International Journal of Molecular Sciences

19 pages, 3727 KiB

Open AccessArticle

The Protective Effect of Nimodipine in Schwann Cells Is Related to the Upregulation of LMO4 and SERCA3 Accompanied by the Fine-Tuning of Intracellular Calcium Levels

by Sandra Leisz, Saskia Fritzsche, Christian Strauss and Christian Scheller

Int. J. Mol. Sci. 2025, 26(2), 864; https://doi.org/10.3390/ijms26020864 - 20 Jan 2025

Viewed by 541

Abstract

Nimodipine is the current gold standard in the treatment of subarachnoid hemorrhage, as it is the only known calcium channel blocker that has been proven to improve neurological outcomes. In addition, nimodipine exhibits neuroprotective properties in vitro under various stress conditions. Furthermore, clinical [...] Read more.

Nimodipine is the current gold standard in the treatment of subarachnoid hemorrhage, as it is the only known calcium channel blocker that has been proven to improve neurological outcomes. In addition, nimodipine exhibits neuroprotective properties in vitro under various stress conditions. Furthermore, clinical studies have demonstrated a neuroprotective effect of nimodipine after vestibular schwannoma surgery. However, the molecular mode of action of nimodipine pre-treatment has not been well investigated. In the present study, using real-time cell death assays, we demonstrated that nimodipine not only reduces cell death induced by osmotic and oxidative stress but also protects cells directly at the time of stress induction in Schwann cells. Nimodipine counteracts stress-induced calcium overload and the overexpression of the Cav1.2 calcium channel. In addition, we found nimodipine-dependent upregulation of sarcoplasmic/endoplasmic reticulum calcium ATPase 3 (SERCA3) and LIM domain only 4 (LMO4) protein. Analysis of anti-apoptotic cell signaling showed an inhibition of the pro-apoptotic protein glycogen synthase kinase 3 beta (GSK3β). Nimodipine-treated Schwann cells exhibited higher levels of phosphorylated GSK3β at serine residue 9 during osmotic and oxidative stress. In conclusion, nimodipine prevents cell death by protecting cells from calcium overload by fine-tuning intracellular calcium signaling and gene expression. Full article

(This article belongs to the Special Issue Calcium Signaling in Health and Diseases)

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21 pages, 12651 KiB

Open AccessArticle

Design, Synthesis, Anticancer Screening, and Mechanistic Study of Spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide Derivatives

by Ahmed M. El-Saghier, Hamada Hashem, Sherif A. Maher, Souhaila S. Enaili, Abdullah Alkhammash, Stefan Bräse and Hossameldin A. Aziz

Int. J. Mol. Sci. 2025, 26(2), 863; https://doi.org/10.3390/ijms26020863 - 20 Jan 2025

Viewed by 616

Abstract

The present study aims to create spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide derivatives with anticancer activities. The in vitro anticancer evaluation showed that only the novel spiro-acenaphthylene tethered-[1,3,4]-thiadiazole (compound 1) exhibited significant anticancer efficacy as a selective inhibitor of tumor-associated isoforms of carbonic anhydrase. Compound 1 demonstrated [...] Read more.

The present study aims to create spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide derivatives with anticancer activities. The in vitro anticancer evaluation showed that only the novel spiro-acenaphthylene tethered-[1,3,4]-thiadiazole (compound 1) exhibited significant anticancer efficacy as a selective inhibitor of tumor-associated isoforms of carbonic anhydrase. Compound 1 demonstrated considerable efficacy against the renal RXF393, colon HT29, and melanoma LOX IMVI cancer cell lines, with IC₅₀ values of 7.01 ± 0.39, 24.3 ± 1.29, and 9.55 ± 0.51 µM, respectively. In comparison, doxorubicin exhibited IC₅₀ values of 13.54 ± 0.82, 13.50 ± 0.71, and 6.08 ± 0.32 µM for the corresponding cell lines. Importantly, compound 1 exhibited lower toxicity to the normal WI 38 cell line than doxorubicin, with IC₅₀ values of 46.20 ± 2.59 and 18.13 ± 0.93 µM, respectively, indicating greater selectivity of the target compound compared to the standard anticancer agent doxorubicin. Also, mechanistic experiments demonstrated that compound 1 exhibits inhibitory activity against human carbonic anhydrase hCA IX and XII, with IC₅₀ values of 0.477 ± 0.03 and 1.933 ± 0.11 μM, respectively, indicating enhanced selectivity for cancer-associated isoforms over cytosolic isoforms hCA I and II, with IC₅₀ values of 7.353 ± 0.36 and 12.560 ± 0.74 μM, respectively. Cell cycle studies revealed that compound 1 caused G1 phase arrest in RXF393 cells, and apoptosis experiments verified a substantial induction of apoptosis with significant levels of early and late apoptosis, as well as necrosis (11.69%, 19.78%, and 3.66%, respectively), comparable to those induced by the conventional cytotoxic agent doxorubicin, at 9.91%, 23.37%, and 6.16%, respectively. Molecular docking experiments confirmed the strong binding affinity of compound 1 to the active sites of hCA IX and XII, highlighting significant interactions with zinc-binding groups and hydrophobic residues. These findings underscore the target compound’s potential as a viable anticancer agent via targeting CA. Full article

(This article belongs to the Topic Antitumor Activity of Natural Products and Related Compounds—2nd Edition)

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31 pages, 1840 KiB

Open AccessReview

Exploring How Adipose Tissue, Obesity, and Gender Influence the Immune Response to Vaccines: A Comprehensive Narrative Review

by Juan Bautista De Sanctis, Germán Balda Noria and Alexis Hipólito García

Int. J. Mol. Sci. 2025, 26(2), 862; https://doi.org/10.3390/ijms26020862 - 20 Jan 2025

Viewed by 854

Abstract

Vaccines represent an essential tool for the prevention of infectious diseases. Upon administration, a complex interaction occurs between the vaccine formulation and the recipient’s immune system, ultimately resulting in protection against disease. Significant variability exists in individual and population responses to vaccination, and [...] Read more.

Vaccines represent an essential tool for the prevention of infectious diseases. Upon administration, a complex interaction occurs between the vaccine formulation and the recipient’s immune system, ultimately resulting in protection against disease. Significant variability exists in individual and population responses to vaccination, and these differences remain the focus of the ongoing research. Notably, well-documented factors, such as age, gender, and genetic predisposition, influence immune responses. In contrast, the effects of overweight and obesity have not been as thoroughly investigated. The evidence indicates that a high body mass index (BMI) constitutes a significant risk factor for infections in general, with adipose tissue playing a crucial role in modulating the immune response. Furthermore, suboptimal levels of vaccine seroconversion have been observed among individuals with obesity. This review provides a plausible examination of the immunity and protection conferred by various vaccines in individuals with an overweight status, offering a comprehensive analysis of the mechanisms to enhance vaccination efficiency. Full article

(This article belongs to the Section Molecular Immunology)

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42 pages, 2925 KiB

Open AccessReview

Detection of Circulating Tumor DNA in Liquid Biopsy: Current Techniques and Potential Applications in Melanoma

by Clara Martínez-Vila, Cristina Teixido, Francisco Aya, Roberto Martín, Europa Azucena González-Navarro, Llucia Alos, Natalia Castrejon and Ana Arance

Int. J. Mol. Sci. 2025, 26(2), 861; https://doi.org/10.3390/ijms26020861 - 20 Jan 2025

Viewed by 683

Abstract

The treatment landscape for advanced melanoma has transformed significantly with the advent of BRAF and MEK inhibitors (BRAF/MEKi) targeting BRAFV600 mutations, as well as immune checkpoint inhibitors (ICI) like anti-PD-1 monotherapy or its combinations with anti-CTLA-4 or anti-LAG-3. Despite that, many patients [...] Read more.

The treatment landscape for advanced melanoma has transformed significantly with the advent of BRAF and MEK inhibitors (BRAF/MEKi) targeting BRAFV600 mutations, as well as immune checkpoint inhibitors (ICI) like anti-PD-1 monotherapy or its combinations with anti-CTLA-4 or anti-LAG-3. Despite that, many patients still do not benefit from these treatments at all or develop resistance mechanisms. Therefore, prognostic and predictive biomarkers are needed to identify patients who should switch or escalate their treatment strategies or initiate an intensive follow-up. In melanoma, liquid biopsy has shown promising results, with a potential role in predicting relapse in resected high-risk patients or in disease monitoring during the treatment of advanced disease. Several components in peripheral blood have been analyzed, such as circulating tumor cells (CTCs), cell-free DNA (cfDNA), and circulant tumoral DNA (ctDNA), which have turned out to be particularly promising. To analyze ctDNA in blood, different techniques have proven to be useful, including digital droplet polymerase chain reaction (ddPCR) to detect specific mutations and, more recently, next-generation sequencing (NGS) techniques, which allow analyzing a broader repertoire of the mutation landscape of each patient. In this review, our goal is to update the current understanding of liquid biopsy, focusing on the use of ctDNA as a biological material in the daily clinical management of melanoma patients, in particular those with advanced disease treated with ICI. Full article

(This article belongs to the Special Issue Molecular Basis and Progress of Immunotherapy for Melanoma)

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17 pages, 2718 KiB

Open AccessArticle

Application of Synthetic Microbial Communities of Kalidium schrenkianum in Enhancing Wheat Salt Stress Tolerance

by Jing Zhu, Qiong Jia, Qi-Yong Tang, Ghenijan Osman, Mei-Ying Gu, Ning Wang and Zhi-Dong Zhang

Int. J. Mol. Sci. 2025, 26(2), 860; https://doi.org/10.3390/ijms26020860 - 20 Jan 2025

Viewed by 458

Abstract

Soil salinization poses a significant challenge to global agriculture, particularly in arid and semi-arid regions like Xinjiang. Kalidium schrenkianum, a halophytic plant adapted to saline-alkaline conditions, harbors endophytic microorganisms with potential plant growth-promoting properties. In this study, 177 endophytic bacterial strains were [...] Read more.

Soil salinization poses a significant challenge to global agriculture, particularly in arid and semi-arid regions like Xinjiang. Kalidium schrenkianum, a halophytic plant adapted to saline-alkaline conditions, harbors endophytic microorganisms with potential plant growth-promoting properties. In this study, 177 endophytic bacterial strains were isolated from K. schrenkianum, and 11 key strains were identified through functional screening based on salt tolerance, nutrient solubilization, and growth-promoting traits. Synthetic microbial communities (SMCs) were then constructed using these strains and optimized to enhance wheat growth under salt stress. The SMCs significantly improved seed germination, root length, and seedling vigor in both spring and winter wheat in hydroponic and pot experiments. Furthermore, the SMCs enhanced the activities of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and levels of malondialdehyde (MDA) and proline (PRO). They also reduced oxidative stress and improved chlorophyll content in wheat seedlings. These results demonstrate the potential of microbial consortia derived from extreme environments as eco-friendly biofertilizers for improving crop performance in saline soils, offering a sustainable alternative to chemical fertilizers and contributing to agricultural resilience and productivity. Full article

(This article belongs to the Special Issue Plant–Microbe Interactions)

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30 pages, 7091 KiB

Open AccessArticle

Starch-Assisted Eco-Friendly Synthesis of ZnO Nanoparticles: Enhanced Photocatalytic, Supercapacitive, and UV-Driven Antioxidant Properties with Low Cytotoxic Effects

by Roumaissa Djafarou, Ouarda Brahmia, Soumia Haya, Ertugrul Sahmetlioglu, Fatma Kılıç Dokan and Tarek Hidouri

Int. J. Mol. Sci. 2025, 26(2), 859; https://doi.org/10.3390/ijms26020859 - 20 Jan 2025

Viewed by 525

Abstract

This study presents an efficient and environmentally sustainable synthesis of ZnO nanoparticles using a starch-mediated sol-gel approach. This method yields crystalline mesoporous ZnO NPs with a hexagonal wurtzite structure. The synthesized nanoparticles demonstrated remarkable multifunctionality across three critical applications. In photocatalysis, the ZnO [...] Read more.

This study presents an efficient and environmentally sustainable synthesis of ZnO nanoparticles using a starch-mediated sol-gel approach. This method yields crystalline mesoporous ZnO NPs with a hexagonal wurtzite structure. The synthesized nanoparticles demonstrated remarkable multifunctionality across three critical applications. In photocatalysis, the ZnO NPs exhibited exceptional efficiency, achieving complete degradation of methylene blue within 15 min at pH 11, significantly surpassing the performance of commercial ZnO. Under neutral pH conditions, the nanoparticles effectively degraded various organic dyes, including methylene blue, rhodamine B, and methyl orange, following pseudo-first-order kinetics. The methylene blue degradation process was aligned with the Langmuir–Hinshelwood model, emphasizing their advanced catalytic properties. For supercapacitor applications, the ZnO NPs attained a high specific capacitance of 550 F/g at 1 A/g, underscoring their potential as energy storage solutions. Additionally, the nanoparticles demonstrated strong UV-induced antiradical activity, with an EC₅₀ of 32.2 μg/mL in DPPH assays. Notably, the cytotoxicity evaluation revealed an LC₅₀ of 1648 μg/mL, indicating excellent biocompatibility. This study highlights a sustainable approach for the synthesis of multifunctional ZnO NPs that offers effective solutions for environmental remediation, energy storage, and biomedical applications. Full article

(This article belongs to the Special Issue Molecular Advances in Semiconductor Materials)

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20 pages, 534 KiB

Open AccessArticle

Antiplasmodial Activity of a New Chemotype of Croton sylvaticus Hochst. Ex C. Krauss Essential Oil

by Pierre Leonel K. Tafokeu Taguimjeu, Yannick Stéphane Fotsing Fongang, Manon Genva, Lahngong Methodius Shinyuy, Jana Held, Michel Frederich, Silvère Augustin Ngouela and Marie-Laure Fauconnier

Int. J. Mol. Sci. 2025, 26(2), 858; https://doi.org/10.3390/ijms26020858 - 20 Jan 2025

Viewed by 470

Abstract

Croton sylvaticus, a tropical African plant, is traditionally used to treat several diseases, including fever, inflammation, and malaria. Essential oils (EOs) from the plant’s leaves, roots, and trunk bark were obtained by hydrodistillation, and their chemical composition was analyzed by gas chromatography–mass [...] Read more.

Croton sylvaticus, a tropical African plant, is traditionally used to treat several diseases, including fever, inflammation, and malaria. Essential oils (EOs) from the plant’s leaves, roots, and trunk bark were obtained by hydrodistillation, and their chemical composition was analyzed by gas chromatography–mass spectrometry (GC-MS). The major constituents identified were virdiflorene (18.13 ± 0.46%) in root EO, (E)-β-caryophyllene (18.40 ± 0.60%) in trunk bark EO, and farnesyl acetone (15.26 ± 0.25%) in leaf EO. Notably, Cameroonian C. sylvaticus leaf EO exhibited a distinct and newly described chemotype with high levels of farnesyl acetone, β-copaene-4-α-ol, β-cadinene, α-humulene, and trans-longipinocarveol. In vitro testing revealed significant antiplasmodial activity against Plasmodium falciparum asexual (Pf3D7) and sexual (NF-54 strain) stages, with trunk bark EO showing the highest potency (IC₅₀: 9.06 ± 2.15 µg/mL for Pf3D7 and 0.56 µg/mL for gametocytes). These findings support the traditional antimalarial use of C. sylvaticus and represent the first chemical profile and antiplasmodial efficacy report for its root and trunk bark EOs against both parasite stages. To the best of our knowledge, we also report for the first time the antiplasmodial activity of an EO that exerts significant activity against both the asexual and sexual forms of P. falciparum. Full article

(This article belongs to the Special Issue Bioactive Molecules of Natural Origin: Mechanisms of Action Related to Health Risks and Benefits—3rd Edition)

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20 pages, 2567 KiB

Open AccessReview

Improving Replication in Endometrial Omics: Understanding the Influence of the Menstrual Cycle

by Jessica Chung and Peter Adrian Rogers

Int. J. Mol. Sci. 2025, 26(2), 857; https://doi.org/10.3390/ijms26020857 - 20 Jan 2025

Viewed by 509

Abstract

The dynamic nature of human endometrial tissue presents unique challenges in analysis. Despite extensive research into endometrial disorders such as endometriosis and infertility, recent systematic reviews have highlighted concerning issues with the reproducibility of omics studies attempting to identify biomarkers. This review examines [...] Read more.

The dynamic nature of human endometrial tissue presents unique challenges in analysis. Despite extensive research into endometrial disorders such as endometriosis and infertility, recent systematic reviews have highlighted concerning issues with the reproducibility of omics studies attempting to identify biomarkers. This review examines factors contributing to poor reproducibility in endometrial omics research. Hormonal fluctuations in the menstrual cycle lead to widespread molecular changes in the endometrium, most notably in gene expression profiles. In this review, we examine the variability in omics data due to the menstrual cycle and highlight the importance of accurate menstrual cycle dating for effective statistical modelling. The current standards of endometrial dating lack precision and we make the case for using molecular-based modelling methods to estimate menstrual cycle time for endometrium tissue samples. Additionally, we discuss statistical considerations such as confounding and interaction effects, as well as the importance of recording the detailed and accurate clinical information of patients. By addressing these methodological challenges, we aim to establish more robust and reproducible research practises, increasing the reliability of endometrial omics research and biomarker discovery. Full article

(This article belongs to the Special Issue Molecular Studies of Endometriosis and Associated Diseases)

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18 pages, 2425 KiB

Open AccessReview

Hidden Partner of Immunity: Microbiome as an Innovative Companion in Immunotherapy

by Pyoseung Kim, Sunggeun Joe, Heeyoung Kim, Hyejeong Jeong, Sunghwan Park, Jihwan Song, Wondong Kim and Yong Gu Lee

Int. J. Mol. Sci. 2025, 26(2), 856; https://doi.org/10.3390/ijms26020856 - 20 Jan 2025

Viewed by 614

Abstract

Recent studies have highlighted that the microbiome is the essential factor that can modulate the clinical activity of immunotherapy. However, the role of the microbiome varies significantly across different immunotherapies, suggesting that it is critical to understand the precise function of the microbiome [...] Read more.

Recent studies have highlighted that the microbiome is the essential factor that can modulate the clinical activity of immunotherapy. However, the role of the microbiome varies significantly across different immunotherapies, suggesting that it is critical to understand the precise function of the microbiome in each type of immunotherapy. While many previous studies primarily focus on summarizing the role of the microbiome in immune checkpoint inhibitors, we seek to explore a novel aspect of the microbiome in other immunotherapies such as mesenchymal stem cell therapy, chimeric antigen receptor T cell therapy, and antibodies-based therapy (e.g., adalimumab, infliximab, bevacizumab, denosumab, etc.) which are rarely summarized in previous reviews. Moreover, we highlight innovative strategies for utilizing microbiome and microbial metabolites to enhance the clinical response of immunotherapy. Collectively, we believe that our manuscript will provide novel insights and innovative approaches to the researchers, which could drive the development of the next generation of personalized therapeutic interventions using microbiomes. Full article

(This article belongs to the Special Issue Immunotherapy in Cancer: Molecular Basis and Novel Therapeutic Approaches)

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23 pages, 4696 KiB

Open AccessArticle

Curcumin Solubility and Bioactivity Enhancement Through Amorphization with Tryptophan via Supercritical Fluid Technology

by Ewa Garbiec, Natalia Rosiak, Szymon Sip, Przemysław Zalewski and Judyta Cielecka-Piontek

Int. J. Mol. Sci. 2025, 26(2), 855; https://doi.org/10.3390/ijms26020855 - 20 Jan 2025

Viewed by 531

Abstract

Curcumin, a compound known for its antioxidant and neuroprotective properties, faces challenges due to its low water solubility, which can limit its effectiveness. One effective method to address this issue is through amorphization. Incorporating curcumin into a polymeric matrix to form amorphous solid [...] Read more.

Curcumin, a compound known for its antioxidant and neuroprotective properties, faces challenges due to its low water solubility, which can limit its effectiveness. One effective method to address this issue is through amorphization. Incorporating curcumin into a polymeric matrix to form amorphous solid dispersions is a common approach. Another strategy involves co-amorphous systems, where low-molecular-weight components act as co-formers. A recent innovative approach combines these strategies. This study used tryptophan as a co-former and prepared systems using supercritical fluid technology. The amorphous nature of two systems was confirmed through X-ray powder diffraction: one with 10% curcumin and a polymer, and another with 10% curcumin, a polymer, and tryptophan. Fourier-transform infrared analysis demonstrated molecular interactions among all components in the systems. Scanning electron microscopy revealed that the amorphization process significantly modified the morphology of the powder particles. The ternary system with tryptophan notably increased curcumin solubility by over 300-fold. The amorphous form of curcumin in both systems exhibited significantly higher dissolution rates compared to its crystalline form. The system with tryptophan showed more than a threefold improvement in permeability according to the PAMPA test. The enhanced solubility led to over a sixfold increase in antioxidant activity and a 25-fold improvement in the inhibition of the enzyme butyrylcholinesterase. Full article

(This article belongs to the Special Issue Anticancer and Chemopreventive Activity of Natural Products and Its Derivatives)

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13 pages, 1820 KiB

Open AccessArticle

Adenovirus-Neutralizing and Infection-Promoting Activities Measured in Serum of Human Brain Cancer Patients Treated with Oncolytic Adenovirus Ad5-∆24.RGD

by Ida H. van der Meulen-Muileman, Joana Amado-Azevedo, Martine L. M. Lamfers, Anne Kleijn, Sander Idema, David P. Noske, Clemens M. F. Dirven and Victor W. van Beusechem

Int. J. Mol. Sci. 2025, 26(2), 854; https://doi.org/10.3390/ijms26020854 - 20 Jan 2025

Viewed by 710

Abstract

Oncolytic adenoviruses derived from human serotype 5 (Ad5) are being developed to treat cancer. Treatment efficacy could be affected by pre-existing or induced neutralizing antibodies (NAbs), in particular in repeat administration strategies. Several oncolytic adenoviruses that are currently in clinical development have modified [...] Read more.

Oncolytic adenoviruses derived from human serotype 5 (Ad5) are being developed to treat cancer. Treatment efficacy could be affected by pre-existing or induced neutralizing antibodies (NAbs), in particular in repeat administration strategies. Several oncolytic adenoviruses that are currently in clinical development have modified fiber proteins to increase their infectivity. One example is Ad5-∆24.RGD, which carries a cyclic RGD peptide insert in the fiber protein to allow cell entry via integrins. The effect of anti-Ad5 NAbs on anticancer efficacy could be different for oncolytic adenoviruses with RGD-modified fibers than for unmodified Ad5-based viruses. Here, we determine pre-existing and elicited NAb titers in the serum of patients with glioblastoma who were treated by delivering Ad5-∆24.RGD to the tumor and to the surrounding tumor-infiltrated brain. We show that intracranial infusion of Ad5-∆24.RGD induced mainly neutralization of adenovirus native tropism. Infection of cells with RGD-modified virus was significantly less affected. In cerebrospinal fluid, neutralizing activity against RGD-mediated infection remained very low. Thus, the RGD-mediated alternative cell entry route allowed to bypass pre-existing and induced anti-Ad5 neutralization. Interestingly, in the course of these experiments, we discovered that the serum of most humans promotes the uptake of RGD-modified adenovirus in human cells. The until now unidentified infection-stimulating factor seems distinct from serum proteins known to promote Ad5 infection. Together, our work supports the utility of RGD-modified oncolytic adenoviruses for the treatment of cancer in humans. Since these viruses hardly induced neutralization, they seem particularly suitable for repeat administration treatments. Full article

(This article belongs to the Section Molecular Oncology)

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18 pages, 3123 KiB

Open AccessArticle

Aspirin Inhibits the In Vitro Adipogenic Differentiation of Human Adipose Tissue-Derived Stem Cells in a Dose-Dependent Manner

by Sarah Funke, Paul Severin Wiggenhauser, Anna Grundmeier, Benedikt Fuchs, Konstantin Koban, Wolfram Demmer, Riccardo E. Giunta and Constanze Kuhlmann

Int. J. Mol. Sci. 2025, 26(2), 853; https://doi.org/10.3390/ijms26020853 - 20 Jan 2025

Viewed by 917

Abstract

Aspirin (ASA) is one of the most used medications worldwide and has shown various effects on cellular processes, including stem cell differentiation. However, the effect of ASA on adipogenesis of adipose tissue-derived stem cells (ASCs) remains largely unknown. Considering the potential application of [...] Read more.

Aspirin (ASA) is one of the most used medications worldwide and has shown various effects on cellular processes, including stem cell differentiation. However, the effect of ASA on adipogenesis of adipose tissue-derived stem cells (ASCs) remains largely unknown. Considering the potential application of ASCs in regenerative medicine and cell-based therapies, this study investigates the effects of ASA on adipogenic differentiation in human ASCs. ASCs were exposed to varying concentrations of ASA (0 µM, 400 µM, and 1000 µM) and evaluated for changes in morphology, migration, and adipogenic differentiation. While ASA exposure did not affect self-renewal potential, migration ability, or cell morphology, it significantly reduced lipid vacuole formation at 1000 µM after 21 days of adipogenic differentiation (p = 0.0025). This visible inhibition correlated with decreased expression of adipogenic markers (PPARG, ADIPOQ, and FABP4) and the proliferation marker MKi67 under ASA exposure in comparison to the control (ns). Overall, the findings demonstrate that ASA inhibits adipogenic differentiation of human ASCs in a dose-dependent manner in vitro, contrasting its known role in promoting osteogenic differentiation. This research highlights ASA’s complex effects on ASCs and emphasizes the need for further investigation into its mechanisms and potential therapeutic applications in obesity and metabolic diseases. The inhibitory effects of ASA on adipogenesis should be considered in cell-based therapies using ASCs. Full article

(This article belongs to the Special Issue Fat and Obesity: Molecular Mechanisms and Pathogenesis)

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12 pages, 2893 KiB

Open AccessArticle

One-Step Fabrication of Water-Dispersible Calcium Phosphate Nanoparticles with Immobilized Lactoferrin for Intraoral Disinfection

by Maki Nakamura, Ayako Oyane, Tomoya Inose, Yukimi Kanemoto and Hirofumi Miyaji

Int. J. Mol. Sci. 2025, 26(2), 852; https://doi.org/10.3390/ijms26020852 - 20 Jan 2025

Viewed by 476

Abstract

Lactoferrin is a highly safe antibacterial protein found in the human body and in foods. Calcium phosphate (CaP) nanoparticles with immobilized lactoferrin could therefore be useful as intraoral disinfectants for the prevention and treatment of dental infections because CaP is a mineral component [...] Read more.

Lactoferrin is a highly safe antibacterial protein found in the human body and in foods. Calcium phosphate (CaP) nanoparticles with immobilized lactoferrin could therefore be useful as intraoral disinfectants for the prevention and treatment of dental infections because CaP is a mineral component of human teeth. In this study, we fabricated CaP nanoparticles with co-immobilized lactoferrin and heparin using a simple one-step coprecipitation process. Heparin, a negatively charged polysaccharide, was used as both an immobilizing agent for lactoferrin and a particle-dispersing agent. The immobilization efficiency for lactoferrin in the CaP nanoparticles depended on the concentrations of both the lactoferrin and heparin in the reaction solution and was over 90% under optimal conditions. The nanoparticles had a hydrodynamic diameter of about 150–200 nm and could be well dispersed in water, owing to their relatively large negative zeta potential derived from heparin. They were found to exhibit antibacterial activity against Actinomyces naeslundii, which is involved in the initial formation of dental plaque that consequently leads to dental caries and periodontal disease. These results indicate the potential of the proposed nanoparticles as intraoral disinfectants. Full article

(This article belongs to the Special Issue Bioceramics: Challenges and Medical Applications of Calcium-Phosphate-Based Biocompatible Ceramics)

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24 pages, 7385 KiB

Open AccessArticle

Lovastatin and Resveratrol Synergistically Improve Wound Healing and Inhibit Bacterial Growth

by Norah A. AlJunaydil, Rhodanne Nicole A. Lambarte, Terrence S. Sumague, Osama G. Alghamdi and Abdurahman A. Niazy

Int. J. Mol. Sci. 2025, 26(2), 851; https://doi.org/10.3390/ijms26020851 - 20 Jan 2025

Viewed by 512

Abstract

Wound healing is a complex physiological process, with scarring and infection caused by Staphylococcus aureus and Pseudomonas aeruginosa being the most common complications. The reutilization of known medications has received increased attention for their role in cell function as small molecules. Examples of [...] Read more.

Wound healing is a complex physiological process, with scarring and infection caused by Staphylococcus aureus and Pseudomonas aeruginosa being the most common complications. The reutilization of known medications has received increased attention for their role in cell function as small molecules. Examples of these include lovastatin, a cholesterol-lowering agent, and resveratrol, which have multiple biological properties. Both molecules have been reported to improve wound healing and possess antibacterial properties, with conflicting results. The wound-healing capabilities of human mesenchymal stem cells were evaluated after exposure to lovastatin, resveratrol, and their combination through scratch test, migrations assay, and qPCR. Protein docking was performed to assess the lovastatin/resveratrol combination as potential wound-healing targets. AlamarBlue assay was used to determine cell viability. Additionally, the impact of lovastatin and resveratrol combination to inhibit the growth of S. aureus and P. aeruginosa was tested using broth microdilution test and checkerboard assay to determine synergism. The combination of lovastatin 0.1 μM and resveratrol 0.1 μM synergistically improved wound healing and demonstrated an additive effect against S. aureus and P. aeruginosa, presenting potential antibacterial applications. Full article

(This article belongs to the Special Issue Novel Functions for Small Molecules)

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13 pages, 2060 KiB

Open AccessArticle

Enhancing HDAC Inhibitor Screening: Addressing Zinc Parameterization and Ligand Protonation in Docking Studies

by Rocco Buccheri, Alessandro Coco, Lorella Pasquinucci, Emanuele Amata, Agostino Marrazzo and Antonio Rescifina

Int. J. Mol. Sci. 2025, 26(2), 850; https://doi.org/10.3390/ijms26020850 - 20 Jan 2025

Viewed by 494

Abstract

Precise binding free-energy predictions for ligands targeting metalloproteins, especially zinc-containing histone deacetylase (HDAC) enzymes, require specialized computational approaches due to the unique interactions at metal-binding sites. This study evaluates a docking algorithm optimized for zinc coordination to determine whether it could accurately differentiate [...] Read more.

Precise binding free-energy predictions for ligands targeting metalloproteins, especially zinc-containing histone deacetylase (HDAC) enzymes, require specialized computational approaches due to the unique interactions at metal-binding sites. This study evaluates a docking algorithm optimized for zinc coordination to determine whether it could accurately differentiate between protonated and deprotonated states of hydroxamic acid ligands, a key functional group in HDAC inhibitors (HDACi). By systematically analyzing both protonation states, we sought to identify which state produces docking poses and binding energy estimates most closely aligned with experimental values. The docking algorithm was applied across HDAC 2, 4, and 8, comparing protonated and deprotonated ligand correlations to experimental data. The results demonstrate that the deprotonated state consistently yielded stronger correlations with experimental data, with R² values for deprotonated ligands outperforming protonated counterparts in all HDAC targets (average R² = 0.80 compared to the protonated form where R² = 0.67). These findings emphasize the significance of proper ligand protonation in molecular docking studies of zinc-binding enzymes, particularly HDACs, and suggest that deprotonation enhances predictive accuracy. The study’s methodology provides a robust foundation for improved virtual screening protocols to evaluate large ligand libraries efficiently. This approach supports the streamlined discovery of high-affinity, zinc-binding HDACi, advancing therapeutic exploration of metalloprotein targets. A comprehensive, step-by-step tutorial is provided to facilitate a thorough understanding of the methodology and enable reproducibility of the results. Full article

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

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18 pages, 2200 KiB

Open AccessArticle

Comparative Transcriptomic Analysis Reveals New Insights into Spawn Aging in Agaricus bisporus: Mitochondrial Dysfunction

by Lili Shu, Zhiheng Zeng, Meiyuan Chen, Jiazhi Zhao, Xiaoyan Zhang, Jianqing Dai, Zhixin Cai, Yuanping Lu, Zhiheng Qiu and Hui Zeng

Int. J. Mol. Sci. 2025, 26(2), 849; https://doi.org/10.3390/ijms26020849 - 20 Jan 2025

Viewed by 461

Abstract

Spawn aging poses a substantial challenge to the Agaricus bisporus industry. This study focuses on the role of mitochondrial dysfunction in the aging process of A. bisporus spawn. We conducted a comprehensive comparative transcriptome analysis to elucidate the molecular mechanisms underlying A. bisporus [...] Read more.

Spawn aging poses a substantial challenge to the Agaricus bisporus industry. This study focuses on the role of mitochondrial dysfunction in the aging process of A. bisporus spawn. We conducted a comprehensive comparative transcriptome analysis to elucidate the molecular mechanisms underlying A. bisporus spawn aging. A total of 1620 genes with significant expression changes between the normal and aged spawn were identified, including 917 up-regulated genes and 703 down-regulated genes. Our results revealed a notable down-regulation of genes involved in carbohydrate metabolism, mitochondrial energy metabolism, reactive oxygen species (ROS) scavenging, repair mechanisms for oxidative stress-induced damage, fatty acid β-oxidation, and amino acid degradation in aged A. bisporus spawn. Additionally, we observed a decreased expression of genes involved in critical signal transduction pathways associated with mitochondrial function in aged mycelium as well as genes responsible for maintaining mitochondrial stability. The up-regulated genes in aged spawn mainly affect mitochondrial fission and programmed cell death, impacting mitochondrial function. Overall, the present study first provides evidence for the pivotal role of mitochondrial dysfunction in the aging process of A. bisporus spawn and contributes to the development of targeted strategies to enhance mitochondrial function, mitigate spawn aging, and improve the yield and quality of A. bisporus cultivation. Full article

(This article belongs to the Special Issue Transcriptional Regulation in Plant Development: 2nd Edition)

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27 pages, 1449 KiB

Open AccessReview

Proteins and DNA Sequences Interacting with Tanshinones and Tanshinone Derivatives

by Piotr Szymczyk, Małgorzata Majewska and Jadwiga Nowak

Int. J. Mol. Sci. 2025, 26(2), 848; https://doi.org/10.3390/ijms26020848 - 20 Jan 2025

Viewed by 597

Abstract

Tanshinones, biologically active diterpene compounds derived from Salvia miltiorrhiza, interact with specific proteins and DNA sequences, influencing signaling pathways in animals and humans. This study highlights tanshinone–protein interactions observed at concentrations achievable in vivo, ensuring greater physiological relevance compared to in vitro [...] Read more.

Tanshinones, biologically active diterpene compounds derived from Salvia miltiorrhiza, interact with specific proteins and DNA sequences, influencing signaling pathways in animals and humans. This study highlights tanshinone–protein interactions observed at concentrations achievable in vivo, ensuring greater physiological relevance compared to in vitro studies that often employ supraphysiological ligand levels. Experimental data suggest that while tanshinones interact with multiple proteomic targets, only a few enzymes are significantly affected at biologically relevant concentrations. This apparent paradox may be resolved by tanshinones’ ability to bind DNA and influence enzymes involved in gene expression or mRNA stability, such as RNA polymerase II and human antigen R protein. These interactions trigger secondary, widespread changes in gene expression, leading to complex proteomic alterations. Although the current understanding of tanshinone–protein interactions remains incomplete, this study provides a foundation for deciphering the molecular mechanisms underlying the therapeutic effects of S. miltiorrhiza diterpenes. Additionally, numerous tanshinone derivatives have been developed to enhance pharmacokinetic properties and biological activity. However, their safety profiles remain poorly characterized, limiting comprehensive insights into their medicinal potential. Further investigation is essential to fully elucidate the therapeutic and toxicological properties of both native and modified tanshinones. Full article

(This article belongs to the Special Issue Extraction, Identification and Quantification of Bioactive Molecules)

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17 pages, 2557 KiB

Open AccessArticle

Establishment of iPSC-Derived MSCs Expressing hsa-miR-4662a-5p for Enhanced Immune Modulation in Graft-Versus-Host Disease (GVHD)

by Susie Lee, Eung-Won Kim, Hae-Ri Lee, Sun-Ung Lim, Chan Kwon Jung, Young-Ju Kang, Gyung-Ah Jung and Il-Hoan Oh

Int. J. Mol. Sci. 2025, 26(2), 847; https://doi.org/10.3390/ijms26020847 - 20 Jan 2025

Viewed by 473

Abstract

The immune-modulatory effects of mesenchymal stromal cells (MSCs) are widely used to treat inflammatory disorders, with indoleamine 2,4-dioxygenase-1 (IDO-1) playing a pivotal role in suppressing stimulated T-cell proliferation. Taking that three-dimensional (3D) cultures enhance MSCs’ anti-inflammatory properties compared with two-dimensional (2D) cultures, the [...] Read more.

The immune-modulatory effects of mesenchymal stromal cells (MSCs) are widely used to treat inflammatory disorders, with indoleamine 2,4-dioxygenase-1 (IDO-1) playing a pivotal role in suppressing stimulated T-cell proliferation. Taking that three-dimensional (3D) cultures enhance MSCs’ anti-inflammatory properties compared with two-dimensional (2D) cultures, the differentially expressed miRNAs were examined. Thus, we identified hsa-miR-4662a-5p (miR-4662a) as a key inducer of IDO-1 via its suppression of bridging integrator-1 (BIN-1), a negative regulator of the IDO-1 gene. The IDO-1-inducing potential of miR-4662a was conserved across primary MSCs from various donors and sources but exhibited variability. Notably, iPSC-derived MSCs (iMSCs) demonstrated superior IDO-1 induction and immune-modulatory efficacy compared with their donor-matched primary MSCs. Accordingly, iMSCs expressing miR-4662a (4662a/iMSC) exhibited stronger suppressive effects on T-cell proliferation and more potent suppressive effects on graft-versus-host disease (GVHD), improving survival rates and reducing tissue damage in the liver and gut. Our results point to the therapeutic potential of standardized, off-the-shelf 4662a/iMSC as a robust immune-modulating cell therapy for GVHD. Full article

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

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18 pages, 3448 KiB

Open AccessCase Report

De Novo DNM1L Pathogenic Variant Associated with Lethal Encephalocardiomyopathy—Case Report and Literature Review

by Martina Magistrati, Luisa Zupin, Eleonora Lamantea, Enrico Baruffini, Daniele Ghezzi, Andrea Legati, Fulvio Celsi, Flora Maria Murru, Valeria Capaci, Maurizio Pinamonti, Rossana Bussani, Marco Carrozzi, Cristina Dallabona, Massimo Zeviani and Maria Teresa Bonati

Int. J. Mol. Sci. 2025, 26(2), 846; https://doi.org/10.3390/ijms26020846 - 20 Jan 2025

Viewed by 505

Abstract

Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome [...] Read more.

Pathogenic variants in DNM1L, encoding dynamin-like protein-1 (DRP1), cause a lethal encephalopathy. DRP1 defective function results in altered mitochondrial networks, characterized by elongated/spaghetti-like, highly interconnected mitochondria. We validated in yeast the pathogenicity of a de novo DNM1L variant identified by whole exome sequencing performed more than 10 years after the patient’s death. Meanwhile, we reviewed the broadness and specificities of DNM1L-related phenotype. The patient, who exhibited developmental delay in her third year, developed a therapy-refractory myoclonic status epilepticus, followed by neurological deterioration with brain atrophy and refractory epilepsy. She died of heart failure due to hypertrophic cardiomyopathy. She was found to be heterozygous for the DNM1L variant (NM_ 012062.5):c.1201G>A, p.(Gly401Ser). We demonstrated its deleterious impact and dominant negative effect by assessing haploid and diploid mutant yeast strains, oxidative growth, oxygen consumption, frequency of petite, and architecture of the mitochondrial network. Structural modeling of p.(Gly401Ser) predicted the interference of the mutant protein in the self-oligomerization of the DRP1 active complex. DNM1L-related phenotypes include static or (early) lethal encephalopathy and neurodevelopmental disorders. In addition, there may be ophthalmological impairment, peripheral neuropathy, ataxia, dystonia, spasticity, myoclonus, and myopathy. The clinical presentations vary depending on mutations in different DRP1 domains. Few pathogenic variants, the p.(Gly401Ser) included, cause an encephalocardiomyopathy with refractory status epilepticus. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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31 pages, 1501 KiB

Open AccessReview

Alcohol Consumption and Autoimmune Diseases

by Sergio Terracina, Brunella Caronti, Marco Lucarelli, Silvia Francati, Maria Grazia Piccioni, Luigi Tarani, Mauro Ceccanti, Micaela Caserta, Loredana Verdone, Sabrina Venditti, Marco Fiore and Giampiero Ferraguti

Int. J. Mol. Sci. 2025, 26(2), 845; https://doi.org/10.3390/ijms26020845 - 20 Jan 2025

Viewed by 934

Abstract

Alcohol is the second-most misused substance after tobacco. It has been identified as a causal factor in more than 200 diseases and 5.3% of all deaths and is associated with significant behavioral, social, and economic difficulties. As alcohol consumption may modulate the immune [...] Read more.

Alcohol is the second-most misused substance after tobacco. It has been identified as a causal factor in more than 200 diseases and 5.3% of all deaths and is associated with significant behavioral, social, and economic difficulties. As alcohol consumption may modulate the immune system’s regulatory mechanisms to avoid attacking the body’s tissues, it has been proven to play a dichotomic role in autoimmune diseases (ADs) based on the quantity of consumption. In this review, we report updated evidence on the role of alcohol in ADs, with a focus on alcohol addiction and the human biological immune system and the relationship between them, with alcohol as a risk or protective factor. Then, in this narrative review, we report the main evidence on the most studied ADs where alcohol represents a key modulator, including autoimmune thyroiditis, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, diabetes, allergic rhinitis, and primary biliary cholangitis. Alcohol at low–moderate dosages seems mostly to have a protective role in these diseases, while at higher dosages, the collateral risks surpass possible benefits. The specific mechanisms by which low-to-moderate alcohol intake relieves AD symptoms are not yet fully understood; however, emerging studies suggest that alcohol may have a systemic immunomodulatory effect, potentially altering the balance of anti-inflammatory innate and adaptive immune cells, as well as cytokines (via the NF-κB or NLRP3 pathways). It might influence the composition of the gut microbiome (increasing amounts of beneficial gut microbes) and the production of their fatty acid metabolites, such as short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs), as well as elevated concentrations of acetate, high-density lipoprotein (HDL), and nitric oxide (NO). Unfortunately, a definite acceptable daily intake (ADI) of ethanol is complicated to establish because of the many mechanisms associated with alcohol consumption such that despite the interesting content of these findings, there is a limit to their applicability and risks should be weighed in cases of alcoholic drinking recommendations. The aim of future studies should be to modulate those beneficial pathways involved in the alcohol-protective role of ADs with various strategies to avoid the risks associated with alcohol intake. Full article

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

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61 pages, 5717 KiB

Open AccessReview

Ellagic Acid: A Green Multi-Target Weapon That Reduces Oxidative Stress and Inflammation to Prevent and Improve the Condition of Alzheimer’s Disease

by Silvana Alfei and Guendalina Zuccari

Int. J. Mol. Sci. 2025, 26(2), 844; https://doi.org/10.3390/ijms26020844 - 20 Jan 2025

Viewed by 677

Abstract

Oxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer’s disease [...] Read more.

Oxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer’s disease (AD). AD is a multifactorial chronic neurodegenerative syndrome indicated by a form of progressive dementia associated with aging. While one-target drugs only soften its symptoms while generating drug resistance, multi-target polyphenols from fruits and vegetables, such as ellagitannins (ETs), ellagic acid (EA), and urolithins (UROs), having potent antioxidant and radical scavenging effects capable of counteracting OS, could be new green options to treat human degenerative diseases, thus representing hopeful alternatives and/or adjuvants to one-target drugs to ameliorate AD. Unfortunately, in vivo ETs are not absorbed, while providing mainly ellagic acid (EA), which, due to its trivial water-solubility and first-pass effect, metabolizes in the intestine to yield UROs, or irreversible binding to cellular DNA and proteins, which have very low bioavailability, thus failing as a therapeutic in vivo. Currently, only UROs have confirmed the beneficial effect demonstrated in vitro by reaching tissues to the extent necessary for therapeutic outcomes. Unfortunately, upon the administration of food rich in ETs or ETs and EA, URO formation is affected by extreme interindividual variability that renders them unreliable as novel clinically usable drugs. Significant attention has therefore been paid specifically to multitarget EA, which is incessantly investigated as such or nanotechnologically manipulated to be a potential “lead compound” with protective action toward AD. An overview of the multi-factorial and multi-target aspects that characterize AD and polyphenol activity, respectively, as well as the traditional and/or innovative clinical treatments available to treat AD, constitutes the opening of this work. Upon focus on the pathophysiology of OS and on EA’s chemical features and mechanisms leading to its antioxidant activity, an all-around updated analysis of the current EA-rich foods and EA involvement in the field of AD is provided. The possible clinical usage of EA to treat AD is discussed, reporting results of its applications in vitro, in vivo, and during clinical trials. A critical view of the need for more extensive use of the most rapid diagnostic methods to detect AD from its early symptoms is also included in this work. Full article

(This article belongs to the Special Issue The Role of Bioactive Compounds in Human Health and Disease: 2nd Edition)

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24 pages, 9961 KiB

Open AccessArticle

Genome-Wide Analysis of bZIP Transcription Factors and Expression Patterns in Response to Salt and Drought Stress in Vaccinium corymbosum

by Xinghua Feng, Chuchu Wang, Sijin Jia, Jiaying Wang, Lianxia Zhou, Yan Song, Qingxun Guo and Chunyu Zhang

Int. J. Mol. Sci. 2025, 26(2), 843; https://doi.org/10.3390/ijms26020843 - 20 Jan 2025

Viewed by 543

Abstract

The basic leucine zipper (bZIP) transcription factors play essential roles in multiple stress responses and have been identified and functionally characterized in many plant species. However, the bZIP family members in blueberry are unclear. In this study, we identified 102 VcbZIP genes in [...] Read more.

The basic leucine zipper (bZIP) transcription factors play essential roles in multiple stress responses and have been identified and functionally characterized in many plant species. However, the bZIP family members in blueberry are unclear. In this study, we identified 102 VcbZIP genes in Vaccinium corymbosum. VcbZIPs were divided into 10 groups based on phylogenetic analysis, and each group shared similar motifs, domains, and gene structures. Predictions of cis-regulatory elements in the upstream sequences of VcbZIP genes indicated that VcbZIP proteins are likely involved in phytohormone signaling pathways and abiotic stress responses. Analyses of RNA deep sequencing data showed that 18, 13, and 7 VcbZIP genes were differentially expressed in response to salt, drought, and ABA stress, respectively, for the blueberry cultivar Northland. Ten VcbZIP genes responded to both salt and drought stress, indicating that salt and drought have unique and overlapping signals. Of these genes, VcbZIP1–3 are responsive to salt, drought, and abscisic acid treatments, and their encoded proteins may integrate salt, drought, and ABA signaling. Furthermore, VcbZIP1–3 from group A and VcbZIP83–84 and VcbZIP75 from group S exhibited high or low expression under salt or drought stress and might be important regulators for improving drought or salt tolerance. Pearson correlation analyses revealed that VcbZIP transcription factors may regulate stress-responsive genes to improve drought or salt tolerance in a functionally redundant manner. Our study provides a useful reference for functional analyses of VcbZIP genes and for improving salt and drought stress tolerance in blueberry. Full article

(This article belongs to the Special Issue Physiology and Molecular Biology of Plant Stress Tolerance: 2nd Edition)

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17 pages, 5434 KiB

Open AccessArticle

An Evaluation of the Safety of Intravenous Injections of the Natural Extracellular Hemoglobin M101 in Dogs and Monkeys

by Elisabeth Leize-Zal, Leïla Demini, Benoît Barrou and Franck Zal

Int. J. Mol. Sci. 2025, 26(2), 842; https://doi.org/10.3390/ijms26020842 - 20 Jan 2025

Viewed by 660

Abstract

Hemoglobin-based oxygen carriers have been developed to compensate the needs of blood for transfusions. Most of them were based on intracellular hemoglobin extracted from bovine or human blood, but unfortunately, this type of hemoglobin did not pass through the last steps of clinical [...] Read more.

Hemoglobin-based oxygen carriers have been developed to compensate the needs of blood for transfusions. Most of them were based on intracellular hemoglobin extracted from bovine or human blood, but unfortunately, this type of hemoglobin did not pass through the last steps of clinical trials. In this context, HEMARINA discovered a natural extracellular hemoglobin, possessing several advantages avoiding intracellular hemoglobin-related side effects. Many preclinical studies assessed the safety of M101 used in intravenous (IV) injection in rodents. To explore the safety of IV injections of M101 in large mammals, six dogs received each a single injection of liquid M101 according to a dose escalation with a 48 h follow-up. Then, two monkeys received multiple IV injections of the same dose of M101 every hour for seven hours. This study showed that single and multiple IV injections in dogs and monkeys did not cause clinical or histological lesions, nor did they induce immunological reactions. This makes M101 the best candidate to date for human use in emergency situations requiring blood and, in several diseases, causing hypoxia problems. Full article

(This article belongs to the Special Issue Blood Cells in Human Health and Disease)

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15 pages, 1708 KiB

Open AccessArticle

Insulin Receptor Substrate-2 Regulates the Secretion of Growth Factors in Response to Amino Acid Deprivation

by Ayaka Takahashi, Haruka Furuta, Hiroki Nishi, Hiroyasu Kamei, Shin-Ichiro Takahashi and Fumihiko Hakuno

Int. J. Mol. Sci. 2025, 26(2), 841; https://doi.org/10.3390/ijms26020841 - 20 Jan 2025

Viewed by 392

Abstract

Insulin receptor substrates (IRSs) are well-known mediators of the insulin and insulin-like growth factor (IGF)-I signaling pathways. We previously reported that the protein levels of IRS-2, a molecular species of IRS, were upregulated in the livers of rats fed a protein-restricted diet. This [...] Read more.

Insulin receptor substrates (IRSs) are well-known mediators of the insulin and insulin-like growth factor (IGF)-I signaling pathways. We previously reported that the protein levels of IRS-2, a molecular species of IRS, were upregulated in the livers of rats fed a protein-restricted diet. This study aimed to elucidate the physiological role of IRS-2, whose level increases in response to protein restriction in cultured hepatocyte models. Hepatocyte-derived cell lines subjected to amino acid deprivation showed increased IRS2 mRNA and IRS-2 protein levels due to increased IRS2 transcription and translation, respectively. Amino acid deprivation markedly increased vascular endothelial growth factor-D (VEGF-D) secretion. Remarkably, the amino acid deprivation-induced VEGF-D secretion was suppressed by IRS-2 knockdown and enhanced by IRS-2 overexpression. These results suggest that IRS-2 is an intercellular signaling molecule that extracellularly transmits information on amino acid deprivation stress by regulating the secretion of growth factors such as VEGF-D. Moreover, this function of IRS-2 is distinct from its currently accepted function as a mediator of the insulin/IGF-I signaling pathways. This study demonstrates that IRS-2 can modulate protein secretion in an insulin-independent manner and greatly expands our understanding of the role of IRS-2, which is upregulated in response to amino acid deprivation. Full article

(This article belongs to the Special Issue The Role of the IGF Axis in Disease, 4th Edition)

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15 pages, 4078 KiB

Open AccessArticle

NLRC3 Attenuates Antiviral Innate Immune Response by Targeting IRF7 in Grass Carp (Ctenopharyngodon idelus)

by Lei Zhang, Haitai Chen, Xiang Zhao, Youcheng Chen, Shenpeng Li, Tiaoyi Xiao and Shuting Xiong

Int. J. Mol. Sci. 2025, 26(2), 840; https://doi.org/10.3390/ijms26020840 - 20 Jan 2025

Viewed by 398

Abstract

NLRC3 belongs to the NOD-like receptor family and is recognized as a modulator of innate immune mechanisms. In this study, we firstly report that Ctenopharyngodon idelus NLRC3 (CiNLRC3) acts as a negative regulator in the antiviral immune response. Cinlrc3 is ubiquitously [...] Read more.

NLRC3 belongs to the NOD-like receptor family and is recognized as a modulator of innate immune mechanisms. In this study, we firstly report that Ctenopharyngodon idelus NLRC3 (CiNLRC3) acts as a negative regulator in the antiviral immune response. Cinlrc3 is ubiquitously expressed across tested tissues, displaying particularly high expression in the intestine, spleen, gill and kidney. Notably, Cinlrc3 expression is markedly upregulated following grass carp reovirus (GCRV) infection both in vivo and in vitro. Functional assays reveal that the overexpression of CiNLRC3 hampers cellular antiviral responses, thereby facilitating viral replication. Conversely, the silencing of CiNLRC3 through siRNA transfection enhances these antiviral activities. Additionally, CiNLRC3 substantially diminishes the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)-mediated interferon (IFN) response in fish. Subsequent molecular investigations indicates that CiNLRC3 interacts with the RLR molecule node, IRF7 but not IRF3, by degrading the IRF7 protein in a proteasome-dependent manner. Furthermore, CiNLRC3 co-localizes with CiIRF7 in the cytoplasm and impedes the IRF7-induced IFN response, resulting in impairing IRF7-mediated antiviral immunity. Summarily, these findings underscore the critical inhibitory role of teleost NLRC3 in innate immunity, offering new perspectives on its regulatory functions and potential as a target for resistant breeding in fish. Full article

(This article belongs to the Section Molecular Immunology)

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16 pages, 521 KiB

Open AccessReview

Understanding Deep Endometriosis: From Molecular to Neuropsychiatry Dimension

by Magdalena Pszczołowska, Kamil Walczak, Weronika Kołodziejczyk, Magdalena Kozłowska, Gracjan Kozłowski, Martyna Gachowska and Jerzy Leszek

Int. J. Mol. Sci. 2025, 26(2), 839; https://doi.org/10.3390/ijms26020839 - 20 Jan 2025

Viewed by 462

Abstract

Endometriosis is a widely spread disease that affects about 8% of the world’s female population. This condition may be described as a spread of endometrial tissue apart from the uterine cavity, but this process’s pathomechanism is still unsure. Apart from classic endometriosis symptoms, [...] Read more.

Endometriosis is a widely spread disease that affects about 8% of the world’s female population. This condition may be described as a spread of endometrial tissue apart from the uterine cavity, but this process’s pathomechanism is still unsure. Apart from classic endometriosis symptoms, which are pelvic pain, infertility, and bleeding problems, there are neuropsychiatric comorbidities that are usually difficult to diagnose. In our review, we attempted to summarize some of them. Conditions like migraine, anxiety, and depression occur more often in women with endometriosis and have a significant impact on life quality and pain perception. Interestingly, 77% of endometriosis patients with depression also have anxiety. Neuroimaging gives an image of the so-called endometriosis brain, which means alternations in pain processing and cognition, self-regulation, and reward. Genetic factors, including mutations in KRAS, PTEN, and ARID1A, influence cellular proliferation, differentiation, and chromatin remodeling, potentially exacerbating lesion severity and complicating treatment. In this review, we focused on the aspects of sciatic and obturator nerve endometriosis, the emotional well-being of endometriosis-affected patients, and the potential influence of endometriosis on dementia, also focusing on prolonged diagnosis. Addressing endometriosis requires a multidisciplinary approach, encompassing molecular insights, innovative therapies, and attention to its psychological and systemic effects. Full article

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

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15 pages, 4484 KiB

Open AccessArticle

Identification of HXK Gene Family and Expression Analysis of Salt Tolerance in Buchloe dactyloides

by Haole Qi, Sining Wang, Yuehan Liu, Xueping Wang, Xiaoxia Li and Fengling Shi

Int. J. Mol. Sci. 2025, 26(2), 838; https://doi.org/10.3390/ijms26020838 - 20 Jan 2025

Viewed by 458

Abstract

Buchloe dactyloides is one of the typical ecological grass species, characterized by its strong salt tolerance. Hexokinase (HXK) plays a crucial role in plant growth, development, and resistance to abiotic stresses. To understand the function of HXKs in the salt tolerance of B. [...] Read more.

Buchloe dactyloides is one of the typical ecological grass species, characterized by its strong salt tolerance. Hexokinase (HXK) plays a crucial role in plant growth, development, and resistance to abiotic stresses. To understand the function of HXKs in the salt tolerance of B. dactyloides, this study identified and analyzed the HXK gene family members using the whole-genome data of B. dactyloides. Additionally, transcriptomic methods were employed to investigate the expression levels and stress response patterns of the HXK family genes under salt stress. The results showed that 25 HXK genes were identified in the B. dactyloides HXK gene family, which were classified into three subfamilies based on the phylogenetic tree. Members within the same subfamily exhibited similar gene structures and conserved motifs. The promoter regions of BdHXKs contained numerous cis-regulatory elements associated with plant hormone responses, plant growth and development, and resistance to abiotic stresses. Quantitative real-time PCR analysis provided preliminary evidence that the BdHXK5, BdHXK7, and BdHXK23 genes might play important roles in the salt tolerance regulation of B. dactyloides. These findings offer a theoretical foundation for further elucidating the functions and molecular regulatory mechanisms of BdHXKs under salt stress. This study has provided a theoretical basis for the breeding of new varieties of ecological restoration grasses with stronger salt tolerance and better growth and development. This is of great significance for the improvement and ecological restoration of saline–alkali land. Full article

(This article belongs to the Special Issue Molecular Research in Bamboo, Tree, Grass, and Other Forest Products)

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17 pages, 2238 KiB

Open AccessReview

Regeneration of Vascular Endothelium in Different Large Vessels

by Irina S. Sesorova, Eugeny V. Bedyaev, Pavel S. Vavilov, Sergei L. Levin and Alexander A. Mironov

Int. J. Mol. Sci. 2025, 26(2), 837; https://doi.org/10.3390/ijms26020837 - 20 Jan 2025

Viewed by 345

Abstract

The regeneration of endothelial cells (ECs) lining arteries, veins, and large lymphatic vessels plays an important role in vascular pathology. To understand the mechanisms of atherogenesis, it is important to determine what happens during endothelial regeneration. A comparison of these processes in the [...] Read more.

The regeneration of endothelial cells (ECs) lining arteries, veins, and large lymphatic vessels plays an important role in vascular pathology. To understand the mechanisms of atherogenesis, it is important to determine what happens during endothelial regeneration. A comparison of these processes in the above-mentioned vessels reveals both similarities and some significant differences. Regeneration is carried out by moving intact ECs from the edges of the viable endothelial layer towards the centre of the EC damage zone. A sharp decrease in contact inhibition leads to the spreading of the edges of the ECs situated on the damage border. This stimulates the second row of ECs to enter the S-phase, then the G2 phase of cell cycle, and finally mitosis. In all three types of vessels studied, mitotically dividing ECs were found using correlation light and electron microscopy. These ECs have a body protruding into the lumen of the vessel, covered with micro-villi and other outgrowths. The level of EC rounding and protruding is highest in the arteries and least pronounced in the lymphatic vessels. The intercellular contacts of mitotically dividing cells become wider. The EC division leads to an increase in the density of ECs. ECs moving over the damaged area and partially outside the damaged area acquire a fusiform shape. In the process of regeneration of arterial endothelium, the damaged ECs are removed. Then health ECs move to a surface devoid of endothelium, and detach spreading out, flattened platelets from the luminal surface of the vessel. In the veins, ECs grow on the surface of platelets and microthrombi. In lymphatic vessels, ECs detach from the basement membrane slower than in the veins and arteries. There, the migrating ECs grow under fibrin fibres. After some time (usually after 30 days), the EC mosaic returns to normal in all three types of vessels. Full article

(This article belongs to the Special Issue New Applications in the Diagnosis and Therapy of Diseases, 2nd Edition)

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23 pages, 2304 KiB

Open AccessReview

Diagnostic and Therapeutic Utility of Extracellular Vesicles in Ocular Disease

by Vladimir Khristov, Sarah R. Weber, Mireille Caton-Darby, Gregory Campbell and Jeffrey M. Sundstrom

Int. J. Mol. Sci. 2025, 26(2), 836; https://doi.org/10.3390/ijms26020836 - 20 Jan 2025

Viewed by 569

Abstract

Extracellular vesicles (EVs) are lipid bilayer particles released by virtually all cells, with prominent roles in both physiological and pathological processes. The size, number, and molecular composition of released EVs correlate to the cells of origin, modulated by the cell’s environment and pathologic [...] Read more.

Extracellular vesicles (EVs) are lipid bilayer particles released by virtually all cells, with prominent roles in both physiological and pathological processes. The size, number, and molecular composition of released EVs correlate to the cells of origin, modulated by the cell’s environment and pathologic state. The proteins, DNA, RNA, and protein cargo carried by EVs are protected by degradation, with a prominent role in targeted intercellular signaling. These properties make EVs salient targets as both carriers of biomarkers and potential therapeutic delivery vehicles. The majority of EV research has focused on blood, urine, saliva, and cerebrospinal fluid due to easy accessibility. EVs have also been identified and studied in all ocular biofluids, including the vitreous humor, the aqueous humor, and the tear film, and the study of EVs in ocular disease is a new, promising, and underexplored direction with unique challenges and considerations. This review covers recent advances in the diagnostic and therapeutic use of ocular EVs, with a focus on human applications and key preceding in vitro and in vivo animal studies. We also discuss future directions based on the study of EVs in other organ systems and disease sates. Full article

(This article belongs to the Special Issue The Role of Extracellular Vesicles in Cancers)

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22 pages, 1547 KiB

Open AccessReview

Pathophysiology of Group 3 Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxia

by Kazufumi Nakamura, Satoshi Akagi, Kentaro Ejiri, Satoshi Taya, Yukihiro Saito, Kazuhiro Kuroda, Yoichi Takaya, Norihisa Toh, Rie Nakayama, Yuki Katanosaka and Shinsuke Yuasa

Int. J. Mol. Sci. 2025, 26(2), 835; https://doi.org/10.3390/ijms26020835 - 20 Jan 2025

Viewed by 584

Abstract

Pulmonary hypertension associated with lung diseases and/or hypoxia is classified as group 3 in the clinical classification of pulmonary hypertension. The efficacy of existing selective pulmonary vasodilators for group 3 pulmonary hypertension is still unknown, and it is currently associated with a poor [...] Read more.

Pulmonary hypertension associated with lung diseases and/or hypoxia is classified as group 3 in the clinical classification of pulmonary hypertension. The efficacy of existing selective pulmonary vasodilators for group 3 pulmonary hypertension is still unknown, and it is currently associated with a poor prognosis. The mechanisms by which pulmonary hypertension occurs include hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, a decrease in pulmonary vascular beds, endothelial dysfunction, endothelial-to-mesenchymal transition, mitochondrial dysfunction, oxidative stress, hypoxia-inducible factors (HIFs), inflammation, microRNA, and genetic predisposition. Among these, hypoxic pulmonary vasoconstriction and subsequent pulmonary vascular remodeling are characteristic factors involving the pulmonary vasculature and are the focus of this review. Several factors have been reported to mediate vascular remodeling induced by hypoxic pulmonary vasoconstriction, such as HIF-1α and mechanosensors, including TRP channels. New therapies that target novel molecules, such as mechanoreceptors, to inhibit vascular remodeling are awaited. Full article

(This article belongs to the Special Issue Lung Diseases Molecular Pathogenesis and Therapy)

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