International Journal of Molecular Sciences

34 pages, 2026 KiB

Open AccessReview

Review of Applications of Zeolites in Dermatology: Molecular Perspectives and Translational Potentials

by James Curtis Dring, Matthew Kaczynski, Rina Maria Zureikat, Michael Kaczynski, Alicja Forma and Jacek Baj

Int. J. Mol. Sci. 2025, 26(14), 6821; https://doi.org/10.3390/ijms26146821 (registering DOI) - 16 Jul 2025

Abstract

Zeolites, microporous aluminosilicates with tuneable physicochemical properties, have garnered increasing attention in dermatology due to their antimicrobial, detoxifying, and drug delivery capabilities. This review evaluates the structural characteristics, therapeutic mechanisms, and clinical applications of zeolites—including clinoptilolite, ZSM-5, ZIF-8, and silver/zinc-functionalized forms—across skin infections, [...] Read more.

Zeolites, microporous aluminosilicates with tuneable physicochemical properties, have garnered increasing attention in dermatology due to their antimicrobial, detoxifying, and drug delivery capabilities. This review evaluates the structural characteristics, therapeutic mechanisms, and clinical applications of zeolites—including clinoptilolite, ZSM-5, ZIF-8, and silver/zinc-functionalized forms—across skin infections, wound healing, acne management, and cosmetic dermatology. Zeolites demonstrated broad-spectrum antibacterial and antifungal efficacy, enhanced antioxidant activity, and biocompatible drug delivery in various dermatological models. Formulations such as silver–sulfadiazine–zeolite composites, Zn–clinoptilolite for acne, and zeolite-integrated microneedles offer innovative avenues for targeted therapy. Zeolite-based systems represent a promising shift toward multifunctional, localized dermatologic treatments. However, further research into long-term safety, formulation optimization, and clinical validation is essential to transition these materials into mainstream therapeutic use. Full article

(This article belongs to the Special Issue Skin Diseases: From Molecular Pathology to Novel Therapeutic Approaches)

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14 pages, 2226 KiB

Open AccessArticle

Investigation of the Effect of C-Terminal Adjacent Phenylalanine Residues on Asparagine Deamidation by Quantum Chemical Calculations

by Koichi Kato, Haruka Asai, Tomoki Nakayoshi, Ayato Mizuno, Akifumi Oda and Yoshinobu Ishikawa

Int. J. Mol. Sci. 2025, 26(14), 6819; https://doi.org/10.3390/ijms26146819 (registering DOI) - 16 Jul 2025

Abstract

The deamidation rate is relatively high for Asn residues with Phe as the C-terminal adjacent residue in γS-crystallin, which is one of the human crystalline lens proteins. However, peptide-based experiments indicated that bulky amino acid residues on the C-terminal side impaired Asn deamination. [...] Read more.

The deamidation rate is relatively high for Asn residues with Phe as the C-terminal adjacent residue in γS-crystallin, which is one of the human crystalline lens proteins. However, peptide-based experiments indicated that bulky amino acid residues on the C-terminal side impaired Asn deamination. In this study, we hypothesized that the side chain of Phe affects the Asn deamidation rate and investigated the succinimide formation process using quantum chemical calculations. The B3LYP density functional theory was used to obtain optimized geometries of energy minima and transition states, and MP2 and M06-2X calculations were used to obtain the single-point energy. Activation barriers and rate-determining step changed depending on the orientation of the Phe side chain. In pathways where an interaction occurred between the benzene ring and the amide group of the Asn residue, the activation barrier was lower than in pathways where this interaction did not occur. Since the aromatic ring is oriented toward the Asn side in experimentally determined structures of γS-crystallin, the above interaction is considered to enhance the Asn deamidation. Full article

(This article belongs to the Section Molecular Biophysics)

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25 pages, 765 KiB

Open AccessReview

The Latest Advances in Omics Technology for Assessing Tissue Damage: Implications for the Study of Sudden Cardiac Death

by Raluca-Maria Căținaș and Sorin Hostiuc

Int. J. Mol. Sci. 2025, 26(14), 6818; https://doi.org/10.3390/ijms26146818 (registering DOI) - 16 Jul 2025

Abstract

Sudden cardiac death (SCD) is a major public health concern, being a leading cause of death worldwide. SCD is particularly alarming for individuals with apparently good health, as it often occurs without preceding warning signs. Unfortunately, traditional autopsy methods frequently fail to identify [...] Read more.

Sudden cardiac death (SCD) is a major public health concern, being a leading cause of death worldwide. SCD is particularly alarming for individuals with apparently good health, as it often occurs without preceding warning signs. Unfortunately, traditional autopsy methods frequently fail to identify the precise cause of death in these cases, highlighting the need for advanced techniques to elucidate underlying mechanisms. Recent advances in molecular biology over the past few years, particularly in proteomics, transcriptomics, and metabolomics techniques, have led to an expanded understanding of gene expression, protein activity, and metabolic changes, offering valuable insights into fatal cardiac events. Combining multi-omics methods with bioinformatics and machine learning algorithms significantly enhances our ability to uncover the processes behind lethal cardiac dysfunctions by identifying new useful biomarkers (like cardiac myosin-binding protein C, acylcarnitines, or microRNAs) to reveal molecular pathways linked to SCD. This narrative review summarizes the role of multi-omics approaches in forensic diagnosis by exploring current applications in unexplained cases and the benefits of integrating merged techniques in otherwise negative autopsies. We also discuss the potential for developing personalized and preventive forensic medicine, the technical limitations of currently available methods, and the ethical considerations arising from these advancements. Full article

(This article belongs to the Special Issue Molecular Biological Determination of Physical Injury)

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20 pages, 1593 KiB

Open AccessReview

Circulating Extracellular Vesicles in Cardiovascular Disease

by Ilenia Pia Cappucci, Elena Tremoli, Barbara Zavan and Letizia Ferroni

Int. J. Mol. Sci. 2025, 26(14), 6817; https://doi.org/10.3390/ijms26146817 (registering DOI) - 16 Jul 2025

Abstract

Despite notable advancements in clinical care, cardiovascular disease (CVD) remains a leading global cause of mortality. Encompassing a wide range of heart and blood vessel disorders, CVD requires targeted prevention and treatment strategies to mitigate its public health impact. In recent years, extracellular [...] Read more.

Despite notable advancements in clinical care, cardiovascular disease (CVD) remains a leading global cause of mortality. Encompassing a wide range of heart and blood vessel disorders, CVD requires targeted prevention and treatment strategies to mitigate its public health impact. In recent years, extracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, influencing key processes such as vascular remodeling, inflammation, and immune responses in CVDs. EVs, including exosomes and microvesicles, carry bioactive molecules such as miRNAs, proteins, and lipids that contribute to disease progression. They are released by various cell types, including platelets, erythrocytes, leukocytes, endothelial cells, and cardiomyocytes, each playing distinct roles in cardiovascular homeostasis and pathology. Given their presence in circulating blood and other body fluids, EVs are increasingly recognized as promising non-invasive biomarkers for CVD diagnosis and prognosis. Furthermore, EV-based therapeutic strategies, including engineered EVs for targeted drug delivery, are being explored for treating atherosclerosis, myocardial infarction, heart failure, and hypertension. However, challenges remain regarding the standardization of EV isolation and characterization techniques, which are critical for their clinical implementation. This review highlights the diverse roles of EVs in CVD pathophysiology, their potential as diagnostic and prognostic biomarkers, and emerging therapeutic applications, clearing the way for their integration into cardiovascular precision medicine. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases: 3rd Edition)

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23 pages, 3343 KiB

Open AccessArticle

Dietary Fermentation with Lactobacillus sp. and Bacillus sp. Modulates Rumen Transcriptomic and Microbiota Profiles in Bos taurus

by Jeong Sung Jung, Dahye Kim, Anand Singaravelu, Ilavenil Soundharrajan and Ki Choon Choi

Int. J. Mol. Sci. 2025, 26(14), 6816; https://doi.org/10.3390/ijms26146816 (registering DOI) - 16 Jul 2025

Abstract

Animal feed made from fermented agricultural residues using Lactobacillus sp. and Bacillus sp. has received significant attention. However, interactions between differentially expressed genes (DEGs) in adipose, liver, and muscle tissues and bacteria or fungi in the rumen remain largely unknown. This study determined [...] Read more.

Animal feed made from fermented agricultural residues using Lactobacillus sp. and Bacillus sp. has received significant attention. However, interactions between differentially expressed genes (DEGs) in adipose, liver, and muscle tissues and bacteria or fungi in the rumen remain largely unknown. This study determined effects of normal diet feed (NF) and alternative diet feed made by Lactobacillus sp. and Bacillus sp. (AF) on gene expression in major metabolic organs and on microbial populations in the rumen of Bos-Taurus using high-throughput sequencing methods. Rumen bacteria/fungi interaction with DEGs in key metabolic organs was also investigated. According to our findings, 34, 36, and 28 genes were differentially expressed in adipose, liver, and muscle tissues, respectively. Most DEGs were associated with osteoclast differentiation and immune functions. Microbial dynamics analysis showed that the AF diet significantly (p < 0.05) increased Firmicutes but reduced Bacterioidetes abundances. At the genus level, Faecalicatena, Intestinimonas, Lachnoclostridium, Faecalicatena, and Intestinimonas were significantly higher (p < 0.05) in animals fed with the AF diet. Regarding fungal populations, Neocallimastigomycota accounted for 98.2% in the NF diet and 86.88% in the AF diet. AF feeding increased Orpinomyces and Piromyces but decreased Neocallimastix abundances. These findings highlight the potential of fermented feeds to improve metabolic responses and rumen microbial balance, contributing to enhanced animal performance. Full article

(This article belongs to the Special Issue Studies on Lactic Acid Bacteria and Their Products in Health and Diseases: 2nd Edition)

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14 pages, 5036 KiB

Open AccessArticle

Intermolecular Charge Transfer Induced Sensitization of Yb³⁺ in β-Diketone Coordination Compounds with Excellent Luminescence Efficiency

by Trofim A. Polikovskiy, Daniil D. Shikin, Vladislav M. Korshunov, Victoria E. Gontcharenko, Mikhail T. Metlin, Nikolay P. Datskevich, Marat M. Islamov, Victor O. Kompanets, Sergey V. Chekalin, Yuriy A. Belousov and Ilya V. Taydakov

Int. J. Mol. Sci. 2025, 26(14), 6814; https://doi.org/10.3390/ijms26146814 (registering DOI) - 16 Jul 2025

Abstract

Achieving high quantum yields for Yb³⁺ ion emission in complexes with organic ligands is a challenging task, as most Yb³⁺ complexes with such ligands typically exhibit efficiencies below 3.5%. Our research demonstrates that the introduction of heavy atom-containing ancillary ligands, such [...] Read more.

Achieving high quantum yields for Yb³⁺ ion emission in complexes with organic ligands is a challenging task, as most Yb³⁺ complexes with such ligands typically exhibit efficiencies below 3.5%. Our research demonstrates that the introduction of heavy atom-containing ancillary ligands, such as TPPO or TPAO, along with the careful engineering of the main β-diketone ligand, can increase the luminescence efficiency up to 20-fold by the alteration of the energy migration pathway. It is demonstrated that the combination of two distinct organic ligands leads to the blockage of singlet–triplet intersystem crossing (ISC), alongside electronic energy transfer from β-diketone to Yb³⁺ ions through charge transfer states. The synthesized complexes exhibit quantum yields of 6.5% and 7.0% in the solid state, which places them at the top globally among this class of materials with simple non-deuterated and non-fluorinated ligands. Full article

(This article belongs to the Special Issue Design of Functional Supramolecular Architectures Based on Coordination Compounds)

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60 pages, 3898 KiB

Open AccessReview

The Therapeutic Potential of Phytochemicals Unlocks New Avenues in the Management of Rheumatoid Arthritis

by Kalina A. Nikolova-Ganeva, Nikolina M. Mihaylova, Lidiya A. Kechidzhieva, Kristina I. Ivanova, Alexander S. Zarkov, Daniel L. Parzhanov, Momchil M. Ivanov and Andrey S. Marchev

Int. J. Mol. Sci. 2025, 26(14), 6813; https://doi.org/10.3390/ijms26146813 (registering DOI) - 16 Jul 2025

Abstract

Rheumatoid arthritis (RA) is a progressive and systemic autoimmune disease, characterized by a chronic inflammatory process, affecting the lining of the synovial joints, many body organs/systems, and blood vessels. Its pathological hallmarks are hyperplasic synovium, bone erosion, and progressive joint destruction. Rheumatoid arthritis [...] Read more.

Rheumatoid arthritis (RA) is a progressive and systemic autoimmune disease, characterized by a chronic inflammatory process, affecting the lining of the synovial joints, many body organs/systems, and blood vessels. Its pathological hallmarks are hyperplasic synovium, bone erosion, and progressive joint destruction. Rheumatoid arthritis affects over 20 million people, with a worldwide prevalence of 0.5–1.0%, exhibiting gender, ethnic, and geographical differences. The progressive disability severely impairs physical motion and quality of life and is finally leading to a shortened life span. The pathogenesis of RA is a complex and still poorly understood process in which genetic and environmental factors are principally associated. Current treatment mostly relies on conventional/non-biological disease-modifying anti-rheumatic drugs (cDMARDs), analgesics, non-steroidal anti-inflammatory drugs, glucocorticoids, steroids, immunosuppresants, and biologic DMARDs, which only control inflammation and pain. Along with side effects (drug toxicity and intolerance), these anti-rheumatic drugs possess limited efficacy. Therefore, the discovery of novel multi-target therapeutics with an improved safety profile that function as inhibitors of RA-linked signaling systems are in high demand, and this is in the interest of both patients and clinicians. Plant-derived extracts, nutritional supplements, dietary medicine, and molecules with anti-inflammatory activity represent promising adjuvant agents or alternatives for RA therapeutics. This review not only aims to discuss the basic features of RA pathogenesis, risk factors, and signaling pathways but also highlights the research progress in pre-clinical RA in in vitro and in vivo models, revealing new avenues in the management of the disease in terms of comprehensive multidisciplinary strategies originating from medicinal plants and plant-derived molecules. Full article

(This article belongs to the Special Issue Natural Products as Multitarget Agents in Human Diseases)

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17 pages, 3248 KiB

Open AccessArticle

Interneuron-Driven Ictogenesis in the 4-Aminopyridine Model: Depolarization Block and Potassium Accumulation Initiate Seizure-like Activity

by Elena Yu. Proskurina, Julia L. Ergina and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2025, 26(14), 6812; https://doi.org/10.3390/ijms26146812 (registering DOI) - 16 Jul 2025

Abstract

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K⁺]_o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine [...] Read more.

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K⁺]_o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine model of epileptiform activity), we identified a critical transition sequence: interneurons displayed high-frequency firing during the preictal phase before entering depolarization block (DB). DB onset coincided with the peak of rate of extracellular [K⁺] accumulation. Pyramidal cells remained largely silent during interneuronal hyperactivity but started firing within 1.1 ± 0.3 s after DB onset, marking the transition to ictal discharges. This consistent sequence (interneuron DB → [K⁺]_o rate peak → pyramidal cell firing) was observed in 100% of entorhinal cortex recordings. Importantly, while neurons across all entorhinal cortical layers synchronously fired during the first ictal discharge, hippocampal CA1 neurons showed fundamentally different activity: they generated high-frequency interictal bursts but did not participate in ictal events, indicating region-specific seizure initiation mechanisms. Our results demonstrate that interneuron depolarization block acts as a precise temporal switch for ictogenesis and suggest that the combined effect of disinhibition and K⁺-mediated depolarization triggers synchronous pyramidal neuron recruitment. These findings provide a mechanistic framework for seizure initiation in focal epilepsy, highlighting fast-spiking interneurons dysfunction as a potential therapeutic target. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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26 pages, 2868 KiB

Open AccessArticle

Resonant Oscillations of Ion-Stabilized Nanobubbles in Water as a Possible Source of Electromagnetic Radiation in the Gigahertz Range

by Nikolai F. Bunkin, Yulia V. Novakovskaya, Rostislav Y. Gerasimov, Barry W. Ninham, Sergey A. Tarasov, Natalia N. Rodionova and German O. Stepanov

Int. J. Mol. Sci. 2025, 26(14), 6811; https://doi.org/10.3390/ijms26146811 (registering DOI) - 16 Jul 2025

Abstract

It is well known that aqueous solutions can emit electromagnetic waves in the radio frequency range. However, the physical nature of this process is not yet fully understood. In this work, the possible role of gas nanobubbles formed in the bulk liquid is [...] Read more.

It is well known that aqueous solutions can emit electromagnetic waves in the radio frequency range. However, the physical nature of this process is not yet fully understood. In this work, the possible role of gas nanobubbles formed in the bulk liquid is considered. We develop a theoretical model based on the concept of gas bubbles stabilized by ions, or “bubstons”. The role of bicarbonate and hydronium ions in the formation and stabilization of bubstons is explained through the use of quantum chemical simulations. A new model of oscillating bubstons, which takes into account the double electric layer formed around their gas core, is proposed. Theoretical estimates of the frequencies and intensities of oscillations of such compound species are obtained. It was determined that oscillations of negatively charged bubstons can occur in the GHz frequency range, and should be accompanied by the emission of electromagnetic waves. To validate the theoretical assumptions, we used dynamic light scattering (DLS) and showed that, after subjecting aqueous solutions to vigorous shaking with a force of 4 or 8 N (kg·m/s²) and a frequency of 4–5 Hz, the volume number density of bubstons increased by about two orders of magnitude. Radiometric measurements in the frequency range of 50 MHz to 3.5 GHz revealed an increase in the intensity of radiation emitted by water samples upon the vibrational treatment. It is argued that, according to our new theoretical model, this radiation can be caused by oscillating bubstons. Full article

(This article belongs to the Section Physical Chemistry and Chemical Physics)

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11 pages, 653 KiB

Open AccessReview

Lactate in Heart Failure

by Piotr Gajewski, Michał Maksymilian Wilk, Krzysztof Aleksandrowicz, Beata Ponikowska and Robert Zymliński

Int. J. Mol. Sci. 2025, 26(14), 6810; https://doi.org/10.3390/ijms26146810 (registering DOI) - 16 Jul 2025

Abstract

This narrative review explores the multifaceted role of lactate in heart failure (HF), focusing on its diagnostic and prognostic significance in both acute and chronic HF. Lactate functions not only as a marker of hypoperfusion and anaerobic metabolism but also as an active [...] Read more.

This narrative review explores the multifaceted role of lactate in heart failure (HF), focusing on its diagnostic and prognostic significance in both acute and chronic HF. Lactate functions not only as a marker of hypoperfusion and anaerobic metabolism but also as an active metabolic substrate. In acute HF, elevated lactate levels often signal circulatory insufficiency and predict adverse outcomes. In chronic HF, especially HFpEF, lactate dynamics during exercise reflect metabolic inefficiency and correlate with functional impairment. This review emphasizes the dual nature of lactate and discusses its potential utility in risk stratification and therapeutic guidance. Full article

(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Cardiac Disease)

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23 pages, 12860 KiB

Open AccessArticle

Antimicrobial Composite Films Based on Alginate–Chitosan with Honey, Propolis, Royal Jelly and Green-Synthesized Silver Nanoparticles

by Corina Dana Dumitru, Cornelia-Ioana Ilie, Ionela Andreea Neacsu, Ludmila Motelica, Ovidiu Cristian Oprea, Alexandra Ripszky, Silviu Mirel Pițuru, Bianca Voicu Bălașea, Florica Marinescu and Ecaterina Andronescu

Int. J. Mol. Sci. 2025, 26(14), 6809; https://doi.org/10.3390/ijms26146809 (registering DOI) - 16 Jul 2025

Abstract

Honey, propolis or royal jelly are considered natural remedies with therapeutic properties since antiquity. Many papers explore the development of antimicrobial biomaterials based on individual bee products, but there is a lack of studies on their synergistic effects. Combining honey, propolis and royal [...] Read more.

Honey, propolis or royal jelly are considered natural remedies with therapeutic properties since antiquity. Many papers explore the development of antimicrobial biomaterials based on individual bee products, but there is a lack of studies on their synergistic effects. Combining honey, propolis and royal jelly with silver nanoparticles in a biopolymer matrix offers a synergistic strategy to combat antibiotic-resistant bacterial infections. This approach supports progress in wound healing, soft tissue engineering and other domains where elimination of the microorganisms is needed like food packaging. In this study we have obtained antimicrobial films based on bee products and silver nanoparticles (AgNPs) incorporated in an alginate–chitosan blend. The novel biomaterials were analyzed by UV-Vis, fluorescence and FTIR spectroscopy or microscopy, SEM and thermal analysis. Antibacterial tests were conducted against both Gram-positive and Gram-negative bacteria, while the antifungal properties were tested against Candida albicans. The diameters for growth inhibition zones were up to 10 mm for bacterial strains and 8 mm for the fungal strain. Additionally, cytotoxicity assays were performed to evaluate the biocompatibility of the materials, the results indicating that the combination of honey, propolis, royal jelly and AgNPs does not produce synergistic toxicity. Full article

(This article belongs to the Section Materials Science)

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22 pages, 1889 KiB

Open AccessReview

DNA-Barcoding for Cultivar Identification and Intraspecific Diversity Analysis of Agricultural Crops

by Lidiia S. Samarina, Natalia G. Koninskaya, Ruset M. Shkhalakhova, Taisiya A. Simonyan and Daria O. Kuzmina

Int. J. Mol. Sci. 2025, 26(14), 6808; https://doi.org/10.3390/ijms26146808 (registering DOI) - 16 Jul 2025

Abstract

DNA barcoding of intraspecific diversity of agricultural crops is important to develop the genetic passports of valuable genotypes and cultivars. The advantage of DNA-barcoding as compared to traditional genotyping of cultivars is that the procedure can be unified and applied for the broad [...] Read more.

DNA barcoding of intraspecific diversity of agricultural crops is important to develop the genetic passports of valuable genotypes and cultivars. The advantage of DNA-barcoding as compared to traditional genotyping of cultivars is that the procedure can be unified and applied for the broad range of accessions. This not only makes it cost efficient, but also allows to develop open access genetic databases to accumulate information of the world’s germplasm collections of different crops. In this regard, the aim of the review was to analyze the latest research in this field, including the selection of loci, universal primers, strategies of amplicons analysis, bioinformatic tools, and the development of databases. We reviewed the advantages and disadvantages of each strategy with the focus of cultivars identification. The data indicates that following chloroplast loci are the most prominent for the intraspecific diversity analysis: (trnE-UUC/trnT-GUU, rpl23/rpl2.l, psbA-trnH, trnL-trnF, trnK, rpoC1, ycf1-a, rpl32-trnL, trnH-psbA and matK). We suggest that the combination of three or four of these loci can be a sufficient DNA barcode for cultivar-level identification. This combination has to be selected for each crop. Advantages and disadvantages of different approaches of amplicons analysis are discussed. The bioinformatic tools and databases for the plant barcoding are reviewed. This review will be useful for selecting appropriate strategies for barcoding of intraspecific diversity of agricultural crops to develop genetic passports of valuable cultivars in germplasm collections worldwide. Full article

(This article belongs to the Special Issue Plant Biology and Biotechnology: Focus on Genomics, Bioinformatics and AI)

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42 pages, 6065 KiB

Open AccessReview

Digital Alchemy: The Rise of Machine and Deep Learning in Small-Molecule Drug Discovery

by Abdul Manan, Eunhye Baek, Sidra Ilyas and Donghun Lee

Int. J. Mol. Sci. 2025, 26(14), 6807; https://doi.org/10.3390/ijms26146807 (registering DOI) - 16 Jul 2025

Abstract

This review provides a comprehensive analysis of the transformative impact of artificial intelligence (AI) and machine learning (ML) on modern drug design, specifically focusing on how these advanced computational techniques address the inherent limitations of traditional small-molecule drug design methodologies. It begins by [...] Read more.

This review provides a comprehensive analysis of the transformative impact of artificial intelligence (AI) and machine learning (ML) on modern drug design, specifically focusing on how these advanced computational techniques address the inherent limitations of traditional small-molecule drug design methodologies. It begins by outlining the historical challenges of the drug discovery pipeline, including protracted timelines, exorbitant costs, and high clinical failure rates. Subsequently, it examines the core principles of structure-based virtual screening (SBVS) and ligand-based virtual screening (LBVS), establishing the critical bottlenecks that have historically impeded efficient drug development. The central sections elucidate how cutting-edge ML and deep learning (DL) paradigms, such as generative models and reinforcement learning, are revolutionizing chemical space exploration, enhancing binding affinity prediction, improving protein flexibility modeling, and automating critical design tasks. Illustrative real-world case studies demonstrating quantifiable accelerations in discovery timelines and improved success probabilities are presented. Finally, the review critically examines prevailing challenges, including data quality, model interpretability, ethical considerations, and evolving regulatory landscapes, while offering forward-looking critical perspectives on the future trajectory of AI-driven pharmaceutical innovation. Full article

(This article belongs to the Special Issue Advances in Computer-Aided Drug Design Strategies)

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21 pages, 4205 KiB

Open AccessArticle

Safety Evaluation and Biodistribution of Fetal Umbilical Cord Mesenchymal Stem Cells-Derived Small Extracellular Vesicles in Sprague Dawley Rats

by Illayaraja Krishnan, Ubashini Vijakumaran, Ng Min Hwei, Law Jia Xian, Mohd Rafizul Mohd Yusof, Thavachelvi Thangarajah, Tan Geok Chin, Yin Ping Wong, Anusha Kalyanasundaram, Zalina Mahmood, Shathiya Rajamanickam, Baskar Subramani and Yogeswaran Lokanathan

Int. J. Mol. Sci. 2025, 26(14), 6806; https://doi.org/10.3390/ijms26146806 (registering DOI) - 16 Jul 2025

Abstract

Umbilical cord mesenchymal stem cells (UCMSCs)-derived small extracellular vehicles (sEVs) are reported to offer therapeutic effects in regenerative medicine, but they lack safety and biodistribution profiles to support smooth translation at the clinical stage and regulatory requirements. Our study aimed to determine the [...] Read more.

Umbilical cord mesenchymal stem cells (UCMSCs)-derived small extracellular vehicles (sEVs) are reported to offer therapeutic effects in regenerative medicine, but they lack safety and biodistribution profiles to support smooth translation at the clinical stage and regulatory requirements. Our study aimed to determine the safety and biodistribution profile in a healthy animal model before application in the metabolic syndrome model. Method: Healthy male Sprague Dawley (SD) rats were given an intravenous (IV) injection of normal saline (control group) or pooled fetal UCMSCs-derived sEVs (treated group) every three weeks for 90 days. Morbidity and mortality observation (daily), physical measurements (weekly), selected serum biochemistry (every three weeks), and hematology (every three weeks) were performed for 90 days. Acute toxicity (on day 14) and sub-chronic toxicity (on day 90) were assessed for gross necropsy, relative organ weight, and histopathological assessment of lungs, liver, spleen, kidney, and lymph nodes. Separately, a biodistribution study was conducted with the sEVs preparations labeled with PKH26 fluorescent dye, given intravenously to the rats. The organs were harvested 24 h post-injection. There were no drastic changes in either group’s morbidity or mortality, physical, hematological, and biochemistry evaluation. The histopathological assessment concluded moderate (focal) inflammation in the treated group’s kidneys and signs of recovery from the inflammation and vascular congestion in the liver. A biodistribution study revealed a higher accumulation of sEVs in the spleen. Multiple IV injections of the pooled fetal UCMSCs-derived sEVs in healthy male SD rats were deemed safe. The sEVs were abundantly distributed in the spleen 24 h post-injection. Full article

(This article belongs to the Special Issue Advanced Therapy Using Human Mesenchymal Stem Cells (MSCs) and MSC Extracellular Vesicles)

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27 pages, 5846 KiB

Open AccessArticle

Agrocybe cylindracea Polysaccharides Ameliorate DSS-Induced Colitis by Restoring Intestinal Barrier Function and Reprogramming Immune Homeostasis via the Gut–Liver Axis

by Aamna Atta, Muhammad Naveed, Mujeeb Ur Rahman, Yamina Alioui, Immad Ansari, Sharafat Ali, Eslam Ghaleb, Nabeel Ahmed Farooqui, Mohammad Abusidu, Bin Feng and Yi Xin

Int. J. Mol. Sci. 2025, 26(14), 6805; https://doi.org/10.3390/ijms26146805 (registering DOI) - 16 Jul 2025

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by immune dysregulation, microbiota imbalance, and intestinal barrier dysfunction. Despite its global burden, effective therapies remain limited. This study explores the therapeutic potential of Agrocybe cylindracea polysaccharides (ACP) in a dextran sulfate sodium [...] Read more.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by immune dysregulation, microbiota imbalance, and intestinal barrier dysfunction. Despite its global burden, effective therapies remain limited. This study explores the therapeutic potential of Agrocybe cylindracea polysaccharides (ACP) in a dextran sulfate sodium (DSS)-induced murine colitis model. High-performance liquid chromatography (HPLC)-characterized ACP was administered orally to BALB/c mice following colitis induction. ACP treatment significantly reduced Disease Activity Index (DAI) scores, preserved colon length, and restored intestinal barrier integrity by upregulating tight junction proteins. Mechanistically, ACP modulated immune homeostasis, suppressing pro-inflammatory cytokines (IL-17, IL-23, CRP) while enhancing anti-inflammatory mediators (IL-4, TGF-β). Furthermore, ACP inhibited hepatic TLR4/MyD88/NF-κB signaling, attenuated systemic inflammation, and reshaped gut microbiota composition by enriching beneficial taxa and reducing pathogenic Bacteroides. These findings demonstrate ACP multi-target efficacy in colitis, positioning it as a promising natural therapeutic for UC. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bioactive Nutrients Promoting Health Through Gut Microbiota: 3rd Edition)

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26 pages, 1399 KiB

Open AccessReview

Clinical and Molecular Advances on the Black Yeast Exophiala dermatitidis

by Jakub Suchodolski, Mateusz Parol, Karolina Pawlak, Agata Piecuch and Rafał Ogórek

Int. J. Mol. Sci. 2025, 26(14), 6804; https://doi.org/10.3390/ijms26146804 (registering DOI) - 16 Jul 2025

Abstract

Exophiala dermatitidis is an emerging black yeast recognized in both superficial and life-threatening infections, including those in immunocompetent hosts. This narrative review focuses on recent developments (mostly between 2019 and 2025) in two major areas. First, we examined the clinical and epidemiological background [...] Read more.

Exophiala dermatitidis is an emerging black yeast recognized in both superficial and life-threatening infections, including those in immunocompetent hosts. This narrative review focuses on recent developments (mostly between 2019 and 2025) in two major areas. First, we examined the clinical and epidemiological background of E. dermatitidis, with particular focus on its involvement in cystic fibrosis and CARD9 deficiency, as well as central nervous system, ocular, and systemic infections. Second, we address the molecular basis of its pathogenicity, with particular attention to melanin production, capsule formation, and metabolic adaptation. We also discuss diagnostic challenges and antifungal susceptibility, highlighting gaps between laboratory studies and clinical outcomes. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Pathology, Drug Resistance and Diagnostics of Human Fungal Diseases)

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16 pages, 4472 KiB

Open AccessArticle

Effect of Low-Level Laser Therapy on Periodontal Host Cells and a Seven-Species Periodontitis Model Biofilm

by Selma Dervisbegovic, Susanne Bloch, Vera Maierhofer, Christian Behm, Xiaohui Rausch-Fan, Andreas Moritz, Christina Schäffer and Oleh Andrukov

Int. J. Mol. Sci. 2025, 26(14), 6803; https://doi.org/10.3390/ijms26146803 (registering DOI) - 16 Jul 2025

Abstract

Low-level laser therapy (LLLT) is gaining attention as an effective adjunct to non-surgical periodontal treatment. This study evaluates the potential of LLLT to reduce bacterial load in a clinically relevant in vitro subgingival biofilm model and its impact on the inflammatory response. A [...] Read more.

Low-level laser therapy (LLLT) is gaining attention as an effective adjunct to non-surgical periodontal treatment. This study evaluates the potential of LLLT to reduce bacterial load in a clinically relevant in vitro subgingival biofilm model and its impact on the inflammatory response. A subgingival biofilm model consisting of seven bacterial species was established. Primary human gingival fibroblasts (GFs) and periodontal ligament cells (PDLs) were cultured. Both biofilms and host cells were treated with the DenLase Diode Laser (980 nm) under various clinically relevant settings. The composition and structure of the seven-species biofilms were evaluated using quantitative PCR and fluorescence microscopy, respectively. The inflammatory response in host cells was analyzed by measuring the gene and protein expression levels of various inflammatory mediators. Laser treatment at power outputs ranging from 0.3 to 2 W had no significant effect on biofilm composition or architecture. LLLT, particularly at higher power settings, reduced the viability in both GFs and PDLs up to 70%. Gene expression levels of inflammatory mediators were only minimally influenced by laser treatment. However, LLLT significantly decreased the secretion of all examined cytokines. These findings suggest that LLLT with a 980 nm diode laser, under clinically relevant conditions, exerts anti-inflammatory rather than antimicrobial effects. Full article

(This article belongs to the Special Issue Periodontal Disease: From Molecular Pathogenesis to Precision Diagnostics and Innovative Therapeutics)

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10 pages, 1668 KiB

Open AccessArticle

Hepatic Inflammation Primes Vascular Dysfunction Following Treatment with LPS in a Murine Model of Pediatric Fatty Liver Disease

by Hong Huang, Robin Shoemaker, Yasir Alsiraj, Margaret Murphy, Troy E. Gibbons and John A. Bauer

Int. J. Mol. Sci. 2025, 26(14), 6802; https://doi.org/10.3390/ijms26146802 (registering DOI) - 16 Jul 2025

Abstract

Obesity and pediatric fatty liver disease are increasingly prevalent, yet the underlying mechanisms linking these conditions to heightened inflammatory and immune responses remain poorly understood. Using a murine model reflecting early-life obesity and hepatic steatosis, we tested the hypothesis that obesity-driven hepatic inflammation [...] Read more.

Obesity and pediatric fatty liver disease are increasingly prevalent, yet the underlying mechanisms linking these conditions to heightened inflammatory and immune responses remain poorly understood. Using a murine model reflecting early-life obesity and hepatic steatosis, we tested the hypothesis that obesity-driven hepatic inflammation intensifies systemic immune responses and exacerbates vascular dysfunction following innate immune activation. Newly weaned C57BL/6 mice were fed either a high-saturated-fat, high-cholesterol diet (HFD) or a control diet (CD) for four weeks, modeling adolescence in humans. HFD-fed mice exhibited hepatic and splenic enlargement, elevated plasma cholesterol levels, increased activity levels of liver enzymes (alanine and aspartate aminotransferases), and higher plasma serum amyloid A (SAA) concentrations. Following a sublethal dose of lipopolysaccharide (LPS), the expression of hepatic inflammatory genes (VCAM-1 and iNOS) was significantly elevated in HFD-fed mice, indicating an exaggerated local immune response. Mice fed an HFD also showed significant impairment in endothelium-dependent vasorelaxation compared to CD mice and saline-treated controls, while endothelium-independent responses remained intact. These vascular changes occurred in the context of hepatic inflammation, suggesting that early-life diet-induced steatosis sensitizes the vasculature to inflammatory insult. These findings suggest that obesity-driven hepatic inflammation primes exaggerated systemic immune responses to innate immune stimuli, potentially contributing to the vascular dysfunction and variable clinical morbidity observed in pediatric inflammatory conditions. Full article

(This article belongs to the Special Issue Obesity: From Molecular Mechanisms to Clinical Aspects)

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21 pages, 3038 KiB

Open AccessArticle

Exploring the Interplay Between Gut Microbiota and the Melatonergic Pathway in Hormone Receptor-Positive Breast Cancer

by Aurora Laborda-Illanes, Soukaina Boutriq, Lucía Aranega-Martín, Daniel Castellano-Castillo, Lidia Sánchez-Alcoholado, Isaac Plaza-Andrades, Jesús Peralta-Linero, Emilio Alba, José Carlos Fernández-García, Alicia González-González and María Isabel Queipo-Ortuño

Int. J. Mol. Sci. 2025, 26(14), 6801; https://doi.org/10.3390/ijms26146801 (registering DOI) - 16 Jul 2025

Abstract

Emerging evidence suggests a bidirectional relationship between gut microbiota, melatonin synthesis, and breast cancer (BC) development in hormone receptor-positive patients (HR+HER2+ and HR+HER2-). This study investigated alterations in gut microbiota composition, the serum serotonin–N-acetylserotonin (NAS)–melatonin axis, fecal short-chain fatty acids (SCFAs) and beta-glucuronidase [...] Read more.

Emerging evidence suggests a bidirectional relationship between gut microbiota, melatonin synthesis, and breast cancer (BC) development in hormone receptor-positive patients (HR+HER2+ and HR+HER2-). This study investigated alterations in gut microbiota composition, the serum serotonin–N-acetylserotonin (NAS)–melatonin axis, fecal short-chain fatty acids (SCFAs) and beta-glucuronidase (βGD) activity, and serum zonulin in HR+ BC patients compared to healthy controls. Blood and fecal samples were analyzed using mass spectrometry for serotonin, NAS, melatonin, and SCFAs; ELISA for AANAT, ASMT, 14-3-3 protein, and zonulin; fluorometric assay for βGD activity; and 16S rRNA sequencing for gut microbiota composition. HR+ BC patients exhibited gut dysbiosis with reduced Bifidobacterium longum and increased Bacteroides eggerthii, alongside elevated fecal βGD activity, SCFA levels (e.g., isovaleric acid), and serum zonulin, indicating increased intestinal permeability. Serum serotonin and N-acetylserotonin (NAS) levels were elevated, while melatonin levels were reduced, with a higher NAS/melatonin ratio in BC patients. AANAT levels were increased, and ASMT levels were decreased, suggesting disrupted melatonin synthesis. Bifidobacterium longum positively correlated with melatonin and negatively with βGD activity, while Bacteroides eggerthii showed a positive correlation with βGD activity. These findings suggested that gut microbiota alterations, disrupted melatonin synthesis, microbial metabolism, and intestinal permeability may contribute to BC pathophysiology. The NAS/melatonin ratio could represent a potential biomarker, necessitating further mechanistic studies to confirm causality and explore therapeutic interventions. Full article

(This article belongs to the Special Issue Interplay Between the Human Microbiome and Diseases)

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