hot-plate test and attenuated naloxone-induced morphine withdrawal signs. Its effect on morphine sensitization to the locomotor activity of mice was poor. The obtained results showed that topiramate might be an effective drug for reducing the physical symptoms of morphine dependence. Full article

(This article belongs to the Special Issue Glutamate and Glutamate Receptors in Health and Diseases, Second Edition)

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15 pages, 531 KiB

Open AccessReview

The Role of Substance P in Corneal Homeostasis

by Irmina Jastrzębska-Miazga, Bartosz Machna, Dorota Wyględowska-Promieńska and Adrian Smędowski

Biomolecules 2025, 15(5), 729; https://doi.org/10.3390/biom15050729 - 16 May 2025

Viewed by 623

Abstract

The cornea, a highly innervated and avascular ocular tissue, relies on intricate neuro-immune interactions to maintain homeostasis. Among key neuromediators, substance P (SP)—a neuropeptide belonging to the tachykinin family—plays a dual role in corneal physiology and pathology. This review synthesizes current knowledge on [...] Read more.

The cornea, a highly innervated and avascular ocular tissue, relies on intricate neuro-immune interactions to maintain homeostasis. Among key neuromediators, substance P (SP)—a neuropeptide belonging to the tachykinin family—plays a dual role in corneal physiology and pathology. This review synthesizes current knowledge on SP’s involvement in corneal innervation, epithelial homeostasis, immune regulation, neovascularization, and wound healing, while highlighting its dichotomous effects in both promoting tissue repair and exacerbating inflammation. SP, primarily signaling through the neurokinin-1 receptor (NK1R), influences corneal epithelial proliferation, barrier function, and wound healing by modulating cytokines, chemokines, and growth factors. However, its overexpression is linked to pain sensitization, inflammatory keratitis, and corneal neovascularization, driven by interactions with immune cells (e.g., mast cells, neutrophils) and pro-angiogenic factors (e.g., VEGF). Clinical studies demonstrate altered SP levels in dry eye disease, neurotrophic keratitis, and post-refractive surgery, correlating with nerve damage and ocular surface dysfunction. Emerging therapies targeting SP pathways- such as NK1R antagonists (e.g., fosaprepitant) and SP-IGF-1 combinations-show promise for treating neurotrophic ulcers but face challenges due to SP’s context-dependent actions. Future research should clarify the roles of NK2R/NK3R receptors and optimize SP-based interventions to balance its reparative and inflammatory effects. Understanding SP’s multifaceted mechanisms could advance the development of therapies for corneal diseases, particularly those involving sensory neuropathy and immune dysregulation. Full article

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

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22 pages, 5584 KiB

Open AccessArticle

Recovery of Lysosomal Acidification and Autophagy Flux by Attapulgite Nanorods: Therapeutic Potential for Lysosomal Disorders

by Yuanjing Hao, Xinru Fan, Xiaodan Huang, Zhaoying Li, Zhiyuan Jing, Guilong Zhang, Yuxue Xu, Na Zhang and Pengfei Wei

Biomolecules 2025, 15(5), 728; https://doi.org/10.3390/biom15050728 - 16 May 2025

Viewed by 572

Abstract

Dysfunction of the lysosome and autophagy–lysosome pathway is closely associated with various diseases, such as neurodegenerative diseases, non-alcoholic fatty liver disease (NAFLD), etc. Additionally, chloroquine is a clinically widely used drug for treating malaria and autoimmune diseases, but long-term or high-dose administration may [...] Read more.

Dysfunction of the lysosome and autophagy–lysosome pathway is closely associated with various diseases, such as neurodegenerative diseases, non-alcoholic fatty liver disease (NAFLD), etc. Additionally, chloroquine is a clinically widely used drug for treating malaria and autoimmune diseases, but long-term or high-dose administration may lead to significant toxic side effects. Attapulgite (ATT), a natural nanomaterial with excellent adsorption capacity and biocompatibility, herein demonstrated a novel biological function in regulating the lysosomal and autophagy–lysosome pathway. ATT could be effectively internalized into lysosome-related acidic compartments. Further study revealed that ATT could restore lysosomal pH, activate cathepsin D, alleviate autophagy blockage in chloroquine-treated cells, and reduce chloroquine-elicited cell death. In a cell model related to Huntington’s disease, treatment with ATT reinforced the degradation of the mutant huntingtin proteins by increasing cathepsin D maturation and autophagy flux. ATT could also promote lipid droplet clearance in hepatocytes with palmitic acid-induced steatosis, reduce hepatic lipid accumulation, and improve fasting blood glucose in high-fat-diet-induced NAFLD mice. These findings establish ATT as a lysosomal modulator, providing a foundation for its therapeutic potential in mitigating the adverse effects associated with long-term chloroquine use, especially improving neurodegenerative and metabolic disorders. Full article

(This article belongs to the Special Issue Nanomaterials and Their Applications in Biomedicine)

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21 pages, 5182 KiB

Open AccessArticle

Tropomodulin–Tropomyosin Interplay Modulates Interaction Between Cardiac Myosin and Thin Filaments

by Galina V. Kopylova, Anastasia M. Kochurova, Evgeniia A. Beldiia, Andrey V. Slushchev, Victoria V. Nefedova, Natalia S. Ryabkova, Ivan A. Katrukha, Daria S. Yampolskaya, Alexander M. Matyushenko and Daniil V. Shchepkin

Biomolecules 2025, 15(5), 727; https://doi.org/10.3390/biom15050727 - 16 May 2025

Viewed by 428

Abstract

Tropomodulin (Tmod) is an actin-binding protein that interacts with tropomyosin and the actin filament at the pointed end. The influence of Tmod on the thin filament activation in the myocardium is not clear. We studied the interactions of Tmod1 and Tmod4 with the [...] Read more.

Tropomodulin (Tmod) is an actin-binding protein that interacts with tropomyosin and the actin filament at the pointed end. The influence of Tmod on the thin filament activation in the myocardium is not clear. We studied the interactions of Tmod1 and Tmod4 with the cardiac tropomyosin isoforms Tpm1.1 and Tpm1.2 using size-exclusion chromatography, a pull-down assay, and cross-linking with glutaraldehyde. We found that Tmod1 and Tmod4 form complexes with both Tpm1.1 and Tpm1.2, indicating durable interactions between these proteins. The effects of both Tmods on the actin–myosin interaction were studied using an in vitro motility assay. Tmod did not affect the sliding velocity of bare F-actin. Tmod1 slightly dose-dependently decreased the sliding velocity of F-actin–Tpm1.1 filaments and had no effect on the velocity of F-actin–Tpm1.2 filaments. With ventricular myosin, Tmod1 reduced the calcium sensitivity of the sliding velocity of thin filaments containing Tpm1.1 but did not affect it with filaments containing Tpm1.2. With atrial myosin, Tmod1 decreased the calcium sensitivity of the sliding velocities of thin filaments containing both Tpm1.1 and Tpm1.2. We can conclude that Tmod takes part in the regulation of actin–myosin interactions in the myocardium through interactions with Tpm. The effect of Tmod on the activation of thin filaments depends on the protein isoforms. Full article

(This article belongs to the Section Cellular Biochemistry)

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16 pages, 2164 KiB

Open AccessArticle

The Hepatoprotective Properties of Gentiopicroside, Sweroside, and Swertiamarin Against Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

by Anthony O. Boateng, Vinood B. Patel and S. W. Annie Bligh

Biomolecules 2025, 15(5), 726; https://doi.org/10.3390/biom15050726 - 16 May 2025

Viewed by 730

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disease characterised by the accumulation of fat in the liver. It is estimated that 30–38% of the world’s adult population have MASLD, making it the most prevalent global chronic liver disease. Due to a [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disease characterised by the accumulation of fat in the liver. It is estimated that 30–38% of the world’s adult population have MASLD, making it the most prevalent global chronic liver disease. Due to a lack of a therapy for MASLD, treatment has been mainly focussed on managing the conditions associated with the disease such as obesity, diabetes mellitus, and hyperlipidaemia. This study aimed to investigate the role played by Gentiana phytochemicals including the following: gentiopicroside, sweroside, and swertiamarin, in promoting hepatocyte protection against the cytotoxic effects of fatty acids. Gentiana species such as lutea, macrophylla, rigescens, and scabra are known to protect and enhance hepatocyte viability via their antioxidant, anti-inflammatory, and bitter components including the following: amarogentin gentianine, iso-orientin, swertiamarin, gentiopicroside, and sweroside. In this study, HepG2 cells pre-treated with phytochemicals gentiopicroside, sweroside, swertiamarin, and silymarin followed by an exposure to arachidonic acid (10, 30, 50 and 80 µM) were assessed for cell viability via MTT, mitochondrial function via seahorse assay, ROS levels via DCF assay, and annexin V-FITC for apoptosis. THLE-2 cells were also assayed for validation. The phytochemicals tested improved ATP production notably gentiopicroside, which improved ATP production by over 60% compared to untreated hepatocytes. Significant hepatocyte protection against lipotoxicity leading to apoptosis was also observed in gentiopicroside in the presence of 30 µM arachidonic acid with apoptosis reduced by over 50%. ROS production was reduced up to 60% by the pre-treatment of HepG2 cells with 20 µM, gentiopicroside, sweroside, swertiamarin, and silymarin, with the highest reduction observed in swertiamarin. It was concluded that phytochemicals gentiopicroside, sweroside, and swertiamarin play key roles in the hepatocyte protection against the cytotoxic effects of fatty acids. This protection is conferred by enhancing mitochondrial function in terms of increasing the maximal respiratory capacity in response to a high influx of fatty acids, promoting ATP production as well as scavenging ROS produced as a result of high fatty acid influx and increased mitochondrial respiration. Highlights: Gentiopicroside may minimise lipotoxicity leading to apoptosis and necrosis in hepatocytes in the presence of arachidonic acid. A pre-treatment of hepatocytes with phytochemicals, namely gentiopicroside, sweroside, and silymarin provides a degree of protection which may be attributed to the enhancement of mitochondrial function. Sweroside, silymarin, and swertiamarin may protect HepG2 and THLE-2 cells by scavenging ROS produced by arachidonic acid and the mitochondrial electron transport chain. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease: From Molecular Mechanisms to Therapeutic Approaches)

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24 pages, 761 KiB

Open AccessReview

Unlocking the Potential of Bioactive Compounds in Pancreatic Cancer Therapy: A Promising Frontier

by Silvia Brugiapaglia, Ferdinando Spagnolo and Claudia Curcio

Biomolecules 2025, 15(5), 725; https://doi.org/10.3390/biom15050725 - 15 May 2025

Viewed by 816

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a highly challenging malignancy to treat, with a high mortality rate and limited therapeutic options. Despite advances in cancer research, the prognosis for patients diagnosed with PDA is often poor due to late-stage detection and resistance to conventional [...] Read more.

Pancreatic ductal adenocarcinoma (PDA) is a highly challenging malignancy to treat, with a high mortality rate and limited therapeutic options. Despite advances in cancer research, the prognosis for patients diagnosed with PDA is often poor due to late-stage detection and resistance to conventional therapies. Consequently, there is growing interest in the potential of bioactive compounds as alternative or adjuvant treatments, given their ability to target multiple aspects of cancer biology, offering a more holistic approach to treatment. In the context of PDA, certain bioactive compounds, such as polyphenols (found in fruits, vegetables, and tea), flavonoids, carotenoids and compounds in cruciferous vegetables, have shown potential in inhibiting cancer cell growth, reducing inflammation, and promoting cancer cell apoptosis. This review aims to elucidate the mechanisms, by which these bioactive compounds exert their effects, modulating the oxidative stress, influencing inflammatory pathways and regulating cell survival and death. It also highlights current clinical trials that are paving the way toward incorporating these natural agents into mainstream treatment strategies, with the goal of boosting the efficacy of conventional therapies for PDA. Full article

(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds for Therapeutic Applications)

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16 pages, 2496 KiB

Open AccessArticle

High Bendability of Short RNA-DNA Hybrid Duplex Revealed by Single-Molecule Cyclization and Molecular Dynamics Simulations

by Bin Wu, Fujia Tian, Yajun Yang, Liang Dai and Xinghua Zhang

Biomolecules 2025, 15(5), 724; https://doi.org/10.3390/biom15050724 - 15 May 2025

Viewed by 583

Abstract

R-loops are nucleic acid structures composed of an RNA-DNA hybrid (RDH) duplex and a displaced single-stranded DNA (ssDNA), which are fundamentally involved in key biological functions, including transcription and the preservation of genome stability. In an R-loop, the RDH duplex is bent by [...] Read more.

R-loops are nucleic acid structures composed of an RNA-DNA hybrid (RDH) duplex and a displaced single-stranded DNA (ssDNA), which are fundamentally involved in key biological functions, including transcription and the preservation of genome stability. In an R-loop, the RDH duplex is bent by the folded secondary structures of the displaced ssDNA. Previous experiments and simulations indicated the high bendability of DNA below the persistence length. However, the bendability of a short RDH duplex remains unclear. Here, we report that an RDH duplex exhibits higher bendability than a DNA duplex on the short length scale using single-molecule cyclization experiments. Our molecular dynamics simulations show that an RDH duplex has larger intrinsic curvature and structural fluctuations and more easily forms kinks than DNA, which promote the bending flexibility of RDH from unlooped structures. Interestingly, we found that an RDH duplex composed of a C-rich DNA strand and a G-rich RNA strand shows significantly higher bendability than that composed of a G-rich DNA strand and a C-rich RNA strand in the same CpG island promoter regions, which may contribute to the formation of an R-loop. These findings shape our understanding towards biological processes involving R-loops through the high and sequence-dependent bendability of an RDH duplex. Full article

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

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13 pages, 2564 KiB

Open AccessArticle

Viable Cryopreservation Strategy for Extending the Timeframe of Circulating Tumor Cell Detection in Breast Cancer Clinical Trials

by Cristina Sánchez-Quesada, Estefanía Toledo, José Juan Jiménez-Moleón and José Juan Gaforio

Biomolecules 2025, 15(5), 723; https://doi.org/10.3390/biom15050723 - 15 May 2025

Viewed by 423

Abstract

Circulating tumor cells (CTCs) hold recognized prognostic value in various cancers, including breast cancer, where their presence correlates with survival outcomes. However, the typical 24 h window for blood processing and CTC isolation poses a logistical challenge, particularly for multicenter studies. This study [...] Read more.

Circulating tumor cells (CTCs) hold recognized prognostic value in various cancers, including breast cancer, where their presence correlates with survival outcomes. However, the typical 24 h window for blood processing and CTC isolation poses a logistical challenge, particularly for multicenter studies. This study aimed to evaluate cryopreservation at different stages of CTC isolation and immunocytological detection to extend the blood sample processing period. Using spiked peripheral blood samples with MDA-MB-231, SKBR3, and MCF7 breast cancer cell lines, four distinct cryopreservation points were assessed: following Ficoll gradient separation, immunomagnetic separation, cytocentrifugation, and cytokeratin labeling. Our findings demonstrated that cryopreservation of the mononuclear and granulocytic cell fraction after double-density Ficoll gradient separation was the only viable method for subsequent CTC detection. This approach allowed for consistent recovery of CK+ CTCs, with an average recovery rate of over 81% after one year of cryopreservation. In contrast, cryopreservation at later stages resulted in undetectable CTCs or only cellular debris. In conclusion, cryopreservation following density gradient centrifugation is a feasible strategy for delaying CTC isolation and immunocytological analysis in breast cancer research, facilitating its application in multicenter clinical trials. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 15016 KiB

Open AccessArticle

Baicalin Alleviates Piglet Immunosuppression Induced by Glaesserella parasuis via Promoting CD163/Tumor Necrosis Factor-like Weak Inducer of Apoptosis-Mediated Autophagy

by Shulin Fu, Ronghui Luo, Jingyang Li, Yunjian Fu, Qiaoli Dong, Siyu Liu, Yamin Sun, Ling Guo, Jin Hu and Yinsheng Qiu

Biomolecules 2025, 15(5), 722; https://doi.org/10.3390/biom15050722 - 15 May 2025

Viewed by 483

Abstract

Glaesserella parasuis (G. parasuis) causes vascular inflammation in piglets, resulting in vascular damage. However, the mechanism causing vascular inflammation remains unclear. Baicalin possesses an anti-inflammatory function. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in immunosuppression. CD163, a [...] Read more.

Glaesserella parasuis (G. parasuis) causes vascular inflammation in piglets, resulting in vascular damage. However, the mechanism causing vascular inflammation remains unclear. Baicalin possesses an anti-inflammatory function. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in immunosuppression. CD163, a scavenger receptor expressed on macrophages that acts as a decoy receptor for TWEAK, plays a crucial role in the regulation of autophagy and inflammation. This research investigated the efficacy of baicalin in reducing immunosuppression elicited by G. parasuis through the regulation of CD163/TWEAK-mediated autophagy. The data demonstrated that G. parasuis altered routine blood indicators and biochemical parameters, increased cytokine production, and induced blood vessel tissue damage. G. parasuis reduced the CD3+ T cell proportion, CD3+CD4+ T cell proportion, and CD3+CD8+ T cell proportion in piglet blood. The proteomic analysis revealed that CD163 was differentially expressed in the blood vessels of challenged piglets. Baicalin was found to regulate CD163/TWEAK axis expression, inhibit Notch/Wnt signaling pathway activation, promote autophagy, and reduce NLRP3/Caspase 1 signaling pathway activation. Baicalin also decreased cytokine production and alleviated pathological tissue damage in the blood vessels of G. parasuis-challenged piglets. Taken together, this study indicates that baicalin alleviates G. parasuis-induced immunosuppression and might promote CD163/TWEAK-mediated autophagy. This finding suggests that baicalin could serve as a potential therapeutic agent to control G. parasuis infection and related vascular inflammation. Full article

(This article belongs to the Topic Recent Advances in Veterinary Pharmacology and Toxicology)

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16 pages, 503 KiB

Open AccessReview

Embryonic Origins of Cancer: Insights from Double Homeobox 4 Regulation

by Bo Fu, Hong Ma, Liang Wang, Zhenhua Guo, Fang Wang, Di Liu and Dongjie Zhang

Biomolecules 2025, 15(5), 721; https://doi.org/10.3390/biom15050721 - 14 May 2025

Viewed by 475

Abstract

Embryogenesis and tumorigenesis share several key biological characteristics, such as rapid cell proliferation, high plasticity, and immune evasion. This similarity indicates that developmental pathways can be hijacked, leading to the formation of malignant cell states. With regard to this, cancer can be regarded [...] Read more.

Embryogenesis and tumorigenesis share several key biological characteristics, such as rapid cell proliferation, high plasticity, and immune evasion. This similarity indicates that developmental pathways can be hijacked, leading to the formation of malignant cell states. With regard to this, cancer can be regarded as a stem cell disease. On the contrary, a fetus, in many ways, has similar characteristics to the “ideal tumor”, such as immune evasion and rapid growth. Therefore, deciphering the molecular mechanisms beneath these phenomena will help us to understand the embryonic origins of cancer. This review discusses the relationship between embryogenesis and tumorigenesis, highlighting the potential roles played by DUX4. DUX4 is involved in the activation of the zygote genome and then facilitates the establishment of totipotency in pre-implantation embryos, whereas the misexpression of DUX4 is associated with different types of cancer. Taken together, this indicates that DUX4 performs analogous functions in these two processes and connects embryogenesis and tumorigenesis. Through examining DUX4, this review underscores the importance of developmental mechanisms in cancer biology, suggesting that the insights gained from studying embryonic processes may provide novel therapeutic strategies. As we continue to explore the complex relationship between cancer and embryogenesis, elucidating the role of DUX4 in linking these two processes will be critical for developing targeted therapies that exploit developmental pathways. Full article

(This article belongs to the Section Molecular Biology)

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13 pages, 5029 KiB

Open AccessFeature PaperArticle

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

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

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

Viewed by 381

Abstract

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

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

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

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25 pages, 3667 KiB

Open AccessReview

Nicotinamide N-Methyltransferase (NNMT) and Liver Cancer: From Metabolic Networks to Therapeutic Targets

by Shi-Yan Lai, Xiao-Juan Zhu, Wei-Dong Sun, Shuang-Zhou Bi, Chen-Ying Zhang, An Liu and Jiang-Hua Li

Biomolecules 2025, 15(5), 719; https://doi.org/10.3390/biom15050719 - 14 May 2025

Viewed by 966

Abstract

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains a global health challenge with limited therapeutic options and high mortality rates. Despite advances in understanding its molecular pathogenesis, the role of metabolic reprogramming in HCC progression and therapy resistance demands further [...] Read more.

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, remains a global health challenge with limited therapeutic options and high mortality rates. Despite advances in understanding its molecular pathogenesis, the role of metabolic reprogramming in HCC progression and therapy resistance demands further exploration. Nicotinamide N-methyltransferase (NNMT), a metabolic enzyme central to NAD⁺ and methionine cycles, has emerged as a critical regulator of tumorigenesis across cancers. However, its tissue-specific mechanisms in HCC—particularly in the context of viral hepatitis and methionine cycle dependency—remain understudied. This review systematically synthesizes current evidence on NNMT’s dual role in HCC: (1) driving NAD⁺ depletion and homocysteine (Hcy) accumulation via metabolic dysregulation, (2) promoting malignant phenotypes (proliferation, invasion, metastasis, and drug resistance), and (3) serving as a prognostic biomarker and therapeutic target. We highlight how NNMT intersects with epigenetic modifications, immune evasion, and metabolic vulnerabilities unique to HCC. Additionally, we critically evaluate NNMT inhibitors, RNA-based therapies, and non-pharmacological strategies (e.g., exercise) as novel interventions. By bridging gaps between NNMT’s molecular mechanisms and clinical relevance, this review provides a roadmap for advancing NNMT-targeted therapies and underscores the urgency of addressing challenges in biomarker validation, inhibitor specificity, and translational efficacy. Our work positions NNMT not only as a metabolic linchpin in HCC but also as a promising candidate for precision oncology. Full article

(This article belongs to the Section Molecular Biology)

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