Biomolecules

19 pages, 1548 KiB

Open AccessArticle

Engineered Glibenclamide-Loaded Nanovectors Hamper Inflammasome Activation in an Ex Vivo Alzheimer’s Disease Model—A Novel Potential Therapy for Neuroinflammation: A Pilot Study

by Francesca La Rosa, Simone Agostini, Elisabetta Bolognesi, Ivana Marventano, Roberta Mancuso, Franca Rosa Guerini, Ambra Hernis, Lorenzo Agostino Citterio, Federica Piancone, Pietro Davide Trimarchi, Jorge Navarro, Federica Rossetto, Arianna Amenta, Pierfausto Seneci, Silvia Sesana, Francesca Re, Mario Clerici and Marina Saresella

Biomolecules 2025, 15(8), 1074; https://doi.org/10.3390/biom15081074 - 24 Jul 2025

Abstract

Background: Inflammasomes regulate the activation of caspases resulting in inflammation; inflammasome activation is dysregulated in Alzheimer’s disease (AD) and plays a role in the pathogenesis of this condition. Glibenclamide, an anti-inflammatory drug, could be an interesting way to down-modulate neuroinflammation. Methods: In this [...] Read more.

Background: Inflammasomes regulate the activation of caspases resulting in inflammation; inflammasome activation is dysregulated in Alzheimer’s disease (AD) and plays a role in the pathogenesis of this condition. Glibenclamide, an anti-inflammatory drug, could be an interesting way to down-modulate neuroinflammation. Methods: In this pilot study we verified with ex vivo experiments whether a glibenclamide-loaded nanovector (GNV) could reduce the NLRP3-inflammasome cascade in cells of AD patients. Monocytes isolated from healthy controls (HC) and AD patients were cultured in medium, alone or stimulated with LPS + nigericin in presence/absence of GNV. ASC-speck positive cells and inflammasome-related genes, proteins, and miRNAs expressions were measured. The polymorphisms of ApoE (Apolipoprotein E), specifically rs7412 and rs429358, as well as those of NLRP3, namely rs35829419, rs10733113, and rs4925663, were also investigated. Results: Results showed that ASC-speck+ cells and Caspase-1, IL-1β, and IL-18 production was significantly reduced (p < 0.005 in all cases) by GNV in LPS + nigericin-stimulated cells of both AD and HC. Notably, the NLRP3 rs10733113 AG genotype was associated with excessive inflammasome-related gene and protein expression. GNV significantly down-regulates inflammasome activation in primary monocytes, at least at protein levels, and its efficacy seems to partially depend on the presence of the NLRP3 rs10733113 genotype. Conclusions: All together, these results showed that GNV is able to dampen inflammation and NLRP-3 inflammasome activation in an ex vivo monocyte model, suggesting a possible role for GNV in controlling AD-associated neuroinflammation. Full article

(This article belongs to the Special Issue Inflammatory Mechanisms and Molecular Targets in Neurological Disorders: Effects of Neuroprotective Drugs)

27 pages, 2366 KiB

Open AccessReview

S-Nitrosylation in Cardiovascular Disorders: The State of the Art

by Caiyun Mao, Jieyou Zhao, Nana Cheng, Zihang Xu, Haoming Ma, Yunjia Song and Xutao Sun

Biomolecules 2025, 15(8), 1073; https://doi.org/10.3390/biom15081073 - 24 Jul 2025

Abstract

Protein S-nitrosylation is a selective post-translational modification in which a nitrosyl group is covalently attached to the reactive thiol group of cysteine, forming S-nitrosothiol. This modification plays a pivotal role in modulating physiological and pathological cardiovascular processes by altering protein conformation, activity, stability, [...] Read more.

Protein S-nitrosylation is a selective post-translational modification in which a nitrosyl group is covalently attached to the reactive thiol group of cysteine, forming S-nitrosothiol. This modification plays a pivotal role in modulating physiological and pathological cardiovascular processes by altering protein conformation, activity, stability, and other post-translational modifications. It is instrumental in regulating vascular and myocardial systolic and diastolic functions, vascular endothelial cell and cardiomyocyte apoptosis, and cardiac action potential and repolarization. Aberrant S-nitrosylation levels are implicated in the pathogenesis of various cardiovascular diseases, including systemic hypertension, pulmonary arterial hypertension, atherosclerosis, heart failure, myocardial infarction, arrhythmia, and diabetic cardiomyopathy. Insufficient S-nitrosylation leads to impaired vasodilation and increased vascular resistance, while excessive S-nitrosylation contributes to cardiac hypertrophy and myocardial fibrosis, thereby accelerating ventricular remodeling. This paper reviews the S-nitrosylated proteins in the above-mentioned diseases and their impact on these conditions through various signaling pathways, with the aim of providing a theoretical foundation for the development of novel therapeutic strategies or drugs targeting S-nitrosylated proteins. Full article

(This article belongs to the Section Cellular Biochemistry)

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18 pages, 4381 KiB

Open AccessArticle

Glucocorticoid-Induced Muscle Satellite Cell-Derived Extracellular Vesicles Mediate Skeletal Muscle Atrophy via the miR-335-5p/MAPK11/iNOS Pathway

by Pei Ma, Jiarui Wu, Ruiyuan Zhou, Linli Xue, Xiaomao Luo, Yi Yan, Jiayin Lu, Yanjun Dong, Jianjun Geng and Haidong Wang

Biomolecules 2025, 15(8), 1072; https://doi.org/10.3390/biom15081072 - 24 Jul 2025

Abstract

Prolonged high-dose administration of synthetic glucocorticoids (GCs) leads to limb muscle atrophy and weakness, yet its underlying mechanisms remain incompletely understood. Muscle fibers and muscle satellite cells (MSCs) are essential for skeletal muscle development and associated pathologies. This study demonstrates that dexamethasone (Dex) [...] Read more.

Prolonged high-dose administration of synthetic glucocorticoids (GCs) leads to limb muscle atrophy and weakness, yet its underlying mechanisms remain incompletely understood. Muscle fibers and muscle satellite cells (MSCs) are essential for skeletal muscle development and associated pathologies. This study demonstrates that dexamethasone (Dex) induced MSC-derived extracellular vesicles (EVs) impair myogenesis in muscle fiber-like cells (MFLCs) via inducible nitric oxide synthase (iNOS) suppression. High-throughput sequencing revealed a marked upregulation of miR-335-5p in MSC-derived EVs following Dex treatment. Mechanistically, EV miR-335-5p targeted MAPK11, leading to iNOS downregulation and subsequent UPS activation in MFLCs, which directly promoted muscle protein degradation. Collectively, our findings identify the EV miR-335-5p/MAPK11/iNOS axis as a critical mediator of GC-induced muscle atrophy, offering novel insights into therapeutic strategies targeting EV-mediated signaling in muscle wasting disorders. Full article

(This article belongs to the Section Molecular Medicine)

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22 pages, 1771 KiB

Open AccessArticle

Optimization and Characterization of Bioactive Metabolites from Cave-Derived Rhodococcus jialingiae C1

by Muhammad Rafiq, Umaira Bugti, Muhammad Hayat, Wasim Sajjad, Imran Ali Sani, Nazeer Ahmed, Noor Hassan, Yanyan Wang and Yingqian Kang

Biomolecules 2025, 15(8), 1071; https://doi.org/10.3390/biom15081071 - 24 Jul 2025

Abstract

Extremophilic microorganisms offer an untapped potential for producing unique bioactive metabolites with therapeutic applications. In the current study, bacterial isolates were obtained from samples collected from Chamalang cave located in Kohlu District, Balochistan, Pakistan. The cave-derived isolate C1 (Rhodococcus jialingiae) exhibits [...] Read more.

Extremophilic microorganisms offer an untapped potential for producing unique bioactive metabolites with therapeutic applications. In the current study, bacterial isolates were obtained from samples collected from Chamalang cave located in Kohlu District, Balochistan, Pakistan. The cave-derived isolate C1 (Rhodococcus jialingiae) exhibits prominent antibacterial activity against multidrug-resistant pathogens (MDR), including Escherichia coli, Staphylococcus aureus, and Micrococcus luteus. It also demonstrates substantial antioxidant activity, with 71% and 58.39% DPPH radical scavenging. Optimization of physicochemical conditions, such as media, pH, temperature, and nitrogen and carbon sources and concentrations substantially enhanced both biomass and metabolite yields. Optimal conditions comprise specialized media, a pH of 7, a temperature of 30 °C, peptone (1.0 g/L) as the nitrogen source, and glucose (0.5 g/L) as the carbon source. HPLC and QTOF-MS analyses uncovered numerous metabolites, including a phenolic compound, 2-[(E)-3-hydroxy-3-(4-methoxyphenyl) prop-2-enoyl]-4-methoxyphenolate, Streptolactam C, Puromycin, and a putative aromatic polyketide highlighting the C1 isolate chemical. Remarkably, one compound (C₁₄H₃₆N₇) demonstrated a special molecular profile, signifying structural novelty and warranting further characterization by techniques such as ¹H and ¹³C NMR. These findings highlight the biotechnological capacity of the C1 isolate as a source of novel antimicrobials and antioxidants, linking environmental adaptation to metabolic potential and supporting natural product discovery pipelines against antibiotic resistance. Full article

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

16 pages, 5151 KiB

Open AccessArticle

Design and Characterization of Curcumin-Modified Polyurethane Material with Good Mechanical, Shape-Memory, pH-Responsive, and Biocompatible Properties

by Man Wang, Hongying Liu, Wei Zhao, Huafen Wang, Yuwei Zhuang, Jie Yang, Zhaohui Liu, Jing Zhu, Sichong Chen and Jinghui Cheng

Biomolecules 2025, 15(8), 1070; https://doi.org/10.3390/biom15081070 - 24 Jul 2025

Abstract

In the context of critical challenges in curcumin-modified polyurethane synthesis—including limited curcumin bioavailability and suboptimal biodegradability/biocompatibility—a novel polyurethane material (Cur-PU) with good mechanical, shape memory, pH-responsive, and biocompatibility was synthesized via a one-pot, two-step synthetic protocol in which HO-PCL-OH served as the soft [...] Read more.

In the context of critical challenges in curcumin-modified polyurethane synthesis—including limited curcumin bioavailability and suboptimal biodegradability/biocompatibility—a novel polyurethane material (Cur-PU) with good mechanical, shape memory, pH-responsive, and biocompatibility was synthesized via a one-pot, two-step synthetic protocol in which HO-PCL-OH served as the soft segment and curcumin was employed as the chain extender. The experimental results demonstrate that with the increase in Cur units, the crystallinity of the Cur-PU material decreases from 32.6% to 5.3% and that the intensities of the diffraction peaks at 2θ = 21.36°, 21.97°, and 23.72° in the XRD pattern gradually diminish. Concomitantly, tensile strength decreased from 35.5 MPa to 19.3 MPa, and Shore A hardness declined from 88 HA to 65 HA. These observations indicate that the sterically hindered benzene ring structure of Cur imposes restrictions on HO-PCL-OH crystallization, leading to lower crystallinity and retarded crystallization kinetics in Cur-PU. As a consequence, the material’s tensile strength and hardness are diminished. Except for the Cur-PU-3 sample, all other variants exhibited exceptional shape-memory functionality, with R_f and R_r exceeding 95%, as determined by three-point bending method. Analogous to pure curcumin solutions, Cur-PU solutions demonstrated pH-responsive chromatic transitions: upon addition of hydroxide ion (OH⁻) solutions at increasing concentrations, the solutions shifted from yellow-green to dark green and finally to orange-yellow, enabling sensitive pH detection across alkaline gradients. Hydrolytic degradation studies conducted over 15 weeks in air, UPW, and pH 6.0/8.0 phosphate buffer solutions revealed mass loss <2% for Cur-PU films. Surface morphological analysis showed progressive etching with the formation of micro-to-nano-scale pores, indicative of a surface-erosion degradation mechanism consistent with pure PCL. Biocompatibility assessments via L929 mouse fibroblast co-culture experiments demonstrated ≥90% cell viability after 72 h, while relative red blood cell hemolysis rates remained below 5%. Collectively, these findings establish Cur-PU as a biocompatible material with tunable mechanical properties, and pH responsiveness, underscoring its translational potential for biomedical applications such as drug delivery systems and tissue engineering scaffolds. Full article

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32 pages, 2854 KiB

Open AccessReview

Yin Yang 1 (YY1) as a Central Node in Drug Resistance Pathways: Potential for Combination Strategies in Cancer Therapy

by Zhiyan Li, Xiang Jia, Ian Timothy Sembiring Meliala, Yanjun Li and Vivi Kasim

Biomolecules 2025, 15(8), 1069; https://doi.org/10.3390/biom15081069 - 24 Jul 2025

Abstract

Tumor drug resistance, a major cause of treatment failure, involves complex multi-gene networks, remodeling of signaling pathways, and interactions with the tumor microenvironment. Yin Yang 1 (YY1) is a critical oncogene overexpressed in many tumors and mediates multiple tumor-related processes, such as cell [...] Read more.

Tumor drug resistance, a major cause of treatment failure, involves complex multi-gene networks, remodeling of signaling pathways, and interactions with the tumor microenvironment. Yin Yang 1 (YY1) is a critical oncogene overexpressed in many tumors and mediates multiple tumor-related processes, such as cell proliferation, metabolic reprogramming, immune evasion, and drug resistance. Notably, YY1 drives resistance through multiple mechanisms, such as upregulation of drug efflux, maintenance of cancer stemness, enhancement of DNA repair capacity, modulation of the tumor microenvironment, and epithelial–mesenchymal transition, thereby positioning it as a pivotal regulator of drug resistance. This review examines the pivotal role of YY1 in resistance, elucidating its molecular mechanisms and clinical relevance. We demonstrate that YY1 inhibition could effectively reverse drug resistance and restore therapeutic sensitivity across various treatment modalities. Importantly, we highlight the promising potential of YY1-targeted strategies, particularly combined with anti-tumor agents, to overcome resistance barriers. Furthermore, we discuss critical translational considerations for advancing these combinatorial approaches into clinical practice. Full article

(This article belongs to the Section Molecular Biomarkers)

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23 pages, 34957 KiB

Open AccessArticle

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

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

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

Abstract

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

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

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

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39 pages, 1137 KiB

Open AccessReview

Spatial Transcriptomics Decodes Breast Cancer Microenvironment Heterogeneity: From Multidimensional Dynamic Profiling to Precision Therapy Blueprint Construction

by Aolong Ma, Lingyan Xiang, Jingping Yuan, Qianwen Wang, Lina Zhao and Honglin Yan

Biomolecules 2025, 15(8), 1067; https://doi.org/10.3390/biom15081067 - 24 Jul 2025

Abstract

Background: Breast cancer, the most prevalent malignancy among women worldwide, exhibits significant heterogeneity, particularly in the tumor microenvironment (TME), which poses challenges for treatment. Spatial transcriptomics (ST) has emerged as a transformative technology, enabling gene expression analysis while preserving tissue spatial architecture. This [...] Read more.

Background: Breast cancer, the most prevalent malignancy among women worldwide, exhibits significant heterogeneity, particularly in the tumor microenvironment (TME), which poses challenges for treatment. Spatial transcriptomics (ST) has emerged as a transformative technology, enabling gene expression analysis while preserving tissue spatial architecture. This provides unprecedented insights into tumor heterogeneity, cellular interactions, and disease mechanisms, offering a powerful tool for advancing breast cancer research and therapy. This review aims to synthesize the applications of ST in breast cancer research, focusing on its role in decoding tumor heterogeneity, characterizing the TME, elucidating progression and metastasis dynamics, and predicting therapeutic responses. We also explore how ST can bridge molecular profiling with clinical translation to enhance precision therapy. The key scientific concepts of review included the following: We summarize the technological advancements in ST, including imaging-based and sequencing-based methods, and their applications in breast cancer. Key findings highlight how ST resolves spatial heterogeneity across molecular subtypes and histological variants. ST reveals the dynamic interplay between tumor cells, immune cells, and stromal components, uncovering mechanisms of immune evasion, metabolic reprogramming, and therapeutic resistance. Additionally, ST identifies spatial prognostic markers and predicts responses to chemotherapy, targeted therapy, and immunotherapy. We propose that ST serves as a hub for integrating multi-omics data, offering a roadmap for precision oncology and personalized treatment strategies in breast cancer. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Breast Cancer)

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18 pages, 1984 KiB

Open AccessReview

Progress on 3-Nitropropionic Acid Derivatives

by Meng-Lin Feng, Zheng-Hui Li and Bao-Bao Shi

Biomolecules 2025, 15(8), 1066; https://doi.org/10.3390/biom15081066 - 24 Jul 2025

Abstract

3-Nitropropionic acid (3-NPA) is a deadly neurotoxic nitroalkane found in numerous fungi and leguminous plants. 3-NPA, known as an antimetabolite of succinate, irreversibly inhibits succinate dehydrogenase and disrupts mitochondrial oxidative phosphorylation. Its utility in modeling Huntington’s disease (HD) and oxidative stress has garnered [...] Read more.

3-Nitropropionic acid (3-NPA) is a deadly neurotoxic nitroalkane found in numerous fungi and leguminous plants. 3-NPA, known as an antimetabolite of succinate, irreversibly inhibits succinate dehydrogenase and disrupts mitochondrial oxidative phosphorylation. Its utility in modeling Huntington’s disease (HD) and oxidative stress has garnered significant research interest. Derivatives of 3-NPA, formed through esterification, have a wide range of biological activities including neurotoxic, antiviral, insecticidal, antimicrobial and antioxidant properties. This review systematically summarizes the structural characteristics, biological activities, and chemical synthesis of 3-NPA-derived compounds, providing valuable insights for further research and therapeutic applications. Full article

(This article belongs to the Special Issue Natural Products and Their Derivatives with Antiviral Activity)

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28 pages, 2329 KiB

Open AccessReview

Myocardial Infarction in Young Adults: A Case Series and Comprehensive Review of Molecular and Clinical Mechanisms

by Bogdan-Sorin Tudurachi, Larisa Anghel, Andreea Tudurachi, Răzvan-Liviu Zanfirescu, Silviu-Gabriel Bîrgoan, Radu Andy Sascău and Cristian Stătescu

Biomolecules 2025, 15(8), 1065; https://doi.org/10.3390/biom15081065 - 23 Jul 2025

Abstract

Acute myocardial infarction (AMI) in young adults, though less common than in older populations, is an emerging clinical concern with increasing incidence and diverse etiologies. Unlike classic atherosclerotic presentations, a significant proportion of AMI cases in individuals under 45 years are due to [...] Read more.

Acute myocardial infarction (AMI) in young adults, though less common than in older populations, is an emerging clinical concern with increasing incidence and diverse etiologies. Unlike classic atherosclerotic presentations, a significant proportion of AMI cases in individuals under 45 years are due to nonatherothrombotic mechanisms such as coronary vasospasm, spontaneous coronary artery dissection (SCAD), vasculitis, hypercoagulable states, and drug-induced coronary injury. This manuscript aims to explore the multifactorial nature of AMI in young adults through a focused review of current evidence and a series of illustrative clinical cases. We present and analyze four distinct cases of young patients with AMI, each demonstrating different pathophysiological mechanisms and risk profiles—including premature atherosclerosis, substance use, human immunodeficiency virus (HIV)-related coronary disease, and SCAD. Despite the heterogeneity of underlying causes, early diagnosis, individualized management, and aggressive secondary prevention were key to favorable outcomes. Advanced imaging, lipid profiling, and risk factor modification played a central role in guiding therapy. AMI in young adults requires heightened clinical suspicion and a comprehensive, multidisciplinary approach. Early intervention and recognition of nontraditional risk factors are essential to improving outcomes and preventing recurrent events in this vulnerable population. Full article

(This article belongs to the Special Issue Cardiometabolic Disease: Molecular Basis and Therapeutic Approaches)

16 pages, 2129 KiB

Open AccessArticle

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

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

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

Abstract

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

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

(This article belongs to the Section Molecular Biology)

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31 pages, 4621 KiB

Open AccessPerspective

Current Flow in Nerves and Mitochondria: An Electro-Osmotic Approach

by Robert S. Eisenberg

Biomolecules 2025, 15(8), 1063; https://doi.org/10.3390/biom15081063 - 22 Jul 2025

Abstract

The electrodynamics of current provide much of our technology, from telegraphs to the wired infrastructure powering the circuits of our electronic technology. Current flow is analyzed by its own rules that involve the Maxwell Ampere law and magnetism. Electrostatics does not involve magnetism, [...] Read more.

The electrodynamics of current provide much of our technology, from telegraphs to the wired infrastructure powering the circuits of our electronic technology. Current flow is analyzed by its own rules that involve the Maxwell Ampere law and magnetism. Electrostatics does not involve magnetism, and so current flow and electrodynamics cannot be derived from electrostatics. Practical considerations also prevent current flow from being analyzed one charge at a time. There are too many charges, and far too many interactions to allow computation. Current flow is essential in biology. Currents are carried by electrons in mitochondria in an electron transport chain. Currents are carried by ions in nerve and muscle cells. Currents everywhere follow the rules of current flow: Kirchhoff’s current law and its generalizations. The importance of electron and proton flows in generating ATP was discovered long ago but they were not analyzed as electrical currents. The flow of protons and transport of electrons form circuits that must be analyzed by Kirchhoff’s law. A chemiosmotic theory that ignores the laws of current flow is incorrect physics. Circuit analysis is easily applied to short systems like mitochondria that have just one internal electrical potential in the form of the Hodgkin Huxley Katz (HHK) equation. The HHK equation combined with classical descriptions of chemical reactions forms a computable model of cytochrome c oxidase, part of the electron transport chain. The proton motive force is included as just one of the components of the total electrochemical potential. Circuit analysis includes its role just as it includes the role of any other ionic current. Current laws are now needed to analyze the flow of electrons and protons, as they generate ATP in mitochondria and chloroplasts. Chemiosmotic theory must be replaced by an electro-osmotic theory of ATP production that conforms to the Maxwell Ampere equation of electrodynamics while including proton movement and the proton motive force. Full article

(This article belongs to the Special Issue Advances in Cellular Biophysics: Transport and Mechanics)

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21 pages, 2670 KiB

Open AccessArticle

Regulatory Effect of PGE₂-EP2/EP4 Receptor Pathway on Staphylococcus aureus-Induced Inflammatory Factors in Dairy Cow Neutrophils

by Yi Zhao, Chao Wang, Bo Liu, Shuangyi Zhang, Yongfei Wang, Yinghong Qian, Zhiguo Gong, Jiamin Zhao, Xiaolin Yang, Yuting Bai and Wei Mao

Biomolecules 2025, 15(8), 1062; https://doi.org/10.3390/biom15081062 - 22 Jul 2025

Abstract

Naturally occurring prostaglandin E₂ (PGE₂) influences cytokine production regulation in bovine neutrophils exposed to Staphylococcus aureus Rosenbach. Here, we employed bovine neutrophils as the primary experimental system, and administered specific inhibitors targeting various receptors, which were subsequently exposed to S. [...] Read more.

Naturally occurring prostaglandin E₂ (PGE₂) influences cytokine production regulation in bovine neutrophils exposed to Staphylococcus aureus Rosenbach. Here, we employed bovine neutrophils as the primary experimental system, and administered specific inhibitors targeting various receptors, which were subsequently exposed to S. aureus. Cytokine expression levels in dairy cow neutrophils induced by S. aureus via the endogenous PGE₂-EP2/4 receptor pathway were investigated, and its effects on P38, extracellular signal-regulated kinase (ERK), P65 activation, and phagocytic function in Staphylococcus aureus Rosenbach-induced dairy cow neutrophils, were examined. Blocking cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) enzymes substantially decreased PGE₂ production and release in S. aureus-exposed bovine neutrophils. Cytokine output showed significant reduction compared to that in SA113-infected controls. Phosphorylation of P38, ERK, and P65 signaling molecules was depressed in the infected group. Pharmacological interference with EP2/EP4 receptors similarly diminished cytokine secretion and phosphorylation patterns of P38, ERK, and P65, with preserved cellular phagocytic function. During S. aureus infection of bovine neutrophils, COX-2 and mPGES-1 participated in controlling PGE₂ biosynthesis, and internally produced PGE₂ molecules triggered NF-κB and MAPK inflammatory pathways via EP2/EP4 receptor activation, later adjusting the equilibrium between cytokine types that promote or suppress inflammation. This signaling mechanism coordinated inflammatory phases through receptor-mediated processes. Full article

(This article belongs to the Section Molecular Biology)

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22 pages, 2985 KiB

Open AccessReview

Class IIa HDACs Are Important Signal Transducers with Unclear Enzymatic Activities

by Claudio Brancolini

Biomolecules 2025, 15(8), 1061; https://doi.org/10.3390/biom15081061 - 22 Jul 2025

Abstract

Class IIa histone deacetylases (HDACs) are pleiotropic regulators of various differentiation pathways and adaptive responses. They form complexes with other co-repressors and can bind to DNA by interacting with selected transcription factors, with members of the Myocyte Enhancer Factor-2 (MEF2) family being the [...] Read more.

Class IIa histone deacetylases (HDACs) are pleiotropic regulators of various differentiation pathways and adaptive responses. They form complexes with other co-repressors and can bind to DNA by interacting with selected transcription factors, with members of the Myocyte Enhancer Factor-2 (MEF2) family being the best characterized. A notable feature of class IIa HDACs is the substitution of tyrosine for histidine in the catalytic site, which has occurred over the course of evolution and has a profound effect on the efficiency of catalysis against acetyl-lysine. Another distinctive feature of this family of “pseudoenzymes” is the regulated nucleus–cytoplasm shuttling associated with several non-histone proteins that have been identified as potential substrates, including proteins localized in the cytosol. Within the complexity of class IIa HDACs, several aspects deserve further investigation. In the following, I will discuss some of the recent advances in our knowledge of class IIa HDACs. Full article

(This article belongs to the Special Issue Recent Advances in Chromatin and Chromosome Molecular Research)

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29 pages, 1763 KiB

Open AccessReview

Inorganic Polyphosphate: An Emerging Regulator of Neuronal Bioenergetics and Its Implications in Neuroprotection

by Marcela Montilla, Norma Pavas-Escobar, Iveth Melissa Guatibonza-Arévalo, Alejandro Múnera, Renshen Eduardo Rivera-Melo and Felix A. Ruiz

Biomolecules 2025, 15(8), 1060; https://doi.org/10.3390/biom15081060 - 22 Jul 2025

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Abstract

Inorganic polyphosphate (polyP) is an evolutionarily conserved polymer that has recently gained relevance in neuronal physiology and pathophysiology. Although its roles, such as mitochondrial bioenergetics, calcium homeostasis, and the oxidative stress response, for example, are increasingly recognized, its specific implications in neurological disorders [...] Read more.

Inorganic polyphosphate (polyP) is an evolutionarily conserved polymer that has recently gained relevance in neuronal physiology and pathophysiology. Although its roles, such as mitochondrial bioenergetics, calcium homeostasis, and the oxidative stress response, for example, are increasingly recognized, its specific implications in neurological disorders remain underexplored. This review focuses on synthesizing the current knowledge of polyP in the context of central nervous system (CNS) diseases, highlighting how its involvement in key mitochondrial processes may influence neuronal survival and function. In particular, we examine recent evidence linking polyP to mechanisms relevant to neurodegeneration, such as the modulation of the mitochondrial permeability transition pore (mPTP), regulation of amyloid fibril formation, and oxidative stress responses. In addition, we analyze the emerging roles of polyP in inflammation and related cell signaling in CNS disorders. By organizing the existing data around the potential pathological and protective roles of polyP in the CNS, this review identifies it as a candidate of interest in the context of neurodegenerative disease mechanisms. We aim to clarify its relevance and stimulate future research on its molecular mechanisms and translational potential. Full article

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

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26 pages, 1899 KiB

Open AccessReview

Extracellular Matrix (ECM) Aging in the Retina: The Role of Matrix Metalloproteinases (MMPs) in Bruch’s Membrane Pathology and Age-Related Macular Degeneration (AMD)

by Ali A. Hussain and Yunhee Lee

Biomolecules 2025, 15(8), 1059; https://doi.org/10.3390/biom15081059 - 22 Jul 2025

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Abstract

The extracellular matrix (ECM) is a collagen-based scaffold that provides structural support and regulates nutrient transport and cell signaling. ECM homeostasis depends on a dynamic balance between synthesis and degradation, the latter being primarily mediated by matrix metalloproteinases (MMPs). These enzymes are secreted [...] Read more.

The extracellular matrix (ECM) is a collagen-based scaffold that provides structural support and regulates nutrient transport and cell signaling. ECM homeostasis depends on a dynamic balance between synthesis and degradation, the latter being primarily mediated by matrix metalloproteinases (MMPs). These enzymes are secreted as pro-forms and require activation to degrade ECM components. Their activity is modulated by tissue inhibitors of metalloproteinases (TIMPs). Aging disrupts this balance, leading to the accumulation of oxidized, cross-linked, and denatured matrix proteins, thereby impairing ECM function. Bruch’s membrane, a penta-laminated ECM structure in the eye, plays a critical role in supporting photoreceptor and retinal pigment epithelium (RPE) health. Its age-related thickening and decreased permeability are associated with impaired nutrient delivery and waste removal, contributing to the pathogenesis of age-related macular degeneration (AMD). In AMD, MMP dysfunction is characterized by the reduced activation and sequestration of MMPs, which further limits matrix turnover. This narrative review explores the structural and functional changes in Bruch’s membrane with aging, the role of MMPs in ECM degradation, and the relevance of these processes to AMD pathophysiology, highlighting emerging regulatory mechanisms and potential therapeutic targets. Full article

(This article belongs to the Special Issue Role of Matrix Metalloproteinase in Health and Disease)

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15 pages, 6089 KiB

Open AccessArticle

Molecular Fingerprint of Cold Adaptation in Antarctic Icefish PepT1 (Chionodraco hamatus): A Comparative Molecular Dynamics Study

by Guillermo Carrasco-Faus, Valeria Márquez-Miranda and Ignacio Diaz-Franulic

Biomolecules 2025, 15(8), 1058; https://doi.org/10.3390/biom15081058 - 22 Jul 2025

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Abstract

Cold environments challenge the structural and functional integrity of membrane proteins, requiring specialized adaptations to maintain activity under low thermal energy. Here, we investigate the molecular basis of cold tolerance in the peptide transporter PepT1 from the Antarctic icefish (Chionodraco hamatus, [...] Read more.

Cold environments challenge the structural and functional integrity of membrane proteins, requiring specialized adaptations to maintain activity under low thermal energy. Here, we investigate the molecular basis of cold tolerance in the peptide transporter PepT1 from the Antarctic icefish (Chionodraco hamatus, ChPepT1) using molecular dynamics simulations, binding free energy calculations (MM/GBSA), and dynamic network analysis. We compare ChPepT1 to its human ortholog (hPepT1), a non-cold-adapted variant, to reveal key features enabling psychrophilic function. Our simulations show that ChPepT1 displays enhanced global flexibility, particularly in domains adjacent to the substrate-binding site and the C-terminal domain (CTD). While hPepT1 loses substrate binding affinity as temperature increases, ChPepT1 maintains stable peptide interactions across a broad thermal range. This thermodynamic buffering results from temperature-sensitive rearrangement of hydrogen bond networks and more dynamic lipid interactions. Importantly, we identify a temperature-responsive segment (TRS, residues 660–670) within the proximal CTD that undergoes an α-helix to coil transition, modulating long-range coupling with transmembrane helices. Dynamic cross-correlation analyses further suggest that ChPepT1, unlike hPepT1, reorganizes its interdomain communication in response to temperature shifts. Our findings suggest that cold tolerance in ChPepT1 arises from a combination of structural flexibility, resilient substrate binding, and temperature-sensitive interdomain dynamics. These results provide new mechanistic insight into thermal adaptation in membrane transporters and offer a framework for engineering proteins with enhanced functionality in extreme environments. Full article

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

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28 pages, 53408 KiB

Open AccessReview

Changes in Epithelial Cell Polarity and Adhesion Guide Human Endometrial Receptivity: How In Vitro Systems Help to Untangle Mechanistic Details

by Irmgard Classen-Linke, Volker U. Buck, Anna K. Sternberg, Matthias Kohlen, Liubov Izmaylova and Rudolf E. Leube

Biomolecules 2025, 15(8), 1057; https://doi.org/10.3390/biom15081057 - 22 Jul 2025

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Abstract

Tissue remodeling of human endometrium occurs during the menstrual cycle to prepare for embryo adhesion and invasion. The ovarian steroid hormones 17β-estradiol and progesterone control the menstrual cycle to achieve the receptive state during the “window of implantation” (WOI). Here, we focus on [...] Read more.

Tissue remodeling of human endometrium occurs during the menstrual cycle to prepare for embryo adhesion and invasion. The ovarian steroid hormones 17β-estradiol and progesterone control the menstrual cycle to achieve the receptive state during the “window of implantation” (WOI). Here, we focus on the human endometrial epithelium and its changes in polarity, adhesion, cytoskeletal organization and the underlying extracellular matrix enabling embryo implantation. The adhesion and invasion of the trophoblast via the apical plasma membrane of epithelial cells is a unique cell biological process, which is coupled to partial epithelial–mesenchymal transition (EMT). Given the fundamental species differences during implantation, we restrict the review mainly to the human situation and focus on cell culture systems to study the interaction between human trophoblast and endometrial cells. We summarize current knowledge based on the relatively scarce in vivo data and the steadily growing in vitro observations using various cell culture systems. Full article

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

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14 pages, 1573 KiB

Open AccessArticle

Association of 17q12-q21 Asthma Risk Locus with Clinical Severity of Infant Respiratory Syncytial Virus Infection

by Kedir N. Turi, Christopher McKennan, Christian Rosas-Salazar, Tebeb Gebretsedik, Dawn C. Newcomb, Emma E. Thompson, James Gern, James Chappell, Larry Anderson, Carole Ober and Tina Hartert

Biomolecules 2025, 15(8), 1056; https://doi.org/10.3390/biom15081056 - 22 Jul 2025

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Abstract

This study examined whether SNPs at the 17q12-q21 locus that are associated with childhood asthma are also associated with severe respiratory syncytial virus (RSV) infection and viral load. We conducted a candidate SNP association study in the subset of RSV-infected infants who were [...] Read more.

This study examined whether SNPs at the 17q12-q21 locus that are associated with childhood asthma are also associated with severe respiratory syncytial virus (RSV) infection and viral load. We conducted a candidate SNP association study in the subset of RSV-infected infants who were parent-identified as White (n = 159) in the INSPIRE cohort. Nine SNPs at the 17q12-q21 locus were genotyped. We used an additive model to evaluate each SNP’s association with RSV infection severity and viral load. Replication of significant associations was tested in the TCRI cohort: infants with severe RSV illness. In INSPIRE, an SNP rs8069202-G in the GSDMA gene was associated with increased RSV viral load (and marginally associated with RSV severity). SNP rs2941504, in the PGAP3 gene, was associated with a reduced risk of RSV severity. All significant associations were directionally replicated in the TCRI cohort but were insignificant at a p-value < 0.05. The association of a SNP in GSDMA with RSV viral load and RSV infection severity suggests that GSDMA may be contributing to both severe RSV infection and asthma development. On the other hand, the association between an SNP in PGAP3 and reduced RSV infection severity suggests distinct pathways link PGAP3 to these two respiratory outcomes. Full article

(This article belongs to the Section Molecular Medicine)

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31 pages, 4179 KiB

Open AccessReview

Plant-Derived Vesicle-like Nanoparticles: Pioneering Sustainable and Effective Approaches for Tissue Repair and Regeneration

by Qinjing Wang, Zhijie Huang, Jiming Guo, Weixing Chen, Min Wang, Yue Ming, Hongyu Liu, Mingshu Huang, Yisheng Huang, Zhengming Tang and Bo Jia

Biomolecules 2025, 15(8), 1055; https://doi.org/10.3390/biom15081055 - 22 Jul 2025

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Abstract

Plant-derived vesicle-like nanoparticles (PDVLNs) are bioactive nanovesicles secreted by plant cells, emerging as a novel therapeutic tool for tissue repair and regeneration due to their low immunogenicity, intrinsic bioactivity, and potential as drug delivery carriers. This review examines PDVLNs’ biogenesis mechanisms, isolation techniques, [...] Read more.

Plant-derived vesicle-like nanoparticles (PDVLNs) are bioactive nanovesicles secreted by plant cells, emerging as a novel therapeutic tool for tissue repair and regeneration due to their low immunogenicity, intrinsic bioactivity, and potential as drug delivery carriers. This review examines PDVLNs’ biogenesis mechanisms, isolation techniques, and compositional diversity, emphasizing their roles in promoting essential regenerative processes—cell proliferation, differentiation, migration, immune modulation, and angiogenesis. We explore their therapeutic applications across multiple tissue types, including skin, bone, neural, liver, gastrointestinal, cardiovascular, and dental tissues, using both natural and engineered PDVLNs in various disease models. Compared to mammalian exosomes, PDVLNs offer advantages such as reduced immune rejection and ethical concerns, enhancing their sustainability and appeal for regenerative medicine. However, challenges in clinical translation, including scalability, standardization, and safety remain. This paper consolidates current knowledge on PDVLNs, highlighting their versatility and providing insights into engineering strategies to optimize efficacy, ultimately outlining future research directions to advance their clinical potential. Plant vesicle-like nanoparticles (PDVLNs) may become a new avenue for the treatment of tissue injury, promoting tissue repair and regeneration through their intrinsic bioactivity or as drug delivery carriers. In addition, PDVLNs can be engineered and modified to achieve better results. Full article

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

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Biomolecules, Volume 15, Issue 8 (August 2025) – 20 articles

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