International Journal of Molecular Sciences

16 pages, 409 KB

Open AccessReview

Heavy Metals Like Aluminum, Arsenic, Cadmium, Chromium, Copper, Iron, Lead, Manganese, Mercury, Nickel, and Zinc Polluting the Drinking Water: Their Individual Health Hazards

by Rolf Teschke and Tran Dang Xuan

Int. J. Mol. Sci. 2025, 26(23), 11656; https://doi.org/10.3390/ijms262311656 (registering DOI) - 1 Dec 2025

Abstract

Heavy metals (HMs) were originally formed in the universe long before human evolution and are now ubiquitous in the environment, where some HMs are good as essential elements for human health while others are not. The purpose of this analytical review is to [...] Read more.

Heavy metals (HMs) were originally formed in the universe long before human evolution and are now ubiquitous in the environment, where some HMs are good as essential elements for human health while others are not. The purpose of this analytical review is to provide an updated clinical overview on health risks attributable to drinking water containing specific HMs and to discuss new aspects of molecular steps leading to disrupted diseases. This approach was favored because the study cohorts were homogeneous, since exposed individuals lived in households where all members had access to the same drinking water of constant quality. Among the HMs under consideration, aluminum, arsenic, cadmium, chromium, copper, iron, lead, manganese, and mercury were detected in drinking water and represented a health risk if levels were above thresholds recommended by national and international regulatory authorities. For example, (1) aluminum increased the risk of dementia and Alzheimer’s disease; (2) arsenic was associated with the development of bladder cancer; (3) cadmium increased the no-carcinogenic, as well as the carcinogenic, health risk; (4) chromium was considered as a risk factor for liver and kidney injury, as well cancer development; (5) copper contributed to cognitive impairment in the aging population and Alzheimer’s disease; (6) iron increased the non-carcinogenic health risk; (7) lead impaired neurodevelopmental functions in children; (8) manganese increased the risk of attention-deficit hyperactivity disorder (ADHD); and (9) mercury was causally related to chronic kidney disease. In contrast, for nickel and zinc, no overt health risks have been reported, likely due to low levels in the drinking water, attributable to their low water solubility. Of note is the good news that some HMs represent essential elements for human health. In essence, many HMs were detected in drinking water and exerted non-carcinogenic or carcinogenetic health risks, requiring proactive management of national and international regulatory authorities. Full article

(This article belongs to the Special Issue Heavy Metal Exposure on Health)

18 pages, 676 KB

Open AccessReview

Elevated Cardiac Troponin in Non-Cardiac Conditions Unrelated to Acute Myocardial Infarction

by Lidija Savic, Sanja Stankovic, Nebojsa Antonijevic, Dragan Matic, Ratko Lasica, Gordana Krljanac and Milika Asanin

Int. J. Mol. Sci. 2025, 26(23), 11655; https://doi.org/10.3390/ijms262311655 (registering DOI) - 1 Dec 2025

Abstract

Cardiac troponins (cTn) T and I are biochemical markers of myocardial injury. In this review article, we aim to summarize the mechanisms and significance of cardiac troponin (cTn) elevation unrelated to acute myocardial infarction (AMI) in the most frequently occurring non-cardiac conditions, where [...] Read more.

Cardiac troponins (cTn) T and I are biochemical markers of myocardial injury. In this review article, we aim to summarize the mechanisms and significance of cardiac troponin (cTn) elevation unrelated to acute myocardial infarction (AMI) in the most frequently occurring non-cardiac conditions, where the accurate interpretation of elevated cTn levels is often challenging. Different mechanisms in non-cardiac conditions can cause non-ischemic myocardial injury. Understanding the pathophysiology of cTn release is an essential precondition for minimizing unnecessary, costly, and potentially risky (cardiac) interventions and for providing timely and appropriate medical care. Elevated cTn in critically ill patients and in patients with chronic disease/conditions is an independent predictor (risk factor) of cardiovascular and overall mortality. Treatment of underlying conditions is of primary importance, and close monitoring for the occurrence of cardiovascular complications during hospitalizations should be considered in these patients. Also, when the patient recovers from the underlying disease, clinical judgement should be employed to decide whether and to what extent further cardiological evaluation is indicated. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

29 pages, 436 KB

Open AccessReview

Proteome-Based Biomarkers for Alzheimer’s Disease: Old Acquisitions and Innovative Proposals

by Valeria Magnelli, Corinna Anais Pagano and Maurizio Sabbatini

Int. J. Mol. Sci. 2025, 26(23), 11654; https://doi.org/10.3390/ijms262311654 (registering DOI) - 1 Dec 2025

Abstract

Alzheimer’s disease (AD) is one of the most widespread neurodegenerative disorders, primarily affecting individuals over the age of 65. It is characterized by severe cognitive impairment, memory loss, difficulties in performing daily activities, ventricular enlargement, and ultimately, dementia. AD is associated with the [...] Read more.

Alzheimer’s disease (AD) is one of the most widespread neurodegenerative disorders, primarily affecting individuals over the age of 65. It is characterized by severe cognitive impairment, memory loss, difficulties in performing daily activities, ventricular enlargement, and ultimately, dementia. AD is associated with the accumulation of amyloid

β (A β)

protein plaques, intracellular neurofibrillary tangles (NFTs), progressive inflammation, and impairment of both synaptic transmission and mitochondrial function. Due to the limited diagnostic tools available for detecting the disease in its early stages, proteomic biomarkers have gained paramount importance, as they can monitor prodromal molecular alterations linked to AD. Furthermore, proteomic biomarkers can facilitate the longitudinal assessment of disease progression and contribute to the development of personalized therapeutic strategies before the devastating onset of dementia. Research has primarily focused on identifying proteomic biomarkers in cerebrospinal fluid (CSF) and plasma, as discussed in this review, but also in alternative matrices such as saliva and urine. These studies highlight both the high potential of proteomic approaches and the ongoing challenge of identifying clinically available, sensitive, and specific biomarkers for the various stages of the disease. Full article

(This article belongs to the Special Issue New Advances in Proteomics in Disease)

12 pages, 457 KB

Open AccessArticle

Genomic Characteristics of Bladder Cancer: An AACR Project GENIE Study

by John Paul Braun, Kenneth A. D. Palattao, Jr., Elijah Torbenson, Beau Hsia and Abubakar Tauseef

Int. J. Mol. Sci. 2025, 26(23), 11653; https://doi.org/10.3390/ijms262311653 (registering DOI) - 1 Dec 2025

Abstract

Bladder and urothelial carcinoma are marked by profound genomic diversity. Using a large, multi-institutional dataset, we performed comprehensive genomic profiling of 4631 tumor samples from 4050 individuals. A retrospective analysis of bladder and urothelial cancer was performed using the AACR Project GENIE database. [...] Read more.

Bladder and urothelial carcinoma are marked by profound genomic diversity. Using a large, multi-institutional dataset, we performed comprehensive genomic profiling of 4631 tumor samples from 4050 individuals. A retrospective analysis of bladder and urothelial cancer was performed using the AACR Project GENIE database. Demographic associations, mutation frequencies, copy number changes, and survival correlations were analyzed with a p-value < 0.05. Frequent mutations were identified in TP53, TERT, KDM6A, KMT2D, ARID1A, and FGFR3. Mutation frequencies varied by sex and race, with specific alterations enriched in female and Asian patients. Distinct patterns of co-occurrence, including TP53 with RB1, and mutual exclusivity, including TP53 with FGFR3 or KDM6A, revealed distinct molecular subtypes. This study highlights the extensive heterogeneity of bladder cancer, and our findings emphasize the clinical importance of molecular stratification and support the need for further mechanistic and prospective studies to inform the development of targeted therapies. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Therapeutic Targets in Bladder Cancer (Second Edition))

27 pages, 774 KB

Open AccessReview

Lights and Shadows of Nutrient-Driven Keratinocyte Inflammation in Psoriasis

by Desirèe Speranza, Alice Pantano, Chiara Cullotta, Giovanni Pallio, Mario Vaccaro, Michele Scuruchi and Natasha Irrera

Int. J. Mol. Sci. 2025, 26(23), 11652; https://doi.org/10.3390/ijms262311652 (registering DOI) - 1 Dec 2025

Abstract

Priasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation, impaired differentiation, and dysregulated immune responses. Emerging evidence highlights the central role of keratinocytes as immune-competent cells that integrate signals from cytokines, metabolic cues, the gut–skin axis, and the tissue microenvironment. Key [...] Read more.

Priasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation, impaired differentiation, and dysregulated immune responses. Emerging evidence highlights the central role of keratinocytes as immune-competent cells that integrate signals from cytokines, metabolic cues, the gut–skin axis, and the tissue microenvironment. Key intracellular signaling pathways, including NF-κB, JAK/STAT, MAPK, and PI3K/AKT/mTOR, along with the IL-23/IL-17 axis, orchestrate keratinocyte-mediated inflammation and epidermal hyperplasia. Metabolic factors, nutrients, and redox balance further modulate these responses, while the intestinal microbiota and its metabolites, such as short-chain fatty acids, shape systemic and cutaneous inflammation. This review offers a critical, integrated perspective, that moves beyond descriptive summaries. We propose a conceptual framework in which the keratinocyte metabolic state, particularly the sirtuin/NAD+ axis, acts as a crucial convergence point for systemic nutritional, microbial, and inflammatory signals. Targeting sirtuins and associated pathways with natural or synthetic modulators represents a promising, host-centric strategy to restore keratinocyte function and reduce chronic inflammation. This synthesis underscores the potential of combining molecular, metabolic, microbial, and nutritional insights to develop personalized and effective approaches for psoriasis management. Full article

(This article belongs to the Special Issue Psoriasis: Molecular Research and Novel Therapy)

19 pages, 644 KB

Open AccessArticle

Development and In Vitro Evaluation of [⁶⁴Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer

by Hoda Talebian, Samia Ait-Mohand, Prenitha Mercy Ignatius Arokia Doss, Léon Sanche and Brigitte Guérin

Int. J. Mol. Sci. 2025, 26(23), 11651; https://doi.org/10.3390/ijms262311651 (registering DOI) - 1 Dec 2025

Abstract

Prostate cancer (PCa), particularly in its metastatic form, remains a major clinical challenge due to limited diagnostic and therapeutic options. To address this, we developed a novel radiotheranostic agent, [⁶⁴Cu]Cu-NOTA-TP-PSMA, by conjugating a prostate-specific membrane antigen (PSMA) ligand to a ⁶⁴ [...] Read more.

Prostate cancer (PCa), particularly in its metastatic form, remains a major clinical challenge due to limited diagnostic and therapeutic options. To address this, we developed a novel radiotheranostic agent, [⁶⁴Cu]Cu-NOTA-TP-PSMA, by conjugating a prostate-specific membrane antigen (PSMA) ligand to a ⁶⁴Cu-radiolabeled terpyridine-platinum (TP) compound previously shown to exert selective cytotoxicity against cancer cells. In this study, the biological performance of [⁶⁴Cu]Cu-NOTA-TP-PSMA was compared with the monomeric analogs [⁶⁴Cu]Cu-NOTA-PSMA and [⁶⁴Cu]Cu-NOTA-TP through in vitro studies in PSMA-positive LNCaP prostate cancer cells and non-malignant HEK-293 cells. [⁶⁴Cu]Cu-NOTA-TP-PSMA showed high stability, PSMA binding affinity and exhibited substantially enhanced uptake, internalization, retention, and nuclear localization in LNCaP cells relative to the monomers, whereas uptake and nuclear accumulation in HEK-293 cells were negligible. Cytotoxicity assays further demonstrated potent and selective activity in LNCaP cells, with EC₅₀ values in the low nanomolar range, and minimal toxicity in HEK-293 cells. Collectively, these results identify [⁶⁴Cu]Cu-NOTA-TP-PSMA as a promising radiotheranostic agent, warranting further in vivo evaluation for prostate cancer imaging and targeted radiotherapy. Full article

(This article belongs to the Special Issue Emerging Topics in Metal Complexes: Pharmacological Activity, 2nd Edition)

18 pages, 8867 KB

Open AccessArticle

Modulation of α-Mannosidase 8 by Antarctic Endophytic Fungi in Strawberry Plants Under Heat Waves and Water Deficit Stress

by Daniel Bustos, Luis Morales-Quintana, Gabriela Urra, Francisca Arriaza-Rodríguez, Stephan Pollmann, Angela Méndez-Yáñez and Patricio Ramos

Int. J. Mol. Sci. 2025, 26(23), 11650; https://doi.org/10.3390/ijms262311650 (registering DOI) - 1 Dec 2025

Abstract

Plant–microbe interactions exert a significant influence on host stress responses; however, the molecular mechanisms underlying these effects remain inadequately understood. In this study, we characterize FaMAN8, an α-mannosidase from Fragaria × ananassa, to explore its role in adaptation to heat waves and [...] Read more.

Plant–microbe interactions exert a significant influence on host stress responses; however, the molecular mechanisms underlying these effects remain inadequately understood. In this study, we characterize FaMAN8, an α-mannosidase from Fragaria × ananassa, to explore its role in adaptation to heat waves and water deficit, as well as its modulation by fungal endophytes. Transcriptomic analysis identified FaMAN8 as the sole α-mannosidase isoform highly conserved across reported sequences, with root-specific induction under conditions of heat stress, deficient irrigation, and endophytic colonization. Structural modeling revealed that FaMAN8 exhibits the canonical domain organization of glycoside hydrolase family 38 (GH38) enzymes, featuring a conserved catalytic architecture and metal-binding site. Molecular docking and dynamics simulations with the Man₃GlcNAc₂ ligand indicated a stable binding pocket involving key catalytic residues and strong electrostatic complementarity. MM-GBSA and free energy landscape analyses further supported the thermodynamic stability of the protein–ligand complex. Cavity analysis revealed a larger active site in FaMAN8 compared to its homolog JbMAN, suggesting broader substrate accommodation. Collectively, these findings identify FaMAN8 as a stress-responsive glycosidase potentially involved in glycan remodeling during beneficial root–fungus interactions. This work provides molecular insights into plant–microbe symbiosis and lays the groundwork for microbiome-informed strategies to enhance crop stress resilience. Full article

(This article belongs to the Special Issue The Molecular Basis of Plant–Microbe Interactions)

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23 pages, 1348 KB

Open AccessReview

A Generalized AI View of Tricopeptide Repeats: What’s in a Name

by Sailen Barik

Int. J. Mol. Sci. 2025, 26(23), 11649; https://doi.org/10.3390/ijms262311649 (registering DOI) - 1 Dec 2025

Abstract

Tricopeptide repeats refer to 30 or more amino acid (aa) repeats, of which the best studied ones are 34-aa and 35-aa long, named Tetratricopeptide and Pentatricopeptide repeats, respectively, and abbreviated as TPR and PPR. Recently, 37-aa and 38-aa repeats (Heptatricopeptide, HPR; Octatricopeptide, OPR) [...] Read more.

Tricopeptide repeats refer to 30 or more amino acid (aa) repeats, of which the best studied ones are 34-aa and 35-aa long, named Tetratricopeptide and Pentatricopeptide repeats, respectively, and abbreviated as TPR and PPR. Recently, 37-aa and 38-aa repeats (Heptatricopeptide, HPR; Octatricopeptide, OPR) have been reported, but 36-aa repeats or repeats outside the 34–38 range (such as 33-aa or 39-aa) are apparently missing. This review is an analytical discourse of the structural and functional commonalities as well as differences among all tricopeptide repeats. In structure, the use of Artificial Intelligence (AI)-based prediction and experimental 3D structures revealed that regardless of the number of amino acids, these repeats are all alpha-helical in nature, whereby the tandem helices are joined by relatively flexible linkers or spacers to form a superhelix. In function, many tricopeptide repeats bind specific RNA, thus playing important roles in RNA processing and stability. The specificity is determined by the interaction between specific amino acid residues with the nucleotides in the RNA, while the helices offer a scaffold that holds the interacting residues in position. Detailed analysis of various known TPR and PPR revealed conserved amino acids at specific positions, such that they serve as signature motifs. Moreover, extra helices upstream or downstream of the repeat domains often maintain the continuum of the superhelical vortex. Evidently, the overall helicity and the presence of critical amino acid residues in strategic places are more important for the biological function of the tricopeptide repeats than the exact amino acid length of the repeat. Full article

(This article belongs to the Special Issue Protein Structure and Its Interactions)

19 pages, 3400 KB

Open AccessArticle

Identification of the Splicing Factor GmSR34b as a Negative Regulator of Salt Stress Response in Soybean Through Transcriptome and Alternative Splicing Analysis

by Jin-Bao Gu, Yin-Jie Cheng, Cong Li, Bai-Hong Zhang, Yu-Hang Zhang, Xiao-Yan Liang, Yang Li and Yan Lin

Int. J. Mol. Sci. 2025, 26(23), 11648; https://doi.org/10.3390/ijms262311648 (registering DOI) - 1 Dec 2025

Abstract

Soil salinity severely threatens soybean productivity worldwide. While transcriptional responses to salt stress are well-documented, the role of post-transcriptional regulation, particularly alternative splicing (AS), remains underexplored. This study combines physiological phenotyping, transcriptome-wide analysis, and molecular genetics to uncover the mechanisms behind the differences [...] Read more.

Soil salinity severely threatens soybean productivity worldwide. While transcriptional responses to salt stress are well-documented, the role of post-transcriptional regulation, particularly alternative splicing (AS), remains underexplored. This study combines physiological phenotyping, transcriptome-wide analysis, and molecular genetics to uncover the mechanisms behind the differences in salt tolerance between the salt-sensitive variety Huachun 6 (HC6) and the resistant variety Fiskeby III. Under salt stress, Fiskeby III exhibited superior survival rates and maintained ion homeostasis, as evidenced by a lower Na⁺/K⁺ ratio, compared with HC6. Transcriptomic and splicing analysis revealed extensive salt-induced alternative splicing reprogramming. Genes undergoing differential AS were enriched in pathways related to stress response, ion transport, and RNA splicing. Based on the overlap with both differentially expressed genes (DEG) and alternative splicing (DAS) genes under salt stress, a key splicing factor, GmSR34b, was identified as a central regulator of AS under salt stress. Under NaCl stress, the expression of GmSR34b in leaves peaked at 1 h and a salt stress-specific splicing variant was rapidly induced. A comparative analysis showed that the Fiskeby III cultivar prioritized maintenance of the full-length transcript during prolonged stress, whereas the HC6 cultivar accumulated higher levels of the splicing variant. This indicates differences in the regulation of alternative splicing between these two cultivars. Functional validation confirmed that overexpression of GmSR34b in soybean hairy roots inhibited salt tolerance. This study provides novel insights into the molecular mechanisms of salt tolerance in soybean, suggesting potential strategies for breeding resilient crops through the manipulation of splicing regulators. Full article

(This article belongs to the Special Issue Latest Advances in Plant Abiotic Stress)

19 pages, 2971 KB

Open AccessArticle

NRas Nanoclusters Mediate Crosstalk Between BRAF/ERK and PI3K/AKT Signaling in Melanoma Cells

by Oren Yakovian, Julia Sajman and Eilon Sherman

Int. J. Mol. Sci. 2025, 26(23), 11647; https://doi.org/10.3390/ijms262311647 (registering DOI) - 1 Dec 2025

Abstract

Melanocyte signaling through the MAPK pathway is orchestrated by NRas and relayed downstream via multiple effectors, such as RAF, Ral, and PI3K. In spite of their significance, the molecular mechanisms of signaling relay by NRas, their dynamics, and their potential as therapeutic targets [...] Read more.

Melanocyte signaling through the MAPK pathway is orchestrated by NRas and relayed downstream via multiple effectors, such as RAF, Ral, and PI3K. In spite of their significance, the molecular mechanisms of signaling relay by NRas, their dynamics, and their potential as therapeutic targets remain unclear. Using multi-color single molecule localization microscopy (PALM and dSTORM), we resolved the mutual nanoscale organization of NRas, PI3K, and BRAF at the plasma membrane of fixed and live melanoma cells. Surprisingly, NRas and its oncogenic mutation Q61R colocalized with PI3K in mutual nanoclusters, where BRAF was also frequently present. In live cells, NRas and PI3K co-clustering declined, yet persisted over minutes. Clinically relevant perturbations revealed unexpected crosstalk within these nanoclusters and consequently, between the MAPK and PI3K pathways. Specifically, overexpression of the Ras binding domain (RBD) and PI3K inhibition by wortmannin disrupted NRAS-PI3K interactions, and reduced both pAKT and pERK levels and cancer cell proliferation. MEK inhibition with trametinib resulted in similar, yet more pronounced effects. Thus, our findings provide novel insights into NRAS-mediated signaling through nanoscale clusters and underscore their potential as therapeutic targets. Full article

(This article belongs to the Special Issue Melanoma: Molecular Mechanism and Therapy, 2nd Edition)

24 pages, 3261 KB

Open AccessCase Report

Fatal Myocarditis Following Adjuvant Immunotherapy: A Case Report and Literature Review

by Nanteznta Torounidou, Melina Yerolatsite, Vasileios Bouratzis, Anna-Lea Amylidi, George Zarkavelis, Katerina K. Naka, Paraskevi V. Voulgari and Stergios Boussios

Int. J. Mol. Sci. 2025, 26(23), 11646; https://doi.org/10.3390/ijms262311646 (registering DOI) - 1 Dec 2025

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing the immune response against tumors. However, they can cause immune-related adverse events (irAEs), including rare but potentially fatal myocarditis. We describe a 71-year-old man with stage IIIA lung adenocarcinoma treated with adjuvant pembrolizumab [...] Read more.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing the immune response against tumors. However, they can cause immune-related adverse events (irAEs), including rare but potentially fatal myocarditis. We describe a 71-year-old man with stage IIIA lung adenocarcinoma treated with adjuvant pembrolizumab who developed severe ICI-associated myocarditis. Despite early diagnosis, treatment with intensive immunosuppression and mechanical support, he suffered fatal cardiac complications. A systematic review of the literature up to May 2025 identified 44 cases of ICI-associated myocarditis. Data on clinical features, diagnostics, treatment, and outcomes were extracted and analyzed. Most cases involved older patients with lung cancer treated with pembrolizumab or nivolumab. Onset varied from days to years after therapy initiation. Presentations included dyspnea, chest pain, arrhythmias, and elevated cardiac biomarkers. The biopsy showed T-cell and macrophage infiltration. High-dose corticosteroids were the primary treatment; additional immunosuppressants were used in cases that were refractory. Mortality was 45%, mainly due to cardiac failure and sepsis. Discussion: ICI-associated myocarditis arises from immune dysregulation affecting cardiac tissue, potentially involving shared antigens and systemic inflammation. Early detection and aggressive immunosuppression are crucial but often insufficient, resulting in high mortality. This underscores the urgent need for a better understanding of pathogenesis and the development of effective management strategies to improve patient outcomes. Finally, a multidisciplinary approach is important to improve outcomes in ICI-associated myocarditis. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 3rd Edition)

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34 pages, 1389 KB

Open AccessReview

An AAV-Based Therapy Approach for Neurological Phenotypes of X-Linked Adrenoleukodystrophy

by Ekaterina Gornostal, Almaqdad Alsalloum, Egor Degtyarev, Ekaterina Kuznetsova, Aygun Levashova, Daria Mishina, Natalia Mingaleva, Ali Mazloum, Viktor Bogdanov, Julia Krupinova, Sergey Mikhalkov, Irina Rybkina, Olga Mityaeva and Pavel Volchkov

Int. J. Mol. Sci. 2025, 26(23), 11645; https://doi.org/10.3390/ijms262311645 - 1 Dec 2025

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus [...] Read more.

X-linked adrenoleukodystrophy (X-ALD) is a monogenic progressive neurodegenerative disorder, being simultaneously a systemic metabolic disease and demonstrating severe neurological manifestations with effects to the brain and spinal cord. The objective of the current review is to provide a detailed approach to adeno-associated virus (AAV)-based gene therapy for neurological manifestations of X-ALD. The development of a successful AAV-mediated gene therapy hinges on its ability to deliver ABCD1 cDNA effectively to the relevant organs and cell types, induce therapeutic levels of protein expression, and ultimately, restore normal very-long chain fatty acids (VLCFA) metabolic function. Thus, several key considerations should be addressed when designing AAV-based gene therapy for X-ALD, including the genetic background of the disease and requisite transgene expression levels, the biochemical function of the adrenoleukodystrophy protein (ALDP), the identification of target cells and their role in pathogenesis, the regulation of expression within the genetic construct, the route of administration, the selection of an AAV serotype with high tropism for the central and peripheral nervous systems, and the development of robust in vitro and in vivo models. Full article

(This article belongs to the Special Issue Neurodegenerative Disease: From Molecular Basis to Therapy, 4th Edition)

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17 pages, 2515 KB

Open AccessArticle

Potyvirus HcPro Suppressor of RNA Silencing Induces PVY Superinfection Exclusion in a Strain-Specific Manner

by Vincent N. Fondong and Prakash M. Niraula

Int. J. Mol. Sci. 2025, 26(23), 11644; https://doi.org/10.3390/ijms262311644 - 1 Dec 2025

Abstract

The potyvirus helper component proteinase (HcPro) is a multifunctional protein, with one of its most documented functions being host antiviral RNA silencing suppression. This study shows that the HcPro of potato virus Y (PVY), an important member of the potyvirus group, prevents the [...] Read more.

The potyvirus helper component proteinase (HcPro) is a multifunctional protein, with one of its most documented functions being host antiviral RNA silencing suppression. This study shows that the HcPro of potato virus Y (PVY), an important member of the potyvirus group, prevents the replication of a related competing secondary virus. This phenomenon, referred to as superinfection exclusion (SIE), is common in bacterial, human, and plant virus infections. We also report that HcPro’s induction of SIE is strain-specific and that this specificity is provided by the first four amino acid residues of the protein. Consistent with the mechanism of SIE, the study found that HcPro does not exclude a resident virus. Additionally, HcPro’s induction of SIE was observed to function independently of its ability to suppress antiviral RNA silencing. HcPro’s induction of SIE is relevant given the prevalence of multiple PVY strains that routinely co-infect the same cell and that may lead to recombination and emergence of new and more virulent strains. Furthermore, cross-protection or systemic acquired resistance (SAR) that is employed in plant virus disease management occurs when SIE moves from the cellular level and spreads systemically, emphasizing the importance of studying SIE. Full article

(This article belongs to the Special Issue Viral Infections and Viral Pathogenesis)

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14 pages, 1016 KB

Open AccessReview

Anti-Müllerian Hormone as a Biomarker for Predicting Testicular Sperm Extraction Outcomes in Azoospermic Patients: A Comprehensive Systematic Review and Meta-Analysis

by Dragoș Puia, Marius Ivănuță, Mihaela Corlade-Andrei, Ovidiu Daniel Bîcă, Bogdan Doroftei and Cătălin Pricop

Int. J. Mol. Sci. 2025, 26(23), 11643; https://doi.org/10.3390/ijms262311643 - 1 Dec 2025

Abstract

Male infertility represents a major clinical and societal issue, with azoospermia being one of its most severe forms. Anti-Müllerian Hormone (AMH) has been proposed as a potential biomarker for predicting testicular sperm extraction (TESE) outcomes in men with non-obstructive azoospermia (NOA). This study [...] Read more.

Male infertility represents a major clinical and societal issue, with azoospermia being one of its most severe forms. Anti-Müllerian Hormone (AMH) has been proposed as a potential biomarker for predicting testicular sperm extraction (TESE) outcomes in men with non-obstructive azoospermia (NOA). This study aimed to systematically evaluate the association between AMH levels and sperm retrieval success. We included studies on men with NOA reporting TESE outcomes by AMH level, excluding those without full text or with insufficient data. When cohorts overlapped, the most complete study was used, following PICO criteria focused on AMH measurements and sperm retrieval rates (SRR). A comprehensive search identified 133 potentially relevant publications. Of these, 11 studies published between 2006 and 2023, including 1280 patients, met the inclusion criteria. Pooled analyses were performed using random-effects models. This meta-analysis was recorded in the PROSPERO database (registration ID: CRD420251065256). Reported SRRs ranged from 30.35% to 76.27%. Meta-analysis of nine studies assessing serum AMH concentrations revealed significant heterogeneity (I² = 88%). Elevated serum AMH was negatively associated with SRR (standardized mean difference [SMD] = −2.58; 95% CI: −4.73 to −0.44; p < 0.00001). In contrast, seminal plasma AMH levels (two studies) showed no significant association with SRR (I² = 82%). Similarly, preoperative FSH levels (nine studies) did not demonstrate a consistent association with SRR, despite higher mean concentrations in patients with successful TESE (p = 0.02; SMD = −4.86; 95% CI: −9.07 to −0.66). Serum AMH levels are significantly associated with TESE outcomes in men with NOA. However, the predictive value of AMH and other hormonal markers is limited by high inter-individual variability and overlapping values between successful and unsuccessful cases. These findings underscore the complexity of NOA and highlight the need to interpret hormonal markers within a broader clinical and biochemical context. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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18 pages, 1475 KB

Open AccessReview

Immune-Guided Bone Healing: The Role of Osteoimmunity in Tissue Engineering Approaches

by Serena Munaò, Alessandra Armeli, Desirèe Bonfiglio, Antonella Iaconis and Giovanna Calabrese

Int. J. Mol. Sci. 2025, 26(23), 11642; https://doi.org/10.3390/ijms262311642 - 1 Dec 2025

Abstract

The skeletal and immune systems are intricately linked, forming a dynamic interface that regulates both bone homeostasis and immune function. This bidirectional relationship, central to the field of osteoimmunology, highlights how bone and immune cells interact via shared progenitors and signaling pathways. Osteoclasts [...] Read more.

The skeletal and immune systems are intricately linked, forming a dynamic interface that regulates both bone homeostasis and immune function. This bidirectional relationship, central to the field of osteoimmunology, highlights how bone and immune cells interact via shared progenitors and signaling pathways. Osteoclasts and osteoblasts not only coordinate bone remodeling but also influence hematopoietic and immune functions within the bone marrow microenvironment. The concept of the “bone immune system” underscores this crosstalk, particularly in pathological and regenerative contexts. Despite progress, contradictory findings complicate our understanding of cytokine activity. Pro-inflammatory mediators such as TNF-α and IL-17 are typically associated with bone loss, yet under certain conditions, they paradoxically promote repair by stimulating osteoblast differentiation. Conversely, anti-inflammatory cytokines like IL-10 and TGF-β are generally protective, but their effects vary depending on local context, sometimes even impairing regeneration. These inconsistencies highlight unresolved questions and gaps in mechanistic insight into immune–bone interactions. Bone tissue engineering (BTE) has advanced through biomimetic scaffolds, osteogenic cells, and bioactive molecules, offering hope for large defect repair. However, clinical translation remains limited, largely because immune modulation is not fully integrated into scaffold design. Current preclinical models often fail to capture the complexity of immune–skeletal interplay, reducing predictive value. Addressing these gaps requires improved models and systematic evaluation of immunoregulatory biomaterials, paving the way for more effective and personalized regenerative therapies. Full article

(This article belongs to the Section Molecular Immunology)

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15 pages, 2079 KB

Open AccessArticle

Liproxstatin-1 Protects SH-SY5Y Cells by Inhibiting H₂O₂-Induced Excessive Mitophagy and Apoptosis

by Tingting Yan, Feng Ding, Zhongyuan Fang and Yan Zhao

Int. J. Mol. Sci. 2025, 26(23), 11641; https://doi.org/10.3390/ijms262311641 - 1 Dec 2025

Abstract

Oxidative stress is a critical factor in the pathogenesis of various neuronal disorders, causing cellular damage and mitochondrial dysfunction. This study aimed to explore the protective effects of liproxstatin-1 against H₂O₂-induced neural oxidative damage and elucidate the underlying mechanisms. [...] Read more.

Oxidative stress is a critical factor in the pathogenesis of various neuronal disorders, causing cellular damage and mitochondrial dysfunction. This study aimed to explore the protective effects of liproxstatin-1 against H₂O₂-induced neural oxidative damage and elucidate the underlying mechanisms. Our findings demonstrated that 500 μmol/L H₂O₂ treatment induced mitochondrial dysfunction and apoptosis in SH-SY5Y cells, while 1 μmol/L liproxstatin-1 effectively mitigated these cytotoxic effects by restoring mitochondrial integrity and enhancing cell viability. Furthermore, 500 μmol/L H₂O₂ exposure significantly suppressed the activation of the protein kinase B/ mammalian target of rapamycin signaling pathway and triggered excessive mitophagy. Pretreatment with 1 μmol/L liproxstatin-1 attenuated the damage by H₂O₂, suggesting its protective role. Collectively, our results indicated that 500 μmol/L H₂O₂ induces cytotoxicity through oxidative damage, protein kinase B/ mammalian target of rapamycin pathway inhibition, and aberrant mitophagy, ultimately leading to apoptosis; meanwhile, 1 μmol/L liproxstatin-1 counteracted these effects by preserving mitochondrial function, suppressing excessive mitophagy, and inhibiting apoptotic pathways, thereby protecting SH-SY5Y cells from H₂O₂-induced cytotoxicity. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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1 pages, 137 KB

Open AccessCorrection

Correction: Salloum-Asfar et al. MicroRNA Profiling Identifies Age-Associated MicroRNAs and Potential Biomarkers for Early Diagnosis of Autism. Int. J. Mol. Sci. 2025, 26, 2044

by Salam Salloum-Asfar, Samia M. Ltaief, Rowaida Z. Taha, Wared Nour-Eldine, Sara A. Abdulla and Abeer R. Al-Shammari

Int. J. Mol. Sci. 2025, 26(23), 11640; https://doi.org/10.3390/ijms262311640 - 1 Dec 2025

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Section Molecular Genetics and Genomics)

2 pages, 1096 KB

Open AccessCorrection

Correction: Zou et al. Transportin-3 Facilitates Uncoating of Influenza A Virus. Int. J. Mol. Sci. 2022, 23, 4128

by Jiahui Zou, Luyao Yu, Yinxing Zhu, Shuaike Yang, Jiachang Zhao, Yaxin Zhao, Meijun Jiang, Shengsong Xie, Hailong Liu, Changzhi Zhao and Hongbo Zhou

Int. J. Mol. Sci. 2025, 26(23), 11639; https://doi.org/10.3390/ijms262311639 - 1 Dec 2025

Abstract

Error in Figure [...] Full article

(This article belongs to the Section Molecular Biology)

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11 pages, 1318 KB

Open AccessArticle

Antibody-Dependent Cytotoxicity of Monocytes in Preeclampsia Is Associated with Soluble Forms of HLA

by Aleksey M. Krasnyi, Leya E. Sorokina, Anastacia Maria Argentova-Stevens, Diana N. Kokoeva, Aleksey A. Alekseev, Tatjana Jankevic, Natalia E. Kan, Victor L. Tyutyunnik and Gennady T. Sukhikh

Int. J. Mol. Sci. 2025, 26(23), 11638; https://doi.org/10.3390/ijms262311638 - 1 Dec 2025

Abstract

Preeclampsia (PE) is a serious gestational complication that affects the lives of the mother and the child. Women with PE showed higher levels of pro-inflammatory cytokines secreted by leukocytes compared with women with normal pregnancies. The differences are most noticeable in the percentage [...] Read more.

Preeclampsia (PE) is a serious gestational complication that affects the lives of the mother and the child. Women with PE showed higher levels of pro-inflammatory cytokines secreted by leukocytes compared with women with normal pregnancies. The differences are most noticeable in the percentage of CD16+ monocytes, although the mechanism underlying this increase remains unclear. The CD16 receptor is critical for antibody-dependent cellular cytotoxicity, and by binding to antibodies on the surface of target cells, it activates their death. In this study, we examined the effect of soluble placental factors on the expression of CD16 monocytes and the potential role the soluble form of human leukocyte antigen (HLA) has on CD16 monocyte expression. At the first stage of our study, we collected samples of placental villi fragments from 58 pregnant women (38 women with PE and 20 with a healthy pregnancy). Then we studied the effect of placental villus-conditioned culture medium on CD16 expression by monocytes derived from the same women. It was shown that the content of CD16+ monocytes increased significantly in women with PE within 3 h and to a lesser extent in women with a healthy pregnancy (p = 0.009). Also, the addition of the recombinant histocompatibility HLA-B to the placental villus-conditioned culture medium blocks the induction of CD16 expression on monocytes. At the second stage of our study, we typed HLA class I and class II alleles in the umbilical cord blood samples and the venous blood samples taken from 38 women with PE and 40 women with a normal pregnancy. It was found that certain HLA class II alleles predominate in women with preeclampsia. The DRB1*01:01:01G allele showed the greatest difference (p < 0.001). Analyzing five alleles simultaneously makes it possible to predict the PE with AUC = 0.76. Evaluation of unique children’s alleles also showed that class II alleles have greater differences among them than class I alleles. The DQB1*06:03:01G allele had the greatest differences with p = 0.03 (the number was higher in the control group). Performing an analysis of four alleles of children simultaneously allowed us to predict PE with an AUC of 0.64. This work suggests that the activation of CD16+ monocyte expression occurs due to the interaction of soluble placental antigens with monocytes. The most likely way to activate CD16 expression on monocytes is by HLA class II (both maternal and fetal) interaction with CD4 receptors on the surface of monocytes, whereas HLA class I is capable of blocking this process. Evaluation of maternal HLA alleles may be a significant marker for predicting PE. Full article

(This article belongs to the Special Issue Pathogenesis of Preeclampsia: From a Molecular Perspective)

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