International Journal of Molecular Sciences

11 pages, 216 KB

Open AccessArticle

Potential Association of BRAF and PIK3CA Copy Number Alterations with Long-Term Survival in IDH-Wildtype Glioblastoma: A Pilot Study

by Silvia Tomoszková, Denisa Drozdková, Jana Vaculová, Patricie Delongová, Martin Palička, Jozef Škarda and Radim Lipina

Int. J. Mol. Sci. 2026, 27(11), 4688; https://doi.org/10.3390/ijms27114688 (registering DOI) - 22 May 2026

Abstract

IDH-wildtype glioblastoma remains the most aggressive primary brain tumor, with a median overall survival (OS) of 14–16 months despite maximal treatment. A small subset of patients, however, survive beyond 30 months, suggesting distinct underlying biological features. The aim of this pilot study was [...] Read more.

IDH-wildtype glioblastoma remains the most aggressive primary brain tumor, with a median overall survival (OS) of 14–16 months despite maximal treatment. A small subset of patients, however, survive beyond 30 months, suggesting distinct underlying biological features. The aim of this pilot study was to explore whether selected molecular alterations detectable by FISH show differing distribution patterns between patients with prolonged and poor survival in IDH-wildtype glioblastoma. We retrospectively analyzed 20 patients with newly diagnosed primary IDH-wildtype glioblastoma who underwent gross-total resection followed by standard radiotherapy and temozolomide treatment between 2016 and 2022. Patients were categorized into two predefined groups according to survival outcomes: long-term survivors (OS > 30 months) and short-term survivors (OS < 10 months). Fluorescence in situ hybridization (FISH) was used to evaluate alterations in ATRX, BRAF, and PIK3CA. MGMT promoter methylation, EGFR amplification, and TERT promoter mutation status were obtained from routine diagnostic reports. Because survival groups were intentionally pre-selected as extreme phenotypes, time-to-event analysis was not appropriate. Therefore, statistical comparisons were performed using Fisher’s exact test and multivariable logistic regression with long-term versus short-term survival as a binary outcome. Short-term survivors had a significantly higher median age (57.5 vs. 46.5 years, p = 0.043) and a higher rate of EGFR amplification (100% vs. 50%, p = 0.033). Strikingly, combined BRAF and PIK3CA alterations (predominantly polysomy) were detected in 8 out of 10 (80%) long-term survivors, compared to 0 out of 10 (0%) short-term survivors (p = 0.0007). In multivariable logistic regression adjusted for age and MGMT promoter methylation, BRAF/PIK3CA alteration remained strongly associated with long-term survival, though the effect size was mathematically inflated due to perfect separation (0 events in Group B). BRAF and PIK3CA copy number alterations were observed exclusively in long-term survivors in this small exploratory cohort, suggesting a possible association with prolonged survival. However, given the limited sample size, the selection of extreme survival groups, and the predominance of chromosomal polysomy detected by FISH, these findings should be interpreted as hypothesis-generating only. Further validation in larger cohorts using high-resolution genomic methods is warranted. Full article

(This article belongs to the Special Issue Molecular Insights into Glioblastoma Pathogenesis and Therapeutics)

20 pages, 4839 KB

Open AccessArticle

Comparative Genomics Analysis Reveals the Genomic Basis of S8 Proteases, CAZymes, and Secondary Metabolism Associated with Nematode Biocontrol in Purpureocillium lilacinum

by Xiaoxi Cheng, Li Liu, Zhimin Zhu, Minghao Chen, Wenbo Wang, Jialin Li, Ramon Santos Bermudez, Xiujun Zhang and Wenxing He

Int. J. Mol. Sci. 2026, 27(11), 4687; https://doi.org/10.3390/ijms27114687 (registering DOI) - 22 May 2026

Abstract

Biological control fungi play an important role in the management of plant-parasitic nematodes; however, the molecular basis underlying their diverse biocontrol strategies remains incompletely understood. In this study, a comparative genomic analysis was performed on four representative biocontrol fungi: Purpureocillium lilacinum PLFJ-1, Trichoderma [...] Read more.

Biological control fungi play an important role in the management of plant-parasitic nematodes; however, the molecular basis underlying their diverse biocontrol strategies remains incompletely understood. In this study, a comparative genomic analysis was performed on four representative biocontrol fungi: Purpureocillium lilacinum PLFJ-1, Trichoderma harzianum CBS 226.95, Pochonia chlamydosporia 170, and Aspergillus niger CBS 513.88. Genome comparison revealed substantial variation: genome size ranged from 34.0 Mb (A. niger) to 44.2 Mb (P. chlamydosporia), GC content from 47.5% (T. harzianum) to 58.5% (P. lilacinum), and predicted gene models also differed markedly among the four fungi. Phylogenetic analysis based on the Internal Transcribed Spacer divided these fungi into two major clades corresponding to distinct evolutionary lineages. Orthogroup analysis identified both a conserved core gene set and species-specific gene repertoires. Functional annotation using KEGG, KOG, and GO indicated a high degree of conservation across core metabolic processes, catalytic activities, and cellular components, with distinct differences within specific functional categories. Further comparative analyses demonstrated pronounced variation in the composition and abundance of carbohydrate-active enzymes (CAZymes) and peptidases, as well as a notable expansion and enrichment of S8 subtilisin-like serine peptidases in the nematode-parasitic fungi P. lilacinum and P. chlamydosporia. Secondary metabolite analysis revealed lineage-specific biosynthetic gene clusters (BGCs). Notably, P. lilacinum and P. chlamydosporia carried PKS/NRPS clusters potentially linked to nematicidal activity, while A. niger and T. harzianum displayed broader but less infection-specific metabolic profiles. Together, these findings suggest that distinct enzymatic and metabolic gene repertoires, particularly expansions of S8 serine peptidases and specific CAZyme families, may contribute to the biocontrol potential of these fungi. Full article

(This article belongs to the Special Issue Fungal Genetics and Functional Genomics Research)

25 pages, 1840 KB

Open AccessReview

Acetylcholine in Brain–Body Communication: Biological Mechanisms and Physiological Roles

by Yuan Gao, Tian Zhou, Xinsheng Lai and Erkang Fei

Int. J. Mol. Sci. 2026, 27(11), 4686; https://doi.org/10.3390/ijms27114686 (registering DOI) - 22 May 2026

Abstract

Acetylcholine (ACh) is an evolutionarily conserved neurotransmitter that is widely distributed in the central and peripheral nervous systems and plays essential roles in multiple physiological processes. This review summarizes the full biological cycle of ACh, including its synthesis, vesicular storage, release, degradation, and [...] Read more.

Acetylcholine (ACh) is an evolutionarily conserved neurotransmitter that is widely distributed in the central and peripheral nervous systems and plays essential roles in multiple physiological processes. This review summarizes the full biological cycle of ACh, including its synthesis, vesicular storage, release, degradation, and reuptake, and discusses the regulatory mechanisms underlying its functions in the nervous system and peripheral organs. Through nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), ACh is involved in central nervous system functions such as cognition, learning and memory, attention, arousal, reward, and decision-making, as well as peripheral processes including motor control, autonomic regulation, and immune modulation. In addition, ACh plays a pivotal role in the brain–body axis. At the central level, the nervous system regulates peripheral organ function through autonomic and neuroendocrine pathways. At the peripheral level, cholinergic signals derived from the enteric nervous system and immune cells convey information about the body’s internal state to the central nervous system through vagal and other afferent pathways, forming an important bottom-up regulatory network. Collectively, these findings indicate that ACh is not only a classical neurotransmitter but also a key molecular mediator of brain–body communication. A more comprehensive understanding of cholinergic signaling may provide new insights into physiological regulation and the pathogenesis of neurological, psychiatric, cardiovascular, and inflammatory diseases. Full article

(This article belongs to the Topic Applications of Biomedical Technology and Molecular Biological Approach in Brain Diseases, 2nd Edition)

19 pages, 1238 KB

Open AccessArticle

Liver Matrix Stiffening Modulates Tumor-Associated Hepatocyte Polyploid Homeostasis via Piezo1/RUNX2/Anillin Mechanosensitive Axis

by Xinyi Luo, Yifan Zhang, Yiquan Lu, Nan Wang, Fengjie Hao, Yongjun Chen, Xiaochun Fei and Junqing Wang

Int. J. Mol. Sci. 2026, 27(11), 4685; https://doi.org/10.3390/ijms27114685 (registering DOI) - 22 May 2026

Abstract

The human liver is a polyploid organ, dominantly featured by a high proportion of binuclear polyploid hepatocytes. Our recent study demonstrates that decline of the abundance of binuclear hepatocytes (ABH) plays a critical role in contributing to Hepatocellular carcinoma (HCC) formation, involving the [...] Read more.

The human liver is a polyploid organ, dominantly featured by a high proportion of binuclear polyploid hepatocytes. Our recent study demonstrates that decline of the abundance of binuclear hepatocytes (ABH) plays a critical role in contributing to Hepatocellular carcinoma (HCC) formation, involving the cytokinesis regulator Anillin. However, the relevance between liver stiffness and the acquired ABH attenuation remains unclear. In this study, we set a mechanical environment gel with different gradients to simulate different liver stiffness environments, combined with the paired paracancerous liver tissues from real-world patients with HCC who underwent radical surgery. A mechanosensitive Piezo1/RUNX2/Anillin axis was discovered. As observed, the decline of ABH in paracancerous liver tissues is a noteworthy measurable value for tumor formation, correlated with the extent of liver matrix stiffness and dismal phenotypes. A stiffened culture environment may promote quick polyploid attenuation of hepatocytes, accompanied by high expression of Piezo1, a critical mechanosensitive ion channel, and a consequential nuclear translocation of RUNX2. Importantly, RUNX2 functions as an upstream transcription factor of Anillin. Regulating Piezo1/RUNX2 or using Piezo1 agonist remarkably affected Anillin expression and hepatocyte polyploidy homeostasis. Thus, we propose that the Piezo1/RUNX2/Anillin axis transduces the microenvironment mechanical signal from liver stiffening and impairs hepatocyte polyploidy homeostasis in HCC formation. Full article

(This article belongs to the Section Molecular Oncology)

15 pages, 1466 KB

Open AccessArticle

Integrative Multi-Omics Analysis Prioritizes Candidate Therapeutic Targets for Primary Open-Angle Glaucoma

by Hao Kan, Lei Wen, Yuan Liu, Ka Zhang, Aiqin Mao, Li Geng, Fan Yu and Lei Feng

Int. J. Mol. Sci. 2026, 27(11), 4684; https://doi.org/10.3390/ijms27114684 (registering DOI) - 22 May 2026

Abstract

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework [...] Read more.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework integrating UK Biobank plasma proteomics (N = 53,022) and large-scale POAG GWAS summary statistics. We performed a Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality. Identified candidates were mapped to human and mouse ocular scRNA-seq atlases to characterize cell-type specificity, followed by druggability assessments. We prioritized five putative causal proteins, with SEL1L and TFPI demonstrating the strongest evidence. Cross-species scRNA-seq revealed that SEL1L and SERPINF1 are robustly expressed in the trabecular meshwork (TM), particularly the juxtacanalicular tissue, implicating them in outflow resistance. Conversely, TFPI and SLC9A3R2 localize to Schlemm’s canal endothelium, suggesting a role in modulating barrier function. Pathway analyses highlighted endoplasmic reticulum protein processing and coagulation cascades. This study maps putative causal POAG proteins to conventional outflow pathway cells, highlighting SEL1L as a novel target for TM homeostasis and TFPI for drug repurposing, thereby providing data-driven hypotheses to facilitate precision glaucoma therapeutics. Full article

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

15 pages, 580 KB

Open AccessArticle

Downregulating Nrl Expression and Rod Photoreceptor Protection

by Yiwen Li, Shuliang Jiao, Weng Tao and Rong Wen

Int. J. Mol. Sci. 2026, 27(11), 4683; https://doi.org/10.3390/ijms27114683 (registering DOI) - 22 May 2026

Abstract

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal degenerations with primary degeneration of rod photoreceptors followed by secondary cone loss. We investigated whether downregulating Nrl (neural retina leucine zipper), a key transcription factor specifying rod fate, can reprogram rods into [...] Read more.

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal degenerations with primary degeneration of rod photoreceptors followed by secondary cone loss. We investigated whether downregulating Nrl (neural retina leucine zipper), a key transcription factor specifying rod fate, can reprogram rods into a more resilient state. In a transgenic Nrl^N/N mouse in which Nrl was markedly downregulated, the rod phenotype became more like a rod precursor, particularly in the inferior retina. Crossing Nrl^N/N mice with two rod degeneration models, rd1 (Pde6b^rd1/rd1) and rhodopsin P23H knock-in (Rho^P23H/P23H) mice, showed significantly improved photoreceptor survival in double-mutant mice. In addition, AAV-mediated delivery of shRNA targeting Nrl mRNA substantially enhanced photoreceptor survival in rd10 (Pde6b^rd10/rd10) mice. These findings demonstrate that downregulation of Nrl reprograms rods and confers broad resistance to degeneration across multiple RP models. AAV-mediated Nrl knockdown represents a promising mutation-independent therapeutic strategy for autosomal recessive and dominant forms of RP. Full article

(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches—4th Edition)

16 pages, 1730 KB

Open AccessArticle

Coevolution of NK and Tumor Cell States Along Multiple Myeloma Progression from Precursor Conditions

by Cristina Aquilina, Andrea Romano, Anna Maria Corsale, Marta Biondo, Maria Speciale, Elena Tofacchi, Marta Di Simone, Emilia Gigliotta, Costanza Dieli, Claudia Avellone, Angelo Toscano, Lawrence Camarda, Alessandra Romano, Daniela Cambria, Gianluca Giavaresi, Lavinia Raimondi, Antonino Neri, Stefania Campana, Nadia Caccamo, Francesco Dieli, Sergio Siragusa, Serena Meraviglia and Cirino Botta Show full author list Hide full author list

Int. J. Mol. Sci. 2026, 27(11), 4682; https://doi.org/10.3390/ijms27114682 (registering DOI) - 22 May 2026

Abstract

Multiple myeloma (MM) develops through asymptomatic precursor stages characterized by progressive remodeling of the bone marrow (BM) immune microenvironment and disruption of bone homeostasis. To delineate changes in natural killer (NK) cell states during disease evolution, we investigated coordinated immune-tumor remodeling by integrating [...] Read more.

Multiple myeloma (MM) develops through asymptomatic precursor stages characterized by progressive remodeling of the bone marrow (BM) immune microenvironment and disruption of bone homeostasis. To delineate changes in natural killer (NK) cell states during disease evolution, we investigated coordinated immune-tumor remodeling by integrating NK cell functional states with plasma cell-intrinsic susceptibility programs derived from CRISPR-based screens across healthy donors (HD), monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed MM patients. The integration of NK cell state-associated gene signatures with plasma cell transcriptional programs revealed stage-specific co-variation between immune and tumor compartments. Public single-cell RNA sequencing datasets were interrogated to resolve NK cell heterogeneity, identifying cytotoxic CD56^dim and regulatory CD56^bright subsets. NK cell dynamics displayed stage-dependent changes, with early expansion followed by the contraction of CD56^dim cells in BM, whereas CD56^bright cells showed predominantly compositional remodeling. Within the CD56^bright subset, transcriptional changes included an increased expression of KLRC1 (encoding NKG2A), subsequently validated by multiparametric flow cytometry. In parallel, plasma cell programs associated with NK sensitivity progressively decreased along disease stages, supporting tumor adaptation to immune pressure. The NKG2A ligand HLA-E displayed selective expression within CD16⁺ monocytes and followed a distinct variable pattern across disease stages, highlighting a microenvironmental contribution to NK cell regulation. Collectively, these findings indicate a coordinated process of immune-tumor co-evolution, characterized by dynamic remodeling of NK cell states and plasma cell susceptibility, with the NKG2A–HLA-E axis emerging as a central interface during MM progression. Full article

(This article belongs to the Special Issue Insights into Immunodeficiency and Immunotherapy in Multiple Myeloma)

11 pages, 527 KB

Open AccessCommunication

Inflammasome Gene Polymorphisms (NLRP3 and NLRC4) and Vitamin D Status in Patients with Multiple Sclerosis

by Concetta Scazzone, Luisa Agnello, Caterina Maria Gambino, Chiara Bellia, Giuseppe Salemi, Anna Masucci, Sabrina Novara and Marcello Ciaccio

Int. J. Mol. Sci. 2026, 27(11), 4681; https://doi.org/10.3390/ijms27114681 - 22 May 2026

Abstract

Multiple Sclerosis (MS) is a neuroinflammatory disorder in which genetic and environmental factors contribute to disease onset. Evidence implicates the inflammasome pathway in MS pathophysiology. However, the interaction between inflammasome-related genetic variants and 25-OH-vitamin D₃ (25(OH)D₃) levels remains unclear. 105 [...] Read more.

Multiple Sclerosis (MS) is a neuroinflammatory disorder in which genetic and environmental factors contribute to disease onset. Evidence implicates the inflammasome pathway in MS pathophysiology. However, the interaction between inflammasome-related genetic variants and 25-OH-vitamin D₃ (25(OH)D₃) levels remains unclear. 105 MS patients and 109 healthy controls were enrolled. Genotyping of NLRP3 (rs10754558, rs3806265) and NLRC4 (rs479333) polymorphisms was performed using real-time PCR. Serum 25(OH)D₃ levels were measured by high-performance liquid chromatography. Clinical severity was assessed using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS), annualized relapse rate (ARR), and age at onset. MS patients showed significantly lower serum 25(OH)D₃ levels than controls. Genotype distributions did not differ significantly under an additive model; however, the NLRP3 rs10754558 GG genotype was more frequent in MS patients under a recessive model and was significantly associated with disease status after adjustment for sex. Subjects carrying the GG genotype also had significantly lower serum 25(OH)D₃ levels than CC/CG carriers, independently of sex. No significant associations were observed for NLRP3 rs3806265 or NLRC4 rs479333, and none of the investigated variants was associated with EDSS, MSSS, ARR, or age at onset. The NLRP3 rs10754558 polymorphism may be associated with MS susceptibility and reduced circulating vitamin D levels, suggesting a potential link between inflammasome-related genetic variability and immunometabolic regulation in MS. Full article

(This article belongs to the Section Molecular Immunology)

20 pages, 1187 KB

Open AccessReview

Resolving Sub-Nuclear Architecture from Compartments to Functional Domains

by Margherita Cavallo, Adel Diaf, Gloria Milanesi, Marco Biggiogera and Claudio Casali

Int. J. Mol. Sci. 2026, 27(11), 4680; https://doi.org/10.3390/ijms27114680 (registering DOI) - 22 May 2026

Abstract

The cell nucleus is a highly dynamic and complex organelle that orchestrates fundamental cellular processes through its spatial organization. Far from being merely the repository of genetic information, it acts as a regulatory hub whose architecture profoundly influences transcription, RNA maturation and genome [...] Read more.

The cell nucleus is a highly dynamic and complex organelle that orchestrates fundamental cellular processes through its spatial organization. Far from being merely the repository of genetic information, it acts as a regulatory hub whose architecture profoundly influences transcription, RNA maturation and genome maintenance. Dissecting such a multilayered organization requires approaches that integrate molecular profiling with spatially resolved technologies capable of capturing nuclear architecture in situ. In this Review, we discuss classical and emerging imaging strategies that are transforming our understanding of nuclear organization across scales, from multiplexed and super-resolution light microscopy to barcoding-based spatial methods, live-cell imaging, and ultrastructural electron microscopy. Together, these methods are providing crucial insights into the localization and dynamics of RNAs and genomic regions within distinct compartments revealing how nuclear architecture governs genome function. Full article

(This article belongs to the Special Issue DNA, Chromatin and Genome Structure)

21 pages, 1959 KB

Open AccessArticle

Molecular Evolution of the Archaeal DNA-Dependent RNA Polymerase: Cooperative Changes in Subunit Composition and Specific Domains of Small Subunits

by Elena K. Shematorova and George V. Shpakovski

Int. J. Mol. Sci. 2026, 27(11), 4679; https://doi.org/10.3390/ijms27114679 - 22 May 2026

Abstract

The subunit composition and tertiary structure of DNA-dependent RNA polymerases in archaea, bacteria, and eukaryotes are currently well understood. The single RNA polymerase of archaea resembles the nuclear RNA polymerase II of eukaryotes in its composition and consists of 10–12 subunits. Perhaps the [...] Read more.

The subunit composition and tertiary structure of DNA-dependent RNA polymerases in archaea, bacteria, and eukaryotes are currently well understood. The single RNA polymerase of archaea resembles the nuclear RNA polymerase II of eukaryotes in its composition and consists of 10–12 subunits. Perhaps the only exception that seems to confirm this rule is the Rpo8 subunit (homologue of the eukaryotic Rpb8), which only some classes of archaea have. The development of metagenomic sequencing has led to a significant revision of the classification system of prokaryotes, in particular to the identification of a number of new Archaea evolutionary lineages. This makes it possible to analyze the subunit composition and structure of RNA polymerase of all currently isolated archaeal phyla. Our analysis shows that the Rpo8 subunit is present only in the RNA polymerase of Archaea species from the Thermoproteota of the Thermoproteati superphylum and from the whole superphylum Promethearchaeati, formerly known as the Asgard. After analyzing the changes in the small Rpo6 subunit (homologue of eukaryotic Rpb6), functionally interacting with Rpo8, we noticed that the largest number of changes in the primary and domain structures of this small subunit occurred in archaeal phyla that lack Rpo8. Shortened forms of Rpo6 without N- or C-terminal regions were observed only in representatives of archaea with an RNA polymerase that does not contain the Rpo8 subunit. Our analysis shows that the changes in Rpo6 are an adaptation of a multisubunit transcription complex to the disappearance of Rpo8. Most likely, the Rpo8 subunit was present in the RNA polymerase of the Last Common Ancestor of Archaea (LCAA) and, in the course of evolution, disappeared in the superphyla Euryarchaeota and Nanobdellati and two divisions of the Thermoproteati superphylum: Bathyarchaeota and Thaumarchaeota. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Archaea)

18 pages, 1192 KB

Open AccessArticle

The Proteomics-Based Stratification of Obese Subjects Allows for a Second Selective Level Beyond Gender Classification

by Raffaello Viganò, Jonica Campolo, Francesca Brambilla, Dario Di Silvestre, Ettore Corradi, Marina Parolini, Cinzia Dellanoce, Patrizia Tarlarini, Paolo Iadarola, Francesco Scaglione and Pierluigi Mauri

Int. J. Mol. Sci. 2026, 27(11), 4678; https://doi.org/10.3390/ijms27114678 - 22 May 2026

Abstract

Obesity is a major global health challenge characterized by chronic low-grade inflammation, oxidative stress, and an increased risk of cardiometabolic disorders. Although sex-related differences in inflammatory and redox biomarkers have been reported in obese populations, the molecular mechanisms underlying this heterogeneity remain incompletely [...] Read more.

Obesity is a major global health challenge characterized by chronic low-grade inflammation, oxidative stress, and an increased risk of cardiometabolic disorders. Although sex-related differences in inflammatory and redox biomarkers have been reported in obese populations, the molecular mechanisms underlying this heterogeneity remain incompletely understood. In this study, we applied a proteomics-based approach to investigate urinary extracellular vesicles from 45 obese individuals (BMI 30–40 kg/m²; age 50–70 years) in order to identify molecular signatures associated with metabolic dysregulation. Shotgun proteomics analysis performed by nanoLC–MS/MS enabled the identification of 3822 proteins. Hierarchical clustering of proteomic profiles revealed two distinct molecular groups, predominantly enriched in males (Group I) and females (Group II). Label-free quantitative analysis identified 466 differentially abundant proteins between the two clusters. Functional enrichment analysis highlighted pathways associated with immune response, metabolic regulation, and redox homeostasis, including glycolysis/gluconeogenesis, lysosome activity, leukocyte transendothelial migration, and glutathione, cysteine and methionine metabolism. Notably, proteins related to ferroptosis were enriched, suggesting the involvement of iron-dependent oxidative cell death mechanisms in the metabolic imbalance observed in a subset of subjects. Furthermore, the non-enzymatic glycosylation of urinary proteins was significantly higher in Group I compared with Group II (p = 0.0002), indicating increased formation of advanced glycation products in individuals with a more pronounced pro-oxidant state. Preliminary follow-up data suggested a higher incidence of pathological events, including cardiovascular complications, among individuals belonging to Group I. Overall, these findings demonstrate that urinary proteomic profiling can identify distinct molecular phenotypes among obese individuals and highlight oxidative stress, ferroptosis, and protein glycation as potential determinants of metabolic vulnerability, supporting the use of non-invasive proteomic approaches for improved risk stratification in obesity. Full article

(This article belongs to the Special Issue Obesity and Obesity-Associated Co-Morbidities: From Mechanisms to Mechanism-Based Therapies)

34 pages, 627 KB

Open AccessReview

Paraneoplastic Endocrine Changes in Gastrointestinal Tumors: A Clinical and Mechanistic Review

by Dragoș Forțofoiu, Victor-Mihai Sacerdoțianu, Robert-Emmanuel Șerban, Petrică Popa, Ioana-Gabriela Dragne, Ion Rogoveanu, Mihail Virgil Boldeanu, Dragoș-Marian Popescu and Cristin-Constantin Vere

Int. J. Mol. Sci. 2026, 27(11), 4677; https://doi.org/10.3390/ijms27114677 - 22 May 2026

Abstract

Paraneoplastic endocrine syndromes (PESs) are hormonal disturbances associated with malignancies that result from tumor-related production of hormone-like substances, immune-mediated mechanisms, or dysregulated signaling pathways. While they are well recognized in lung and neuroendocrine cancers, their relevance in gastrointestinal tumors remains less clearly defined. [...] Read more.

Paraneoplastic endocrine syndromes (PESs) are hormonal disturbances associated with malignancies that result from tumor-related production of hormone-like substances, immune-mediated mechanisms, or dysregulated signaling pathways. While they are well recognized in lung and neuroendocrine cancers, their relevance in gastrointestinal tumors remains less clearly defined. This narrative review synthesizes current knowledge on paraneoplastic endocrine manifestations in gastrointestinal malignancies, based on a structured search of the literature in major databases, including PubMed, Scopus, and Web of Science. The analysis focuses on clinically relevant syndromes such as hypercalcemia, Cushing-like manifestations, disorders of water balance, hypoglycemia, and acromegaly, with emphasis on underlying mechanisms, associated tumor types, diagnostic approaches, and therapeutic considerations. Available evidence indicates that gastrointestinal tumors can produce a range of biologically active substances, leading to diverse endocrine manifestations that may precede tumor detection and influence disease course. Among these, hypercalcemia and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) are among the most frequently reported, while other syndromes, such as ectopic Cushing syndrome or tumor-related hypoglycemia, are less common but often associated with more severe clinical outcomes. Recognition of these manifestations has direct clinical implications, as they may support earlier diagnosis, contribute to prognostic assessment, and guide therapeutic management. Improved awareness and a multidisciplinary approach remain essential for optimizing outcomes in patients with gastrointestinal malignancies. Full article

(This article belongs to the Special Issue Recent Advances in Gastrointestinal Cancer, 3rd Edition)

32 pages, 4751 KB

Open AccessPerspective

In Vivo Fate of Diatom-Based Nanocarriers: Advances, Challenges, and Future Perspectives

by Kshipra Naik, Luca De Stefano and Ilaria Rea

Int. J. Mol. Sci. 2026, 27(11), 4676; https://doi.org/10.3390/ijms27114676 (registering DOI) - 22 May 2026

Abstract

Diatom nanotechnology offers significant potential for the development of innovative diatom-based nanocarriers for drug delivery and bioimaging, with promising implications for the treatment and diagnosis of diverse diseases. However, clinical translation of these nanocarriers remains limited due to an incomplete understanding of their [...] Read more.

Diatom nanotechnology offers significant potential for the development of innovative diatom-based nanocarriers for drug delivery and bioimaging, with promising implications for the treatment and diagnosis of diverse diseases. However, clinical translation of these nanocarriers remains limited due to an incomplete understanding of their in vivo fate. Current studies on the biodistribution, intracellular behavior, biodegradation, and clearance of diatom-based nanocarriers are inadequate and often lack systematic evaluation, leaving critical knowledge gaps. A comprehensive understanding of how these nanocarriers traverse biological barriers, interact with cellular components, and are ultimately eliminated from the body is essential for their rational design and safe clinical implementation. This perspective critically examines the in vivo fate of diatom-based nanocarriers, highlighting recent advances while identifying key challenges and unresolved questions. By integrating insights into their biodistribution, intracellular interactions, toxicological profile, biodegradation, and clearance mechanisms, this article provides a framework to guide the development of more effective and clinically relevant diatom-based nanoplatforms. Furthermore, it outlines future research directions and design strategies for next-generation nanoformulations, aiming to accelerate their translation from bench to the bedside. Full article

(This article belongs to the Special Issue Molecular Advancements in Functional Materials)

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21 pages, 2169 KB

Open AccessReview

Chloroplasts and Plant Sustainability: Key Roles and Emerging Insights

by Nunzia Scotti and Rachele Tamburino

Int. J. Mol. Sci. 2026, 27(11), 4675; https://doi.org/10.3390/ijms27114675 - 22 May 2026

Abstract

Chloroplasts are the primary sites of photosynthesis, but growing evidence highlights their broader role as central hubs that coordinate plant responses to environmental challenges. They retain a semi-autonomous genetic system and communicate extensively with the nucleus through anterograde and retrograde signalling pathways, enabling [...] Read more.

Chloroplasts are the primary sites of photosynthesis, but growing evidence highlights their broader role as central hubs that coordinate plant responses to environmental challenges. They retain a semi-autonomous genetic system and communicate extensively with the nucleus through anterograde and retrograde signalling pathways, enabling coordinated cellular regulation. Beyond energy conversion, chloroplasts host key biosynthetic pathways and dynamically adjust their metabolic and redox states in response to developmental and environmental cues. This review summarizes the current knowledge of chloroplast functions in response to abiotic and biotic stresses, emphasizing their contribution to plant resilience, productivity and sustainability. Under abiotic stress, chloroplasts undergo structural, metabolic and redox reprogramming to maintain photosynthetic efficiency and metabolic homeostasis. During biotic stress, they act as a powerful signalling platform that integrates immune responses with metabolic and redox regulation. These functions rely on overlapping signalling pathways that are differentially tuned to support acclimation or defence. By coordinating stress responses with photosynthetic activity and metabolic efficiency, chloroplasts play a central role in sustaining plant productivity and represent promising targets for enhancing crop resilience and agricultural sustainability under climate change and increasing pathogen pressure. Full article

(This article belongs to the Special Issue Plant Chloroplasts and Mitochondria: Key Organelles for Sustainable Agriculture)

33 pages, 937 KB

Open AccessReview

Transcriptomic Meta-Analysis as a Framework for Robust Cross-Study Biological Inference

by Cinthia Alejandra Olivas-Bernal, Francisco Vargas-Albores, Estefanía Garibay-Valdez, Francesco Cicala and Marcel Martínez-Porchas

Int. J. Mol. Sci. 2026, 27(11), 4674; https://doi.org/10.3390/ijms27114674 - 22 May 2026

Abstract

The increasing availability of transcriptomic data has created new opportunities for integrating gene expression studies across biological systems and conditions. However, differences in experimental design, sequencing platforms, and sample composition introduce substantial heterogeneity, limiting direct comparability between studies. Transcriptomic meta-analysis provides a framework [...] Read more.

The increasing availability of transcriptomic data has created new opportunities for integrating gene expression studies across biological systems and conditions. However, differences in experimental design, sequencing platforms, and sample composition introduce substantial heterogeneity, limiting direct comparability between studies. Transcriptomic meta-analysis provides a framework to address these challenges by identifying expression patterns that are reproducible across independent datasets. In this review, we outline the key methodological steps involved in transcriptomic meta-analysis, including dataset selection, preprocessing, normalization, batch-effect correction, and statistical integration. We discuss how these steps are influenced by the type of data being analyzed, from microarrays and bulk RNA sequencing to single-cell and spatial transcriptomics. Particular attention is given to the role of technical and biological heterogeneity, which must be explicitly considered to avoid misleading conclusions. Rather than treating heterogeneity solely as a source of noise, we argue that it defines the limits of reproducibility and interpretation in cross-study analyses. By focusing on consistent signals across diverse datasets, transcriptomic meta-analysis enables more robust biological inference and supports applications such as biomarker discovery and disease stratification. Full article

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

23 pages, 1098 KB

Open AccessReview

HER2-Low Gastric and Gastroesophageal Junction Adenocarcinoma: From Assessment to Treatment Strategies

by Alexandra Georgiana Scurtu, Daniela Tatiana Sala, Ioan Jung, Tivadar Bara, Radu Mircea Neagoe, Zsolt Zoltán Fülöp and Simona Gurzu

Int. J. Mol. Sci. 2026, 27(11), 4673; https://doi.org/10.3390/ijms27114673 - 22 May 2026

Abstract

Human epidermal growth factor receptor 2 (HER2) dysregulation contributes to tumorigenesis in gastric and gastroesophageal junction adenocarcinomas (GC/GEJ). HER2 overexpression has been associated in multiple cohorts with aggressive behavior and poor outcomes. While HER2 amplification has long guided therapy in HER2-positive disease, antibody–drug [...] Read more.

Human epidermal growth factor receptor 2 (HER2) dysregulation contributes to tumorigenesis in gastric and gastroesophageal junction adenocarcinomas (GC/GEJ). HER2 overexpression has been associated in multiple cohorts with aggressive behavior and poor outcomes. While HER2 amplification has long guided therapy in HER2-positive disease, antibody–drug conjugates (ADCs) have shifted attention toward the HER2-low category, typically defined as immunohistochemistry (IHC) 1+ or IHC 2+ with negative in situ hybridization (ISH). This narrative review integrates evidence from the peer-reviewed literature, current testing recommendations, and registered clinical trials. It clarifies practical issues in HER2-low assessment and maps the evolving therapeutic landscape of HER2-targeted ADCs including rational combination strategies that may extend benefit beyond conventionally HER2-positive tumors. A cross-tumor perspective contrasts GC/GEJ testing and biology with the breast cancer paradigm and summarizes the importance of HER2-low expression in non-gastric malignancies. Finally, we discuss the therapeutic strategies in HER2-low GC/GEJ and highlight key safety and monitoring considerations for HER2-directed ADCs. Full article

(This article belongs to the Special Issue Advances in Molecular Genetics and Molecular Therapy for Gastric Cancers)

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18 pages, 1826 KB

Open AccessArticle

Comparative Biocontrol Efficacy and Mechanisms of Indirect and Direct Application Methods Against Leaf Spot Caused by Pseudomonas syringae pv. aptata in Sugar Beet

by Tamara Krstić Tomić, Marija Nedeljković, Aleksandra Mesaroš, Jovana Todorović, Marijana Pešaković, Slaviša Stanković and Jelena Lozo

Int. J. Mol. Sci. 2026, 27(11), 4672; https://doi.org/10.3390/ijms27114672 - 22 May 2026

Abstract

Using beneficial bacteria from the plant microbiome to combat pathogens is an environmentally friendly strategy for biological control. Although significant progress has been made in characterizing microorganisms with biocontrol potential, the optimal methods for applying such biological preparations to achieve maximum effectiveness against [...] Read more.

Using beneficial bacteria from the plant microbiome to combat pathogens is an environmentally friendly strategy for biological control. Although significant progress has been made in characterizing microorganisms with biocontrol potential, the optimal methods for applying such biological preparations to achieve maximum effectiveness against plant pathogens remain insufficiently defined. Our goal was to select rhizobacteria from the sugar beet microbiome and analyze their biocontrol capacity in both indirect and direct applications to protect the plant from Pseudomonas syringae pv. aptata P21. The methodological approach differed: indirect application involved seed priming with selected strains, Bacillus safensis MRh275, B. pseudomycoides JRh226, Stenotrophomonas maltophilia JRh266, or the T2 consortium (MRh275 and JRh266), while direct application involved simultaneous treatment of both the pathogen and the biocontrol strain. Although the direct approach resulted in a greater reduction in lesions and a lower concentration of H₂O₂, the indirect approach showed higher activity of peroxidase and superoxide dismutase as antioxidant enzymes, as well as phenylalanine ammonia-lyase, which is involved in the phenylpropanoid pathway and plant defense mechanisms. Infected plants showed higher expression of NPR1, MYC2, and LOX defense-related genes only under indirect biocontrol with all three strains, except in the T2 application. The T2 consortium performed best in direct biocontrol, where it most effectively reduced lesions. Since encounters between plants and pathogens cannot be accurately predicted, and the application of biological preparations should be easy and accessible for farmers, this study highlights the use of indirect biocontrol through seed priming to enhance the plant’s intrinsic defense capacity. Full article

(This article belongs to the Special Issue Molecular Insights into Rhizospheric Microbial Interactions)

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36 pages, 756 KB

Open AccessReview

The Role of Vitamin D in Neuropathic Pain: Biological Mechanisms and Clinical Relevance

by Mario García-Domínguez

Int. J. Mol. Sci. 2026, 27(11), 4671; https://doi.org/10.3390/ijms27114671 - 22 May 2026

Abstract

Neuropathic pain remains a major clinical challenge due to its complex pathophysiology and limited treatment efficacy. Recent evidence suggests that vitamin D, beyond its classical role in bone and mineral metabolism, exerts neuroprotective and immunomodulatory effects that may influence pain perception. This review [...] Read more.

Neuropathic pain remains a major clinical challenge due to its complex pathophysiology and limited treatment efficacy. Recent evidence suggests that vitamin D, beyond its classical role in bone and mineral metabolism, exerts neuroprotective and immunomodulatory effects that may influence pain perception. This review synthesizes current findings on the relationship between vitamin D status and neuropathic pain, highlighting potential mechanisms such as modulation of neuroinflammation, regulation of neuronal excitability, and influence on neurotransmitter pathways. Observational studies frequently report an association between vitamin D deficiency and increased pain severity, while interventional trials indicate that supplementation may alleviate neuropathic symptoms in specific populations. However, results remain heterogeneous, and mechanistic studies are still emerging. Understanding the interplay between vitamin D and neuropathic pain could open new avenues for adjunctive therapeutic strategies and personalized medicine approaches. Further high-quality clinical trials and mechanistic research are warranted to clarify causality and optimize clinical applications. Full article

(This article belongs to the Special Issue Natural Product-Based Therapeutics: Molecular Mechanisms and Cellular Modulation)

18 pages, 1528 KB

Open AccessArticle

Identification of Mango Cross-Reactive Allergens and Cross-Reactive Linear Epitopes Using Serum from Patients with Mango Allergy

by Wenxuan Zhao, Honglei Guo and Yanjun Cong

Int. J. Mol. Sci. 2026, 27(11), 4670; https://doi.org/10.3390/ijms27114670 - 22 May 2026

Abstract

Although mango is not classified among the nine major allergenic foods reported by the Food and Drug Administration (FDA), the increasing global and domestic consumption of mango has been accompanied by a growing number of reported cases of mango allergy. Currently, reports on [...] Read more.

Although mango is not classified among the nine major allergenic foods reported by the Food and Drug Administration (FDA), the increasing global and domestic consumption of mango has been accompanied by a growing number of reported cases of mango allergy. Currently, reports on cross-reactive allergens and cross-reactive linear epitopes in mango are limited. This study employed BLASTp (version 2.11.0+) to predict potential allergens that may cross-react with mango protein allergens and other food protein allergens. Subsequently, cross-reactive allergens were identified using sera from mango-allergic patients. Furthermore, similar sequences of the identified cross-reactive allergens were predicted by BLAST. These similar sequences were then synthesized by the solid-phase peptide synthesis method. Finally, the cross-reactive linear epitopes were determined by assessing their IgE-binding capacity using serum IgE from the same patient cohort. The results demonstrated that the sera from mango-allergic patients exhibited IgE-binding cross-reactivity with those from peanut, wheat, cashew, pistachio, and hazelnut, particularly with IgE-binding cross-reactivity to wheat and hazelnut, which has not been previously reported. The following novel cross-reactive linear epitopes were identified: the AA80–88 sequence of mango chitinase with the AA37–45 sequence of wheat Tri a 27 and the AA15–22 sequence of mango profilin with the AA65–72 sequence of pistachio Pis v 1. Furthermore, multiple cross-reactive epitopes were mapped between mango profilin and peanut Ara h 5, corresponding to the sequences AA31–51/AA31–50, AA50–65/AA52–65, AA76–96/AA76–96, and AA103–117/AA104–117, respectively. Full article

(This article belongs to the Special Issue Molecular Understanding of Allergen Exposome)

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37 pages, 8260 KB

Open AccessReview

Primary Blast-Induced Traumatic Brain Injury as a Risk Factor for (Cerebro)vascular Disorder: Clinical Manifestations, Blast Physics, Biomechanics, Pathobiology, and Critical Gaps

by Denes V. Agoston and James S. Meabon

Int. J. Mol. Sci. 2026, 27(11), 4669; https://doi.org/10.3390/ijms27114669 - 22 May 2026

Abstract

Exposure to blast waves without kinetic, penetrating, thermal, or toxic components causes a distinct form of traumatic brain injury, termed primary blast-induced TBI (pbTBI). Clinical manifestations of pbTBI span a wide spectrum, ranging from life-threatening intracranial hemorrhage, hyperemia, and delayed cerebral edema to [...] Read more.

Exposure to blast waves without kinetic, penetrating, thermal, or toxic components causes a distinct form of traumatic brain injury, termed primary blast-induced TBI (pbTBI). Clinical manifestations of pbTBI span a wide spectrum, ranging from life-threatening intracranial hemorrhage, hyperemia, and delayed cerebral edema to mild and transient neurological symptoms without detectable structural abnormalities on routine imaging. At the mild end of the spectrum, symptoms after a single exposure may resolve quickly, yet repeated exposures—even at very low levels, termed “subconcussive”—can develop into post-concussive syndrome (PCS) or persistent post-concussive symptoms (PPCS) in a subset of individuals. Despite extensive studies, the molecular pathobiology linking primary blast exposure to delayed and sometimes chronic neurobehavioral deficits remains incompletely understood. A mechanistic framework connecting blast-wave physics to biomechanics to biological vulnerability may therefore help define exposure hazards, interpret clinical symptomatology, and guide diagnostic and therapeutic development. This review summarizes the physics of primary blast waves, the resulting biomechanical responses, and candidate biological substrates, emphasizing structures and interfaces with distinct acoustic impedances across anatomical, tissue, cellular, and molecular scales. We synthesize evidence supporting the hypothesis that the cerebral vasculature and endothelial cells represent critically vulnerable substrates of primary blast-wave injury, in part because the vascular tree constitutes the brain’s largest and most widely distributed interface between compartments with different acoustic impedances. Across experimental and human studies, endothelial stress, vascular injury, and downstream neuroinflammation emerge as convergent molecular responses to primary blast exposure. Temporal dynamics are central to understanding pbTBI because many blast-induced processes unfold in sequential phases. These observations support conceptualizing pbTBI as a condition characterized by prominent cerebrovascular injury of varying severity with secondary consequences for neuronal signaling, network function, and behavior. Within this framework, cerebrovascular and neurovascular unit (NVU) dysfunction provides a parsimonious bridge between primary blast-wave exposure and chronic symptom trajectories, where vascular pathology may offer more accessible therapeutic targets than neuronal injury. Key knowledge gaps include identifying which physical component(s) of the blast are most injurious, establishing biologically meaningful dose–response relationships at molecular and physiological levels, and defining windows of vulnerability during recovery that are relevant to repeated exposures. Addressing these gaps is essential for refining safety protocols, improving diagnostic specificity through mechanism-informed biomarkers, and developing evidence-based molecular and vascular therapeutic targets for pbTBI-associated conditions. Progress will require integrating waveform-aware dosimetry with longitudinal physiological and molecular monitoring across both preclinical and human cohorts. Such integration offers a practical path toward translating blast physics into actionable medical guidance for prevention, triage, and recovery management. Full article

(This article belongs to the Special Issue Emerging Insights into the Pathobiology and Biomarkers of Traumatic Brain Injury (TBI))

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21 pages, 21662 KB

Open AccessArticle

Exploring the Toxicological Relationship Between Diisononyl Cyclohexane-1,2-dicarboxylate and Atherosclerosis Through Network Toxicology, Machine Learning, and Multi-Dimensional Bioinformatics

by Jingbo Cao, Ziyao Yang, Qi Zhang, Siwei Zou, Huning Zhang, Anning Yang and Yue Sun

Int. J. Mol. Sci. 2026, 27(11), 4668; https://doi.org/10.3390/ijms27114668 - 22 May 2026

Abstract

This study integrates multidimensional computational approaches—network toxicology, machine learning, molecular docking, and molecular dynamics simulation—to systematically elucidate the toxic mechanism by which the environmental pollutant diisononyl cyclohexane-1,2-dicarboxylate (DINCH) contributes to atherosclerosis. By jointly mining multiple databases, we obtained 246 targets common to DINCH [...] Read more.

This study integrates multidimensional computational approaches—network toxicology, machine learning, molecular docking, and molecular dynamics simulation—to systematically elucidate the toxic mechanism by which the environmental pollutant diisononyl cyclohexane-1,2-dicarboxylate (DINCH) contributes to atherosclerosis. By jointly mining multiple databases, we obtained 246 targets common to DINCH and atherosclerosis. LASSO regression and support vector machine–recursive feature elimination (SVM-RFE) then identified 8 significantly upregulated core targets (CSF1R, CD36, CCL3, CCR2, ADAM8, TLR1, CTSS, and MMP1). Functional enrichment analysis showed that these core targets were significantly associated with key signaling pathways, including lipid and atherosclerosis, the PPAR signaling pathway, the PI3K–Akt signaling pathway, and the AGE–RAGE signaling pathway in diabetic complications. Differential gene analysis confirmed that these genes were significantly upregulated in diseased tissues, and receiver operating characteristic (ROC) analysis demonstrated excellent diagnostic performance (AUC = 0.87–0.96). Immune cell infiltration analysis further revealed a strong association between the core targets and immune cell populations, notably macrophages and T cells. Molecular docking and molecular dynamics simulations showed that DINCH had high affinity for the core targets, and its binding to CCR2 was the most stable (binding free energy = −7.6 kcal/mol). The final AOP framework systematically presented the cascade by which DINCH may contribute to atherosclerosis through metabolic disruption and immune activation. This study provides new mechanistic insights into the development of DINCH-induced atherosclerosis and offers a theoretical basis for health risk assessment of environmental pollutants. Full article

(This article belongs to the Section Molecular Informatics)

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24 pages, 1776 KB

Open AccessReview

Developmental Programming of Drug Response: Microbiota as a Missing Dimension in Perinatal Drug Discovery

by Yanan Zhang, Liangkun Ma and Yan Wang

Int. J. Mol. Sci. 2026, 27(11), 4667; https://doi.org/10.3390/ijms27114667 - 22 May 2026

Abstract

Drug exposure during pregnancy and early life is typically considered a short-term clinical intervention rather than a determinant of long-term pharmacological outcomes. Consequently, the developmental context is largely absent from drug discovery and drug development paradigms, where efficacy, safety and target engagement are [...] Read more.

Drug exposure during pregnancy and early life is typically considered a short-term clinical intervention rather than a determinant of long-term pharmacological outcomes. Consequently, the developmental context is largely absent from drug discovery and drug development paradigms, where efficacy, safety and target engagement are evaluated predominantly in adult, steady-state systems. This disconnect may contribute to unexplained variability in drug response and toxicity later in life. Pregnancy is accompanied by dynamic remodeling of the maternal gut microbiota and its metabolic output, generating bioactive microbial metabolites that regulate immune tone, metabolic homeostasis and the expression of drug-metabolizing enzymes and transporters. These microbial signals intersect with pharmacological interventions across gestation, shaping maternal pharmacokinetics, placental regulation and fetal drug exposure during developmentally sensitive windows. Importantly, microbiota–drug interactions initiated during pregnancy do not terminate at birth. Instead, they extend into infancy through vertical microbial transmission, breast milk-mediated metabolic signaling, and the immaturity of neonatal drug-handling systems, collectively contributing to developmental programming of drug responsiveness beyond early life. In this review, we propose a microbiota-informed framework that reframes perinatal drug exposure as a developmentally embedded signal operating across a maternal–placental–infant continuum. This perspective introduces a missing developmental dimension into drug discovery and highlights new opportunities to improve translational predictability and precision pharmacotherapy across the life course. Full article

(This article belongs to the Section Molecular Microbiology)

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25 pages, 451 KB

Open AccessReview

Extracellular Vesicles in Endometriosis: A Comprehensive Review of Biological Insights and Methodological Challenges

by Aleksander Chodowiec, Magdalena Dec, Krzysztof Łuszczyński, Robert Zdanowski, Monika Szafarowska, Ludmiła Szewczak, Agnieszka Synowiec, Paweł Mitkowski, Paweł K. Włodarski, Anna Lutyńska and Aneta Ścieżyńska

Int. J. Mol. Sci. 2026, 27(11), 4666; https://doi.org/10.3390/ijms27114666 - 22 May 2026

Abstract

Endometriosis is a complex disorder associated with dysregulated immune, hormonal, and microenvironmental signaling. Extracellular vesicles (EVs) are important mediators of intercellular communication and may contribute to disease pathogenesis, biomarker discovery, and therapeutic targeting. Here, we systematically reviewed the literature on EVs in endometriosis, [...] Read more.

Endometriosis is a complex disorder associated with dysregulated immune, hormonal, and microenvironmental signaling. Extracellular vesicles (EVs) are important mediators of intercellular communication and may contribute to disease pathogenesis, biomarker discovery, and therapeutic targeting. Here, we systematically reviewed the literature on EVs in endometriosis, focusing on EV classification, isolation and characterization methods, and the functional relevance of EV-associated cargo. A total of 50 original studies were included and evaluated in the context of current International Society for Extracellular Vesicles (ISEV) recommendations. Our analysis revealed marked heterogeneity in EV nomenclature, biological sources, and methodological approaches. Although most studies used standard EV markers, the assessment of sample purity and inclusion of negative controls was inconsistent. Further studies using standardized workflows and well-characterized cohorts are needed to clarify their biological and clinical significance. Full article

(This article belongs to the Special Issue Recent Progress in Extracellular Vesicles)

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17 pages, 3014 KB

Open AccessArticle

Development and Applications of a 1K SNP Panel for Whiteleg Shrimp: From Pedigree Reconstruction to Genomic Selection

by Qiang Fu, Guangfeng Qiang, Ping Wang, Mianyu Liu, Kun Luo, Baolong Chen, Xianhong Meng, Xiang Zou, Ping Dai, Junyu Liu, Shiwei Zhang, Jie Kong and Sheng Luan

Int. J. Mol. Sci. 2026, 27(11), 4665; https://doi.org/10.3390/ijms27114665 - 22 May 2026

Abstract

Litopenaeus vannamei, the most widely farmed crustacean, relies on family-based selection where accurate pedigree information is essential. Although SNP-based tools offer high-accuracy pedigree assignment, adoption in commercial breeding remains limited. In this study, we developed a commercially viable 1K SNP panel with [...] Read more.

Litopenaeus vannamei, the most widely farmed crustacean, relies on family-based selection where accurate pedigree information is essential. Although SNP-based tools offer high-accuracy pedigree assignment, adoption in commercial breeding remains limited. In this study, we developed a commercially viable 1K SNP panel with 1125 markers. Markers were selected from a 55K SNP dataset comprising 2330 individuals. We established a practical pedigree reconstruction workflow and implemented the panel in a field breeding population. The population included a selection group where families were reared separately and a test group where individuals were communally reared. We introduced anchor individuals from the selection group to enable pedigree linkage. All 1818 individuals from 72 families were accurately assigned. Family reconstruction achieved 100% consistency with known records, even when parents were partially missing. Heritability estimates for harvest weight ranged from 0.32 to 0.36 using pedigree-based BLUP (PBLUP), genomic BLUP (GBLUP), and single-step genomic BLUP (ssGBLUP). The ssGBLUP model, using a 0.15 to 0.85 weighting of G and A, achieved 6.67% and 19.40% higher accuracy than PBLUP and GBLUP. The panel also supported population structure analysis and diversity monitoring, demonstrating its value for genomic evaluation in commercial L. vannamei breeding. Full article

(This article belongs to the Special Issue Molecular Biology and the Genetic Breeding of Aquatic Animals: Breakthroughs and Challenges (2nd Edition))

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4 pages, 291 KB

Open AccessCorrection

Correction: Agbemade et al. Synthesis and Evaluation of Powerful Antioxidant Dendrimers Derived from D-Mannitol and Syringaldehyde. Int. J. Mol. Sci. 2025, 26, 10966

by Blessed Agbemade, Amanda R. Clark, Cyprien N. Nanah, Fati Haruna, Aundrea E. Stengard, Skylar A. Medes, Ashlyn M. Lapratt, Samara L. Morehouse, Rebecca L. Uzarski and Choon Young Lee

Int. J. Mol. Sci. 2026, 27(11), 4664; https://doi.org/10.3390/ijms27114664 - 22 May 2026

Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Special Issue Antioxidants: Design, Synthesis, and Mechanism of Actions)

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21 pages, 1368 KB

Open AccessReview

Enhancement of Therapeutic mRNA Translation in Cellular Stress Conditions

by Edyta Trepkowska-Mejer

Int. J. Mol. Sci. 2026, 27(11), 4663; https://doi.org/10.3390/ijms27114663 - 22 May 2026

Abstract

This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of [...] Read more.

This review summarizes mechanisms regulating mRNA translation under cellular stress and highlights design strategies to improve translation efficiency and stability in the gene therapy of human diseases. mRNA-based therapeutics are emerging as a versatile gene therapy platform enabling transient and controllable expression of therapeutic proteins for the treatment of cancer, genetic disorders, and inflammatory diseases. The efficacy of mRNA-based gene therapy is strongly influenced by sequence design, chemical modifications, and structural features. Evidence shows that rational mRNA engineering can significantly enhance translation efficiency even under stress conditions that impair canonical protein synthesis, as observed in many pathological states. Cellular stress activates regulatory pathways that suppress global translation; however, optimized mRNA constructs can partially bypass these inhibitory mechanisms, enabling sustained protein expression. By improving mRNA stability and resistance to stress-responsive translational control, robust therapeutic protein production can be achieved even in challenging cellular environments. This article was prepared as a narrative review focused on translational regulation mechanisms relevant to therapeutic mRNA design under cellular stress conditions. Literature was collected from PubMed, Google Scholar, and Web of Science using keywords including “mRNA therapeutics,” “cellular stress,” “translation regulation,” “UTR engineering,” and “cap-independent translation.” Studies published mainly between 2010 and 2025 were considered. Original articles and reviews related to stress-responsive translation and therapeutic mRNA optimization were included, while studies outside the scope of translational control and mRNA engineering were excluded. Priority was given to recent and mechanistically relevant publications. Full article

(This article belongs to the Topic Advances in Gene Therapy of Human Diseases)

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22 pages, 1920 KB

Open AccessReview

O-GlcNAcylation as a Metabolic Integrator in Cardiovascular Physiology and Disease

by Saima Shakil Malik, Xinchun Pi and Liang Xie

Int. J. Mol. Sci. 2026, 27(11), 4662; https://doi.org/10.3390/ijms27114662 - 22 May 2026

Abstract

O-GlcNAcylation is a ubiquitous post-translational modification regulated by O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) in response to environmental and genetic alterations. It occurs in the nucleus, mitochondrion, and cytoplasm and is implicated in cardiovascular disease (CVD) development. O-GlcNAcylation modulates [...] Read more.

O-GlcNAcylation is a ubiquitous post-translational modification regulated by O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) in response to environmental and genetic alterations. It occurs in the nucleus, mitochondrion, and cytoplasm and is implicated in cardiovascular disease (CVD) development. O-GlcNAcylation modulates diverse cellular processes, including metabolic pathways, signaling networks, and transcriptional programs. Acute increase in O-GlcNAcylation serves as an adaptive response that preserves cardiac function, whereas chronic elevation leads to persistent metabolic dysregulation and promotes pathological cardiac remodeling. In this review, we provide a comprehensive overview of the role of O-GlcNAcylation across diverse disease contexts. We also summarize the current understanding of its complex interplay with CVD, including the underlying mechanisms. Finally, we highlight existing knowledge gaps and discuss the therapeutic potential of targeting O-GlcNAcylation in various cardiovascular events, emphasizing key priorities for future research. Full article

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

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34 pages, 3617 KB

Open AccessReview

From Toxin to Therapy: Biomedical Applications of Bee Venom in Cancer, Diabetes, and Neurodegenerative Disorders

by Kassyane de Amorim Lourenço, Mariana Valenhes dos Santos, Adriano C. Araujo, Elen L. Guiguer, Rui Curi, Márcia Gabaldi Rocha, Everton Salgado Monteiro, José Luiz Yanaguizawa Junior, Tânia Pithon-Curi, Karina Quesada, Luiz Carlos de Abreu, Camila de Oliveira Marcondes, Sandra Maria Barbalho, Vitor E. Valenti and Maria Angélica Miglino

Int. J. Mol. Sci. 2026, 27(11), 4661; https://doi.org/10.3390/ijms27114661 - 22 May 2026

Abstract

Apitherapy is a complementary therapeutic approach based on the use of bee-derived products, particularly bee venom (BV), also known as apitoxin. Bee venom is a complex mixture of biologically active compounds, including peptides, enzymes, and biogenic amines, that exhibit diverse pharmacological activities. Major [...] Read more.

Apitherapy is a complementary therapeutic approach based on the use of bee-derived products, particularly bee venom (BV), also known as apitoxin. Bee venom is a complex mixture of biologically active compounds, including peptides, enzymes, and biogenic amines, that exhibit diverse pharmacological activities. Major bioactive constituents such as melittin, apamin, adolapin, and phospholipase A2 have attracted increasing scientific interest due to their anti-inflammatory, antioxidant, antimicrobial, analgesic, and immunomodulatory properties. This review provides a comprehensive overview of the biological effects and therapeutic potential of bee venom in the management of chronic diseases, particularly diabetes, cancer, and neurological disorders. Evidence from experimental and clinical studies suggests that BV and its components can modulate multiple molecular pathways associated with oxidative stress, inflammation, apoptosis, and immune responses. These mechanisms contribute to potential benefits in glycemic control, tumor suppression, neuroprotection, and pain management. Additionally, bee venom has been investigated for its capacity to influence signaling pathways involved in cellular proliferation and survival, highlighting its potential as a complementary strategy in the treatment of complex diseases such as neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. Despite these promising therapeutic effects, the clinical use of BV remains limited due to safety concerns, particularly the risk of allergic reactions, systemic toxicity, and anaphylaxis. Recent advances in drug delivery systems and nanotechnology may help improve the safety and efficacy of BV-based therapies by enabling targeted delivery and controlled dosing. Overall, bee venom represents a promising source of bioactive compounds with potential applications in translational and integrative medicine; however, further well-designed clinical trials and mechanistic studies are necessary to establish its safety, efficacy, and long-term therapeutic value. Full article

(This article belongs to the Special Issue Natural Compounds in Cancer Treatment and Prevention: Mechanisms, Evidence, and Clinical Perspectives)

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23 pages, 3943 KB

Open AccessArticle

Pregabalin Depresses Cerebellar Parallel Fiber–Purkinje Cell Synaptic Transmission by Modulating Glun2a-Containing Nmda Receptors in Mice In Vitro

by Mei-Rui Li, Xu-Dong Zhang, Li Chen, Yi-Dan Zhang, Chun-Yan Wang, Zi-Yu Zhao, Mo Zhou, Chun-Ping Chu and De-Lai Qiu

Int. J. Mol. Sci. 2026, 27(11), 4660; https://doi.org/10.3390/ijms27114660 - 22 May 2026

Abstract

Pregabalin (PGB) exerts its therapeutic effects by binding to the α₂δ auxiliary subunits of voltage-gated calcium channels and modulates synaptic transmission in the brain. However, its influence on cerebellar parallel fiber–Purkinje cell (PF–PC) synaptic transmission remains unclear. In the present study, [...] Read more.

Pregabalin (PGB) exerts its therapeutic effects by binding to the α₂δ auxiliary subunits of voltage-gated calcium channels and modulates synaptic transmission in the brain. However, its influence on cerebellar parallel fiber–Purkinje cell (PF–PC) synaptic transmission remains unclear. In the present study, we investigated the effects of PGB on PF–PC synaptic transmission using whole-cell patch-clamp recording, glutamate fluorescence imaging, immunohistochemistry, co-immunoprecipitation, Western blotting, and pharmacological approaches. Micro-application of PGB to the cerebellar molecular layer induced a concentration-dependent inhibition of PF–PC excitatory postsynaptic currents (EPSCs), accompanied by an increased paired-pulse ratio. The inhibitory effect of PGB on PF–PC EPSCs was abolished by extracellular blockade of N-methyl-D-aspartate receptors (NMDAR) or their GluN2A subtype, as well as by disruption of α₂δ-1–NMDAR complexes, but not by intracellular NMDAR inhibition. Glutamate sensor imaging further showed that PGB markedly reduced the fluorescence intensity of glutamate release evoked by PF stimulation. In the presence of tetrodotoxin (TTX) and a gamma-aminobutyric acid type A (GABAA) receptor antagonist, PGB reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) without affecting their amplitude. The PGB-induced reduction in mEPSC frequency was fully abolished by extracellular blockade of GluN2A-containing NMDARs or disruption of α₂δ-1–NMDAR complexes. Similarly, the inhibitory effects of PGB on PF–PC EPSCs and mEPSCs were eliminated by extracellular PKA inhibition, but not by intracellular protein kinase A (PKA) inhibition. Western blot analysis showed that PGB significantly increased PKA phosphorylation in the molecular layer of the cerebellar cortex. Immunoreactivity for GluN2A and α₂δ-1 subunits was colocalized within the molecular layer and abundantly distributed around the dendrites and somata of PCs. Co-immunoprecipitation further verified that α₂δ-1 was co-precipitated with GluN1 in cerebellar molecular layer tissue samples. The results indicate that PGB depresses glutamate release from parallel-fiber terminals in the mouse cerebellar cortex through the presynaptic α₂δ-1-coupled GluN2A-containing NMDAR/PKA signaling pathway, thereby attenuating PF–PC synaptic transmission. Full article

(This article belongs to the Special Issue Ion Channels as Therapeutic Target: Drug Design and Pharmacological Investigation (3rd Edition))

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17 pages, 1606 KB

Open AccessArticle

Unraveling the Role of Zonulin in Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter Study

by Alexandre Soares Ferreira Junior, Nathalia Linares Silva, Danielle Amanda Niz Alvarez, Larissa da Silva Souza, Luiza Dias Machado, Bianca Fernanda Rodrigues da Silva, Welinton Yoshio Hirai, Rozana Mesquita Ciconelli, Joao Victor Piccolo Feliciano, Iago Colturato, George Maurício Navarro Barros, Phillip Scheinberg and Gislane Lelis Vilela de Oliveira

Int. J. Mol. Sci. 2026, 27(11), 4659; https://doi.org/10.3390/ijms27114659 - 22 May 2026

Abstract

The role of zonulin as a biomarker of intestinal permeability in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting remains poorly understood. In this study, we aimed to evaluate serum zonulin dynamics, identify its predictors, and assess its prognostic significance in patients undergoing [...] Read more.

The role of zonulin as a biomarker of intestinal permeability in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting remains poorly understood. In this study, we aimed to evaluate serum zonulin dynamics, identify its predictors, and assess its prognostic significance in patients undergoing allo-HSCT. This multicenter, prospective cohort study was conducted across four Brazilian hospitals. Eligible participants were patients aged ≥12 years who provided at least one blood sample during the allo-HSCT course. A control group of 15 healthy adult individuals was also included. Serum zonulin levels were quantified using enzyme-linked immunosorbent assay multiple times over the allo-HSCT course. Outcomes included acute graft-versus-host disease, overall survival, and bloodstream infections. A total of 477 blood samples were collected from 140 patients. Compared with the control group, zonulin levels were persistently elevated at all evaluated time points throughout the allo-HSCT course. However, no significant differences were observed among the different time points assessed during transplantation. No clinical or transplantation-related characteristics were identified as significant predictors of elevated zonulin levels. Finally, zonulin did not demonstrate prognostic value for allo-HSCT-related outcomes. Future studies should investigate whether other intestinal permeability biomarkers have prognostic relevance in the allo-HSCT setting. Full article

(This article belongs to the Special Issue Mechanistic Studies on Microbiota–Host Interactions)

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Int. J. Mol. Sci., Volume 27, Issue 11 (June-1 2026) – 37 articles

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