International Journal of Molecular Sciences

56 pages, 1035 KiB

Open AccessReview

Trace Elements—Role in Joint Function and Impact on Joint Diseases

by Łukasz Bryliński, Katarzyna Brylińska, Filip Woliński, Jolanta Sado, Miłosz Smyk, Olga Komar, Robert Karpiński, Marcin Prządka and Jacek Baj

Int. J. Mol. Sci. 2025, 26(15), 7493; https://doi.org/10.3390/ijms26157493 (registering DOI) - 2 Aug 2025

Abstract

Proper joint function has a significant impact on people’s quality of life. Joints are the point of connection between two or more bones and consist of at least three elements: joint surfaces, the joint capsule, and the joint cavity. Joint diseases are a [...] Read more.

Proper joint function has a significant impact on people’s quality of life. Joints are the point of connection between two or more bones and consist of at least three elements: joint surfaces, the joint capsule, and the joint cavity. Joint diseases are a serious social problem. Risk factors for the development of these diseases include overweight and obesity, gender, and intestinal microbiome disorders. Another factor that is considered to influence joint diseases is trace elements. Under normal conditions, elements such as iron (Fe), copper (Cu), cobalt (Co), iodine (I), manganese (Mn), zinc (Zn), silver (Ag), cadmium (Cd), mercury (Hg), lead (Pb), nickel (Ni) selenium (Se), boron (B), and silicon (Si) are part of enzymes involved in reactions that determine the proper functioning of cells, regulate redox metabolism, and determine the maturation of cells that build joint components. However, when the normal concentration of the above-mentioned elements is disturbed and toxic elements are present, dangerous joint diseases can develop. In this article, we focus on the role of trace elements in joint function. We describe the molecular mechanisms that explain their interaction with chondrocytes, osteocytes, osteoblasts, osteoclasts, and synoviocytes, as well as their proliferation, apoptosis, and extracellular matrix synthesis. We also focus on the role of these trace elements in the pathogenesis of joint diseases: rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE). We describe the roles of increased or decreased concentrations of individual elements in the pathogenesis and development of joint diseases and their impact on inflammation and disease progression, referring to molecular mechanisms. We also discuss their potential application in the treatment of joint diseases. Full article

(This article belongs to the Special Issue Musculoskeletal Disorders: From Molecular Pathology to Novel Therapeutic Approach)

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17 pages, 2547 KiB

Open AccessArticle

A Host Cell Vector Model for Analyzing Viral Protective Antigens and Host Immunity

by Sun-Min Ahn, Jin-Ha Song, Seung-Eun Son, Ho-Won Kim, Gun Kim, Seung-Min Hong, Kang-Seuk Choi and Hyuk-Joon Kwon

Int. J. Mol. Sci. 2025, 26(15), 7492; https://doi.org/10.3390/ijms26157492 (registering DOI) - 2 Aug 2025

Abstract

Avian influenza A viruses (IAVs) pose a persistent threat to the poultry industry, causing substantial economic losses. Although traditional vaccines have helped reduce the disease burden, they typically rely on multivalent antigens, emphasize humoral immunity, and require intensive production. This study aimed to [...] Read more.

Avian influenza A viruses (IAVs) pose a persistent threat to the poultry industry, causing substantial economic losses. Although traditional vaccines have helped reduce the disease burden, they typically rely on multivalent antigens, emphasize humoral immunity, and require intensive production. This study aimed to establish a genetically matched host–cell system to evaluate antigen-specific immune responses and identify conserved CD8+ T cell epitopes in avian influenza viruses. To this end, we developed an MHC class I genotype (B21)-matched host (Lohmann VALO SPF chicken) and cell vector (DF-1 cell line) model. DF-1 cells were engineered to express the hemagglutinin (HA) gene of clade 2.3.4.4b H5N1 either transiently or stably, and to stably express the matrix 1 (M1) and nucleoprotein (NP) genes of A/chicken/South Korea/SL20/2020 (H9N2, Y280-lineage). Following prime-boost immunization with HA-expressing DF-1 cells, only live cells induced strong hemagglutination inhibition (HI) and virus-neutralizing (VN) antibody titers in haplotype-matched chickens. Importantly, immunization with DF-1 cells transiently expressing NP induced stronger IFN-γ production than those expressing M1, demonstrating the platform’s potential for differentiating antigen-specific cellular responses. CD8+ T cell epitope mapping by mass spectrometry identified one distinct MHC class I-bound peptide from each of the HA-, M1-, and NP-expressing DF-1 cell lines. Notably, the identified HA epitope was conserved in 97.6% of H5-subtype IAVs, and the NP epitope in 98.5% of pan-subtype IAVs. These findings highlight the platform’s utility for antigen dissection and rational vaccine design. While limited by MHC compatibility, this approach enables identification of naturally presented epitopes and provides insight into conserved, functionally constrained viral targets. Full article

(This article belongs to the Special Issue Molecular Research on Immune Response to Virus Infection and Vaccines)

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15 pages, 1899 KiB

Open AccessArticle

Lipidomic Profile of Individuals Infected by Schistosoma mansoni

by Thainá Rodrigues de Souza Fialho, Ronald Alves dos Santos, Yuri Tabajara, Ane Caroline Casaes, Michael Nascimento Macedo, Bruna Oliveira Lopes Souza, Kelvin Edson Marques de Jesus, Leonardo Paiva Farias, Camilla Almeida Menezes, Isadora Cristina de Siqueira, Carlos Arterio Sorgi, Adriano Queiroz and Ricardo Riccio Oliveira

Int. J. Mol. Sci. 2025, 26(15), 7491; https://doi.org/10.3390/ijms26157491 (registering DOI) - 2 Aug 2025

Abstract

Schistosoma mansoni infection is associated with hepatic inflammation and fibrosis, but its systemic metabolic effects remain poorly understood. This study aimed to investigate changes in the serum lipidomic profile associated with S. mansoni infection and parasite load in individuals from an endemic area. [...] Read more.

Schistosoma mansoni infection is associated with hepatic inflammation and fibrosis, but its systemic metabolic effects remain poorly understood. This study aimed to investigate changes in the serum lipidomic profile associated with S. mansoni infection and parasite load in individuals from an endemic area. This cross-sectional analysis was nested within a longitudinal cohort study conducted in northeastern Brazil. Parasitological diagnosis and quantification were performed using the Kato–Katz technique. A total of 45 individuals were selected and divided into three groups: high parasite load (HL), low parasite load (LL), and uninfected controls (NegE). Serum samples were analyzed using mass-spectrometry-based lipidomics. The most abundant lipid subclasses across all groups were phosphatidylcholines (PC), triacylglycerols (TAG), and phosphatidylethanolamines (PE). However, individuals in the HL group exhibited distinct lipidomic profiles, with increased levels of specific phosphatidylinositols (PI) and reduced levels of certain TAG species compared to the NegE group. These changes may reflect host–parasite interactions and immune–metabolic alterations driven by intense infection. Our findings suggest that S. mansoni infection, particularly at higher parasite burdens, can influence the host’s serum lipid profile and may contribute to metabolic disturbances in endemic populations. Full article

(This article belongs to the Special Issue Omics Science and Research in Human Health and Disease)

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16 pages, 8522 KiB

Open AccessArticle

Plant Extracts as Modulators of the Wound Healing Process—Preliminary Study

by Anna Herman, Aleksandra Leska, Patrycja Wińska and Andrzej Przemysław Herman

Int. J. Mol. Sci. 2025, 26(15), 7490; https://doi.org/10.3390/ijms26157490 (registering DOI) - 2 Aug 2025

Abstract

The treatment of chronic wounds is one of the most complex therapeutic problems of modern medicine. It leads to patients’ protracted recovery, generating high treatment costs. Herbal products may be useful in the treatment of chronic wounds via a wide range of pharmacological [...] Read more.

The treatment of chronic wounds is one of the most complex therapeutic problems of modern medicine. It leads to patients’ protracted recovery, generating high treatment costs. Herbal products may be useful in the treatment of chronic wounds via a wide range of pharmacological properties and multidirectional effects on the wound healing phases. The study aims to determine the ability of selected plant extracts to modulate the processes involved in wound healing. The antimicrobial (MIC, MBC, MFC) and antioxidant (ABTS, DPPH) activities, cytotoxicity (MTT test), scratch wound test, and collagen assay were tested. R. canina (MBC 0.39 mg/mL) and V. venifera (MBC 3.13 mg/mL) extracts had bactericidal activities against P. aeruginosa and S. aureus, respectively. The V. vinifera extract showed the highest antioxidant activity in both ABTS (EC50 0.078 mg/mL) and DPPH (EC50 0.005 mg/mL) methods. The percentage of wound closure observed for C. cardunculus, R. rosea, and R. canina extracts with HaCaT, and V. vinifera extract with Hs27 cells was set as 100%. V. vinifera extract (50 μg/mL) stimulated collagen synthesis 5.16 times more strongly than ascorbic acid. Our preliminary study showed that some plant extracts may be promising modulators of the wound healing process, although further in-depth studies are necessary to determine their effectiveness in the in vivo model. Full article

(This article belongs to the Special Issue Novel Natural Compound for Wound and Tissue Repair and Regeneration: 3rd Edition)

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23 pages, 8591 KiB

Open AccessArticle

Targeting Cellular Senescence with Liposome-Encapsulated Fisetin: Evidence of Senomorphic Effect

by Agata Henschke, Bartosz Grześkowiak, Olena Ivashchenko, María Celina Sánchez-Cerviño, Emerson Coy and Sergio Moya

Int. J. Mol. Sci. 2025, 26(15), 7489; https://doi.org/10.3390/ijms26157489 (registering DOI) - 2 Aug 2025

Abstract

Cellular senescence is closely connected with cancer progression, recurrence, and metastasis. Senotherapy aims to soothe the harmful effects of senescent cells either by inducing their apoptosis (senolytic) or by suppressing the senescence-associated secretory phenotype (SASP) (senomorphic). Fisetin, a well-studied senotherapeutic drug, was selected [...] Read more.

Cellular senescence is closely connected with cancer progression, recurrence, and metastasis. Senotherapy aims to soothe the harmful effects of senescent cells either by inducing their apoptosis (senolytic) or by suppressing the senescence-associated secretory phenotype (SASP) (senomorphic). Fisetin, a well-studied senotherapeutic drug, was selected for this study to evaluate its efficiency when delivered in a liposomal formulation. The experiment evaluated the impact of liposome-encapsulated fisetin on senescent cells induced by doxorubicin (DOX) from two cell lines: WI-38 (normal lung fibroblasts) and A549 (lung carcinoma). Senescence was characterized by SA-β-galactosidase (SA-β-gal) activity, proliferation, morphology, and secretion of pro-inflammatory interleukin 6 (IL-6) and interleukin 8 (IL-8). Due to fisetin’s hydrophobic nature, it was encapsulated in liposomes to enhance cellular delivery. Cellular uptake studies confirmed that the liposomes were effectively internalized by both senescent cell types. Treatment with fisetin-loaded liposomes revealed a lack of senolytic effects but showed senomorphic activity, as evidenced by a significant reduction in IL-6 and IL-8 secretion in senescent cells. The liposomal formulation enhanced fisetin’s therapeutic efficacy, showing comparable results even at the lowest tested concentration. Full article

(This article belongs to the Section Molecular Pharmacology)

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13 pages, 2812 KiB

Open AccessArticle

Fungal Laccases with High and Medium Redox Potential: Is the T1 Center Potential a Key Characteristic of Catalytic Efficiency in Heterogeneous and Homogeneous Reactions?

by Olga Morozova, Maria Khlupova, Irina Vasil’eva, Alexander Yaropolov and Tatyana Fedorova

Int. J. Mol. Sci. 2025, 26(15), 7488; https://doi.org/10.3390/ijms26157488 (registering DOI) - 2 Aug 2025

Abstract

Catalytic and bioelectrocatalytic properties of four white rot fungal laccases (Trametes hirsuta, ThL; Coriolopsis caperata, CcL; Steccherinum murashkinskyi, SmL; and Antrodiella faginea, AfL) from different orthologous groups were comparatively studied in homogeneous reactions of electron donor substrate oxidation [...] Read more.

Catalytic and bioelectrocatalytic properties of four white rot fungal laccases (Trametes hirsuta, ThL; Coriolopsis caperata, CcL; Steccherinum murashkinskyi, SmL; and Antrodiella faginea, AfL) from different orthologous groups were comparatively studied in homogeneous reactions of electron donor substrate oxidation and in a heterogeneous reaction of dioxygen electroreduction. The ThL and CcL laccases belong to high-redox-potential enzymes (E⁰_T1 = 780 mV), while the AfL and SmL laccases are medium-redox-potential enzymes (E⁰_T1 = 620 and 650 mV). We evaluated the efficiency of laccases in mediatorless bioelectrocatalytic dioxygen reduction by the steady-state potential (E_ss), onset potential (E_onset), half-wave potential (E_1/2), and the slope of the linear segment of the polarization curve. A good correlation was observed between the T1 center potential of the laccases and their electrocatalytic characteristics; however, no correlation with the homogeneous reactions of electron donor substrates’ oxidation was detected. The results obtained are discussed in the light of the known data on the three-dimensional structures of the laccases studied. Full article

(This article belongs to the Special Issue Advanced Research on Enzymes in Biocatalysis)

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16 pages, 2407 KiB

Open AccessArticle

Transcriptional Analysis of Spodoptera frugiperda Sf9 Cells Infected with Daphnis nerii Cypovirus-23

by Wendong Kuang, Jian Yang, Jinchang Wang, Chenghua Yan, Junhui Chen, Xinsheng Liu, Chunhua Yang, Zhigao Zhan, Limei Guan, Jianghuai Li, Tao Deng, Feiying Yang, Guangqiang Ma and Liang Jin

Int. J. Mol. Sci. 2025, 26(15), 7487; https://doi.org/10.3390/ijms26157487 (registering DOI) - 2 Aug 2025

Abstract

Daphnis nerii cypovirus-23 (DnCPV-23) is a new type of cypovirus that has a lethal effect on many species of Sphingidae pests. DnCPV-23 can replicate in Spodoptera frugiperda Sf9 cells, but the replication characteristics of the virus in this cell line are still unclear. [...] Read more.

Daphnis nerii cypovirus-23 (DnCPV-23) is a new type of cypovirus that has a lethal effect on many species of Sphingidae pests. DnCPV-23 can replicate in Spodoptera frugiperda Sf9 cells, but the replication characteristics of the virus in this cell line are still unclear. To determine the replication characteristics of DnCPV-23 in Sf9 cells, uninfected Sf9 cells and Sf9 cells at 24 and 72 h after DnCPV-23 infection were collected for transcriptome analysis. Compared to uninfected Sf9 cells, a total of 188 and 595 differentially expressed genes (DEGs) were identified in Sf9 cells collected at 24 hpi and 72 h, respectively. KEGG analyses revealed that 139 common DEGs in two treatment groups were related to nutrition and energy metabolism-related processes, cell membrane integrity and function-related pathways, detoxification-related pathways, growth and development-related pathways, and so on. We speculated that these cellular processes might be manipulated by viruses to promote replication. This study provides an important basis for further in-depth research on the mechanism of interaction between viruses and hosts. It provides additional basic information for the future exploitation of DnCPV-23 as a biological insecticide. Full article

(This article belongs to the Special Issue Functional Genomics of Insects: Unraveling Genetic Mechanisms and Applications)

12 pages, 757 KiB

Open AccessBrief Report

DNA-Programmable Oligonucleotide Insecticide Eriola-11 Targets Mitochondrial 16S rRNA and Exhibits Strong Insecticidal Activity Against Woolly Apple Aphid (Eriosoma lanigerum) Hausmann

by Vol Oberemok, Kate Laikova, Oksana Andreeva, Anastasia Dmitrienko, Tatiana Rybareva, Jamin Ali and Nikita Gal’chinsky

Int. J. Mol. Sci. 2025, 26(15), 7486; https://doi.org/10.3390/ijms26157486 (registering DOI) - 2 Aug 2025

Abstract

The potent and selective ‘genetic zipper’ method for insect pest control consists of three essential components: an antisense DNA (the finder), its complementary mature rRNA or pre-rRNA of the pest (the target), and the host’s endogenous DNA-guided rRNase (the degrader). Although this approach [...] Read more.

The potent and selective ‘genetic zipper’ method for insect pest control consists of three essential components: an antisense DNA (the finder), its complementary mature rRNA or pre-rRNA of the pest (the target), and the host’s endogenous DNA-guided rRNase (the degrader). Although this approach has been validated, the spectrum of effective rRNA targets remains insufficiently explored. In this study, we report for the first time the insecticidal efficacy of a novel oligonucleotide insecticide, Eriola-11, which targets the mitochondrial 16S rRNA of the woolly apple aphid Eriosoma lanigerum Hausmann. We hypothesized that the antisense-mediated silencing of mitochondrial rRNA would impair aphid viability and lead to physiological disruptions associated with mitochondrial energy metabolism. Eriola-11 was applied either once or twice (with a 24 h interval) to aphid-infested plants, and aphid mortality was recorded over 14 days. Mitochondrial 16S rRNA expression levels were quantified using molecular assays, and the degradation kinetics of Eriola-11 were assessed in aphid tissue homogenates. Results showed significant insecticidal activity, with 67.55% mortality after a single treatment and 83.35% after two treatments. Treated aphids exhibited the loss of their characteristic white woolly wax covering, and mitochondrial 16S rRNA expression was reduced 0.66-fold relative to the control. Additionally, Eriola-11 was fully degraded by aphid DNases from tissue homogenates within 3 h, highlighting its rapid biodegradability. These findings establish mitochondrial 16S rRNA as a viable target for antisense insecticides and expand the catalogue of potential rRNA-based targets, offering a promising avenue for environmentally sustainable pest control strategies. Full article

(This article belongs to the Special Issue Antisense Oligonucleotides: Versatile Tools with Broad Applications)

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22 pages, 1496 KiB

Open AccessReview

Drosophila melanogaster: How and Why It Became a Model Organism

by Maria Grazia Giansanti, Anna Frappaolo and Roberto Piergentili

Int. J. Mol. Sci. 2025, 26(15), 7485; https://doi.org/10.3390/ijms26157485 (registering DOI) - 2 Aug 2025

Abstract

Drosophila melanogaster is one of the most known and used organisms worldwide, not just to study general biology problems but above all for modeling complex human diseases. During the decades, it has become a central tool to understand the genetics of human disease, [...] Read more.

Drosophila melanogaster is one of the most known and used organisms worldwide, not just to study general biology problems but above all for modeling complex human diseases. During the decades, it has become a central tool to understand the genetics of human disease, how mutations alter the behavior and health of cells, tissues, and organs, and more recently to test new compounds with a potential therapeutic use. But how did this small insect become so crucial in genetics? And how is it currently used in the study of human conditions affecting millions of people? In this review, we retrace the historical origins of its adoption in genetics laboratories and list all the advantages it provides to scientific research, both for its daily usage and for the fine tuning of gene regulation through genetic engineering approaches. We also provide some examples of how it is used to study human diseases such as cancer, neurological and infectious diseases, and its importance in drug discovery and testing. Full article

(This article belongs to the Special Issue Drosophila: A Versatile Model in Biology and Medicine—2nd Edition)

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36 pages, 8123 KiB

Open AccessArticle

Enhanced Methodology for Peptide Tertiary Structure Prediction Using GRSA and Bio-Inspired Algorithm

by Diego A. Soto-Monterrubio, Hernán Peraza-Vázquez, Adrián F. Peña-Delgado and José G. González-Hernández

Int. J. Mol. Sci. 2025, 26(15), 7484; https://doi.org/10.3390/ijms26157484 (registering DOI) - 2 Aug 2025

Abstract

Recent advancements have been made in the precise prediction of protein structures within the Protein Folding Problem (PFP), particularly in relation to minimizing the energy function to achieve stable and biologically relevant protein structures. This problem is classified as NP-hard within computational theory, [...] Read more.

Recent advancements have been made in the precise prediction of protein structures within the Protein Folding Problem (PFP), particularly in relation to minimizing the energy function to achieve stable and biologically relevant protein structures. This problem is classified as NP-hard within computational theory, necessitating the development of various techniques and algorithms. Bio-inspired algorithms have proven effective in addressing NP-hard challenges in practical applications. This study introduces a novel hybrid algorithm, termed GRSABio, which integrates the strategies of Jumping Spider Algorithm (JSOA) with the Golden Ratio Simulated Annealing (GRSA) for peptide prediction. Furthermore, the GRSABio algorithm incorporates a Convolutional Neural Network for fragment prediction (FCNN), forms an enhanced methodology called GRSABio-FCNN. This integrated framework achieves improved structure refinement based on energy for protein prediction. The proposed enhanced GRSABio-FCNN approach was applied to a dataset of 60 peptides. The Wilcoxon and Friedman statistics test were employed to compare the GRSABio-FCNN results against recent state-of-the-art-approaches. The results of these tests indicate that the GRSABio-FCNN approach is competitive with state-of-the-art methods for peptides up to 50 amino acids in length and surpasses leading PFP algorithms for peptides with up to 30 amino acids. Full article

(This article belongs to the Special Issue Advances in Biomathematics, Computational Biology, and Bioengineering)

25 pages, 1623 KiB

Open AccessReview

Genome-Editing Tools for Lactic Acid Bacteria: Past Achievements, Current Platforms, and Future Directions

by Leonid A. Shaposhnikov, Aleksei S. Rozanov and Alexey E. Sazonov

Int. J. Mol. Sci. 2025, 26(15), 7483; https://doi.org/10.3390/ijms26157483 (registering DOI) - 2 Aug 2025

Abstract

Lactic acid bacteria (LAB) are central to food, feed, and health biotechnology, yet their genomes have long resisted rapid, precise manipulation. This review charts the evolution of LAB genome-editing strategies from labor-intensive RecA-dependent double-crossovers to state-of-the-art CRISPR and CRISPR-associated transposase systems. Native homologous [...] Read more.

Lactic acid bacteria (LAB) are central to food, feed, and health biotechnology, yet their genomes have long resisted rapid, precise manipulation. This review charts the evolution of LAB genome-editing strategies from labor-intensive RecA-dependent double-crossovers to state-of-the-art CRISPR and CRISPR-associated transposase systems. Native homologous recombination, transposon mutagenesis, and phage-derived recombineering opened the door to targeted gene disruption, but low efficiencies and marker footprints limited throughput. Recent phage RecT/RecE-mediated recombineering and CRISPR/Cas counter-selection now enable scar-less point edits, seamless deletions, and multi-kilobase insertions at efficiencies approaching model organisms. Endogenous Cas9 systems, dCas-based CRISPR interference, and CRISPR-guided transposases further extend the toolbox, allowing multiplex knockouts, precise single-base mutations, conditional knockdowns, and payloads up to 10 kb. The remaining hurdles include strain-specific barriers, reliance on selection markers for large edits, and the limited host-range of recombinases. Nevertheless, convergence of phage enzymes, CRISPR counter-selection and high-throughput oligo recombineering is rapidly transforming LAB into versatile chassis for cell-factory and therapeutic applications. Full article

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

19 pages, 2574 KiB

Open AccessArticle

The Neuroregenerative Effects of IncobotulinumtoxinA (Inco/A) in a Nerve Lesion Model of the Rat

by Oscar Sánchez-Carranza, Wojciech Danysz, Klaus Fink, Maarten Ruitenberg, Andreas Gravius and Jens Nagel

Int. J. Mol. Sci. 2025, 26(15), 7482; https://doi.org/10.3390/ijms26157482 (registering DOI) - 2 Aug 2025

Abstract

The use of Botulinum Neurotoxin A (BoNT/A) to treat peripheral neuropathic pain from nerve injury has garnered interest for its long-lasting effects and safety. This study examined the effects of IncobotulinumtoxinA (Inco/A), a BoNT/A variant without accessory proteins, on nerve regeneration in rats [...] Read more.

The use of Botulinum Neurotoxin A (BoNT/A) to treat peripheral neuropathic pain from nerve injury has garnered interest for its long-lasting effects and safety. This study examined the effects of IncobotulinumtoxinA (Inco/A), a BoNT/A variant without accessory proteins, on nerve regeneration in rats using the chronic constriction injury (CCI) model. Inco/A was administered perineurally at two time points: on days 0 and 21 post CCI. Functional and histological assessments were conducted to evaluate the effect of Inco/A on nerve regeneration. Sciatic Functional Index (SFI) measurements and Compound Muscle Action Potential (CMAP) recordings were conducted at different time points following CCI. Inco/A-treated animals exhibited a 65% improved SFI and 22% reduction in CMAP onset latencies compared to the vehicle-treated group, suggesting accelerated functional nerve recovery. Tissue analysis revealed enhanced remyelination in Inco/A-treated animals and 60% reduction in CGRP and double S100β signal expression compared to controls. Strikingly, 30% reduced immune cell influx into the injury site was observed following Inco/A treatment, suggesting that its anti-inflammatory effect contributes to nerve regeneration. These findings show that two injections of Inco/A promote functional recovery by enhancing neuroregeneration and modulating inflammatory processes, supporting the hypothesis that Inco/A has a neuroprotective and restorative role in nerve injury conditions. Full article

(This article belongs to the Section Molecular Neurobiology)

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18 pages, 2432 KiB

Open AccessArticle

Alkali Lignin-Based Biopolymer Formulations for Electro-Assisted Drug Delivery of Natural Antioxidants in Breast Cancer Cells—A Preliminary Study

by Severina Semkova, Radina Deneva, Georgi Antov, Donika Ivanova and Biliana Nikolova

Int. J. Mol. Sci. 2025, 26(15), 7481; https://doi.org/10.3390/ijms26157481 (registering DOI) - 2 Aug 2025

Abstract

Recently, a number of natural biologically active substances have been proven to be attractive alternatives to conventional anticancer medicine or as adjuvants in contemporary combination therapies. Although lignin-based materials were previously accepted as waste materials with limited usefulness, recent studies increasingly report the [...] Read more.

Recently, a number of natural biologically active substances have been proven to be attractive alternatives to conventional anticancer medicine or as adjuvants in contemporary combination therapies. Although lignin-based materials were previously accepted as waste materials with limited usefulness, recent studies increasingly report the possibility of their use for novel applications in various industrial branches, including biomedicine. In this regard, the safety, efficiency, advantages and limitations of lignin compounds for in vitro/in vivo applications remain poorly studied and described. This study was carried out to investigate the possibility of using newly synthesized, alkali lignin-based micro-/nano-biopolymer formulations (Lignin@Formulations/L@F) as carriers for substances with antioxidant and/or anticancer effectiveness. Moreover, we tried to assess the opportunity for using an electro-assisted approach for achieving improved intracellular internalization. An investigation was conducted on an in vitro panel of breast cell lines, namely two breast cancer lines with different metastatic potentials and one non-tumorigenic line as a control. The characterization of all tested formulations was performed via DLS (dynamic light scattering) analysis. We developed an improved separation procedure via size/charge unification for all types of Lignin@Formulations. Moreover, in vitro applications were investigated. The results demonstrate that compared to healthy breast cells, both tested cancer lines exhibited slight sensitivity after treatment with different formulations (empty or loaded with antioxidant substances). This effect was also enhanced after applying electric pulses. L@F loaded with Quercetin was also explored only on the highly metastatic cancer cell line as a model for the breast cancer type most aggressive and non-responsive to traditional treatments. All obtained data suggest that the tested formulations have potential as carriers for the electro-assisted delivery of natural antioxidants such as Quercetin. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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23 pages, 4116 KiB

Open AccessArticle

A Naturally Occurring Urinary Collagen Type I Alpha 1-Derived Peptide Inhibits Collagen Type I-Induced Endothelial Cell Migration at Physiological Concentrations

by Hanne Devos, Ioanna K. Mina, Foteini Paradeisi, Manousos Makridakis, Aggeliki Tserga, Marika Mokou, Jerome Zoidakis, Harald Mischak, Antonia Vlahou, Agnieszka Latosinska and Maria G. Roubelakis

Int. J. Mol. Sci. 2025, 26(15), 7480; https://doi.org/10.3390/ijms26157480 (registering DOI) - 2 Aug 2025

Abstract

Collagen type I (COL(I)) is a key component of the extracellular matrix (ECM) and is involved in cell signaling and migration through cell receptors. Collagen degradation produces bioactive peptides (matrikines), which influence cellular processes. In this study, we investigated the biological effects of [...] Read more.

Collagen type I (COL(I)) is a key component of the extracellular matrix (ECM) and is involved in cell signaling and migration through cell receptors. Collagen degradation produces bioactive peptides (matrikines), which influence cellular processes. In this study, we investigated the biological effects of nine most abundant, naturally occurring urinary COL(I)-derived peptides on human endothelial cells at physiological concentrations, using cell migration assays, mass spectrometry-based proteomics, flow cytometry, and AlphaFold 3. While none of the peptides significantly altered endothelial migration by themselves at physiological concentrations, full-length COL(I) increased cell migration, which was inhibited by Peptide 1 (²²⁹NGDDGEAGKPGRPGERGPpGp²⁴⁹). This peptide uniquely contains the DGEA and GRPGER motifs, interacting with integrin α2β1. Flow cytometry confirmed the presence of integrin α2β1 on human endothelial cells, and AlphaFold 3 modeling predicted an interaction between Peptide 1 and integrin α2. Mass spectrometry-based proteomics investigating signaling pathways revealed that COL(I) triggered phosphorylation events linked to integrin α2β1 activation and cell migration, which were absent in COL(I) plus peptide 1-treated cells. These findings identify Peptide 1 as a biologically active COL(I)-derived peptide at a physiological concentration capable of modulating collagen-induced cell migration, and provide a foundation for further investigation into its mechanisms of action and role in urine excretion. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix Proteins in Pathogenesis: 2nd Edition)

15 pages, 1691 KiB

Open AccessArticle

tRNA Modifications: A Tale of Two Viruses—SARS-CoV-2 and ZIKV

by Patrick Eldin and Laurence Briant

Int. J. Mol. Sci. 2025, 26(15), 7479; https://doi.org/10.3390/ijms26157479 (registering DOI) - 2 Aug 2025

Abstract

tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage [...] Read more.

tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage can lead to a limited availability of specific tRNA leading to ribosome stalling, posing a significant challenge for efficient protein translation. While some viruses address this challenge through codon optimization, we show here that SARS-CoV-2 (Coronavirus) and the Zika virus (ZIKV; Flavivirus) adopt a different approach, manipulating the host tRNA epitranscriptome. Analysis of codon bias indices confirmed a substantial divergence between viral and host codon usage, revealing a strong preference in viral genes for codons decoded by tRNAs requiring U34 wobble modification. Monitoring tRNA modification dynamics in infected cells showed that both SARS-CoV2 and ZIKV enhance U34 tRNA modifications during infection. Strikingly, impairing U34 tRNAs profoundly impacted viral replication, underscoring the strict reliance of SARS-CoV-2 and ZIKV on manipulating the host tRNA epitranscriptome to support the efficient translation of their genome. Full article

(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)

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15 pages, 611 KiB

Open AccessReview

Role of Dyadic Proteins in Proper Heart Function and Disease

by Carter Liou and Michael T. Chin

Int. J. Mol. Sci. 2025, 26(15), 7478; https://doi.org/10.3390/ijms26157478 (registering DOI) - 2 Aug 2025

Abstract

Cardiovascular disease encompasses a wide group of conditions that affect the heart and blood vessels. Of these diseases, cardiomyopathies and arrhythmias specifically have been well-studied in their relationship to cardiac dyads, nanoscopic structures that connect electrical signals to muscle contraction. The proper development [...] Read more.

Cardiovascular disease encompasses a wide group of conditions that affect the heart and blood vessels. Of these diseases, cardiomyopathies and arrhythmias specifically have been well-studied in their relationship to cardiac dyads, nanoscopic structures that connect electrical signals to muscle contraction. The proper development and positioning of dyads is essential in excitation–contraction (EC) coupling and, thus, beating of the heart. Three proteins, namely CMYA5, JPH2, and BIN1, are responsible for maintaining the dyadic cleft between the T-tubule and junctional sarcoplasmic reticulum (jSR). Various other dyadic proteins play integral roles in the primary function of the dyad—translating a propagating action potential (AP) into a myocardial contraction. Ca²⁺, a secondary messenger in this process, acts as an allosteric activator of the sarcomere, and its cytoplasmic concentration is regulated by the dyad. Loss-of-function mutations have been shown to result in cardiomyopathies and arrhythmias. Adeno-associated virus (AAV) gene therapy with dyad components can rescue dyadic dysfunction, which results in cardiomyopathies and arrhythmias. Overall, the dyad and its components serve as essential mediators of calcium homeostasis and excitation–contraction coupling in the mammalian heart and, when dysfunctional, result in significant cardiac dysfunction, arrhythmias, morbidity, and mortality. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: Histopathological and Molecular Diagnostics)

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30 pages, 4011 KiB

Open AccessArticle

Multitarget Design of Steroidal Inhibitors Against Hormone-Dependent Breast Cancer: An Integrated In Silico Approach

by Juan Rodríguez-Macías, Oscar Saurith-Coronell, Carlos Vargas-Echeverria, Daniel Insuasty Delgado, Edgar A. Márquez Brazón, Ricardo Gutiérrez De Aguas, José R. Mora, José L. Paz and Yovanni Marrero-Ponce

Int. J. Mol. Sci. 2025, 26(15), 7477; https://doi.org/10.3390/ijms26157477 (registering DOI) - 2 Aug 2025

Abstract

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha [...] Read more.

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

(This article belongs to the Special Issue Recent Research on Biomimetic Chromatography, QSAR and Chemoinformatics in Molecular Modeling and Drug Design)

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Graphical abstract

17 pages, 2225 KiB

Open AccessArticle

The Persistence of Cross-Reactive Immunity to Influenza B/Yamagata Neuraminidase Despite the Disappearance of the Lineage: Structural and Serological Evidence

by Yulia Desheva, Polina Kudar, Maria Sergeeva, Pei-Fong Wong, Tamara Shvedova, Ekaterina Bazhenova, Evelyna Krylova, Maria Kurpiaeva, Ekaterina Romanovskaya-Romanko, Vera Krivitskaya, Kira Kudria, Irina Isakova-Sivak and Marina Stukova

Int. J. Mol. Sci. 2025, 26(15), 7476; https://doi.org/10.3390/ijms26157476 (registering DOI) - 2 Aug 2025

Abstract

Influenza B viruses, divided into B/Victoria and B/Yamagata lineages, have not had B/Yamagata isolates after 2020. A study evaluated immunity to influenza B surface antigens hemagglutinin (HA) and neuraminidase (NA) in 138 patient sera from 2023 and 23 pairs of sera from 2018 [...] Read more.

Influenza B viruses, divided into B/Victoria and B/Yamagata lineages, have not had B/Yamagata isolates after 2020. A study evaluated immunity to influenza B surface antigens hemagglutinin (HA) and neuraminidase (NA) in 138 patient sera from 2023 and 23 pairs of sera from 2018 to 2019 vaccine recipients. The phylogenetic tree of the influenza B virus, based on HA and NA genes, shows that the Yamagata lineage evolves gradually, while the Victoria lineage exhibits rapid mutations with short branches. In 2023, mean levels of antibodies to HA and NA of B/Yamagata virus were higher than to B/Victoria, despite no cases of B/Yamagata lineage isolation after 2020. The titers of antibodies to NA of B/Yamagata statistically significantly differed among individuals born before and after 1988. Among patients examined in 2018–2019, neuraminidase-inhibiting (NI) antibody titers before vaccination were higher to B/Yamagata than to B/Victoria, and NI antibodies to B/Victoria and B/Yamagata positively correlated with neutralizing antibodies to B/Victoria virus before and after vaccination. Immunity to B/Yamagata virus was stronger in 2023, despite no isolation since 2020, probably due to the presence of cross-reactive antibodies from B/Victoria infections or vaccinations. Antibodies to NA of B/Victoria and B/Yamagata in 2023 correlated significantly in patients born before 1988, potentially supporting the concept of ‘antigenic sin’ phenomenon for influenza B viruses. The fact that NI antibody titers to B/Victoria and B/Yamagata correlated with neutralizing antibody titers to B/Victoria may suggest broad cross-protection. Studying influenza B virus NA antigenic properties helps understand the evolution and antigenic competition of HA and NA. Full article

(This article belongs to the Special Issue Respiratory Virus Infection)

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39 pages, 2336 KiB

Open AccessReview

Omics-Mediated Treatment for Advanced Prostate Cancer: Moving Towards Precision Oncology

by Yasra Fatima, Kirubel Nigusu Jobre, Enrique Gomez-Gomez, Bartosz Małkiewicz, Antonia Vlahou, Marika Mokou, Harald Mischak, Maria Frantzi and Vera Jankowski

Int. J. Mol. Sci. 2025, 26(15), 7475; https://doi.org/10.3390/ijms26157475 (registering DOI) - 2 Aug 2025

Abstract

Prostate cancer accounts for approximately 1.5 million new diagnoses and 400,000 deaths every year worldwide, and demographic projections indicate a near-doubling of both figures by 2040. Despite existing treatments, 10–20% of patients eventually progress to metastatic castration-resistant disease (mCRPC). The median overall survival [...] Read more.

Prostate cancer accounts for approximately 1.5 million new diagnoses and 400,000 deaths every year worldwide, and demographic projections indicate a near-doubling of both figures by 2040. Despite existing treatments, 10–20% of patients eventually progress to metastatic castration-resistant disease (mCRPC). The median overall survival (OS) after progression to mCPRC drops to 24 months, and efficacy drops severely after each additional line of treatment. Omics platforms have reached advanced levels and enable the acquisition of high-resolution large datasets that can provide insights into the molecular mechanisms underlying PCa pathology. Genomics, especially DDR (DNA damage response) gene alterations, detected via tissue and/or circulating tumor DNA, efficiently guides therapy in advanced prostate cancer. Given recent developments, we have performed a comprehensive literature search to cover recent research and clinical trial reports (over the last five years) that integrate omics along three converging trajectories in therapeutic development: (i) predicting response to approved agents with demonstrated survival benefits, (ii) stratifying patients to receive therapies in clinical trials, (iii) guiding drug development as part of drug repurposing frameworks. Collectively, this review is intended to serve as a comprehensive resource of recent advancements in omics-guided therapies for advanced prostate cancer, a clinical setting with existing clinical needs and poor outcomes. Full article

(This article belongs to the Special Issue Molecular Research on Prostate Cancer)

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