International Journal of Molecular Sciences

24 pages, 1205 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

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)

14 pages, 787 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

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)

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

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)

► Show Figures

Figure 1

15 pages, 1630 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

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)

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

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)

► Show Figures

Figure 1

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

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)

► Show Figures

Figure 1

11 pages, 910 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

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)

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

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)

► Show Figures

Figure 1

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

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)

► Show Figures

Figure 1

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

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)

► Show Figures

Figure 1

24 pages, 1322 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

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)

► Show Figures

Figure 1

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

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)

► Show Figures

Figure 1

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

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)

► Show Figures

Figure 1

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

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)

► Show Figures

Figure 1

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

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)

► Show Figures

Figure 1

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

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

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)

► Show Figures

Figure 1

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

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

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)

► Show Figures

Figure 1

Journal Description

International Journal of Molecular Sciences

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI