International Journal of Molecular Sciences

19 pages, 2265 KB

Open AccessReview

Estrogen Receptors and Enzymes Involved in Estrogen Synthesis as Breast Cancer Treatment Targets

by Barbara Licznerska, Hanna Szaefer, Hanna Sobierajska and Wanda Baer-Dubowska

Int. J. Mol. Sci. 2026, 27(15), 6823; https://doi.org/10.3390/ijms27156823 (registering DOI) - 30 Jul 2026

Estrogens, particularly the most active 17β-estradiol (E2), play a crucial role in the initiation and development of breast cancer. Therefore, current treatment strategies are based on interfering with estrogen receptors (ERs) via pure antiestrogens or selective modulators (SERMs) or by inhibiting estrogen synthesis [...] Read more.

Estrogens, particularly the most active 17β-estradiol (E2), play a crucial role in the initiation and development of breast cancer. Therefore, current treatment strategies are based on interfering with estrogen receptors (ERs) via pure antiestrogens or selective modulators (SERMs) or by inhibiting estrogen synthesis through key enzymes in this pathway. While SERMs are generally effective, resistance often develops. Moreover, they cannot be used to treat triple-negative breast cancers (TNBCs). Three critical enzymes in the estrogen synthesis pathway, namely aromatase, sulfatase, and 17β-hydroxysteroid dehydrogenases, are of particular interest as drug targets. Some, such as aromatase inhibitors, are already used in clinical practice, while the other two remain under intensive investigation. Several comprehensive reviews have been published on ER modulators or individual enzyme inhibitors. This paper attempts to summarize recent data on modulators/inhibitors of both the ER and the major enzymes involved in estrogen biosynthesis and offers a perspective on their further development. Full article

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

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27 pages, 1131 KB

Open AccessReview

Post-Stroke Epileptogenesis as a Dynamic Network Process: State-Dependent Biomarkers, Longitudinal Monitoring, and the Concept of an Irritable Brain State

by Ekaterina Andreevna Narodova

Int. J. Mol. Sci. 2026, 27(15), 6822; https://doi.org/10.3390/ijms27156822 - 29 Jul 2026

Abstract

Post-stroke epilepsy (PSE) is one of the most common long-term neurological complications of stroke and represents a major contributor to disability, reduced quality of life, and increased healthcare burden. Although numerous risk factors and biomarkers have been proposed, many current risk models still [...] Read more.

Post-stroke epilepsy (PSE) is one of the most common long-term neurological complications of stroke and represents a major contributor to disability, reduced quality of life, and increased healthcare burden. Although numerous risk factors and biomarkers have been proposed, many current risk models still emphasize lesion-related predictors and do not fully account for the temporal evolution of post-stroke network excitability. This narrative review aims to examine post-stroke epileptogenesis as a dynamic process of network reconfiguration and to summarize current evidence on biological, neurophysiological, imaging, and clinical biomarkers across different stages following stroke. A structured narrative review of the literature was performed using major biomedical databases. Studies addressing mechanisms of post-stroke epileptogenesis, biomarkers, network dysfunction, neuroinflammation, EEG findings, neuroimaging correlates, and longitudinal monitoring strategies were evaluated and synthesized qualitatively. Evidence suggests that post-stroke epileptogenesis is driven by complex interactions among structural injury, neuroinflammation, blood–brain barrier dysfunction, neurotransmitter imbalance, maladaptive plasticity, and large-scale network reorganization. Importantly, many biomarkers demonstrate substantial temporal variability, and their clinical significance depends on the stage of recovery and the evolving state of brain networks. Emerging data indicate that sleep disturbances, stress, mood disorders, metabolic factors, and other state-dependent influences may further modulate seizure susceptibility after stroke. Post-stroke epileptogenesis may be better conceptualized as a dynamic process of network instability rather than a fixed consequence of focal brain damage. It is proposed that the post-stroke brain can transiently or persistently enter an “irritable brain state”, characterized by increased vulnerability to pathological synchronization under the influence of biological and behavioral modulators. This framework may facilitate the development of longitudinal biomarker strategies and personalized monitoring approaches in future research. However, it should be emphasized that the “irritable brain state” remains a conceptual and hypothesis-generating construct; no validated diagnostic criteria exist, and prospective evidence demonstrating that interventions targeting this state reduce the incidence of post-stroke epilepsy is currently lacking. Full article

(This article belongs to the Special Issue Neurological Diseases: From Pathogenesis to Molecular Diagnosis and Treatment)

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35 pages, 2403 KB

Open AccessArticle

Identification of Natural Flavonoids Targeting PLK-1 as Potential Anti-Metastatic Agents: A Computational Approach

by Yudith Cañizares-Carmenate, Erix W. Hernández-Rodríguez, Yunier Perera-Sardiña, Dina B. Aguado-Herrera, Roberto Díaz-Amador, Francisco Torrens and Juan A. Castillo-Garit

Int. J. Mol. Sci. 2026, 27(15), 6821; https://doi.org/10.3390/ijms27156821 - 29 Jul 2026

Abstract

This study combines ligand- and structure-based in silico strategies to predict the inhibitory activity of natural flavonoids on the Polo-Like Kinase-1 (PLK-1) enzyme as candidate anticancer agents. This enzyme participates in mitosis and is overexpressed in cancer cells. Furthermore, it has been shown [...] Read more.

This study combines ligand- and structure-based in silico strategies to predict the inhibitory activity of natural flavonoids on the Polo-Like Kinase-1 (PLK-1) enzyme as candidate anticancer agents. This enzyme participates in mitosis and is overexpressed in cancer cells. Furthermore, it has been shown to have important implications for tumor metastasis, and its inhibitors are attractive starting points for drug development. First, classification models are developed using linear discriminant analysis and a multilayer perceptron neural network. Models with accuracy greater than 80%, validated using standard statistical performance metrics and applicability domain, are used for virtual screening identifying four compounds as potential antitumor drugs. Subsequently, the identified compounds are evaluated using a molecular docking methodology to verify their binding mode and interactions with the catalytic domain of PLK-1. Finally, the integration of molecular dynamics simulations, at 300 ns, with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) thermodynamic calculations demonstrates that the hydroxylation pattern of ring B in the flavonol scaffold is the fundamental chemical-structural determinant of electrostatic interactions and the architecture of water-mediated networks. Among the evaluated flavonoids, myricetin showed the most favorable overall computational profile, including the highest virtual-screening score and the most favorable mean MM/GBSA estimate, supporting its prioritization for experimental evaluation as a potential PLK-1 inhibitor. The integration of these approaches offers a robust methodological framework for proposing candidates with a higher probability of success, in subsequent stages of experimental validation, reducing time and costs in the early stages of drug development. Full article

(This article belongs to the Special Issue Benchmarking of Modeling and Informatic Methods in Molecular Sciences)

17 pages, 1850 KB

Open AccessArticle

Berberine Alleviates Citrobacter rodentium-Induced Colitis with Reduced Epithelial Gasdermin E-Mediated Pyroptosis

by Meiqi Zhang, Sixian Wei, Zheng Lou, Qiqi Li, Lingdong Kong, Shiqi Wu, Meiqi Jia, Yingying Wang, Yao Wang, Anlong Xu and Xin Jia

Int. J. Mol. Sci. 2026, 27(15), 6820; https://doi.org/10.3390/ijms27156820 - 29 Jul 2026

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestine. Although current therapies can provide symptomatic relief, they are often associated with high costs and adverse effects. Coptis chinensis Franch., a traditional Chinese medicine long used for inflammatory intestinal conditions such [...] Read more.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestine. Although current therapies can provide symptomatic relief, they are often associated with high costs and adverse effects. Coptis chinensis Franch., a traditional Chinese medicine long used for inflammatory intestinal conditions such as bacterial dysentery, is a promising alternative. However, the specific alkaloid components that inhibit cell death and alleviate colitis remain unclear. Major isoquinoline alkaloids from Coptis chinensis Franch. were screened in a TNF-α/cycloheximide (CHX)-induced epithelial cell death model using CCK-8 and Annexin V staining. Caspase-3 and GSDME cleavage, HMGB1 release, phosphorylation of ERK and JNK, and inflammatory gene expression were assessed by Western blotting and qPCR. In vivo, a Citrobacter rodentium-induced colitis model was established and mice were treated with a specific alkaloid. Disease severity, histopathological injury, bacterial burden, barrier-related structural markers, and colonic GSDME cleavage were then evaluated. Berberine (BBR) exhibited the strongest cytoprotective activity in the screening system, reducing epithelial cell death, reversing pyroptosis-associated morphology, and inhibiting GSDME cleavage. BBR also reduced HMGB1 release, attenuated the phosphorylation of ERK and JNK, and downregulated pro-inflammatory gene expression. In the C. rodentium-induced infectious colitis model, BBR alleviated body weight loss, diarrhea, colon shortening, and histopathological injury without significantly reducing bacterial burden under the present experimental conditions. In parallel, BBR enhanced Tjp1 and Muc2 expression, and diminished colonic GSDME cleavage in vivo. Collectively, these findings suggest that BBR is a promising candidate for colitis involving bacterial infection-associated epithelial pyroptosis, potentially via GSDME modulation. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

25 pages, 3620 KB

Open AccessArticle

Identifying Epithelial-Cell Progression Signatures (ECPSs) from Multi-Resolution Multi-Omics Data for Translational Clinical Applications in Lung Adenocarcinoma

by Xueyao Chen, Tongxin Lv, Yang Wu, Fangfang Fan, Shaobo Kang, Renjie Dou, Wanmei Zhang, Dongxue Li, Rui Li and Yanyan Ping

Int. J. Mol. Sci. 2026, 27(15), 6819; https://doi.org/10.3390/ijms27156819 - 29 Jul 2026

Abstract

Dynamic transcriptomic remodeling of epithelial cells represents a critical hallmark of lung adenocarcinoma (LUAD) progression, yet epithelial-cell progression signatures (ECPSs) linked to this process remain incompletely characterized, impeding our understanding of malignant LUAD transformation. Here, we performed a multi-resolution multi-omics study and identified [...] Read more.

Dynamic transcriptomic remodeling of epithelial cells represents a critical hallmark of lung adenocarcinoma (LUAD) progression, yet epithelial-cell progression signatures (ECPSs) linked to this process remain incompletely characterized, impeding our understanding of malignant LUAD transformation. Here, we performed a multi-resolution multi-omics study and identified two functionally opposing ECPSs: a Cancer-Promoting Signature (CPS) and a Cancer-Suppressing Signature (CSS). The CPS was progressively upregulated from normal to early- and advanced-stage lesions, while the CSS was gradually downregulated, and both were validated by multi-resolution transcriptomic data. Both the CPS and CSS demonstrated robust diagnostic value for LUAD, particularly in early-stage detection (median AUC > 0.95). In seven independent validation cohorts, the CPS and CSS served as robust prognostic risk and protective factors, respectively. Their combination could better stratify LUAD patients into distinct prognostic subgroups, with the CPS_high–CSS_low subgroup showing the worst prognosis, accompanied by high genomic instability, an immunosuppressive tumor microenvironment, and resistance to chemotherapy. Notably, the CPS and CSS exhibited broad translational value in other epithelium-derived cancers. HMGA1, a key CPS gene, showed epithelium- and advanced-stage-specific high expression, which was significantly associated with poor prognosis, genomic instability, and immune escape. Collectively, our study identifies the CPS and CSS as clinically reliable ECPSs, providing valuable biomarkers for clinical application to LUAD. Full article

(This article belongs to the Special Issue Computational and Multi-Omics Bioinformatics in Cancer Biology and Therapy Response)

16 pages, 571 KB

Open AccessReview

Gene–Air Pollution Interaction in Cardiovascular Disease: Lights and Shadows in a Tangled Risk Factor Network

by Melania Gaggini and Cristina Vassalle

Int. J. Mol. Sci. 2026, 27(15), 6818; https://doi.org/10.3390/ijms27156818 - 29 Jul 2026

Abstract

Cardiovascular disease (CVD) is the result of a complex interaction between genetic, lifestyle, and environmental factors, which may vary over the course of life. Traditional risk factors do not explain all patients' risks; thus, the research of additional biomarkers to refine cardiovascular risk [...] Read more.

Cardiovascular disease (CVD) is the result of a complex interaction between genetic, lifestyle, and environmental factors, which may vary over the course of life. Traditional risk factors do not explain all patients' risks; thus, the research of additional biomarkers to refine cardiovascular risk prediction has attracted considerable interest in recent years. Genetic factors, as well as air pollution exposure, among nontraditional factors, have been found to be critical determinants of CV risk. Accordingly, this narrative review aims to provide a comprehensive summary of the literature (PubMed) on the combined effects of air pollution and genetic susceptibility on CVD risk. Although different limitations and pitfalls are still to be solved, available evidence suggests that genetic variants (especially genes related to detoxification and inflammation) are involved in the association between air pollution exposure and CV adverse events. Thus, this research area could provide further knowledge of the etiology of CVD, offering new tools for targeted prevention and treatment of more susceptible subjects from a more personalized medicine point of view. Full article

(This article belongs to the Topic Future Directions in Cardiology: How the Clinic Will Change in the Coming Years, the Laboratory Always Standing)

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14 pages, 279 KB

Open AccessArticle

Dose-Dependent Effects of Protocatechuic Acid on Motility, Redox Balance, and DNA Integrity of Frozen–Thawed Ram Spermatozoa

by Umut Taşdemir, Fatih Avdatek, Muhammed Enes İnanç, Şükrü Güngör, Mehmet Fuat Gülhan, Barış Denk, Murat Kırıkkulak and Deniz Yeni

Int. J. Mol. Sci. 2026, 27(15), 6817; https://doi.org/10.3390/ijms27156817 - 29 Jul 2026

Abstract

This study investigated the effects of supplementing Tris semen extender with protocatechuic acid (PCA) at doses of 25, 50, and 100 µg/mL on the quality of ram spermatozoa after cryopreservation. We evaluated motility, kinematic parameters, DNA integrity, redox status, plasma membrane–acrosome integrity (PMAI), [...] Read more.

This study investigated the effects of supplementing Tris semen extender with protocatechuic acid (PCA) at doses of 25, 50, and 100 µg/mL on the quality of ram spermatozoa after cryopreservation. We evaluated motility, kinematic parameters, DNA integrity, redox status, plasma membrane–acrosome integrity (PMAI), viability, and high mitochondrial membrane potential (HMMP). PCA supplementation produced concentration-dependent and parameter-specific responses. The 25 µg/mL PCA group exhibited the most favorable functional profile, demonstrating improved progressive and total motility alongside reduced DNA damage. This protective effect was evidenced by lower tail length, tail DNA percentage, and tail moment in the comet assay. Conversely, treatment with 100 µg/mL PCA appeared to exert a notable effect on the redox balance, indicated by lower malondialdehyde, total oxidant status, and oxidative stress index levels, alongside an elevated total antioxidant status (p < 0.05). However, this higher concentration (100 µg/mL) did not provide parallel DNA protection and was associated with increased comet assay indices. PMAI, viability, and HMMP were not significantly affected by PCA supplementation (p > 0.05). These findings indicate that PCA exerts dose-dependent but parameter-specific effects on frozen–thawed ram spermatozoa. Low-dose PCA, particularly 25 µg/mL, appears more suitable for preserving motility and nuclear integrity, whereas 100 µg/mL mainly improves oxidative balance. Full article

23 pages, 921 KB

Open AccessReview

The Gut Mucosal Barrier–Neuroinflammation Axis in Vascular Cognitive Impairment Induced by Chronic Cerebral Ischemia: A Narrative Review of Candidate Mechanisms

by Jiarong Du, Lan Sun, Shanshan Wang, Yanxin Chen, Wenjuan Long, Bo Wang, Zhongyang Hu, Yujun Feng, Qiongrong Long, Mincong Huang, Xiaoya Li and Xiaoman Lv

Int. J. Mol. Sci. 2026, 27(15), 6816; https://doi.org/10.3390/ijms27156816 - 29 Jul 2026

Abstract

Vascular cognitive impairment (VCI) is a major form of dementia with a complex pathogenesis. Emerging evidence indicates a strong interaction between intestinal mucosal barrier integrity and neuroinflammation, which has been proposed as a candidate contributor in VCI progression. This review comprehensively reviews the [...] Read more.

Vascular cognitive impairment (VCI) is a major form of dementia with a complex pathogenesis. Emerging evidence indicates a strong interaction between intestinal mucosal barrier integrity and neuroinflammation, which has been proposed as a candidate contributor in VCI progression. This review comprehensively reviews the initiation and amplification of neuroinflammation in chronic cerebral ischemia. It highlights how impairment of the intestinal mucosal barrier, gut microbiota dysbiosis, and translocation of microbial metabolites contribute to central neuroinflammation via circulatory and neural pathways, suggesting a potential self-sustaining pathological cycle within the gut–brain axis. Furthermore, we analyze the underlying molecular mechanisms, critique current limitations, and suggest promising directions for future research. Full article

(This article belongs to the Section Molecular Immunology)

26 pages, 1182 KB

Open AccessArticle

Evaluation of the Antioxidant, Anti-Inflammatory, and Antimicrobial Activity of a Cannabis sativa-Infused African Product Used for Wound Healing

by Siboniso Sithole, Xolani Shezi, Mlondolo Mavundla, Carl Mateta, Sphamandla Hlatshwayo, Sanele Mhlungu, Nokukhanya Thembane, Phumzile Afrika, Sibusiso Senzani, Exnevia Gomo, Nceba Gqaleni and Mlungisi Ngcobo

Int. J. Mol. Sci. 2026, 27(15), 6815; https://doi.org/10.3390/ijms27156815 - 29 Jul 2026

Abstract

Product Shezi (PS) is a polyherbal African traditional medicine (ATM) formulated from six known South African medicinal plants and is used for treating cutaneous wounds. However, its ethnopharmacological properties have not been scientifically validated. This study aimed to evaluate the antioxidant, anti-inflammatory, and [...] Read more.

Product Shezi (PS) is a polyherbal African traditional medicine (ATM) formulated from six known South African medicinal plants and is used for treating cutaneous wounds. However, its ethnopharmacological properties have not been scientifically validated. This study aimed to evaluate the antioxidant, anti-inflammatory, and antimicrobial activities of PS in vitro. Aqueous and methanolic extracts were prepared and qualitatively screened for phytochemical constituents. Cytotoxicity in fibroblasts and macrophages was assessed using an ATP-based viability assay. Antioxidant activity was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and a hydrogen peroxide (H₂O₂)-induced oxidative stress model. Anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated macrophages were measured using the Griess reagent system, a human prostaglandin E₂ (PGE₂) ELISA, and a bovine serum albumin (BSA) anti-denaturation assay. Antimicrobial activity was assessed by twofold serial broth microdilution, agar well diffusion, and a crystal violet biofilm assay. Phytochemical screening confirmed the presence of saponins, alkaloids, tannins, glycosides, terpenoids, flavonoids, and steroids. PS exhibited IC₁₀ values of 3 and 10 μg/mL in fibroblasts and macrophages, respectively. PS (1–5 μg/mL) showed 70% DPPH scavenging potential and potent H₂O₂ cytoprotection (p < 0.001). Nitric oxide inhibition was non-significant (p > 0.05) whilst PGE₂ decreased significantly (p < 0.05) compared to LPS-stimulated cells. BSA denaturation was inhibited in a dose-dependent manner (p < 0.05). Staphylococcus aureus and S. epidermidis were the only microorganisms susceptible to PS (MIC 650–5000 μg/mL) with low SI (SI ≈ 0.05–0.06), while others were resistant. PS showed no antibiofilm activity (crystal-violet assay). Overall, PS demonstrated antioxidant and anti-inflammatory activities and selective antibacterial effects against planktonic bacteria in vitro. However, further optimization of extraction methods, detailed mechanistic studies, and in vivo investigations are warranted to substantiate therapeutic relevance. Full article

(This article belongs to the Special Issue Natural Products: Potential Anti-Inflammatory or Anti-Oxidative Mechanisms)

27 pages, 1263 KB

Open AccessReview

The Gut–Brain–Skin Axis: Systemic Effects of Functional Ingredients in Healthy Skin Aging

by Yeojin Kim and Sung-Joon Lee

Int. J. Mol. Sci. 2026, 27(15), 6814; https://doi.org/10.3390/ijms27156814 - 29 Jul 2026

Abstract

Interactions among the gut, brain, and skin are increasingly understood as a systemic regulatory network connecting intestinal activity, neuroimmune communication, and cutaneous homeostasis. Microbiota-derived metabolites, immune mediators, and neuroendocrine pathways can influence central nervous system activity and subsequently regulate skin homeostasis. This review [...] Read more.

Interactions among the gut, brain, and skin are increasingly understood as a systemic regulatory network connecting intestinal activity, neuroimmune communication, and cutaneous homeostasis. Microbiota-derived metabolites, immune mediators, and neuroendocrine pathways can influence central nervous system activity and subsequently regulate skin homeostasis. This review summarizes current evidence on how functional ingredients modulate the gut–brain–skin axis in the context of aging and skin health. Polyphenols, probiotics, and omega-3 fatty acids appear to act through overlapping biological routes, including reshaping microbial communities, supporting epithelial barrier function, regulating immune activity, and limiting oxidative stress. These gut-derived signals may affect the brain through neural, endocrine, and immune pathways, thereby modulating neuroinflammation, hypothalamic–pituitary–adrenal (HPA) axis activity, and neurotransmitter balance. Through brain–skin communication, these changes may influence inflammation, epidermal barrier integrity, collagen remodeling, and skin aging processes. Emerging clinical evidence suggests potential improvements in skin-related outcomes and systemic inflammatory markers; however, studies remain heterogeneous, and integrated assessments of gut, brain, and skin endpoints are limited. Further studies that integrate multi-omics profiling with carefully designed clinical trials will be required to define causal pathways and support the development of evidence-based nutritional approaches targeting this axis. Full article

(This article belongs to the Collection Latest Review Papers in Bioactives and Nutraceuticals)

21 pages, 7952 KB

Open AccessArticle

Recognition of ErbB Family Dimers by the EGF-like Domain of NRG1alpha and Beta: Implications for Ligand-Based CAR Therapy

by Alex Novikov, Alon Naumchik, Rajashri Banerji, Yariv Greenshpan, Kamran Waidha, Baisali Bhattacharya, Moshe Elkabets, Olga Radinsky and Angel Porgador

Int. J. Mol. Sci. 2026, 27(15), 6813; https://doi.org/10.3390/ijms27156813 - 29 Jul 2026

Abstract

HER-positive cancers comprise a heterogeneous group of malignancies driven by dysregulated activation of the human epidermal growth factor receptor (HER/ERBB) family. While chimeric antigen receptor (CAR) T-cell therapies targeting HER2 have demonstrated potent anti-tumor capabilities, their clinical translation remains hampered by safety hurdles [...] Read more.

HER-positive cancers comprise a heterogeneous group of malignancies driven by dysregulated activation of the human epidermal growth factor receptor (HER/ERBB) family. While chimeric antigen receptor (CAR) T-cell therapies targeting HER2 have demonstrated potent anti-tumor capabilities, their clinical translation remains hampered by safety hurdles and antigen escape. We developed a modular “Targeted Chimeric Artificial Reporter” (TcAR) system using the natural epidermal growth factor (EGF)-like binding domains of neuregulin-1 (NRG1) isoforms to decode complex HER dimerization profiles. Leveraging the superior targeting plasticity of the β-isoform, we engineered NRG1β-based CAR-T and CAR-natural killer (NK) cells. Our study demonstrates that NRG1β-directed therapy overcomes therapeutic antigen escape in HER2-depleted models and exerts potent anti-tumor activity within complex three-dimensional (3D) tissue microenvironments ex vivo, exhibiting a significantly safer, muted inflammatory profile compared to clinical standards. Full article

(This article belongs to the Special Issue T Cells in Cancer: From Effectors to Regulators and Therapeutic Targeting)

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23 pages, 3019 KB

Open AccessArticle

Interaction of High-Density Polyethylene Microplastics with Freshwater Microalgae Chlorella vulgaris and Scenedesmus quadricauda

by Alicja Faszczewska, Alicja Piotrowska-Niczyporuk, Urszula Klekotka and Joanna Karpińska

Int. J. Mol. Sci. 2026, 27(15), 6812; https://doi.org/10.3390/ijms27156812 - 29 Jul 2026

Abstract

The objective of the present study was to evaluate the impact of high-density polyethylene (HDPE) used in two particle sizes (40 and 125 µm) on selected biochemical parameters in two species of green algae: Chlorella vulgaris and Scenedesmus quadricauda. Exposure to microplastics [...] Read more.

The objective of the present study was to evaluate the impact of high-density polyethylene (HDPE) used in two particle sizes (40 and 125 µm) on selected biochemical parameters in two species of green algae: Chlorella vulgaris and Scenedesmus quadricauda. Exposure to microplastics resulted in decreased cell numbers (up to 43%) and reductions in protein (up to 42%), monosaccharide, and chlorophyll contents in both algal species. Oxidative stress, as reflected by increased hydrogen peroxide levels (up to 120%) and enhanced lipid peroxidation, was observed in HDPE-treated cells. This was accompanied by elevated antioxidant enzyme activity, changes in ascorbate and proline content, and alterations in carotenoid composition. Thus, toxicity of HDPE and the induction of defense mechanisms involved in adaptation to environmental pollutants were confirmed in both microalgae. Changes in the physicochemical properties of the tested polymer surface were investigated using Fourier-Transform Infrared Spectroscopy, scanning electron microscopy (SEM), and porosimetry analysis. The presence of biofilm, hydroxyl groups, higher total pore volume, and maximum pore width on the surface of the microplastic confirmed that green algae may be responsible for the first step in HDPE structure modifications. Understanding the interactions between such micropollutants and green algae, key primary producers in aquatic food webs, is therefore essential. Full article

(This article belongs to the Special Issue Metal Toxicity and Particle Toxicity)

23 pages, 3402 KB

Open AccessArticle

Product Nkabinde Mediates Cytokine Modulation and Antiviral Activity in HIV-Infected MT4 Cells

by Boitumelo Setlhare, Mlungisi Ngcobo, Gila Lustig, Herbert Chikafu, Nomusa Zondo, Siphathimandla Authority Nkabinde, Magugu Nkabinde and Nceba Gqaleni

Int. J. Mol. Sci. 2026, 27(15), 6811; https://doi.org/10.3390/ijms27156811 - 29 Jul 2026

Abstract

During HIV infection, the immune system initiates an immune response to control the viremia. In this in vitro study, we investigated the immunomodulatory and anti-HIV potential of a traditional medicine formulation, Product Nkabinde (PN). A freeze-dried extract of PN was used to determine [...] Read more.

During HIV infection, the immune system initiates an immune response to control the viremia. In this in vitro study, we investigated the immunomodulatory and anti-HIV potential of a traditional medicine formulation, Product Nkabinde (PN). A freeze-dried extract of PN was used to determine cytotoxicity in MT4 cells. Non-cytotoxic doses were used to evaluate the immunomodulatory and anti-HIV effects of PN using neutralization, prophylactic and treatment approaches. Post-treatment, cytokine quantification and p24 detection were performed. In the neutralization strategy, PN restored IL-1α (p = 0.0389) and IL-10 (p = 0.0443) to levels of uninfected cells. It also reduced HIV-induced elevations in IL-8 (p = 0.035), IP-10 (p = 0.0886), and MCP-1 (p = 0.0733) compared to HIV-infected cells. In the prophylactic approach, HIV infection upregulated IL-1α (p = 0.676), which was suppressed by PN. In the treatment strategy, PN reversed the elevated levels of IL-1α (p = 0.049). IL-10 was fully restored by PN to levels of uninfected cells. In all strategies, PN induced a significant and dose-dependent decrease in HIV replication. These findings demonstrate that PN exerts potent immunomodulatory effects all strategies used by reversing HIV-induced cytokine dysregulation, thereby inducing significant anti-HIV effects. Full article

(This article belongs to the Special Issue Plant Natural Products for Human Health and Disease)

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23 pages, 2645 KB

Open AccessArticle

Functional and Evolutionary Insights of NR1J1 Nuclear Receptors: A Diversified Sensing Weapon in Bivalves

by Maria Paula Gómez-Román, Elza Fonseca, Mário Jorge Araújo, Vitor Vasconcelos and Alexandre Campos

Int. J. Mol. Sci. 2026, 27(15), 6810; https://doi.org/10.3390/ijms27156810 - 29 Jul 2026

Abstract

Nuclear receptors (NRs) of the NR1J1 group have been described in aquatic invertebrates and proposed as the evolutionary counterparts of vertebrate NR1I receptors, known for their role in xenobiotic-sensing and detoxification. In bivalves, previous studies have shown that NR1J1 activity and gene expression [...] Read more.

Nuclear receptors (NRs) of the NR1J1 group have been described in aquatic invertebrates and proposed as the evolutionary counterparts of vertebrate NR1I receptors, known for their role in xenobiotic-sensing and detoxification. In bivalves, previous studies have shown that NR1J1 activity and gene expression are modulated by pharmaceuticals, toxins, natural compounds, and algal extracts. However, their functional properties and diversification remain poorly understood. Here, we investigated the function and evolution of NR1J1 receptors in the bivalves Mytilus galloprovincialis and Ruditapes decussatus. We first identified four nr1j1 paralogs in R. decussatus and then integrated phylogenetic analysis, domain identity comparisons, tissue distribution profiling, and luciferase-based transactivation assays to characterize NR1J1 paralogs from both species. The receptors displayed distinct but partially overlapping transactivation profiles in response to confirmed ligands of NR1I and NR1H receptors, natural compounds, plant extracts, and fish bile, indicating paralog- and species-specific differences in ligand responsiveness. Allocholic acid emerged as the most consistent agonist across paralogs, whereas curcumin, carnosic acid, and Ptychopetalum olacoides extract showed more selective response patterns. Tissue profiling revealed broad but non-uniform expression of nr1j1 paralogs across bivalve tissues. Together, these findings underscore that bivalve NR1J1 receptors constitute a functionally diversified chemical-sensing system and provide a framework for future studies addressing ligand-dependent regulation and detoxification pathways. Full article

(This article belongs to the Special Issue New Insights into the Structure and Function of Nuclear Receptors)

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35 pages, 5499 KB

Open AccessArticle

SARS-CoV-2 Infection-Induced Alterations in ADAR Editing Patterns Differ Between Patients Who Developed Critical Compared to Non-Critical COVID-19

by Aiswarya Mukundan Nair and Helen Piontkivska

Int. J. Mol. Sci. 2026, 27(15), 6809; https://doi.org/10.3390/ijms27156809 - 29 Jul 2026

Abstract

COVID-19, caused by the SARS-CoV-2 virus, has a wide spectrum of clinical presentations even among individuals with similar demographics. Disease severity has been linked with viral-mediated expression of interferons and interferon-stimulated genes. Among the interferon-stimulated genes are members of adenosine deaminases acting on [...] Read more.

COVID-19, caused by the SARS-CoV-2 virus, has a wide spectrum of clinical presentations even among individuals with similar demographics. Disease severity has been linked with viral-mediated expression of interferons and interferon-stimulated genes. Among the interferon-stimulated genes are members of adenosine deaminases acting on the RNA (ADAR) family that contribute to transcriptome diversity and modulate immune response. Previous studies identified altered ADAR expression and editing patterns during SARS-CoV-2 infection, although it remains unclear whether ADAR expression and activity differ between patients with varying severities of COVID-19. We used whole-blood transcriptomes from individuals with critical or non-critical COVID-19 and matched for age, sex, and presence of comorbidities. Results show differential expression of numerous genes, including those involved in neutrophil degranulation, and upregulation of ADAR1 and its isoform ADARp110 in patients with critical COVID-19. We identified severity-specific editing events, including nonsynonymous edits, within distinct biological pathways. Differentially edited sites—that could serve as molecular markers for COVID-19 severity—were found within genes enriched in signal transduction, RNA and protein metabolism, and inflammatory pathways. Our results demonstrate differences in expression and editing patterns of ADARs between critical and non-critical patients, supporting a potential role of ADAR editing in COVID-19 pathogenesis. Full article

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

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32 pages, 7477 KB

Open AccessArticle

Proteome-Level Autophagy–Lysosome Remodelling Marks Ageing in Human Dermal Fibroblasts and Nominates Hydroxytyrosol as a Candidate Nutraceutical

by Meng Cai and Meihong Xu

Int. J. Mol. Sci. 2026, 27(15), 6808; https://doi.org/10.3390/ijms27156808 - 29 Jul 2026

Abstract

Autophagy–lysosome dysfunction accompanies dermal fibroblast ageing, yet whether remodelling is transcriptional or post-transcriptional in primary human cells remains unresolved. We reanalysed the Genetic and Epigenetic Signatures of Translational Ageing Laboratory Testing(GESTALT) paired RNA sequencing (RNA-seq) and tandem mass tag (TMT) proteome from 82 [...] Read more.

Autophagy–lysosome dysfunction accompanies dermal fibroblast ageing, yet whether remodelling is transcriptional or post-transcriptional in primary human cells remains unresolved. We reanalysed the Genetic and Epigenetic Signatures of Translational Ageing Laboratory Testing(GESTALT) paired RNA sequencing (RNA-seq) and tandem mass tag (TMT) proteome from 82 donors (aged 22–89) using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) for supervised multi-omics integration, weighted gene co-expression network analysis (WGCNA), external Genotype-Tissue Expression(GTEx) transcriptomic comparison, network medicine proximity mapping and CDOCKER molecular docking. Three analyses converged on the autophagy–lysosome axis: Kyoto Encyclopaedia of Genes and Genomes (KEGG) Lysosome ranked first in discordant-quadrant analysis; gene set enrichment analysis (GSEA) identified vacuole organisation and macroautophagy as the top age-upregulated Gene Ontology (GO) terms; and WGCNA recovered KEGG Lysosome in the brown module. Module regression localised most proteomic age signals to the lysosomal degradative-capacity module, whereas the proteasome was unaffected. McNemar testing and GTEx comparison supported a protein-side, post-transcriptional origin. TCIRG1, CTSA and ATP6V0D1 were recurrent hubs. Network proximity computationally prioritised hydroxytyrosol as a lysosomal-degradative-capacity-preferential candidate, and CDOCKER on cathepsin A linked its advantage over tyrosol to an ortho-hydroxyl group forming additional hydrogen bonds. These results support protein-layer-dominant autophagy–lysosome remodelling as a feature of dermal fibroblast ageing and suggest a cell-type-resolved computational route from ageing proteomics to testable dietary candidates. Full article

(This article belongs to the Special Issue Discovery and Development of Functional Ingredients for Anti-Aging, Cognitive Enhancement and Skin Health)

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33 pages, 1350 KB

Open AccessReview

Matricellular Proteins in Bladder Cancer: Context-Dependent Roles in Tumor Promotion and Suppression

by Azamat Akhmetkaliyev, José Héctor Gibrán Fritz García, Eva Sonnenberg-Riethmacher and Dieter Riethmacher

Int. J. Mol. Sci. 2026, 27(15), 6807; https://doi.org/10.3390/ijms27156807 - 29 Jul 2026

Abstract

Bladder cancer (BLCA) is a common and heterogeneous malignancy in which disease progression is driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Increasing evidence positions the extracellular matrix (ECM) as a critical regulator of these [...] Read more.

Bladder cancer (BLCA) is a common and heterogeneous malignancy in which disease progression is driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Increasing evidence positions the extracellular matrix (ECM) as a critical regulator of these processes. Matricellular proteins (MCPs), a group of nonstructural ECM-associated molecules, have emerged as key modulators of tumor–stroma communication. In BLCA, MCPs have been reported to display divergent, and in some cases opposing, associations or functions, with the same protein participating in both tumor promotion and suppression. Here, we review current evidence on the function of MCPs in BLCA and synthesize their bidirectional roles in carcinogenesis. MCPs contribute to tumor progression by promoting invasion, epithelial–mesenchymal transition (EMT), angiogenesis, and metastatic niche formation. At the same time, MCPs can restrain tumor growth by inhibiting angiogenesis, stabilizing ECM organization, inducing cell cycle arrest, and maintaining epithelial integrity. A key concept emerging from this body of evidence is the context-dependent functional plasticity of MCPs. We propose that MCP-associated phenotypes in BLCA may be influenced by contextual factors, including isoform diversity arising from alternative splicing and post-translational modifications, spatial compartmentalization within tumor and stromal niches, tumor microenvironmental composition, and molecular subtype. However, the level of supporting evidence differs substantially among MCPs, and direct BLCA-specific mechanistic evidence remains limited for many proposed relationships. These factors, therefore, provide a framework for interpreting divergent findings rather than representing universally established determinants of MCP function. Recognizing MCPs as context-sensitive regulators rather than fixed tumor-promoting or tumor-suppressing entities provides a unifying framework for understanding their roles in BLCA. This could be an important step for therapeutic targeting, encouraging effective strategies to consider and incorporate the molecular and microenvironmental context in which MCPs operate. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Bladder Cancer)

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31 pages, 13011 KB

Open AccessArticle

Neurovascular Involvement in Arterial Tortuosity Syndrome Associated with a Homozygous SLC2A10 p.(Trp162Ter) Variant: Clinical, Molecular, and In Silico Characterization

by Serdar Bozlak, Cuneyd Yavas, Evrim Yalcin, Yusuf Seflekci, Tunay Dogan, Abdulilah Ece, Nazli Gulsum Akyel and Adnan Yuksel

Int. J. Mol. Sci. 2026, 27(15), 6806; https://doi.org/10.3390/ijms27156806 - 29 Jul 2026

Abstract

Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive connective tissue disorder caused by pathogenic variants in SLC2A10, which encodes the facilitative glucose transporter GLUT10. Although its vascular features are well recognized, the molecular consequences of many truncating variants remain poorly understood. [...] Read more.

Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive connective tissue disorder caused by pathogenic variants in SLC2A10, which encodes the facilitative glucose transporter GLUT10. Although its vascular features are well recognized, the molecular consequences of many truncating variants remain poorly understood. We report a patient with ATS carrying a homozygous nonsense variant, c.485G > A (p.Trp162Ter), identified by whole-exome sequencing. Quantitative real-time PCR assessed SLC2A10 expression, and integrated bioinformatic analyses (structural modeling, druggability prediction, transmembrane topology, molecular docking, and molecular dynamics) explored its structural impact. The patient presented with severe systemic arterial tortuosity, congenital cardiovascular anomalies, hernias, connective tissue abnormalities, and neurovascular involvement involving cerebral tortuosity and distal intracranial narrowing. Structural modeling revealed extensive truncation of GLUT10 and loss of multiple α-helical domains, with transmembrane helices reduced from twelve to five. Docking of nine known ligands showed weaker binding to the mutant, and Compound 892 bound most strongly to the wild type (−7.469 kcal/mol). Across 300 ns simulations, the mutant complex proved markedly less stable. qRT-PCR showed no significant transcript differences among patient, carriers, and controls. Our findings broaden the neurovascular spectrum of SLC2A10-related ATS and demonstrate that p.(Trp162Ter) severely disrupts GLUT10 architecture, topology, and ligand binding. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying the Pathogenesis of Genetic Diseases)

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41 pages, 1845 KB

Open AccessReview

Phylogeography of Bone Metastasis: Clonal Evolution, Skeletal Niche Adaptation, and Clinical Implications

by Samaa Alotab, Rasha Alissa, Mariam Zainab, Labibah Labib Khamies and Khalid Said Mohammad

Int. J. Mol. Sci. 2026, 27(15), 6805; https://doi.org/10.3390/ijms27156805 - 29 Jul 2026

Abstract

Bone metastasis is often treated clinically as a late complication of advanced cancer, yet accumulating evidence indicates that it is also a spatial evolutionary process shaped by clonal selection, niche adaptation, dormancy, and reseeding. This review examines BoM through a phylogeographic framework that [...] Read more.

Bone metastasis is often treated clinically as a late complication of advanced cancer, yet accumulating evidence indicates that it is also a spatial evolutionary process shaped by clonal selection, niche adaptation, dormancy, and reseeding. This review examines BoM through a phylogeographic framework that links tumor ancestry with anatomical location and time. We discuss how heterogeneous primary tumors generate bone-tropic subclones, how circulating tumor cells pass through dissemination bottlenecks, and how disseminated tumor cells enter perivascular and endosteal niches that either maintain dormancy or support early micrometastatic outgrowth. We then compare clonal architectures across breast, prostate, lung, and renal cell carcinomas, emphasizing both lineage-specific programs and convergent bone-adaptive states, including osteomimicry, immune evasion, metabolic plasticity, and epigenetic remodeling. Methodological platforms such as multiregion sequencing, single-cell and spatial transcriptomics, lineage tracing, and liquid biopsy are evaluated with attention to the technical limitations imposed by mineralized tissue. Finally, we consider how bone lesions may function as reservoirs for secondary dissemination and how evolutionary thinking could improve biomarker development, dormancy prediction, trial design, and therapy selection. Viewing BoM as an evolving ecosystem may help shift the field from reactive skeletal management toward earlier, biology-informed intervention. Full article

(This article belongs to the Special Issue Bone Microenvironment and Bone Metastasis)

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