International Journal of Molecular Sciences

11 pages, 704 KiB

Open AccessArticle

Purification of Prudu6 from Almond and Its Cross-Reactivity with Glym6 from Soybean

by Changbao Hu, Qishu Luo, Lihua Zhou, Weichao Zhu, Kuan Gao, Qin Geng, Xin Li, Anshu Yang, Ping Tong, Zhihua Wu and Hongbing Chen

Int. J. Mol. Sci. 2025, 26(11), 5425; https://doi.org/10.3390/ijms26115425 - 5 Jun 2025

Viewed by 435

Abstract

Almond (Prunus dulcis) is a tree nut with high nutritional value that is widely cultivated and consumed globally. Prudu6, an 11S globulin, is one of the main allergens in almond, which can trigger a series of severe allergic reactions. To our [...] Read more.

Almond (Prunus dulcis) is a tree nut with high nutritional value that is widely cultivated and consumed globally. Prudu6, an 11S globulin, is one of the main allergens in almond, which can trigger a series of severe allergic reactions. To our knowledge, its correlation with Glym6, another 11S globulin, in terms of allergenicity has not yet been studied. In this study, natural Prudu6 was obtained by the optimized column chromatography method. Its structure was studied by the CD spectra, ultraviolet spectra and bioinformatics method. Then, WB and ELISA were performed to analyze the cross-reactivity. Prudu6 of high purity (>85%) was obtained by one-step chromatography. Strong cross-reactivity was found between Prudu6 and Glym6, which were also the main actors in the cross-reactivity between almond and soybean. For IgE in sera from almond-allergic patients, Glym6 demonstrated considerable affinity compared with Prudu6, while Prudu6 could hardly inhibit Glym6 in the soybean group. Three groups of epitope structures were found to be common in both proteins. These similar epitopes were regarded as the core structures causing the cross-reactivity between Prudu6 and Glym6. Full article

(This article belongs to the Special Issue Genetics and Novel Techniques for Soybean Pivotal Characters)

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24 pages, 3308 KiB

Open AccessArticle

The Latest Achievements in the Design of Permanent Fillings for Conservative Dentistry Based on Indenoquinoxaline Derivatives as Photoinitiators of Visible-Light Polymerization: Mass and Colour Stability

by Ilona Pyszka, Oliwia Szczepańska and Beata Jędrzejewska

Int. J. Mol. Sci. 2025, 26(11), 5424; https://doi.org/10.3390/ijms26115424 - 5 Jun 2025

Viewed by 301

Abstract

The demand for polymer composite materials in the dental market is increasing every year. This rise is due to their excellent properties and ongoing technological advancements. The goal of this study was to develop new photoinitiators included in the liquid organic matrix, which [...] Read more.

The demand for polymer composite materials in the dental market is increasing every year. This rise is due to their excellent properties and ongoing technological advancements. The goal of this study was to develop new photoinitiators included in the liquid organic matrix, which is one of the main components of dental composites. Therefore, a series of compounds based on the indenoquinoxaline skeleton was synthesized, differing in the substituent. The spectroscopic properties of these compounds allowed their use as visible-light photoinitiators of radical polymerization in combination with (phenylthio)acetic acid. In addition to the polymerization kinetics, the lifetime and quantum yield of the triplet-state formation and the rate constants of its quenching by (phenylthio)acetic acid were determined. The durability of the designed composites was also assessed. Ageing tests included hydrothermal ageing, allowing for the determination of sorption, solubility, and mass change. Solutions imitating the oral cavity environment—distilled water, artificial saliva, n-heptane, and 3% acetic acid—as well as solutions containing pigments were used for these studies. Determination of the mass change and colour stability allowed for the assessment of how these materials react to long-term exposure in the oral environment. It was found that the solution simulating the natural oral environment has a significant impact on the hydrolytic stability and colour stability of the materials. Full article

(This article belongs to the Special Issue Application of Biotechnology to Dental Treatment)

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14 pages, 1542 KiB

Open AccessBrief Report

Brief Weekly Magnetic Field Exposure Enhances Avian Oxidative Muscle Character During Embryonic Development

by Jasmine Lye Yee Yap, Kwan Yu Wu, Yee Kit Tai, Charlene Hui Hua Fong, Neha Manazir, Anisha Praiselin Paul, Olivia Yeo and Alfredo Franco-Obregón

Int. J. Mol. Sci. 2025, 26(11), 5423; https://doi.org/10.3390/ijms26115423 - 5 Jun 2025

Viewed by 519

Abstract

Maternal metabolic dysfunction adversely influences embryonic muscle oxidative capacity and mitochondrial biogenesis, increasing the child’s long-term risks of developing obesity and metabolic syndrome in later life. This pilot study explored the mechanistic basis of embryonic muscle metabolic programming, employing non-invasive magnetic field exposures. [...] Read more.

Maternal metabolic dysfunction adversely influences embryonic muscle oxidative capacity and mitochondrial biogenesis, increasing the child’s long-term risks of developing obesity and metabolic syndrome in later life. This pilot study explored the mechanistic basis of embryonic muscle metabolic programming, employing non-invasive magnetic field exposures. Brief (10 min) exposure to low-energy (1.5 milliTesla at 50 Hertz) pulsing electromagnetic fields (PEMFs) has been shown in mammals to promote oxidative muscle development, associated with enhanced muscular mitochondriogenesis, augmented lipid metabolism, and attenuated inflammatory status. In this study, quail eggs were used as a model system to investigate the potential of analogous PEMF therapy to modulate embryonic muscle oxidative capacity independently of maternal influence. Quail eggs were administered five 10-min PEMF exposures to either upward-directed or downward-directed magnetic fields over 13 days. Embryos receiving magnetic treatment exhibited increased embryo weight, size, and survival compared to non-exposed controls. Upward exposure was associated with larger embryos, redder breast musculature, and upregulated levels of PPAR-α and PGC-1α, transcriptional regulators promoting oxidative muscle development, mitochondriogenesis, and angiogenesis, whereas downward exposure augmented collagen levels and reduced angiogenesis. Exposure to upward PEMFs may hence serve as a method to promote embryonic growth and oxidative muscle development and improve embryonic mortality. Full article

(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease: 2nd Edition)

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Graphical abstract

24 pages, 1398 KiB

Open AccessArticle

iNOS Mediates High-Fat Diet-Associated Aggravation of Complete Freund’s Adjuvant-Induced Inflammatory Pain

by Elmo Wing-Yiu Lee, Lin Wang, Jessica Ai-Jia Liu and Chi-Wai Cheung

Int. J. Mol. Sci. 2025, 26(11), 5422; https://doi.org/10.3390/ijms26115422 - 5 Jun 2025

Viewed by 483

Abstract

Chronic inflammatory pain (IP) remains a therapeutic challenge under the worldwide prevalence of the high-fat dietary lifestyle. This study aimed at identifying mediators of the IP augmented by short-term high-fat diet (HFD). IP was induced on C57BL/6J mice by unilateral, intra-plantar, injection of [...] Read more.

Chronic inflammatory pain (IP) remains a therapeutic challenge under the worldwide prevalence of the high-fat dietary lifestyle. This study aimed at identifying mediators of the IP augmented by short-term high-fat diet (HFD). IP was induced on C57BL/6J mice by unilateral, intra-plantar, injection of Complete Freund’s Adjuvant (CFA). Von Frey test for mechanical hyperalgesia and Hargreaves’ test for thermal hyperalgesia were performed at pre-injection baseline and post-injection 6th h. and days 1/3/5/7/10/14. Ad libitum HFD feeding started 2 weeks pre-injection in assigned groups. Body weight and random blood glucose levels were measured. RT-qPCR and ELISA helped quantify expression levels of the selected candidate genes at manipulated hind-paws. After CFA injection, at 1400 W, a highly selective inducible nitric oxide synthase (iNOS) inhibitor was administered regularly to elicit differences in CFA-induced pain behaviors and gene expression in HFD-fed mice. Results showed that HFD-fed mice were heavier (p < 0.001) and relatively hyperglycemic (p = 0.013) at baseline. HFD aggravated CFA-induced mechanical and thermal pain (mechanical: p = 0.0004, thermal: p = 0.003), showing prolonged hyperalgesic durations and reduced pain thresholds at multiple timepoints. HFD-influenced paws showed accentuated overexpression of pro-inflammatory cytokines and iNOS (RT-qPCR for IL-1β: p = 0.015, IL-6: p = 0.019, TNF: p = 0.04; ELISA for iNOS: p = 0.011). At 1400 W, exertion of analgesic effects (mechanical: p < 0.0001, thermal: p < 0.0001) but pro-inflammatory (RT-qPCR for IL-1β: p = 0.004, IL-6: p = 0.03, TNF: p = 0.04) were exerted on the inflamed paw on day 5 post-injection. In conclusion, short-term HFD aggravated CFA-induced inflammatory pain. Pharmacological inhibition of iNOS attenuated the CFA-induced pain in HFD-fed mice. Future research might uncover signaling pathways mediating such effects, potentially benefiting obese patients with chronic IP. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 3875 KiB

Open AccessReview

Mediation of Osseointegration, Osteoimmunology, and Osteoimmunologic Integration by Tregs and Macrophages: A Narrative Review

by Jong Il Yun, Su In Yun, Jae Hong Kim, Duk Gyu Kim and Deok-Won Lee

Int. J. Mol. Sci. 2025, 26(11), 5421; https://doi.org/10.3390/ijms26115421 - 5 Jun 2025

Viewed by 602

Abstract

Osseointegration is the direct contact between living bone and a dental implant, with supporting evidence confirming the direct connection between bone and titanium, found using an electron microscope. However, the fundamental mechanisms and interconnections between the bone and titanium are not clearly understood. [...] Read more.

Osseointegration is the direct contact between living bone and a dental implant, with supporting evidence confirming the direct connection between bone and titanium, found using an electron microscope. However, the fundamental mechanisms and interconnections between the bone and titanium are not clearly understood. At present, osteoimmunology explores the interaction between bone and immune cells not only in the medical field but also in dentistry. Immunology in bone cell formation has long been a research topic; however, interest in these effects has recently surged. Through subsequent studies, osteoimmune reaction occurs in response to dental implant insertion into the bone and this mechanism portrays more accurate tissue response compared to the traditional term osseointegration. Additionally, osseointegration is a foreign body defense mechanism to protect the implant when bone forms at the contact surface between the dental implant and the alveolar bone. The term “osteoimmunology” refers to the relationship between the immune system and bone tissues. Understanding osteoimmunologic concepts may enable the development of immunomodulatory strategies to improve, maintain, and ultimately restore osseointegration. In order for biocompatible materials such as dental implants to settle and be maintained in the body, it is necessary to understand the complex interrelationships of the bone immune environment, which will enable the development of biomaterials that are more favorable to osteoimmune environments. Therefore, this review presents previous insights into cellular and molecular interactions between bone and the immune system, specifies the roles of T-regulatory cells (Tregs) and macrophages, and demonstrates their potential for translational applications worldwide. Full article

(This article belongs to the Special Issue Osteoimmunology: Interactions of the Bone and Immune System)

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12 pages, 2997 KiB

Open AccessCommunication

Spherified Pd_0.33Ni_0.67/BCNT Catalyst for Nitrobenzene Hydrogenation

by Csenge Nagy, Emőke Sikora, Ádám Prekob, Kitti Gráczer, Gábor Muránszky, László Vanyorek, Ferenc Kristály and Zsolt Fejes

Int. J. Mol. Sci. 2025, 26(11), 5420; https://doi.org/10.3390/ijms26115420 - 5 Jun 2025

Viewed by 275

Abstract

A separable bamboo-like carbon nanotube-based catalyst was prepared by the spherfication method using sodium alginate and nickel. The spheres were carbonized and then decorated with palladium nanoparticles before they were tested in nitrobenzene hydrogenation. The test was repeated with five different commonly used [...] Read more.

A separable bamboo-like carbon nanotube-based catalyst was prepared by the spherfication method using sodium alginate and nickel. The spheres were carbonized and then decorated with palladium nanoparticles before they were tested in nitrobenzene hydrogenation. The test was repeated with five different commonly used solvents (methanol, ethanol, isopropanol, tetrahydrofuran, and acetonitrile). According to the results, polar solvents showed a significantly higher aniline yield than the more apolar solvents and exceptional results were reported for ethanol (~100%). The catalyst was reused two more times (four hours each) to check the Pd leaching where the spheres kept their shape (despite the high mechanical friction caused by the mixer) and only a relatively low Pd amount was lost (5.48 rel.%). The catalyst was easily retrievable. Full article

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

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17 pages, 1198 KiB

Open AccessArticle

Anti-Inflammatory Potential of Essential Oil from the Heart-Wood of the Folk Medicinal Tree Cinnamomum kanehirai Hayata in Macrophages

by May-Lan Liu, Pang-Yen Liu, Louis Kuoping Chao, Tzu-Jung Yang, Lan-Hui Li, Yih-Ming Weng, Sarana Rose Sommano, Yuwalee Unpaprom, Rameshprabu Ramaraj, Chen-Lung Ho and Kuo-Feng Hua

Int. J. Mol. Sci. 2025, 26(11), 5419; https://doi.org/10.3390/ijms26115419 - 5 Jun 2025

Viewed by 379

Abstract

Inflammation is a vital physiological response that plays a crucial role in regulating host defense against pathogens while maintaining tissue homeostasis. Inflammasomes, a family of protein complexes, are responsible for controlling the expression of pro-inflammatory cytokines IL-1β and IL-18, and they play significant [...] Read more.

Inflammation is a vital physiological response that plays a crucial role in regulating host defense against pathogens while maintaining tissue homeostasis. Inflammasomes, a family of protein complexes, are responsible for controlling the expression of pro-inflammatory cytokines IL-1β and IL-18, and they play significant roles in inflammatory responses. However, dysregulated inflammation can become a risk factor for the pathogenesis of various diseases. The discovery of anti-inflammatory substances derived from natural products represents an important strategy for new drug development. In this study, we found that the essential oil derived from the heartwood of Cinnamomum kanehirai Hayata (EOC) exhibits anti-inflammatory activities by inhibiting the NLRP3, NLRP1, NLRC4, AIM2, and non-canonical inflammasomes in macrophages. EOC also suppresses the expression of NLRP3, TNF-α, IL-6, and NO in LPS-activated macrophages. The mechanisms underlying the anti-inflammatory activity of EOC were shown to involve a reduction in reactive oxygen species production and NF-κB activation. Furthermore, terpinen-4-ol may be the key anti-inflammatory compound present in EOC. These results suggest that EOC has potential as an anti-inflammatory agent for future development. Full article

(This article belongs to the Special Issue Updates on Synthetic and Natural Antioxidants)

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11 pages, 5119 KiB

Open AccessCommunication

Ursolic Acid-Based Nutraceutical Mitigates Muscle Atrophy and Improves Exercise Performance in Mouse Model of Peripheral Neuropathy

by Caterina Miro, Fortuna Iannuzzo, Lucia Acampora, Annunziata Gaetana Cicatiello, Serena Sagliocchi, Elisabetta Schiano, Annarita Nappi, Federica Restolfer, Mariano Stornaiuolo, Gian Carlo Tenore, Monica Dentice and Ettore Novellino

Int. J. Mol. Sci. 2025, 26(11), 5418; https://doi.org/10.3390/ijms26115418 - 5 Jun 2025

Viewed by 261

Abstract

Peripheral nerve injuries, caused by trauma or iatrogenic damage, often lead to permanent disabilities with limited effectiveness of current therapeutic treatments. This has driven the growing interest toward natural bioactive molecules, including ursolic acid (UA). Literature studies have shown that white grape pomace [...] Read more.

Peripheral nerve injuries, caused by trauma or iatrogenic damage, often lead to permanent disabilities with limited effectiveness of current therapeutic treatments. This has driven the growing interest toward natural bioactive molecules, including ursolic acid (UA). Literature studies have shown that white grape pomace oleolyte (WGPO), a natural source of UA, is a promising candidate for promoting peripheral nerve regeneration. Considering that many neurological injuries involve compression or partial damage, the present study examined the effects of WGPO on peripheral neuropathy using a neuropathic pain mouse model. Briefly, 14 days after starting the WGPO-enriched diet, mice underwent cuffing of the right sciatic nerve to induce nerve injury and inflammation. At sacrifice, the WGPO-fed mice exhibited reduced muscle atrophy, as indicated by a greater number and larger diameter of muscle fibers, along with decreased expression of Atrogin-1 and Murf-1, compared with the injured control-diet group. To determine the functional impact of the WGPO treatment, the WGPO-supplemented group was compared with a control group receiving only sunflower oil, evaluating exercise performance post-cuffing via a treadmill test. Mice on the WGPO diet exhibited improved physical performance and a significantly lower expression of pro-inflammatory interleukins than controls. Our findings suggest WGPO as a promising candidate for managing peripheral neuropathy and related muscular impairments. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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26 pages, 724 KiB

Open AccessReview

Molecular Basis of Anxiety: A Comprehensive Review of 2014–2024 Clinical and Preclinical Studies

by Ermis Merkouris, Alexandra Brasinika, Meropi Patsiavoura, Chrysanthi Siniosoglou, Dimitrios Tsiptsios, Andreas S. Triantafyllis, Christoph Mueller, Ioulia Mpikou, Myrto T. Samara, Nikolaos Christodoulou and Konstantinos Tsamakis

Int. J. Mol. Sci. 2025, 26(11), 5417; https://doi.org/10.3390/ijms26115417 - 5 Jun 2025

Viewed by 523

Abstract

Anxiety disorders are among the most common psychiatric conditions that significantly impair one’s quality of life and place a significant burden on healthcare systems. Conventional treatments have certain restraints, such as potential side effects and limited efficacy. Τhe underlying pathophysiological mechanisms of anxiety [...] Read more.

Anxiety disorders are among the most common psychiatric conditions that significantly impair one’s quality of life and place a significant burden on healthcare systems. Conventional treatments have certain restraints, such as potential side effects and limited efficacy. Τhe underlying pathophysiological mechanisms of anxiety are not fully understood. A comprehensive literature search was performed in MEDLINE and Scopus databases for original English-language articles published between January 2014 and December 2024. Study selection, data extraction, and screening were independently carried out by multiple investigators using predefined criteria. Our review aimed to help better comprehend the molecular basis of anxiety, focusing on the hypothalamic–pituitary–adrenal (HPA) axis, serotonergic signaling, and gamma-aminobutyric acid (GABA) neurotransmission. In addition, we addressed the role of epigenetics and pharmacogenomics in personalized treatment. Although novel anxiety treatments are promising, they are predominantly preclinical and highly heterogeneous, which poses a challenge to achieving reliable therapeutic efficacy. Our findings could potentially contribute to the development of new therapeutic interventions. Further research is warranted, especially in human subjects, with an aim to combine genetic and epigenetic profiles to refine treatment approaches and develop innovative therapeutics. Full article

(This article belongs to the Special Issue Molecular Basis of Neuropsychiatric Disorders: Recent and Future Developments)

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26 pages, 1989 KiB

Open AccessReview

The Role of the AGPAT2 Gene in Adipose Tissue Biology and Congenital Generalized Lipodystrophy Pathophysiology

by Maria Eduarda Cardoso de Melo, Letícia Marques Gomes da Silva, Ana Carolina Costa Cavalcante, Josivan Gomes Lima and Julliane Tamara Araújo de Melo Campos

Int. J. Mol. Sci. 2025, 26(11), 5416; https://doi.org/10.3390/ijms26115416 - 5 Jun 2025

Viewed by 348

Abstract

1-Acylglycerol-3-phosphate O-acyltransferase (1-AGPAT) is an enzyme family composed of 11 isoforms. Notably, 1-AGPAT 2, the most studied isoform since its discovery, is a critical enzyme in the triglyceride synthesis pathway, converting lysophosphatidic acid to phosphatidic acid. In addition, AGPAT2 gene expression is shown [...] Read more.

1-Acylglycerol-3-phosphate O-acyltransferase (1-AGPAT) is an enzyme family composed of 11 isoforms. Notably, 1-AGPAT 2, the most studied isoform since its discovery, is a critical enzyme in the triglyceride synthesis pathway, converting lysophosphatidic acid to phosphatidic acid. In addition, AGPAT2 gene expression is shown to be essential for adipocyte development and maturation. Defects in AGPAT2 are responsible for significant pathophysiological alterations related to adipose tissue (AT). Pathogenic variants in this gene are the molecular etiology of Congenital Generalized Lipodystrophy type 1 (CGL1), in which fatty tissue is absent from birth. Metabolically, these individuals have several metabolic complications, including hypoleptinemia, hypoadiponectinemia, hyperglycemia, and hypertriglyceridemia. Furthermore, numerous AGPAT2 pathogenic variants that enormously affect the amino acid sequence, the tertiary structure of 1-AGPAT 2, and their transmembrane and functional domains were found in CGL1 patients. However, studies investigating the genotype–phenotype relationship in this disease are scarce. Here, we used bioinformatics tools to verify the effect of the main pathogenic variants reported in the AGPAT2 gene: c.366-588del, c.589-2A>G, c.646A>T, c.570C>A, c.369-372delGCTC, c.202C>T, c.514G>A, and c.144C>A in the 1-AGPAT 2 membrane topology. We also correlated the phenotype of CGL1 subjects harboring these variants to understand the genotype–phenotype relationship. We provided an integrative view of clinical, genetic, and metabolic features from CGL1 individuals, helping to understand the role of 1-AGPAT 2 in the pathogenesis of this rare disease. Data reviewed here highlight the importance of new molecular studies to improve our knowledge concerning clinical and genetic heterogeneity in CGL1. Full article

(This article belongs to the Special Issue Metabolic Syndrome: New Insights in Pathogenesis, Diagnosis, Prevention, and Management)

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20 pages, 3643 KiB

Open AccessArticle

High-Throughput Screens of Repurposing Hub and DOS Chemical Libraries Reveal Compounds with Novel and Potent Inhibitory Activity Against the Essential Non-Neuronal Acetylcholinesterase of Schistosoma mansoni (SmTAChE)

by Patrick J. Skelly and Akram A. Da’dara

Int. J. Mol. Sci. 2025, 26(11), 5415; https://doi.org/10.3390/ijms26115415 - 5 Jun 2025

Viewed by 292

Abstract

Schistosomiasis is a parasitic disease caused by helminth parasites of the genus Schistosoma, affecting >200 million people worldwide. Current schistosomiasis treatment relies on a single drug, praziquantel, highlighting the urgent need for new therapies. We have identified a non-neuronal tegumental acetylcholinesterase from [...] Read more.

Schistosomiasis is a parasitic disease caused by helminth parasites of the genus Schistosoma, affecting >200 million people worldwide. Current schistosomiasis treatment relies on a single drug, praziquantel, highlighting the urgent need for new therapies. We have identified a non-neuronal tegumental acetylcholinesterase from Schistosoma mansoni (SmTAChE) as a rational and molecularly defined drug target. Molecular modeling reveals significant structural differences between SmTAChE and human AChE, suggesting the potential for identifying parasite-specific inhibitors. Here, we screened recombinant SmTAChE (rSmTAChE) against two chemical libraries: the Broad Institute Drug Repurposing Hub (5440 compounds) and the Diversity-Oriented Synthesis (DOS)-A library (3840 compounds). High-throughput screening identified 116 hits from the Repurposing Hub (2.13% hit rate) and 44 from the DOS-A (1.14% hit rate) library that inhibited rSmTAChE ≥60% at 20 µM. Dose–response assays using both rSmTAChE and recombinant human AChE (rHsAChE) revealed 19 Repurposing Hub compounds (IC₅₀: 0.4–24 µM) and four DOS-A scaffolds (IC₅₀: 13–29 µM), with higher selectivity for rSmTAChE. Selective inhibitors such as cepharanthine, primaquine, mesalazine, and embelin emerged as promising candidates for further evaluation in schistosomiasis treatment. These 23 newly identified selective hits provide a foundation for the further development of novel anti-schistosome therapies. Full article

(This article belongs to the Section Molecular Biology)

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24 pages, 1321 KiB

Open AccessReview

Therapeutic Potential and Mechanisms of Mesenchymal Stem Cells in Coronary Artery Disease: Narrative Review

by Tejas Patel, Jana Mešić, Shai Meretzki, Tomer Bronshtein, Petar Brlek, Vered Kivity, Samir B. Pancholy, Matko Petrović and Dragan Primorac

Int. J. Mol. Sci. 2025, 26(11), 5414; https://doi.org/10.3390/ijms26115414 - 5 Jun 2025

Viewed by 467

Abstract

Coronary artery disease (CAD) remains a leading cause of global morbidity and mortality despite advances in medical and interventional therapies. Mesenchymal stem cell (MSC) therapy has emerged as a promising regenerative approach for patients with refractory or non-revascularizable CAD. MSCs exhibit unique immunomodulatory, [...] Read more.

Coronary artery disease (CAD) remains a leading cause of global morbidity and mortality despite advances in medical and interventional therapies. Mesenchymal stem cell (MSC) therapy has emerged as a promising regenerative approach for patients with refractory or non-revascularizable CAD. MSCs exhibit unique immunomodulatory, pro-angiogenic, and anti-fibrotic properties, primarily through paracrine mechanisms involving the secretion of cytokines, growth factors, and exosomal microRNAs. Clinical and preclinical studies have demonstrated improvements in myocardial perfusion, left ventricular ejection fraction (LVEF), and functional capacity following MSC-based interventions, particularly in patients with low baseline LVEF and heightened inflammation. Various MSC sources—including bone marrow, adipose tissue, and umbilical cord—offer distinct advantages, while delivery strategies such as intracoronary, intramyocardial, intravenous, and subcutaneous administration impact cell retention and efficacy. Advances in genetic modification, hypoxic preconditioning, and exosome-based therapies aim to enhance MSC survival and therapeutic potency. However, challenges persist regarding cell engraftment, cryopreservation effects, and inter-patient variability. Moving toward precision cell therapy, future approaches may involve stratifying patients by inflammatory status, ischemic burden, and comorbidities to optimize treatment outcomes. MSCs may not yet replace conventional therapies but are increasingly positioned to complement them within a personalized, regenerative framework for CAD management. Full article

(This article belongs to the Special Issue Advancing Regenerative Medicine: Basic Research and Translation in Clinics)

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25 pages, 1365 KiB

Open AccessReview

Regulators and Conductors of Immunity: Natural Immune System in Health and Autoimmunity

by Katalin Böröcz, Dávid Szinger, Diána Simon, Timea Berki and Péter Németh

Int. J. Mol. Sci. 2025, 26(11), 5413; https://doi.org/10.3390/ijms26115413 - 5 Jun 2025

Viewed by 488

Abstract

Natural autoantibodies (nAAbs) recognize self-antigens and are an important component of the immune system, having evolved from invertebrates to vertebrates, and are viewed as stable byproducts of immune function and essential players in health and disease. Initially characterized by their conserved nature and [...] Read more.

Natural autoantibodies (nAAbs) recognize self-antigens and are an important component of the immune system, having evolved from invertebrates to vertebrates, and are viewed as stable byproducts of immune function and essential players in health and disease. Initially characterized by their conserved nature and multi-reactivity, primarily as IgM isotypes, nAAbs are now recognized for their adaptability in response to infections and vaccinations, bridging innate and adaptive immunity. The nAAbs and the cellular elements, such as γδ T, iNKT, and MAIT cells, of the natural immune system perform a primary defense network with moderate antigen-specificity. This comprehensive literature review was conducted to analyze the role of natural autoantibodies (nAAbs) in health and disease. The review focused on research published over the past 40 years, emphasizing studies related to infectious diseases, vaccinations, and autoimmune disorders. Recent studies suggest that nAAbs engage in complex interactions in autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and type 1 diabetes. Their roles in immunological processes, such as maternal tolerance during pregnancy, further underscore their complexity. Emerging evidence indicates that nAAbs and the cellular elements of the natural immune system may contribute to both disease pathogenesis and protective mechanisms, highlighting their dual nature. Continued research on nAAbs is vital for improving our understanding of immune responses and developing therapeutic strategies for autoimmune disorders and infectious diseases. Full article

(This article belongs to the Special Issue Basic Mechanisms of Physiological and Pathological Autoimmunity and Their Role in the Development of Autoimmune Diseases)

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23 pages, 8307 KiB

Open AccessArticle

Knockdown of Claudin-8 (CLDN8) Indicates a Link Between Breast Cancer Cell Sensitivity to Chemotherapeutics and Reveals a Potential Use of CLDN8 as a Molecular Diagnostic and Target for Therapy

by Wenxiao Ji, Yufei Lou, Wen G. Jiang, Fiona Ruge and Tracey A. Martin

Int. J. Mol. Sci. 2025, 26(11), 5412; https://doi.org/10.3390/ijms26115412 - 5 Jun 2025

Viewed by 290

Abstract

Breast cancer is a heterogeneous disease, and treatment resistance remains a critical challenge. Claudin-8 (CLDN8), a tight junction protein, has emerged as a potential indicator of therapeutic response and prognosis in breast cancer patients. In this study, we evaluated CLDN8 as a predictive [...] Read more.

Breast cancer is a heterogeneous disease, and treatment resistance remains a critical challenge. Claudin-8 (CLDN8), a tight junction protein, has emerged as a potential indicator of therapeutic response and prognosis in breast cancer patients. In this study, we evaluated CLDN8 as a predictive biomarker and a potential therapeutic target. We analyzed CLDN8 gene expression in breast cancer patient cohorts to assess its association with clinical outcomes and response to therapy. We also established breast cancer cell models with altered CLDN8 expression to examine its effects on cell behavior and drug sensitivity. High CLDN8 expression was significantly associated with improved disease-free survival, particularly in estrogen receptor-negative patients (p = 0.007), suggesting a favorable prognostic role. Notably, tumors with elevated CLDN8 showed better outcomes in patients treated with surgery alone or endocrine therapy, whereas in those receiving chemotherapy (including neoadjuvant) or anti-HER2 therapy, high CLDN8 levels were paradoxically linked to poorer survival and therapy resistance. In vitro, CLDN8 knockdown reduced sensitivity to endocrine treatments, HER2-targeted agents, and chemotherapeutic drugs, mirroring clinical patterns. In conclusion, our findings identify CLDN8 as an important prognostic factor in breast cancer and as a novel predictor of treatment response. These results underscore the potential utility of CLDN8 status in guiding personalized therapy and highlight CLDN8 as a candidate target for overcoming treatment resistance in breast cancer. Full article

(This article belongs to the Special Issue Molecular Research and Cellular Biology of Breast Cancer)

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22 pages, 1159 KiB

Open AccessReview

Advances in Management of Mitochondrial Myopathies

by Athanasios Bangeas, Vasiliki Poulidou, Ioannis Liampas, Chrysa Marogianni, Athina-Maria Aloizou, Zisis Tsouris, Markos Sgantzos, Marianthi Arnaoutoglou, Dimitrios P. Bogdanos, Efthimios Dardiotis and Vasileios Siokas

Int. J. Mol. Sci. 2025, 26(11), 5411; https://doi.org/10.3390/ijms26115411 - 5 Jun 2025

Viewed by 781

Abstract

Mitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to [...] Read more.

Mitochondria, the energy factories of human organisms, can be the cause of a variety of genetic disorders called mitochondrial myopathies. Mitochondrial diseases arise from genetic alterations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) and can manifest with great heterogeneity, leading to multiorgan dysfunction. The purpose of this article is to concisely review the pathophysiology, genetics and main clinical features of mitochondrial myopathies, focusing mainly on the treatment and management of these disorders. Currently, a particular treatment for mitochondrial myopathies does not exist, while the available guidelines concerning management are based on experts’ opinions. The therapeutic options currently applied largely aim at symptom relief and amelioration of patients’ quality of life. The most commonly used regimens involve the administration of vitamins and cofactors, although hard evidence regarding their true benefit for patients is still lacking. Recent studies have demonstrated promising results for elamipretide; however, phase III clinical trials are still ongoing. Regarding patient management, a multidisciplinary approach with the collaboration of different specialties is required. Further clinical trials for the already applied treatment options, as well as on novel experimental therapies, are of utmost importance in order to improve patients’ outcomes. Full article

(This article belongs to the Special Issue Advances in the Genetics, Epidemiology and Management of Myopathies)

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15 pages, 3408 KiB

Open AccessArticle

Pharmacological HIF-PH Inhibition Suppresses Myoblast Differentiation Through Continued HIF-1α Stabilization

by Yuya Miki, Akinobu Ochi, Hideki Uedono, Yoshinori Kakutani, Mitsuru Ichii, Yuki Nagata, Katsuhito Mori, Yasuo Imanishi, Tetsuo Shoji, Tomoaki Morioka and Masanori Emoto

Int. J. Mol. Sci. 2025, 26(11), 5410; https://doi.org/10.3390/ijms26115410 - 5 Jun 2025

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Abstract

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors continually stabilize hypoxia-inducible factor-1α (HIF-1α). These inhibitors are effective in the clinical treatment of renal anemia. However, the effects of continued HIF-1α stabilization on skeletal muscle differentiation remain unclear. This study aimed to investigate the effects of [...] Read more.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors continually stabilize hypoxia-inducible factor-1α (HIF-1α). These inhibitors are effective in the clinical treatment of renal anemia. However, the effects of continued HIF-1α stabilization on skeletal muscle differentiation remain unclear. This study aimed to investigate the effects of continued HIF-1α stabilization on skeletal muscle differentiation using a HIF-PH inhibitor in both in vitro and in vivo models. We cultured mouse C2C12 myoblasts to differentiate into myotubes with or without FG-4592, a HIF-PH inhibitor. Additionally, we treated nine-week-old male C57BL/6 mice with either FG-4592 or vehicle via intraperitoneal injections three times a week for four weeks. In vitro, FG-4592 treatment stabilized HIF-1α continually. Morphological analysis revealed that 72 h FG-4592 treatment suppressed differentiation of C2C12 myoblasts into myotubes. This treatment decreased the gene and protein expression of MyoD and myogenin, reduced the protein expression of myosin heavy chain (MHC), and increased the gene and protein expression of myostatin. HIF-1α knockdown mitigated the decrease in MHC protein expression induced by FG-4592. In vivo, FG-4592 treatment increased HIF-1α protein expression and decreased MyoD, myogenin, and MHC protein expression in gastrocnemius muscle. These findings suggest that pharmacological HIF-PH inhibition suppresses myoblast differentiation through continued HIF-1α stabilization. Full article

(This article belongs to the Special Issue Molecular Insight into Skeletal Muscle Atrophy and Regeneration, 2nd Edition)

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1 pages, 142 KiB

Open AccessRetraction

RETRACTED: Léon et al. 6-Pyrazolylpurine as an Artificial Nucleobase for Metal-Mediated Base Pairing in DNA Duplexes. Int. J. Mol. Sci. 2016, 17, 554

by J. Christian Léon, Indranil Sinha and Jens Müller

Int. J. Mol. Sci. 2025, 26(11), 5409; https://doi.org/10.3390/ijms26115409 - 5 Jun 2025

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Abstract

The Journal retracts the article “6-Pyrazolylpurine as an artificial nucleobase for metal-mediated base pairing in DNA duplexes” [...] Full article

(This article belongs to the Section Biochemistry)

19 pages, 2183 KiB

Open AccessArticle

Perfluorooctanoic Acid and Its Short-Chain Substitutes Induce Cytotoxic and Prooxidative Changes in Human Peripheral Blood Mononuclear Cells: A Comparative Study

by Izabela Kaczmarska, Katarzyna Mokra and Jaromir Michałowicz

Int. J. Mol. Sci. 2025, 26(11), 5408; https://doi.org/10.3390/ijms26115408 - 5 Jun 2025

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Abstract

Perfluorooctanoic acid (PFOA) and its short-chain substitutes, perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA), are persistent environmental pollutants associated with widespread human exposure through occupational and environmental routes. The aim of this was to investigate the effects of PFOA, PFHxA, and PFBA on [...] Read more.

Perfluorooctanoic acid (PFOA) and its short-chain substitutes, perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA), are persistent environmental pollutants associated with widespread human exposure through occupational and environmental routes. The aim of this was to investigate the effects of PFOA, PFHxA, and PFBA on the intracellular level of adenosine-5’-triphosphate (ATP) in human peripheral blood mononuclear cells (PBMCs) and their viability, size, and granularity. Moreover, oxidative and nitrosative stress was assessed based on the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), and highly reactive oxygen species (hROS, mainly hydroxyl radical). Finally, oxidative damage to protein and lipids in PBMCs was measured. The cells were incubated for 1 h and 24 h at concentrations correlated to human occupational and environmental exposure (0.001–200 µg/mL) to the substances. Our findings indicate that PFOA and its short-chain analogs cause different effects in human PBMCs. PFOA induced statistically significant alterations almost in all studied parameters, substantially decreasing cell viability and ATP level and altering the size and granularity of tested cells; in contrast, PFHxA and PFBA induced significant changes only at some studied parameters. PFOA also induced a notable increase in intracellular ROS and RNS levels, which suggest that both oxidative stress and nitrosative stress influence its cytotoxic potential. Interestingly, the shortest-chain compound, PFBA, induced changes that were not observed for PFHxA. This suggests that the length of the chain determines the triggering of certain alterations in PBMCs. Importantly, the changes were noted at concentrations corresponding to those associated with occupational exposure. These findings contribute to our understanding of the immunotoxicity of PFOA and its substitutes, indicating the potential health risks associated with chronic exposure, particularly in populations with occupational exposure or high environmental PFOA burdens. Full article

(This article belongs to the Section Molecular Biology)

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1 pages, 155 KiB

Open AccessRetraction

RETRACTED: Cejuela et al. Metformin and Breast Cancer: Where Are We Now? Int. J. Mol. Sci. 2022, 23, 2705

by Mónica Cejuela, Begoña Martin-Castillo, Javier A. Menendez and Sonia Pernas

Int. J. Mol. Sci. 2025, 26(11), 5407; https://doi.org/10.3390/ijms26115407 - 5 Jun 2025

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Abstract

The journal retracts the article titled “Metformin and Breast Cancer: Where Are We Now [...] Full article

(This article belongs to the Special Issue Metformin: The Scope for New Applications)

10 pages, 984 KiB

Open AccessCase Report

Life-Threatening Macrophage Activation Syndrome in Pregnancy: First Manifestation of SLE Induced by Parvovirus B19

by Aleksandra Plavsic, Rada Miskovic, Dragana Jovanovic, Uros Karic, Zikica Jovicic, Sara Radovic, Ana Drazic, Aleksandra Dasic and Snezana Arandjelovic

Int. J. Mol. Sci. 2025, 26(11), 5406; https://doi.org/10.3390/ijms26115406 - 4 Jun 2025

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Abstract

Macrophage activation syndrome (MAS) is a complex, life-threatening, hyperinflammatory condition occurring as a form of hemophagocytic lymphohistiocytosis (HLH), commonly associated with several autoimmune and autoinflammatory diseases, and certain infections such as Parvovirus B19 (P19V). The onset of systemic lupus erythematosus (SLE) presenting as [...] Read more.

Macrophage activation syndrome (MAS) is a complex, life-threatening, hyperinflammatory condition occurring as a form of hemophagocytic lymphohistiocytosis (HLH), commonly associated with several autoimmune and autoinflammatory diseases, and certain infections such as Parvovirus B19 (P19V). The onset of systemic lupus erythematosus (SLE) presenting as MAS during pregnancy is uncommon, posing significant diagnostic and therapeutic challenges. We present a case of a 30-year-old woman at the 12th gestational week with fever, arthralgia, rash, cervical lymphadenopathy, cytopenia, and elevated liver enzyme. Bone marrow biopsy revealing hemophagocytosis, elevated ferritin and triglycerides, high interleukin-2, fever and cytopenia, confirmed the diagnosis of HLH. Further evaluation revealed the diagnosis of SLE. Treatment was initiated with intravenous immunoglobulin and corticosteroids. Given the deterioration in the patient’s clinical condition, a decision was made to terminate the pregnancy. She continued in the following months to receive SLE treatment with corticosteroids, cyclophosphamide, hydroxychloroquine, and later with mycophenolate mofetil due to the development of Class IV of lupus nephritis. P19V IgM antibodies were initially positive, later seroconverted to IgG, indicating that infection may have acted as a trigger for the onset of SLE and MAS development during pregnancy. The overlapping clinical features of P19V infection, SLE, and MAS pose significant diagnostic and therapeutic challenges. Early recognition and comprehensive diagnostic evaluation are crucial for the management of these conditions, especially during pregnancy, where both maternal outcomes are at risk. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Autoimmune Diseases—2nd Edition)

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43 pages, 2656 KiB

Open AccessReview

α-Synuclein Pathology in Synucleinopathies: Mechanisms, Biomarkers, and Therapeutic Challenges

by Oscar Arias-Carrión, Magdalena Guerra-Crespo, Francisco J. Padilla-Godínez, Luis O. Soto-Rojas and Elías Manjarrez

Int. J. Mol. Sci. 2025, 26(11), 5405; https://doi.org/10.3390/ijms26115405 - 4 Jun 2025

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Abstract

Parkinson’s disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the α-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, [...] Read more.

Parkinson’s disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the α-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, including its structure, aggregation mechanisms, cellular interactions, and systemic influences. We highlight the structural diversity of aSyn aggregates, ranging from oligomers to fibrils, their strain-like properties, and their prion-like propagation. While the role of prion-like mechanisms in disease progression remains a topic of ongoing debate, these processes may contribute to the clinical heterogeneity of synucleinopathies. Dysregulation of protein clearance pathways, including chaperone-mediated autophagy and the ubiquitin–proteasome system, exacerbates aSyn accumulation, while post-translational modifications influence its toxicity and aggregation propensity. Emerging evidence suggests that immune responses and alterations in the gut microbiome are key modulators of aSyn pathology, linking peripheral processes—particularly those of intestinal origin—to central neurodegeneration. Advances in biomarker development, such as cerebrospinal fluid assays, post-translationally modified aSyn, and real-time quaking-induced conversion technology, hold promise for early diagnosis and disease monitoring. Furthermore, positron emission tomography imaging and conformation-specific antibodies offer innovative tools for visualising and targeting aSyn pathology in vivo. Despite significant progress, challenges remain in accurately modelling human synucleinopathies, as existing animal and cellular models capture only specific aspects of the disease. This review underscores the need for more reliable aSyn biomarkers to facilitate the development of effective treatments. Achieving this goal requires an interdisciplinary approach integrating genetic, epigenetic, and environmental insights. Full article

(This article belongs to the Special Issue Molecular Insights in Neurodegeneration)

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17 pages, 2031 KiB

Open AccessReview

Protein Kinase CK2 Inhibition Represents a Pharmacological Chance for the Treatment of Skin Diseases

by Michele Scuruchi, Desirèe Speranza, Giuseppe Bruschetta, Federico Vaccaro, Mariarosaria Galeano, Giovanni Pallio, Mario Vaccaro, Francesco Borgia, Federica Li Pomi, Massimo Collino and Natasha Irrera

Int. J. Mol. Sci. 2025, 26(11), 5404; https://doi.org/10.3390/ijms26115404 - 4 Jun 2025

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Abstract

Protein kinase CK2 has emerged as a pivotal regulator of cellular processes involved in skin homeostasis, including cell proliferation, differentiation and inflammatory response regulation. In fact, CK2 activity dysregulation is implicated in the pathogenesis of different skin diseases, such as psoriasis, cancer and [...] Read more.

Protein kinase CK2 has emerged as a pivotal regulator of cellular processes involved in skin homeostasis, including cell proliferation, differentiation and inflammatory response regulation. In fact, CK2 activity dysregulation is implicated in the pathogenesis of different skin diseases, such as psoriasis, cancer and inflammatory dermatoses. CK2 overactivation fosters keratinocyte proliferation and pro-inflammatory cytokine production through the STAT3 and Akt pathways in psoriasis, thus contributing to epidermal hyperplasia and inflammation. In the realm of oncology, CK2 overexpression correlates with tumor progression, facilitating cell survival and metastasis in melanoma and non-melanoma skin cancers. Pharmacological inhibition of CK2 has demonstrated therapeutic potential, with CX-4945 (Silmitasertib) as the most studied adenosine triphosphate-competitive inhibitor (ATP-competitive inhibitor). Preclinical models reveal that CK2 inhibitors effectively mitigate pathological features of psoriasis, regulate keratinocyte differentiation, and suppress tumor growth in skin cancers. These inhibitors also potentiate the efficacy of conventional chemotherapeutics and exhibit anti-inflammatory effects in dermatological conditions. Future research will aim to enhance the specificity and delivery of CK2-targeting therapies, including topical formulations, to minimize systemic side effects. Combination therapies integrating CK2 inhibitors with other agents might offer synergistic benefits in managing skin diseases. This review underscores CK2’s critical role in skin and its therapeutic potential as a pharmacological target, advocating for innovative approaches to harness CK2 inhibition in dermatology. Full article

(This article belongs to the Special Issue The Role of Protein Kinase in Health and Diseases)

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22 pages, 1582 KiB

Open AccessReview

Preclinical Evidence of Withania somnifera and Cordyceps spp.: Neuroprotective Properties for the Management of Alzheimer’s Disease

by Gabriele Tancreda, Silvia Ravera and Isabella Panfoli

Int. J. Mol. Sci. 2025, 26(11), 5403; https://doi.org/10.3390/ijms26115403 - 4 Jun 2025

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Abstract

Alzheimer’s disease (AD) is considered one of the main pathologies of our time, whose incidence and prevalence are suggested to be strongly underestimated. AD presents as a complex neurodegenerative condition characterized by marked neuroinflammation and a significant decline in the cognitive and mnemonic [...] Read more.

Alzheimer’s disease (AD) is considered one of the main pathologies of our time, whose incidence and prevalence are suggested to be strongly underestimated. AD presents as a complex neurodegenerative condition characterized by marked neuroinflammation and a significant decline in the cognitive and mnemonic functions of affected patients. Recognized AD pathological hallmarks include amyloid beta plaque and neurofibrillary tangle formation, synaptic dysfunction with considerable apoptosis of cholinergic and dopaminergic neurons, and high levels of oxidative stress and neuroinflammation. The available pharmacological treatments are represented by acetylcholinesterase inhibitors to treat the mild to moderate form of the disease and N-methyl-D-aspartate inhibitors alone or in combination with the previously cited ones in the late stage of the neurodegenerative condition. Furthermore, emerging drug therapies such as monoclonal antibodies are promising agents in AD management. Although scientific evidence highlights these chemicals as effective in slowing down disease progression, significant limitations behind their employment derive from the notable dose-dependent side effects and the single-target mechanism of action. In this context, two well-studied phytotherapeutics, W. somnifera (W. somnifera) and fungi belonging to the genus Cordyceps, have gained attention for their chemical composition regarding their neuroprotective and anti-inflammatory effects. Ashwagandha (obtained principally from the roots of W. somnifera) is an adaptogen that relieves stress and anxiety. It contains several ergostane-type steroidal lactones—such as withanolides and withaferin A—and various alkaloids, contributing to its antioxidant and neuroprotective effects. Likewise, cordycepin is the main bioactive principle found in Cordyceps fungi. This natural nucleoside has been reported to possess therapeutic potential as an anti-cancer, immunomodulatory, and anti-inflammatory agent, with some studies suggesting a beneficial role in AD treatment. The purpose of the present review is to investigate the pharmacological properties of W. somnifera and Cordyceps species in the context of AD treatment and explore the therapeutic potential of the constitutive bioactive molecules in preclinical models mimicking this neurodegenerative condition. Full article

(This article belongs to the Special Issue New Therapies and Strategies in the Treatment of Neurodegenerative Diseases)

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22 pages, 2570 KiB

Open AccessArticle

Tacrolimus Modulates TGF-β Signaling–Related Genes and MicroRNAs in Human Retinal Pigment Epithelial Cells Activated by Lipopolysaccharide

by Aleksandra Kiełbasińska, Katarzyna Krysik, Dominika Janiszewska-Bil, Martyna Machaj, Zuzanna Lelek, Joanna Sułkowska, Olga Nawotny-Czupryna and Beniamin Oskar Grabarek

Int. J. Mol. Sci. 2025, 26(11), 5402; https://doi.org/10.3390/ijms26115402 - 4 Jun 2025

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Abstract

The retinal pigment epithelium (RPE) plays a crucial role in maintaining retinal homeostasis, and dysregulation of the transforming growth factor-beta (TGF-β) signaling pathways contributes to retinal fibrosis and inflammatory diseases, including proliferative vitreoretinopathy (PVR). Tacrolimus (FK506), an immunosuppressant, has shown potential antifibrotic properties, [...] Read more.

The retinal pigment epithelium (RPE) plays a crucial role in maintaining retinal homeostasis, and dysregulation of the transforming growth factor-beta (TGF-β) signaling pathways contributes to retinal fibrosis and inflammatory diseases, including proliferative vitreoretinopathy (PVR). Tacrolimus (FK506), an immunosuppressant, has shown potential antifibrotic properties, but its effects on TGF-β-related genes and microRNAs (miRNAs) in RPE cells remain unclear. Human RPE (H-RPE) cells were treated with lipopolysaccharide (LPS) to induce inflammation and subsequently exposed to tacrolimus. Gene and miRNA expression profiling related to TGF-β signaling pathways were conducted using microarrays, followed by Quantitative Reverse-Transcription Polymerase Chain Reaction (RT-qPCR) validation. Protein levels were assessed via enzyme-linked immunosorbent assay (ELISA), and interactions were analyzed using STRING database network analysis. Tacrolimus modulated key components of the TGF-β pathway, upregulating TGF-β2, TGF-β3, SMAD2, and SMAD4 while downregulating TGF-βR1 and SMAD7. JAK/STAT and MAPK pathways were also affected, indicating broad regulatory effects. miRNA profiling identified hsa-miR-200a-3p, hsa-miR-589-3p, hsa-miR-21, and hsa-miR-27a-5p as key regulators. STRING analysis confirmed strong functional interactions within the TGF-β network. In conclusion, tacrolimus modulates both canonical (upregulation of SMAD2/4 and downregulation of SMAD7) and non-canonical (JAK/STAT and MAPK) TGF-β signaling pathways in LPS-stimulated RPE cells. These changes collectively suggest a dual anti-inflammatory and anti-fibrotic effect. The increased TGF-β2 and decreased SMAD7 levels, alongside altered miRNA expression (e.g., downregulation of miR-200a-3p), indicate that tacrolimus may inhibit key profibrotic mechanisms underlying PVR. These findings support the potential therapeutic repurposing of tacrolimus in PVR and warrant further in vivo validation. Full article

(This article belongs to the Special Issue Eye Diseases: From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 696 KiB

Open AccessReview

A Comprehensive Review of Radiotherapy-Induced Coronary Artery Disease—Epidemiology, Biological Mechanisms, and Preventive Strategies

by Jalil Daher, Antonio Rizza, Alessandro Tonacci and Andrea Borghini

Int. J. Mol. Sci. 2025, 26(11), 5401; https://doi.org/10.3390/ijms26115401 - 4 Jun 2025

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Abstract

Radiation-induced cardiac toxicity is a recognized complication in patients undergoing thoracic radiotherapy. A crucial manifestation of this toxicity is the damage caused to coronary arteries, which can result in accelerated atherosclerosis that may remain undetected for many years. As cancer survival rates continue [...] Read more.

Radiation-induced cardiac toxicity is a recognized complication in patients undergoing thoracic radiotherapy. A crucial manifestation of this toxicity is the damage caused to coronary arteries, which can result in accelerated atherosclerosis that may remain undetected for many years. As cancer survival rates continue to improve, the incidence of radiation-induced coronary artery disease (RICAD) is increasing, making it one of the leading causes of morbidity and mortality among patients treated with radiotherapy for mediastinal cancers. The pathophysiology of RICAD involves a complex interplay of cellular mechanisms, including endothelial dysfunction, inflammation, and fibrosis. These processes are related to several molecular insults such as DNA damage, telomere erosion, and mitochondrial dysfunction. However, to fully understand the initiation and progression of the disease, further research is critical to uncover additional contributing factors. Different strategies for preventing cardiovascular complications in cancer patients are gaining significant attention. Recent advancements in radiotherapy, particularly the new FLASH radiotherapy technique, show promise in reducing the incidence of these complications. This review focuses on the effects of radiotherapy on coronary artery disease, exploring the underlying cellular and molecular mechanisms, as well as potential strategies to prevent RICAD. Full article

(This article belongs to the Special Issue Cellular and Molecular Progression of Cardiovascular Diseases)

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20 pages, 1365 KiB

Open AccessArticle

Alpha1-Antitrypsin in Lung Diseases: A Cross-Sectional Observational Study

by Csilla Páska, Imre Barta, Zsuzsanna Csoma, Réka Gajdócsi, Viktória Szél, Anna Kerpel-Fronius, Diána Solymosi, Zoltán Örlős and Balázs Antus

Int. J. Mol. Sci. 2025, 26(11), 5400; https://doi.org/10.3390/ijms26115400 - 4 Jun 2025

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Abstract

Major mutations of SERPINA1, the gene encoding alpha1-antitrypsin (A1AT), are known to cause severe emphysema. Our study aimed to investigate the role of major mutations modulating A1AT levels in several lung pathologies and control groups. Blood samples were collected from healthy non-smokers [...] Read more.

Major mutations of SERPINA1, the gene encoding alpha1-antitrypsin (A1AT), are known to cause severe emphysema. Our study aimed to investigate the role of major mutations modulating A1AT levels in several lung pathologies and control groups. Blood samples were collected from healthy non-smokers (N⁰ = 85), healthy smokers (N⁰ = 291), healthy ex-smokers (N⁰ = 127), smokers with chronic obstructive lung disease (COPD, N⁰ = 187), ex-smokers with COPD (N⁰ = 64), and patients with asthma (N⁰ = 194), interstitial lung disease (ILD) (N⁰ = 93), sarcoidosis (N⁰ = 30) and cystic fibrosis (N⁰ = 26). Clinical and respiratory parameters, A1AT levels, the extent of emphysema and comorbidities on low-dose CT scans were evaluated, and patients answered a smoking history and comorbidity questionnaire. A1AT single-nucleotide polymorphisms were determined for the S, Z, M2/M4, 0 and eQTL locations by SNP probes using real-time PCR. A1AT levels showed significant differences between cigarette smoke-induced and other lung diseases. Compared to controls, A1AT levels were found to be lower in sarcoidosis and increasingly higher in smokers and patients with COPD, ILD and CF, respectively. The presence and pattern of emphysema were found to influence A1AT levels: lower values were observed in COPD patients without emphysema, while higher values were observed in patients with central and panlobular emphysema. Antitrypsin levels increased with COPD GOLD stages and asthma GINA stages. Variable A1AT levels were also found in ILD subgroups. The distribution of variants at the S, Z, M2/M4 and 0 polymorphic sites and the eQTL location showed no significant differences between patient groups with impaired lung function, except for Z heterozygotes, which were prevalent in patients with severe asthma. The eQTL TT genotypes had higher A1AT levels and the occurrence of emphysema and/or bronchitis was increased. A1AT levels correlated with several clinical and respiratory parameters in pulmonary patients, while FEV1/FVC inversely correlated with levels of A1AT. Molar antielastase activity was increased in smokers and patients with lung diseases; however, in COPD, antielastase activity decreased. The most reduced antielastase activity could be found in CF. Certain genotypes were characterized by increased cardiovascular comorbidity scores and antitrypsin levels. Our data suggest that in addition to emphysema, A1AT may play an important role in the development of a wide variety of lung diseases and cardiovascular comorbidities. Further research is needed to clarify the role of A1AT and its regulation in lung pathologies. Full article

(This article belongs to the Special Issue Biomarkers of Lung Disorders)

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16 pages, 2294 KiB

Open AccessArticle

Use of Multi-Locus Metabarcoding to Inform an Australian Government Biosecurity Response on the Origins of Suspected Illegal Plant Products

by Jennifer A. Soroka, Matias Silva-Campos, Frank Bedon, Adrian Dinsdale, Dianne M. Gleeson and Alejandro Trujillo-González

Int. J. Mol. Sci. 2025, 26(11), 5399; https://doi.org/10.3390/ijms26115399 - 4 Jun 2025

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Abstract

Biosecurity is vital to Australia’s efforts to prevent and respond to pests and diseases. Here, we report on testing suspected illegal goods (SIGs) as part of an active Australian biosecurity response in Sydney. The Australian Government, Department of Agriculture, Fisheries and Forestry detected [...] Read more.

Biosecurity is vital to Australia’s efforts to prevent and respond to pests and diseases. Here, we report on testing suspected illegal goods (SIGs) as part of an active Australian biosecurity response in Sydney. The Australian Government, Department of Agriculture, Fisheries and Forestry detected and secured consignments containing tuber products of unknown biosecurity risk and origin. Swab samples were collected from vacuum-sealed yam products, organic packing material (background negative controls), and field negative controls to assess possible cross-contamination from the storage facility. DNA from all samples was analysed using high-throughput metabarcoding targeting the Internal Transcribed Spacer 2 (ITS2) and the chloroplast trnL (UAA) P6 Loop gene regions by two independent teams in Australia. A plant community profile comprising Australian native species and other non-native established species would support the notion of produce being harvested and/or packaged domestically, while their absence would suggest foreign production. Of the 5,764,942 total reads produced, the bioinformatic analysis generated 5,181,530 amplicon sequencing variants employed for species identification. Twenty plant taxa were identified via ITS2 and 15 via trnL, corresponding to worldwide distributed plants, non-native species established in Australia, or species not recorded in Australia. No Australian endemic species were detected. The absence of common Australian native plants, combined with the presence of species not known to occur in Australia, provided strong evidence that the suspect tuber products were illegally imported. Full article

(This article belongs to the Section Molecular Plant Sciences)

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24 pages, 6213 KiB

Open AccessArticle

Transmembrane Protease Serine 11B Modulates Lactate Transport Through SLC16A1 in Pancreatic Ductal Adenocarcinoma—A Functional Link to Phenotype Heterogeneity

by Dinara Baiskhanova, Maike Menzel, Claudia Geismann, Christoph Röcken, Eric Beitz, Susanne Sebens, Anna Trauzold and Heiner Schäfer

Int. J. Mol. Sci. 2025, 26(11), 5398; https://doi.org/10.3390/ijms26115398 - 4 Jun 2025

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Abstract

Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells [...] Read more.

Tumor cell heterogeneity, e.g., in stroma-rich pancreatic ductal adenocarcinoma (PDAC), includes a differential metabolism of lactate. While being secreted as waste product by most cancer cells characterized by the glycolytic Warburg metabolism, it is utilized by a subset of highly malignant cancer cells running the reverse Warburg metabolism. Key drivers of lactate transport are the carrier proteins SLC16A1 (import/export) and SLC16A3 (export). Expression and function of both carriers are controlled by the chaperone Basigin (BSG), which itself is functionally controlled by the transmembrane protease serine 11B (TMPRSS11B). In this study we explored the impact of TMPRSS11B on the phenotype of PDAC cells under reverse Warburg conditions. Amongst a panel of PDAC cell lines, Panc1 and BxPc3 cells were identified to express TMPRSS11B at a high level, whilst other cell lines such as T3M4 did not. ShRNA-mediated TMPRSS11B knock-down in Panc1 and BxPc3 cells enhanced lactate import through SLC16A1, as shown by GFP/iLACCO1 lactate uptake assay, whereas TMPRSS1B overexpression in T3M4 dampened SLC16A1-driven lactate uptake. Moreover, knock-down and overexpression of TMPRSS11B differentially impacted proliferation and chemoresistance under reverse Warburg conditions in Panc1 or BxPc3 and T3M4 cells, respectively, as well as their stemness properties indicated by altered colony formation rates and expression of the stem cell markers Nanog, Sox2, KLF4 and Oct4. These effects of TMPRSS11B depended on both SLC16A1 and BSG as shown by gene silencing. Immunohistochemical analysis revealed a reciprocal expression of TMPRSS11B and BSG together with SLC16A1 in some areas of tumor tissues from PDAC patients. Those regions exhibiting low or no TMPRSS11B expression but concomitant high expression of SLC16A1 and BSG revealed greater amounts of KLF4. In contrast, other tumor areas exhibiting high expression of TMPRSS11B together with BSG and SLC16A1 were largely negative for KLF4 expression. Thus, the differential expression of TMPRSS11B adds to metabolic heterogeneity in PDAC and its absence supports the reverse Warburg metabolism in PDAC cells by the enhancement of BSG-supported lactate uptake through SLC16A1 and subsequent phenotype alterations towards greater stemness. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Pancreatic Cancer: 2nd Edition)

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16 pages, 4557 KiB

Open AccessArticle

A Fluid Dynamic In Vitro System to Study the Effect of Hyaluronic Acid Administration on Collagen Organization in Human Skin Explants

by Andrea Galvan, Maria Assunta Lacavalla, Federico Boschi, Barbara Cisterna, Edoardo Dalla Pozza, Enrico Vigato, Flavia Carton, Manuela Malatesta and Laura Calderan

Int. J. Mol. Sci. 2025, 26(11), 5397; https://doi.org/10.3390/ijms26115397 - 4 Jun 2025

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Abstract

Hyaluronic acid (HA) is an unbranched polysaccharide particularly abundant in the extracellular matrix (ECM) of soft connective tissues. In humans, about 50% of the total HA in the organism is localized in the skin. HA plays an essential role in the hydration of [...] Read more.

Hyaluronic acid (HA) is an unbranched polysaccharide particularly abundant in the extracellular matrix (ECM) of soft connective tissues. In humans, about 50% of the total HA in the organism is localized in the skin. HA plays an essential role in the hydration of the ECM, in the regulation of tissue homeostasis, in the resistance to mechanical stimuli/forces, and in the modulation of tissue regeneration. For these reasons, HA is widely used in regenerative medicine and cosmetics. In this study we used an innovative fluid dynamic system to investigate the effects of a cross-linked macrostructural HA formulation on dermal collagen of healthy human skin explants. The good preservation of skin explants provided by the bioreactor allowed applying refined high-resolution microscopy techniques to analyze in situ the HA-induced modifications on the ECM collagen fibrils up to 48 h from the application on the skin surface. Results demonstrated that this HA formulation, commercially proposed for subcutaneous injection, may act on dermal ECM also when applied transcutaneously, improving ECM hydration and modifying the organization of the collagen fibrils. These findings, obtained by the original combination of explanted human skin use with an advanced culture system and multiscale imaging techniques, are consistent with the volumizing and anti-aging effect of HA. Full article

(This article belongs to the Special Issue 3D Technology in Biomedicine: Studying Molecular Mechanisms in Health and Disease)

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Open AccessArticle

Antitumor Activity of Tetrahydro-β-carboline Derivatives via Inhibition of Kinesin Spindle Protein: Validation by Molecular Docking, Molecular Dynamics, and In Vitro Assays

by Saizhen Guo, Ming Zhang, Xingyuan Zhang, Wenjuan Yuan, Chengting Zi, Zemin Xiang and Yongkai Xi

Int. J. Mol. Sci. 2025, 26(11), 5396; https://doi.org/10.3390/ijms26115396 - 4 Jun 2025

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Abstract

The tetrahydro-β-carboline heterocycle is a privileged scaffold found in numerous natural products and bioactive drugs, demonstrating significant potential for cancer therapy. In this study, we designed and synthesized 33 novel tetrahydro-β-carboline derivatives (2–34) based on this core structure and [...] Read more.

The tetrahydro-β-carboline heterocycle is a privileged scaffold found in numerous natural products and bioactive drugs, demonstrating significant potential for cancer therapy. In this study, we designed and synthesized 33 novel tetrahydro-β-carboline derivatives (2–34) based on this core structure and evaluated their anticancer activity against human lung cancer (A549). Among them, compounds 8 and 16 exhibited potent cytotoxicity against A549 cells, effectively suppressing cell migration and colony formation. Mechanistic studies revealed that these compounds promoted apoptosis by upregulating pro-apoptotic Bax, downregulating anti-apoptotic Bcl-2, and activating caspase proteins. Molecular docking and dynamics simulations demonstrated that compounds 8 and 16 form stable complexes with the Eg5 protein through multiple hydrogen bonds, which was further validated by thermal shift assays. Collectively, these findings indicate that compounds 8 and 16 induce apoptosis in A549 cells by selectively targeting and stabilizing Eg5, highlighting their potential as lead candidates for lung cancer therapy. Full article

(This article belongs to the Special Issue Natural Compounds: Structural Diversity, Modifications, and Biological Activities)

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Int. J. Mol. Sci., Volume 26, Issue 11 (June-1 2025) – 464 articles

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