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Biomolecules, Volume 15, Issue 10 (October 2025) – 124 articles

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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
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
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
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
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
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
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
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
Abstract
In the present study, seven previously undescribed resin glycosides, designated cusponins I-VII (17), 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 (17), 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 37 contained the uncommon aglycone, 11S-hydroxypentadecanoic acid. Bioactivity assessments demonstrated that compounds 14, 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 24
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 200
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
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 189
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 133
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 133
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 293
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 192
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
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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 229
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, 1687 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 316
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 233
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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20 pages, 2585 KB  
Review
An Overview of Contrasting Experimental Results on Dynamics of Kinesin-1 Molecular Motors: Insight into the Underlying Mechanism
by Ping Xie
Biomolecules 2025, 15(10), 1453; https://doi.org/10.3390/biom15101453 - 14 Oct 2025
Viewed by 296
Abstract
The conventional kinesin (kinesin-1) molecular motor is a prototypical member of the kinesin superfamily. It can processively step on microtubules toward the plus end by hydrolyzing ATP molecules, performing the biological function of shuttling cargos in cells. Its dynamics have been thoroughly studied [...] Read more.
The conventional kinesin (kinesin-1) molecular motor is a prototypical member of the kinesin superfamily. It can processively step on microtubules toward the plus end by hydrolyzing ATP molecules, performing the biological function of shuttling cargos in cells. Its dynamics have been thoroughly studied using various methods including biochemical measurement, single molecule imaging, single molecule optical trapping, and so on. While most of the experiments yielded consistent results on the dynamics of the motor, a lot of conflicting experimental results have also been presented. Here, a brief review is given of the diverse conflicting experimental results. Furthermore, a model for the chemomechanical coupling of the motor is briefly reviewed, which can consistently and quantitatively explain these conflicting experimental results in addition to the other experimental results. A consistent explanation of the diverse conflicting experimental results with the same model is an essential criterion for determining the correctness of the model. Full article
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26 pages, 1599 KB  
Review
Inflammaging and Senescence-Driven Extracellular Matrix Remodeling in Age-Associated Cardiovascular Disease
by Ewelina Młynarska, Adrianna Kowalik, Agnieszka Krajewska, Natalia Krupińska, Weronika Marcinkowska, Jakub Motor, Aleksandra Przybylak, Katarzyna Tłustochowicz, Jacek Rysz and Beata Franczyk
Biomolecules 2025, 15(10), 1452; https://doi.org/10.3390/biom15101452 - 14 Oct 2025
Viewed by 387
Abstract
Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and [...] Read more.
Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and heart failure. Central to this process are chronic low-grade inflammation (inflammaging), oxidative stress, cellular senescence, and maladaptive extracellular matrix remodeling. These hallmarks of aging interact to impair endothelial function, promote fibrosis, and compromise cardiac and vascular integrity. Key molecular pathways—including the renin–angiotensin–aldosterone system, NF-κB, NLRP3 inflammasome, IL-6, and TGF-β signaling—contribute to the transdifferentiation of vascular cells, immune dysregulation, and progressive tissue stiffening. We also highlight the role of the senescence-associated secretory phenotype and mitochondrial dysfunction in perpetuating inflammatory and fibrotic cascades. Emerging molecular therapies offer promising strategies to reverse or halt maladaptive remodeling. These include senescence-targeting agents (senolytics), Nrf2 activators, RNA-based drugs, and ECM-modulating compounds such as MMP inhibitors. Additionally, statins and anti-inflammatory biologics (e.g., IL-1β inhibitors) exhibit pleiotropic effects that extend beyond traditional risk factor control. Understanding the molecular basis of remodeling is essential for guiding future research and improving outcomes in older adults at risk of CVD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Cardiovascular Remodeling)
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22 pages, 2320 KB  
Article
Evaluation of the Emulsification Properties of Marine-Derived Rhamnolipids for Encapsulation: A Comparison with Commercial Surfactants
by Sara Gorrieri, Carmine Buonocore, Giulia Donà, Chiara Pezzoli, Martina Vakarelova, Daniela Coppola, Fortunato Palma Esposito, Donatella de Pascale, Gerardo Della Sala, Francesca Zanoni and Pietro Tedesco
Biomolecules 2025, 15(10), 1451; https://doi.org/10.3390/biom15101451 - 14 Oct 2025
Viewed by 245
Abstract
Rhamnolipids are a class of glycolipids known for their surface and emulsifying activity. These molecules, produced by a few Gram-negative genera, mostly Pseudomonas, offer natural alternatives to synthetic surfactants in different industrial fields. This study examines the emulsifying and encapsulation performance of Rhamnolipids [...] Read more.
Rhamnolipids are a class of glycolipids known for their surface and emulsifying activity. These molecules, produced by a few Gram-negative genera, mostly Pseudomonas, offer natural alternatives to synthetic surfactants in different industrial fields. This study examines the emulsifying and encapsulation performance of Rhamnolipids derived from the marine Antarctic bacterium Pseudomonas gessardii M15, comparing its emulsification ability and stability with those of commercial surfactants, Sodium dodecyl sulfate (SDS) and sucrose esters (SE), under extreme conditions of temperature and pH. The Rhamolipids were used to encapsulate Coenzyme Q10 with Arabic gum as the carrier matrix. Rhamnolipids exhibited surface and emulsifying activity comparable to that of SDS and superior to SE at neutral and basic pH levels. Their performance declined under acidic conditions, whereas exposure to 90 °C had no significant effects. The encapsulation efficiency of Coenzyme Q10 was significantly higher in the case of Rhamnolipids, with a percentage of encapsulated compound of 99.6 ± 0.2%, compared to the 38.2 ± 7.1% found when SDS was used. Rhamnolipids extracted from Pseudomonas gessardii M15 exhibit strong potential as a natural surfactant, particularly in formulations that require thermal stability and effective encapsulation. These findings support its use as a sustainable alternative to synthetic agents in diverse industrial settings. Full article
(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)
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12 pages, 1205 KB  
Article
Alterations of Bioactive Lipid Profiles in the Retina Following Traumatic Optic Neuropathy in Mice
by Min Young Kim, Nandini Koneru, Gieth Alahdab, Michael Risner, Ahmed S. Ibrahim, Krishna Rao Maddipati and Mohamed Al-Shabrawey
Biomolecules 2025, 15(10), 1450; https://doi.org/10.3390/biom15101450 - 14 Oct 2025
Viewed by 232
Abstract
Traumatic optic neuropathy (TON) causes vision loss through compression and contusion, yet there is no consensus on the most effective treatment. Polyunsaturated fatty acid (PUFA)-derived bioactive lipids metabolized by lipoxygenase (LOX), cytochrome P450 (CYP), and cyclooxygenase (COX) enzymes are known mediators of inflammation [...] Read more.
Traumatic optic neuropathy (TON) causes vision loss through compression and contusion, yet there is no consensus on the most effective treatment. Polyunsaturated fatty acid (PUFA)-derived bioactive lipids metabolized by lipoxygenase (LOX), cytochrome P450 (CYP), and cyclooxygenase (COX) enzymes are known mediators of inflammation and neurodegeneration. However, their role in TON-related retinal pathology remains unclear. Controlled orbital impact (COI) was used to induce unilateral TON in mice with controlled velocity (2–3 m/s), with the fellow eye serving as an internal control. Retina tissues were collected three days post-injury and analyzed by LC/MS to quantify bioactive lipid metabolites from ω−6 and ω−3 PUFAs. Statistical analysis was performed using paired, nonparametric Wilcoxon signed-rank tests with Benjamini–Hochberg false discovery rate (FDR) correction. Results showed that among 38 reliably detected metabolites, no individual lipid showed a statistically significant difference between TON and control eyes after FDR correction (q < 0.05). However, both individual and pathway-level analysis revealed consistent trends toward increased expression of LOX- and CYP-derived metabolites across FDA PUFA substrates, including arachidonic acid (AA), linoleic acid (LA), and docosahexaenoic acid (DHA). These findings support further investigation into lipid-mediated inflammation in TON and its potential as a therapeutic target, particularly through expanding both the sample size and the post-TON time periods. Full article
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17 pages, 4126 KB  
Article
Mechanistic Insights into the Protective Effects of Cryptotanshinone Against CCl4-Induced Acute Liver Injury in Mice via Network Pharmacology and Transcriptomics
by Xin Zhang, Qiulin Luo, Yanting Hu, Puyang Gong, Yunsong Zhang and Li Zhang
Biomolecules 2025, 15(10), 1449; https://doi.org/10.3390/biom15101449 - 14 Oct 2025
Viewed by 207
Abstract
Cryptotanshinone (CPT), the main active compound of Salvia miltiorrhiza, is known for its anti-inflammatory, antioxidative, and antifibrotic effects. In this study, the hepatoprotective effect and mechanisms of CPT were explored using transcriptome and network pharmacology. A carbon tetrachloride-induced acute liver injury (ALI) [...] Read more.
Cryptotanshinone (CPT), the main active compound of Salvia miltiorrhiza, is known for its anti-inflammatory, antioxidative, and antifibrotic effects. In this study, the hepatoprotective effect and mechanisms of CPT were explored using transcriptome and network pharmacology. A carbon tetrachloride-induced acute liver injury (ALI) mouse model was established. The anti-ALI effects of different doses of CPT were evaluated by analysis of biochemical indicators, histopathological staining, and immunohistochemical analysis. Combining network pharmacology with transcriptomic analysis revealed therapeutic targets, which were subsequently validated through polymerase chain reaction and Western blotting. CPT (40 mg/kg) treatment significantly reduced the levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, tumor necrosis factor-α, interleukin-6, and interleukin-1β in model mice and regulated oxidative stress indicators, including malonaldehyde, superoxide dismutase, glutathione, and catalase. MCP-1 protein expression in the liver was inhibited by treatment with CPT. Network pharmacology revealed 72 core targets involved in the treatment of ALI by CPT. By combining transcriptomic data from liver tissue, three key targets—TNF-α, TLR9, and ADORA2B—were identified, along with the TLR, IL-17, and TNF signaling pathways. Furthermore, PCR and Western blot assays revealed that CPT significantly decreased TNF-α, TLR9, and ADORA2B expression levels in the livers of ALI mice. In conclusion, the hepatoprotective effects of CPT may be related to the suppression of TNF-α-, TLR9-, and ADORA2B-mediated inflammation, oxidative stress, and apoptosis. These results provide a foundation for the development of CPT as a potential therapeutic agent for ALI. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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28 pages, 1285 KB  
Review
Mucopolysaccharidoses—What Clinicians Need to Know: A Clinical, Biochemical, and Molecular Overview
by Patryk Lipiński, Agnieszka Różdżyńska-Świątkowska, Karolina Wiśniewska, Joanna Rusecka, Agnieszka Ługowska, Zbigniew Żuber, Aleksandra Jezela-Stanek, Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, Grzegorz Węgrzyn and Anna Tylki-Szymańska
Biomolecules 2025, 15(10), 1448; https://doi.org/10.3390/biom15101448 - 14 Oct 2025
Viewed by 284
Abstract
The classification of mucopolysaccharidoses (MPSs) includes the classical types (I; II; III with subtypes A, B, C, and D; IV with subtypes A and B; VI; VII; IX; X), associated with impaired lysosomal degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs), as a [...] Read more.
The classification of mucopolysaccharidoses (MPSs) includes the classical types (I; II; III with subtypes A, B, C, and D; IV with subtypes A and B; VI; VII; IX; X), associated with impaired lysosomal degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs), as a result of deficiency in the specific enzymes responsible for GAG degradation (MPS IIIE has so far been identified only in animal models) and MPS-plus syndrome (MPSPS), which is characterized by an accumulation of undegraded GAGs, arising from impaired endosomal trafficking and inefficient delivery of these compounds to lysosomes (due to the VPS33A protein deficiency with normal GAG-degrading enzyme activities assessed in vitro). The aim of this comprehensive review is to provide physicians with a clinical, biochemical, and molecular overview of MPS manifestation. A brief summary of available and emerging therapies is also presented. Full article
(This article belongs to the Special Issue Updates on Molecular Mechanisms of Lysosomal Storage Disease)
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29 pages, 2056 KB  
Review
From Gut to Heart: Targeting Trimethylamine N-Oxide as a Novel Strategy in Heart Failure Management
by Zehui Ding, Yunfeng Yu, Jiaming Wei, Ziyan Wang, Ruifang Lin, Ya Li and Zhihua Guo
Biomolecules 2025, 15(10), 1447; https://doi.org/10.3390/biom15101447 - 13 Oct 2025
Viewed by 409
Abstract
Heart failure (HF) marks the culmination of numerous cardiac pathologies, presenting a major medical hurdle in prevention and treatment. In recent years, with the advancements in genomics and metabolomics, research has demonstrated that gut microbiota plays a significant role in the pathogenesis of [...] Read more.
Heart failure (HF) marks the culmination of numerous cardiac pathologies, presenting a major medical hurdle in prevention and treatment. In recent years, with the advancements in genomics and metabolomics, research has demonstrated that gut microbiota plays a significant role in the pathogenesis of HF. Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite and primarily sourced from foods abundant in choline, L-carnitine, and betaine. Research has shown that patients with HF exhibit higher levels of TMAO. Accumulating evidence has indicated that TMAO directly or indirectly mediates the occurrence and development of HF through multiple mechanisms. Furthermore, TMAO functions as a crucial prognostic marker in HF. Therefore, TMAO emerges as a potential therapeutic target for HF. This article reviews the generation and metabolic pathways of TMAO, emphasizes its pathophysiological mechanisms in HF, and explores promising therapeutic approaches targeting TMAO, offering novel insights and strategies for HF management. Full article
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17 pages, 2437 KB  
Article
Bacterial Lysates Modulate Human Macrophage Responses by Inducing BPI Production and Autophagy
by Yael García-González, María Teresa Herrera, Esmeralda Juárez, Teresa Santos-Mendoza, Yolanda González, Eduardo Becerril-Vargas and Silvia Guzmán-Beltrán
Biomolecules 2025, 15(10), 1446; https://doi.org/10.3390/biom15101446 - 13 Oct 2025
Viewed by 241
Abstract
Bacterial lysates have emerged as promising immunomodulatory agents that can enhance innate immune responses. Given the crucial role of macrophages in recognizing and controlling intracellular pathogens such as Mycobacterium tuberculosis, this study aimed to evaluate the immunological effects of selected bacterial lysates on [...] Read more.
Bacterial lysates have emerged as promising immunomodulatory agents that can enhance innate immune responses. Given the crucial role of macrophages in recognizing and controlling intracellular pathogens such as Mycobacterium tuberculosis, this study aimed to evaluate the immunological effects of selected bacterial lysates on human monocyte-derived macrophages (MDMs). We examined the ability of commercial bacterial lysates, Pulmonarom, Ismigen, Uro-Vaxom, and a lysate of M. tuberculosis H37 Ra (LMtb) to stimulate the production of key pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-8. In addition, we investigated whether these lysates could modulate the expression of bactericidal/permeability-increasing protein (BPI), a critical antimicrobial effector, and assessed their ability to reduce the intracellular burden of mycobacteria and induce autophagy. The results demonstrate diverse immunostimulatory profiles among the lysates, highlighting differences in both inflammatory and antimicrobial responses that may be relevant for host-directed therapeutic strategies against tuberculosis. Notably, beyond the in vitro antimycobacterial activity observed for BPI, this protein was also found to be elevated in both serum and bronchoalveolar lavage fluid from patients with active TB, reflecting local and systemic immune activation. Furthermore, the reduction in BPI levels after treatment suggests its potential utility for following the dynamics of infection. Full article
(This article belongs to the Section Cellular Biochemistry)
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17 pages, 800 KB  
Review
Sirtuin Family in Acute Kidney Injury: Insights into Cellular Mechanisms and Potential Targets for Treatment
by Songyuan Yang, Wu Chen, Siqi Li, Sheng Zhao and Fan Cheng
Biomolecules 2025, 15(10), 1445; https://doi.org/10.3390/biom15101445 - 13 Oct 2025
Viewed by 334
Abstract
Acute kidney injury (AKI) is a frequent clinical and pathological condition, often resulting from factors like ischemia, toxins, or infections, which cause a sudden and severe decline in renal function. This, in turn, significantly affects patients’ overall health and quality of life. The [...] Read more.
Acute kidney injury (AKI) is a frequent clinical and pathological condition, often resulting from factors like ischemia, toxins, or infections, which cause a sudden and severe decline in renal function. This, in turn, significantly affects patients’ overall health and quality of life. The Sirtuin family (SIRTs), a group of Nicotinamide Adenine Dinucleotide (NAD+)-dependent deacetylases, is critically involved in key biological processes such as cellular metabolism, stress responses, aging, and DNA repair. Recent research has highlighted the vital role of SIRTs, such as SIRT1, SIRT3, and SIRT6, in the development and progression of AKI. These proteins help mitigate renal injury and facilitate kidney repair through mechanisms like antioxidant activity, anti-inflammatory responses, cellular repair, and energy metabolism. Additionally, the deacetylase activity of the SIRTs confers protection against AKI by modulating mitochondrial function, decreasing oxidative stress, and regulating autophagy. Although the precise mechanisms underlying the role of Sirtuins in AKI are still being explored, their potential as therapeutic targets is increasingly being recognized. This paper will discuss the mechanisms by which the SIRTs influence AKI and examine their potential in a future therapeutic strategy. Full article
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24 pages, 1507 KB  
Article
Glycan Signatures on Neutrophils in an Equine Model for Autoimmune Uveitis
by Carolin J. Sprenzel, Barbara Amann, Cornelia A. Deeg and Roxane L. Degroote
Biomolecules 2025, 15(10), 1444; https://doi.org/10.3390/biom15101444 - 12 Oct 2025
Viewed by 272
Abstract
Glycosylation of surface proteins is a crucial post-translational modification that reflects the activation status of neutrophils, the predominant leukocyte subset in humans and horses. Neutrophils have emerged as active contributors to diseases mediated by the adaptive immune system, such as equine recurrent uveitis [...] Read more.
Glycosylation of surface proteins is a crucial post-translational modification that reflects the activation status of neutrophils, the predominant leukocyte subset in humans and horses. Neutrophils have emerged as active contributors to diseases mediated by the adaptive immune system, such as equine recurrent uveitis (ERU), a sight-threatening disease in horses and a unique model for studying the pathogenesis of autoimmune uveitis in humans. Since changes in surface glycosylation can impact neutrophil function, we were interested in the surface glycosylation landscape on neutrophils from healthy horses and the potential changes in surface glyco-signatures in ERU. Using 35 different plant lectins, we outlined a profile of surface-exposed glycan moieties on equine neutrophils and detected significantly increased O-glycosylation in a diseased state through Jacalin (JAC) binding via flow cytometry. Subsequent molecular weight comparison of JAC pull-down assay data and neutrophil proteomics indicated the surface proteins Integrin beta-2 and CUB domain-containing protein 1 as potential anchors for increased O-glycan levels in ERU. These findings give novel insights into neutrophil surface glycosylation in health and disease and propose O-glycosylation as a possible biomarker for autoimmune uveitis. Full article
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21 pages, 939 KB  
Review
Recent Advances in the Development and Clinical Use of HER2 Inhibitors in Non-Small Cell Lung Cancer
by Richy Ekyalongo, Toshimitsu Yamaoka and Junji Tsurutani
Biomolecules 2025, 15(10), 1443; https://doi.org/10.3390/biom15101443 - 12 Oct 2025
Viewed by 419
Abstract
Alterations in the human epidermal growth factor receptor 2 (HER2) gene are well-recognized oncogenic drivers and therapeutic targets in non-small cell lung cancer (NSCLC). The first anti-HER2 inhibitor, trastuzumab-deruxtecan, was approved for previously treated advanced NSCLC with HER2 mutations, which accounts [...] Read more.
Alterations in the human epidermal growth factor receptor 2 (HER2) gene are well-recognized oncogenic drivers and therapeutic targets in non-small cell lung cancer (NSCLC). The first anti-HER2 inhibitor, trastuzumab-deruxtecan, was approved for previously treated advanced NSCLC with HER2 mutations, which accounts for 2–4% of NSCLC. The first anti-HER2 antibody, trastuzumab, was approved for HER2-positive metastatic breast cancer in 1998, and a combination therapy comprising trastuzumab, pertuzumab, and docetaxel demonstrated efficacy in the first-line setting. Some EGFR-tyrosine kinase inhibitors (TKIs) have been evaluated as pan-HER TKIs but have shown limited benefits in HER2-altered NSCLC. However, HER2-specific TKIs, such as zongertinib and BAY2927088, have demonstrated encouraging results. Zongertinib was the first HER2-specific TKI to be approved by the FDA in 2025 for previously treated ERBB2-mutated advanced NSCLC. In this narrative review, we have summarized the latest research on the biology of HER2 signaling, HER2 alterations, HER2-targeting therapies, and challenges of treating HER2-overexpressing or -mutated NSCLC. Despite different targets of HER2 mutations in NSCLC and HER2 amplification/overexpression in breast cancer, the development of HER2-targeting agents has been more advanced in breast cancer than in NSCLC. Therefore, pivotal clinical studies in breast cancer may help in identifying more effective therapies for NSCLC. Full article
(This article belongs to the Special Issue Molecular Pathology, Diagnostics, and Therapeutics of Lung Disease)
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