International Journal of Molecular Sciences

22 pages, 24215 KB

Open AccessArticle

Tripterygium Glycosides Extract-Induced Hepatic Cholestasis: A Mechanistic Study Using a Microfluidic Liver-on-a-Chip System

by Yifei Yang, Ya Zhang, Yun Yang, Bing Xia, Haijing Zhang, Guozhuang Zhang, Ping Gong, Ying Qi, Zhe Wu, Chun Li and Ting Liu

Int. J. Mol. Sci. 2026, 27(9), 4154; https://doi.org/10.3390/ijms27094154 - 6 May 2026

Viewed by 649

Abstract

Tripterygium glycosides extract (TGE), the primary active component of tripterygium glycosides tablets, is widely used for immune-related disorders but raises significant clinical concerns regarding cholestatic drug-induced liver injury. As conventional models fail to fully recapitulate the complex pathogenesis of traditional Chinese medicine toxicity, [...] Read more.

Tripterygium glycosides extract (TGE), the primary active component of tripterygium glycosides tablets, is widely used for immune-related disorders but raises significant clinical concerns regarding cholestatic drug-induced liver injury. As conventional models fail to fully recapitulate the complex pathogenesis of traditional Chinese medicine toxicity, this study aimed to elucidate the mechanisms of TGE-induced cholestatic injury using a biomimetic microfluidic liver-on-a-chip platform. The chip integrated rat precision-cut liver slices (PCLSs) and human endothelial cells (EA.hy926) to simulate the hepatic sinusoidal microenvironment. Following TGE exposure (15–135 μg/mL for 12 and 24 h), vascular barrier integrity was maintained, while liver injury markers (ALT, AST, TBA, DBIL) significantly increased in a dose- and time-dependent manner, accompanied by progressive histopathological deterioration in PCLSs. Mechanistically, TGE triggered severe oxidative stress (decreased SOD/GSH/GSH-Px and increased MDA) and upregulated pro-inflammatory cytokines (IL-4 and IL-1β). Consequently, the expression of the bile acid receptor FXR and transporters (BSEP and MRP2) was significantly downregulated. In conclusion, TGE induces cholestatic liver injury via a sequential pathway: oxidative stress initiates an immune-inflammatory response, which subsequently suppresses the FXR/BSEP/MRP2 axis. Future studies should focus on developing fully humanized liver-on-a-chip systems to further validate these mechanisms and improve clinical translational significance. Full article

(This article belongs to the Section Molecular Toxicology)

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22 pages, 24766 KB

Open AccessArticle

Therapeutic Effects of Glycyrrhizic Acid on Dry Eye Disease: Targeting Pyroptosis, Oxidative Stress, and Epithelial Barrier Dysfunction

by Yiran Chu, Chengxiao Zhang, Zeying Chen, Qi Zhang, Yun Tang, Jiaxuan Jiang and Kai Hu

Int. J. Mol. Sci. 2026, 27(9), 4153; https://doi.org/10.3390/ijms27094153 - 6 May 2026

Viewed by 612

Abstract

Dry eye disease (DED) is a common ocular surface disorder characterized by instability of the tear film, inflammatory responses, and epithelial damage, and therapeutic interventions directed at these fundamental pathogenetic processes are still insufficient. This research aimed to evaluate the medicinal efficacy of [...] Read more.

Dry eye disease (DED) is a common ocular surface disorder characterized by instability of the tear film, inflammatory responses, and epithelial damage, and therapeutic interventions directed at these fundamental pathogenetic processes are still insufficient. This research aimed to evaluate the medicinal efficacy of glycyrrhizic acid (GA) and to unravel the underlying molecular pathways through which it exerts its protective role in DED. A benzalkonium chloride-induced mouse model and a hyperosmolarity-induced human corneal epithelial cell model were established. Corneal epithelial injury, tear secretion, and goblet cell density were evaluated in vivo, while cellular responses and related signaling pathways were examined using RT-qPCR, Western blotting, flow cytometry, and immunofluorescence. GA treatment alleviated corneal epithelial damage, increased tear secretion, and improved goblet cell density in mice. In vitro, GA reduced inflammatory responses, as evidenced by decreased tumor necrosis factor-α (TNF-α) expression, and helped preserve epithelial barrier integrity, accompanied by reduced matrix metalloprotease 9 (MMP9) levels. Further analysis suggested that GA suppressed pyroptosis through regulation of the high mobility group box 1 (HMGB1)/lysosomal membrane permeabilization (LMP)/cathepsin B (CTSB) pathway and attenuated oxidative stress via activation of the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/NAD (P)H:quinone oxidoreductase 1 (NQO1) axis. In addition, GA improved mitochondrial function, as indicated by decreased reactive oxygen species levels, restored membrane potential, and enhanced adenosine triphosphate (ATP) production. Taken together, these findings indicate that GA may alleviate hyperosmolarity-induced DED by modulating inflammation, oxidative stress, mitochondrial dysfunction, and epithelial barrier damage, underscoring its viability as a remedial candidate. Full article

(This article belongs to the Special Issue Advances in Bioactivity and Molecular Mechanisms of Natural Products)

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19 pages, 1687 KB

Open AccessArticle

Inflammatory Proteomic Heterogeneity Beyond Glycemia Status in Severe Obesity

by Melissa M. Milito, Mattia Chiesa, Alice Mallia, Giulia G. Papaianni, Julia T. Regalado, Claudio Tiribelli, Deborah Bonazza, Natalia Rosso, Silvia Palmisano, Cristina Banfi and Pablo J. Giraudi

Int. J. Mol. Sci. 2026, 27(9), 4152; https://doi.org/10.3390/ijms27094152 - 6 May 2026

Viewed by 384

Abstract

Chronic low-grade inflammation is a key feature of obesity-associated dysglycemia, yet substantial heterogeneity exists in inflammatory responses among individuals with normoglycemia, prediabetes, and type 2 diabetes mellitus (T2DM). Whether circulating inflammatory protein profiles define distinct patient phenotypes beyond conventional glycemic classification remains incompletely [...] Read more.

Chronic low-grade inflammation is a key feature of obesity-associated dysglycemia, yet substantial heterogeneity exists in inflammatory responses among individuals with normoglycemia, prediabetes, and type 2 diabetes mellitus (T2DM). Whether circulating inflammatory protein profiles define distinct patient phenotypes beyond conventional glycemic classification remains incompletely understood. In this cross-sectional analysis of 142 individuals with severe obesity, plasma inflammatory proteins were quantified using Olink proximity extension assay technology. Subjects were stratified by glycemic status (noDM, normoglycemia; PreDM, prediabetes and T2DM) while maintaining comparable distributions of metabolic dysfunction-associated steatotic liver disease. Differential expression analyses were performed across glycemic groups, and unsupervised topological data analysis (TDA) was applied to identify inflammatory protein-based patient subgroups. Several inflammatory proteins were significantly upregulated in T2DM and PreDM compared with noDM, with interleukin-8 (IL-8), Fms-relatedlike tyrosine kinase 3 ligand (Flt3L), and CUB domain containing protein (CDCP1) showing the largest significant differences. NPX distributions of these proteins exhibited gradual increases across glycemic stages with substantial inter-individual variability. TDA identified seven clusters defined by distinct inflammatory protein signatures. One cluster was enriched for individuals with T2DM and characterized by coordinated upregulation of IL-8, Flt3L, CDCP1, and additional immune- and cytokine-related proteins, whereas other clusters displayed alternative inflammatory profiles that were not explained by glycemic status alone. Inflammatory proteomic profiling in severe obesity reveals both glycemia-associated protein changes and distinct inflammatory phenotypes that transcend conventional clinical classification. Integration of differential expression analysis with TDA highlights heterogeneity in inflammatory states, supporting a hypothesis-generating framework for future studies aimed at validating these proteomic patterns and clarifying their longitudinal relevance in obesity-related dysglycemia. Full article

(This article belongs to the Special Issue Molecular Aspects of Diabetes and Its Complications)

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17 pages, 3775 KB

Open AccessArticle

Targeting TLR4 Attenuates Endometriosis Progression by Suppressing NF-κB/NLRP3 Inflammasome Activation and Angiogenesis

by Yunlei Cao, Xiangxiang Zhu, Xinxin Hou and Ding Ding

Int. J. Mol. Sci. 2026, 27(9), 4151; https://doi.org/10.3390/ijms27094151 - 6 May 2026

Viewed by 507

Abstract

Endometriosis is a chronic inflammatory disorder affecting approximately 10% of reproductive-age women, yet non-hormonal therapeutic options remain limited. This study investigates the role of the TLR4/NF-κB/NLRP3 inflammasome axis in endometriosis pathogenesis and evaluates the therapeutic potential of pharmacologic TLR4 inhibition. Ectopic endometriotic tissues, [...] Read more.

Endometriosis is a chronic inflammatory disorder affecting approximately 10% of reproductive-age women, yet non-hormonal therapeutic options remain limited. This study investigates the role of the TLR4/NF-κB/NLRP3 inflammasome axis in endometriosis pathogenesis and evaluates the therapeutic potential of pharmacologic TLR4 inhibition. Ectopic endometriotic tissues, eutopic endometrium, and peritoneal fluid were collected from 15 patients with ovarian endometriosis and 15 control subjects. The endometriotic epithelial cell line 11Z was stimulated with LPS and ATP with or without the TLR4 inhibitor TAK-242. A murine endometriosis model was established in wild-type C57BL/6 and TLR4⁻/⁻ mice treated with TAK-242. Expression of TLR4, p-p65, NLRP3, caspase-1, cleaved caspase-1 (p20), GSDMD-N, IL-1β, PCNA, and CD31 was assessed by qPCR, Western blot, IHC, and ELISA. Ectopic lesions showed significantly elevated TLR4/NF-κB/NLRP3/IL-1β signaling compared with eutopic and control endometrium (all p < 0.05). Peritoneal fluid IL-1β was increased in patients, indicating a localized pelvic inflammatory response. In vitro, TAK-242 suppressed LPS/ATP-induced NF-κB/NLRP3 activation, pyroptosis, and IL-1β secretion (p < 0.05). Furthermore, the NLRP3-specific inhibitor MCC950 confirmed the essential role of NLRP3 inflammasome activation in IL-1β maturation. In vivo, TLR4 deletion or TAK-242 treatment reduced lesion weight, PCNA proliferation, and CD31 microvessel density (all p < 0.05). TLR4 inhibition blocks NF-κB nuclear translocation and subsequent inflammasome activation, suggesting a potential role in attenuating inflammation and angiogenesis. The TLR4/NF-κB/NLRP3 axis may drive endometriosis progression by linking innate immunity, inflammasome activation, pyroptosis, with possible involvement in angiogenesis warranting further investigation. Pharmacological inhibition of TLR4 attenuates lesion growth, supporting TLR4 as a promising non-hormonal therapeutic target for endometriosis. Full article

(This article belongs to the Section Molecular Immunology)

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23 pages, 4653 KB

Open AccessArticle

Novel Superabsorbent Hydrogels Based on Polyacrylamide and White Angico Gum Enhanced with Kaolinitic Clay and Soapstone for Potential Agricultural Applications

by Angelina Santos de Carvalho, Arthur Francisco de Paiva Alcântara, Vicente de Sousa Marques, Ariane Maria da Silva Santos, Ronaldo Cunha Coelho and Edvani Curti Muniz

Int. J. Mol. Sci. 2026, 27(9), 4150; https://doi.org/10.3390/ijms27094150 - 6 May 2026

Viewed by 307

Abstract

Population growth and climate change demand technologies for the efficient use of water in agriculture. This study aimed to synthesize and characterize hybrid hydrogels of polyacrylamide and white angico gum (Anadenanthera colubrina), reinforced with kaolinitic clay and soapstone, for potential application [...] Read more.

Population growth and climate change demand technologies for the efficient use of water in agriculture. This study aimed to synthesize and characterize hybrid hydrogels of polyacrylamide and white angico gum (Anadenanthera colubrina), reinforced with kaolinitic clay and soapstone, for potential application as soil conditioners and nutrient carriers. The hydrogels were obtained via radical polymerization, followed by alkaline hydrolysis (0.1 mol L⁻¹ NaOH) to convert amide groups into carboxylates. The results indicated that the HPAD formulation [constituted by white angico gum (1:1); 5% (w/w) kaolin and 5% (w/w) steatite (soapstone)] presented the best balance, with a maximum compressive force greater than 200 N, thermal stability up to 310 °C, and a swelling capacity of 60 g/g in saline medium, surpassing the limits of viability for use in soil. The kinetics followed the pseudo-second-order model, and the point of zero charge (pH 9.0–11.7) favored phosphate retention. It is concluded that the HPAD hydrogel, one of several hydrogel formulations developed in this study, is a viable and safe technical alternative, with non-toxicity exceeding 80% in Artemia salina assays and capable of optimizing water and nutrient efficiency in agricultural systems. Full article

(This article belongs to the Special Issue Applications of Polysaccharides in Biomedicine and Agriculture)

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25 pages, 5684 KB

Open AccessReview

Chemical Constituents, Pharmacological Activities, and Cardiovascular Protective Mechanisms of Dendrobium Species: A Review

by Yue Hu, Zhiyong Li, Jian Li, Xiaowen Li and Meina Wang

Int. J. Mol. Sci. 2026, 27(9), 4149; https://doi.org/10.3390/ijms27094149 - 6 May 2026

Viewed by 491

Abstract

The genus Dendrobium, a well-known traditional Chinese medicinal herb, contains complex and diverse chemical constituents. The plant has been widely used in traditional medicine and has attracted increasing attention in modern pharmacological research due to its therapeutic potential. Bibliographic searches were conducted [...] Read more.

The genus Dendrobium, a well-known traditional Chinese medicinal herb, contains complex and diverse chemical constituents. The plant has been widely used in traditional medicine and has attracted increasing attention in modern pharmacological research due to its therapeutic potential. Bibliographic searches were conducted across various recognized databases. The exploration covered the years 1965–2025, and the connectors ‘and’ and ‘or’ were used with keywords such as “Dendrobium”, “phytochemistry”, “pharmacology”, “Cardiovascular diseases”, and “extracts”. The chemical composition of the genus Dendrobium mainly includes alkaloids, bibenzyls, flavonoids, phenanthrenes, phenylpropanoids, and terpenoids. Modern pharmacological studies have demonstrated that the genus Dendrobium exhibits multiple biological effects, including anti-tumor, antibacterial, anti-inflammatory, hypoglycemic, and neuroprotective activities. Notably, the genus Dendrobium shows significant potential in cardiovascular disease prevention and treatment through mechanisms such as antioxidant stress, anti-inflammation, regulation of lipid metabolism, anti-atherosclerosis, and inhibition of myocardial fibrosis. This review provides a comprehensive overview of the chemical components and pharmacological activities of Dendrobium plants, with emphasis on their cardiovascular protective effects. These findings offer a scientific basis for the further development and clinical application of Dendrobium medicinal resources. Full article

(This article belongs to the Section Molecular Pharmacology)

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19 pages, 347 KB

Open AccessReview

Improving the Precision of Etiological Diagnosis in Bacterial Infections Using Molecular Technologies: A Comparative Analysis of Platforms, AI Integration, and Point-of-Care Deployment

by Alina-Marinela Cotelici, Andrei Theodor Bălășoiu, Mihail Virgil Boldeanu, Mohamed-Zakaria Assani, Marius Bogdan Novac, Lidia Boldeanu and Alice Elena Ghenea

Int. J. Mol. Sci. 2026, 27(9), 4148; https://doi.org/10.3390/ijms27094148 - 6 May 2026

Viewed by 419

Abstract

Bacterial infections remain a major global health burden, further exacerbated by the rapid emergence of antimicrobial resistance (AMR), which increases the need for accurate and timely etiological diagnosis. Conventional culture-based methods are limited by prolonged turnaround times, reduced sensitivity in patients receiving prior [...] Read more.

Bacterial infections remain a major global health burden, further exacerbated by the rapid emergence of antimicrobial resistance (AMR), which increases the need for accurate and timely etiological diagnosis. Conventional culture-based methods are limited by prolonged turnaround times, reduced sensitivity in patients receiving prior antimicrobial therapy, and restricted ability to characterize resistance mechanisms at the molecular level. Molecular diagnostic technologies have significantly transformed bacteriological diagnostics by enabling rapid, sensitive, and specific pathogen detection directly from clinical specimens. This review provides a structured comparative analysis of major molecular platforms, including polymerase chain reaction (PCR) and its variants, isothermal amplification technologies, next-generation sequencing (NGS), clustered regularly interspaced short palindromic repeats (CRISPR) based diagnostics, and digital PCR (dPCR). Key analytical parameters such as sensitivity, specificity, limit of detection (LOD), time to result, and multiplexing capacity are evaluated to highlight platform-specific strengths and limitations. In addition, the integration of artificial intelligence and machine learning (AI/ML) into molecular diagnostic workflows for AMR prediction and clinical decision support is critically examined. The translational potential of these technologies toward point-of-care (POC) implementation is also discussed, with consideration of clinical validation, operational constraints, and real-world applicability. Overall, this review provides an integrated perspective on current molecular diagnostic strategies, emphasizing the balance between analytical performance and clinical interpretability, and outlines key challenges and future directions for advancing culture-independent bacteriological diagnostics. Full article

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

20 pages, 4164 KB

Open AccessArticle

LA-GM-CSF, a Long-Acting Cytokine Mitigates and Prevents H-ARS Mediated Lethality in Mice Exposed to Total Body Gamma Radiation

by Gregory P. Holmes-Hampton, Kaylee Valenzia, Vidya P. Kumar, Venkateshwara Rao Dronamraju, Ashley Woods, Sean B. Joseph and Sanchita P. Ghosh

Int. J. Mol. Sci. 2026, 27(9), 4147; https://doi.org/10.3390/ijms27094147 - 6 May 2026

Viewed by 432

Abstract

Widespread uses of nuclear materials increase the risk of accidental or intentional radiation exposure, which can result in acute radiation syndrome (ARS). Hematopoietic ARS (H-ARS) occurs at relatively low doses and is potentially lethal without intervention. While several FDA-approved cytokine-based radiomitigators exist, many [...] Read more.

Widespread uses of nuclear materials increase the risk of accidental or intentional radiation exposure, which can result in acute radiation syndrome (ARS). Hematopoietic ARS (H-ARS) occurs at relatively low doses and is potentially lethal without intervention. While several FDA-approved cytokine-based radiomitigators exist, many require repeated dosing, complicating deployment in mass-casualty scenarios. This study evaluated a novel long-acting, murine-reactive granulocyte–macrophage colony-stimulating factor (LA-GM-CSF; mPDM608) as a prophylactic and mitigative countermeasure for H-ARS. Male and female C57BL/6 mice were exposed to lethal or sublethal total body irradiation (TBI) and treated with LA-GM-CSF using single- or multi-dose regimens administered before or after TBI. Safety, 30-day survival, hematologic recovery, bone marrow cellularity, serum GM-CSF pharmacokinetics, endothelial injury markers, and cytokine profiles were assessed using standard hematology, histopathology, ELISA, and multiplex assays. LA-GM-CSF was well tolerated at doses up to 30 mg/kg. Single or limited dosing conferred significant survival benefits compared with vehicle controls, with optimal efficacy observed at lower doses (3 mg/kg). Post-TBI administration as a single dose 24 h after exposure markedly improved survival in both sexes, with stronger hematopoietic recovery in males. LA-GM-CSF accelerated recovery of neutrophils, red blood cells, platelets, hematocrit, and sternal megakaryocytes, prolonged circulating GM-CSF levels, and favorably modulated endothelial injury markers and select cytokines. LA-GM-CSF demonstrates strong potential as a next-generation radiation countermeasure, providing robust survival benefit and hematopoietic recovery with minimal dosing. The results shown here support further development for H-ARS management under the FDA Animal Rule. Full article

(This article belongs to the Special Issue New Insight into Radiation Biology and Radiation Exposure)

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15 pages, 3097 KB

Open AccessArticle

Atorvastatin Attenuates Human Cardiac Fibroblast Activation, with Associated Changes in GATA4/MEF2C and Selected Fibrosis-Related microRNAs

by Nikola Chomaničová, Adriana Adamičková, Zdenko Cervenak, Simona Valášková, Andrea Gažová and Jan Kyselovic

Int. J. Mol. Sci. 2026, 27(9), 4146; https://doi.org/10.3390/ijms27094146 - 6 May 2026

Viewed by 333

Abstract

Cardiac fibroblast activation into α-smooth muscle actin (α-SMA)-expressing myofibroblasts is a central event in the progression of cardiac fibrosis. Therapeutic strategies capable of reversing or inhibiting this phenotypic transition are therefore of critical interest. Here, we explore associative changes in transcriptional and post-transcriptional [...] Read more.

Cardiac fibroblast activation into α-smooth muscle actin (α-SMA)-expressing myofibroblasts is a central event in the progression of cardiac fibrosis. Therapeutic strategies capable of reversing or inhibiting this phenotypic transition are therefore of critical interest. Here, we explore associative changes in transcriptional and post-transcriptional regulators linked to fibroblast activation following atorvastatin exposure in primary human cardiac fibroblasts (HCFs). Atorvastatin treatment (10 µM) was associated with a reduction in α-SMA expression, consistent with decreased myofibroblast activation. This change co-occurred with reduced expression of the transcription factors GATA4 and MEF2C, which are implicated in cardiac cell identity and plasticity. Concurrently, atorvastatin treatment was associated with selective increase in specific fibrosis-related microRNAs, including miR-24, miR-26a, and miR-133a, whereas the expression of miR-21 and miR-23a remained unchanged. Together, these findings describe a coordinated pattern of transcriptional and post-transcriptional changes associated with atorvastatin exposure in HCFs, consistent with a shift away from the myofibroblast phenotype. These observations provide descriptive, hypothesis-generating insight into potential regulatory patterns associated with atorvastatin treatment, although further functional studies are required to establish causal relationships and translational relevance. Full article

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24 pages, 2671 KB

Open AccessArticle

Injectable Sodium Hyaluronate Hydrogels Modified by Ionic and Nonionic Polymers Loaded with Prednisolone Disodium Phosphate: Molecular Interactions and Intra-Articular Drug Delivery

by Dorota Wójcik-Pastuszka, Weronika Pacześniak and Witold Musiał

Int. J. Mol. Sci. 2026, 27(9), 4145; https://doi.org/10.3390/ijms27094145 - 6 May 2026

Viewed by 387

Abstract

Degenerative joint disease is a major cause of disability, and although glucocorticosteroids and hyaluronic acid are widely used to reduce inflammation and improve joint mobility, the development of effective delivery systems remains a challenge. This study describes injectable sodium hyaluronate (HA)-based hydrogels modified [...] Read more.

Degenerative joint disease is a major cause of disability, and although glucocorticosteroids and hyaluronic acid are widely used to reduce inflammation and improve joint mobility, the development of effective delivery systems remains a challenge. This study describes injectable sodium hyaluronate (HA)-based hydrogels modified with synthetic polymers, including polyacrylic acid (PA), ammonium acryloyldimethyltaurate/VP copolymer (AX), a polyvinyl acetate–polyvinylpyrrolidone mixture (PVA–PVP), and polyethylene glycol 4000 (PEG), loaded with prednisolone disodium phosphate (PSP). The aim was to investigate molecular interactions between PSP and HA-based polymer networks and to determine how these interactions influence hydrogel structure, viscosity, and drug release. Viscosity was measured using a Brookfield rotational viscometer, while intermolecular interactions were analyzed by ATR–FTIR and DSC. Drug release was evaluated using a paddle-over-disc apparatus and quantified spectrophotometrically. Release kinetics were analyzed using zero-, first-, and second-order models as well as the Higuchi, Korsmeyer–Peppas, and Peppas–Sahlin equations. PSP incorporation affected the dynamic viscosity of all formulations, and excipient type also significantly influenced hydrogel viscosity. ATR–FTIR and DSC analyses indicated hydrogen bond formation between PSP and the macromolecules of HA, PA, AX, and PEG. The PA-containing formulation formed the most extensive polymer network structure and exhibited the highest viscosity. Drug release followed mainly first-order, Higuchi, and Korsmeyer–Peppas models, while the release exponent n (0.58 ± 0.01–0.60 ± 0.01) indicated anomalous transport. These findings provide molecular insight into drug–polymer interactions in HA-based hydrogels and highlight their potential as injectable systems for intra-articular delivery of PSP. Full article

(This article belongs to the Special Issue Recent Advances in Polymeric Biomaterials)

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33 pages, 765 KB

Open AccessReview

Molecular Insights into Oral Manifestations in Sjögren’s Disease

by Konstantina Xanthopoulou, Anna Siatra, Konstantinos I. Tosios and Eleni-Marina Kalogirou

Int. J. Mol. Sci. 2026, 27(9), 4144; https://doi.org/10.3390/ijms27094144 - 6 May 2026

Viewed by 460

Abstract

Sjögren’s Disease is an autoimmune epithelitis targeting the exocrine glands, predominantly the salivary and lacrimal glands, resulting in the major symptoms of dry mouth and dry eyes. The aim of this study is to review the pertinent literature on studies linking the oral [...] Read more.

Sjögren’s Disease is an autoimmune epithelitis targeting the exocrine glands, predominantly the salivary and lacrimal glands, resulting in the major symptoms of dry mouth and dry eyes. The aim of this study is to review the pertinent literature on studies linking the oral manifestations of SjD patients, with the underlying molecular events driving SjD pathogenesis. These include mechanisms inducing innate sensing in salivary gland epithelial cells, activation of interferon signaling pathway, amplification of cytokines and chemokines, and orchestration of the inflammatory milieu in salivary glands, as well as mechanisms inducing salivary epithelial tissue destruction and secretory dysfunction, such as programmed cell death pathways, mitochondrial dysfunction, structural disorganization, loss of junctional integrity, and quantitative and qualitative aberrations in salivary secretory process. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome, 4th Edition)

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21 pages, 721 KB

Open AccessReview

Systematic Review of Monocyte Transcriptomic Profiles as Diagnostic and Prognostic Biomarkers in Colorectal Cancer

by Alicia Podadera-Herreros, Jesús Pilo, Alejandro Rego-Calvo, María Ortega-Castan, Carolina Muriel-López, Daniel Hinojosa-Nogueira, Isabel Moreno-Indias, María del Mar Amaya-Campos, Julia Alcaide-García, Hatim Boughanem, Libia Alejandra García Flores and Manuel Macías-González

Int. J. Mol. Sci. 2026, 27(9), 4143; https://doi.org/10.3390/ijms27094143 - 6 May 2026

Viewed by 450

Abstract

Colorectal cancer (CRC) remains a major global health burden and a leading cause of cancer-related morbidity and mortality. Current blood-based biomarkers lack sufficient sensitivity and specificity, particularly for early detection. In this context, circulating immune-cell transcriptomic profiling has emerged as a promising minimally [...] Read more.

Colorectal cancer (CRC) remains a major global health burden and a leading cause of cancer-related morbidity and mortality. Current blood-based biomarkers lack sufficient sensitivity and specificity, particularly for early detection. In this context, circulating immune-cell transcriptomic profiling has emerged as a promising minimally invasive approach. This systematic review was conducted following a PROSPERO-registered protocol (CRD42024604757) and PRISMA 2020 guidelines to evaluate the diagnostic and prognostic potential of circulating monocyte-related transcriptomic profiles in CRC. Of 295 records identified, six studies met the inclusion criteria. The available evidence consistently supports the diagnostic value of circulating transcriptomic profiles in distinguishing patients with CRC from healthy individuals and in reflecting tumour-associated immune alterations. Monocyte-related signatures, including CXCR2⁺ monocytes, were associated with disease stage and metastatic features. Epitranscriptomic modifications, such as m6A and m5C, further reinforced their diagnostic relevance, with some studies reporting higher diagnostic accuracy than classical biomarkers. In contrast, evidence for prognostic value remains limited, heterogeneous, and often indirect, largely due to small sample sizes, methodological variability, and reliance on public datasets. Overall, circulating immune-cell transcriptomic profiles are promising non-invasive biomarkers for CRC detection and characterization, although their prognostic utility remains unclear. Methodological heterogeneity limits clinical applicability, highlighting the need for standardized, CRC-specific studies with cell-type-resolved approaches. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in “Molecular Immunology”)

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21 pages, 774 KB

Open AccessReview

Transfer RNA Fragments in Diseases of Sensory Organs

by Nikita Gulati, Zhongyu Yang, Yan X. Lin, Hameed Sanusi, Bianca Gonda, Dylan C. McNally, Alaina Stellwag, Madison C. Holmes, Rabiba Chaudhary, Johannah Stevenson, Kelly Lepouski, Lanae Johnson-Kleinpeter, Sathyanarayanan Vaidhyanathan, Maria E. Solesio and Andrey Grigoriev

Int. J. Mol. Sci. 2026, 27(9), 4142; https://doi.org/10.3390/ijms27094142 - 6 May 2026

Viewed by 617

Abstract

Transfer RNA-derived fragments (tRFs) have been recently recognized for their multiple roles in gene expression, including modulation of translation, mRNA stability, and cellular signaling pathways. Sensory organs, such as the eyes, skin, and oral cavity, are continuously exposed to environmental stressors, including oxidative [...] Read more.

Transfer RNA-derived fragments (tRFs) have been recently recognized for their multiple roles in gene expression, including modulation of translation, mRNA stability, and cellular signaling pathways. Sensory organs, such as the eyes, skin, and oral cavity, are continuously exposed to environmental stressors, including oxidative stress, ultraviolet radiation, microbial challenges, and mechanical stimuli, making them particularly susceptible to dysregulation of RNA-mediated processes. This review comprehensively summarizes current evidence on the role of tRFs in sensory organ physiology and pathology with a focus on their involvement in key processes, such as angiogenesis, inflammation, immune regulation, and fibrosis. tRFs have been shown to influence critical signaling pathways that are central to diseases such as retinal neovascularization, inflammatory skin conditions, wound healing, tissue remodeling, etc. Despite these advances, the field remains limited by a lack of experimentally validated tRF-target interactions, as most available data rely on computational predictions. The findings from the literature emphasize the need for rigorous functional validation in disease-relevant models of tRFs in biofluids, such as saliva and serum, to support their potential as minimally invasive biomarkers. Further translational studies are required to fully elucidate their biological roles and explore their potential in diagnostic and therapeutic applications. Full article

(This article belongs to the Collection Advances in Cell and Molecular Biology)

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19 pages, 20073 KB

Open AccessArticle

Prunus mume Concentrate and Ca²⁺ Dual Cross-Linking Facilitate Sodium Alginate/Carboxymethyl Chitosan/Gelatin Microcapsules for Probiotic Encapsulation

by Tenglong Miao, Ni An, Huhu Wang, Chuang Zhang, Xin Rui, Qiuqin Zhang and Xinglian Xu

Int. J. Mol. Sci. 2026, 27(9), 4141; https://doi.org/10.3390/ijms27094141 - 6 May 2026

Viewed by 319

Abstract

This study presents a novel dual cross-linking method using Prunus mume concentrate (PMC) as a source of H⁺ and Ca²⁺ to enhance polysaccharide (sodium alginate/carboxymethyl chitosan/gelatin) microcapsule formation. The structure and release characteristics of microcapsules were influenced more by PMC pH [...] Read more.

This study presents a novel dual cross-linking method using Prunus mume concentrate (PMC) as a source of H⁺ and Ca²⁺ to enhance polysaccharide (sodium alginate/carboxymethyl chitosan/gelatin) microcapsule formation. The structure and release characteristics of microcapsules were influenced more by PMC pH than by its concentration. SEM results showed that as the pH decreased, the microcapsules had a more compact structure. The FTIR results showed that acid enhances hydrogen bonding and electrostatic interactions within the polysaccharide, leading to more stable microcapsule structures. XRD patterns showed that acid enhanced the stability of the polysaccharide crystal structure. Microcapsules significantly increased viable counts by 1 log(CFU/mL) in simulated gastric fluid (SGF) and 1.25 log(CFU/mL) in simulated intestinal fluid (SIF) after 3 h of digestion. This study provides a basis for investigating the dual cross-linking of natural plant concentrates and Ca²⁺ construction of polysaccharide microcapsules to enhance probiotic resistance. Full article

(This article belongs to the Section Macromolecules)

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14 pages, 1975 KB

Open AccessArticle

Effects of Early Treatment with Lipid Core Nanoparticles-Associated Methotrexate on Cardiac Remodeling and Soleus Muscle Inflammasomes in Infarcted Rats

by Anna Clara C. Santos, Mariana Gatto, Gustavo A. F. Mota, Patrícia A. Borim, Rafael C. F. Silva, Ana Luisa B. Meirelles, Lidiane M. Souza, Elida P. B. Ojopi, Eder A. Rodrigues, Luana U. Pagan, Ana Paula S. Marreiros, Gabriela Brandao, Leonardo A. M. Zornoff, Raul C. Maranhão, Katashi Okoshi and Marina P. Okoshi

Int. J. Mol. Sci. 2026, 27(9), 4140; https://doi.org/10.3390/ijms27094140 - 6 May 2026

Viewed by 542

Abstract

Substances released by cardiomyocytes after myocardial infarction (MI) lead to inflammasome assembly. Heart failure (HF) is associated with skeletal muscle inflammation. Methotrexate (MTX) reduces cardiovascular outcomes in chronic inflammation patients. Lipid core nanoparticle-associated MTX (MTX-LDE) attenuated cardiac remodeling in MI rats. We investigated [...] Read more.

Substances released by cardiomyocytes after myocardial infarction (MI) lead to inflammasome assembly. Heart failure (HF) is associated with skeletal muscle inflammation. Methotrexate (MTX) reduces cardiovascular outcomes in chronic inflammation patients. Lipid core nanoparticle-associated MTX (MTX-LDE) attenuated cardiac remodeling in MI rats. We investigated the effects of early MTX-LDE administration on cardiac remodeling and inflammasomes in soleus muscle of MI rats. Wistar rats were separated into Sham, MI, and MI-MTX groups. MTX was initiated 24 h after MI at 1 mg/kg/week intraperitoneally for 10 weeks. Soleus protein expression of NLRP1, NLRP3, NLRC4, ASC, procaspase-1, Caspase-1, pro-IL-1β, and IL-1β was quantified by Western blotting; Nlrp1a, Nlrp3, Nlrc4, Pycard (Asc), Casp1, and Il1b gene expression was assessed by qPCR; and statistical analysis used Student’s t test and ANOVA. Rats with infarction size > 35% total left ventricle (LV) area were included in the study; infarction size did not differ between groups. Echocardiogram showed infarcted groups with LV dilation and dysfunction. Diastolic function was worse in MI-MTX than MI. NLRP1 and NLRC4 protein expression was lower in MI-MTX than Sham. Expression of other proteins and gene expression did not differ between groups. Early MTX-LDE administration reduces NLRP1 and NLRC4 protein expression in soleus muscle without improving cardiac remodeling in rats. Full article

(This article belongs to the Section Molecular Nanoscience)

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19 pages, 2504 KB

Open AccessArticle

Immunological Profiling of Leukocyte Subset Proportions and Novel Blood Biomarkers in the Acute Phase of Ocular Sarcoidosis and Vogt–Koyanagi–Harada Disease: An Exploratory Pilot Study

by Tomohito Sato, Yuki Takenaka, Yoshiaki Nishio, Masataka Ito and Masaru Takeuchi

Int. J. Mol. Sci. 2026, 27(9), 4139; https://doi.org/10.3390/ijms27094139 - 6 May 2026

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Abstract

Aberrant pathogenic immune responses drive autoimmune uveitides; however, comprehensive leukocyte profiling in the conditions remains limited. Here, this exploratory pilot study aimed to elucidate the immunodynamics of ocular sarcoidosis (OS) and Vogt–Koyanagi–Harada disease (VKH) to identify blood diagnostic biomarkers during their acute phases. [...] Read more.

Aberrant pathogenic immune responses drive autoimmune uveitides; however, comprehensive leukocyte profiling in the conditions remains limited. Here, this exploratory pilot study aimed to elucidate the immunodynamics of ocular sarcoidosis (OS) and Vogt–Koyanagi–Harada disease (VKH) to identify blood diagnostic biomarkers during their acute phases. We performed a prospective observational analysis of ten newly diagnosed, treatment-naïve OS patients and seven VKH patients during their acute phases, along with eight healthy controls (HCs). Mass cytometry was utilized to quantify the proportions of 37 distinct leukocyte subsets. In OS group, the proportion of CD8⁺ naive was lower than in both VKH and control groups. Furthermore, the proportions of CD8⁺ central memory and γδ T cells were decreased compared to HC group. Hierarchical cluster analysis categorized the leukocyte subsets into four principal clusters: Cluster A (Th17-like, monocytes, neutrophils, etc.), Cluster B (Tregs, B cells, NK cells, basophils, etc.), Cluster C (CD8⁺ T cells, Th1-like, Th2-like, DCs, etc.), and Cluster D (CD4⁺ terminal effector, CD8⁺ terminal effector, and CD66b⁻ neutrophils). Compared to HC group, the abundance of Cluster A was relatively high in OS group, and the abundance of cluster B was relatively high in VKH group. In OS group, the proportions of CD8⁺ T cells and CD8⁺ terminal effector correlated negatively with serum ACE and sIL-2R levels. ROC curve analysis estimated that CD4⁺/CD8⁺ ratio (cut-off value: ≥3.46), the proportion of monocytes (≥9.41%), and the decreased proportions of CD3⁺ T cells (≤43.9%) and CD8⁺ T cells (≤10.0%) in peripheral blood may serve as potential blood biomarkers for diagnosing OS. The exploratory pilot study provides a comprehensive and simultaneous data of leukocyte subset proportions in the acute phase of OS and VKH, and our preliminary findings suggest that the proportions of specific leukocyte subsets may represent potential candidates for blood-based biomarkers in the diagnosis of OS. Full article

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

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2 pages, 147 KB

Open AccessCorrection

Correction: İlhan et al. Exploratory Analysis of Circulating Serum miR-197-3p, miR-1236, and miR-1271 Expression in Early Breast Cancer. Int. J. Mol. Sci. 2025, 26, 8944

by Burak İlhan, Sibel Kuraş, Berkay Kılıç, Ceren Tilgen Yasasever, Hilal Oğuz Soydinç, Hani Alsaadoni, Gözde Öztan, Arash Adamnejad Ghafour, Muhammed Ucuncu, Enver Kunduz and Süleyman Bademler

Int. J. Mol. Sci. 2026, 27(9), 4138; https://doi.org/10.3390/ijms27094138 - 6 May 2026

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Abstract

The following reference [45] has been retracted and should be replaced from the original publication [...] Full article

(This article belongs to the Section Molecular Biology)

30 pages, 5401 KB

Open AccessArticle

Differential Acute Kidney Injury Profiles of GLP-1RAs and SGLT2is: A Network Meta-Analysis

by Chih-Sung Liang, Chih-Wei Hsu, Jiann-Jy Chen, Chao-Ming Hung, Bing-Yan Zeng, Wei-Chieh Yang, Mein-Woei Suen, Hung-Yu Wang, Andre F. Carvalho, Brendon Stubbs, Yen-Wen Chen, Tien-Yu Chen, Wei-Te Lei, Shih-Pin Hsu, Yow-Ling Shiue, Cheng-Ta Li, Kuan-Pin Su, Bing-Syuan Zeng and Ping-Tao Tseng

Int. J. Mol. Sci. 2026, 27(9), 4137; https://doi.org/10.3390/ijms27094137 - 6 May 2026

Viewed by 919

Abstract

Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose co-transporter 2 inhibitors (SGLT2is) have demonstrated protective effects against chronic kidney disease, their impact on acute kidney injury (AKI) remains unclear. AKI and chronic kidney disease share overlapping clinical features but differ in pathogenesis and [...] Read more.

Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose co-transporter 2 inhibitors (SGLT2is) have demonstrated protective effects against chronic kidney disease, their impact on acute kidney injury (AKI) remains unclear. AKI and chronic kidney disease share overlapping clinical features but differ in pathogenesis and risk profiles. Previous analyses often grouped diverse agents into single categories, potentially concealing medication-specific renal risks. Given the widespread assumption of renoprotection, particularly among newer agents, there is a need to evaluate the comparative AKI risk of GLP-1RAs and SGLT2is at the individual drug and dose level. We performed a Bayesian network meta-analysis (NMA) following Cochrane-recommended methodology for safety-focused assessments. A systematic literature search across eight databases identified 67 randomized controlled trials (RCTs), including 199,877 participants. Eligible trials reported AKI outcomes or sufficiently explicit acute renal injury-related events associated with GLP-1RA or SGLT2i interventions. The primary outcome was the incidence of AKI; all-cause dropout was analyzed as a general tolerability measure. Odds ratios (ORs) with 95% credible intervals (CrIs) were calculated, and surface under the cumulative ranking curves (SUCRA) were used to estimate relative safety rankings. Only high-dose tirzepatide (10–15 mg/week) was associated with a significantly increased risk of AKI compared to controls (absolute risk difference: 0.28%; number needed to harm: 357). In contrast, lixisenatide, high-dose canagliflozin (300 mg/day), empagliflozin, and dapagliflozin were associated with reduced AKI risk. Risk rankings consistently identified high-dose tirzepatide as the most likely to induce AKI. Subgroup analyses excluding patients with baseline renal impairment yielded consistent results. High-dose tirzepatide may elevate AKI risk despite its metabolic benefits. Clinicians should assess renal vulnerability when prescribing GLP-1RAs or SGLT2is, particularly in patients with preserved kidney function. Further prospective trials are needed to clarify causal mechanisms and inform clinical decision-making. Full article

(This article belongs to the Special Issue Molecular Metabolism in Human Health and Disease)

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36 pages, 5917 KB

Open AccessArticle

Epidermal PPARγ Signaling as a Suppressor of Toll-like Receptor-Mediated Inflammation and Fibrosis: Relevance to Cutaneous Squamous Cell Carcinoma

by Raymond L. Konger and Ethel Derr-Yellin

Int. J. Mol. Sci. 2026, 27(9), 4136; https://doi.org/10.3390/ijms27094136 - 5 May 2026

Viewed by 707

Abstract

Mice lacking epidermal Pparg (Pparg-/-^epi) exhibit increased cutaneous carcinogenesis, while PPARγ signaling is reduced in actinic keratoses (AKs) and cutaneous squamous cell carcinomas (cSCCs). Using transcriptomic analysis, we now show that the top upregulated genes in Pparg-/-^epi [...] Read more.

Mice lacking epidermal Pparg (Pparg-/-^epi) exhibit increased cutaneous carcinogenesis, while PPARγ signaling is reduced in actinic keratoses (AKs) and cutaneous squamous cell carcinomas (cSCCs). Using transcriptomic analysis, we now show that the top upregulated genes in Pparg-/-^epi mouse skin, human AKs and cSCCs encode multiple damage-associated molecular patterns (DAMPs) that are TLR4 ligands, while the TLR4 agonist lipopolysaccharide (LPS) is also predicted to be the top common activated upstream regulator in both Pparg-/-^epi mouse skin and in tumor datasets. By single-cell sequencing, DAMP expression was particularly elevated in myeloid cells and myofibroblasts of Pparg-/-^epi mice, and these cell types exhibit transcriptional changes consistent with TLR4 signaling. Myeloid cells also exhibited a loss of Pparg expression and activity. Transcriptional analysis of published LPS-treated macrophages also reveals a decrease in PPARγ activity. Fibroblasts from Pparg-/-^epi mice included cells with a gene expression profile resembling myofibroblasts found in cancer and fibrotic diseases. This was accompanied by increased dermal fibrosis in aged mice and a transcriptomic profile that indicates a key role for both TLR4 and TGFβ signaling. These data suggest that loss of epidermal PPARγ may disrupt counterbalancing PPARγ–TLR4 signals, leading to chronic inflammation and fibrosis, hallmarks of cutaneous neoplasia. Full article

(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer (2nd Edition))

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21 pages, 4974 KB

Open AccessArticle

TGBWDriver: A Cancer Driver Gene Identification Method Based on GraphSAGE and Bidirectional Weighted Feature Aggregation

by Jiaxin Chen, Yingzan Ren, Haihui Wang, Cong Zhan and Yusen Zhang

Int. J. Mol. Sci. 2026, 27(9), 4135; https://doi.org/10.3390/ijms27094135 - 5 May 2026

Viewed by 522

Abstract

Identifying cancer driver genes is fundamental for understanding tumor initiation and guiding therapeutic strategies. However, most existing methods assess gene importance from a global or static perspective, overlooking sample-specific functional differences in the same gene. To address this, we propose TGBWDriver, which integrates [...] Read more.

Identifying cancer driver genes is fundamental for understanding tumor initiation and guiding therapeutic strategies. However, most existing methods assess gene importance from a global or static perspective, overlooking sample-specific functional differences in the same gene. To address this, we propose TGBWDriver, which integrates a two-layer GraphSAGE with bidirectional weighted feature aggregation to capture structural characteristics while distinguishing context-dependent gene functions. An exponential pairwise voting strategy prioritizes candidate driver genes, improving ranking stability and accuracy. Systematic experiments on BRCA, LUAD, and PRAD datasets show that TGBWDriver outperforms five existing methods in precision, recall, and F1-score. Ablation studies confirm the critical role of each component. Moreover, TGBWDriver demonstrates strong capability in identifying potential novel cancer driver genes, with predictions showing significant biological relevance in GO enrichment and KEGG pathway analyses. The method provides an effective computational framework for cancer driver gene identification. The source code and datasets are freely available at https://github.com/SCSMDyeah/TGBW [Accessed on 4 May 2026]. Full article

(This article belongs to the Special Issue Advances in Bioinformatics and Multi-Omics Applications in Cancer Research)

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21 pages, 1634 KB

Open AccessReview

Mediterranean Diet Can Reduce Fat Accumulation and Obesity Progression Through Action of Plant Bioactive Molecules

by Paola Sportiello, Miriam Piccioni, Vito Flavio Licciulli, Giuseppe Cananzi, Stefania Crispi and Domenico Catalano

Int. J. Mol. Sci. 2026, 27(9), 4134; https://doi.org/10.3390/ijms27094134 - 5 May 2026

Viewed by 638

Abstract

Obesity is a multifactorial disease associated with a chronic imbalance between energy intake and energy consumption, as well as the ingestion of high-fat foods. It is widely reported that the Mediterranean Diet (MD), a dietary regimen rich in vegetables, fruits, fiber and complex [...] Read more.

Obesity is a multifactorial disease associated with a chronic imbalance between energy intake and energy consumption, as well as the ingestion of high-fat foods. It is widely reported that the Mediterranean Diet (MD), a dietary regimen rich in vegetables, fruits, fiber and complex polyunsaturated lipids, can positively act on obesity onset. These aliments contain bioactive molecules that exert beneficial effects on two traits often associated with obesity: lipid accumulation and imbalance in oxidative homeostasis. Additionally, they can act on metabolic pathways linked to obesity through the cross-kingdom activity of plant miRNAs. In this review, we provide an overview of the studies describing the anti-obesogenic effect of plant-based foods typical of the Mediterranean Diet. We describe the results of recent studies that link the effect of lipid reduction with the ingestion of bioactive molecules or plant miRNAs typical of MD foods. We also report how advances in bioinformatic analyses have elucidated the role of plant-derived miRNAs in metabolic homeostasis, revealing how the cross-kingdom interaction results in the anti-obesogenic action of the MD. These findings shed light on the molecular mechanisms through which the MD dietary pattern exerts its metabolic effects, suggesting new perspectives on MD nutrition-based strategies as novel therapeutic approaches for obesity. Full article

(This article belongs to the Special Issue Natural and Synthetic Compounds for Management, Prevention and Treatment of Obesity, 3rd Edition)

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23 pages, 529 KB

Open AccessReview

Trained Immunity Induced by Vaccines: A Shifting Paradigm for Infant and Adult Immunity

by Shana Singh-Anderson, Gio Aguilar, Lina Zhang, Kuang-Chih Hsiao and Gergely Toldi

Int. J. Mol. Sci. 2026, 27(9), 4133; https://doi.org/10.3390/ijms27094133 - 5 May 2026

Viewed by 771

Abstract

In addition to inducing pathogen-specific adaptive immune responses, vaccines can train the innate immune system, thereby providing broader host protection. This concept of trained immunity (TRIM) is well-established in benchtop laboratory science. This review aims to evaluate the current evidence of vaccine-induced TRIM [...] Read more.

In addition to inducing pathogen-specific adaptive immune responses, vaccines can train the innate immune system, thereby providing broader host protection. This concept of trained immunity (TRIM) is well-established in benchtop laboratory science. This review aims to evaluate the current evidence of vaccine-induced TRIM and translate these findings into a clinical context. Various laboratory methods are used to assess TRIM; however, inconsistent results have been reported across non-BCG vaccine studies. Existing analyses lack exploration of the mechanistic basis of vaccine-induced TRIM, particularly epigenetic reprogramming and metabolic rewiring. Patterns emerge between vaccines: live-attenuated vaccines generally induce TRIM, as evidenced by increased inflammatory cytokine production upon restimulation, whereas non-live vaccines tend to demonstrate reduced trained immunity. Such findings are not consistently observed for mRNA vaccines, which show heterogeneous patterns. The limited variety of studies on non-BCG vaccines impacts the reliability of findings. A more comprehensive understanding of the mechanisms and outputs of TRIM induced by specific vaccines could better inform rational vaccine design. Furthermore, various modifiers can alter vaccine-induced TRIM responses, including sequence and route of administration, sex, and age. Consideration of these modifiers has important clinical implications in optimising vaccine administration for enhanced immune protection. Full article

(This article belongs to the Special Issue Advances in Vaccine Immunology)

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28 pages, 15111 KB

Open AccessArticle

A Post-GWAS Analysis of the Shared Genetic Architecture Between COVID-19 and Coronary Artery Disease

by Muhammad Sarfraz Ali, Waseem Haider, Sana Aziz, Anwaruddin Mohammad, Ani Manichaikul and Weibin Shi

Int. J. Mol. Sci. 2026, 27(9), 4132; https://doi.org/10.3390/ijms27094132 - 5 May 2026

Viewed by 797

Abstract

An individual’s host genetics influence its susceptibility to both COVID-19 and coronary artery disease (CAD). We analyzed large-scale GWAS datasets encompassing 7.7 million SNPs to identify shared genetic architecture between the two diseases. We identified 24 pleiotropic risk loci for both COVID-19 and [...] Read more.

An individual’s host genetics influence its susceptibility to both COVID-19 and coronary artery disease (CAD). We analyzed large-scale GWAS datasets encompassing 7.7 million SNPs to identify shared genetic architecture between the two diseases. We identified 24 pleiotropic risk loci for both COVID-19 and CAD, with three loci (1p31.1, 8p21.3, and 18q11.2) showing strong evidence for a single shared causal variant. Loci in the 8p21.3 and 18q11.2 regions showed a bidirectional causal association: COVID-19 to CAD or vice versa, while the 1p31.1 locus only showed a CAD to COVID-19 unilateral casual association in a Mendelian randomization analysis (GSMR). A fine mapping analysis of the three loci identified three lead pleiotropic variants (rs7515509, rs8192330, and rs4800403). The variant rs7515509 was spatially associated with AK5, PIGK, USP33, and ZZZ3; rs8192330 with DMTN, PIWIL2, and several other genes; and rs4800403 with GATA6 and CTAGE1. Transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients validated proxitropic variants (rs8192330 and rs4800403) with distinct expression signatures and prioritized DMTN and PIWIL2 as the likely causal genes. Overexpression of DMTN has been linked to the heme metabolism hallmark, disrupted iron distribution in COVID-19 patients with comorbid CAD, and subsequent stress erythropoiesis, oxidative stress, immunological dysfunction, and altered wound healing, while a lower expression of PIWIL2 has been observed in the cytoplasmic translation and regulation of mRNA metabolism. In conclusion, we identified shared genetic components for COVID-19 and CAD and prioritized DMTN and PIWIL2 as the likely causal genes for the observed shared genetic risk. COVID-19 may act as an acute stressor that unmask or accelerates underlying CAD. Full article

(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)

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19 pages, 2367 KB

Open AccessArticle

Differential Antioxidant Capacities of Human Endometriotic and Endometrial Cell Models Under H₂O₂ Exposure

by Julia A. Coelho, Kaio S. Gomes and Giselle Cerchiaro

Int. J. Mol. Sci. 2026, 27(9), 4131; https://doi.org/10.3390/ijms27094131 - 5 May 2026

Viewed by 510

Abstract

Endometriosis is associated with oxidative stress and debilitating symptoms, yet its pathophysiology remains incompletely understood, and current treatments are still limited. In this study, oxidative stress responses were compared in 2D and 3D cultures of 12Z and Ishikawa cells using hydrogen peroxide (H [...] Read more.

Endometriosis is associated with oxidative stress and debilitating symptoms, yet its pathophysiology remains incompletely understood, and current treatments are still limited. In this study, oxidative stress responses were compared in 2D and 3D cultures of 12Z and Ishikawa cells using hydrogen peroxide (H₂O₂) as a pro-oxidant and N-acetylcysteine (NAC) as an antioxidant. We evaluated H₂O₂ sensitivity, Reactive Oxygen Species (ROS) production, glutathione redox homeostasis, and biomolecular damage. The results showed that 12Z cells display greater vulnerability to oxidative stress than Ishikawa cells, with higher basal ROS levels (p < 0.01) and increased sensitivity to H₂O₂. In 3D culture, 12Z cells exhibited a 72% depletion of total glutathione under oxidative stress, a response not observed in 2D cultures, which instead showed a compensatory pattern. This vulnerability was further supported by increased lipid peroxidation and protein carbonylation. Although NAC restored cell viability and protected lipids and proteins, it did not prevent DNA damage. Together, these findings demonstrate marked differences in antioxidant responses between the two cell models and reinforce the value of 3D systems for investigating oxidative stress-related mechanisms. These results provide mechanistic insights relevant to endometriosis-associated redox imbalance and support further investigation of glutathione dysregulation and ROS-mediated damage in disease-related contexts. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research, 2nd Edition)

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16 pages, 1454 KB

Open AccessReview

The Prognostic Value of Tumor HER2 Expression in Predicting Oncological Outcomes of Patients with Advanced Urothelial Carcinoma: A Systematic Review and Meta-Analysis

by Mohammad Hossein Alibeiginejad, Alireza Esmaielpour, Ichiro Tsuboi, Akihiro Matsukawa, Takafumi Yanagisawa, Keiichiro Mori and Mehdi Kardoust Parizi

Int. J. Mol. Sci. 2026, 27(9), 4130; https://doi.org/10.3390/ijms27094130 - 5 May 2026

Viewed by 600

Abstract

The biologic and prognostic value of tumor human epidermal growth factor receptor 2 (HER2) expression in patients with advanced urothelial carcinoma (UC) who undergo systemic therapies remains controversial. A systematic search of English-language literature using PubMed, Scopus, and Cochrane Library was performed in [...] Read more.

The biologic and prognostic value of tumor human epidermal growth factor receptor 2 (HER2) expression in patients with advanced urothelial carcinoma (UC) who undergo systemic therapies remains controversial. A systematic search of English-language literature using PubMed, Scopus, and Cochrane Library was performed in October 2025 according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) protocol to evaluate the prognostic value of tumor HER2 expression in predicting oncological outcomes of patients with advanced UC. The primary endpoints were recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Seventeen studies comprising 4909 patients were eligible. HER2 expression was significantly associated with inferior RFS (HR 1.68, 95% CI 1.16–2.42; p = 0.005) and CSS (HR 1.36, 95% CI 1.10–1.68; p = 0.004), but not with OS (HR 1.03, 95% CI 0.54–1.80) or PFS (HR 0.97, 95% CI 0.50–1.89), in patients with advanced UC. In conclusion, tumor HER2 expression may identify a subgroup of patients with advanced UC at increased risk of recurrence and cancer-specific mortality, supporting its potential role as a prognostic biomarker. However, standardized assessment and prospective studies are warranted to define its utility for risk stratification and therapeutic targeting. Full article

(This article belongs to the Special Issue Precision Medicine in Cancers)

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18 pages, 533 KB

Open AccessOpinion

Piezo2-Initiated Ultrafast Signaling and Its Acquired Channelopathy in Light of Quantum Gravity Theory

by Balázs Sonkodi

Int. J. Mol. Sci. 2026, 27(9), 4129; https://doi.org/10.3390/ijms27094129 - 5 May 2026

Viewed by 620

Abstract

Big Bang theories are connected to gravity by force of attraction. Forced lengthening, like eccentric contractions, instigate proprioception as a result of working against gravity. Piezo2, as the principal mechanosensory ion channel responsible for proprioception, is theorized to fine-modulate these anti-gravitational contractions in [...] Read more.

Big Bang theories are connected to gravity by force of attraction. Forced lengthening, like eccentric contractions, instigate proprioception as a result of working against gravity. Piezo2, as the principal mechanosensory ion channel responsible for proprioception, is theorized to fine-modulate these anti-gravitational contractions in order to provide system-wide ultrafast postural control. This mechanism may instantaneously emit energy and force through Piezo2 in order to offset gravity by anti-gravity entropic-spring-like stochastic mechanics and it is suggested to be propagated by quantum tunneling of protons (and electrons). However, a Piezo2-initiated wormhole-like mechanism with the contribution of cryptochromes should be considered as part of this ultrafast long-distance non-synaptic neurotransmission, although the quantum gravity concept is short of being unequivocally proven to be unified with quantum theory. The impairment of this theoretical ultrafast signaling is analogous to a Big Bang-like mechanism within a given compartment, or acquired Piezo2 channelopathy, leading to the principal gateway to pathophysiology. Full article

(This article belongs to the Collection Feature Papers in Molecular Biophysics)

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24 pages, 16904 KB

Open AccessArticle

Proof-of-Concept Evaluation of Primary Human FAP-CAR-NK Cells Targeting Activated Fibroblasts in Pulmonary Fibrosis

by Geping Wu, Zhiming Ling, Wei Lin, Yi Wang, Xiuying Liu and Jianxun Wang

Int. J. Mol. Sci. 2026, 27(9), 4128; https://doi.org/10.3390/ijms27094128 - 5 May 2026

Viewed by 667

Abstract

In recent years, the feasibility of immunotherapy targeting activated fibroblasts in pulmonary fibrosis has received further support. Recent studies have shown that transient FAP-targeted immunotherapy can alleviate pulmonary fibrosis by eliminating excessively activated fibroblasts, improving the aberrant extracellular matrix environment, and promoting alveolar [...] Read more.

In recent years, the feasibility of immunotherapy targeting activated fibroblasts in pulmonary fibrosis has received further support. Recent studies have shown that transient FAP-targeted immunotherapy can alleviate pulmonary fibrosis by eliminating excessively activated fibroblasts, improving the aberrant extracellular matrix environment, and promoting alveolar cell lineage remodeling, suggesting that FAP-associated pathological stromal cells are amenable to therapeutic intervention. Based on this, research on FAP-centered engineered cell therapies is being gradually extended from settings such as myocardial fibrosis to pulmonary fibrosis. In this context, primary human NK cells represent a promising effector cell platform, as they are generally associated with a lower risk of severe treatment-related toxicities and relatively limited in vivo persistence, which may confer a more controllable therapeutic window. This feature is particularly important in fibrotic diseases, because long-term and continuous depletion of fibroblast populations may disrupt tissue homeostasis and injury repair. In addition, current studies of FAP-targeted CAR-NK therapy have mainly relied on NK cell lines such as NK-92, but these systems may not fully reflect the functional characteristics, receptor signaling, or clinical potential of primary human NK cells. Based on these considerations, it is necessary to develop a FAP-targeted cell therapy platform with greater clinical relevance for pulmonary fibrosis. In this study, we established a primary human FAP-CAR-NK-cell platform and conducted a proof-of-concept evaluation in pulmonary fibrosis-related models, including in vitro systems, a human pulmonary fibrosis-like organoid model, and an acute in vivo observation model. The main novelty of this study lies in the use of primary human NK cells for FAP-targeted intervention in pulmonary fibrosis-related models. We focused on whether these engineered cells could selectively target and eliminate FAP-positive activated fibroblasts, retain effector function in a fibrotic microenvironment, and show short-term feasibility after adoptive transfer. The study was not intended to assess long-term therapeutic efficacy or systemic safety, but rather to examine the feasibility of FAP-directed fibroblast targeting by primary human CAR-NK cells in pulmonary fibrosis and to provide a basis for further preclinical investigation. Full article

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

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17 pages, 14634 KB

Open AccessArticle

Antifungal Activity of Punica granatum L. Peel Extract and Chitosan Nanoparticle-Coated Formulation Against Candida Infections

by Kazim Sahin, Sena Sahin Aktura, Ilkay Bahceci, Derya Bal Altuntas and Muharrem Mert Otegeceli

Int. J. Mol. Sci. 2026, 27(9), 4127; https://doi.org/10.3390/ijms27094127 - 5 May 2026

Viewed by 620

Abstract

Increasing incidence of candidiasis and emergence of antifungal resistance necessitate the development of alternative antifungal strategies. In this context, the antifungal activity of the crude extract of Punica granatum L. peel (PGPE) and its chitosan nanoparticle-coated formulation (PGPE-CSNPs) was investigated against Candida albicans [...] Read more.

Increasing incidence of candidiasis and emergence of antifungal resistance necessitate the development of alternative antifungal strategies. In this context, the antifungal activity of the crude extract of Punica granatum L. peel (PGPE) and its chitosan nanoparticle-coated formulation (PGPE-CSNPs) was investigated against Candida albicans (ATCC 10231), Candida glabrata (ATCC 66032), Candida kefyr (ATCC 46764), Candida parapsilosis (ATCC 22019), and Candida tropicalis (ATCC 13803). Although the individual antimicrobial activities of PGPE and CSNPs have been investigated, their combined application against Candida spp. remains unexplored in the literature. The antifungal efficacy was evaluated using agar well diffusion, disk diffusion, minimum inhibitory concentration (MIC), and minimum fungicidal concentration (MFC) testing, and compared with fluconazole and amphotericin B. The morphological characterization of PGPE-CSNPs was performed using scanning electron microscopy (SEM), which confirmed successful encapsulation and revealed a smoother surface with uniformly distributed nanometric pore structures and reduced aggregation compared to uncoated CSNPs. PGPE-CSNPs showed greater inhibition zones than amphotericin B, except against C. albicans. The CSNPs formulation reduced the MIC from 8 µg/mL to 4 µg/mL and the MFC from 16 µg/mL to 8 µg/mL, representing a two-fold enhancement against C. albicans. No enhancement in activity was observed against C. glabrata, whereas for C. kefyr, only MFC values decreased from 8 µg/mL to 4 µg/mL. For both C. parapsilosis and C. tropicalis, MIC values reduced from 16 µg/mL to 8 µg/mL, and MFC values reduced from 32 µg/mL to 16 µg/mL for both species. PGPE-CSNPs exhibited significantly lower MIC and MFC values than the crude extract alone (p < 0.05). These findings suggest that chitosan-based nanocarriers may enhance the antifungal efficacy of plant-derived bioactive compounds, highlighting their potential as a promising alternative antifungal strategy, a combinatorial approach not previously reported in the literature. Full article

(This article belongs to the Special Issue Advances in Antimicrobial Nanomaterials 2.0)

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22 pages, 6497 KB

Open AccessArticle

Genome-Wide Identification and Functional Characterization of the Dof Gene Family in Flax (Linum usitatissimum)

by Chenmeng Xu, Limin Wang, Zhao Dang, Wenjuan Li, Wei Zhao, Yaping Xie, Yan Wang, Jianping Zhang and Yanni Qi

Int. J. Mol. Sci. 2026, 27(9), 4126; https://doi.org/10.3390/ijms27094126 - 5 May 2026

Viewed by 520

Abstract

DNA-binding with one finger (Dof) transcription factors are plant-specific regulators of growth, development, and stress responses. Despite extensive characterization in various species, Dof genes in flax (Linum usitatissimum L.), an important oil and fiber crop, remain largely uncharacterized. Through genome-wide identification and [...] Read more.

DNA-binding with one finger (Dof) transcription factors are plant-specific regulators of growth, development, and stress responses. Despite extensive characterization in various species, Dof genes in flax (Linum usitatissimum L.), an important oil and fiber crop, remain largely uncharacterized. Through genome-wide identification and comprehensive characterization of the Dof gene family in flax, this study identified 47 LuDof genes in the high-oil Longya-10 variety, distributed non-uniformly across 15 chromosomes. Phylogenetic analysis grouped these genes into 12 distinct clusters, reflecting evolutionary conservation and lineage-specific characteristics, including the absence of LuDof members in Group XII. Gene structure and conserved motif analyses revealed strong structural conservation, particularly within the canonical zf-Dof domain. Segmental duplication was identified as the primary driver of LuDof family expansion, with all paralogous pairs evolving under strong purifying selection. Collinearity analysis revealed that 80.9% of LuDof genes have homologs in other species, highlighting strong evolutionary conservation. Promoter analysis identified multiple hormone- and stress-responsive elements, and qRT-PCR under drought, heat, cold, and methyl jasmonate (MeJA) treatments confirmed their roles in environmental stress responses. Transcriptome profiling indicated their involvement in stem and capsule development. This study represents the first systematic characterization of the evolution, structure, and functional potential of the flax Dof gene family, establishing a foundation for functional studies and for developing genetically superior, stress-tolerant flax varieties. Full article

(This article belongs to the Special Issue Omics Approach to Uncovering Signalling and Gene Regulation in Plants)

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30 pages, 4671 KB

Open AccessReview

Synovial Sarcoma: Molecular Biology, Pathology, and Therapeutic Strategies

by Joon Hyuk Choi

Int. J. Mol. Sci. 2026, 27(9), 4125; https://doi.org/10.3390/ijms27094125 - 5 May 2026

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Abstract

Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with variable epithelial differentiation. SS is defined by the presence of a specific SS18::SSX fusion gene. Moreover, SS can occur at any age, shows no significant sex predilection, and most commonly arises in [...] Read more.

Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with variable epithelial differentiation. SS is defined by the presence of a specific SS18::SSX fusion gene. Moreover, SS can occur at any age, shows no significant sex predilection, and most commonly arises in the deep soft tissues of the extremities, typically in juxta-articular locations (approximately 70% of cases), with a variable prognosis. SS accounts for 5–10% of all soft tissue sarcomas. Meanwhile, despite recent advances in diagnosis and therapy, SS remains a diagnostic and clinical challenge due to the associated broad anatomical distribution and diverse histological patterns. This review aims to provide a comprehensive update on the clinical, molecular, and pathological features of SS, with emphasis on diagnostic strategies and treatment approaches. Full article

(This article belongs to the Special Issue Recent Advances in Molecular Targets for Treatment and Drug Delivery in Tumors: 2nd Edition)

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Int. J. Mol. Sci., Volume 27, Issue 9 (May-1 2026) – 448 articles

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