International Journal of Molecular Sciences

12 pages, 1301 KB

Open AccessArticle

Nanomaterials Covered with Cell Membranes for Intracellular Delivery Without Lysosomal Degradation and Innate Immunity Induction

by Olga Morozova, Ekaterina Obraztsova and Dmitry Klinov

Int. J. Mol. Sci. 2025, 26(20), 10244; https://doi.org/10.3390/ijms262010244 - 21 Oct 2025

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Abstract

Cellular uptake of nanomaterials is based on endocytosis with their endosomal–lysosomal entrapment resulting in enzymatic hydrolysis. Besides biodegradation, the antigen presentation induces innate and adaptive immunity. Our goal was isolation of extracellular particles to study their structures, penetration into cells, stability, intracellular distribution, [...] Read more.

Cellular uptake of nanomaterials is based on endocytosis with their endosomal–lysosomal entrapment resulting in enzymatic hydrolysis. Besides biodegradation, the antigen presentation induces innate and adaptive immunity. Our goal was isolation of extracellular particles to study their structures, penetration into cells, stability, intracellular distribution, and interferon (IFN) production. Extracellular nanomaterials were isolated from conditioned culture media of human embryonic and cancer cells by two-stage differential centrifugation. Cellular uptake of Cy5-labeled particles was evaluated using spectrofluorimetry and confocal fluorescent microscopy. IFN gene expression was analyzed by reverse transcription with real-time PCR and ELISA. Vesicles of 10–200 nm were isolated by centrifugation at 20,800× g at +4 °C for 30 min. The fluorescent vesicles were gradually accumulated inside cells for seven days. Intracellular distribution patterns of the Cy5-labeled vesicles differed from lysosomes stained with LysoRed tracker. IFNs α, β and γ were not detected after treatment with the vesicles. IFN λ was found in cells in the presence of allogenic but not autologous particles. The gradual cellular uptake occurred without significant differences between autologous and heterologous vesicles. Different localization of the extracellular vesicles (EV) and lysosomes along with weak innate immune response (if any) suggested membrane fusion. Full article

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

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18 pages, 2118 KB

Open AccessArticle

Combined XPO1 Inhibition and Parthenolide Treatment Can Be Efficacious in Treating Triple-Negative Breast Cancer

by Amy L. Paulson, Radwa M. Elmorsi, Adam M. Lee and R. Stephanie Huang

Int. J. Mol. Sci. 2025, 26(20), 10243; https://doi.org/10.3390/ijms262010243 - 21 Oct 2025

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Abstract

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer with limited treatment options. Our previous work explored repurposing selinexor, an XPO1 inhibitor, as a novel therapeutic option for TNBC. To enhance its efficacy, this study aimed to identify beneficial combination [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer with limited treatment options. Our previous work explored repurposing selinexor, an XPO1 inhibitor, as a novel therapeutic option for TNBC. To enhance its efficacy, this study aimed to identify beneficial combination therapies with selinexor and experimentally evaluate their effects in TNBC. Using the computational tool IDACombo, we nominated drugs predicted to improve the efficacy of XPO1 inhibition. The top candidate, parthenolide, was tested in vitro using three transcriptionally distinct TNBC cell lines. Fluorescently labeled cells were co-cultured and treated with selinexor, parthenolide, or their combination. Growth inhibition was assessed across the mixed population and by individual cell line after 96 h, and potential synergy was evaluated using Combenefit. While selinexor and parthenolide monotherapy inhibited the growth of TNBC subtypes, the combination was more effective in suppressing the overall cell population. Synergistic interactions between the two agents were observed in specific TNBC lines but not all, reflecting the combination effect in heterogeneous TNBC patients. Our findings suggest the selinexor–parthenolide combination as a potential therapeutic strategy for TNBC, warranting further investigation. Our study also demonstrates the value of integrative computational–experimental approaches in guiding heterogeneity-informed drug combinations for preclinical evaluation. Full article

(This article belongs to the Special Issue Molecular Advances and Views in Triple-Negative Breast Cancer)

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15 pages, 1310 KB

Open AccessArticle

Discovery of Blood-Based Proteins That Mark Benzo[a]pyrene Modulation of Autoimmunity

by Kameron Kennicott, Yilin Nie and Yun Liang

Int. J. Mol. Sci. 2025, 26(20), 10242; https://doi.org/10.3390/ijms262010242 - 21 Oct 2025

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Abstract

Environmental pollutants are thought to shape our immune landscape and drive the rise in autoimmune disease incidence worldwide. However, the molecular underpinnings of environmental impact on autoimmunity remain elusive and a quantitative measurement for immune dysfunction as a result of environmental exposure is [...] Read more.

Environmental pollutants are thought to shape our immune landscape and drive the rise in autoimmune disease incidence worldwide. However, the molecular underpinnings of environmental impact on autoimmunity remain elusive and a quantitative measurement for immune dysfunction as a result of environmental exposure is yet to be developed. To this end, we have performed a discovery study to identify blood-based, immune-associated proteins regulated by benzo[a]pyrene (BaP) using the autoimmune-prone murine model MRL. We report the upregulation of autoimmune-associated cytokines including IL1a and IFNg by BaP, months before the manifestation of autoimmune phenotypes. Additionally, the increased levels of proteins such as IL16, IL22 and SNCA in male MRL mice upon BaP exposure may be a molecular link to the increased risk in end organ damage in subsets of autoimmune disease patients. Further comparison with the transcriptomic analysis of BaP-stimulated skin and lungs suggests distinct patterns of immune regulation in peripheral organs versus blood. Altogether, our study supports the need for the early detection of BaP-induced immune changes for the prevention and management of autoimmune diseases and provides leads for the future development of these blood-based biomarkers. Full article

(This article belongs to the Special Issue Environmental Pollutants Exposure and Toxicity)

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16 pages, 980 KB

Open AccessArticle

Markers of Antiviral Response in SLE Patients After Vaccination Against SARS-CoV-2

by Michał Komorniczak, Katarzyna Aleksandra Lisowska, Barbara Bułło-Piontecka, Alicja Dębska-Ślizień and Anna Wardowska

Int. J. Mol. Sci. 2025, 26(20), 10241; https://doi.org/10.3390/ijms262010241 - 21 Oct 2025

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Abstract

Patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) are at increased risk of severe infections, making effective vaccination strategies essential. While antibody responses to SARS-CoV-2 vaccination have been studied in SLE, less is known about innate immune correlates. Therefore, we evaluated [...] Read more.

Patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) are at increased risk of severe infections, making effective vaccination strategies essential. While antibody responses to SARS-CoV-2 vaccination have been studied in SLE, less is known about innate immune correlates. Therefore, we evaluated cytokines with a particular emphasis on interferon and chemokine profiles. To fulfill the immunological picture, we also assessed neutralizing antibodies against SARS-CoV-2 variants, lymphocyte subpopulations, and selected gene expression signatures in 33 patients stratified by vaccination status: fully vaccinated (FV, n = 23) and partially vaccinated (PV, n = 10). Serum analyses showed that FV patients exhibited increased type I (IFN-α2, IFN-β) and type III (IFN-λ1, IFN-λ2/3) interferons, as well as elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-12p70) and IL-10, whereas neutralizing antibody (Neut. Ab.) titers against wild-type and variant strains, including Omicron, were comparable between groups. Immunophenotyping demonstrated preserved T- and B-cell subset distributions, except for reduced CD8⁺CD197⁺CD45RA⁻ (central memory) T cells in FV patients. ISG15 gene expression was upregulated in the T cells of FV patients. Correlation analyses linked IL-6 with disease activity and IL-8, GM-CSF, IFN-β, IL-10, and Alpha Neut. Ab. with organ damage. Complement C3 correlated inversely with IFN-α2 and IFN-γ, while C4 correlated positively with Alpha and Omicron Neut. Ab. These findings highlight that vaccination in SLE induces distinct interferon and cytokine signatures without consistent enhancement of neutralizing antibodies against SARS-CoV-2, underscoring the importance of integrated immune correlates in assessing vaccine responses in this population. Full article

(This article belongs to the Special Issue The Role of SARS-CoV-2 in Immunomodulation—Post-Pandemic Reflection on the Role of Viruses in Human Immunology)

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49 pages, 8236 KB

Open AccessReview

Reactive Oxygen Species Across Death Pathways: Gatekeepers of Apoptosis, Ferroptosis, Pyroptosis, Paraptosis, and Beyond

by Noah Sendtner, Rebecca Seitz, Noah Brandl, Martina Müller and Karsten Gülow

Int. J. Mol. Sci. 2025, 26(20), 10240; https://doi.org/10.3390/ijms262010240 - 21 Oct 2025

Viewed by 480

Abstract

Reactive oxygen species (ROS) are versatile determinants of cell fate, tipping the balance between survival and death. By exceeding critical thresholds or perturbing compartment-specific signaling, ROS can initiate, modulate, or suppress regulated cell death (RCD). Importantly, their influence extends across the full spectrum [...] Read more.

Reactive oxygen species (ROS) are versatile determinants of cell fate, tipping the balance between survival and death. By exceeding critical thresholds or perturbing compartment-specific signaling, ROS can initiate, modulate, or suppress regulated cell death (RCD). Importantly, their influence extends across the full spectrum of currently characterized RCD modalities. 19 distinct forms of cell death—including both long-established and recently described entities—are shaped by ROS, either as triggers, modulators, or inhibitors. Beyond pathway-specific effects, ROS promote crosstalk between death programs, enabling switches from one mode to another and determining whether outcomes are inflammatory or non-inflammatory. By systematically integrating 19 RCD types, the unifying role of ROS emerges as both gatekeeper and connector of diverse death pathways. Such a comprehensive perspective underscores the centrality of redox imbalance in cell fate control and highlights its broader implications for inflammation and disease. Full article

(This article belongs to the Special Issue ROS Signalling and Cell Turnover)

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33 pages, 3225 KB

Open AccessArticle

Discovery of N-Hydroxypyridinedione-Based Inhibitors of HBV RNase H: Design, Synthesis, and Extended SAR Studies

by Dea Chotzalli, Vasiliki Pardali, Holly M. Walden, Dimitrios Perivolaris, Dimitrios Moianos, Maria Makri, Antonios Drakopoulos, Erofili Giannakopoulou, Razia Tajwar, Molly E. Woodson, John E. Tavis and Grigoris Zoidis

Int. J. Mol. Sci. 2025, 26(20), 10239; https://doi.org/10.3390/ijms262010239 - 21 Oct 2025

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Abstract

Hepatitis B Virus (HBV) continues to pose a significant global health challenge, with over 254 million chronic infections and current therapies being non-curative, necessitating lifelong treatment. The HBV ribonuclease H (RNase H) is essential during HBV reverse transcription by cleaving the viral pregenomic [...] Read more.

Hepatitis B Virus (HBV) continues to pose a significant global health challenge, with over 254 million chronic infections and current therapies being non-curative, necessitating lifelong treatment. The HBV ribonuclease H (RNase H) is essential during HBV reverse transcription by cleaving the viral pregenomic RNA after it has been copied into the (−) polarity DNA strand, enabling the viral polymerase to synthesize the (+) DNA strand. Although RNase H inhibition terminates viral replication and thus viral infectiveness, its targeting as an HBV treatment is unexploited. Its catalytic site contains four carboxylates that bind to two Mg²⁺ ions essential for RNA hydrolysis. As part of our ongoing research on RNase H inhibitors, we developed 23 novel N-hydroxypyridinedione (HPD) analogues. Specifically, 17 HPD imines, 4 HPD oximes, 1 2,6-diamino-4-((substituted)oxy)pyrimidine 1-oxide derivative, and 1 barbituric acid analogue were designed, synthesized, and tested for their anti-HBV activity. The HPD derivatives could be docked in the RNase H active site to coordinate the two Mg²⁺ ions and effectively inhibited viral replication in cellular assays. The 50% effective concentration (EC₅₀) values of these HPD compounds ranged from 0.5 to 73 μM, while the 50% cytotoxic concentration (CC₅₀) values ranged from 15 to 100 μM, resulting in selectivity indexes (SIs) up to 112. Furthermore, the novel HPD derivatives exhibited favourable pharmacokinetic-relevant characteristics, including high cellular permeability, good aqueous solubility, and overall drug-like properties. These findings indicate that HPD imines and oximes possess substantial antiviral potency and selectivity against HBV, underscoring the potential of the HPD scaffold as a promising framework for the development of next-generation anti-HBV agents. Full article

(This article belongs to the Special Issue Antiviral Drug Targets: Structure, Function, and Drug Design—3rd Edition)

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13 pages, 313 KB

Open AccessEditorial

Special Issue “Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies”

by Masaru Tanaka

Int. J. Mol. Sci. 2025, 26(20), 10238; https://doi.org/10.3390/ijms262010238 - 21 Oct 2025

Viewed by 365

Abstract

Psychiatry stands at a turning point, where molecular insights promise to revolutionize how we diagnose, monitor, and treat neuropsychiatric conditions, including Alzheimer’s, Parkinson’s, depression, dementia, and schizophrenia (SCZ), among others [...] Full article

(This article belongs to the Special Issue Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies)

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21 pages, 6252 KB

Open AccessArticle

Decomposition Analysis of Theoretical Raman Spectra for Efficient Interpretation of Experimental Spectra of Thin-Film Functional Materials

by Marek Doskocz, Łukasz Laskowski, Jacek Kujawski, Agnieszka Karczmarska, Krzysztof Cpałka, Ewelina Lipiec and Magdalena Laskowska

Int. J. Mol. Sci. 2025, 26(20), 10237; https://doi.org/10.3390/ijms262010237 - 21 Oct 2025

Viewed by 270

Abstract

This study introduces a novel approach for analyzing theoretical Raman spectra, designed to facilitate spectral interpretation, particularly for complex systems such as functional mesoporous silica-based thin films. The proposed methodology relies on spectral decomposition supported by theoretical calculations, representing a step toward the [...] Read more.

This study introduces a novel approach for analyzing theoretical Raman spectra, designed to facilitate spectral interpretation, particularly for complex systems such as functional mesoporous silica-based thin films. The proposed methodology relies on spectral decomposition supported by theoretical calculations, representing a step toward the development of autonomous research laboratories. The method assigns vibrational shifts to individual atoms within a molecular model and uses this information to generate partial spectra corresponding to specific atomic groupings. Unlike separate calculations for isolated components, this approach preserves the mutual interactions within the entire molecular structure, providing a more accurate representation of the vibrational environment. Decomposing the theoretical spectrum into contributions from atomic groups significantly simplifies the assignment of Raman bands to specific structural units, thereby enhancing the interpretative power of theoretical spectra and their correlation with experimental data. The method was demonstrated using real Raman spectroscopic data obtained from mesoporous SBA-15 silica thin films containing copper phosphonate groups. This work also highlights the critical role of molecular modeling and DFT calculations in Raman spectral analysis and outlines future perspectives for the use of artificial intelligence to automate and optimize the spectral interpretation process. Full article

(This article belongs to the Special Issue Molecular Advances in Macroporous, Mesoporous, and Microporous Materials)

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19 pages, 1616 KB

Open AccessArticle

Thermal Cycling Stimulation via Nasal Inhalation Attenuates Aβ_25–35-Induced Cognitive Deficits in C57BL/6 Mice

by Guan-Bo Lin, Hsu-Hsiang Liu, Yu-Yi Kuo, You-Ming Chen, Fang-Tzu Hsu, Yu-Wei Wang, Yi Kung, Chien Ching and Chih-Yu Chao

Int. J. Mol. Sci. 2025, 26(20), 10236; https://doi.org/10.3390/ijms262010236 - 21 Oct 2025

Viewed by 275

Abstract

Alzheimer’s disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood–brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet [...] Read more.

Alzheimer’s disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood–brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL/6 mice, TCSNI showed no adverse olfactory effects. In β-amyloid (Aβ)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in Aβ accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment. Full article

(This article belongs to the Special Issue New Therapies and Strategies in the Treatment of Neurodegenerative Diseases)

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14 pages, 3927 KB

Open AccessArticle

Polysorbate-Based Carriers Encapsulating Oxygen-Deficient Nanoparticles for Targeted and Effective Chemo-Sonodynamic Therapy of Glioblastoma

by Hyeon Ju Kang, Quan Truong Hoang, Nguyen Cao Nguyen, Binh Thi Thanh Pham, Thuy Giang Nguyen Cao, Vasanthan Ravichandran and Min Suk Shim

Int. J. Mol. Sci. 2025, 26(20), 10235; https://doi.org/10.3390/ijms262010235 - 21 Oct 2025

Viewed by 344

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with a high recurrence rate and mortality. A major obstacle to the effective treatment of GBM is the blood–brain barrier (BBB), which hinders the transfer of therapeutic cargo to the tumor lesion. Polysorbate-coated drug [...] Read more.

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with a high recurrence rate and mortality. A major obstacle to the effective treatment of GBM is the blood–brain barrier (BBB), which hinders the transfer of therapeutic cargo to the tumor lesion. Polysorbate-coated drug carriers are known to efficiently cross the BBB via apolipoprotein E (ApoE)-mediated transcytosis. In this study, we developed cancer-targeted nanocarriers using folic acid (FA)-conjugated polysorbate (Tween 80, T80) for safe and efficient chemo-sonodynamic combination therapy against GBM. T80-based nanocarriers effectively co-encapsulated doxorubicin (DOX, chemotherapeutic agent) and oxygen-deficient MnWOx nanoparticles (sonosensitizer). FA-conjugated T80 nanocarriers encapsulating DOX and MnWOx (FA-T-DOX@MnWOx) boosted the cellular uptake of DOX in human glioblastoma U87MG cells. The efficient ability of the T80-based drug carriers to cross the BBB was demonstrated using an in vitro transwell BBB model. In addition, sonosensitizer MnWOx nanoparticles in the T80-based carriers triggered GSH depletion, synergistically enhancing intracellular reactive oxygen species (ROS) generation in U87MG cells upon US irradiation. As a result, FA-T-DOX@MnWOx combined with US triggered significant apoptosis in U87MG cells. This study demonstrated that FA-conjugated, MnWOx-loaded, T80-based nanocarriers capable of crossing the BBB hold significant potential for treating GBM through a combined chemo-sonodynamic therapy. Full article

(This article belongs to the Special Issue Drug Delivery to the Central Nervous System: From Design, Synthesis, and Evaluation)

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30 pages, 1360 KB

Open AccessReview

Molecular Biomarkers and Therapeutic Approach of Patients with Diabetes and Obstructive Sleep Apnea

by Viviana Elian, Violeta Popovici, Alexandru Tudor Steriade, Gabriela Radulian, Emma Adriana Ozon, Elena Moroșan and Madalina Musat

Int. J. Mol. Sci. 2025, 26(20), 10234; https://doi.org/10.3390/ijms262010234 - 21 Oct 2025

Viewed by 699

Abstract

The bidirectional relationship between obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM) represents a critical intersection in metabolic medicine. Therefore, the present review examines the most recent data regarding molecular mechanisms linking OSA and T2DM, analyzing key biomarkers including hypoxia-inducible factors [...] Read more.

The bidirectional relationship between obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM) represents a critical intersection in metabolic medicine. Therefore, the present review examines the most recent data regarding molecular mechanisms linking OSA and T2DM, analyzing key biomarkers including hypoxia-inducible factors (HIF 1α), inflammatory mediators, adipokines, microRNAs, hormones, and neuropeptides that serve as both diagnostic indicators and potential therapeutic targets. Key molecular findings from the scientific literature report elevated HIF-1α promoting insulin resistance, decreased SIRT1 levels, dysregulated microRNA-181a and microRNA-199a, increased inflammatory cytokines (TNF-α, IL-6, CRP), and altered adipokine profiles with reduced adiponectin and elevated leptin and resistin. Current clinical evidence reveals significant therapeutic potential for modern antidiabetic medications in the management of OSA. GLP-1 receptor agonists, particularly tirzepatide, received FDA approval as the first medication for moderate-to-severe OSA in obese adults, showing a 55–63% AHI reduction. SGLT2 inhibitors also demonstrate promising results through weight loss and cardiovascular protection mechanisms. This integrated approach represents the evolution toward comprehensive OSA management beyond traditional mechanical ventilation strategies. Future research should focus on developing personalized treatment algorithms based on individual molecular biomarker profiles, investigating combination therapies, and exploring novel targets, including chronotherapy agents. Full article

(This article belongs to the Special Issue Diabetes: From Molecular Basis to Therapy, 2nd Edition)

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32 pages, 1863 KB

Open AccessReview

Gamma-Aminobutyric Acid (GABA) as a Dietary Strategy for Enhancing Temperature Stress Resilience in Aquaculture Species

by Abayomi Oladimeji Ogun, Mohammad Moniruzzaman, Hyuncheol Jeon, Haham Kim, Deni Aulia, Junhyeok Hur, Sooa Yoon, Suhyun Lee, Taesun Min and Seunghyung Lee

Int. J. Mol. Sci. 2025, 26(20), 10233; https://doi.org/10.3390/ijms262010233 - 21 Oct 2025

Viewed by 520

Abstract

The sustainability of aquaculture is increasingly threatened by rising ocean temperatures occasioned by the continued prevalence of global warming, which can have severe consequences for fish health and productivity. Fish, as ectothermic organisms, are susceptible to temperature fluctuations and prolonged exposure to extreme [...] Read more.

The sustainability of aquaculture is increasingly threatened by rising ocean temperatures occasioned by the continued prevalence of global warming, which can have severe consequences for fish health and productivity. Fish, as ectothermic organisms, are susceptible to temperature fluctuations and prolonged exposure to extreme temperatures can lead to physiological disruptions, including altered metabolic rates, oxidative stress, and immune suppression, ultimately affecting their growth and reproductive success. In response, several strategies, including dietary supplementation, have been proposed to alleviate temperature stress in aquaculture. One such supplement, gamma (γ)-aminobutyric acid (GABA), a non-proteinogenic amino acid, has garnered attention for its potential to enhance stress resilience in aquatic species. In this review, we examine the physiological responses of fish to temperature stress and evaluate the role of GABA in alleviating non-temperature stress. By synthesizing the available evidence, we aim to highlight the potential of GABA as a dietary supplement to improve the resilience of farmed fish to temperature fluctuations, ultimately contributing to sustainable aquaculture in the face of climate change. GABA acts as an inhibitory neurotransmitter in the central nervous system, promoting relaxation and reducing stress. We not only spotlight GABA’s role in the central nervous system, where it has been shown to modulate stress responses by enhancing antioxidant defenses, improving growth performance, and boosting disease resistance, but also emphasize the limited exploration of its potential to mitigate temperature stress in some aquaculture species, particularly economically important fish like olive flounder. Finally, in this review, we provide additional insights into how GABA might help mitigate temperature stress by identifying factors that may influence its supplementation, thereby laying the groundwork for future research on its use as a potential tool for mitigating temperature stress in aquaculture species. Full article

(This article belongs to the Special Issue The Latest Development of Molecular Research in Animal Nutrition)

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22 pages, 4166 KB

Open AccessArticle

Characterization of Recombinant Human Type II Collagen from CHO Cells, Functional Assessment of Chondrocytes and Alleviation of Cartilage Degeneration

by Chuan Wang, Zhijie Zhang, Zhengqi Zha, Chunyang Lu, Hang Wang, Long Yue and Hongping Yin

Int. J. Mol. Sci. 2025, 26(20), 10232; https://doi.org/10.3390/ijms262010232 - 21 Oct 2025

Viewed by 316

Abstract

Type II collagen (Col2), a crucial structural protein in hyaline cartilage, is essential for cartilage integrity and facilitating injury repair. However, research on recombinant type II collagen still faces many challenges, such as structure and yield, which limit the application of recombinant Col2 [...] Read more.

Type II collagen (Col2), a crucial structural protein in hyaline cartilage, is essential for cartilage integrity and facilitating injury repair. However, research on recombinant type II collagen still faces many challenges, such as structure and yield, which limit the application of recombinant Col2 in biomedical fields. In this study, we achieved high-yield expression of full-length human Col2 (rhCol2) in CHO cells. The physical and chemical properties of rhCol2 were very close to native Col2, including molecular weight, triple helix structure, thermal stability and self-assembly capacity. Functional assays of primary chondrocytes have demonstrated that rhCol2 can effectively promote chondrocyte proliferation and increase the expression levels of cartilage-specific genes (Col2a1, Aggrecan, and Sox-9). Moreover, a cartilage defect model was surgically created in SD rats demonstrated that rhCol2 significantly enhanced cartilage repair, and the severity of the defect was assessed through histological and micro-CT analyses. Human chondrocytes were utilized to compare the effects of different collagens and verified through a series of functional experiments. In conclusion, these findings indicate that rhCol2 is an effective biomaterial and is expected to promote the application of recombinant collagen in the field of cartilage repair. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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25 pages, 7937 KB

Open AccessArticle

The UHPLC-Orbitrap MS/MS and Network Pharmacology Strategies Reveal the Active Antioxidants of Bleeding Sap from Sponge Gourd in Treating Tuberculosis

by Di Zhang, Lu Jiang, Yujiang Dai, Xinxin Si, Huifang Li and Komal Anjum

Int. J. Mol. Sci. 2025, 26(20), 10231; https://doi.org/10.3390/ijms262010231 - 21 Oct 2025

Viewed by 246

Abstract

The bleeding sap of Luffa cylindrica (L.) Roem has been used for the treatment of tuberculosis since the record of Supplements to Compendium of Materia Medica. The active components and possible mechanism of it are yet ambiguous. Hence, this study is focused [...] Read more.

The bleeding sap of Luffa cylindrica (L.) Roem has been used for the treatment of tuberculosis since the record of Supplements to Compendium of Materia Medica. The active components and possible mechanism of it are yet ambiguous. Hence, this study is focused on investigating the possible mechanism underpinning this effect on the perspective of the antioxidant ingredients from the bleeding sap. Through organic solvents extraction, HPLC fractionation, DPPH trials evaluation, and UHPLC-Orbitrap tandem MS identification, a total of 37 compounds were identified from the bleeding sap with the strongest antioxidant ability. Network pharmacology, bioinformatics, and molecular docking as well as literature review revealed 13 compounds, including linoleic acid, abietic acid, and tretinoin, that might exert their anti-tuberculosis function via actions with PPARγ or MAPK pathway. These findings offer guidance for the potential applications of Luffa cylindrica (L.) Roem as a functional food. Full article

(This article belongs to the Special Issue Marine Natural Products as a Source of Therapeutics—Recent Trends)

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24 pages, 1246 KB

Open AccessReview

Mannose Derivatives as Anti-Infective Agents

by Rosana Ribić

Int. J. Mol. Sci. 2025, 26(20), 10230; https://doi.org/10.3390/ijms262010230 - 21 Oct 2025

Viewed by 482

Abstract

Mannose is a natural monosaccharide that plays a central role in host–pathogen interactions and has emerged as a versatile scaffold for designing anti-infective agents. This review summarizes recent advances in mannose-based glycoconjugates with antibacterial, antiviral, antifungal, and antiparasitic activity. In bacteria, FimH antagonists [...] Read more.

Mannose is a natural monosaccharide that plays a central role in host–pathogen interactions and has emerged as a versatile scaffold for designing anti-infective agents. This review summarizes recent advances in mannose-based glycoconjugates with antibacterial, antiviral, antifungal, and antiparasitic activity. In bacteria, FimH antagonists prevent Escherichia coli adhesion, while mannose-functionalized materials disrupt Pseudomonas and Burkholderia biofilms or enhance delivery of anti-tubercular drugs. In virology, mannose-containing dendrimers, glycopolymers, and nanoparticles inhibit HIV, SARS-CoV-2, Ebola, HPV, and HSV by targeting viral glycoproteins or blocking lectin-mediated transmission. Mannose-decorated vaccines and nanocarriers also show promise against fungal pathogens and parasites. Continued optimization of presented structures could lead to the promising candidates for clinically applicable therapies. Full article

(This article belongs to the Special Issue Glycoconjugates: From Structure to Therapeutic Application)

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15 pages, 3067 KB

Open AccessArticle

Transcriptomic Profiling of the Tumor Microenvironment in High-Grade Serous Carcinoma: A Pilot Study of Morphologic and Molecular Distinctions Between Classic and SET Patterns

by Riccardo Giannini, Francesco Bartoli, Katia De Ieso, Tiziano Camacci, Andrea Bertolucci, Lorenzo Piccini, Erion Rreka, Duccio Volterrani, Federica Gemignani, Stefano Landi, Clara Ugolini, Piero Vincenzo Lippolis and Pinuccia Faviana

Int. J. Mol. Sci. 2025, 26(20), 10229; https://doi.org/10.3390/ijms262010229 - 21 Oct 2025

Viewed by 321

Abstract

High-grade serous carcinoma (HGSC) of the ovary is characterized by two major histological patterns: a classic papillary/micropapillary architecture and a solid pseudo-endometrioid transitional (SET) variant. We investigated whether the distinct morphologic subtypes are underpinned by transcriptomic differences in the tumor microenvironment (TME). We [...] Read more.

High-grade serous carcinoma (HGSC) of the ovary is characterized by two major histological patterns: a classic papillary/micropapillary architecture and a solid pseudo-endometrioid transitional (SET) variant. We investigated whether the distinct morphologic subtypes are underpinned by transcriptomic differences in the tumor microenvironment (TME). We profiled 21 HGSC tumors (7 SET, 14 classic) using a 770-gene NanoString PanCancer Progression panel. Differential expression analysis revealed ~20 genes with significantly different expression (>4-fold, adjusted p < 0.01) between SET and classic tumors. Unsupervised clustering partially separated SET and classic tumors, suggesting that global gene expression patterns correlate with histologic subtype. SET tumors exhibited upregulation of cell-cycle and epithelial genes (e.g., PTTG1, TRAIL, HER3) and downregulation of genes involved in epithelial–mesenchymal transition (EMT), extracellular matrix (ECM) organization, and angiogenesis (e.g., TWIST2, FGF2, decorin) relative to classic tumors. Notably, PTTG1 and TRAIL were upregulated ~6–9-fold in SET tumors, whereas TWIST2 was ~7-fold downregulated, consistent with reduced EMT in SET tumors. Pathway analysis indicated that SET tumors appear to have an immune-active, stroma-poor microenvironment, in line with an “immunoreactive” phenotype, whereas classic tumors showed a mesenchymal, stroma-rich profile. These molecular distinctions could have diagnostic utility and may inform therapeutic stratification, with key dysregulated genes (e.g., HER3, TRAIL, FGF2) representing potential prognostic or predictive biomarkers. For example, high HER3 expression in SET tumors might predict sensitivity to ERBB3/PI3K inhibitors, whereas stromal factors (e.g., FGF2) enriched in classic HGSC could be targeted with microenvironment-modulating therapies. These preliminary findings require validation before translation into pathology practice via immunohistochemical (IHC) assays (e.g., for HER3 or TRAIL), potentially enabling improved classification and personalized treatment of HGSC. We report effect sizes as log₂ fold change with 95% confidence intervals and emphasize FDR-adjusted q-values. Given the small sample size and the absence of outcome data (OS/PFS/PFI), results are preliminary and hypothesis-generating. Orthogonal protein-level validation and replication in larger, independent cohorts are required before any translational inference. Full article

(This article belongs to the Special Issue Tumor Microenvironment and Cancer Progression: Molecular Insights for Targeted Therapy)

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18 pages, 3948 KB

Open AccessArticle

Integrating Experimental and Computational Approaches to Cardioprotection: Vascular Reactivity, Molecular Docking, and ADMET Modeling of Melicoccus bijugatus (Guinep)

by Keaton Logan, Javier Palacios, Sussan Lopez, Wesley Gray and Chukwuemeka R. Nwokocha

Int. J. Mol. Sci. 2025, 26(20), 10228; https://doi.org/10.3390/ijms262010228 - 21 Oct 2025

Viewed by 315

Abstract

Melicoccus bijugatus (Guinep) is traditionally consumed in the Caribbean and Latin America for its health benefits, yet its cardiovascular effects remain underexplored. This study investigated the therapeutic potential of Guinep by combining experimental and computational approaches. The biological evaluation of the Guinep extract [...] Read more.

Melicoccus bijugatus (Guinep) is traditionally consumed in the Caribbean and Latin America for its health benefits, yet its cardiovascular effects remain underexplored. This study investigated the therapeutic potential of Guinep by combining experimental and computational approaches. The biological evaluation of the Guinep extract was conducted by assessing the effects of modulating Angiotensin-Converting Enzyme (ACE), Angiotensin II Type 1 Receptor (AT1R), and Voltage-Gated Calcium Channels (VGCC) on vascular reactivity. Metabolites previously identified by high-resolution UHPLC-Q-Orbitrap mass spectrometry were further examined using in silico tools, including ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) prediction (pkCSM), biological activity prediction (PASS server), and molecular docking (AutoDock Vina) against cardiovascular targets (ACE: PDB 1O86, AT1R: PDB 4ZUD, VGCC: PDB 8WE8). Docking results revealed that phytochemicals such as isorhamnetin-3-O-glucoside and 3-O-caffeoylquinic acid displayed strong binding affinities with ACE (−9.3 and −8.5 kcal/mol), AT1R (−8.2 and −7.6 kcal/mol), and VGCC (−8.6 and −7.6 kcal/mol), in several cases matching or surpassing standard antihypertensive drugs. Key hydrogen bond interactions closely resembled those of reference ligands, suggesting pharmacophoric similarity. ADMET modeling confirmed favorable pharmacokinetic profiles and low predicted toxicity, supporting their drug-like potential. These findings are consistent with in vivo evidence of Guinep’s hypotensive, antioxidant, and vasodilatory properties. Vascular relaxation of Guinep extract was predominantly mediated by blockade of VGCC (53%) and AT1R (48%), while ACE inhibition accounted for 24%. Collectively, the results demonstrate that Guinep contains bioactive phytochemicals with multitarget cardiovascular activity, particularly as ACE, AT1R, and VGCC modulators. This study validates the traditional use of Guinep. Full article

(This article belongs to the Special Issue Biological Study of Plant Bioactive Compounds)

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20 pages, 5854 KB

Open AccessArticle

Berbamine Targets TNFAIP3: A Bioactive Compound Alleviates Oxidative Stress and Inflammation in the Comorbidity of Insomnia and Chronic Obstructive Pulmonary Disease Through Multi-Omics Integration

by Xinliao Deng, Shuaiyu Jiang, Ziyi Liu, Xinyu Liu, Tao Lu and Xiaodan Liu

Int. J. Mol. Sci. 2025, 26(20), 10227; https://doi.org/10.3390/ijms262010227 - 21 Oct 2025

Viewed by 409

Abstract

Chronic obstructive pulmonary disease (COPD) and insomnia are highly comorbid, yet their shared pathogenesis and therapeutic targets remain unclear. This study employed multidimensional approaches—including bidirectional Mendelian randomization (MR), transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), and computational drug repositioning—to investigate causal relationships, [...] Read more.

Chronic obstructive pulmonary disease (COPD) and insomnia are highly comorbid, yet their shared pathogenesis and therapeutic targets remain unclear. This study employed multidimensional approaches—including bidirectional Mendelian randomization (MR), transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), and computational drug repositioning—to investigate causal relationships, shared pathways, and therapeutic strategies for COPD–insomnia comorbidity. MR analysis indicated that insomnia is a causal risk factor for COPD (OR = 2.04, 95% CI: 1.18–3.51; p = 0.011), with no reverse causality. Integrated transcriptomics of COPD (GSE148004) and insomnia (GSE208668) identified 230 co-dysregulated genes enriched in immune-inflammatory pathways (e.g., NF-κB signaling and cytokine response) and oxidative stress. Protein–protein interaction networks highlighted TNFAIP3 as a hub gene, confirmed by LASSO regression as a shared diagnostic biomarker. A co-expression network of 190 overlapping genes linked circadian disruption and airway inflammation. Drug repositioning nominated TNFAIP3-targeting agents, and molecular docking revealed high-affinity binding between berbamine and the TNFAIP3 OTU domain (ΔG = −9.25 kcal/mol). TNFAIP3 emerges as a dual regulator of inflammatory signaling and redox homeostasis. Our systems pharmacology approach bridges epidemiological causality and molecular mechanisms, supporting single-agent polypharmacology for COPD–insomnia comorbidity. Full article

(This article belongs to the Special Issue Effects of Bioactive Compounds in Oxidative Stress and Inflammation)

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27 pages, 41569 KB

Open AccessArticle

Deacidification of the Endolysosomal System by the Vesicular Proton Pump V-ATPase Inhibitor Bafilomycin A1 Affects EGF Receptor Endocytosis Differently in Endometrial MSC and HeLa Cells

by Anna V. Salova, Tatiana N. Belyaeva, Ilia K. Litvinov, Marianna V. Kharchenko and Elena S. Kornilova

Int. J. Mol. Sci. 2025, 26(20), 10226; https://doi.org/10.3390/ijms262010226 - 21 Oct 2025

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Abstract

It is well-known that EGF binding to EGFR stimulates signal transduction and endocytosis, with the latter leading to lysosomal degradation of EGFR. However, the majority of data on the regulation of endocytosis have been obtained in tumor-derived cells. Here, we perform a comprehensive [...] Read more.

It is well-known that EGF binding to EGFR stimulates signal transduction and endocytosis, with the latter leading to lysosomal degradation of EGFR. However, the majority of data on the regulation of endocytosis have been obtained in tumor-derived cells. Here, we perform a comprehensive analysis of the role of endolysosome acidification in the regulation of endocytic pathway in tumor cells and in endometrial MSCs as a model of proliferating, undifferentiated, non-immortalized cells. Using QD-labeled EGF, the dynamics of co-localization of EGF-receptor complexes with endocytic markers in the control and upon inhibition of V-ATPase by Bafilomycin A1 (BafA1) were studied using confocal microscopy. Image analysis showed that in HeLa and A549 cells, BafA1 significantly slowed down EGFR entry into and exit from EEA1-positive early endosomes without disrupting passage through Rab7, CD63, and Lamp1 compartments, but rather shifting it to later times. In enMSCs, only a portion of EGF-containing endosomes entered the degradation pathway, and lysosomal delivery was significantly delayed. Unlike HeLa, in enMSC early endosomes, BafA1 increased the association of EGF-QDs with EEA1, suggesting a lower pH level, which is suboptimal for EEA1-dependent fusions. It is concluded that, unlike HeLa, enMSCs form a population of pH-independent endosomes containing activated EGFR for a long time. Full article

(This article belongs to the Special Issue Latest Research on Mesenchymal Stem Cells)

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15 pages, 1807 KB

Open AccessArticle

SUMF1 Common Variant rs793391 Is Associated with Response to Inhaled Corticosteroids in Patients with COPD

by Charikleia Ntenti, Eleni Papakonstantinou, Leticia Grize, Maria Pascarella, Björn C. Frye, Sebastian Fähndrich, Despoina Ioannidou, Spasenija Savic Prince, Antonis Goulas and Daiana Stolz

Int. J. Mol. Sci. 2025, 26(20), 10225; https://doi.org/10.3390/ijms262010225 - 21 Oct 2025

Viewed by 1003

Abstract

This study investigated whether specific sulfatase modifying factor-1 (SUMF1) SNPs—previously linked to lung function—are associated with COPD progression and response to inhaled corticosteroid (ICS) treatment, specifically budesonide, given that SUMF1 expression is altered in COPD and its variants linked to increased [...] Read more.

This study investigated whether specific sulfatase modifying factor-1 (SUMF1) SNPs—previously linked to lung function—are associated with COPD progression and response to inhaled corticosteroid (ICS) treatment, specifically budesonide, given that SUMF1 expression is altered in COPD and its variants linked to increased disease risk. A subgroup of 165 COPD patients from the HISTORIC study were genotyped for two common SUMF1 SNPs, rs11915920 and rs793391. Patients first underwent a six-week run-in phase with open-label triple inhaled therapy (LAMA/LABA/ICS), then were randomized to receive either LAMA/LABA/placebo or LAMA/LABA/ICS for 12 months. Associations between SNPs, baseline characteristics, and response to ICS—based on FEV₁ change over 12 months—were evaluated. Heterozygotes (TG) for the rs793391 polymorphism treated with LAMA/LABA/ICS showed a significant and clinically meaningful FEV₁ improvement compared to the placebo group. This was supported by improved patient-reported outcomes, with lower SGRQ and CAT scores and a clinically relevant increase in General Health Questionnaire scores. These findings suggest that rs793391 may be linked to both COPD progression and ICS response and could contribute to more personalized treatment strategies in COPD. Full article

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

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23 pages, 4914 KB

Open AccessArticle

Genetic Variation and Genome-Enabled Prediction of White Lupin Frost Resistance in Different Reference Populations

by Nicolò Franguelli, Daniele Cavalli, Nelson Nazzicari, Luciano Pecetti, Tommaso Notario and Paolo Annicchiarico

Int. J. Mol. Sci. 2025, 26(20), 10224; https://doi.org/10.3390/ijms262010224 - 21 Oct 2025

Viewed by 270

Abstract

In various European regions, white lupin (Lupinus albus L) production could increase by autumn sowing of winter-hardy varieties. This study aimed to explore the genetic variation, the genetic architecture, and the genomic prediction of frost resistance in two reference populations, one including [...] Read more.

In various European regions, white lupin (Lupinus albus L) production could increase by autumn sowing of winter-hardy varieties. This study aimed to explore the genetic variation, the genetic architecture, and the genomic prediction of frost resistance in two reference populations, one including 144 landrace and cultivar genotypes, and the other comprising 144 breeding lines. These populations were genotyped by 40,914 and 32,951 SNP markers, respectively, issued by genotyping-by-sequencing. The genotypes were phenotyped for mortality and a biomass injury score at freezing temperature of −11 °C under controlled conditions. Both traits, highly correlated, exhibited large genetic variation and high broad-sense heritability (H² = 0.76–0.82). A genome-wide association study highlighted their polygenic architecture and detected markers linked to candidate genes. The intra-population predictive ability of plant mortality achieved 0.41 for landrace and cultivar germplasm, and 0.67 for breeding lines. The cross-population predictive ability was higher when using the model constructed for landrace and cultivar germplasm to predict breeding lines (0.39) than the reverse (0.26). Landrace field survival was largely influenced by late phenology in addition to frost resistance. Our results revealed frost-resistant germplasm, confirmed the polygenic control of frost resistance, and highlighted genomic prediction opportunities for line selection and the identification of elite genetic resources. Full article

(This article belongs to the Special Issue New Insights into Plant Stress)

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16 pages, 2871 KB

Open AccessArticle

Proteomic Profiling of Cardiomyocytes Revealed Potential Radioprotective Effects of Different Resveratrol Pretreatment Regimens

by Michalina Gramatyka, Marta Gawin, Agata Kurczyk, Adam Gądek, Monika Pietrowska and Piotr Widłak

Int. J. Mol. Sci. 2025, 26(20), 10223; https://doi.org/10.3390/ijms262010223 - 21 Oct 2025

Viewed by 217

Abstract

Resveratrol may protect against radiation by modulating cellular metabolism and enhancing the cellular response to stress. Here, we explored its effects on human cardiomyocytes exposed to ionizing radiation. Resveratrol (5 µM) was administered for 1, 7, and 30 days before a single 2 [...] Read more.

Resveratrol may protect against radiation by modulating cellular metabolism and enhancing the cellular response to stress. Here, we explored its effects on human cardiomyocytes exposed to ionizing radiation. Resveratrol (5 µM) was administered for 1, 7, and 30 days before a single 2 Gy dose of irradiation, and then radiation toxicity and changes in the proteome were evaluated. Extended resveratrol treatment (7 or 30 days) induced more profound proteomic changes than one-day treatment and partially counteracted toxic effects of radiation, leading to increased cell survival, reduced cell death, and fewer cells arrested in the G1 phase. Though resveratrol administration itself had a greater impact on the proteome than radiation alone, we identified three subsets of proteins differently affected by radiation depending on the resveratrol context. The first subset (84 differentially expressed proteins; DEPs) represented proteins influenced by radiation in all resveratrol pretreatment regimens. The second subset (228 DEPs), linked to DNA repair, cell cycle checkpoints, and apoptosis, was affected by radiation only in the absence of resveratrol preconditioning, indicating the compound’s protective effect. The third subset (252 DEPs) involved in metabolism regulation appeared only after extended resveratrol preconditioning. In conclusion, the results demonstrate that hypothetical time-dependent cardioprotective effects of resveratrol are linked to significant proteomic reprogramming of cardiomyocytes caused by long-term pretreatment. Full article

(This article belongs to the Special Issue Innovative Approaches to Enhancing Bioavailability and Bioaccessibility of Bioactive Compounds from Plant and Food Extracts)

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17 pages, 1286 KB

Open AccessArticle

Structural Characterization and Molecular Docking Studies of Fresh Coconut Meat Polysaccharides

by Jiayuan Huang, Mingyang Ma, Miaomiao Qin, Xinyun Li and Yongshen Ren

Int. J. Mol. Sci. 2025, 26(20), 10222; https://doi.org/10.3390/ijms262010222 - 21 Oct 2025

Viewed by 200

Abstract

Fresh coconut meat polysaccharides (FCMPs) are high-value natural active polysaccharides with both medicinal and edible uses, but their structural characteristics and potential biological activities have not been well studied. In this work, FFCMP was separated and purified by sequential application of water extraction [...] Read more.

Fresh coconut meat polysaccharides (FCMPs) are high-value natural active polysaccharides with both medicinal and edible uses, but their structural characteristics and potential biological activities have not been well studied. In this work, FFCMP was separated and purified by sequential application of water extraction and alcohol precipitation methods, the Sevag method, DEAE-52 cellulose column chromatography, and Sephadex G-100 gel column chromatography, yielding four components (FCMP 1-FCMP 4). High-performance liquid chromatography (HPLC) was used to determine their molecular weights as 343,016.9, 2279.4, 1363.2, and 2228.9 Da, respectively. Structural characterization and monosaccharide analysis revealed that the FCMP series primarily consists of mannose, glucose, galactose, arabinose, and rhamnose. Methylation experiments and nuclear magnetic resonance (NMR) indicated that FCMP 1 exhibits a complex topological structure with a β-1→4 main chain, β-1→6 branches, and an α-L-rhamnose terminal; FCMP 2 is a heteropolysaccharide with a β-(1→3)-mannan main chain containing β-(1→6)-galactose branches; the main chain of FCMP 3 consists of β-D-mannose and β-D -galactose, with side chains containing α-L-rhamnose and terminal α-L-arabinose and β-D-mannose; and FCMP 4 has a main chain primarily composed of glucose and mannose linked via 1→4 bonds, with some C6 positions exhibiting 1→6 branch structures. Molecular docking predictions suggest that the FCMP series of polysaccharides possess immunomodulatory, anti-inflammatory, and edema-treating properties, providing a theoretical basis for their application in pharmacology and food science research. Full article

(This article belongs to the Special Issue Isolation and Biological Activities of Natural Products: Focus on Molecular Advance)

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17 pages, 2854 KB

Open AccessArticle

Induction of Extrinsic Apoptotic Pathway in Pancreatic Cancer Cells by Apteranthes europaea Root Extract

by Rinat Bar-Shalom, Lana Abdelhak, Wafa Zennouhi, Farid Khallouki, Laila Benbacer and Fuad Fares

Int. J. Mol. Sci. 2025, 26(20), 10221; https://doi.org/10.3390/ijms262010221 - 21 Oct 2025

Viewed by 227

Abstract

Pancreatic cancer is an extremely deadly disease with few effective treatment options and the lowest survival rate among all types of cancer. As a result, there is an urgent need for the development of new and more effective treatment strategies. Natural products have [...] Read more.

Pancreatic cancer is an extremely deadly disease with few effective treatment options and the lowest survival rate among all types of cancer. As a result, there is an urgent need for the development of new and more effective treatment strategies. Natural products have long been a vital source of drug discovery, offering unique bioactive compounds, and representing a promising source for new, effective, and less toxic treatments. In the present study, we aimed to investigate the effects of Apteranthes europaea (Guss.) Murb (A. europaea) root extract on the growth of pancreatic cancer cells. The proliferation assay (XTT) and real-time analysis using the IncuCyte Live-Cell Analysis System, following treatment of PL45 and Mia PaCa-2 pancreatic cancer cells with escalating concentrations (50–200 µL) to A. europaea root extract, demonstrated the progression of apoptosis. Apoptosis induction was confirmed through cell cycle analysis and Annexin V/PI double staining assays. Western blot analysis revealed the distinct activation of caspase-8, accompanied by the cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Interestingly, no activation of caspase-9 was observed, suggesting the involvement of the extrinsic apoptotic pathway. Our findings suggest that A. europaea extract may be a potential novel strategy for treating pancreatic cancer. Full article

(This article belongs to the Special Issue Antitumor Activity of Natural Product)

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28 pages, 1659 KB

Open AccessReview

Disrupting the Gut–Brain Axis: How Artificial Sweeteners Rewire Microbiota and Reward Pathways

by Roberto Coccurello

Int. J. Mol. Sci. 2025, 26(20), 10220; https://doi.org/10.3390/ijms262010220 - 21 Oct 2025

Viewed by 694

Abstract

Artificial sweeteners, or non-caloric sweeteners (NCSs), are widely consumed as sugar substitutes to reduce energy intake and manage obesity. Once considered inert, accumulating evidence now shows that NCSs interact with host physiology, altering gut microbiota composition and neural circuits that regulate feeding. This [...] Read more.

Artificial sweeteners, or non-caloric sweeteners (NCSs), are widely consumed as sugar substitutes to reduce energy intake and manage obesity. Once considered inert, accumulating evidence now shows that NCSs interact with host physiology, altering gut microbiota composition and neural circuits that regulate feeding. This review synthesizes current knowledge on how NCSs disrupt the gut–brain axis (GBA), with particular focus on microbiota-mediated effects and neural reward processing. In homeostatic regulation, NCS-induced dysbiosis reduces beneficial taxa such as Akkermansia muciniphila and Faecalibacterium prausnitzii, diminishes short-chain fatty acid production, impairs gut barrier integrity, and promotes systemic inflammation. These changes blunt satiety signaling and favor appetite-promoting pathways. Beyond homeostasis, NCSs also rewire hedonic circuits: unlike caloric sugars, which couple sweet taste with caloric reinforcement to robustly activate dopaminergic and hypothalamic pathways, NCSs provide sensory sweetness without energy, weakening reward prediction error signaling and altering neuropeptidergic modulation by orexin, neurotensin, and oxytocin. Microbial disruption further exacerbates dopaminergic instability by reducing precursors and metabolites critical for reward regulation. Together, these top-down (neural) and bottom-up (microbial) mechanisms converge to foster maladaptive food seeking, metabolic dysregulation, and increased vulnerability to overeating. Identifying whether microbiome-targeted interventions can counteract these effects is a key research priority for mitigating the impact of NCSs on human health. Full article

(This article belongs to the Special Issue Molecular Research of Gut Microbiota in Human Health and Diseases)

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31 pages, 2842 KB

Open AccessReview

Bottom Sediments as Dynamic Arenas for Anthropogenic Pollutants: Profiling Sources, Unraveling Fate Mechanisms, and Assessing Ecological Consequences

by Abdullah Maqsood and Ewa Łobos-Moysa

Int. J. Mol. Sci. 2025, 26(20), 10219; https://doi.org/10.3390/ijms262010219 - 21 Oct 2025

Viewed by 409

Abstract

Bottom sediments play a central role in regulating contaminant dynamics in aquatic systems. They act as both storage sites and reactive zones where contaminants undergo transformation, sequestration, or remobilization. Contaminants primarily enter sediments through anthropogenic activities, including agricultural runoff, industrial effluents, wastewater discharge, [...] Read more.

Bottom sediments play a central role in regulating contaminant dynamics in aquatic systems. They act as both storage sites and reactive zones where contaminants undergo transformation, sequestration, or remobilization. Contaminants primarily enter sediments through anthropogenic activities, including agricultural runoff, industrial effluents, wastewater discharge, urban runoff, and mining operations. This review focuses on six major contaminant groups, including nutrients, heavy metals, pharmaceutical residues, pesticides, polycyclic aromatic hydrocarbons, and microplastics, and examines the mechanistic processes that govern their fate in sediments. The main mechanisms includesorption–desorption on minerals and organic materials, sedimentation, and redox processes that regulate metal immobilization and sulfide formation. The persistence and mobility of contaminants are also influenced by synergistic or antagonistic interactions among pollutants, microbial transformation of organic compounds, and oxidative degradation of microplastics by reactive oxygen species. Contaminants can affect benthic communities by causing toxic effects and oxygen depletion. They also may alter microbial and macrofaunal populations and contribute to bioaccumulation and biomagnification. Ultimately, these insights are important for predicting contaminant behavior and assessing ecological risks, which directly informs the development of effective environmental monitoring programs and sustainable sediment remediation strategies for the long-term protection of aquatic ecosystems. Full article

(This article belongs to the Section Macromolecules)

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19 pages, 849 KB

Open AccessArticle

Genetic Variants in SDC3, KCNA2, KCNK1, KCNK16, and Heat Shock Transcription Factor-1 Genes: An Exploratory Analysis Supporting the Piezo2 Channelopathy Hypothesis in Amyotrophic Lateral Sclerosis Onset

by Balázs Sonkodi, Zsófia Flóra Nagy, Anikó Keller-Pintér, Péter Klivényi, Mária Judit Molnár and Márta Széll

Int. J. Mol. Sci. 2025, 26(20), 10218; https://doi.org/10.3390/ijms262010218 - 21 Oct 2025

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Abstract

Amyotrophic lateral sclerosis (ALS) is a multisystem progressive neurodegenerative disease. A recent theory of ALS onsetting pathogenesis proposed that the initiating primary damage is an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. This Piezo2 channelopathy may [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a multisystem progressive neurodegenerative disease. A recent theory of ALS onsetting pathogenesis proposed that the initiating primary damage is an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. This Piezo2 channelopathy may also disrupt the ultrafast proton-based oscillatory signaling to motor neurons through vesicular transporter 1 (VGLUT1) and to the hippocampus through VGLUT2. As a result, it may gradually degenerate motor neurons in which process K_v1.2 ion channels are gradually depleted. It also gradually depletes heat shock transcription factor-1 (HSF-1) in the hippocampus, hence negatively affecting adult hippocampal neurogenesis. Syndecans, especially syndecan-3 (SDC3) in the nervous system, may act as critical players in the maintenance of the crosstalk between Piezo ion channels. Hence, our goal was to reanalyze the potential pathogenic gene variants from the cohort of our previous ALS study with a special focus on the aforementioned genes. Reanalysis of data formerly acquired by whole-exome sequencing of 21 non-related adult ALS patients was carried out with a focus on 28 genes. Accordingly, we identified charge-altering variants of SDC3 in 13 patients out of 21 that may contribute to the impairment of the Piezo crosstalk, and the progressive loss of the proposed proton-based signaling to motor neurons and to the hippocampus. A variant of uncertain significance was identified in the KCNA2 gene that may facilitate the faster loss of K_v1.2 ion function on motor neurons when Piezo2 channelopathy prevails. Not to mention that one variant was identified in the potassium current rectifying ion channels encoding KCNK1 and KCNK16 genes that may also propel the ALS disease process and provide the autoimmune-like pathogenic background. Moreover, Piezo2 channelopathy likely promotes diminishing HSF1 function in the hippocampus in the presence of the identified HSF1 variant. The current findings may support the ALS onsetting acquired irreversible Piezo2 channelopathy-induced pathogenesis. However, the preliminary nature of these findings needs validation and further functional studies on cohorts with a larger sample size in the future. Full article

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

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2 pages, 179 KB

Open AccessCorrection

Correction: Enríquez-Rodríguez et al. Metabolomic Signatures Predict Seven-Year Mortality in Clinically Stable COPD Patients. Int. J. Mol. Sci. 2025, 26, 6373

by César Jessé Enríquez-Rodríguez, Bella Agranovich, Sergi Pascual-Guàrdia, Rosa Faner, Ramon Camps-Ubach, Ady Castro-Acosta, José Luis López-Campos, Germán Peces-Barba, Luis Seijo, Oswaldo Antonio Caguana-Vélez, Diego Rodríguez-Chiaradia, Esther Barreiro, Eduard Monsó, Borja G. Cosío, Ifat Abramovich, Alvar Agustí, Carme Casadevall, Joaquim Gea and on behalf of the BIOMEPOC Group

Int. J. Mol. Sci. 2025, 26(20), 10217; https://doi.org/10.3390/ijms262010217 - 21 Oct 2025

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Abstract

In the original publication, the authors identified a mistake in Table 4 as published [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Chronic Obstructive Pulmonary Disease)

19 pages, 3526 KB

Open AccessArticle

Selective Endocytosis-Mediated Omicron S1-RBD Internalization Revealed by Reconstitution of ACE2-S1-RBD Interaction on Micropatterned Membrane Substrates

by Angelin M. Philip, S. M. Nasir Uddin, Zeyaul Islam, Prasanna R. Kolatkar and Kabir H. Biswas

Int. J. Mol. Sci. 2025, 26(20), 10216; https://doi.org/10.3390/ijms262010216 - 21 Oct 2025

Viewed by 238

Abstract

The SARS-CoV-2 spike protein, through its receptor binding domain (S1-RBD), binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane, leading to viral infection. Several mutations in S1-RBD in SARS-CoV-2 variants are known to enhance infection through an increased affinity [...] Read more.

The SARS-CoV-2 spike protein, through its receptor binding domain (S1-RBD), binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane, leading to viral infection. Several mutations in S1-RBD in SARS-CoV-2 variants are known to enhance infection through an increased affinity for ACE2. While many reports are available describing the SARS-CoV-2 infection mechanism, there is a dearth of studies towards understanding the initial interaction of the S1-RBD with ACE2 on living host cells and the role of endocytosis and cytoskeleton in the process. Here, we reconstituted the interaction between S1-RBD- and ACE2-expressing host cells in a hybrid live cell-supported lipid bilayer (SLB) platform enabling live monitoring of the interaction between S1-RBD on SLBs and the ACE2 receptor on living cells and showed that cells depleted Omicron S1-RBD from SLB corrals, likely through endocytosis. Specifically, interaction of living host cells with S1-RBD-functionalized SLB substrates resulted in the enrichment of S1-RBD and ACE2 at the cell–SLB interface. Interaction of host cells with wild type (WT), Omicron, and Omicron Revertant S1-RBD functionalized on micron-scale SLB corrals, which mimic viral membranes but are flat, also resulted in their enrichment. However, cells interacting with Omicron S1-RBD revealed a depletion of the protein from many corrals, which was generally not observed with the WT S1-RBD and was reduced with the Omicron Revertant, which contains the Q493R mutation reversion, S1-RBD. Further, S1-RBD depletion coincided with the localization of the early endosomal marker EEA1. Importantly, treatment of cells with the clathrin inhibitor, pitstop 2, but not the myosin II inhibitor, blebbistatin, significantly reduced Omicron S1-RBD depletion. Collectively, these observations suggest that the SARS-CoV-2 Omicron variant has evolved, through mutations in its S1-RBD, to take advantage of the cellular endocytic pathway for enhanced infection, which is not observed with the parental SARS-CoV-2 and appears to be lost in the Omicron Revertant variant. Additionally, these results underscore the significance of the hybrid live cell–SLB platform in studying SARS-CoV-2 S1-RBD-ACE2 interaction and the potential impact of mutations in the S1-RBD on adapting to a specific cellular entry mechanism. Full article

(This article belongs to the Section Biochemistry)

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