Biomolecules

13 pages, 250 KB

Open AccessReview

Nanocomposite Biomaterials for Tissue-Engineered Hernia Repair: A Review of Recent Advances

by Octavian Andronic, Alexandru Cosmin Palcau, Alexandra Bolocan, Alexandru Dinulescu, Daniel Ion and Dan Nicolae Paduraru

Biomolecules 2025, 15(9), 1348; https://doi.org/10.3390/biom15091348 - 22 Sep 2025

Viewed by 749

Abstract

Hernia repair is among the most frequent procedures in general surgery, traditionally performed with synthetic meshes such as polypropylene. While effective in reducing recurrence, these materials are biologically inert and often trigger chronic inflammation, fibrosis, pain, and impaired abdominal wall function, with a [...] Read more.

Hernia repair is among the most frequent procedures in general surgery, traditionally performed with synthetic meshes such as polypropylene. While effective in reducing recurrence, these materials are biologically inert and often trigger chronic inflammation, fibrosis, pain, and impaired abdominal wall function, with a significant impact on long-term quality of life. A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus databases, and relevant preclinical, clinical, and review articles were synthesized within a narrative review framework. Recent advances in tissue engineering propose a shift from passive reinforcement to regenerative strategies based on biomimetic scaffolds, nanomaterials, and nanocomposites that replicate the extracellular matrix, enhance cell integration, and provide controlled drug delivery. Nanotechnology enables localized release of anti-inflammatory, antimicrobial, and pro-angiogenic agents, while electrospun nanofibers and composite scaffolds improve strength and elasticity. In parallel, 3D printing allows for patient-specific implants with tailored architecture and regenerative potential. Although preclinical studies show encouraging results, clinical translation remains limited by cost, regulatory constraints, and long-term safety uncertainties. Overall, these innovations highlight a transition toward personalized and regenerative hernia repair, aiming to improve durability, function, and patient quality of life. Full article

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

19 pages, 629 KB

Open AccessReview

Nutraceuticals Against Oxidative Stress in Allergic Diseases

by Marilena Di Salvo, Alessandra Ventre, Enrica Dato, Marco Casciaro and Sebastiano Gangemi

Biomolecules 2025, 15(9), 1347; https://doi.org/10.3390/biom15091347 - 20 Sep 2025

Viewed by 998

Abstract

Antioxidant mechanisms consist of both enzymatic and non-enzymatic compounds, which can be either endogenous or exogenous and play a crucial role in counteracting oxidative stress. These compounds are primarily obtained through the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, [...] Read more.

Antioxidant mechanisms consist of both enzymatic and non-enzymatic compounds, which can be either endogenous or exogenous and play a crucial role in counteracting oxidative stress. These compounds are primarily obtained through the diet. Vegetables, plants, and fruits contain a wide range of alkaloids, polyphenols, and terpenoids, collectively referred to as “phytochemicals.” Many of these substances are responsible for the beneficial properties of fruits and vegetables, which are essential components of a healthy lifestyle, contributing to the prevention of chronic diseases and the promotion of longevity. Nutraceuticals are bioactive substances present in food—or its components—that exert positive effects on health and may help prevent or treat various disorders. In this review, we examine the main applications of nutraceuticals in allergic disorders. The literature reports numerous studies on exogenous dietary antioxidant supplementation in various allergic conditions, including bronchial asthma, atopic dermatitis, food allergies, allergic rhino-conjunctivitis, urticaria, and angioedema. In some of these conditions, promising results have been observed. These positive outcomes are generally associated with a reduction in oxidative stress markers, enhancement of antioxidant systems, and, in some cases, anti-inflammatory effects. The administration of exogenous substances through food derivatives or dietary supplements, when scientifically standardized, has been proven to be effective. However, further large-scale, unbiased studies are needed—particularly those that include a broader range of oxidative stress biomarkers. Full article

(This article belongs to the Special Issue Antioxidant Effects of Bioactive Compounds)

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16 pages, 1769 KB

Open AccessReview

MYC and Metabolomics: Can We Use What We Know for DLBCL Subtyping and Diagnosis?

by Adrian Florentin Suman, Davide De Luca, Melania Gaggini and Francesco Cucco

Biomolecules 2025, 15(9), 1346; https://doi.org/10.3390/biom15091346 - 20 Sep 2025

Viewed by 485

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a molecular and clinical heterogenous entity, and, over the past 30 years, many efforts have been made in trying to dissect this diverseness and identify biomarkers capable of efficiently stratifying DLBCL patients and spotting the ones showing [...] Read more.

Diffuse large B-cell lymphoma (DLBCL) is a molecular and clinical heterogenous entity, and, over the past 30 years, many efforts have been made in trying to dissect this diverseness and identify biomarkers capable of efficiently stratifying DLBCL patients and spotting the ones showing a worse clinical outcome. Despite the achievement in this research field, only a few biomarkers have been validated and introduced in a clinical setting. Among those, approximately 5–15% of DLBCL cases harbor MYC gene translocations, often involving immunoglobulin genes as a translocation partner, and concomitant point mutations, correlating with a poor response to standard therapies. However, given the difficulty in detecting these abnormalities requiring specialized techniques and high-quality specimens, the use of metabolomics (i.e., the study of small metabolites in body fluids and tissues) can offer a useful alternative for the identification of high-risk DLBCL patients. Amino acids (AAs) are metabolites essential in the process of tumorigenesis and can increase immune escape and drug resistance. Therefore, we review the use of metabolomics to improve the diagnosis and prognosis in DLBCL patients in relation to the MYC role in the regulation of amino acid metabolism, as these metabolites may be used as potential biomarkers in a clinical environment. Full article

(This article belongs to the Special Issue Omics Data Integration: Focusing on Molecular Biomarkers for Cancers and Diseases)

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25 pages, 639 KB

Open AccessReview

Perspectives on Alzheimer’s Disease Treatment Based on Counteracting Oxidative Stress

by Rafał Bilski, Stanisław Dąbkowski, Igor Kozieł, Michał Kozicki, Anna Małachowska, Mikołaj Przygocki and Oliwia Tyska

Biomolecules 2025, 15(9), 1345; https://doi.org/10.3390/biom15091345 - 19 Sep 2025

Viewed by 1659

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and one of the most pressing global health challenges. Increasing evidence highlights oxidative stress as a key factor in its pathogenesis, contributing to amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, and mitochondrial dysfunction. Oxidative stress markers, detected [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and one of the most pressing global health challenges. Increasing evidence highlights oxidative stress as a key factor in its pathogenesis, contributing to amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, and mitochondrial dysfunction. Oxidative stress markers, detected in the bodily fluids of AD patients, are considered promising diagnostic and prognostic tools. Despite extensive research, currently available therapies remain largely symptomatic, which emphasizes the need to develop novel, disease-modifying strategies. The aim of this review is to summarize current knowledge on the role of oxidative stress in the pathogenesis of AD and to evaluate therapeutic approaches aimed at its reduction. We discuss molecular mechanisms linking reactive oxygen species to neurodegeneration and present pharmacological strategies such as monoamine oxidase inhibitors and multifunctional agents, as well as natural antioxidants, dietary interventions, and novel therapeutic technologies. We pay particular attention to their efficacy, limitations, and translational challenges. A more profound understanding of oxidative stress-related mechanisms may facilitate the development of combined antioxidant, anti-inflammatory, and neuroprotective approaches, offering new perspectives for delaying disease progression and improving patient outcomes. Full article

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17 pages, 1784 KB

Open AccessReview

NLRP3 Inflammasome in Stress-Related Neuropsychiatric Disorders: Mechanisms of Neuron–Microglia–Astrocyte Crosstalk, HPA Axis Dysregulation, and Therapeutic Perspective

by Izabela Woźny-Rasała and Ewa Alicja Ogłodek

Biomolecules 2025, 15(9), 1344; https://doi.org/10.3390/biom15091344 - 19 Sep 2025

Viewed by 1492

Abstract

Chronic stress disrupts neuroimmune homeostasis and initiates CNS inflammation. This paper examines the molecular and cellular mechanisms that connect stress to the interplay among the nervous, endocrine, and immune systems, with a focus on the role of the NLRP3 inflammasome in neuroinflammatory processes. [...] Read more.

Chronic stress disrupts neuroimmune homeostasis and initiates CNS inflammation. This paper examines the molecular and cellular mechanisms that connect stress to the interplay among the nervous, endocrine, and immune systems, with a focus on the role of the NLRP3 inflammasome in neuroinflammatory processes. It discusses the dynamics of HPA axis, stress-induced changes in glucocorticoid and mineralocorticoid signaling, sympathetic nervous system activation, and the contribution of pro-inflammatory cytokines in brain immune activation. The NLRP3 inflammasome is described in terms of its structure, activation via a two-signal model, and its role in IL-1β and IL-18 maturation in neurons, microglia, and astrocytes. Preclinical evidence highlights the therapeutic potential of targeting NLRP3 in stress-related disorders, underscoring its key role in their pathophysiology. Full article

(This article belongs to the Section Cellular Biochemistry)

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19 pages, 2960 KB

Open AccessArticle

Interaction Between Heparan Sulfate Oligosaccharide and the Receptor-Binding Domain of the Wild-Type and Omicron Variant of the SARS-CoV-2 Spike Protein

by Marco Mandalari, Michela Parafioriti, Minghong Ni, Francesca Benevelli, Monica Civera, Stefano Elli and Marco Guerrini

Biomolecules 2025, 15(9), 1343; https://doi.org/10.3390/biom15091343 - 19 Sep 2025

Viewed by 581

Abstract

Heparan sulfate proteoglycans serve as initial attachment sites for several viruses and bacteria. Recent studies suggest that SARS-CoV-2 similarly exploits these glycosaminoglycans, facilitating conformational changes in the spike protein that promote the interaction between the receptor-binding domain (S1-RBD) and the cellular angiotensin-converting enzyme [...] Read more.

Heparan sulfate proteoglycans serve as initial attachment sites for several viruses and bacteria. Recent studies suggest that SARS-CoV-2 similarly exploits these glycosaminoglycans, facilitating conformational changes in the spike protein that promote the interaction between the receptor-binding domain (S1-RBD) and the cellular angiotensin-converting enzyme 2 receptor (ACE2), thereby triggering the virus internalization process. The molecular details that drive this process, particularly the co-receptor role of heparan sulfate (HS), remain incompletely understood. The interaction between an HS hexasaccharide (hexa) and the N343 glycosylated S1-RBD of the wild-type (WT) and Omicron variant of SARS-CoV-2 was investigated. The conformational properties of hexa with these S1-RBDs in unbound and bound states are explored using multiple independent MD simulations; the protein binding epitope of hexa, as well as the details of its interaction with S1-RBD of the Omicron variant, are characterized by comparing experimental and theoretical ¹H STD NMR signals. This investigation identifies the role played by the glycosyl moiety at N343 in potentially affecting this interaction in both WT and Omicron S1-RBD, explaining the observed low specificity and multi-modal nature of the interaction between HS oligosaccharides and these S1-RBDs. Full article

(This article belongs to the Special Issue Genetic and Structural Analyses of Coronaviruses: Insights into SARS-CoV-2 and Beyond)

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Graphical abstract

21 pages, 487 KB

Open AccessReview

Role of Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) in Patients with Chronic Heart Failure

by Pasqual Llongueras-Espí, Elena García-Romero, Josep Comín-Colet and José González-Costello

Biomolecules 2025, 15(9), 1342; https://doi.org/10.3390/biom15091342 - 19 Sep 2025

Viewed by 1097

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes and obesity due to their metabolic benefits. Beyond weight loss and glycemic control, emerging evidence suggests they may also exert cardioprotective effects. In the context of heart failure [...] Read more.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes and obesity due to their metabolic benefits. Beyond weight loss and glycemic control, emerging evidence suggests they may also exert cardioprotective effects. In the context of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF), GLP-1RAs have been associated with improvement in symptoms, physical capacity, biomarkers, and structural cardiac remodeling. These benefits appear to be independent of weight loss, suggesting additional mechanisms including anti-inflammatory effects, improved myocardial metabolism or modulation of epicardial adipose tissue. However, current data largely come from non-HF dedicated trials, with limited standardization of the HF phenotype. Results are overall inconsistent and may suggest potential harm in some cases, particularly in HF with reduced ejection fraction (HFrEF). This review aims to summarize the current evidence on the role of GLP-1RAs in heart failure, explore possible underlying mechanisms and highlight key gaps in knowledge. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders: 2nd Edition)

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29 pages, 2617 KB

Open AccessArticle

Investigation of the Effect of 2,3-Dihydrobenzoic Acid Acid (2,3-DHBA) on the Lipid Profiles of MCF-7 and MDA-MB-231 Human Breast Cancer Cells via an Untargeted Lipidomic Approach

by Büşra Daş and Serap Şahin

Biomolecules 2025, 15(9), 1341; https://doi.org/10.3390/biom15091341 - 19 Sep 2025

Viewed by 683

Abstract

Breast cancer (BC) is a primary cause of cancer-related mortality in women, making the development of novel therapeutic strategies essential. Altered lipid metabolism is a recognized hallmark of cancer, presenting a key therapeutic vulnerability. This study investigated the cytotoxic effects of the natural [...] Read more.

Breast cancer (BC) is a primary cause of cancer-related mortality in women, making the development of novel therapeutic strategies essential. Altered lipid metabolism is a recognized hallmark of cancer, presenting a key therapeutic vulnerability. This study investigated the cytotoxic effects of the natural phenolic compound 2,3-DHBA on MCF-7 (luminal A) and MDA-MB-231 (triple-negative) human breast cancer cells and characterized the associated changes in their lipid profiles via an untargeted lipidomic approach. The in vitro cytotoxicity of 2,3-DHBA was assessed using the MTT assay at 24, 48, and 72 h against both cancer cell lines and non-cancerous L-929 fibroblasts. Following treatment with the 48-h IC₅₀ concentrations (8.61 mM for MCF-7, 5.84 mM for MDA-MB-231), total lipids were extracted and analyzed. The results showed that 2,3-DHBA exerted potent time- and dose-dependent cytotoxic effects against both BC cell lines, with significantly higher selectivity for cancer cells over healthy fibroblasts. The more aggressive MDA-MB-231 line exhibited greater sensitivity. The lipidomic analysis revealed that 2,3-DHBA induced profound cell-specific alterations across all major lipid classes, including fatty acids, glycerolipids (GLs), glycerophospholipids (GPs), and sphingolipids (SPs). These changes suggest a multi-pronged mechanism involving the disruption of membrane integrity through GP remodeling, the attenuation of survival signaling via the GL network, and a critical shift in the sphingolipid rheostat towards pro-apoptotic ceramide accumulation. This study establishes a direct link between the cytotoxic activity of 2,3-DHBA and its ability to comprehensively reprogram the cancer cell lipidome, highlighting its potential as a sophisticated metabolic modulator for breast cancer therapy. Full article

(This article belongs to the Section Lipids)

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28 pages, 4648 KB

Open AccessArticle

Allosteric Control Overcomes Steric Limitations for Neutralizing Antibodies Targeting Conserved Binding Epitopes of the SARS-CoV-2 Spike Protein: Exploring the Intersection of Binding, Allostery, and Immune Escape with a Multimodal Computational Approach

by Mohammed Alshahrani, Vedant Parikh, Brandon Foley and Gennady Verkhivker

Biomolecules 2025, 15(9), 1340; https://doi.org/10.3390/biom15091340 - 18 Sep 2025

Viewed by 663

Abstract

Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic [...] Read more.

Understanding the atomistic basis of multi-layer mechanisms employed by broadly reactive neutralizing antibodies of the SARS-CoV-2 spike protein without directly blocking receptor engagement remains an important challenge in coronavirus immunology. Class 4 antibodies represent an intriguing case: they target a deeply conserved, cryptic epitope on the receptor-binding domain yet exhibit variable neutralization potency across subgroups F1 (CR3022, EY6A, COVA1-16), F2 (DH1047), and F3 (S2X259). The molecular basis for this variability is not fully understood. Here, we employed a multi-modal computational approach integrating atomistic and coarse-grained molecular dynamics simulations, binding free energy calculations, mutational scanning, and dynamic network analysis to elucidate how these antibodies engage the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and influence its function. Our results reveal that neutralization efficacy arises from the interplay of direct interfacial interactions and allosteric effects. Group F1 antibodies (CR3022, EY6A, COVA1-16) primarily operate via classic allostery, modulating flexibility in RBD loop regions to indirectly interfere with the ACE2 receptor binding through long-range effects. Group F2 antibody DH1047 represents an intermediate mechanism, combining partial steric hindrance—through engagement of ACE2-critical residues T376, R408, V503, and Y508—with significant allosteric influence, facilitated by localized communication pathways linking the epitope to the receptor interface. Group F3 antibody S2X259 achieves potent neutralization through a synergistic mechanism involving direct competition with ACE2 and localized allosteric stabilization, albeit with potentially increased escape vulnerability. Dynamic network analysis identified a conserved “allosteric ring” within the RBD core that serves as a structural scaffold for long-range signal propagation, with antibody-specific extensions modulating communication to the ACE2 interface. These findings support a model where Class 4 neutralization strategies evolve through the refinement of peripheral allosteric connections rather than epitope redesign. This study establishes a robust computational framework for understanding the atomistic basis of neutralization activity and immune escape for Class 4 antibodies, highlighting how the interplay of binding energetics, conformational dynamics, and allosteric modulation governs their effectiveness against SARS-CoV-2. Full article

(This article belongs to the Special Issue Protein Biophysics)

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29 pages, 1962 KB

Open AccessReview

Mitochondrial Reactive Oxygen Species: A Unifying Mechanism in Long COVID and Spike Protein-Associated Injury: A Narrative Review

by Eunseuk Lee, Adaobi Amelia Ozigbo, Joseph Varon, Mathew Halma, Madison Laezzo, Song Peng Ang and Jose Iglesias

Biomolecules 2025, 15(9), 1339; https://doi.org/10.3390/biom15091339 - 18 Sep 2025

Cited by 1 | Viewed by 2624

Abstract

Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral [...] Read more.

Post-acute sequelae of SARS-CoV-2 infection (long COVID) present with persistent fatigue, cognitive impairment, and autonomic and multisystem dysfunctions that often go unnoticed by standard diagnostic tests. Increasing evidence suggests that mitochondrial dysfunction and oxidative stress are central drivers of these post-viral sequelae. Viral infections, particularly SARS-CoV-2, disrupt mitochondrial bioenergetics by altering membrane integrity, increasing mitochondrial reactive oxygen species (mtROS), and impairing mitophagy, leading to sustained immune activation and metabolic imbalance. This review synthesizes an understanding of how mitochondrial redox signaling and impaired clearance of damaged mitochondria contribute to chronic inflammation and multisystem organ symptoms in both long COVID and post-vaccine injury. We discuss translational biomarkers and non-invasive techniques, exploring therapeutic strategies that include pharmacological, non-pharmacological, and nutritional approaches, as well as imaging modalities aimed at assessing and restoring mitochondrial health. Recognizing long COVID as a mitochondrial disorder that stems from redox imbalance will open new options for personalized treatment and management guided by biomarkers. Future clinical trials are essential to validate these approaches and translate mitochondrial resuscitation into effective care for patients suffering from long COVID and related post-viral syndromes. Full article

(This article belongs to the Special Issue Mitochondrial ROS in Health and Disease)

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43 pages, 12764 KB

Open AccessArticle

Exploring the Inhibitory Potential of Six Porphyrin Compounds Against α-Amylase and α-Glucosidase Linked to Diabetes

by Shuo Zhang, Zi Liu, Qiurui Ma, Yangyuxin Liu, Shuren Yin, Zhihan Zhou, Jie Zhou, Helong Bai and Tianjiao Li

Biomolecules 2025, 15(9), 1338; https://doi.org/10.3390/biom15091338 - 18 Sep 2025

Viewed by 529

Abstract

Diabetes mellitus is a characteristic metabolic disorder with diverse complications. α-Amylase and α-glucosidase, as key digestive enzymes regulating blood glucose, are important targets for diabetes prevention and management through their inhibition. This study investigated the inhibitory effects of six porphyrin compounds (TAPP, TCPP, [...] Read more.

Diabetes mellitus is a characteristic metabolic disorder with diverse complications. α-Amylase and α-glucosidase, as key digestive enzymes regulating blood glucose, are important targets for diabetes prevention and management through their inhibition. This study investigated the inhibitory effects of six porphyrin compounds (TAPP, TCPP, THPP, Cu–TCPP, Fe–TCPP, Ni–TCPP) on two enzymes through in vitro inhibition assays, spectroscopic experiments, and molecular docking techniques. All six compounds effectively inhibited the activities of both enzymes. For α-amylase, the inhibitory potency (IC₅₀ = 13.03–245.04 μg/mL) followed the order TAPP > THPP > TCPP > Fe–TCPP > Ni–TCPP > Cu–TCPP. All six compounds exhibited more potent inhibitory activity against α-glucosidase (IC₅₀ = 0.24–25.43 μg/mL), with potency in the order of THPP > Ni–TCPP > Fe–TCPP > TCPP > Cu–TCPP > TAPP. Fluorescence quenching experiments revealed that all compounds statically quenched the intrinsic fluorescence of both enzymes (with Fe–TCPP exhibiting static-dominant mixed quenching against α-amylase), indicating complex formation. These interactions significantly altered the enzymes’ conformations, the microenvironments of Tyr/Trp residues, and secondary structure content, consequently reducing their catalytic activity. By examining the inhibitory impact of porphyrin compounds on α-amylase and α-glucosidase, this research establishes a vital experimental and theoretical basis for diabetes therapeutics. Full article

(This article belongs to the Section Chemical Biology)

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14 pages, 3484 KB

Open AccessArticle

The First Heterozygous TWNK Nonsense Mutation Associated with Progressive External Ophthalmoplegia: Evidence for a New Piece in the Puzzle of Mitochondrial Diseases

by Diego Lopergolo, Gianna Berti, Gian Nicola Gallus, Silvia Bianchi, Filippo Maria Santorelli, Alessandro Malandrini and Nicola De Stefano

Biomolecules 2025, 15(9), 1337; https://doi.org/10.3390/biom15091337 - 18 Sep 2025

Viewed by 561

Abstract

Background: The TWNK gene encodes a protein that colocalizes with mitochondrial DNA (mtDNA) in mitochondrial nucleoids. It acts as mtDNA helicase during replication, thus playing a pivotal role in the replication and maintenance of mtDNA stability. TWNK mutations are associated with a wide [...] Read more.

Background: The TWNK gene encodes a protein that colocalizes with mitochondrial DNA (mtDNA) in mitochondrial nucleoids. It acts as mtDNA helicase during replication, thus playing a pivotal role in the replication and maintenance of mtDNA stability. TWNK mutations are associated with a wide spectrum of clinical phenotypes and a marked heterogeneity. However, heterozygous nonsense variants in the gene have never been described in association with disease. Methods: We analyzed a next-generation sequencing (NGS) targeted gene panel in a cohort including 40 patients with high clinical suspicion of mitochondrial disorders. Selected patients underwent a complete neurological examination, electrophysiology tests, and muscle biopsy. Segregation analysis was performed in available family members. The 3D structure of twinkle was visualized and analyzed using Swiss Model and Pymol version 3.1.6.1. Results: We found four TWNK-mutated subjects from two unrelated families. They exhibited a variable clinical spectrum, ranging from asymptomatic individuals to subjects with psychiatric disorder, chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus. All the subjects shared the heterozygous TWNK p.Glu665Ter variant. Discussion and Conclusions: We describe the clinical phenotype and muscle biopsy findings associated with the first reported heterozygous nonsense TWNK variant, thus expanding the current knowledge of Twinkle-related disorders. Our findings are in line with the high intrafamilial clinical variability associated with TWNK mutations. Although PEO and skeletal muscle involvement remain hallmarks of the disease, extra-muscular features should be carefully assessed. Full article

(This article belongs to the Special Issue Molecular Diagnosis and Regulation of Mitochondrial Dysfunction)

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18 pages, 2522 KB

Open AccessArticle

Therapeutic Effect of Selenium Nanoparticles, Sorafenib, and Selenium–Sorafenib Nanocomplex in the Lungs and Kidneys of Mice with TAA-Induced HCC

by Egor A. Turovsky, Sergey V. Gudkov and Elena G. Varlamova

Biomolecules 2025, 15(9), 1336; https://doi.org/10.3390/biom15091336 - 18 Sep 2025

Viewed by 640

Abstract

Hepatocellular carcinoma is a primary malignant tumor of the liver, which is a serious health problem due to its aggressive nature, late diagnosis, and metastasis to other organs. We present, for the first time, the mRNA expression patterns of a wide range of [...] Read more.

Hepatocellular carcinoma is a primary malignant tumor of the liver, which is a serious health problem due to its aggressive nature, late diagnosis, and metastasis to other organs. We present, for the first time, the mRNA expression patterns of a wide range of genes involved in inflammation, fibrosis, endoplasmic reticulum stress, various forms of cell death, and signaling cascades in the lungs and kidneys of mice with thioacetamide-induced HCC. It is known that HCC often metastasizes to the lungs, and it is also important to understand which pathological processes occur in the kidneys, since the liver and kidneys are key target organs of toxicity. The main goal of this work was to study the pathological processes in the lungs and kidneys in HCC and the effectiveness of selenium nanocomplexes, as well as the well-known drug sorafenib, in mitigating these pathological consequences. These results present a significant contribution to the study of HCC metastasis to the lungs and kidneys and to the development of drugs that are most effective in the late stages of HCC. In addition, a hierarchy of the distribution of the selenium in the liver, kidneys, and lungs was established after the treatment of mice with HCC with selenium nanoparticles and a selenium–sorafenib nanocomplex. These data are important for developing a treatment protocol and determining optimal dosages of the drugs under study, which allows for achieving the desired therapeutic effect and neutralizing the toxic effect of selenium on healthy tissues and organs. Full article

(This article belongs to the Special Issue Advances in Nano-Based Drug Delivery Systems)

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22 pages, 2624 KB

Open AccessReview

The Skin Microenvironment: A Dynamic Regulator of Hair Follicle Development, Cycling and Disease

by Weiguo Song, Mingli Peng, Qiqi Ma, Xiaoyu Han, Chunyan Gao, Wenqi Zhang and Dongjun Liu

Biomolecules 2025, 15(9), 1335; https://doi.org/10.3390/biom15091335 - 18 Sep 2025

Viewed by 1575

Abstract

As essential skin appendages, hair follicles exhibit complex developmental and regenerative processes shaped by the skin microenvironment. Imbalances in skin microenvironmental homeostasis are often accompanied by follicle miniaturization and even hair loss. In studying the mechanisms of hair follicle development, in addition to [...] Read more.

As essential skin appendages, hair follicles exhibit complex developmental and regenerative processes shaped by the skin microenvironment. Imbalances in skin microenvironmental homeostasis are often accompanied by follicle miniaturization and even hair loss. In studying the mechanisms of hair follicle development, in addition to focusing on the self-regulation of intrinsic signaling within the follicle, it is also crucial to examine the remodeling of the follicular microenvironment triggered by dynamic changes in the skin microenvironment. Herein, we review the individual and combined roles of various cells, tissues, signaling molecules, and metabolic alterations within the skin microenvironment in hair follicle development. Moreover, we summarize the potential applications of the skin microenvironment in treating hair-related diseases, highlight the existing challenges and limitations in the research field, and provide perspectives on future research directions, aiming to elucidate the critical role of the skin microenvironment in regulating hair follicle development. Full article

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36 pages, 3419 KB

Open AccessReview

The Years 2015–2025 as a Prospective Decade for the Identification of Specific Methylation Biomarkers of Prostate Cancer

by Zohair Selmani, Paul Peixoto, Alexis Overs and Eric Hervouet

Biomolecules 2025, 15(9), 1334; https://doi.org/10.3390/biom15091334 - 18 Sep 2025

Viewed by 852

Abstract

For ten years, DNA methylation appeared as a major step in the understanding and issues of prostate cancers. Indeed, although classical biochemical parameters are still useful for prostate cancer diagnosis, they have poor sensitivity and are not specific for prostate cancer subtypes. The [...] Read more.

For ten years, DNA methylation appeared as a major step in the understanding and issues of prostate cancers. Indeed, although classical biochemical parameters are still useful for prostate cancer diagnosis, they have poor sensitivity and are not specific for prostate cancer subtypes. The recent boom in the identification of specific DNA methylation profiles and the rapid development of liquid biopsies have completely modified the care of patients and may greatly influence outcomes in the future. Indeed, DNA methylation modifications could substantially improve the diagnosis by identifying specific prostate subtypes, improve follow-up to monitor residual disease, improve therapeutic efficiency by predicting the response to treatment, and improve the health quality of patients since these epigenetic modifications can easily be detected in non-invasive liquid biopsies. Full article

(This article belongs to the Special Issue Advances in the Pathology of Prostate Cancer: 2nd Edition)

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5 pages, 168 KB

Open AccessEditorial

Therapeutic Convergence in Neurodegeneration: Natural Products, Drug Repurposing, and Biomolecular Targets

by Caterina Vicidomini and Giovanni N. Roviello

Biomolecules 2025, 15(9), 1333; https://doi.org/10.3390/biom15091333 - 18 Sep 2025

Cited by 1 | Viewed by 887

Abstract

Neurodegenerative diseases pose an escalating global health burden, caused by their intricate pathophysiological mechanisms, and consequently, a persistent lack of curative therapies [...] Full article

(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration)

14 pages, 2453 KB

Open AccessArticle

Patterny: A Troupe of Decipherment Helpers for Intrinsic Disorder, Low Complexity and Compositional Bias in Proteins

by Paul M. Harrison

Biomolecules 2025, 15(9), 1332; https://doi.org/10.3390/biom15091332 - 18 Sep 2025

Viewed by 471

Abstract

Intrinsically disordered regions (IDRs) are sometimes considered parts of the ‘dark proteomes’, i.e., protein parts that have been largely under-appreciated, as are the overlapping phenomena of low-complexity or compositionally biased regions (LCRs/CBRs). Experimentalists and computationalists alike are still learning how to decrypt the [...] Read more.

Intrinsically disordered regions (IDRs) are sometimes considered parts of the ‘dark proteomes’, i.e., protein parts that have been largely under-appreciated, as are the overlapping phenomena of low-complexity or compositionally biased regions (LCRs/CBRs). Experimentalists and computationalists alike are still learning how to decrypt the functionally meaningful features of such regions. Here, I report the creation of the support troupe Patterny to aid such protein cryptanalysis. The current troupe members are named Blocky, Bandy, Moduley, Repeaty, and Runny. To discern important features, protein regions are compared to ideal assortments wherein everything is sampled proportionally and dispersed randomly. Blocky discerns the segregation of amino-acids by type, and scores them for it. Bandy is focused on picking out compositional bands and calculating their evenness. Moduley labels the boundaries of optimized compositional modules (‘CModules’) and other possible boundary sets for compositionally biased regions. Repeaty concisely summarizes repetitiveness using an information entropy of amino-acid interval diversity. Runny enumerates homopeptide content and assesses its significance. Both original whole sequences and CModules from Moduley, are fed into the other Patterny members. Patterny is applied to some illustrative sample data from yeast proteome and the DISPROT database. It is available at Github, and might aid those aiming to intensify light-shedding and hypothesis generation for protein regions with function encoded in a distributed manner, such as IDRs and LCRs/CBRs more generally. Full article

(This article belongs to the Special Issue Advances in Computational Biology of Intrinsically Disordered Proteins)

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22 pages, 4024 KB

Open AccessArticle

Inorganic Polyphosphate Modulates Chromosome Transmission Fidelity in the Fission Yeast Schizosaccharomyces pombe

by Sarune Bollé, Elisa Koc, Adolfo Saiardi, Lisa Juhran, Eva Walla, Ursula Fleig and Abel Alcázar-Román

Biomolecules 2025, 15(9), 1331; https://doi.org/10.3390/biom15091331 - 18 Sep 2025

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Abstract

Chromosome transmission fidelity is vital for organism fitness. Yet, extrinsic and intrinsic changes can affect this process, leading to aneuploidy, the loss/gain of chromosomes, which is a hallmark of cancer. Here, using a haploid fission yeast Schizosaccharomyces pombe strain with a segmental aneuploidy, [...] Read more.

Chromosome transmission fidelity is vital for organism fitness. Yet, extrinsic and intrinsic changes can affect this process, leading to aneuploidy, the loss/gain of chromosomes, which is a hallmark of cancer. Here, using a haploid fission yeast Schizosaccharomyces pombe strain with a segmental aneuploidy, we assayed genome stability under different temperatures and altered gene dosage. We find that S. pombe genome stability is temperature-dependent and is unexpectedly modulated by intracellular levels of inorganic polyphosphate polymers (polyP). The vtc4⁺ gene, encoding a subunit of the polyP-generating VTC complex, is present twice due to the segmental aneuploidy resulting in a gene-dosage-coupled increase in polyP. Using strains with different amounts of polyP, we find a direct negative correlation between polyP and chromosome segregation fidelity. PolyP modulates the function of the conserved CCAN kinetochore subcomplex, as the abnormal growth phenotype caused by the mutant CCAN protein Fta2-291 was rescued in the absence of polyP, while extra polyP had the opposite effect. Importantly, this appears to occur in part by modulation of the nucleolin Gar2. Gar2 is the functional homolog of the Saccharomyces cerevisiae Nsr1 protein, whose function is modulated by posttranslational polyP-mediated polyphosphorylation. Thus, polyP modulates genome stability, linking cellular metabolism to chromosome transmission fidelity. Full article

(This article belongs to the Special Issue Polyphosphate (PolyP) in Health and Disease)

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23 pages, 5731 KB

Open AccessArticle

MiR-92 Controls Synaptic Development Through Glial Vha55 Regulation

by Simon M. Moe, Alicia Taylor, Alan P. Robertson, David Van Vactor and Elizabeth M. McNeill

Biomolecules 2025, 15(9), 1330; https://doi.org/10.3390/biom15091330 - 18 Sep 2025

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Abstract

MicroRNAs (miRNAs) have emerged as important biomarkers for complex neurological conditions. Modifications in synaptic morphology characterize several of these disease states, indicating a possible role of miRNA in modulating synaptic formation and plasticity. Within the third-instar larvae of Drosophila melanogaster, we uncovered a [...] Read more.

MicroRNAs (miRNAs) have emerged as important biomarkers for complex neurological conditions. Modifications in synaptic morphology characterize several of these disease states, indicating a possible role of miRNA in modulating synaptic formation and plasticity. Within the third-instar larvae of Drosophila melanogaster, we uncovered a functional role for highly human-conserved miR-92 in synaptogenesis of the glutamatergic peripheral nervous system. Loss of miR-92 results in underdeveloped synaptic architecture, coinciding with significantly reduced physiological activity. We demonstrate a novel role for miR-92 glial-specific expression to support synaptic growth function and plasticity. Modifications of miR-92 within glial tissue result in aberrant glial barrier properties, including an increased uptake of external dyes. Within the glia, miR-92 regulates a V-ATPase subunit (Vha55), impairing the glial cells from forming appropriate insulating layers around the nervous system. These modifications may impact how the nervous system adapts to its environment, increasing immature ‘ghost bouton’ budding and impairing responses to changes in environmental conditions. Our work highlights the importance of glial-specific miR-92 on synaptic development, affecting glial health and function through its downstream target Vha55, and demonstrates a novel mechanism for glia in synaptogenesis and homeostatic plasticity. Full article

(This article belongs to the Section Molecular Genetics)

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13 pages, 694 KB

Open AccessArticle

Tetrahydrocannabivarin (THCV) Dose Dependently Blocks or Substitutes for Tetrahydrocannabinol (THC) in a Drug Discrimination Task in Rats

by Hakan Kayir, Larissa Kouroukis, Iman Aziz and Jibran Younis Khokhar

Biomolecules 2025, 15(9), 1329; https://doi.org/10.3390/biom15091329 - 18 Sep 2025

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Abstract

Delta-9-Tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid and structural analog of THC, exhibits a dual pharmacological profile as a CB1 receptor agonist/antagonist and a partial CB2 agonist. This study evaluated the effects of THCV in a THC discrimination model in rats. Male Sprague-Dawley rats [...] Read more.

Delta-9-Tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid and structural analog of THC, exhibits a dual pharmacological profile as a CB1 receptor agonist/antagonist and a partial CB2 agonist. This study evaluated the effects of THCV in a THC discrimination model in rats. Male Sprague-Dawley rats (n = 16, 300–340 g, PND60) were trained under a fixed ratio 20 (FR20) schedule to discriminate THC (3 mg/kg) from vehicle. Substitution tests were conducted with THC (0.325–3 mg/kg), THCV (0.75–6 mg/kg), and THC-THCV combinations. THCV produced an inverted U-shaped substitution curve, significantly differing from vehicle (p = 0.008). At 3 mg/kg, THCV partially substituted for THC (54.6% ± 17.82, p = 0.003). Response rate significantly increased during the substitution test with 3 mg/kg of THCV (p = 0.042). THCV (6 mg/kg) reversed THC (0.75 mg/kg)-induced responding (p = 0.040), with no significant change in response rate (p = 0.247). However, THCV combined with THC (1.5 mg/kg) affected response rates (p = 0.012), with 6 mg/kg significantly reducing rates vs. 3 mg/kg (p = 0.013). Blood THC and 11-OH-THC levels remained unchanged when THC was combined with THCV. The findings suggest THCV can partially mimic or block THC’s discriminative effects in a dose-dependent manner, possibly acting as a partial CB1 agonist. Full article

(This article belongs to the Special Issue Cannabinoids in Neurobehavioral Modulation)

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28 pages, 673 KB

Open AccessReview

Proteomics Approaches for Discovering Novel Protein Biomarkers in Inflammatory Bowel Disease-Related Cancer

by Tommaso Saccon, Matilde Bergamo and Cinzia Franchin

Biomolecules 2025, 15(9), 1328; https://doi.org/10.3390/biom15091328 - 17 Sep 2025

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Abstract

Inflammatory bowel disease (IBD) is an autoimmune condition with an increasing incidence worldwide, which manifests in two pathological forms: Crohn’s disease (CD) or ulcerative colitis (UC). Both cause chronic inflammation of the digestive tract, although they can present different locations and with different [...] Read more.

Inflammatory bowel disease (IBD) is an autoimmune condition with an increasing incidence worldwide, which manifests in two pathological forms: Crohn’s disease (CD) or ulcerative colitis (UC). Both cause chronic inflammation of the digestive tract, although they can present different locations and with different symptoms. To date, the pathogenesis of IBD remains unclear. One of the major complications of these diseases is colorectal cancer. Several studies have reported a correlation between chronic intestinal inflammation and an increased risk of malignancy. Persistent inflammation damages the intestinal mucosa and epithelial wall, altering gut permeability and the local microenvironment. Moreover, the heightened activity of the immune system leads to an increased production of reactive oxygen and nitrogen species (ROS and RNS), increasing the risk of DNA mutation and cell transformation. In addition, some current therapies used to treat IBD and induce remission may contribute to carcinogenesis or impair immune surveillance due to their immunosuppressive activity. The management of cancer risk for IBD patients remains a challenge, and existing screening methods are often invasive (endoscopies, biopsies), resulting in low patient compliance. To address this unmet clinical need, researchers have started using proteomics to identify novel biomarkers that could predict cancer risk in IBD patients in a non-invasive manner. This review aims to examine the current state of knowledge regarding the correlation between IBD and cancer, with a special focus on the biomarkers discovered through proteomic approaches, and their potential application in routine clinical screening. In our view, proteomics represents a powerful and rapidly evolving strategy for biomarker discovery, with the potential to complement or even replace invasive procedures. Its future clinical impact will rely on translating current research advances into robust and accessible diagnostic tools. Full article

(This article belongs to the Special Issue Omics Data Integration: Focusing on Molecular Biomarkers for Cancers and Diseases)

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20 pages, 1902 KB

Open AccessReview

Pyruvate Kinase M2 Links Metabolism and Epigenetics: A New Target for Liver Disease Treatment

by Xiaoya Zhang, Danmei Zhang, Jin Guo, Chunxia Shi and Zuojiong Gong

Biomolecules 2025, 15(9), 1327; https://doi.org/10.3390/biom15091327 - 17 Sep 2025

Viewed by 942

Abstract

The aberrant activation of glycolysis plays a pivotal role in the progression of liver diseases. Pyruvate kinase M2 (PKM2), one of the rate-limiting enzymes of glycolysis, not only regulates cellular metabolism but also translocates to the nucleus in its dimeric form, acting as [...] Read more.

The aberrant activation of glycolysis plays a pivotal role in the progression of liver diseases. Pyruvate kinase M2 (PKM2), one of the rate-limiting enzymes of glycolysis, not only regulates cellular metabolism but also translocates to the nucleus in its dimeric form, acting as a co-factor to modulate gene transcription. To further explore the regulatory mechanisms of PKM2, this review outlines the effects of post-translational modifications on PKM2’s structure, activity, and localization, and discusses the integrative role of PKM2 in epigenetics and metabolism, providing a foundation for the development of PKM2 regulators. Due to PKM2’s distinct biochemical properties, targeting PKM2 with specific regulators may offer a promising therapeutic strategy for the treatment of liver diseases. Full article

(This article belongs to the Special Issue Advances and Novel Strategies for Studying Underexplored Post-Translational Modifications (PTMs))

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22 pages, 4007 KB

Open AccessArticle

Bile Acids Are Potential Negative Allosteric Modulators of M1 Muscarinic Receptors

by Wenbo Yu, Alexander D. MacKerell, Jr., David J. Weber and Jean-Pierre Raufman

Biomolecules 2025, 15(9), 1326; https://doi.org/10.3390/biom15091326 - 17 Sep 2025

Viewed by 595

Abstract

The proposed physiological roles of bile acids have expanded beyond the digestion of fats to encompass cell signaling via the activation of a variety of nuclear and plasma membrane receptors in multiple organ systems. The current in silico study was inspired by previous [...] Read more.

The proposed physiological roles of bile acids have expanded beyond the digestion of fats to encompass cell signaling via the activation of a variety of nuclear and plasma membrane receptors in multiple organ systems. The current in silico study was inspired by previous observations from our group and others that bile acids interact functionally with cardiac, pulmonary, and gastrointestinal muscarinic receptors and more recent work demonstrating allosteric binding of cholesterol, the parent molecule for bile acid synthesis, to M₁ muscarinic receptors (M₁R). Here, we computationally tested the hypothesis that bile acids can allosterically bind to M₁R and thereby modulate receptor activation. Utilizing de novo site identification by the ligand competitive saturation (SILCS) method, putative novel allosteric binding sites of bile acid targeting M₁R were identified. Molecular dynamics simulations were used to uncover the molecular details of the activation mechanism of M₁R due to agonist binding along with allosteric modulation of bile acids on M₁R activation. Allosteric binding of bile acids and their glycine and taurine conjugates to M₁R negatively impacts the activation process, findings consistent with recent reports that M₁R expression and activation inhibit colon cancer cell proliferation. Thus, bile acids may augment colon cancer risk by inhibiting the tumor suppressor actions of M₁R. When validated experimentally, these findings are anticipated to shed light on our understanding of how bile acids in the membrane microenvironment can allosterically modulate the function of M₁R and possibly other G protein-coupled receptors. Full article

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

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17 pages, 1742 KB

Open AccessArticle

Pinocembrin Downregulates Vascular Smooth Muscle Cells Proliferation and Migration Leading to Attenuate Neointima Formation in Balloon-Injured Rats

by Hyeonhwa Kim, Jihye Jung, Young-Bob Yu, Dong-Hyun Choi, Leejin Lim and Heesang Song

Biomolecules 2025, 15(9), 1325; https://doi.org/10.3390/biom15091325 - 17 Sep 2025

Viewed by 586

Abstract

The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are a primary cause of cardiovascular diseases such as atherosclerosis and restenosis after angioplasty. Pinocembrin (5,7-dihydroxyflavanone, PCB), a natural flavonoid compound found abundantly in propolis, has been reported to have antibacterial, anti-inflammatory, [...] Read more.

The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are a primary cause of cardiovascular diseases such as atherosclerosis and restenosis after angioplasty. Pinocembrin (5,7-dihydroxyflavanone, PCB), a natural flavonoid compound found abundantly in propolis, has been reported to have antibacterial, anti-inflammatory, antioxidant, and anticancer effects, and cardiac function improvement in ischemic heart disease. In this study, the protective effects of PCB against the migration and proliferation of VSMCs were investigated. MTT and BrdU assays were performed to estimate the cytotoxicity and cell proliferative activity of PCB, respectively. Rat aortic VSMC migrations and neointima formation were evaluated using wound healing, boyden chamber assays, and in balloon-injured (BI) rat, respectively. PCB suppressed the phosphorylated levels of p38 in PDGF-BB-induced VSMCs followed by reducing the expression of MMP2 and 9. PCB downregulated the expression levels of cell cycle regulatory proteins such as PCNA, CDK2, CDK4, and Cyclin D1. Furthermore, the phosphorylated levels of FAK at Y397 and Y925 sites and the expression levels of FAK-related proteins such as Integrin β1, Paxillin, Talin, and Vinculin were significantly reduced by PCB in PDGF-BB-induced VSMCs. The neointima formation was markedly decreased by PCB administration in the carotid artery of a balloon-injured rat. In conclusion, PCB inhibits the proliferation and migration of VSMCs by stimulation of PDGF-BB through the regulation of the p38 and FAK signaling pathway. Therefore, PCB may be a promising therapeutic candidate for preventing and treating cardiovascular diseases such as atherosclerosis and restenosis. Full article

(This article belongs to the Section Cellular Biochemistry)

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21 pages, 6269 KB

Open AccessArticle

EET-Based Therapeutics Mitigate Sorafenib-Associated Glomerular Cell Damage

by Abhishek Mishra, Marcus de Bourg, Rawand S. Mohamed, Md Abdul Hye Khan, Tsigereda Weldemichael, Donald J. Johann, Jr., Samaneh Goorani, Shobanbabu Bommagani, Darin E. Jones, Anders Vik and John D. Imig

Biomolecules 2025, 15(9), 1324; https://doi.org/10.3390/biom15091324 - 16 Sep 2025

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Abstract

Background: This study investigates how sorafenib induces toxicity in glomerular cells and examines the protective role of 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs in reducing this kidney damage. Methods: Human renal mesangial cells (HRMCs) and podocytes were treated with no treatment, sorafenib alone, or sorafenib [...] Read more.

Background: This study investigates how sorafenib induces toxicity in glomerular cells and examines the protective role of 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs in reducing this kidney damage. Methods: Human renal mesangial cells (HRMCs) and podocytes were treated with no treatment, sorafenib alone, or sorafenib combined with 8,9-EET analogs. Cell viability and apoptosis were measured in both cell types. Results: Sorafenib (1–10 µM) lowered cell viability and increased caspase 3/7 activity in a dose-dependent way in HRMCs and podocytes. Five of twenty 8,9-EET analogs significantly enhanced cell survival and decreased apoptosis. RNA sequencing showed that sorafenib altered 1244 genes, including those involved in cell cycle and the Raf/MEK/ERK pathway. The 8,9-EET analog MDB-52a raised ANGPTL4 levels, linked to metabolism and vascular health, and reduced ACTA2, which could activate protective pathways. Nephroseq data correlated these gene changes with glomerulosclerosis. Conclusions: MDB-52 appears to counteract gene disruptions and protect against sorafenib-induced kidney damage. Overall, 8,9-EET analogs targeting glomerular cells could be potential therapeutic agents to lessen sorafenib-related nephrotoxicity. Full article

(This article belongs to the Special Issue New Insights into Kidney Disease Development and Therapy Strategies)

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20 pages, 2385 KB

Open AccessReview

AARS1 and AARS2: From Protein Synthesis to Lactylation-Driven Oncogenesis

by Lingyue Gao, Jihua Guo and Rong Jia

Biomolecules 2025, 15(9), 1323; https://doi.org/10.3390/biom15091323 - 16 Sep 2025

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Abstract

Aminoacyl-tRNA synthetases (AARSs), traditionally recognized for their essential role in protein synthesis, are now emerging as critical players in cancer pathogenesis through translation-independent functions. Lactate-derived lactylation, a post-translational modification, plays an increasingly important role in tumorigenesis in the context of high levels of [...] Read more.

Aminoacyl-tRNA synthetases (AARSs), traditionally recognized for their essential role in protein synthesis, are now emerging as critical players in cancer pathogenesis through translation-independent functions. Lactate-derived lactylation, a post-translational modification, plays an increasingly important role in tumorigenesis in the context of high levels of lactate in tumor cells due to the Warburg effect. Current research has highlighted AARS1/2 as lactate sensors and lactyltransferases that catalyze global lysine lactylation in cancer cells and promote cancer proliferation, providing a new perspective for cancer therapy. This review synthesizes the canonical and non-canonical functions of AARS1/2, with a particular focus on their lactylation-related mechanisms; details how lactylation acts as a mechanistic bridge linking AARS1/2 to diverse oncogenic signaling pathways, thereby promoting cancer hallmarks such as metabolic reprogramming, uncontrolled proliferation, immune escape, and therapy resistance; and proposes strategies to target AARS1/2 or modulate relative lactylation, offering a potential avenue to translate these insights into effective cancer therapies. Full article

(This article belongs to the Section Molecular Medicine)

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18 pages, 3750 KB

Open AccessArticle

LRRK2-Mediated Neuroinflammation Induces Neuronal Dysfunctions in a Parkinson’s and Alzheimer’s Disease Cellular Model

by Veronica Mutti, Giulia Carini, Moira Marizzoni, Alice Filippini, Federica Bono, Chiara Fiorentini, Samantha Saleri, Floriana De Cillis, Annamaria Cattaneo, Massimo Gennarelli, Paolo Martini and Isabella Russo

Biomolecules 2025, 15(9), 1322; https://doi.org/10.3390/biom15091322 - 16 Sep 2025

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Abstract

Chronic neuroinflammation plays a crucial role in the progression of neurodegenerative diseases (NDs), including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Leucine-Rich Repeat Kinase 2 (LRRK2), a gene linked to familial and sporadic PD, has been positively associated with neuroinflammation in both in [...] Read more.

Chronic neuroinflammation plays a crucial role in the progression of neurodegenerative diseases (NDs), including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Leucine-Rich Repeat Kinase 2 (LRRK2), a gene linked to familial and sporadic PD, has been positively associated with neuroinflammation in both in vitro and in vivo systems. These observations suggest that LRRK2 might actively contribute to neuronal damage and degeneration in NDs. Based on these premises, we explored the impact of LRRK2-mediated neuroinflammation on neurons in a PD- and AD-related context. We set up a cellular model composed of human induced pluripotent stem cell (hiPSC)-derived neurons (dopaminergic for PD and cholinergic for AD) exposed to inflamed glial medium [α-synuclein pre-formed fibrils (α-syn pffs) for PD and amyloid-β (Aβ)_1–42 fibrils for AD] for several days. To dissect the effect of neuroinflammation, and specifically, the role of LRRK2, on neuronal functions, we first performed transcriptome analysis, and then, we validated the results at functional levels. Interestingly, we found that LRRK2-dependent neuroinflammation contributes to neuronal dysfunctions and death in both ND contexts and that LRRK2 kinase inhibition prevents these detrimental effects. Overall, our results suggest that lowering neuroinflammation through LRRK2 pharmacological inhibition might limit the progression of NDs and thus be neuroprotective. Full article

(This article belongs to the Section Molecular Medicine)

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26 pages, 586 KB

Open AccessReview

Approach to a Child with Hypophosphatemia

by Agnieszka Antonowicz, Patryk Lipiński, Michał Popow and Piotr Skrzypczyk

Biomolecules 2025, 15(9), 1321; https://doi.org/10.3390/biom15091321 - 15 Sep 2025

Viewed by 889

Abstract

Hypophosphatemia is a rare ion disorder in children, but it carries the risk of serious clinical sequelae in tissues and organs with high energy requirements, such as bone tissue. This article discusses the metabolism of phosphate in the body, the clinical manifestations of [...] Read more.

Hypophosphatemia is a rare ion disorder in children, but it carries the risk of serious clinical sequelae in tissues and organs with high energy requirements, such as bone tissue. This article discusses the metabolism of phosphate in the body, the clinical manifestations of hypophosphatemia, and the diagnostic tests necessary in patients with this disorder. Extra-renal causes are analyzed, and renal forms of hypophosphatemia are discussed in detail. Renal hypophosphatemia, depending on the mechanism, is divided into PTH-dependent (e.g., primary hyperparathyroidism), FGF23-dependent (e.g., X-linked hypophosphatemia), and intrinsic renal hypophosphatemia (e.g., Fanconi syndrome). The treatment of hypophosphatemia involves compensating for phosphate deficiency, often simultaneously with the supply of an active form of vitamin D. Always seek causal treatment, such as parathyroidectomy in primary hyperparathyroidism. In the FGF-23-dependent forms of X-linked hypophosphatemia and tumor-induced osteomalacia, burosumab has proven to be an effective and safe drug. Conclusions: a child with hypophosphatemia requires a multidisciplinary approach and determination of the mechanism of phosphate deficiency in the body. Full article

(This article belongs to the Section Molecular Biomarkers)

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35 pages, 18221 KB

Open AccessArticle

Copper Chelation by Penicillamine Protects Against Doxorubicin-Induced Cardiomyopathy by Suppressing FDX1-Mediated Cuproptosis

by Mohammad El-Nablaway, Hany M. A. Sonpol, Yaser Hosny Ali Elewa, Mohamed A. M. Ali, Mohamed Adel, Eman Serry Zayed, Maha Alhelf, Manar A. Didamoony, Amal Fahmy Dawood, Eman M. Embaby, Khaled S. El-Bayoumi and Wesam S. El-Saeed

Biomolecules 2025, 15(9), 1320; https://doi.org/10.3390/biom15091320 - 15 Sep 2025

Viewed by 1008

Abstract

Background: The cardiotoxic effects of doxorubicin (DOX), a powerful chemotherapeutic drug, are widely recognized. Cuproptosis, a unique copper-dependent form of controlled cell death, may be involved in DOX-induced cardiomyopathy, according to recent findings. This study employs both in vivo and in silico procedures [...] Read more.

Background: The cardiotoxic effects of doxorubicin (DOX), a powerful chemotherapeutic drug, are widely recognized. Cuproptosis, a unique copper-dependent form of controlled cell death, may be involved in DOX-induced cardiomyopathy, according to recent findings. This study employs both in vivo and in silico procedures to investigate the protective effects of the copper chelator penicillamine (PEN) and the role of cuproptosis in DOX-related cardiotoxicity. Methods: Thirty-two adult Sprague Dawley rats were allocated into four groups (n = 8): control, DOX, DOX+PEN, and PEN. Cardiac function was assessed via echocardiography. Serum cardiac biomarkers (LDH, CK-MB, CTnI), oxidative stress markers (SOD, GPX, MDA), and expression levels of cuproptosis-related genes (FDX1, LIAS, SLC31A1, ATP7A) were evaluated. Histopathological examinations and immunohistochemical staining for FDX1, SLC31A1, and DLAT were performed. Molecular docking simulated PEN’s interaction with cuproptosis-related proteins. Network pharmacology and molecular docking studies were also conducted to identify core molecular targets and simulate PEN’s binding interactions with key cuproptosis regulators. Results: DOX administration induced significant cardiac dysfunction, oxidative stress, and upregulation of cuproptosis markers. PEN treatment mitigated these effects, improved cardiac function, reduced fibrosis, and suppressed the expression of cuproptosis-related genes and proteins. Docking results confirmed strong interactions between PEN and cuproptosis-regulatory proteins. Network pharmacology revealed 14 key overlapping targets linking PEN with cuproptosis and DOX-induced cardiotoxicity. Conclusion: This study provides experimental evidence implicating cuproptosis in DOX-induced cardiomyopathy. PEN exerts cardioprotection, potentially by targeting this pathway, offering a promising therapeutic strategy. Full article

(This article belongs to the Section Cellular Biochemistry)

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15 pages, 514 KB

Open AccessReview

Population-Level Dynamics and Community-Mediated Resistance to Antimicrobial Peptides

by Theresia Mekdessi, Aracely Devora and Sattar Taheri-Araghi

Biomolecules 2025, 15(9), 1319; https://doi.org/10.3390/biom15091319 - 15 Sep 2025

Viewed by 647

Abstract

Antimicrobial peptides (AMPs) are crucial components of innate immunity and promising leads for new anti-infective therapies, prized for their broad-spectrum activity and membrane-disruptive mechanisms. However, traditional models of antimicrobial action and resistance often focus on single-cell responses or genetically encoded resistance, overlooking the [...] Read more.

Antimicrobial peptides (AMPs) are crucial components of innate immunity and promising leads for new anti-infective therapies, prized for their broad-spectrum activity and membrane-disruptive mechanisms. However, traditional models of antimicrobial action and resistance often focus on single-cell responses or genetically encoded resistance, overlooking the complex collective behaviors of bacteria at the population level. A growing body of evidence indicates that bacterial communities can profoundly influence AMP efficacy through emergent, community-level resistance mechanisms. In this review, we examine how population-level dynamics and interactions enable bacteria to withstand AMPs beyond what is predicted by cell-autonomous models. We first describe the mechanisms of peptide sequestration by bacterial debris, dead cells, outer membrane vesicles, and biofilm matrix polymers, which diminish the concentration of active peptide available to kill neighboring cells. We then analyze how population-level traits—including inoculum effects, phenotypic heterogeneity, and persister subpopulations—shape survival outcomes and promote regrowth after treatment. Cooperative processes such as protease secretion further enhance communal defenses by coordinating or amplifying protective responses. Beyond cataloging these mechanisms, we highlight recent advances in microfluidic tools, single-cell imaging, and biophysical modeling that reveal the spatial and temporal dynamics of AMP action in structured populations. Collectively, these insights show how bacterial communities absorb, neutralize, or delay AMP activity without genetic resistance, with important implications for therapeutic design and the evaluation of AMP efficacy. Full article

(This article belongs to the Special Issue Antimicrobial Peptides in Nature: Inspiration for Rationally Designed Antimicrobials)

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