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Biomolecules
Volume 15
Issue 10
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Biomolecules, Volume 15, Issue 10 (October 2025) – 135 articles

Cover Story (view full-size image): Reactive oxygen species (ROS) are key effectors of innate immunity. During the respiratory burst (RB), human neutrophils reduce oxygen to superoxide, forming hydrogen peroxide (H₂O₂) and altering membrane potential. We tested whether extracellular potassium affects H₂O₂ production, as potassium levels can rise during necrosis or trauma. H₂O₂ release was measured over 2 h under varying potassium concentrations, with no clear effects. Substituting potassium or chloride with sodium or methanesulfonate likewise caused no change. Thus, unlike electrically excitable cells such as neurons and muscles, the strongly depolarizing RB of human neutrophils appears independent of monovalent ion concentrations, though hyperosmolar solutions do affect it. View this paper
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26 pages, 4441 KB  
Article
Rapid Biochemical Analysis of Postmortem Serum and Myocardial Homogenates—An Exploratory Study
by Niki Sarri, Henrik Druid, Ali-Reza Rezaie, Klaske Osinga, Nargis Sultana and Kanar Alkass
Biomolecules 2025, 15(10), 1483; https://doi.org/10.3390/biom15101483 - 21 Oct 2025
Viewed by 464
Abstract
Postmortem diagnosis of sudden cardiac death (SCD) may escape detection due to the absence of thrombi and slow development of structural and immunohistochemical changes. Therefore, this study explores the possibility of analyzing relevant clinical chemistry biomarkers in myocardial homogenates and serum. Following an [...] Read more.
Postmortem diagnosis of sudden cardiac death (SCD) may escape detection due to the absence of thrombi and slow development of structural and immunohistochemical changes. Therefore, this study explores the possibility of analyzing relevant clinical chemistry biomarkers in myocardial homogenates and serum. Following an initial pilot study, myocardial samples from 113 autopsy cases were homogenized with distilled water, T-PER or 2 M urea. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK-MB), lactate dehydrogenase (LDH), orosomucoid and total protein were analyzed with an IndikoPlus and a subset was also analyzed with a Roche Cobas 8000 c701 analyzer, which also provided results for cardiac Troponin T, myoglobin and NT-proBNP. Although the yields varied with different extraction buffers depending on the analyte, distilled water was often as effective as T-PER and 2 M urea extraction for most analytes. Biomarker levels were consistently higher in the myocardial homogenates than in serum. Proteomic profiling on a subset confirmed higher concentrations of the cardiac markers in the tissue samples than in serum. Finally, we investigated whether selected markers could support the diagnosis of acute cardiac disease by classifying cases as sudden cardiac death (SCD) or controls. There was no significant difference in serum concentrations of the selected biomarkers between SCD cases and controls, whereas a significant loss of several markers was observed in SCD myocardial samples as compared to controls. Hence, our results suggest that analysis of tissue homogenates is likely better for detecting early ischemia, and we show that an in-house benchtop multi-analyzer can provide rapid results to assist the pathologist’s decision-making during autopsy. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cardiology 2025)
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17 pages, 2192 KB  
Article
Arctic Diatoms as a Source of Antibiofilm Compounds: Identification of Methyl 3-Hydroxyoctadecanoate and Pheophorbide a
by Marit Huizer, Renate Osvik, Espen H. Hansen, Terje Vasskog, Jeanette H. Andersen, Kim van Wezel, Hans Christian Eilertsen, Johan Isaksson, Kine Ø. Hansen and Richard A. Ingebrigtsen
Biomolecules 2025, 15(10), 1482; https://doi.org/10.3390/biom15101482 - 21 Oct 2025
Viewed by 355
Abstract
Marine diatoms are prolific producers of bioactive metabolites, but Arctic species remain underexplored as sources of antibacterial and antibiofilm agents. Here, seven species were grown in photobioreactors (PBRs) and systematically screened for antibacterial, antibiofilm, and cytotoxic activities. All strains inhibited Gram-positive bacteria, and [...] Read more.
Marine diatoms are prolific producers of bioactive metabolites, but Arctic species remain underexplored as sources of antibacterial and antibiofilm agents. Here, seven species were grown in photobioreactors (PBRs) and systematically screened for antibacterial, antibiofilm, and cytotoxic activities. All strains inhibited Gram-positive bacteria, and four reduced Staphylococcus epidermidis biofilm formation. Porosira glacialis emerged as a lead species, combining potent antibiofilm activity with favourable traits for large-scale cultivation, and no detectable cytotoxicity. Bioactivity-guided fractionation of P. glacialis yielded two antibiofilm compounds: methyl 3-hydroxyoctadecanoate, the first time reported in diatoms and newly associated with antibiofilm bioactivity, and pheophorbide a, a chlorophyll degradation product. Both inhibited S. epidermidis biofilm formation without any observed cytotoxicity. Notably, Cylindrotheca closterium exhibited cultivation-dependent antibiofilm activity, underscoring the importance of growth conditions for metabolite production. These findings highlight the potential of Arctic diatoms as a sustainable source of antibiofilm agents and support further exploration of their metabolites for antimicrobial and industrial applications. Full article
(This article belongs to the Special Issue Recent Advances in Bioactive Compounds from Microalgae)
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24 pages, 3969 KB  
Article
Kynurenic Acid Protects Against Myocardial Ischemia/Reperfusion Injury by Activating GPR35 Receptors and Preserving Mitochondrial Structure and Function
by Dóra Nógrádi-Halmi, Barbara Erdélyi-Furka, Dóra Csóré, Éva Plechl, Nóra Igaz, László Juhász, Marietta Zita Poles, Bernát Nógrádi, Roland Patai, Tamás Ferenc Polgár, Mónika Kiricsi, László Vécsei, Renáta Gáspár and Tamás Csont
Biomolecules 2025, 15(10), 1481; https://doi.org/10.3390/biom15101481 - 21 Oct 2025
Viewed by 539
Abstract
Acute myocardial infarction, often associated with ischemia/reperfusion injury (I/R), is a major healthcare issue ranking among the leading causes of death globally. Although kynurenic acid (KYNA), an endogenous tryptophan metabolite, has been previously shown to protect the cardiac tissue against I/R injury, its [...] Read more.
Acute myocardial infarction, often associated with ischemia/reperfusion injury (I/R), is a major healthcare issue ranking among the leading causes of death globally. Although kynurenic acid (KYNA), an endogenous tryptophan metabolite, has been previously shown to protect the cardiac tissue against I/R injury, its mechanism of action remains unclear. Therefore, here, we examined whether KYNA administration rescues H9c2 cardiac cells exposed to I/R through the preservation of the structural and functional integrity of the mitochondria. In addition, we assessed whether KYNA-derived agonism on G-protein coupled receptor 35 (GPR35) is involved in the protection of cardiac cells against simulated I/R (SI/R)-induced cellular demise. Our results demonstrated that KYNA attenuated the SI/R-induced calcium overload as well as impairments in the mitochondrial ultrastructure. Furthermore, administration of KYNA was shown to reduce mitochondrial superoxide production and preserve mitochondrial function in cells exposed to SI/R. Activation of the GPR35 receptors using an agonist other than KYNA rescued cardiac cells undergoing SI/R, attenuated the apoptotic activity, and improved various parameters of mitochondrial respiration. The administration of a synthetic GPR35 antagonist in parallel with KYNA attenuated the KYNA-induced cytoprotection. Our findings provide evidence that the protective effect of KYNA against SI/R-induced cardiac cell injury involves mitoprotective mechanisms, acting, at least in part, through the activation of GPR35 receptors. Full article
(This article belongs to the Special Issue Bioactive Compounds as Modifiers of Mitochondrial Function)
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20 pages, 4626 KB  
Article
Predicting the Impact of Glycosylation on the Structure and Thermostability of Helicobacter pylori Blood Group Binding Adhesin
by Daniel Sijmons, Heber Islas Rios, Benjamin R. Turner, Emma Wanicek, Jessica K. Holien, Anna K. Walduck and Paul A. Ramsland
Biomolecules 2025, 15(10), 1480; https://doi.org/10.3390/biom15101480 - 21 Oct 2025
Viewed by 475
Abstract
Post-translational modifications (PTMs) are critically important for protein structure and function, with glycosylation being one of the most common forms of PTM. The gastric pathogen Helicobacter pylori has a general glycosylation system, which performs complex glycosylation of lipopolysaccharide, flagella proteins, and outer membrane [...] Read more.
Post-translational modifications (PTMs) are critically important for protein structure and function, with glycosylation being one of the most common forms of PTM. The gastric pathogen Helicobacter pylori has a general glycosylation system, which performs complex glycosylation of lipopolysaccharide, flagella proteins, and outer membrane proteins (OMPs). One of the best-described OMPs of H. pylori is the blood group binding adhesin (BabA), which interacts with the Lewis histo-blood group antigen, Lewis b. The 3D structure for BabA has been determined, and the ligand specifically described. Although BabA is reported to be a glycoprotein, there are limited data examining the effects of glycosylation on the structure and function of this protein. This study examined the folding and thermostability of non-glycosylated recombinant BabA and used computational approaches to predict the effect of glycosylation on the protein, with a focus on its possible heterologous expression in mammalian cells. Three potential O-linked and three potential N-linked glycosylation sites were predicted. Furthermore, the effect of glycan shielding on the solvent-accessible surface area of BabA was examined. Molecular dynamics simulations highlighted local indicators, including root mean square fluctuation and the number of protein-glycan contacts that were affected by glycosylation. Taken together, the findings support a role of glycans in surface shielding and promoting local stabilization in specific areas of the BabA protein. This study helps to strengthen the understanding of the importance of glycosylation and the role it plays in the structure, function, and stability of H. pylori proteins. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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16 pages, 4279 KB  
Article
Surfactin Structural Variants Differentially Modulate Plant Immune Responses
by Ning Ding, Hansong Dong, Romain Thomas, Guillaume Gilliard, Jelena Pršić and Marc Ongena
Biomolecules 2025, 15(10), 1479; https://doi.org/10.3390/biom15101479 - 21 Oct 2025
Viewed by 381
Abstract
Cyclic lipopeptides (CLPs), produced by beneficial rhizobacteria such as Bacillus and Pseudomonas species, are specialized metabolites retaining key functions for the plant protective activity of the producers, which shows their potential as biocontrol agents in agriculture. Beyond their strong antimicrobial properties, CLPs can [...] Read more.
Cyclic lipopeptides (CLPs), produced by beneficial rhizobacteria such as Bacillus and Pseudomonas species, are specialized metabolites retaining key functions for the plant protective activity of the producers, which shows their potential as biocontrol agents in agriculture. Beyond their strong antimicrobial properties, CLPs can act as potent elicitors of plant immunity and systemic resistance. However, the molecular mechanisms underlying these immune-modulatory effects and the role of CLPs’ structural diversity remain poorly understood. Here, we demonstrate that specific structural features of surfactin-type CLPs critically influence their ability to trigger early immune responses in plants, including reactive oxygen species bursts, nitric oxide (NO) production, calcium fluxes, and systemic resistance. In Arabidopsis thaliana roots, we show that surfactin-induced NO generation requires calcium signaling. Moreover, we reveal that contrasting immune effects of CLPs may stem from the ecological lifestyles of their microbial producers, shedding light on the evolutionary basis of plant–microbe interactions. Altogether, our findings underscore the importance of CLP structural variation in shaping plant defense responses and highlight the potential for structure-informed design of next-generation biosourced small molecules with broad-spectrum efficacy as plant protectants. Full article
(This article belongs to the Special Issue Probiotics and Their Metabolites, 2nd Edition)
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17 pages, 1523 KB  
Article
Oxidative Stress and Iron Addiction: A Comparative Study of 1321N1 Astrocytoma and T98G Glioblastoma Cells with Differential Expression of L-Cysteine-Metabolizing Enzymes
by Halina Jurkowska, Ewa Jasek-Gajda, Konrad Kaleta, Leszek Rydz, Dominika Szlęzak and Maria Wróbel
Biomolecules 2025, 15(10), 1478; https://doi.org/10.3390/biom15101478 - 20 Oct 2025
Viewed by 456
Abstract
Gliomas are central nervous system primary tumors that are distinguished by heterogeneity, broad-based infiltration, and metabolic reprogramming that sustains proliferation, invasion, and therapy refractoriness. Oxidative stress—a state of imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense—and disturbed iron [...] Read more.
Gliomas are central nervous system primary tumors that are distinguished by heterogeneity, broad-based infiltration, and metabolic reprogramming that sustains proliferation, invasion, and therapy refractoriness. Oxidative stress—a state of imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense—and disturbed iron metabolism are central drivers of glioma biology. The aim of this study was to evaluate ROS production, sulfane sulfur levels, the expression of proteins with antioxidant properties, such as L-cysteine-metabolizing enzymes (cystathionine β-synthase, CBS; cysteine dioxygenase 1, CDO1; cystathionine γ-lyase, CTH; 3-mercaptopyruvate sulfurtransferase, MPST; thiosulfate sulfurtransferase, TST) and non-enzymatic proteins (p53; transferrin receptor 1, TfR1), in human brain cancer cells differing in malignancy: 1321N1 astrocytoma and T98G glioblastoma. Western blotting analysis demonstrated that the expression of CBS, CDO1, and TfR1 was significantly increased in T98G cells, while CTH, MPST, TST, and p53 were comparably expressed in both cell lines. Quantitative assays revealed that T98G cells harbored significantly higher sulfane sulfur levels and higher numbers of ROS-positive cells compared to 1321N1 cells. Our results suggest that glioblastoma but not astrocytoma cells adapt sulfur and iron metabolism to provide proliferation capacity against chronic oxidative stress. It seems that CBS as well as CDO1 may significantly increase the antioxidant potential of T98G cells. In summary, this study suggests a differing metabolic vulnerability identifiable only in high-grade glioma cells and provides a potential novel molecular target for therapy. Full article
(This article belongs to the Special Issue Cysteine and Selenocysteine in Antioxidant Defense, Protein Synthesis and Signaling Pathways)
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25 pages, 1099 KB  
Review
Bispecific Antibody and Antibody-Drug Conjugate as Novel Candidates for Treating Pancreatic Ductal Adenocarcinoma
by Hyeryeon Seo, Dabin Go, Se Young Jung, Shinwoo Han, Van Quy Nguyen, Minseok Kwak and Wooram Um
Biomolecules 2025, 15(10), 1477; https://doi.org/10.3390/biom15101477 - 20 Oct 2025
Viewed by 1137
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterized by a dense and immunosuppressive tumor microenvironment. With the limited actions of drugs and conventional monovalent antibodies, the success of existing cancer therapies is restricted so far. Recently, bispecific antibodies (BsAbs) [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterized by a dense and immunosuppressive tumor microenvironment. With the limited actions of drugs and conventional monovalent antibodies, the success of existing cancer therapies is restricted so far. Recently, bispecific antibodies (BsAbs) have emerged as a promising therapeutic platform, capable of overcoming the limitations of current PDAC treatments by engaging T cells and delivering drugs to multiple targets in a selective manner. Furthermore, the recruitment of additional payloads expands their therapeutic potential, offering more selective drug delivery and presenting new possibilities for treating PDAC. However, a limited number of relevant studies and a lack of comprehensive research have hindered trials for the development of BsAbs and bispecific antibody-drug conjugates (BsADCs) in PDAC therapeutics. This review aims to provide the characteristics of BsAbs and BsADCs and their recent applications in PDAC treatment. Additionally, frequent targets of PDAC treatments will be discussed to suggest how to design BsAbs and BsADCs for PDAC treatments. Full article
(This article belongs to the Special Issue Advances in Nano-Based Drug Delivery Systems)
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18 pages, 1248 KB  
Review
Multiple Organ Phenotype of Fatigue
by Xiaohua Liu, Zhonghan Zhao, Yuan Zhang, Jun Zou and Lingli Zhang
Biomolecules 2025, 15(10), 1476; https://doi.org/10.3390/biom15101476 - 20 Oct 2025
Viewed by 438
Abstract
Fatigue is not only a widespread subjective experience but also a complex physiological and pathological state involving multiple organs and systems. Currently, there is no consensus on the definition and classification of fatigue. Based on its causes, this paper categorizes fatigue into sports [...] Read more.
Fatigue is not only a widespread subjective experience but also a complex physiological and pathological state involving multiple organs and systems. Currently, there is no consensus on the definition and classification of fatigue. Based on its causes, this paper categorizes fatigue into sports fatigue, occupational fatigue, and pathological fatigue. It elaborates on the specific manifestations and underlying mechanisms of fatigue in the motor, nervous, cardiovascular, digestive, urinary, endocrine, and reproductive systems, aiming to uncover the intrinsic connections of fatigue phenotypes across different systems. These findings may provide key targets for gene-assisted therapy of fatigue-related complications, thereby establishing a new theoretical foundation for the clinical management of fatigue and related research. Full article
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12 pages, 240 KB  
Review
Inflammatory Mechanisms in Myocarditis—Recent Therapeutic Strategies
by Stergios Soulaidopoulos, Dimitris Tousoulis, Marios Sagris, Svetlana Aghayan, Konstantinos Platanias, Alexios Giannakodimos, Emilia Lazarou, Konstantinos Tsioufis and George Lazaros
Biomolecules 2025, 15(10), 1475; https://doi.org/10.3390/biom15101475 - 20 Oct 2025
Viewed by 545
Abstract
Myocarditis is an inflammatory disease of the heart characterized by a complex interplay between innate and adaptive immune responses. The innate immune system provides first-line defense and includes soluble molecules, including macrophages, neutrophils, dendritic cells, and molecular mediators, but lacks immunological memory. In [...] Read more.
Myocarditis is an inflammatory disease of the heart characterized by a complex interplay between innate and adaptive immune responses. The innate immune system provides first-line defense and includes soluble molecules, including macrophages, neutrophils, dendritic cells, and molecular mediators, but lacks immunological memory. In contrast, the adaptive immune system, via T and B lymphocytes, offers high specificity and long-term memory, which can sometimes target myocardial tissue, causing autoimmune injury. Particularly, acute myocarditis is characterized by dysregulated immune signaling, with cytokines (IL-2, IFN-γ, IL-12, IL-4, IL-10) and chemokines (MCP-1, CXCL4, CXCL10) driving disease progression, while adhesion molecules (ICAM-1, VCAM-1, VAP-1) promote leukocyte trafficking and cardiac inflammation. The balance between pro-inflammatory and regulatory responses determines disease outcomes, ranging from resolution with recovery to fulminant myocarditis or progression to dilated cardiomyopathy. Emerging therapeutic approaches targeting cytokines, chemokines, and adhesion molecules, along with established immunosuppressive treatments, underline the potential for modulating immune responses in myocarditis and, thereby, improving patient outcomes. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Cardiopathy and Therapeutic Strategies)
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18 pages, 2287 KB  
Article
Metabolomics in the Context of Exercise in Subjects with Multimorbidity: A Pilot Study
by Rebecca Bankamp, Simone Schweda, Nils Janzen, Andreas M. Nieß, Inga Krauß and Barbara Munz
Biomolecules 2025, 15(10), 1474; https://doi.org/10.3390/biom15101474 - 20 Oct 2025
Viewed by 343
Abstract
Lifestyle-related diseases, such as overweight/obesity, diabetes mellitus type 2 (T2DM), cardiovascular disease, or osteoarthritis, are a major health burden in Western societies. Due to common risk factors, most patients suffer from multimorbidity, i.e., have been diagnosed with more than one of these diseases. [...] Read more.
Lifestyle-related diseases, such as overweight/obesity, diabetes mellitus type 2 (T2DM), cardiovascular disease, or osteoarthritis, are a major health burden in Western societies. Due to common risk factors, most patients suffer from multimorbidity, i.e., have been diagnosed with more than one of these diseases. Physical activity (PA) is known to have a positive effect on all of these diseases; however, little is known about the effects of PA on patients with multimorbidity. In particular, so far, no reliable biomarkers have been found to predict and monitor the effects of PA-based lifestyle intervention programs on these subjects. Employing a metabolomics approach with dried blood spots, we analyzed the concentrations of different metabolites in subjects with multimorbidity over the course of the lifestyle intervention program MultiPill-Exercise. We found increased concentrations of all tested amino acids (AAs), total carnitine (Cx), and short- (C2-C6) and long- (>C12) chain acylcarnitines (ACs) after 12 weeks (t1) and/or 24 weeks (t2) of intervention. When correlating baseline (t0) metabolite concentrations with changes in physiological and clinical parameters, we observed associations of various metabolite concentrations with changes in metabolic and cardiovascular parameters. When analyzing metabolite acute reactions in response to exhaustive exercise (ergometer test), however, few overall changes were observed. Nevertheless, a significant negative correlation was found between the mobilization of medium-chain acylcarnitines (MC-ACs) at t2 and changes in peak power output (PPO) between t0 and t2. Taken together, these data suggest that specific AAs and ACs might be candidate biomarkers to predict and monitor the effects of PA-based lifestyle intervention programs in subjects with multimorbidity, a hypothesis that should be further tested in larger cohorts. Full article
(This article belongs to the Section Molecular Biomarkers)
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18 pages, 1617 KB  
Review
ZC3H12A: A Critical Mediator of Inflammation, Tumor Immunotherapy, and Metabolic–Immune Crosstalk—Implications for Disease Treatment
by Mingjun Lu, Jingwei Guo, Chenyang Wang, Bingbing Wan and Teng Ma
Biomolecules 2025, 15(10), 1473; https://doi.org/10.3390/biom15101473 - 19 Oct 2025
Viewed by 574
Abstract
ZC3H12A is a key RNA-binding protein and ribonuclease that plays a central role in negatively regulating inflammation and maintaining immune homeostasis. It does this by degrading the mRNA of multiple inflammatory mediators (such as IL-6 and IL-1β), as well as through its [...] Read more.
ZC3H12A is a key RNA-binding protein and ribonuclease that plays a central role in negatively regulating inflammation and maintaining immune homeostasis. It does this by degrading the mRNA of multiple inflammatory mediators (such as IL-6 and IL-1β), as well as through its deubiquitinating enzyme activity. Not only does it limit excessive immune activation by regulating innate and adaptive immune cells (e.g., macrophages and T cells), but it also exerts bidirectional effects in tumors, acting as an anti-tumor factor to inhibit angiogenesis and oncogenic signal pathways, while promoting tumor progression under specific conditions. In recent years, ZC3H12A has emerged as a critical target for tumor immunotherapy, particularly CAR-T cell therapy. Its knockout significantly enhances T-cell persistence and anti-tumor efficacy, demonstrating broad translational potential. Furthermore, ZC3H12A plays a crucial role in systemic metabolic–immune crosstalk and infectious diseases. This review systematically summarizes the multifunctional roles of ZC3H12A in immune regulation, tumor therapy, metabolic disorders and inflammation-related diseases, with the aim of providing new insights into its potential application in the treatment of human diseases. Full article
(This article belongs to the Section Molecular Medicine)
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23 pages, 996 KB  
Review
The Role of Preimplantation Genetic Testing for Monogenic Disorders (PGT-M) in Hemoglobinopathy Management—Techniques, Accuracy, and the Balancing of Benefits and Drawbacks
by Rasrawee Chantrasiri, Tawiwan Pantasri, Siriporn Chattipakorn, Nipon Chattipakorn, Sirinart Kumfu and Wirawit Piyamongkol
Biomolecules 2025, 15(10), 1472; https://doi.org/10.3390/biom15101472 - 17 Oct 2025
Viewed by 1131
Abstract
Preimplantation genetic testing for monogenic disorders (PGT-M) is a powerful tool for identifying genetic disorders prior to gestation. For hemoglobinopathies like thalassemias and sickle cell disease, PGT-M offers a preventative strategy to ensure that only embryos deemed genetically healthy are transferred. A comprehensive [...] Read more.
Preimplantation genetic testing for monogenic disorders (PGT-M) is a powerful tool for identifying genetic disorders prior to gestation. For hemoglobinopathies like thalassemias and sickle cell disease, PGT-M offers a preventative strategy to ensure that only embryos deemed genetically healthy are transferred. A comprehensive review of 22 original articles explores and summarizes the existing evidence on PGT-M techniques in hemoglobinopathies. The review focuses on key aspects such as accuracy, benefits, and drawbacks related to various hemoglobinopathies. Given the limited quantity of DNA obtained from an embryo biopsy, whole genome amplification (WGA) is a critical step for amplifying the sample. One of the available methods of WGA, multiple displacement amplification (MDA) is one of the most widely adopted method with acceptable allele drop-out (ADO) rates for hemoglobinopathies compared with traditional methods. Dealing with ADO constitutes a primary technical obstacle in PGT-M. The failure to amplify one allele in single-cell analysis is a major factor limiting the overall diagnostic accuracy of the procedure. To mitigate this issue, PCR-based and next-generation sequencing (NGS)-based approaches are employed. These methods incorporate linkage analysis with genetic markers such as short tandem repeats (STRs) or single-nucleotide polymorphisms (SNPs) to reduce the risk of incorrect interpretations from ADO and enhance the proportion of conclusive results. A future direction for PGT-M that involves the development of non-invasive methods (niPGT) will be included and discussed. Full article
(This article belongs to the Section Molecular Genetics)
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23 pages, 5188 KB  
Review
Dynamic Executors of Bacterial Signals: Functional Versatility and Regulatory Networks of c-di-GMP Effectors
by Jia Jia, Ge Yun, Bingxin Liu, Xinxin Li, Meiling Jiang, Xinlu Yu, Jing Zhang, Yufei Han, Dan Liu, Junlong Zhao, Yuanyuan Wang and Gukui Chen
Biomolecules 2025, 15(10), 1471; https://doi.org/10.3390/biom15101471 - 17 Oct 2025
Cited by 1 | Viewed by 458
Abstract
Cyclic di-GMP (c-di-GMP), a universal second messenger in bacteria, orchestrates a wide array of essential life processes. Its intracellular dynamics are meticulously regulated by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), ensuring precise spatiotemporal control. The functional output of c-di-GMP signaling hinges on effector [...] Read more.
Cyclic di-GMP (c-di-GMP), a universal second messenger in bacteria, orchestrates a wide array of essential life processes. Its intracellular dynamics are meticulously regulated by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), ensuring precise spatiotemporal control. The functional output of c-di-GMP signaling hinges on effector proteins—molecular decoders that translate c-di-GMP signals into specific cellular responses. This review systematically examines diverse classes of c-di-GMP effectors, using several representative bacterial species as model systems, to dissect their structural and mechanistic diversity. Particular emphasis is placed on their pivotal roles in bacterial pathogenicity, antibiotic tolerance, and host–pathogen interactions, offering fresh insights into the regulatory mechanisms underlying c-di-GMP signaling. Full article
(This article belongs to the Section Molecular Biology)
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12 pages, 1651 KB  
Article
Engineered N-TIMP2 Variant Specifically Targeting MMP-9 Exhibits Potent Anti-Glioblastoma Activity
by Mark Feldman, Naama Rotenberg and Julia M. Shifman
Biomolecules 2025, 15(10), 1470; https://doi.org/10.3390/biom15101470 - 17 Oct 2025
Viewed by 404
Abstract
Glioblastoma (GB) is the most aggressive form of brain cancer. However, despite intensive intervention, GB almost invariably recurs due to the highly invasive nature of its tumor cells, which infiltrate surrounding healthy brain tissue, underscoring the urgent need for more effective therapies. One [...] Read more.
Glioblastoma (GB) is the most aggressive form of brain cancer. However, despite intensive intervention, GB almost invariably recurs due to the highly invasive nature of its tumor cells, which infiltrate surrounding healthy brain tissue, underscoring the urgent need for more effective therapies. One such approach could be based on targeting matrix metalloproteinase-9 (MMP-9), an enzyme that plays a crucial role in GB progression and is closely associated with enhanced invasiveness and poor prognosis. Previously, we engineered a potent and selective MMP-9 inhibitor derived from the N-terminal domain of the endogenous tissue inhibitor of metalloproteinases-2 (N-TIMP2). In this study, we evaluate the efficacy and toxicity of this engineered N-TIMP2 variant (REY) in adult GB U251 and normal Vero cells using multiple in vitro assays. Our results demonstrate that REY significantly inhibits colony formation and cell invasion, and markedly reduces spheroid spreading at nanomolar concentrations. Importantly, the engineered variant, which is highly specific for MMP-9, consistently outperforms the wild-type N-TIMP2, which broadly targets multiple MMPs, and exhibits no cytotoxicity toward healthy cells. Together, these findings support MMP-9 as a viable therapeutic target in GB and highlight the potential of our engineered N-TIMP2 variant as a promising candidate for further therapeutic development. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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11 pages, 779 KB  
Review
Chemerin in Pulmonary Fibrosis: Advances in Mechanistic and Fundamental Research
by Yongshuai Jiang, Ziyang Li, Zhenghang Huang, Junsheng Dong and Li Qian
Biomolecules 2025, 15(10), 1469; https://doi.org/10.3390/biom15101469 - 17 Oct 2025
Viewed by 467
Abstract
Pulmonary fibrosis is a progressive interstitial lung disease that involves stimulated growth of fibroblasts, over-deposition of extracellular matrix (ECM), and permanent damage of the lung structure. Among its various forms, idiopathic pulmonary fibrosis (IPF) is the most common and life-threatening type with few [...] Read more.
Pulmonary fibrosis is a progressive interstitial lung disease that involves stimulated growth of fibroblasts, over-deposition of extracellular matrix (ECM), and permanent damage of the lung structure. Among its various forms, idiopathic pulmonary fibrosis (IPF) is the most common and life-threatening type with few treatment options and a poor prognosis. Such obstacles highlight the urgency to find new molecular targets by better understanding the cellular and signaling processes that contribute to the pathogenesis of the disease. Chemerin is an adipokine and chemoattractant protein that has recently come into the limelight as a major controller of immune cell trafficking, inflammation, and tissue remodeling. Its biological activity is mainly mediated by binding to its receptors Chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C chemokine receptor-like 2 (CCRL2), and has been linked to numerous pathological conditions, such as metabolic diseases, cancer, and inflammatory diseases. Emerging data now indicate that chemerin can also be a key factor in the initiation and progression of pulmonary fibrosis. The aim of the review is to overview the existing evidence regarding regulatory processes of chemerin expression, signaling pathways, and effects of this protein in cells in the fibrotic lung microenvironment. Moreover, we will comment on the findings of in vitro and in vivo experiments supporting the possibility of chemerin as a promising molecular target in basic research on pulmonary fibrosis. Full article
(This article belongs to the Section Molecular Medicine)
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28 pages, 3654 KB  
Review
Proximity Ligation Assay: From a Foundational Principle to a Versatile Platform for Molecular and Translational Research
by Hengxuan Li, Xiangqi Ma, Dawei Shi and Peng Wang
Biomolecules 2025, 15(10), 1468; https://doi.org/10.3390/biom15101468 - 17 Oct 2025
Viewed by 779
Abstract
The precise analysis of protein interactions in their native cellular context and the sensitive quantification of protein abundance in biological fluids are both fundamental to understanding health and disease. Traditional methods for cellular imaging and biochemical quantification often face limitations in specificity, sensitivity, [...] Read more.
The precise analysis of protein interactions in their native cellular context and the sensitive quantification of protein abundance in biological fluids are both fundamental to understanding health and disease. Traditional methods for cellular imaging and biochemical quantification often face limitations in specificity, sensitivity, or the preservation of spatial information. The proximity ligation assay (PLA) is a versatile technological platform developed to overcome these challenges by converting protein recognition events into amplifiable DNA signals, thereby achieving exceptional sensitivity. This foundational principle has given rise to two major formats: in situ PLA (isPLA) and solution-phase PLA. In basic research, isPLA provides high-resolution visualization of protein–protein interactions (PPIs), post-translational modifications (PTMs), and subcellular architecture directly within fixed cells and tissues. In translational and clinical applications, solution-phase PLA enables the highly sensitive quantification of low-abundance biomarkers in liquid samples, which is critical for diagnostics and prognostics in fields such as oncology, neuroscience, and infectious diseases. This review discusses the foundational principles, development, and diverse applications of PLA platforms. We also highlight significant technological advancements, including the development of high-throughput formats, integration with advanced readouts, and the use of alternative affinity reagents. These innovations continue to transform PLA from a targeted validation method into a powerful and multifaceted platform for both fundamental systems biology and clinical diagnostics. Full article
(This article belongs to the Section Chemical Biology)
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19 pages, 1722 KB  
Review
Natural Compounds with Antiviral Activity Against Clinically Relevant RNA Viruses: Advances of the Last Decade
by David Mauricio Cañedo-Figueroa, Daniela Nahomi Calderón-Sandate, Jonathan Hernández-Castillo, Manuel Josafat Huerta-Garza, Ximena Hernández-Rodríguez, Manuel Adrián Velázquez-Cervantes, Giovanna Berenice Barrera-Aveleida, Juan Valentin Trujillo-Paez, Flor Itzel Lira-Hernández, Blanca Azucena Marquez-Reyna, Moisés León-Juárez, Ana Cristina García-Herrera, Juan Fidel Osuna-Ramos and Luis Adrián De Jesús-González
Biomolecules 2025, 15(10), 1467; https://doi.org/10.3390/biom15101467 - 16 Oct 2025
Viewed by 734
Abstract
RNA viruses remain a significant public health concern due to their rapid evolution, genetic variability, and capacity to trigger recurrent epidemics and pandemics. Over the last decade, natural products have gained attention as a valuable source of antiviral candidates, offering structural diversity, accessibility, [...] Read more.
RNA viruses remain a significant public health concern due to their rapid evolution, genetic variability, and capacity to trigger recurrent epidemics and pandemics. Over the last decade, natural products have gained attention as a valuable source of antiviral candidates, offering structural diversity, accessibility, and favorable safety profiles. This review highlights key replication mechanisms of RNA viruses and their associated therapeutic targets, including RNA-dependent RNA polymerase, viral proteases, and structural proteins mediating entry and maturation. We summarize recent advances in the identification of bioactive compounds such as flavonoids, alkaloids, terpenes, lectins, and polysaccharides that exhibit inhibitory activity against clinically relevant pathogens, including the Influenza A virus (IAV), human immunodeficiency viruses (HIV), dengue virus (DENV), Zika virus (ZIKV), and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Special emphasis is placed on the integration of in silico screening, in vitro validation, and nanotechnology-based delivery systems that address challenges of stability, bioavailability, and specificity. Furthermore, the growing role of artificial intelligence, drug repurposing strategies, and curated antiviral databases is discussed as a means to accelerate therapeutic discovery. Despite persistent limitations in clinical translation and standardization, natural products represent a promising and sustainable platform for the development of next-generation antivirals against RNA viruses. Full article
(This article belongs to the Special Issue Molecular Mechanism and Detection of SARS-CoV-2)
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18 pages, 5373 KB  
Article
High PEEP Activates ITGB1, Inducing Diaphragm Fibrosis During Prolonged Mechanical Ventilation
by Jiahong Gong, Jianwei Jia, Runze He, Xiaolan Yu, Ye Jiang, Weimin Shen, Xiaoli Qian, Peifeng Xu, Ying Xu and Huiqing Ge
Biomolecules 2025, 15(10), 1466; https://doi.org/10.3390/biom15101466 - 16 Oct 2025
Viewed by 387
Abstract
Background: Mechanical ventilation (MV) with high positive end-expiratory pressure (PEEP) is linked to ventilation-induced diaphragm dysfunction (VIDD), but the role of integrin beta-1 (ITGB1) in PEEP-associated diaphragm fibrosis remains unclear. Methods: Eighteen rabbits were divided into control (CON), MV without PEEP(MV), and MV [...] Read more.
Background: Mechanical ventilation (MV) with high positive end-expiratory pressure (PEEP) is linked to ventilation-induced diaphragm dysfunction (VIDD), but the role of integrin beta-1 (ITGB1) in PEEP-associated diaphragm fibrosis remains unclear. Methods: Eighteen rabbits were divided into control (CON), MV without PEEP(MV), and MV with 8 cmH2O PEEP (PEEP) groups. C2C12 underwent cyclic stretching (15% tension), and ITGB1 was knocked down. Fibrosis markers (TGFβ-1, α-SMA), ITGB1/ROCK1 expression, and pathway activation were analyzed via RNA sequencing, immunohistochemistry, and Western blotting. Results: The PEEP group exhibited elevated airway pressure and upregulated fibrosis markers (TGFβ-1 and α-SMA) alongside activated ITGB1/ROCK1 mechanotransduction pathways. Stretched C2C12 showed morphological shrinkage and increased fibrotic protein expression. RNA sequencing confirmed enrichment in fibrosis- and integrin-related pathways. ITGB1 knockdown attenuated TGFβ-1 and α-SMA induction. Conclusions: ITGB1 mediates PEEP-induced diaphragm fibrosis via TGFβ-1 signaling and collagen deposition, suggesting ITGB1 targeting as a potential therapeutic strategy for VIDD. These findings elucidate the mechanotransduction mechanisms underlying MV-associated diaphragm dysfunction. Full article
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19 pages, 3196 KB  
Article
Resin Glycosides with α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitory Activities from the Seeds of Cuscuta japonica
by Su-Peng Guo, Ye He, Xin Lan, Tian-Zi Qi, Jin-Ping Gu, Jia Guo, Xin-Yu Wang, Min Yang, Wen-Li Wang, Guang-Tong Chen and Bo-Yi Fan
Biomolecules 2025, 15(10), 1465; https://doi.org/10.3390/biom15101465 - 16 Oct 2025
Viewed by 348
Abstract
In the present study, seven previously undescribed resin glycosides, designated cusponins I-VII (1–7), together with one known analog (8), were isolated from the seeds of Cuscuta japonica, a traditional medicine used in China. Structural elucidation revealed [...] Read more.
In the present study, seven previously undescribed resin glycosides, designated cusponins I-VII (1–7), together with one known analog (8), were isolated from the seeds of Cuscuta japonica, a traditional medicine used in China. Structural elucidation revealed them to be glycosidic acid methyl esters, generated through on-column methyl esterification of naturally occurring resin glycosides catalyzed by NH2-functionalized silica gel. All isolates were characterized as either pentasaccharides or tetrasaccharides, incorporating D-glucose, L-rhamnose, or D-fucose units as the sugar residues. Notably, compounds 1 and 3–7 contained the uncommon aglycone, 11S-hydroxypentadecanoic acid. Bioactivity assessments demonstrated that compounds 1–4, 6 and 8 suppressed α-glucosidase activity, with IC50 values between 8.02 and 71.39 μM. In addition, compounds 3 and 5 exhibited inhibitory effects on protein tyrosine phosphatase 1B (PTP1B), with IC50 values of 14.19 ± 1.29 μM and 62.31 ± 8.61 μM, respectively, marking the first report of PTP1B inhibitory activity among resin glycosides. Enzyme kinetic analyses indicated that compound 2 acted as an uncompetitive α-glucosidase inhibitor (Kis = 3.02 μM), whereas compound 3 inhibited PTP1B via a mixed-type mechanism (Kᵢ = 24.82 μM; Kis = 64.24 μM). Molecular docking combined with molecular dynamics simulations suggested that compounds 2 and 3 interacted with α-glucosidase-pNPG and PTP1B, respectively, forming stable complexes with favorable binding free energies. Collectively, this study reported eight resin glycosides from C. japonica, seven of them newly identified, with compounds 2 and 3 highlighted as promising scaffolds for antidiabetic drug discovery. Full article
(This article belongs to the Section Natural and Bio-derived Molecules)
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18 pages, 1290 KB  
Review
Ferroptosis of Immune Cells in Infection, Inflammation and Tumor Progression
by Hanxiao Xu, Yanjun Lu, Qingwei Zeng, Xudong Zhu, Wenxian Guan and Song Liu
Biomolecules 2025, 15(10), 1464; https://doi.org/10.3390/biom15101464 - 16 Oct 2025
Viewed by 499
Abstract
Ferroptosis has been described as a unique form of programmed cell death. Its mechanism mainly involves iron metabolism disorders, lipid peroxidation and impaired antioxidant defense systems. The role of ferroptosis in infection, inflammation and tumor development has gained widespread attention. In particular, ferroptosis [...] Read more.
Ferroptosis has been described as a unique form of programmed cell death. Its mechanism mainly involves iron metabolism disorders, lipid peroxidation and impaired antioxidant defense systems. The role of ferroptosis in infection, inflammation and tumor development has gained widespread attention. In particular, ferroptosis in immune cells significantly affects immune responses during disease progression. This review aims to summarize the advanced research progress of ferroptosis in different types of immune cells. It also discusses potential therapeutic targets and strategies to regulate ferroptosis, which may offer novel interventions for diseases, especially cancer. Full article
(This article belongs to the Section Cellular Biochemistry)
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23 pages, 926 KB  
Review
What Is the Involvement of Gut Microbiome in the Pathophysiology of Diabetes?
by Kajetan Kiełbowski, Paulina Plewa, Jan Zadworny, Patrycja Stodolak, Anna Jędrasiak, Estera Bakinowska and Andrzej Pawlik
Biomolecules 2025, 15(10), 1463; https://doi.org/10.3390/biom15101463 - 16 Oct 2025
Viewed by 660
Abstract
Diabetes mellitus (DM) encompasses a group of metabolic diseases characterised by abnormal glucose levels. The pathophysiology of DM involves intricate disruptions in glucose metabolism and immune regulation. The gut microbiome is known to play a crucial role in human health and disease, and [...] Read more.
Diabetes mellitus (DM) encompasses a group of metabolic diseases characterised by abnormal glucose levels. The pathophysiology of DM involves intricate disruptions in glucose metabolism and immune regulation. The gut microbiome is known to play a crucial role in human health and disease, and changes in its composition have been reported in numerous conditions, including DM. In this review, we discuss recent findings on the intricate relationship between the gut microbiome and DM, including its complications. We highlight the involvement of gut microorganisms in inflammation and metabolic processes, and we summarise current evidence on how antidiabetic therapies influence microbiome composition and activity. Finally, we explore the potential role of microbiome monitoring in predicting treatment response. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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20 pages, 2408 KB  
Article
PAX6 Downregulation Triggers HIF-1α-Mediated Ferroptosis in Glioma Cells
by Qizhi Luo, Li Fu, Jie Zhang, Shashuang Zhang, Lixiang Wu, Quan Zhu and Baisheng Huang
Biomolecules 2025, 15(10), 1462; https://doi.org/10.3390/biom15101462 - 16 Oct 2025
Viewed by 397
Abstract
Background: The paired-box gene 6 (PAX6) is an important transcription factor in the central nervous system, mainly regulating the development and differentiation of embryonic eyes and the nervous system. PAX6 expression is significantly decreased in glioma, and the expression levels [...] Read more.
Background: The paired-box gene 6 (PAX6) is an important transcription factor in the central nervous system, mainly regulating the development and differentiation of embryonic eyes and the nervous system. PAX6 expression is significantly decreased in glioma, and the expression levels are closely related to glioma development and prognosis. Therefore, it is important to study and elucidate the biological function of PAX6 in glioma to further our understanding of the occurrence and development of glioma. Methods: This study focused on the expression and regulation of PAX6 and hypoxia-inducing factor (HIF-1α) and investigated the molecular mechanism of ferroptosis regulated by PAX6 and HIF-1α. Firstly, immunohistochemistry, qPCR, Western blot, and other methods were used to detect PAX6 and HIF-1α expression in glioma tissues and cells, as well as the specific way in which PAX6 regulates HIF-1α. Then, some relative indicators of ferroptosis regulated by PAX6 in glioma were studied. Results: The results showed that PAX6 inhibited HIF-1α expression by regulating the levels of reactive oxygen species (ROS); overexpression of PAX6 promoted the expression of ROS and lipid peroxides (LPOs) in glioma cells and decreased the expression of intracellular antioxidant systems glutathione peroxidase 4 (GPX4) and glutathione (GSH). Conclusions: Downregulation of PAX6 plays an important role in regulating ferroptosis in glioma cells. Our research provides a reference basis for a deeper understanding of the role of PAX6 in ferroptosis of glioma. Full article
(This article belongs to the Special Issue The Role and Metabolism of Metals in Cancer)
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23 pages, 1539 KB  
Review
Sex Differences in Oxidative Stress Concerning Allergic Diseases
by Mattia Cristallo, Fabiana Furci, Marco Casciaro, Sebastiano Gangemi and Eustachio Nettis
Biomolecules 2025, 15(10), 1461; https://doi.org/10.3390/biom15101461 - 16 Oct 2025
Viewed by 574
Abstract
In recent years, the role of sexual hormones in the pathogenesis and progression of various diseases has progressively being established, which attempts to explain immune dimorphism. Whether physiological or pathological, variations in hormones influence the inflammatory response and adaptive systems to control increased [...] Read more.
In recent years, the role of sexual hormones in the pathogenesis and progression of various diseases has progressively being established, which attempts to explain immune dimorphism. Whether physiological or pathological, variations in hormones influence the inflammatory response and adaptive systems to control increased productions of reactive oxygen species, reactive nitrogen species, and free radicals. Primary allergic respiratory and skin diseases were taken into consideration, and possible biomarkers of oxidative stress related to sex differences in the onset and development of atopic diseases were analyzed. Understanding how these variables interact with each other, and evaluating the possible common targets, lays the foundation for the development of tailored therapies with an eye to precision medicine. Full article
(This article belongs to the Special Issue The Immune System and Allergies)
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14 pages, 748 KB  
Review
Evolving Cystic Fibrosis Care: Lung Immunology and Emerging Health Challenges in the Era of CFTR Modulators
by Giuseppe Fabio Parisi, Maria Papale, Giulia Pecora, Santiago Presti, Monica Tosto, Enza Mulé, Vittorio Ornato, Donatella Aloisio and Salvatore Leonardi
Biomolecules 2025, 15(10), 1460; https://doi.org/10.3390/biom15101460 - 16 Oct 2025
Viewed by 416
Abstract
The introduction of CFTR modulators has dramatically shifted the clinical management of cystic fibrosis (CF) from a life-limiting pediatric condition to a chronic disease with broader health implications. This review explores the impact of these advancements on lung immunology and the emerging spectrum [...] Read more.
The introduction of CFTR modulators has dramatically shifted the clinical management of cystic fibrosis (CF) from a life-limiting pediatric condition to a chronic disease with broader health implications. This review explores the impact of these advancements on lung immunology and the emerging spectrum of health challenges. While these modulators have reduced traditional pulmonary complications by mitigating inflammation and infection, they also introduce new considerations for long-term health management. As patients experience longer lives, issues such as the increased risk of certain cancers and other systemic complications like CF-related diabetes and liver disease are gaining attention. Understanding the interplay between CFTR modulators, immune response, and the development of these conditions is essential for optimizing patient outcomes. This review highlights the importance of integrated care strategies that address both the respiratory improvements and emerging health risks associated with longer life expectancy in CF patients. By fostering a comprehensive approach, we aim to enhance the overall quality of life and address the complex needs of individuals navigating CF in the modern therapeutic landscape. Full article
(This article belongs to the Section Molecular Medicine)
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13 pages, 3532 KB  
Article
A Mesophilic Argonaute from Cohnella algarum Mediates Programmable DNA/RNA Cleavage with Distinctive Guide Specificity
by Yanhong Peng, Wang Pan, Yang Wang, Yang Liu and Lixin Ma
Biomolecules 2025, 15(10), 1459; https://doi.org/10.3390/biom15101459 - 16 Oct 2025
Viewed by 360
Abstract
Argonaute (Ago) proteins are ubiquitous across all domains of life. Some prokaryotic Agos (pAgos) function as endonucleases that utilize short nucleic acid guides to recognize and cleave complementary targets. Yet, considerable diversity within pAgos leaves many of their biochemical and functional features insufficiently [...] Read more.
Argonaute (Ago) proteins are ubiquitous across all domains of life. Some prokaryotic Agos (pAgos) function as endonucleases that utilize short nucleic acid guides to recognize and cleave complementary targets. Yet, considerable diversity within pAgos leaves many of their biochemical and functional features insufficiently understood. This study characterizes CalAgo, an pAgo from the mesophilic bacterium Cohnella algarum, which demonstrates DNA-guided DNA endonuclease and RNA endonuclease activities at physiological temperatures. CalAgo’s cleavage activity depends on Mn2+ and Mg2+ ions and remains effective across a wide range of temperatures and pH levels. CalAgo utilizes only short guides ranging from 15 to 21 nucleotides (nt) in length, in contrast to other reported pAgos that target both DNA and RNA, which often exhibit broad guide selectivity. CalAgo preferentially loads 5′-phosphorylated guides and shows no significant preference among guides with different 5′-end nucleotides. CalAgo is sensitive to guide–target mismatches, and introducing a single mismatch at positions 12 or 15 of the guide strand abolished detectable activity. Structural modeling suggests that this unique guide specificity may originate from structural features in its PAZ domain involved in 3′-guide binding. In summary, this study deepens insight into mesophilic pAgos and supports their potential utility in nucleic acid-based applications. Full article
(This article belongs to the Section Molecular Genetics)
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24 pages, 3165 KB  
Review
The Clinical Implications of Progesterone in Preeclampsia
by Zhenzhen Liu and Weirong Gu
Biomolecules 2025, 15(10), 1458; https://doi.org/10.3390/biom15101458 - 15 Oct 2025
Viewed by 586
Abstract
Preeclampsia is a severe complication affecting both maternal and neonatal health and is becoming a significant global public health issue. As a vital steroid hormone, progesterone (P4) plays a crucial role during pregnancy and in regulating various physiological processes. Recent studies have indicated [...] Read more.
Preeclampsia is a severe complication affecting both maternal and neonatal health and is becoming a significant global public health issue. As a vital steroid hormone, progesterone (P4) plays a crucial role during pregnancy and in regulating various physiological processes. Recent studies have indicated that P4 is not only involved in pregnancy maintenance, but may also be closely related to preeclampsia pathogenesis and prevention. Previous research has suggested that P4 may participate in the mechanism of preeclampsia by regulating vascular function, immune responses, and placental function. Moreover, key enzymes and metabolites involved in the synthesis and metabolism of P4 are also associated with preeclampsia onset. Additionally, the potential value of clinically applying P4 in preventing and treating preeclampsia has been shown; however, the corresponding clinical practices require further validation and optimization. This study aimed to review the physiological effects, pathological functions, and clinical applications of P4 in preeclampsia, providing evidence for future research and clinical practice. Full article
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20 pages, 11750 KB  
Article
Trandolapril Attenuates Pro-Arrhythmic Downregulation of Cx43 and Cx40 in Atria of Volume Overloaded Hypertensive and Normotensive Rats
by Matúš Sýkora, Katarína Ondreják Andelová, Alexandra Mrvová, Barbara Szeiffová Bačová and Narcis Tribulová
Biomolecules 2025, 15(10), 1457; https://doi.org/10.3390/biom15101457 - 15 Oct 2025
Viewed by 383
Abstract
Pressure overload in non-treated or resistant hypertension (HTN) increases the risk of heart failure (HF) as well as the occurrence of fatal ventricular arrhythmias and stroke-provoking atrial fibrillation (AF), while perturbed connexin-43 (Cx43) and Cx40 might be involved. In addition, kidney dysfunction may [...] Read more.
Pressure overload in non-treated or resistant hypertension (HTN) increases the risk of heart failure (HF) as well as the occurrence of fatal ventricular arrhythmias and stroke-provoking atrial fibrillation (AF), while perturbed connexin-43 (Cx43) and Cx40 might be involved. In addition, kidney dysfunction may facilitate hemodynamic volume overload and congestive HF. We investigated the impact of volume overload on Cx43 and Cx40 in right and left heart atria of hypertensive pressure overloaded Ren-2 transgenic (TGR) strain and normotensive Hannover Sprague Dawley (HSD) rats, as well as the efficacy of renin–angiotensin blockade with trandolapril and losartan. Key novel findings revealed lower levels of Cx43 and Cx40 proteins in left as well as right heart atria in pressure overloaded hypertensive rats compared to normotensive rats. There was a significant decrease in Cx43 and Cx40 proteins due to volume overload in both atria of normotensive as well as hypertensive rats. Treatment with trandolapril increased Cx43 and Cx40 levels in right and left heart atria of normotensive as well as hypertensive volume overloaded rats. While losartan increased Cx43 and did not affect Cx40 in left and right heart atria of volume overloaded rats. Findings of this study point out that right heart atria of normotensive as well as hypertensive rats are more susceptible to volume overload comparing to the left heart atria. Trandolapril attenuated pro-arrhythmic downregulation of Cx43 and Cx40 in atria of volume overloaded normotensive as well as hypertensive rats. This fact as well as examining AF inducibility requires further investigation. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Cardiopathy and Therapeutic Strategies)
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24 pages, 2125 KB  
Article
Enhanced Anti-Nociception by Novel Dual Antagonists for 5-HT2AR and mGluR5 in Preclinical Models of Pain
by Daekyu Choi, Hyun Jin Heo, Haeyoung Shin, Jayzoon Im, Geonho Lee, Ah Hyun Kim, Kwang-Hyun Hur, Yoonmi Nho, Choon-Gon Jang and Hanmi Lee
Biomolecules 2025, 15(10), 1456; https://doi.org/10.3390/biom15101456 - 15 Oct 2025
Viewed by 504
Abstract
Extensive research has focused on developing anti-nociceptive therapy by targeting specific molecular pathways. Among these, the serotonin 2A receptor (5-HT2AR) and metabotropic glutamate receptor 5 (mGluR5) are recognized as key mediators of neuropathic pain. However, the therapeutic potential of their simultaneous inhibition remains [...] Read more.
Extensive research has focused on developing anti-nociceptive therapy by targeting specific molecular pathways. Among these, the serotonin 2A receptor (5-HT2AR) and metabotropic glutamate receptor 5 (mGluR5) are recognized as key mediators of neuropathic pain. However, the therapeutic potential of their simultaneous inhibition remains largely unexplored. In this study, we evaluated the efficacy of dual antagonism of 5-HT2AR and mGluR5 using spinal nerve ligation (SNL) and formalin-induced pain models in male Sprague–Dawley rats. Co-administration of selective antagonists significantly enhanced anti-allodynic and anti-nociceptive effects, as evidenced by increased withdrawal thresholds and reduced pain-related behaviors compared to monotherapy. The analgesic efficacy of dual antagonism was comparable to that of gabapentin and morphine. Additionally, novel small molecules designed to concurrently inhibit 5-HT2AR and mGluR5 exerted dose-dependent anti-nociceptive effects by suppressing excitatory postsynaptic responses and inhibiting the phosphorylation of ERK and AKT signaling molecules. Importantly, unlike morphine, repeated administration of the dual antagonist maintained anti-allodynic efficacy with a low potential of abuse. These findings may indicate the promise of simultaneous 5-HT2AR and mGluR5 antagonism as a novel and potentially safer strategy for managing chronic neuropathic pain. Full article
(This article belongs to the Section Molecular Medicine)
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21 pages, 1688 KB  
Review
Circular RNAs in Cardiovascular Disease: Mechanisms, Biomarkers, and Therapeutic Frontiers
by Rudaynah Alali, Mohammed Almansori, Chittibabu Vatte, Mohammed S. Akhtar, Seba S. Abduljabbar, Hassan Al-Matroud, Mohammed J. Alnuwaysir, Hasan A. Radhi, Brendan Keating, Alawi Habara and Amein K. Al-Ali
Biomolecules 2025, 15(10), 1455; https://doi.org/10.3390/biom15101455 - 15 Oct 2025
Viewed by 775
Abstract
Circular RNAs (circRNAs) have emerged as crucial cardiovascular regulators through gene expression modulation, microRNA sponging, and protein interactions. Their covalently closed structure confers exceptional stability, making them detectable in blood and tissues as potential biomarkers. This review explores current research examining circRNAs across [...] Read more.
Circular RNAs (circRNAs) have emerged as crucial cardiovascular regulators through gene expression modulation, microRNA sponging, and protein interactions. Their covalently closed structure confers exceptional stability, making them detectable in blood and tissues as potential biomarkers. This review explores current research examining circRNAs across cardiovascular diseases, including atherosclerosis, myocardial infarction, and heart failure. We highlight the control that circRNA exerts over endothelial function, smooth muscle switching, inflammatory recruitment, and cardiomyocyte survival. Key findings distinguish frequently disease-promoting circRNAs (circANRIL, circHIPK3) from context-dependent regulators (circFOXO3). Compartment-specific controllers include endothelial stabilizers (circGNAQ), smooth muscle modulators (circLRP6, circROBO2), and macrophage regulators (circZNF609), functioning as tunable rheostats across vascular compartments. Overall, the literature suggests that circRNAs represent promising tools in two translational avenues: (i) blood-based multimarker panels for precision diagnosis and (ii) targeted modulation of pathogenic circuits. Clinical translation will require precise cell-type targeting, efficient delivery to cardiovascular tissues, and rigorous mitigation of off-target effects. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cardiology 2025)
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23 pages, 4583 KB  
Article
Apolipoprotein B48 Knockout Ameliorates High-Fat-Diet-Induced Metabolic Impairment in Mice
by Yale Tang, Chao Wang, Luxuan Li, Xiaoyu Wang, Linquan Yang, Xing Wang, Luping Ren and Guangyao Song
Biomolecules 2025, 15(10), 1454; https://doi.org/10.3390/biom15101454 - 15 Oct 2025
Viewed by 434
Abstract
This study aimed to investigate whether knockout of the ApoB48 gene improves lipid metabolism disorders induced by a high-fat diet (HFD) in mice. Clustered regularly interspaced short palindromic repeats–Cas9 gene editing technology was used to knock out the ApoB48 gene in C57BL/6J mice, [...] Read more.
This study aimed to investigate whether knockout of the ApoB48 gene improves lipid metabolism disorders induced by a high-fat diet (HFD) in mice. Clustered regularly interspaced short palindromic repeats–Cas9 gene editing technology was used to knock out the ApoB48 gene in C57BL/6J mice, and genotype identification showed heterozygosity (HE, ApoB48 +/−). Subsequently, eight HE and eight wild-type (WT) mice were fed a HFD for 12 weeks. Fasting blood glucose, and insulin levels were decreased in ApoB48 +/− mice. The intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test showed mild insulin resistance. Moreover, it delayed the development of atherosclerosis and intestinal tissue damage. Differential metabolites such as ceramide, sphingosine, and sphingosine-1-phosphate were identified using liquid chromatography–mass spectrometry, and differentially expressed proteins, including ceramide synthase 6 (CerS6), protein phosphatase 2A (PP2A), and protein kinase B (AKT), were indicated by the Kyoto Encyclopaedia of Genes and Genomes. Therefore, decreased expression of ApoB48 can ameliorate lipid metabolism disorders induced by an HFD, which may be related to the CerS6/PP2A/AKT pathway. This might represent a new approach for exploring methods to treat hyperlipidaemia. Full article
(This article belongs to the Collection Feature Papers in Lipids)
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