International Journal of Molecular Sciences

56 pages, 21806 KB

Open AccessReview

Recent Advances in ZIF-8 Performance for Electrochemical Applications: A Comprehensive Review

by Omirzak Abdirashev, Assem Temirbayeva, Gaukhar Kabdrakhimova, Balzhan Satanova, Aisulu Abuova, Fatima Abuova, Yerbol Ussen, Yerbolat Kalpakov, Marina Konuhova and Anatoli I. Popov

Int. J. Mol. Sci. 2026, 27(17), 7975; https://doi.org/10.3390/ijms27177975 - 7 Sep 2026

Cited by 1 | Viewed by 636

Abstract

Zeolitic imidazolate framework-8 (ZIF-8) has emerged as a material for electrochemical energy conversion, serving dual primary roles in fuel cell technologies: (i) as an electrocatalyst precursor for oxygen reduction reaction (ORR) and methanol oxidation reaction (MOR) through pyrolysis-derived N-doped porous carbons and metal–nitrogen–carbon [...] Read more.

Zeolitic imidazolate framework-8 (ZIF-8) has emerged as a material for electrochemical energy conversion, serving dual primary roles in fuel cell technologies: (i) as an electrocatalyst precursor for oxygen reduction reaction (ORR) and methanol oxidation reaction (MOR) through pyrolysis-derived N-doped porous carbons and metal–nitrogen–carbon (M–N–C) structures, and (ii) as a membrane component that enhances proton conductivity via imidazole-mediated Grotthuss hopping while suppressing fuel crossover through molecular sieving. This comprehensive review systematically evaluates ZIF-8 performance across multiple fuel cell types, including primarily proton exchange membrane fuel cells (PEMFCs), as well as direct methanol fuel cells (DMFCs), anion exchange membrane fuel cells (AEMFCs), and microbial fuel cells (MFCs), while also covering related electrochemical applications such as zinc–air batteries, supercapacitors, and water splitting devices, where ZIF-8-derived materials demonstrate improved catalytic activity. The review examines structure–performance relationships, highlighting strategies such as heteroatom doping, bimetallic synergy, hierarchical porosity engineering, and polymer composite fabrication that have enabled ZIF-8-based catalysts to achieve ORR half-wave potentials and PEMFC power densities, rivaling commercial Pt/C systems. ZIF-8 composite membranes demonstrate proton conductivities in polybenzimidazole systems and effective methanol blocking. Despite improved progress, challenges persist regarding long-term stability, scalable synthesis, and degradation mechanism understanding. This review critically analyzes recent advances, identifies performance-limiting factors across applications, and outlines future research directions for developing commercially viable ZIF-8-based electrochemical technologies. Full article

(This article belongs to the Section Materials Science)

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19 pages, 5152 KB

Open AccessArticle

A Sesquiterpenoid from Schizophyllum commune Protects C17.2 Neural Stem Cells Against Oxidative Stress Through Modulation of GPCR-Associated Signaling Pathways

by Lu Li, Guowei Zou, Qiaona Wang, Haitao Jiang, Xianghua Wu, Junli Zhao, Honglin Zhang, Xiaoping Wang and Shengjie Li

Int. J. Mol. Sci. 2026, 27(17), 7974; https://doi.org/10.3390/ijms27177974 - 7 Sep 2026

Viewed by 314

Abstract

The chemical constituents and neuroprotective potential of Schizophyllum commune remain insufficiently characterized. Therefore, we isolated and identified five secondary metabolites (A–E) from S. commune, and investigated their neuroprotective activities and underlying mechanisms. Compound C showed the most significant [...] Read more.

The chemical constituents and neuroprotective potential of Schizophyllum commune remain insufficiently characterized. Therefore, we isolated and identified five secondary metabolites (A–E) from S. commune, and investigated their neuroprotective activities and underlying mechanisms. Compound C showed the most significant protective effect against H₂O₂-induced cytotoxicity in C17.2 neural stem cells. Spectroscopy was used to structurally characterize the isolated compounds. Using RNA sequencing (RNA-seq), compound C was found to significantly modulate genes associated with G protein-coupled receptor (GPCR)-related signaling pathways and neuroactive ligand–receptor interactions. Differentially expressed genes, including Adora2a, S1pr1, Adm, Tbxa2r, and Grin3b, were validated using quantitative real-time PCR. They are associated with GPCR-related signaling and neurotransmission pathways, consistent with the RNA-seq data. As indicated by the functional enrichment analysis, compound C may regulate neuronal stress responses through GPCR-associated signaling networks. In the Western blot, compound C markedly attenuated H₂O₂-induced protein kinase A (PKA) C phosphorylation without altering total PKA C expression, suggesting that modulation of the cAMP/PKA signaling pathway may contribute to the neuroprotective effects of compound C. Collectively, compound C may exert neuroprotective effects against oxidative stress-induced neuronal injury, potentially through the modulation of GPCR-mediated PKA signaling. S. commune is a promising natural bioactive compound source for further development in neuroprotective research. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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20 pages, 865 KB

Open AccessReview

Integrative Approaches to Atopic Dermatitis: Exploring Biomarkers, Current Therapies, and the Potential Role of Osteopathic Manipulative Medicine

by Stephanie Sawicki, Anjali Dhawan, Dikshya Devkota, Michelle Elway and Anish R. Maskey

Int. J. Mol. Sci. 2026, 27(17), 7973; https://doi.org/10.3390/ijms27177973 - 7 Sep 2026

Viewed by 1138

Abstract

Atopic dermatitis (AD) is a chronic, relapsing, and remitting condition that affects approximately 10% of the population. It is a multifactorial disease involving immune dysregulation, gene mutations, and environmental factors that ultimately disrupt skin barrier restoration, causing pruritic lesions. Given the marked heterogeneity [...] Read more.

Atopic dermatitis (AD) is a chronic, relapsing, and remitting condition that affects approximately 10% of the population. It is a multifactorial disease involving immune dysregulation, gene mutations, and environmental factors that ultimately disrupt skin barrier restoration, causing pruritic lesions. Given the marked heterogeneity of AD and the presence of multiple immune and clinical endotypes, no single therapeutic strategy is likely to be universally effective. Instead, a growing panel of distinct biomarkers offers an avenue for true precision medicine by enabling more accurate endotype classification, prediction of treatment response, and tailored treatments. In this context, ongoing research is increasingly focused on individualized, biomarker-informed strategies, as well as the evaluation of adjunctive approaches that can be integrated with standard therapies to optimize long-term disease control. Given the central role of systemic inflammation and barrier dysfunction in AD, the mechanistic focus of osteopathic manipulative medicine (OMM) on circulation, lymphatic drainage, and autonomic regulation offers another biological treatment to use alongside conventional therapies. This concise review examines the pathogenesis of AD, current treatments and their limitations, and the expanding role of biomarkers in refining diagnosis, prognosis, and therapeutic decision-making. It also explores the potential integration of OMM as a biologically plausible adjunct to support individualized, endotype-aware treatment strategies, while emphasizing the current lack of empirical evidence and the need for rigorous mechanistic and clinical studies. Full article

(This article belongs to the Special Issue Th2-Mediated Inflammation in Dermatology: Mechanistic and Therapeutic Perspectives)

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36 pages, 4726 KB

Open AccessArticle

Functional Nanostructured Carbon Honeycomb Monoliths for Hemoadsorption: Preliminary Studies on Biocompatibility, Protein-Bound Uremic Toxins and Inflammatory Cytokines Elimination

by Jakpar Jandosov, Carol Howell, Susan Sandeman, Dmitriy Chenchik, Sergey Mikhalovsky, Aitugan Sabitov, Joaquin Silvestre-Albero, Zulkhair Mansurov, Seitkhan Azat, Rosa Busquets, Nurzhamal Zhylybayeva, Mikhail Tsukerman and Alzhan Baimenov

Int. J. Mol. Sci. 2026, 27(17), 7972; https://doi.org/10.3390/ijms27177972 - 7 Sep 2026

Viewed by 674

Abstract

Rice husk (RH) is a renewable siliceous lignocellulosic waste providing a unique, greener and less toxic alternative to conventional synthetic polymeric precursors in the production of carbon-based materials for biomedical applications. In this work we studied the porous structure of RH-lignin-based activated carbon [...] Read more.

Rice husk (RH) is a renewable siliceous lignocellulosic waste providing a unique, greener and less toxic alternative to conventional synthetic polymeric precursors in the production of carbon-based materials for biomedical applications. In this work we studied the porous structure of RH-lignin-based activated carbon produced in the form of honeycomb carbon monoliths and assessed their potential as hemoadsorbents for blood purification in the treatment of patients with serious medical conditions, such as kidney failure and sepsis. To determine their clinical suitability for such an application, the hemocompatibility and cytotoxicity of the monoliths were investigated using the standard ISO guidelines. The monoliths did not cause any changes in the cell viability or cell lysis. High micro/mesoporosity and surface chemistry of the initial monolith-C, N- and P-doped nanostructured carbon honeycomb monoliths were established by low-temperature nitrogen adsorption (LTNA) studies, mercury porosimetry data (MIP), SEM/EDS analysis and FT-IR spectroscopy. The micro-mesoporous, activated carbon-based filtration/adsorbent prototype devices, in the form of three-dimensional (3D) carbon matrix, functionalized with ion-exchange amino- and phosphate groups and encased in polyolefin heat shrink cable sleeve, have been developed with the capacity to remove protein-bound uremic toxins (PBUTs), such us PCS and IS, as well as inflammatory cytokines (IL-6 and IL-8) from human plasma in a flowing model system. The ammoxidized monolith-N, derived from the monolith-C, had the highest removal efficiency (40.05% for PCS, and 28.4% for IL-6). By contrast, phosphorylated monolith-P demonstrated the highest removal efficiency (54.62% for IS, and 54.4% for IL-8), whilst the monolith-C has the lowest removal efficiency for these adsorbates. These results do not correlate with the LTNA and MIP study results, suggesting that the interaction of surface chemical functional groups with the solutes play key roles in the adsorption mechanism. The ion-exchange mechanism of PBUTs and inflammatory cytokine chemisorption by the monoliths, modified with surface N- and P-containing functional groups, has been proposed. Full article

(This article belongs to the Special Issue Recent Research of Nanomaterials in Molecular Science: 3rd Edition)

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21 pages, 3760 KB

Open AccessArticle

Antiparasitic Activity of Sesquiterpene γ-Lactones and the Search for New Pharmaceutical Agents

by Sergazy M. Adekenov, Laura C. Laurella, Shynggys Sergazy, Rachel Napoles Rodriguez, Augusto E. Bivona, Juan M. Viecenz, Orlando G. Elso, Aldana M. Corlatti, Nadia T. Mirakian, Esteban Bontempi, Paola A. Barroso, Dmitriy L. Savchenko, Balzhan Z. Medeubaeva, Gulimzhan S. Adekenova, Artur T. Boldysh, Anar N. Zhabayeva and Valeria P. Sülsen

Int. J. Mol. Sci. 2026, 27(17), 7971; https://doi.org/10.3390/ijms27177971 - 7 Sep 2026

Viewed by 360

Abstract

This study presents a comparative in vitro evaluation of 24 natural sesquiterpene γ-lactones and selected semisynthetic derivatives against three trypanosomatid parasites responsible for neglected tropical diseases: Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania amazonensis. The compounds were screened for antiparasitic [...] Read more.

This study presents a comparative in vitro evaluation of 24 natural sesquiterpene γ-lactones and selected semisynthetic derivatives against three trypanosomatid parasites responsible for neglected tropical diseases: Trypanosoma brucei brucei, Trypanosoma cruzi, and Leishmania amazonensis. The compounds were screened for antiparasitic activity across different parasite life stages, and their cytotoxicity was assessed in mammalian cells. Several compounds demonstrated high inhibitory activity (>95%) at 10 µg/mL, including estafiatin (1), grossheimin (4), cynaropicrin (5), argolide (2) derivatives, and arglabin (23). However, a marked decrease in activity was observed at lower concentrations and in intracellular parasite models, particularly for T. cruzi and L. amazonensis amastigotes. Among the tested compounds, dihydroargolide (3) and pulchellin C (19) exhibited comparatively lower cytotoxicity and were further evaluated, yielding IC₅₀ values of 10.51 ± 1.72 µg/mL and 2.51 ± 1.13 µg/mL against T. b. brucei, respectively. Against L. amazonensis promastigotes, estafiatin (1), 8α-chloroacetoxygrossheimin (12), and arglabin (23) showed IC₅₀ values of 0.16 ± 0.13, 0.35 ± 0.18, and 0.58 ± 0.11 µg/mL, respectively, although their selectivity indices remained limited. Comparative analysis of the dataset indicates that specific structural elements, such as the α-methylene-γ-lactone moiety and selected substituents (e.g., epoxy and acetyl groups), may influence antiparasitic activity in a species-dependent manner. At the same time, the generally low selectivity indices and reduced activity in intracellular models highlight important limitations of these compounds as direct drug leads. Overall, this work provides a systematic comparative dataset and identifies preliminary structure–activity trends that may guide further chemical optimization of sesquiterpene γ-lactones as antiparasitic hit compounds. Full article

(This article belongs to the Special Issue Synthesis and Activity of Natural Products and Analogues)

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47 pages, 1029 KB

Open AccessReview

Closed-Loop Neuromodulation for Brain Fatigue: From Real-Time Biomarkers to Adaptive Intervention

by Hongliang Lu, Yajuan Zhang, Shengjun Wu and Danmin Miao

Int. J. Mol. Sci. 2026, 27(17), 7970; https://doi.org/10.3390/ijms27177970 - 7 Sep 2026

Viewed by 353

Abstract

Brain fatigue is a debilitating condition whose molecular complexity—neurotransmitter imbalance, neuroinflammation, and metabolic failure—has long defied effective intervention. Conventional open-loop neuromodulation offers fixed stimulation, but fatigue fluctuates. Closed-loop neuromodulation, adjusting stimulation in real time, holds real promise. Yet its delivery hinges on a [...] Read more.

Brain fatigue is a debilitating condition whose molecular complexity—neurotransmitter imbalance, neuroinflammation, and metabolic failure—has long defied effective intervention. Conventional open-loop neuromodulation offers fixed stimulation, but fatigue fluctuates. Closed-loop neuromodulation, adjusting stimulation in real time, holds real promise. Yet its delivery hinges on a single, unresolved bottleneck: the sensing–decision chain. In this review, we deconstruct closed-loop systems into sensing, decision, and intervention, and argue that the true challenge is not technological but informational—how to integrate fast electrophysiological signals with slow molecular biomarkers (inflammatory cytokines, neurotrophic factors, adenosine) into a unified control framework. We show that a “fast-slow variable” architecture offers a practical path forward: fast signals guide immediate responses, slow variables set baselines and thresholds, and their integration enables predictive, pre-emptive intervention. We also examine the molecular correlates of neuromodulation—synaptic plasticity, anti-inflammatory signaling, and neurotrophic regulation—as the mechanistic foundation for therapeutic effect. Finally, we confront the translational triad of causality, inter-individual variability, and the information–energy–time trade-off. We conclude that realizing effective closed-loop neuromodulation for brain fatigue will require parallel advances in both stimulation hardware—improving spatial targeting, dose precision, and modality versatility—and individualized sensing–decision algorithms capable of reliably translating multi-modal biomarkers into timely, safe interventions. Both areas remain active fronts of development, and neither can be neglected in clinical translation. Full article

(This article belongs to the Special Issue The Latest Molecular and Psycho-Physiological Insights on “Brain Fatigue”)

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16 pages, 2333 KB

Open AccessArticle

Cardiac Glycoside 3β-Bufalin Suppresses Cancer Cell Proliferation by Coupling with Na⁺,K⁺-ATPase and Volume-Regulated Anion Channel Within Membrane Microdomains

by Takuto Fujii, Takahiro Shimizu, Yasuharu Shimizu, Mizuki Katoh, Tomoyuki Okumura, Tsutomu Fujii and Hideki Sakai

Int. J. Mol. Sci. 2026, 27(17), 7969; https://doi.org/10.3390/ijms27177969 - 7 Sep 2026

Viewed by 290

Abstract

Bufadienolides are toad-derived cardiotonic steroids with anti-cancer activity; however, their Na⁺,K⁺-ATPase-mediated anti-cancer mechanisms remain incompletely understood. Here, we compared the anti-proliferative effects of six bufadienolides, bufalin (3β-bufalin), resibufogenin, cinobufagin, telocinobufagin, cinobufotalin, and desacetylcinobufagin, on human colorectal cancer HT-29 cells. [...] Read more.

Bufadienolides are toad-derived cardiotonic steroids with anti-cancer activity; however, their Na⁺,K⁺-ATPase-mediated anti-cancer mechanisms remain incompletely understood. Here, we compared the anti-proliferative effects of six bufadienolides, bufalin (3β-bufalin), resibufogenin, cinobufagin, telocinobufagin, cinobufotalin, and desacetylcinobufagin, on human colorectal cancer HT-29 cells. Among them, only 3β-bufalin significantly suppressed cell proliferation in a concentration-dependent manner, with an IC₅₀ of 1.8 nM, whereas its hepatic metabolite, 3α-bufalin, showed markedly weaker activity, with an IC₅₀ of 488 nM. 3β-Bufalin inhibited Na⁺,K⁺-ATPase activity with an IC₅₀ of approximately 37 nM, indicating that it suppressed growth at concentrations lower than those required for pump inhibition. The Na⁺,K⁺-ATPase α1-isoform can function as a receptor-type (non-pumping) signaling platform linked to volume-regulated anion channel (VRAC) activation in membrane microdomains of cancer cells. 3β-Bufalin activated the VRAC with an EC₅₀ of 4.6 nM, whereas 3α-bufalin and the other bufadienolides showed no detectable activation. The pharmacological inhibition of the VRAC and the disruption of cholesterol-rich membrane microdomains significantly attenuated the anti-proliferative effect of 3β-bufalin. Furthermore, 3β-bufalin induced G2/M cell cycle arrest, which was attenuated by VRAC inhibition. These findings indicate that 3β-bufalin selectively suppresses cancer cell proliferation by coupling with receptor-type Na⁺,K⁺-ATPase to activate the VRAC in membrane microdomains rather than inhibiting Na⁺,K⁺-ATPase pump activity. Full article

(This article belongs to the Special Issue Ion Channels and Transporters: Regulation and Roles in Human Diseases)

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30 pages, 2285 KB

Open AccessReview

Natural Bioactive Compounds in Rheumatoid Arthritis: Experimental Evidence from Adjuvant Arthritis Model Supporting Combination Strategies with Methotrexate

by Mohammad Umar, Waqar Ahmad and Katarina Bauerova

Int. J. Mol. Sci. 2026, 27(17), 7968; https://doi.org/10.3390/ijms27177968 - 7 Sep 2026

Viewed by 411

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that represents continuous synovial inflammation, oxidative stress, immune dysregulation, and progressive cartilage degradation and bone erosion. Although disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX), have improved clinical outcomes, treatment-limiting adverse effects remain a concern. [...] Read more.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that represents continuous synovial inflammation, oxidative stress, immune dysregulation, and progressive cartilage degradation and bone erosion. Although disease-modifying antirheumatic drugs (DMARDs), including methotrexate (MTX), have improved clinical outcomes, treatment-limiting adverse effects remain a concern. Increasing evidence suggests that natural bioactive compounds may serve as adjunctive approaches by modulating multiple pathogenic pathways. This review summarizes biomarker-based modulation of inflammatory, oxidative, and immune pathways by plant-derived extracts, nutraceuticals, and biologically derived compounds, with particular emphasis on evidence from adjuvant arthritis (AA). AA is a widely used experimental model that reproduces several inflammatory and oxidative features relevant to RA, including cytokine activation, NF-κB/MAPK signaling, Th17/JAK-STAT3 signaling, redox imbalance, and tissue degeneration. Studies in AA indicate that selected natural compounds, alone or in combination with MTX, can reduce inflammatory cytokines (e.g., IL-1β, IL-6, IL-17A), matrix-remodeling markers (e.g., MMP-9), and oxidative-stress markers (e.g., protein carbonyls and lipid peroxidation) while supporting antioxidant defenses (e.g., HO-1 and CAT). Overall, natural bioactive substances may have potential as adjunctive candidates for further investigation in RA, particularly because of their effects on inflammatory and oxidative pathways. Preclinical studies of MTX combinations have reported additional improvements in selected disease-associated outcomes; however, these findings require confirmation in well-designed clinical studies. This review critically evaluates the preclinical evidence for natural bioactive compounds, with a focus on mechanistic studies in AA and the potential for combination strategies with methotrexate. Full article

(This article belongs to the Special Issue Arthritis: Focus on Pathologies, Symptoms and Therapy)

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24 pages, 5503 KB

Open AccessArticle

Morphological, Physiological and Transcriptomic Changes in Response to Water Deficit Stress in Brassica napus L.

by Harsh Raman, Brett McVittie, Niharika Sharma, Maheswaran Rohan and Rosy Raman

Int. J. Mol. Sci. 2026, 27(17), 7967; https://doi.org/10.3390/ijms27177967 - 7 Sep 2026

Viewed by 344

Abstract

Yield losses due to water-deficit (WD) conditions, especially during the reproductive stages of plant development, pose a significant threat to global canola (Brassica napus L.) production. Therefore, it is critical to investigate traits contributing to improved productivity under increased WD conditions. Here [...] Read more.

Yield losses due to water-deficit (WD) conditions, especially during the reproductive stages of plant development, pose a significant threat to global canola (Brassica napus L.) production. Therefore, it is critical to investigate traits contributing to improved productivity under increased WD conditions. Here we present phenotypic, physiological and transcriptomic changes in response to WD across contrasting canola accessions exhibiting variation in drought resistance-related traits. WD significantly reduced shoot biomass, plant height, harvest index, leaf water content, photosynthetic CO₂ assimilation rate, intrinsic water-use efficiency and carbon isotope discrimination. WD caused 49 to 100% of the seed yield reduction: the minimum seed yield reduction (49.66%) was observed in a doubled-haploid (DH) line, 06-5101.137, while the maximum yield reduction (94.1 to 100%) occurred in the late-flowering DH lines (06.5101.088 and 06-5101.306). Seed yield showed a positive correlation (r = 0.29 to 0.95) with shoot biomass and harvest index, leaf water content, photosynthetic CO₂ assimilation rate, intrinsic water use efficiency and carbon isotope discrimination. However, it showed negative correlations with days to flower, leaf specific weight, root length, root biomass (r = −0.04 to −0.79) across water treatments. The specific leaf transcriptome analysis of the two parental lines of DH population that exhibit variation for effective water use under well-watered and water-deficient conditions revealed different categories of differentially expressed genes (DEGs): WD-responsive DEGs in BC1329 parental line (1116) and BC9102 (1205) with 754 and 853 DEGs unique to BC1329 and BC9102, respectively, WD-responsive DEGs (906), genotype-dependent DEGs (8465) and genotype × treatment interaction DEGs (353). DEG annotations revealed that the WD-treatment-affected genes were involved in stress responses and growth and development. We further located 235 DEGs within the QTL regions underlying agronomic and physiological performance. Our study provides a conceptual framework for the morphological, physiological and molecular determinants involved in water-use efficiency. Seedlings’ traits with high heritability values, such as shoot biomass, leaf weight, leaf water content and Δ¹³C, serve as proxies for trait-based selection for improved seed yield under both water-limited and non-water-limited conditions. Full article

(This article belongs to the Special Issue Plant Molecular Regulatory Networks and Stress Responses)

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22 pages, 7951 KB

Open AccessArticle

Integrated Single Cell Analysis Reveals the Transcriptional Heterogeneity of Mouse Double Negative T Cells

by Jun Zhao, Jiang Zhu and Jian Zhang

Int. J. Mol. Sci. 2026, 27(17), 7966; https://doi.org/10.3390/ijms27177966 - 7 Sep 2026

Viewed by 373

Abstract

Double negative T cells (DNT cells) are a rare T cell population involved in immune regulation, inflammation, autoimmunity, transplantation, and tumor immunity. However, their low abundance and dispersed distribution across tissues have limited a systematic understanding of their cellular organization and transcriptional diversity. [...] Read more.

Double negative T cells (DNT cells) are a rare T cell population involved in immune regulation, inflammation, autoimmunity, transplantation, and tumor immunity. However, their low abundance and dispersed distribution across tissues have limited a systematic understanding of their cellular organization and transcriptional diversity. To address this problem, we developed an integrative single cell framework to reconstruct the mouse DNT cell landscape across tissues using multiple public single cell RNA sequencing datasets. Using transcriptomic criteria, we identified and integrated 7984 mouse RNA defined DNT cells. The integrated population was resolved into multiple transcriptionally distinct clusters. These clusters were organized into naive like, proinflammatory, cytotoxic, proliferative, and myeloid associated states, revealing that mouse RNA defined DNT cells constitute a highly heterogeneous yet structured transcriptional compartment. Integrated downstream analyses indicated transcriptional relationships among these subsets. Naive like populations showed inferred transcriptional relationships with inflammatory and cytotoxic programs, while virtual knockout and intercellular communication analyses identified distinct predicted regulatory and signaling features across states. To place these mouse DNT associated genes in a human disease context, selected genes were mapped to their corresponding human homologs and examined using TCGA pan cancer transcriptomic data. Together, these findings define a cross tissue transcriptional framework for mouse RNA defined DNT cells and provide a basis for further evaluating the conservation and relevance of these transcriptional programs in human DNT biology. More broadly, this study provides a generalizable integrative strategy for reconstructing and characterizing rare immune cell populations that are insufficiently represented in individual single cell datasets. Full article

(This article belongs to the Special Issue Intelligent Computational Modeling for Molecular Biomarker Discovery, Prognostic Prediction and Molecular Diagnostics)

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30 pages, 22013 KB

Open AccessArticle

Integration of Single-Cell and Bulk RNA Sequencing Data to Identify Lactylation-Related Gene Signatures in Hepatic Ischemia–Reperfusion Injury Using Machine Learning Algorithms

by Shilei Jing and Zhijun Zhu

Int. J. Mol. Sci. 2026, 27(17), 7965; https://doi.org/10.3390/ijms27177965 - 7 Sep 2026

Viewed by 503

Abstract

Hepatic ischemia–reperfusion injury (HIRI) is not only a common complication of liver transplantation and major hepatic surgery but also a critical determinant of postoperative prognosis. Lactate metabolic reprogramming has been observed in HIRI, yet the role of lactate and its related lactylation in [...] Read more.

Hepatic ischemia–reperfusion injury (HIRI) is not only a common complication of liver transplantation and major hepatic surgery but also a critical determinant of postoperative prognosis. Lactate metabolic reprogramming has been observed in HIRI, yet the role of lactate and its related lactylation in the pathogenesis of HIRI remains unclear. To address this, we integrated single-cell and bulk RNA-seq data with multiple bioinformatic approaches. Five single-cell gene set activity scoring methods (AUCell, UCell, singscore, ssGSEA, and AddModuleScore) were applied to evaluate lactylation activity across cell types, followed by differentially expressed gene (DEG) analysis and high-dimensional Weighted Correlation Network Analysis (hdWGCNA) to identify lactylation-associated genes. Five machine learning algorithms (Random Forest, Boruta, LASSO, GBM, and Decision Tree) were used to screen optimal feature genes, with SHAP analysis further explaining their importance. Bulk RNA sequencing data from the Gene Expression Omnibus (GEO) database were used for validation. Furthermore, NR4A3-related inhibitors were screened using the ChEMBL online tool and assessed by docking and molecular dynamic simulation. We observed significant heterogeneity in lactate metabolism activity across cell types in hepatic ischemia–reperfusion injury (HIRI), with higher activity levels observed for hepatocytes and mononuclear phagocytes. The integration of SHAP and machine learning identified PFKFB3, ZYX, and NR4A3 as closely associated with high lactylation after HIRI, and cross-analysis with bulk RNA data confirmed their consistent upregulation. Candidate gene expression was experimentally validated in a murine liver IRI model through Western blotting and RT-qPCR. Although lactylation has been previously reported in HIRI, this study’s unique contribution is to reveal the cell-type heterogeneity of lactylation-related gene expression at the single-cell level through multi-omics integration and machine learning. The identification of NR4A3, PFKFB3, and ZYX as lactylation-associated regulators proposes novel therapeutic targets for improving graft survival in liver transplantation. Full article

(This article belongs to the Special Issue Molecular Research on Ischemia-Reperfusion Injury)

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23 pages, 2435 KB

Open AccessArticle

Domesticated Argania spinosa in Eastern Morocco: HPLC-DAD/GC-MS Chemical Profiling, Antioxidant and Antidiabetic Activities, and Network Pharmacology-Guided Molecular Docking

by Salah-eddine Azizi, Nour Elhouda Daoudi, Mohammed Roubi, Ilyass Alami Merrouni, Adha Fauzi Hendrawan, Mohamed Bnouham, Abdelbasset Berrichi, Mohammed Dalli, Bouchra Legssyer and Nadia Gseyra

Int. J. Mol. Sci. 2026, 27(17), 7964; https://doi.org/10.3390/ijms27177964 - 7 Sep 2026

Viewed by 433

Abstract

The argan tree (Argania spinosa) is an endemic Moroccan species known for its primary product, argan oil, which possesses exceptional nutritional and medicinal properties. The current study aimed to evaluate and compare the antidiabetic and antioxidant activities of argan oil obtained [...] Read more.

The argan tree (Argania spinosa) is an endemic Moroccan species known for its primary product, argan oil, which possesses exceptional nutritional and medicinal properties. The current study aimed to evaluate and compare the antidiabetic and antioxidant activities of argan oil obtained from the introduced and native argan tree in eastern Morocco, to analyze its chemical composition using HPLC-DAD and GC-MS, and to investigate the molecular mechanisms behind the obtained pharmacological activities through an in silico pharmacological networking and molecular docking study. The results revealed that argan oil from all three regions of Morocco (Oujda, Agadir, and Chouihya) is rich in oleic and linoleic acids as major constituents, along with the presence of significant tocopherols. Regarding the antioxidant assays, including DPPH radical scavenging and iron-reducing power tests, argan oil from Oujda exhibited the highest activity, with the lowest IC₅₀ values of 15.25 ± 0.022 mg/mL and 28.5 ± 1.7 mg/mL, respectively. Concerning the antidiabetic activity, we found that oil from Chaouihya showed the strongest α-amylase inhibition, while Oujda oil had the highest antiglycation activity, indicating that even introduced argan trees retain potent bioactivity. The results of the in silico investigation suggested that tocopherols may contribute to the antioxidant and antidiabetic potential of argan oil, showing predicted antioxidant activity (Pa = 0.843–0.967) and favorable binding affinities toward iNOS (ΔG = −9.3 kcal mol⁻¹) and α-glucosidase (ΔG = −8.2 kcal mol⁻¹). The identified fatty acids also showed predicted insulin-promoting activity (Pa = 0.59–0.75) and moderate enzyme-binding potential. Pharmacological network analysis identified 51 shared genes associated with antioxidant, antidiabetic, and argan-related targets, with enrichment of the AGE–RAGE signaling pathway. These computational findings provide possible molecular associations that may help explain the observed biological activities, although they remain predictive and require experimental validation. Overall, the in silico analysis suggests that tocopherols could be among the contributors to the multi-target profile of Argania spinosa oil, while fatty acids may provide complementary effects related to glycemic regulation. Full article

(This article belongs to the Special Issue Bioactivity and Mechanistic Insights of Plant-Derived Chemical Compounds)

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28 pages, 11018 KB

Open AccessArticle

Darkness Attenuates the Early Transcriptional Response to Phosphate Deficiency in Soybean Roots

by Anamta Shaikh, Izabel Thurber, Nikko R. M. Sacramento, Jennifer Bravo, Lynne Viall, Reemaben Maniyar, Maria Muhammad Ali, Jennifer Nguyen, Kristine Tran, Geronimo Parra, Kayla Magdaleno, Trinidad Cruz, Kamilah Baltrons, Rafael Cazares, Brandon DeLeon, Nathan Flores, Monika Sommerhalter and Claudia Uhde-Stone

Int. J. Mol. Sci. 2026, 27(17), 7963; https://doi.org/10.3390/ijms27177963 - 7 Sep 2026

Viewed by 296

Abstract

Phosphate (P_i) deficiency induces responses that enhance P_i uptake and utilization. Light may influence these responses through photosynthetic carbon supply and signaling. We examined how light affects the early root transcriptional response to P_i deficiency in hydroponically grown soybean. [...] Read more.

Phosphate (P_i) deficiency induces responses that enhance P_i uptake and utilization. Light may influence these responses through photosynthetic carbon supply and signaling. We examined how light affects the early root transcriptional response to P_i deficiency in hydroponically grown soybean. Plants were exposed to phosphate-sufficient (+P) or phosphate-deficient (−P) conditions for 30 h under a light/dark cycle or continuous darkness. Root transcriptomes were analyzed using Oxford Nanopore cDNA sequencing. Principal component analysis (PCA) showed that transcriptomes separated mainly by light, with weaker separation by P_i status. Under light, P_i deficiency induced a broad response involving P_i transport, signaling, transcriptional regulation, lipid remodeling, and metabolism. In darkness, relatively few genes were upregulated under P_i deficiency. This limited response was not caused by a loss of transcriptional responsiveness, because thousands of genes were upregulated by darkness itself. Comparison of fold changes revealed that darkness attenuated, rather than reversed, the −P response. Interaction-ranked gene set enrichment analysis (GSEA) showed that the weaker response in darkness extended across signaling, metabolic, and transport pathways. Light-signaling genes responded strongly to darkness but showed little phosphate-dependent regulation. Root sucrose levels were lower in darkness, consistent with reduced carbon availability as a possible contributor to the attenuated P_i-deficiency response. Full article

(This article belongs to the Special Issue Omics Approaches to Unravel Plant Responses to Habitat Stresses)

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27 pages, 6575 KB

Open AccessReview

Immune Evasion by Neurotropic Viruses: Molecular Strategies, Cellular Targets, and Consequences for CNS Infection

by Antonios Mouzakis, Vasileios Petrakis and Katerina Chlichlia

Int. J. Mol. Sci. 2026, 27(17), 7962; https://doi.org/10.3390/ijms27177962 - 7 Sep 2026

Viewed by 651

Abstract

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen [...] Read more.

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, inhibition of type I interferon induction and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal–glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus–host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function. Full article

(This article belongs to the Special Issue Molecular Interactions Between Bacteria and Viruses: Mechanisms and Pathogenic Insights)

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18 pages, 2661 KB

Open AccessReview

Oxidative Stress and Neuroimaging Alterations in Major Depressive Disorder: A Systematic Review

by Francisco Javier Gutiérrez-Corral, Ana Elizabeth González-Santiago, Alejandro Salvador Gómez-Cabrera, Rolando Castañeda-Arellano, Fernanda Isadora Corona-Meraz and María Guadalupe Sánchez-Parada

Int. J. Mol. Sci. 2026, 27(17), 7961; https://doi.org/10.3390/ijms27177961 - 7 Sep 2026

Viewed by 344

Abstract

Major depressive disorder (MDD) is associated with complex neurobiological alterations in which oxidative stress may play a central role; however, direct evidence linking redox biomarkers to alterations in brain chemistry remains limited. This systematic review aimed to synthesize the available evidence on the [...] Read more.

Major depressive disorder (MDD) is associated with complex neurobiological alterations in which oxidative stress may play a central role; however, direct evidence linking redox biomarkers to alterations in brain chemistry remains limited. This systematic review aimed to synthesize the available evidence on the relationships between oxidative stress and neuroimaging alterations in individuals with MDD. A search was conducted in PubMed, Scopus, and Web of Science (2016–2026) following the PRISMA guidelines, including human studies assessing oxidative biomarkers (central or peripheral) alongside neuroimaging or neurofunctional measures. Four studies met the inclusion criteria (case–control, cross-sectional, and interventional designs). These studies collectively indicate that antioxidant enzymes, glutathione, and malondialdehyde are associated with altered brain activity and connectivity, prefrontal neurochemical changes, and cognitive performance. Overall, the findings support the existence of associations between redox disruption and central nervous system (CNS) alterations in MDD. However, methodological heterogeneity and the limited number of studies highlight the need for further longitudinal and multimodal research to clarify the directionality and clinical relevance of these findings. Full article

(This article belongs to the Special Issue Latest Advances in Oxidative Stress and Brain Injury)

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24 pages, 619 KB

Open AccessSystematic Review

Are Basophil Activation Test (BAT) and IgE Levels Useful Tools in Confirming Penicillin Allergy? Novel Diagnostic Approach in Beta-Lactams Hypersensitivity Reactions: A Systematic Review

by Bernadetta Kosztulska, Magdalena Rydzyńska, Magdalena Grześk-Kaczyńska, Tomasz Rosada, Andrzej Kuźmiński and Natalia Ukleja-Sokołowska

Int. J. Mol. Sci. 2026, 27(17), 7960; https://doi.org/10.3390/ijms27177960 - 7 Sep 2026

Viewed by 355

Abstract

Approximately 15% of the population in developed countries report a penicillin allergy in their medical history. However, this changes considerably following a comprehensive allergological evaluation. Numerous studies have shown that a true penicillin allergy is confirmed in only about 8% of individuals. Recommended [...] Read more.

Approximately 15% of the population in developed countries report a penicillin allergy in their medical history. However, this changes considerably following a comprehensive allergological evaluation. Numerous studies have shown that a true penicillin allergy is confirmed in only about 8% of individuals. Recommended diagnostic protocols are usually complex and time-consuming, as they rely primarily on in vivo diagnostic approaches, such as skin testing and drug provocation tests. To date, there are no clear guidelines regarding the implementation of in vitro tests in diagnostic algorithms for patients with suspected penicillin allergies. Currently available in vitro methods are characterized by limited sensitivity and specificity. On the other hand, they offer the potential to reduce the need for drug provocation testing, which remains the gold standard but carries an inherent risk of inducing clinical reactions. Consequently, researchers continue to explore methodological improvements aimed at enhancing the diagnostic performance and clinical utility of these tests. In this systematic review, we analyze the current possibilities and limitations of the basophil activation test (BAT) and the measurement of specific IgE (sIgE) antibodies, as well as their potential role in the routine diagnostic workup of patients with suspected immediate hypersensitivity reactions to penicillins. Full article

(This article belongs to the Special Issue Trends in Allergy and Autoimmunity: Pathogenesis, Biomarkers, and Treatment (Second Edition))

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25 pages, 794 KB

Open AccessReview

Current Advances in Liver-Targeted Drug Delivery: Synthetic, Biological, and Biomimetic Platforms

by Shynggys Sergazy, Roza B. Seidakhmetova, Yernur Zakirov, Askhat Zhilkaidarov, Damirzhan Amirbek, Zarina Shulgau, Kulzhan Berikkhanova and Alexandr Gulyaev

Int. J. Mol. Sci. 2026, 27(17), 7959; https://doi.org/10.3390/ijms27177959 - 7 Sep 2026

Viewed by 426

Abstract

Liver-targeted drug delivery offers opportunities to increase therapeutic exposure at sites of hepatic disease while limiting systemic toxicity; however, successful targeting requires more than preferential accumulation of a carrier within the liver. This narrative review critically summarizes recent advances in synthetic, biological, and [...] Read more.

Liver-targeted drug delivery offers opportunities to increase therapeutic exposure at sites of hepatic disease while limiting systemic toxicity; however, successful targeting requires more than preferential accumulation of a carrier within the liver. This narrative review critically summarizes recent advances in synthetic, biological, and biomimetic delivery platforms, including lipid, polymeric, inorganic, and protein-based nanoparticles, nucleic acid nanocarriers, extracellular vesicles, plant-derived nanovesicles, cell-mediated systems, and cell membrane-coated nanoparticles. A literature search was conducted using PubMed, Web of Science, and Embase, with emphasis on studies published during the last decade and updated through 24 August 2026. Particular attention is given to the biological determinants of hepatic biodistribution, including sinusoidal architecture, physicochemical carrier properties, protein corona formation, receptor–ligand interactions, and disease-associated alterations in the hepatic microenvironment. The review distinguishes organ-level hepatic accumulation from cell-specific uptake and productive intracellular delivery and discusses strategies directed toward hepatocytes, hepatic stellate cells, Kupffer cells and other macrophages, liver sinusoidal endothelial cells, neutrophils, and additional immune-cell populations. Major delivery platforms are critically compared with respect to the evidence supporting targeting specificity, cargo compatibility, administration route, reported safety and immunogenicity, manufacturability, analytical characterization, and translational maturity. Particular consideration is given to extracellular vesicle- and plant-derived nanovesicle-based approaches, for which biological activity, biodistribution, standardization, and scalability remain important areas of investigation. Overall, current research in liver-targeted delivery is increasingly focused on moving beyond nonspecific organ accumulation toward disease-adapted, cell-specific, and intracellularly productive delivery, although substantial biological, manufacturing, and regulatory challenges remain before many emerging approaches can achieve routine clinical translation. Full article

(This article belongs to the Special Issue Research on Drug Delivery in Health and Disease)

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23 pages, 1412 KB

Open AccessReview

Cognitive and Behavioural Profile of SOD1-ALS Across the ALS-FTD Spectrum: A Systematic Review

by Francesco Ginanni, Francesco Nicoletti, Caterina Meoni, Lucrezia Becattini, Michelangelo Mancuso, Cecilia Carlesi and Francesca Bianchi

Int. J. Mol. Sci. 2026, 27(17), 7958; https://doi.org/10.3390/ijms27177958 - 7 Sep 2026

Viewed by 422

Abstract

Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA [...] Read more.

Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA guidelines, a systematic PubMed search identified 17 eligible studies. Across the included studies, encompassing 222 patients with SOD1 variants, three of the analyzed subjects fulfilled the diagnostic criteria for frontotemporal dementia (FTD), and a larger proportion exhibited multidomain cognitive deficits, including executive dysfunction, language impairment, and working memory decline. Behavioural disturbances, such as apathy, emotional lability, and mental rigidity, were also prominent. The historical assumption that SOD1 mutations completely spare cognitive networks likely reflects an under-recognition of subtle manifestations, compounded by the limited sensitivity of earlier screening tools. These findings indicate that cognitive and behavioural involvement can occur in SOD1-ALS, highlighting a highly heterogeneous phenotype. Encompassing varying degrees of severity—from subtle differences in neuropsychological test scores to formal FTD diagnoses—the current evidence points towards possible variant-specific phenotypes rather than a uniform cognitive syndrome. Routine multidomain cognitive screening is crucial in this population. Properly characterizing these non-motor features allows for more accurate disease staging, better monitoring of clinical progression, and the implementation of truly personalized care strategies. Full article

(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders: 2nd Edition)

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20 pages, 26223 KB

Open AccessArticle

Integrated Transcriptomic Profiling Reveals Distinct and Overlapping Transcriptional Responses and Regulatory Pathways Mediated by Salicylic Acid, Jasmonic Acid, and Abscisic Acid in Lotus (Nelumbo nucifera)

by Junyang Xu, Ziyan Yang, Ji Yang, Yanyan Meng and Xinqiong Liu

Int. J. Mol. Sci. 2026, 27(17), 7957; https://doi.org/10.3390/ijms27177957 - 7 Sep 2026

Viewed by 313

Abstract

Sacred lotus (Nelumbo nucifera) is an important aquatic crop whose growth and productivity are severely constrained by environmental stresses. Salicylic Acid (SA), Jasmonic Acid (JA), and Abscisic Acid (ABA) are key plant growth regulators (PGRs) involved in stress responses, but their [...] Read more.

Sacred lotus (Nelumbo nucifera) is an important aquatic crop whose growth and productivity are severely constrained by environmental stresses. Salicylic Acid (SA), Jasmonic Acid (JA), and Abscisic Acid (ABA) are key plant growth regulators (PGRs) involved in stress responses, but their regulatory mechanisms in lotus remain unclear. In this study, transcriptome sequencing was performed in lotus seedlings treated with exogenous SA, JA, and ABA to characterize hormone-responsive regulatory networks. SA predominantly resulted in transcriptional repression, with responsive genes mainly associated with photosynthesis and ribosome-related pathways, whereas JA and ABA showed similar regulatory patterns with enrichment of hormone signaling and Mitogen-activated protein kinase (MAPK) pathways, but distinct roles in defense regulation and stress adaptation. A total of 607 genes were identified as commonly responsive to the three PGRs and were significantly enriched in cold response, defense response, secondary metabolism, and photosynthesis-related pathways. Protein–protein interaction analysis identified two hub genes encoding light-harvesting chlorophyll a/b-binding proteins, suggesting that the photosynthesis–antenna proteins pathway may represent a convergent regulatory node in hormone-mediated stress responses. This study provides new insights into SA-, JA-, and ABA-mediated stress responses and identifies potential candidate genes for improving stress tolerance in lotus. Full article

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

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28 pages, 6073 KB

Open AccessReview

Circulating Amyloid and Misfolded Biomarkers in Early Myocardial Injury: A Systematic Review and Epistemic Meta-Analysis

by Florencio Alejandro Chable-Guerrero, Diana Romero-Zertuche, Cristina Revilla-Monsalve, Lizett Castrejón-Delgado, Nelly F. Altamirano-Bustamante and Myriam Marlenne Altamirano-Bustamante

Int. J. Mol. Sci. 2026, 27(17), 7956; https://doi.org/10.3390/ijms27177956 - 7 Sep 2026

Viewed by 435

Abstract

Misfolded proteins, including islet amyloid polypeptide (hIAPP), serum amyloid A (SAA), and amyloid-betas (Aβs) such as Aβ1-40 and Aβ1-42 oligomers, collectively referred to in our work as amyloid oligomers, have been implicated in the development of both metabolic and cardiovascular diseases. However, their [...] Read more.

Misfolded proteins, including islet amyloid polypeptide (hIAPP), serum amyloid A (SAA), and amyloid-betas (Aβs) such as Aβ1-40 and Aβ1-42 oligomers, collectively referred to in our work as amyloid oligomers, have been implicated in the development of both metabolic and cardiovascular diseases. However, their potential role as early biomarkers of myocardial damage remains insufficiently explored. We conducted a systematic review following PRISMA guidelines and epistemic meta-analysis to investigate the association between misfolded protein oligomers and early myocardial injury. All English- and Spanish-language articles with titles, abstracts, or keywords relevant to the research topic and indexed in at least one of the following databases—PubMed, BIREME, or Web of Science—were included. A comprehensive search across major databases identified 30 eligible studies. Thirty studies met inclusion criteria, in humans and animals, and in vitro. Amyloid oligomers were consistently elevated in patients with acute myocardial infarction, type 2 diabetes, or coronary artery disease compared with controls. In specific individual cohorts, a higher SAA concentration correlated with major adverse cardiovascular events, where it acted as an independent predictor of mortality in reperfused AMI (RR 5.8; 95% CI: 1.3–27.7) and cardiac rupture (OR 8.8; 95% CI: 1.7–25.6). Our findings support the hypothesis that protein misfolding contributes to early myocardial injury and highlight its potential as a novel source of cardiometabolic biomarkers. Full article

(This article belongs to the Special Issue Chemical Biology Advances in Protein Conformational Diseases)

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15 pages, 14396 KB

Open AccessArticle

PTPN23 Overexpression Is Associated with Reduced Proliferation and Tumor Growth in Murine Models of Colorectal Cancer

by Rocio Sanchez Alvarez, Claudia Gottier, Ana Montalban-Arques, Anna Bircher, Doris Pöhlmann, Marlene Schwarzfischer, Anne Müller, Silvia Lang, Marianne R. Spalinger and Michael Scharl

Int. J. Mol. Sci. 2026, 27(17), 7955; https://doi.org/10.3390/ijms27177955 - 7 Sep 2026

Viewed by 297

Abstract

Protein tyrosine phosphatases (PTPs) are key regulators of intracellular signaling cascades involved in cell growth, proliferation, differentiation, inflammation, and cancer. PTPN23, a non-receptor PTP, is involved in endosomal sorting and thereby regulates the internalization of growth factor receptors, such as the epidermal growth [...] Read more.

Protein tyrosine phosphatases (PTPs) are key regulators of intracellular signaling cascades involved in cell growth, proliferation, differentiation, inflammation, and cancer. PTPN23, a non-receptor PTP, is involved in endosomal sorting and thereby regulates the internalization of growth factor receptors, such as the epidermal growth factor receptor (EGFR). PTPN23 has been proposed to exert tumor-suppressive effects in several epithelial cancers, including breast and lung cancer. PTPN23 is ubiquitously expressed in the body; however, it is particularly highly expressed in the intestine, where it plays an essential role in maintaining intestinal homeostasis. Despite these observations, its involvement in colorectal carcinoma (CRC) remains largely unexplored. To investigate the function of PTPN23 in CRC, we generated PTPN23-overexpressing CRC cell lines and evaluated their effects in vitro and in subcutaneous tumor models. Our in-vitro findings demonstrate that PTPN23 overexpression resulted in reduced proliferation levels and follow-up experiments showed suppression of colorectal cancer growth and proliferation in experimental CRC models. These effects were accompanied by changes in EGFR-associated signaling; however, the underlying mechanism, including a potential role of EGFR trafficking, remains to be established through direct experimental validation. Together, these findings expand current knowledge of PTPN23 in colorectal cancer and provide a basis for future studies addressing its biological function and therapeutic relevance. Full article

(This article belongs to the Special Issue Solid Tumors: From Molecular Mechanisms to Targeted Therapies)

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21 pages, 8437 KB

Open AccessArticle

Mechanism Underlying the Color Differences in Apples Based on Metabolomic and Transcriptomic Analyses

by Haidong Bu, Junling Qiao, Yige Jiang, Wenquan Yu and Hui Yuan

Int. J. Mol. Sci. 2026, 27(17), 7954; https://doi.org/10.3390/ijms27177954 - 7 Sep 2026

Viewed by 250

Abstract

Apple peel color is a key determinant of fruit quality and consumer preference. To elucidate the molecular basis underlying the peel color difference between ‘Jinhong’ (JH) apples and ‘Hongjinhong’ apples (HJH, a deep red bud sport of JH apples), we integrated physiological assays, [...] Read more.

Apple peel color is a key determinant of fruit quality and consumer preference. To elucidate the molecular basis underlying the peel color difference between ‘Jinhong’ (JH) apples and ‘Hongjinhong’ apples (HJH, a deep red bud sport of JH apples), we integrated physiological assays, widely targeted metabolomics, transcriptomics, and quantitative real-time PCR (qRT-PCR) to analyze peel pigment contents, metabolite profiles, and gene expression dynamics during fruit development. The deep red phenotype of HJH peel was primarily attributed to enhanced anthocyanin accumulation rather than alterations in chlorophyll content. Metabolomics identified 418 differentially accumulated metabolites. Among these, three cyanidin-type anthocyanins––cyanidin-3-O-(6″-O-malonyl) glucoside, cyanidin-3-O-(2″-O-xylosyl) galactoside, and cyanidin-3-O-glucoside––were significantly upregulated in HJH peel, serving as the key pigments responsible for its deep red coloration. Transcriptomics revealed 533 differentially expressed genes. Combined with qRT-PCR validation, the anthocyanin biosynthetic gene MdDFR (dihydroflavonol reductase) exhibited consistently high expression during critical developmental stages of HJH fruit, closely mirroring the anthocyanin accumulation pattern. Collectively, the upregulation of MdDFR drives the specific accumulation of cyanidin-type anthocyanins, representing the core molecular event underlying the deep red peel color of HJH apples. This study provides novel insights into the regulatory network of apple coloration and offers candidate genes for the genetic improvement of fruit quality. Full article

(This article belongs to the Special Issue Genomics, Genetics, and the Future of Fruit Improvement)

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28 pages, 23183 KB

Open AccessArticle

Enhancement of Anti-Neoplastic Effects of MGN-3/Biobran Against Solid Ehrlich Carcinoma-Bearing Mice via Lipidic Nanoparticle Based Targeted Drug Delivery System

by Zeinab A. Alerksosy, Mamdooh H. Ghoneum, Mai Alaa El-Dein, Sarah Yahia, Ibrahim M. El-Sherbiny and Nariman K. Badr El-Din

Int. J. Mol. Sci. 2026, 27(17), 7953; https://doi.org/10.3390/ijms27177953 - 7 Sep 2026

Viewed by 450

Abstract

MGN-3 (Biobran), a denatured hemicellulose compound derived from rice bran, possesses potent immunomodulatory and antitumor activity; however, its clinical application is constrained by non-specific tissue distribution, rapid systemic elimination, and poor cellular uptake. To overcome these pharmacological limitations, we engineered MGN-3-loaded lipid nanoparticles [...] Read more.

MGN-3 (Biobran), a denatured hemicellulose compound derived from rice bran, possesses potent immunomodulatory and antitumor activity; however, its clinical application is constrained by non-specific tissue distribution, rapid systemic elimination, and poor cellular uptake. To overcome these pharmacological limitations, we engineered MGN-3-loaded lipid nanoparticles (MGN-3.LNPs) formulated with bioactive cinnamon and avocado oils to optimize targeted drug delivery against solid carcinoma. Mice bearing subcutaneous Ehrlich Ascites Carcinoma (EAC) solid tumors received free MGN-3, plain lipid nanoparticles (plain LNPs), or MGN-3.LNPs three times weekly from day 8 to day 26 post-inoculation. The administration of MGN-3.LNPs achieved superior tumor volume suppression (95.00%) compared to free MGN-3 (69.00%) and plain LNPs (63.00%) (p < 0.0001). Mechanistically, MGN-3.LNPs effectively inhibited cancer cell proliferation by suppressing Ki-67 expression while promoting expression shifts that strongly suggest the engagement of mitochondrial-mediated apoptotic signaling, including upregulation of tumor protein p53, Caspase-3, Caspase-9, poly(ADP-ribose) polymerase (PARP), and cytosolic cytochrome c (Cyt c), alongside an elevated Bax/Bcl-2 ratio and reduced 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. Flow cytometric analysis confirmed that MGN-3.LNPs induced marked G0/G1 cell cycle arrest and promoted sub-G1 apoptotic cell accumulation, which was corroborated by Annexin V/propidium iodide (Annexin V/PI) staining and semiquantitative histopathological evaluation. Furthermore, MGN-3.LNPs downregulated the gene expression of proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) while restoring redox homeostasis in tumor tissues. Overall, lipidic nanoencapsulation significantly enhances the therapeutic efficacy of MGN-3 against solid tumors through superior nanoscale tissue penetration, prolonged retention, and synergistic lipid–drug bioactivity. Full article

(This article belongs to the Section Molecular Oncology)

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11 pages, 1434 KB

Open AccessCase Report

Clinical Variability of Classical Ehlers–Danlos Syndrome: A Family with Rare COL5A1 Variant and Case-Based Review

by Karina E. Akhiiarova, Ekaterina N. Loginova, Rita R. Kildiyarova, Rita I. Khusainova and Anton V. Tyurin

Int. J. Mol. Sci. 2026, 27(17), 7952; https://doi.org/10.3390/ijms27177952 - 7 Sep 2026

Viewed by 411

Abstract

Ehlers–Danlos syndrome (EDS) comprises a heterogeneous group of inherited connective tissue disorders. The 2017 International Classification of EDS delineates 13 subtypes, which are caused by pathogenic variants in 19 distinct genes encoding various collagen types or proteins involved in collagen metabolism. EDS is [...] Read more.

Ehlers–Danlos syndrome (EDS) comprises a heterogeneous group of inherited connective tissue disorders. The 2017 International Classification of EDS delineates 13 subtypes, which are caused by pathogenic variants in 19 distinct genes encoding various collagen types or proteins involved in collagen metabolism. EDS is characterized by considerable clinical variability, both across EDS subtypes and in terms of phenotypic polymorphism and disease severity within individual subtypes. The present study describes a clinical case of classical-type Ehlers–Danlos syndrome segregating across three generations, illustrating the clinical variability observed within a single family carrying a single rare pathogenic variant, NM_000093.5(COL5A1):c.4050dup (p.Gly1351fs). Furthermore, this report clarifies and expands the phenotypic spectrum associated with this specific variant. Full article

(This article belongs to the Special Issue Early Diagnosis and Advanced Therapies of Genetic Disorders)

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25 pages, 5161 KB

Open AccessArticle

Integrated Metabolomics and Multilevel Validation of the Anti-Inflammatory and Skin-Soothing Effects of Bioactive Components from Prinsepia utilis Seeds

by Ruyi He, Changran Li, Xiaoxue Mao, Chao Huang, Mengjiao Yang, Jianqin Li, Xiaoli Wu and Lixin Yang

Int. J. Mol. Sci. 2026, 27(17), 7951; https://doi.org/10.3390/ijms27177951 - 7 Sep 2026

Viewed by 299

Abstract

Prinsepia utilis Royle seeds are traditionally used in Northwestern Yunnan to relieve skin inflammation and irritation. However, its active constituents and potential molecular mechanisms remain unclear. To investigate the bioactive constituents and anti-inflammatory and skin-soothing effects of P. utilis seed-derived extracts, we characterized [...] Read more.

Prinsepia utilis Royle seeds are traditionally used in Northwestern Yunnan to relieve skin inflammation and irritation. However, its active constituents and potential molecular mechanisms remain unclear. To investigate the bioactive constituents and anti-inflammatory and skin-soothing effects of P. utilis seed-derived extracts, we characterized their chemical profiles and investigated the potential molecular mechanisms through phytochemical, computational, and complementary biological approaches, as well as in vitro and in vivo tests in this study. The results of this study show that the 75% ethanol eluate (QC04) of P. utilis seeds exhibited the strongest inhibitory effect on lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages, with an IC₅₀ value of 239.21 ± 6.70 μg/mL. Subsequently, untargeted metabolomics identified 1039 metabolites, and 20 representative compounds were selected for downstream analysis. Furthermore, network pharmacology analysis identified AKT1, MAPK1, MAPK8, and MAPK14 as core targets, which are mainly involved in the TNF and MAPK signaling pathways. Molecular docking confirmed favorable binding interactions between representative metabolites and these core proteins; meanwhile, a 100 ns molecular dynamics simulation verified the conformational stability of the euscaphic acid–AKT1 complex. Moreover, in the UVB-induced 3D epidermal model (EpiKutis^®), QC04 treatment reduced IL-6 and PGE₂ secretion and downregulated TNF-α and NF-κB p65 expression. In vivo zebrafish assays further demonstrated that QC04 inhibited copper sulfate-induced neutrophil recruitment and histamine-induced vasodilation. Overall, these findings link the metabolites identified in the activity-enriched QC04 fraction with predicted molecular targets and anti-inflammatory and skin-soothing effects, providing experimental evidence for the biological potential of P. utilis seed-derived preparations and supporting further investigation of QC04 as a potential skin-soothing active fraction. Full article

(This article belongs to the Special Issue Activity and Efficacy Evaluation of Natural Products)

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15 pages, 790 KB

Open AccessArticle

Left Ventricular Molecular Signature in Chronic Aortic Regurgitation

by Bachar El Oumeiri, Laurence Dewachter, Philippe Van de Borne, Géraldine Hubesch, Pascale Jespers, Constantin Stefanidis, Kathleen Mc Entee and Frédéric Vanden Eynden

Int. J. Mol. Sci. 2026, 27(17), 7950; https://doi.org/10.3390/ijms27177950 - 7 Sep 2026

Viewed by 272

Abstract

Molecular mechanisms underlying the progression from compensated eccentric hypertrophy to heart failure in chronic aortic regurgitation (AR) remain poorly understood. We investigated associated transcriptional changes induced by chronic volume overload in an experimental model of severe AR. AR was induced in male Wistar [...] Read more.

Molecular mechanisms underlying the progression from compensated eccentric hypertrophy to heart failure in chronic aortic regurgitation (AR) remain poorly understood. We investigated associated transcriptional changes induced by chronic volume overload in an experimental model of severe AR. AR was induced in male Wistar rats (n = 10) by retrograde aortic valve perforation and compared with age-matched control rats (n = 8). Sixty days after surgery, cardiac remodeling was evaluated by echocardiography, invasive hemodynamics and myocardial gene-expression profiling using RT-qPCR. Chronic AR induced marked left ventricular dilatation and systolic dysfunction, consistent with decompensated eccentric hypertrophy. These functional alterations were accompanied by coordinated transcriptional changes involving pathways related to apoptosis, oxidative balance, metabolic regulation and calcium handling. AR hearts exhibited an increased BAX/BCL2 ratio, together with reduced SOD2 and increased GPX1 expression, suggesting a transcriptional profile consistent with activation of pro-apoptotic and antioxidant responses. Metabolic remodeling was characterized by decreased AMPKα1, PPARγ and GLUT4 expression, together with increased OLR1 and 15-LOX. KLK10 expression was increased. Reduced SERCA2A expression was observed, consistent with transcriptional alterations involving calcium-handling pathways. Chronic AR is associated with marked structural and functional cardiac remodeling accompanied by coordinated transcriptional alterations across multiple pathways implicated in myocardial dysfunction. This provides potential molecular pathways for further investigation. Full article

(This article belongs to the Special Issue Multifactorial Aspects of Hypertension: Advances and Challenges)

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30 pages, 4856 KB

Open AccessReview

Drosophila melanogaster as a Model for Gastrointestinal Radiation Injury: Conserved Mechanisms, Experimental Approaches, and Countermeasure Discovery

by Robert P. Volpe and Tomoko Y. Steen

Int. J. Mol. Sci. 2026, 27(17), 7949; https://doi.org/10.3390/ijms27177949 - 7 Sep 2026

Viewed by 401

Abstract

The gastrointestinal tract is a critical target of acute radiation exposure. Severe radiation exposure can deplete epithelial stem and progenitor cells, compromise barrier integrity, alter host–microbe interactions, and drive fluid loss, inflammation, and systemic decline. Mammalian models remain essential for clinical translation, but [...] Read more.

The gastrointestinal tract is a critical target of acute radiation exposure. Severe radiation exposure can deplete epithelial stem and progenitor cells, compromise barrier integrity, alter host–microbe interactions, and drive fluid loss, inflammation, and systemic decline. Mammalian models remain essential for clinical translation, but their cost and complexity constrain sample sizes, statistical power, large-scale mechanistic discovery, and countermeasure screening. The adult Drosophila melanogaster midgut provides a complementary in vivo platform containing intestinal stem cells, absorptive enterocytes, enteroendocrine cells, epithelial junctions, an associated microbiota, and conserved innate immune and injury-response pathways. Direct irradiation studies have demonstrated DNA damage, altered stem cell proliferation and differentiation, epithelial plasticity, apoptosis, autophagy-associated responses, morphological disruption, barrier failure, microbiome changes, and reduced survival. These phenotypes can be modulated by genotype, sex, diet, microbial status, antioxidant capacity, and regenerative signaling. This review evaluates the biological rationale, direct evidence, experimental assays, and countermeasure applications supporting the fly midgut as a model for studying gastrointestinal radiation injury. Although Drosophila has a long history of use in radiation research, our analysis indicates that the fly midgut is best positioned not as a miniature model of clinical gastrointestinal acute radiation syndrome, but as a genetically precise and scalable system for identifying conserved mechanisms and prioritizing interventions for validation in mammalian models. Full article

(This article belongs to the Special Issue Drosophila: A Versatile Model in Biology and Medicine—3rd Edition)

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25 pages, 1722 KB

Open AccessReview

Emerging Roles of Dystroglycan in Cardiac Remodeling, Fibrosis, and Heart Failure

by Bhola Shankar Pradhan and Michał Mączewski

Int. J. Mol. Sci. 2026, 27(17), 7948; https://doi.org/10.3390/ijms27177948 - 7 Sep 2026

Viewed by 486

Abstract

The dystrophin–glycoprotein complex (DGC) is a structural and signaling network of cardiac muscle. It connects the extracellular matrix to the intracellular cytoskeleton. Dystroglycan, a component of the DGC, plays an essential role in maintaining the integrity of the sarcolemma of cardiac muscle. It [...] Read more.

The dystrophin–glycoprotein complex (DGC) is a structural and signaling network of cardiac muscle. It connects the extracellular matrix to the intracellular cytoskeleton. Dystroglycan, a component of the DGC, plays an essential role in maintaining the integrity of the sarcolemma of cardiac muscle. It contributes to sarcolemma stability, force transmission, mechanotransduction, calcium homeostasis, and cardiomyocyte survival. While the role of dystroglycan signaling is well established in many inherited disorders such as Duchenne muscular dystrophy, it is less studied in acquired heart failure with reduced ejection fraction (HFrEF). Emerging evidence suggests that dystroglycan remodeling may also occur in HFrEF. This review critically analyzes dystroglycan signaling in healthy and failing hearts, with particular emphasis on its emerging role in acquired HFrEF, including cardiac remodeling and fibrosis. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Targets in Cardiovascular Health and Cardiotoxicity)

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21 pages, 1730 KB

Open AccessArticle

From Chemical Scaffold to Predicted Toxicity: A Scaffold-Aware Pipeline for Reliable In Silico Prioritization of Heracleum Furanocoumarins

by Anna E. Rassabina, Victor S. Safronov and Maxim V. Fedorov

Int. J. Mol. Sci. 2026, 27(17), 7947; https://doi.org/10.3390/ijms27177947 - 7 Sep 2026

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Abstract

In silico methods generate numerous toxicity predictions for natural compounds, yet their mutual consistency and transferability to new structures are rarely verified, and the predictions are often taken at face value. Using furanocoumarins of the genus Heracleum as a model class of natural [...] Read more.

In silico methods generate numerous toxicity predictions for natural compounds, yet their mutual consistency and transferability to new structures are rarely verified, and the predictions are often taken at face value. Using furanocoumarins of the genus Heracleum as a model class of natural products, we developed a reproducible computational pipeline that evaluates not the predictions themselves but their reliability. Two datasets were analyzed: an extended reference set (DS1, 2008 compounds from PubChem) and a taxonomically verified natural set (DS2, 102 Heracleum compounds). The pipeline combined scaffold analysis, molecular docking against 44 off-target proteins, redocking, prediction of ten phenotypic toxicity endpoints, scaffold-resolved separability testing, and scaffold-aware machine learning. The chemical space was concentrated around two scaffolds, and the descriptor space was non-randomly organized with respect to them along all 13 axes (false discovery rate (FDR)-adjusted p < 0.01), indicating that the predicted toxicological profile is determined predominantly by molecular structure. The mean docking score corresponded to only the first principal component of the multidimensional binding profile, and the ten endpoints were largely independent of one another. Critically, scaffold separability did not predict transferability: structurally determined signals were only partially reproduced on unseen scaffolds, and to differing degrees across endpoints. A multi-criteria prioritization identified 21 top-priority candidates for experimental follow-up. The reliability of in silico assessments for this class cannot be assumed without scaffold-aware validation. Full article

(This article belongs to the Special Issue Transformative Computational and AI Approaches for Precision Drug Discovery)

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22 pages, 5932 KB

Open AccessArticle

Conserved Epithelial Remodeling Programs Underlie Pediatric Juvenile Colorectal Polyps Associated with Allergic Sensitization

by María Belén Polo, Manuela Ilid, Viviana Bernedo, Paula Borobia, Lorena Menendez, Anabella Zosi, Cecilia Zubirí, Maximiliano Fernández Rivas, María Florencia Recalde, Barbara Virginia Aguilar Becher, Marcela García, Eugenia Altamirano, Luciana Guzmán, Martin Abba, Cecilia Muglia and Guillermo Docena

Int. J. Mol. Sci. 2026, 27(17), 7946; https://doi.org/10.3390/ijms27177946 - 7 Sep 2026

Viewed by 384

Abstract

Juvenile colorectal polyps (JP) are the most common polypoid lesions of the colon in children and the leading cause of lower gastrointestinal bleeding in pediatric patients. Although histologically classified as benign hamartomatous lesions, they arise in a context of allergic sensitization and IgE-mediated [...] Read more.

Juvenile colorectal polyps (JP) are the most common polypoid lesions of the colon in children and the leading cause of lower gastrointestinal bleeding in pediatric patients. Although histologically classified as benign hamartomatous lesions, they arise in a context of allergic sensitization and IgE-mediated inflammation, suggesting that the epithelial compartment may play an active role in their pathogenesis. To date, most studies have focused on the immune cell infiltrate, leaving the molecular programs operating within the epithelium largely unexplored. Whole-transcriptome RNA sequencing (RNA-seq) was performed on epithelial cells isolated from pediatric JP (n = 8) and paired tissue circumjacent to polyp (TCP) (n = 7) obtained from children with a history of rectal bleeding and IgE sensitization to food allergens. Differential expression, functional enrichment (GO, KEGG, GSEA), and cross-dataset comparison with TCGA colorectal adenocarcinoma (CRC) was conducted. Candidate genes were validated by RT-qPCR in independent samples, including colorectal cancer (CRC) and inflammatory bowel disease (IBD) tissue. Differential expression analysis identified 3273 differentially expressed genes (2342 upregulated, 931 downregulated in JP vs. TCP), with 220 genes exceeding 32-fold change, including SERPINB3 (log2FC = 12.16), MMP1 (log2FC = 10.19), NMUR2 (log2FC = 10.08) and CHI3L1 (log2FC = 8.87). JP epithelium displayed a coherent type 2 inflammatory signature, encompassing upregulation of the alarmin IL33, eosinophil-attracting chemokines (CCL11, CCL24), IgE receptor subunits (FCER1A, FCER1G), and a coordinately activated leukotriene and prostaglandin biosynthetic program (ALOX5, ALOX5AP, PTGS2). Concurrent alterations in epithelial identity were observed, including downregulation of absorptive enterocyte and intestinal stem cell markers (CDX2, LGR5, ASCL2) alongside upregulation of secretory and regenerative programs, including the ectopic gastric-type mucin MUC5AC. Tight junction dysregulation—notably upregulation of the pore-forming claudin CLDN2 and loss of barrier-sealing claudins (CLDN3, CLDN4, CLDN23)—was consistent with impaired epithelial permeability. Pathway analyses confirmed activation of type 2 immune and extracellular matrix remodeling programs, with concurrent suppression of mitochondrial oxidative phosphorylation. Cross-dataset comparison with TCGA CRC data identified 381 co-upregulated and 87 co-downregulated genes shared between JP and CRC, including SERPINE1, CXCL8, ICAM1, and MMP3, several of which were associated with poorer disease-specific survival in CRC patients. RT-qPCR validation confirmed elevation of CHI3L1 and SERPINE1 in both JP and CRC, while SERPINB4 appeared JP-specific. Epithelial cells from pediatric juvenile colorectal polyps associated with allergic sensitization display a comprehensive type 2 inflammatory transcriptome alongside profound alterations in lineage identity, barrier integrity, and metabolic programming. Partial convergence with CRC-associated gene expression programs—in the absence of histological dysplasia—suggests that chronic allergic inflammation activates conserved epithelial remodeling pathways shared across mucosal tissues. CHI3L1, SERPINE1, and SERPINB4 are candidate biomarkers warranting validation in larger cohorts. Full article

(This article belongs to the Special Issue Current Research on the Cellular and Molecular Basis of Allergic Diseases)

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