International Journal of Molecular Sciences

21 pages, 3094 KB

Open AccessArticle

Anticancer Activity of Ethanolic Extract of Tabernaemontana catharinensis in Breast Cancer Lines MCF-7 and MDA-MB-231

by Diana del Carmen Martínez-Méndez, María de la Luz Sánchez-Mundo, María del Rocío Thompson-Bonilla, Luis Marat Álvarez-Salas, Víctor Hugo Rosales-García, Jacobo Rodríguez-Campos and María Eugenia Jaramillo-Flores

Int. J. Mol. Sci. 2025, 26(16), 8111; https://doi.org/10.3390/ijms26168111 - 21 Aug 2025

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Abstract

Breast cancer is a serious public health problem worldwide. Although current treatments with drugs such as cisplatin and paclitaxel are effective, they are associated with severe adverse effects and the development of drug resistance, which has prompted the search for new therapeutic strategies. [...] Read more.

Breast cancer is a serious public health problem worldwide. Although current treatments with drugs such as cisplatin and paclitaxel are effective, they are associated with severe adverse effects and the development of drug resistance, which has prompted the search for new therapeutic strategies. In this context, the present study evaluated the anticancer activity of the ethanolic extract of Tabernaemontana catharinensis (EET) on the breast cancer cell lines MCF-7 (hormone-sensitive) and MDA-MB-231 (triple-negative) using 2D and 3D models. The results showed that EET significantly reduced cell viability in both lines, with IC₅₀ values of 83.06 µg/mL (MCF-7) and 8.3 µg/mL (MDA-MB-231) in 2D and 499.3 µg/mL and 280 µg/mL, respectively, in 3D. In addition, treatment with EET caused cell cycle arrest in the G1 phase, reduced CDK4 activity by 58% and ALDH3A1 activity by 32%, and increased levels of the tumor suppressor protein p53. Significant induction of apoptosis was also observed, evidenced by the activation of caspases -3/7, -8, and -9, along with a decrease in intracellular ATP levels (37% in MCF-7 and 90% in MDA-MB-231), suggesting mitochondrial dysfunction. Finally, EET showed the ability to inhibit cell invasion. Taken together, these results indicate that the ethanolic extract of Tabernaemontana catharinensis has potent antiproliferative, proapoptotic, and antimetastatic activity in breast cancer cells, in both two-dimensional and three-dimensional models. Its effect on various key molecular pathways and its ability to enhance the action of conventional chemotherapeutic agents position it as a promising adjuvant agent in the treatment of breast cancer. Full article

(This article belongs to the Special Issue Natural Products in Cancer Prevention and Treatment)

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15 pages, 1126 KB

Open AccessReview

Maturity-Onset Diabetes of the Young 10 (MODY10): A Comprehensive Review of Genetics, Clinical Features, and Therapeutic Advances

by Ali Mazloum, Sofya G. Feoktistova, Anna Gubaeva, Almaqdad Alsalloum, Olga N. Mityaeva, Alexander Kim, Natalia A. Bodunova, Mary V. Woroncow and Pavel Yu Volchkov

Int. J. Mol. Sci. 2025, 26(16), 8110; https://doi.org/10.3390/ijms26168110 - 21 Aug 2025

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Abstract

Maturity-onset diabetes of the young type 10 (MODY10) is a monogenic diabetes subtype caused by heterozygous mutations in the insulin gene (INS), leading to defective proinsulin processing, endoplasmic reticulum (ER) stress, and β-cell dysfunction. Current management relies on sulfonylureas or insulin [...] Read more.

Maturity-onset diabetes of the young type 10 (MODY10) is a monogenic diabetes subtype caused by heterozygous mutations in the insulin gene (INS), leading to defective proinsulin processing, endoplasmic reticulum (ER) stress, and β-cell dysfunction. Current management relies on sulfonylureas or insulin therapy, but these fail to address the underlying genetic defect. Recent research has elucidated the molecular mechanisms of MODY10, including ER stress induced by proinsulin misfolding, activation of the unfolded protein response (UPR), and β-cell apoptosis. Emerging therapies such as Adeno-Associated Virus (AAV)-mediated gene delivery to induce the glucose-responsive hepatic insulin expression, plasmid-based single-chain insulin analogs, and cell-based therapies show promise in preclinical studies. However, critical challenges remain, including immune responses to AAV vectors, incomplete correction of dominant-negative mutant effects, and the need for long-term safety data. This review summarizes current knowledge on MODY10 genetics, pathophysiology, and therapeutic innovations, while identifying key gaps for future research to enable precision medicine approaches. Full article

(This article belongs to the Special Issue Type 1 Diabetes: Molecular Mechanisms and Therapeutic Approach)

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14 pages, 586 KB

Open AccessReview

Efficacy of Neoadjuvant Cemiplimab Treatment for Cutaneous Squamous Cell Carcinoma—A Systematic Review

by Maria Eduarda Palomba, Julia Adriana Karmirski and Flávio Carneiro Hojaij

Int. J. Mol. Sci. 2025, 26(16), 8109; https://doi.org/10.3390/ijms26168109 - 21 Aug 2025

Viewed by 403

Abstract

Skin cancer is the most common cancer form worldwide, and it is primarily divided into melanoma and non-melanoma types, with non-melanoma being the most prevalent condition. Cutaneous squamous cell carcinoma (cSCC) accounts for 50% of primary skin cancers and is characterized by uncontrolled [...] Read more.

Skin cancer is the most common cancer form worldwide, and it is primarily divided into melanoma and non-melanoma types, with non-melanoma being the most prevalent condition. Cutaneous squamous cell carcinoma (cSCC) accounts for 50% of primary skin cancers and is characterized by uncontrolled keratinocyte proliferation. cSCC’s current standard treatment is surgical resection and chemotherapy. Unfortunately, these methods often lead to disfigurement, functional morbiditly, and compromised function. In contrast to immunotherapy, emerging scenarios have shown promising results, especially in neoadjuvant settings. Cemiplimab (Libtayo^®; Regeneron, Tarrytown, NY, USA), a PD-1 monoclonal antibody, has shown efficacy in treating advanced or metastatic cSCC, and its use as a neoadjuvant therapy has been recently explored. This review aims to evaluate Cemiplimab in the neoadjuvant setting for cSCC treatment. The Methodology followed PRISMA guidelines, this review analyzed studies on Cemiplimab as a neoadjuvant therapy for cSCC that were sourced from PubMed, Web of Science, and Scopus. Only controlled trials, cohort studies, case series, and systematic reviews were included. From 341 records, 21 studies were included, and six clinical trials provided key data about neoadjuvant Cemiplimab’s response rates, efficacy, adverse effects, and safety considerations. The targeted data revealed a neoadjuvant Cemiplimab mean pathologic response rate of 72%, with a 62% objective response rate. Treatment-related adverse events (TRAEs) affect 66% of patients, though most cases are not severe. The most common include fatigue, maculopapular rash, and diarrhea. The studies showed high rates of complete pathological responses (cPRs) and major pathological responses (mPRs), suggesting a strong therapeutic potential. Neoadjuvant Cemiplimab for cSCC therapy shows high response rates, low recurrence, improved survival, and manageable side effects. The current literature indicates that Cemiplimab may also be effective when used in immunosuppressed patients. Despite more research still being needed to confirm its long-term benefits and the effects of the drug’s use outside of clinical trials, there is strong evidence to consider neoadjuvant Cemiplimab as a promising and efficient treatment. Full article

(This article belongs to the Special Issue Molecular Research in Skin Health and Disease)

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19 pages, 3670 KB

Open AccessArticle

Deciphering the Diagnostic Potential of Small Non-Coding RNAs for the Detection of Pancreatic Ductal Adenocarcinoma Through Liquid Biopsies

by Hadas Volkov, Rani Shlayem and Noam Shomron

Int. J. Mol. Sci. 2025, 26(16), 8108; https://doi.org/10.3390/ijms26168108 - 21 Aug 2025

Viewed by 326

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers, accounting for a significant proportion of cancer-related deaths globally. Despite advancements in medical science, treatment options for PDAC remain limited, and the prognosis is often poor. Early detection is a critical factor [...] Read more.

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers, accounting for a significant proportion of cancer-related deaths globally. Despite advancements in medical science, treatment options for PDAC remain limited, and the prognosis is often poor. Early detection is a critical factor in improving patient outcomes, but current diagnostic methods often fail to detect PDAC until it has advanced to a late stage. In this context, the development of more effective diagnostic tools is of paramount importance. In this study, we explored the potential of non-coding RNAs (ncRNAs) as diagnostic markers for PDAC using cell-free nucleotides and liquid biopsies. Leveraging the power of Next Generation Sequencing (NGS), bioinformatics analysis, and machine learning (ML), we were able to identify unique RNA signatures associated with PDAC. Our findings revealed twenty key genes, including microRNAs (miRNAs), long-non-coding RNAs (lncRNAs), and miscellaneous RNAs that demonstrated high classification accuracy. Specifically, our model achieved a classification accuracy of 87% and an area under the receiver operating characteristic curve (AUC) of 91%. These ncRNAs could potentially serve as robust biomarkers for PDAC, offering a promising avenue for the development of a non-invasive diagnostic test. This could revolutionize PDAC diagnosis, enabling earlier detection and intervention, which is crucial for improving patient outcomes. This work lays the groundwork for future research, with the potential to significantly enhance PDAC diagnosis and therapy. Full article

(This article belongs to the Special Issue Hepatopancreatic and Intestine Diseases: From Molecular Basis to Therapy)

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13 pages, 10589 KB

Open AccessArticle

Functional Role of miR-138-5p and miR-200b-3p in Testicular Germ Cell Tumors: Molecular Insights into Seminoma and Teratoma Pathogenesis

by Fatemeh Hooshiar, Hossein Azizi, Mahla Masoudi and Thomas Skutella

Int. J. Mol. Sci. 2025, 26(16), 8107; https://doi.org/10.3390/ijms26168107 - 21 Aug 2025

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Abstract

This study aims to investigate the molecular mechanisms underlying germ cell tumors (GCTs), focusing specifically on seminomas and teratomas. By analyzing gene expression profiles and miRNA interactions, the goal is to identify key regulatory miRNAs and signaling pathways that differentiate these tumor types [...] Read more.

This study aims to investigate the molecular mechanisms underlying germ cell tumors (GCTs), focusing specifically on seminomas and teratomas. By analyzing gene expression profiles and miRNA interactions, the goal is to identify key regulatory miRNAs and signaling pathways that differentiate these tumor types and could serve as important regulators for therapy development. Raw data for seminomas and teratomas were extracted from the GEO database, and gene hubs were identified using STRING and Gephi. Signaling pathways and functional annotations were analyzed using miRPathDB, while miRNA–gene interactions were explored via miRWalk. Hub miRNAs were filtered and confirmed using miRDB. This study highlights significant changes in gene expression diversity between tumor and normal gonadal tissues, providing insights into the molecular dynamics of seminomas and teratomas. Distinctions between seminomas and teratomas were identified, shifting the focus toward miRNAs to discover more precise and novel therapeutic approaches. The hub genes of seminomas and teratomas were identified separately. MiRNAs targeting these hub genes were also determined and confirmed. These miRNAs collectively influence essential oncogenic pathways—confirming hsa-miR-138-5p as a regulator of pathways such as Hippo signaling, transcriptional misregulation in cancer, and microRNA cancer signaling in seminomas, and hsa-miR-200b-3p as a regulator of p53 signaling, T cell receptor signaling, and pathways including PI3K/AKT, MAPK/ERK, and Wnt/β-catenin in teratomas—confirming their potential as promising candidates for subtype-specific therapeutic intervention. MiRNAs identified through bioinformatics analyses, and their predicted regulatory roles in key oncogenic pathways, represent potential therapeutic targets or regulators of biological processes. However, further experimental validation is needed to confirm these findings. Full article

(This article belongs to the Special Issue Signaling Pathways Dysregulation in Cancer: Advances and New Therapeutics Hopes)

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20 pages, 3581 KB

Open AccessArticle

Long-Term Durability and Variant-Specific Modulation of SARS-CoV-2 Humoral and Cellular Immunity over Two Years

by Lilia Matei, Mihaela Chivu-Economescu, Laura Denisa Dragu, Camelia Grancea, Coralia Bleotu, Raluca Hrișcă, Corneliu Petru Popescu, Carmen C. Diaconu and Simona Maria Ruţă

Int. J. Mol. Sci. 2025, 26(16), 8106; https://doi.org/10.3390/ijms26168106 - 21 Aug 2025

Viewed by 385

Abstract

There is an increasing need to understand the long-term dynamics and quality of SARS-CoV-2 immune memory—both humoral and cellular—particularly with emerging variants. This study aimed to evaluate immune durability and variant-specific modulation through a longitudinal analysis of individuals with diverse SARS-CoV-2 exposure histories, [...] Read more.

There is an increasing need to understand the long-term dynamics and quality of SARS-CoV-2 immune memory—both humoral and cellular—particularly with emerging variants. This study aimed to evaluate immune durability and variant-specific modulation through a longitudinal analysis of individuals with diverse SARS-CoV-2 exposure histories, over two years after infection and/or vaccination. The study involved assessing anti-spike IgG and IgA levels over time and analyzing their relationship with neutralizing activity against both ancestral and Omicron SARS-CoV-2 variants. Persistence of T cell responses was evaluated using intracellular cytokine staining (ICS) and activation-induced marker (AIM) assays. Anti-S IgG levels remained stable over time and increased after each immune stimulation, suggesting cumulative immune memory. Neutralizing capacity correlated strongly with IgG levels, showing long-term stability for pre-Omicron variants, but a moderate decline for Omicron. CD4⁺ and CD8⁺ T cell responses persisted across all groups, largely unaffected by Omicron mutations. However, cytokine profiles revealed subtle, variant-dependent changes. These findings underscore the durability of cellular immunity and the comparatively reduced robustness of Omicron-specific humoral responses. Such insights are crucial for understanding long-term protection against evolving SARS-CoV-2 variants and guiding public health strategies. Full article

(This article belongs to the Special Issue COVID-19: Molecular Research and Novel Therapy)

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3 pages, 155 KB

Open AccessEditorial

The Interplay Among Biomolecules and Nanomaterials

by Ran Jia

Int. J. Mol. Sci. 2025, 26(16), 8105; https://doi.org/10.3390/ijms26168105 - 21 Aug 2025

Viewed by 254

Abstract

The unintentional application of nanomaterials by humans dates back over two millennia, though the formal concept emerged only in the late 20th century [...] Full article

(This article belongs to the Special Issue The Interplay among Biomolecules and Nanomaterials)

12 pages, 272 KB

Open AccessArticle

Identification of Non-Invasive Diagnostic Markers for Oral Squamous Cell Carcinoma Through Salivary Microbiome and Gene Expression Analysis

by Mitsuhiro Hishida, Kosuke Nomoto, Kengo Hashimoto, Sei Ueda and Shuji Nomoto

Int. J. Mol. Sci. 2025, 26(16), 8104; https://doi.org/10.3390/ijms26168104 - 21 Aug 2025

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Abstract

Oral squamous cell carcinoma (OSCC) is a malignancy with a poor prognosis, and early diagnosis is essential for improving patient survival and quality of life. This study aimed to develop a non-invasive screening method based on salivary gene expression and microbiome analysis. Unstimulated [...] Read more.

Oral squamous cell carcinoma (OSCC) is a malignancy with a poor prognosis, and early diagnosis is essential for improving patient survival and quality of life. This study aimed to develop a non-invasive screening method based on salivary gene expression and microbiome analysis. Unstimulated saliva samples were collected from patients with OSCC, patients with oral potentially malignant disorders, and healthy controls. Microbiome profiling was performed using 16S ribosomal RNA gene sequencing. The OSCC group showed a significant increase in Fusobacterium and Bacteroidetes and a decrease in Streptococcus. LEfSe analysis indicated microbial changes associated with disease progression. Receiver operating characteristic analysis demonstrated high diagnostic accuracy when multiple bacterial species were combined. An increase in Fusobacteria was also associated with a higher risk of recurrence. Gene expression analysis revealed that NUS1, RCN1, CPLANE1, and CCL20 were significantly upregulated in OSCC, as confirmed by qRT-PCR and tissue expression data. Notably, CCL20 expression positively correlated with Fusobacterium abundance. These findings suggest that integrated analysis of the salivary microbiome and gene expression may offer a useful non-invasive approach for early OSCC detection and disease monitoring. Furthermore, we integrated current evidence from the literature to provide a comprehensive overview. Full article

(This article belongs to the Special Issue Gut Microbiome Stability in Health and Disease)

27 pages, 1791 KB

Open AccessReview

Antimicrobial Peptides of the Cathelicidin Family: Focus on LL-37 and Its Modifications

by Olga Evgenevna Voronko, Victoria Alexandrovna Khotina, Dmitry Alexandrovich Kashirskikh, Arthur Anatolievich Lee and Vagif Ali oglu Gasanov

Int. J. Mol. Sci. 2025, 26(16), 8103; https://doi.org/10.3390/ijms26168103 - 21 Aug 2025

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Abstract

Cathelicidins are a family of antimicrobial peptides (AMPs) with broad-spectrum activity and immunomodulatory functions. Among them, the only human cathelicidin LL-37 has garnered significant interest due to its potent antimicrobial, antiviral, antifungal, antiparasitic, and antitumor properties. However, the clinical application of LL-37 is [...] Read more.

Cathelicidins are a family of antimicrobial peptides (AMPs) with broad-spectrum activity and immunomodulatory functions. Among them, the only human cathelicidin LL-37 has garnered significant interest due to its potent antimicrobial, antiviral, antifungal, antiparasitic, and antitumor properties. However, the clinical application of LL-37 is hindered by several limitations, including low proteolytic stability, cytotoxicity, and high production costs. To overcome these challenges, a wide range of design strategies have been employed to modify LL-37 and improve its therapeutic potential. LL-37-based analogs represent promising candidates for the development of next-generation antimicrobial and immunomodulatory therapies. Despite significant progress, further research is required to optimize peptide design, ensure cost-effective production, and validate long-term safety and efficacy. Advances in computational modeling, high-throughput screening, and nanotechnology will play an important role in the translation of modified cathelicidins into clinical practice. This review summarizes key strategies of chemical and structural modifications of LL-37 aimed at enhancing its functional properties. Particular attention is given to truncated and retro-analogs, which preserve or improve biological activity while exhibiting reduced toxicity and increased proteolytic resistance. Furthermore, we highlight the use of nanoscale delivery systems, which facilitate targeted delivery, prolong peptide half-life, and mitigate cytotoxic effects. Full article

(This article belongs to the Special Issue Antimicrobial and Antiviral Peptides: 2nd Edition)

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24 pages, 3480 KB

Open AccessArticle

Biphasic Electrical Stimulation of Schwann Cells on Conducting Polymer-Coated Carbon Microfibers

by Alexandra Alves-Sampaio and Jorge E. Collazos-Castro

Int. J. Mol. Sci. 2025, 26(16), 8102; https://doi.org/10.3390/ijms26168102 - 21 Aug 2025

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Abstract

Electroactive biomaterials are a key emerging technology for the treatment of neural damage. Conducting polymer-coated carbon microfibers are particularly useful for this application because they provide directional support for cell growth and tissue repair and simultaneously allow for ultrasensitive recording and stimulation of [...] Read more.

Electroactive biomaterials are a key emerging technology for the treatment of neural damage. Conducting polymer-coated carbon microfibers are particularly useful for this application because they provide directional support for cell growth and tissue repair and simultaneously allow for ultrasensitive recording and stimulation of neural activity. Here, we report in vitro experiments investigating the biology of Schwann cells (SCs), a major player in peripheral nerve regeneration, on electroconducting microfibers. The optimal molecular composition of the cell substrate and cell culture medium was studied for SCs dissociated from rat and pig peripheral nerves. The substrate molecules were then attached to carbon microfibers coated with poly (3,4-ethylenedioxythiophene) doped with poly [(4-styrenesulfonic acid)-co-(maleic acid)] (PCMFs), which served as an electroactive scaffold for culturing nerve explants. Biphasic electrical stimulation (ES) was applied through the microfibers, and its effects on cell proliferation and migration were assessed in different cell culture media. Rodent and porcine SCs avidly migrated on PCMFs functionalized with a complex of poly-L-lysine, heparin, basic fibroblast growth factor, and fibronectin. Serum and forskolin/heregulin increased, by two-fold and four-fold, the number of SCs on PCMFs, respectively, and ES further doubled cell numbers without favoring fibroblast proliferation. ES additionally increased SC migration. These results provide a baseline for using biofunctionalized PCMFs in peripheral nerve repair. Full article

(This article belongs to the Special Issue Plasticity of the Nervous System after Injury: 2nd Edition)

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22 pages, 3849 KB

Open AccessArticle

Retinoic Acid-Induced Transglutaminase 2 Expression Reduces Sensitivity to Cisplatin in the Hormone-Positive MCF-7 Breast Cancer Cell Model

by Ebidor U. Lawani-Luwaji, Claire V. S. Pike and Peter J. Coussons

Int. J. Mol. Sci. 2025, 26(16), 8101; https://doi.org/10.3390/ijms26168101 - 21 Aug 2025

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Abstract

Cisplatin is an effective chemotherapeutic drug, but is limited both by its toxicity and its tendency to induce drug resistance rapidly in some patients. Tissue transglutaminase 2 (TG2), which is overexpressed in various cancers, has two main isoforms: a long (TG2-L) and a [...] Read more.

Cisplatin is an effective chemotherapeutic drug, but is limited both by its toxicity and its tendency to induce drug resistance rapidly in some patients. Tissue transglutaminase 2 (TG2), which is overexpressed in various cancers, has two main isoforms: a long (TG2-L) and a short form (TG2-S). While TG2-L supports cell survival, conversely, TG2-S promotes cell death. Evidence increasingly suggests that TG2 may be a suitable target for combating chemoresistance in a variety of human cancers. Here, we show that cisplatin toxicity towards wild-type MCF-7 breast cancer cells is associated with reduced TG2-L and TG2-S expression, whereas approximately doubling the TG2-L expression through the retinoic acid pre-treatment of these cells induces survival in the presence of cisplatin at levels similar to those seen in long-term cisplatin-co-cultured cells, which have reduced sensitivity. The treatment of cisplatin-surviving cells with cisplatin alone did not significantly alter the levels of either TG2 isoform, whereas the cisplatin challenge of cisplatin-surviving MCF-7 cells following 20 µM retinoic acid pre-treatment resulted in increased levels of TG2-L, increased TG2 enzyme activity, and no significant change in TG2-S levels, with increased cell survival. These findings suggest a subtype-specific regulatory effect of RA in cisplatin-surviving MCF-7 cells, with TG2-L upregulated at higher RA concentrations, potentially contributing to altered cisplatin sensitivity. Anti-TG2 siRNA silencing reduced cisplatin IC50 to base levels in both wild-type and cisplatin-surviving MCF-7 cells, supporting the notion that the modulation of TG2 expression could offer a significant benefit to cisplatin efficacy. Preventing excessive retinoic acid exposure may also be a mechanism for maximising cisplatin efficacy, considering TG2 modulation. Full article

(This article belongs to the Special Issue Multidrug Resistance in Cancer: Molecular Mechanisms and Therapeutic Implications)

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26 pages, 6772 KB

Open AccessArticle

Adaptive and Pathological Changes of the Cardiac Muscle in a Mouse Model of Renocardiac Syndrome: The Role of Nestin-Positive Cells

by Polina A. Abramicheva, Ilya A. Sokolov, Arina A. Druzhinina, Daria M. Potashnikova, Nadezda V. Andrianova, Dmitry S. Semenovich, Vasily N. Manskikh, Ljubava D. Zorova, Elmira I. Yakupova, Ivan M. Vikhlyantsev, Olga S. Tarasova, Dmitry B. Zorov and Egor Y. Plotnikov

Int. J. Mol. Sci. 2025, 26(16), 8100; https://doi.org/10.3390/ijms26168100 - 21 Aug 2025

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Abstract

Renocardiac syndrome type 4 (RCS4) is a common comorbid pathology, but the mechanisms of kidney dysfunction-induced cardiac remodeling and the involvement of cardiac progenitor cells (CPCs) in this process remain unclear. The aim of this study was to investigate the structural and functional [...] Read more.

Renocardiac syndrome type 4 (RCS4) is a common comorbid pathology, but the mechanisms of kidney dysfunction-induced cardiac remodeling and the involvement of cardiac progenitor cells (CPCs) in this process remain unclear. The aim of this study was to investigate the structural and functional changes in the cardiac muscle in RCS4 induced by unilateral ureteral obstruction (UUO) and the role of nestin⁺ CPCs in these. Heart function and localization of nestin⁺ cells in the myocardium were assessed using nestin-GFP transgenic mice subjected to UUO for 14 and 28 days. UUO resulted in cardiac hypertrophy, accompanied by an elongation of the QRS wave on the ECG, decreased expression of Cxcl1, Cxcl9, and Il1b, reduced the number of CD11b⁺ cells, and increased in titin isoform parameters, such as T1/MHC and TT/MHC ratios, without changes in fibrosis markers. The number of nestin⁺ cells increased in the myocardium with increased duration of UUO and displayed an SCA-1⁺TBX5⁺ phenotype, consistent with CPCs. Thus, cardiac pathology in RCS4 was manifested by cardiomyocyte hypertrophy with changes in the electrophysiological phenotype of the heart, not accompanied by fibrosis or inflammation. Nestin⁺ cardiac cells retained the CPC phenotype during UUO, and their number increased, which suggests their participation in regenerative processes in the heart. Full article

(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine (Volume 5))

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17 pages, 1509 KB

Open AccessReview

Efficacy of Lactobacillus spp. Interventions to Modulate Mood Symptoms: A Scoping Review of Clinical Trials

by Diego Fernández-Rodríguez, María Consuelo Bravo, Marcela Pizarro, Pablo Vergara-Barra, María José Hormazábal and Marcell Leonario-Rodriguez

Int. J. Mol. Sci. 2025, 26(16), 8099; https://doi.org/10.3390/ijms26168099 - 21 Aug 2025

Viewed by 477

Abstract

Probiotics containing Lactobacillus spp. have demonstrated immunological and gastrointestinal benefits and may aid in recovery from mood disorders. However, evidence of their mood-modulating efficacy remains inconsistent. Aim: To analyze the efficacy of probiotic interventions with Lactobacillus spp. in modulating mood in humans. A [...] Read more.

Probiotics containing Lactobacillus spp. have demonstrated immunological and gastrointestinal benefits and may aid in recovery from mood disorders. However, evidence of their mood-modulating efficacy remains inconsistent. Aim: To analyze the efficacy of probiotic interventions with Lactobacillus spp. in modulating mood in humans. A scoping review was conducted following the PRISMA guidelines. A systematic search of the PubMed and Scopus databases was performed using nine Boolean combinations of the terms “mental”, “mental diseases”, “mental disorders”, “gastrointestinal microbiome”, “gut microbiome”, “gut microbiota”, and “lactobacillus”. The search was limited to clinical trials published in English and limited to ten years of publication. Eligible studies met the following criteria: (a) probiotic interventions in adults, with or without mood disturbances; (b) the use of Lactobacillus spp., either alone or in combination; (c) mood assessment instruments applied pre- and post-intervention; and (d) reporting of probiotic concentrations. Trials involving populations with other psychiatric or neurological diagnoses or those combining probiotics with additional mood-modulating nutrients were excluded. From 3291 records, 17 clinical trials met the inclusion criteria. Data extracted included the author, year, population, country of origin, probiotic strain(s), dosage, intervention mode and duration, and outcomes related to the microbial composition, biomarkers, and microbial metabolites. Trials were categorized by probiotic type (single vs. multi-species) and participant profile (healthy individuals and those with depressive symptoms or specific physiological conditions). Preliminary evidence from single-strain interventions, particularly high-dose L. plantarum administered for ≥8 weeks, suggests potential improvements in anxiety, sleep quality, and inflammatory biomarkers. Multi-species formulations yielded reductions in depressive symptoms and changes in neurobiological markers. Nonetheless, substantial heterogeneity in strains, dosages, durations, and outcome measures limited cross-study comparisons. Lactobacillus spp. interventions show promising mood-modulating potential, especially with specific strains and prolonged administration. Standardized protocols, rigorous controls, and clearly defined clinical cohorts are needed to establish robust, evidence-based recommendations. Full article

(This article belongs to the Special Issue Innovative Therapeutic Approaches in Neuropsychiatric Disorders)

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26 pages, 2797 KB

Open AccessArticle

Heterogeneous Macrophage Activation in Acute Skeletal Muscle Sterile Injury and mdx^5cv Model of Muscular Dystrophy

by Xingyu Wang, Justin K. Moy, Yinhang Wang, Gregory R. Smith, Frederique Ruf-Zamojski, Pawel F. Przytycki, Stuart C. Sealfon and Lan Zhou

Int. J. Mol. Sci. 2025, 26(16), 8098; https://doi.org/10.3390/ijms26168098 - 21 Aug 2025

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Abstract

Monocytes/macrophages promote the repair of acutely injured muscle while contributing to dystrophic changes in chronically injured muscle in Duchenne muscular dystrophy (DMD) patients and animal models including mdx and mdx^5cv mice. To elucidate the molecular mechanisms underlying this functional difference, we compared [...] Read more.

Monocytes/macrophages promote the repair of acutely injured muscle while contributing to dystrophic changes in chronically injured muscle in Duchenne muscular dystrophy (DMD) patients and animal models including mdx and mdx^5cv mice. To elucidate the molecular mechanisms underlying this functional difference, we compared the transcriptomes of intramuscular monocytes/macrophages from wild-typed (WT) uninjured muscles, WT acutely injured muscles, and mdx^5cv dystrophic muscles, using single cell-based RNA sequencing (scRNA-seq) analysis. Our study identified multiple transcriptomically diverse monocyte/macrophage subclusters, which appear to be induced by the intramuscular microenvironment. They expressed feature genes differentially involved in muscle inflammation, regeneration, and extracellular matrix (ECM) remodeling, but none of them conform to strict M1 or M2 activation. The Gpnmb⁺Spp1⁺ macrophage subcluster, an injury-associated subcluster that features the signature genes of reported scar-associated macrophages (SAMs) involved in ECM remodeling and fibrosis, is present transiently in acutely injured muscle and persistently in chronically injured dystrophic muscle, along with the persistence of monocytes. Our findings suggest that the persistent monocyte/macrophage infiltration and activation induced by continuous injury may underlie the pathogenic roles of macrophages in mdx^5cv muscles. Controlling muscle injury and subsequent macrophage infiltration and activation may be important to the treatment of DMD. Full article

(This article belongs to the Section Molecular Immunology)

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26 pages, 832 KB

Open AccessReview

Do Sex and Gender Interact with the Biological Actions of Taurine? A Critical Rereading of the Literature

by Giuseppe Seghieri, Ilaria Campesi, Giancarlo Tonolo, Federico Bennardini, Isabella Stendardi, Rosanna Matucci and Flavia Franconi

Int. J. Mol. Sci. 2025, 26(16), 8097; https://doi.org/10.3390/ijms26168097 - 21 Aug 2025

Viewed by 471

Abstract

In humans, taurine (TAU) is a conditionally essential nutrient that exhibits pleiotropic activity in several and different biological processes suggesting its use in the prevention and therapy for a long time. However, its actual role in prevention and treatment is still incomplete and [...] Read more.

In humans, taurine (TAU) is a conditionally essential nutrient that exhibits pleiotropic activity in several and different biological processes suggesting its use in the prevention and therapy for a long time. However, its actual role in prevention and treatment is still incomplete and unclear. This review focuses on the potential therapeutic effect of TAU in genetic diseases, cardiovascular diseases (heart failure, hypertension), metabolic syndrome, and on the first pandemic of the third millennium, namely, diabetes mellitus and some gestational diseases such as gestational diabetes, intrauterine growth restriction, and pre-eclampsia, discussing the role of TAU in developmental trajectory. Previous preclinical and clinical TAU investigations predominately enrolled male animals, including humans, even though sex and gender differences play a critical role both in numerous physiological and pathological conditions. This review aims to outline some biological actions of TAU and evidences the sex and gender gap must be reduced in order to establish the role of TAU in prevention and therapy for all individuals. Full article

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

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22 pages, 897 KB

Open AccessReview

Targeting Sarcopenia in CKD: The Emerging Role of GLP-1 Receptor Agonists

by Vicente Llinares-Arvelo, Carlos E. Martínez-Alberto, Ainhoa González-Luis, Manuel Macía-Heras, Orlando Siverio-Morales, Juan F. Navarro-González and Javier Donate-Correa

Int. J. Mol. Sci. 2025, 26(16), 8096; https://doi.org/10.3390/ijms26168096 - 21 Aug 2025

Viewed by 373

Abstract

Sarcopenia is a prevalent and disabling complication of chronic kidney disease (CKD), associated with frailty, diminished quality of life, and increased morbidity and mortality. Despite its clinical significance, no pharmacological treatments are currently approved to address muscle wasting in this population. Glucagon-like peptide-1 [...] Read more.

Sarcopenia is a prevalent and disabling complication of chronic kidney disease (CKD), associated with frailty, diminished quality of life, and increased morbidity and mortality. Despite its clinical significance, no pharmacological treatments are currently approved to address muscle wasting in this population. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in the management of type 2 diabetes and obesity, have shown potential to support muscle mass and function through pleiotropic mechanisms. These include anti-inflammatory and antioxidant actions, improvements in insulin sensitivity and energy metabolism, and mitochondrial support. Given the high burden of sarcopenia in CKD and the frequent overlap with metabolic and cardiovascular comorbidities, GLP-1RAs may offer a novel therapeutic approach. This review examines the biological plausibility and emerging evidence supporting the role of GLP-1RAs in preserving muscle health in CKD, highlighting the need for targeted clinical trials and mechanistic investigations to establish their efficacy in this high-risk group. Full article

(This article belongs to the Collection Latest Review Papers in Endocrinology and Metabolism)

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23 pages, 3282 KB

Open AccessArticle

Metabolic Dysfunction-Associated Steatotic Liver Disease Shapes a Distinct Semaphorin–Cytokine Immune Signature in Severe Community-Acquired Pneumonia

by Branimir Gjurašin, Leona Radmanić Matotek, Lara Šamadan Marković and Neven Papić

Int. J. Mol. Sci. 2025, 26(16), 8095; https://doi.org/10.3390/ijms26168095 - 21 Aug 2025

Viewed by 313

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a modulator of infection severity, yet its impact on the immune response in severe community-acquired pneumonia (sCAP) remains poorly understood. In this prospective cohort study of 108 adults with sCAP, we evaluated the [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a modulator of infection severity, yet its impact on the immune response in severe community-acquired pneumonia (sCAP) remains poorly understood. In this prospective cohort study of 108 adults with sCAP, we evaluated the prevalence and prognostic impact of MASLD and performed pathogen-stratified immune profiling of cytokines and semaphorins on hospital days 1 and 5. MASLD was present in 50% of patients and independently associated with early respiratory failure (OR 3.8) and vasopressor-dependent shock (OR 4.0), despite similar sCAP severity at baseline. MASLD patients exhibited distinct immune profiles, including elevated baseline serum levels of SEMA3A, SEMA7A, IL-2, IL-10, IL-17A, CXCL10, and TGF-β1, and reduced SEMA5A. By day 5, the MASLD group exhibited a greater decline in pro-inflammatory mediators compared to non-MASLD patients but failed to upregulate reparative mediators such as SEMA4D and TGF-β1, unlike the non-MASLD group. These kinetics may suggest a maladaptive immune response in MASLD, potentially consistent with early immune exhaustion. Immunokinetic patterns were pathogen-specific, including transient increase in IL-17A and IL-10 in Legionella and Mycoplasma infections, and CXCL10, IL-2, IL-17A, TGF-β1 and IL-10 in influenza. Serum IL-10, CXCL10, SEMA3F, SEMA4D and SEMA7A correlated with organ failure and sCAP complications. These findings underscore the clinical importance of the lung–liver axis and suggest that semaphorins could serve as valuable prognostic biomarkers for identifying high-risk patients. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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17 pages, 2625 KB

Open AccessArticle

Postbiotic pA1c^®HI for Preventing Insulin Resistance and Obesity in a Caenorhabditis elegans Model of Prediabetes

by Deyan Yavorov-Dayliev, Iñaki Iturria, Leyre Iriarte, Miriam Araña, Miguel Barajas and Josune Ayo

Int. J. Mol. Sci. 2025, 26(16), 8094; https://doi.org/10.3390/ijms26168094 - 21 Aug 2025

Viewed by 286

Abstract

Cardiometabolic diseases such as obesity, prediabetes (PreD), and type 2 diabetes (T2D) are global health challenges linked to metabolic dysfunction. While probiotics show promise, postbiotics offer advantages in stability, safety, and food incorporation. This study evaluates the postbiotic pA1c^®HI, a heat-inactivated [...] Read more.

Cardiometabolic diseases such as obesity, prediabetes (PreD), and type 2 diabetes (T2D) are global health challenges linked to metabolic dysfunction. While probiotics show promise, postbiotics offer advantages in stability, safety, and food incorporation. This study evaluates the postbiotic pA1c^®HI, a heat-inactivated form of the probiotic pA1c^®, for its potential in modulating glucose and lipid metabolism in Caenorhabditis elegans, compared to its live form. Worms were supplemented with pA1c^®HI and live pA1c^® in glucose-enriched media. Fat accumulation, gene expression, oxidative stress, and lifespan were measured using Nile Red and DHE staining, qPCR, and longevity assays. pA1c^®HI significantly reduced glucose-induced fat accumulation, achieving fat reduction comparable to the anti-obesity drug orlistat and showing superior efficacy compared to the live probiotic form. It modulated the expression of genes associated with lipid oxidation (acox-1, cpt-2), fatty acid synthesis (fat-5), insulin signaling (daf-2, daf-16), and oxidative stress response (skn-1). Synergistic combinations with chromium picolinate (PC) and zinc (Zn) further enhanced metabolic outcomes. Importantly, pA1c^®HI retained efficacy after thermal treatment (121–135 °C), supporting its potential for use in processed foods. pA1c^®HI is a stable, effective postbiotic that modulates key pathways associated with obesity, PreD, and T2D in C. elegans, with superior performance to the live probiotic and added benefits when combined with PC and Zn. Full article

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

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30 pages, 9603 KB

Open AccessArticle

Pinealectomy-Induced Neuroinflammation Varies with Age in Rats

by Dimitrinka Atanasova, Desislava Krushovlieva, Pavel Rashev, Milena Mourdjeva, Despina Pupaki and Jana Tchekalarova

Int. J. Mol. Sci. 2025, 26(16), 8093; https://doi.org/10.3390/ijms26168093 - 21 Aug 2025

Viewed by 253

Abstract

It is widely accepted that chronic inflammation constitutes a significant mechanism that promotes the biological aging process. The pineal gland is regarded as being closely related to the control of the “life clock”. The present study aimed to determine the inflammation associated with [...] Read more.

It is widely accepted that chronic inflammation constitutes a significant mechanism that promotes the biological aging process. The pineal gland is regarded as being closely related to the control of the “life clock”. The present study aimed to determine the inflammation associated with pinealectomy in the rat hippocampus and to investigate the extent to which age stage impacts the severity of this inflammation. We evaluated the expression of the Akt/NF-kB signaling pathway in neurons and gliosis level in the dorsal hippocampus (dHipp) of rats subjected to sham surgery or pinealectomy at 3, 14, or 18 months of age. The assessment was conducted using immunohistochemistry. Removal of the pineal gland resulted in significant, region-specific increases in NF-kB expression in neurons of the dHipp in the youngest and middle-aged groups. However, the change in expression of the phosphorylated form of Akt (pAkt1) in neurons went in the opposite direction in these two age groups, and there were also regional differences. Pinealectomy triggered microgliosis in both young and old rats, but middle-aged rats were resistant to microglia activation. Conversely, astrogliosis was observed in young adult and middle-aged groups with melatonin deficiency in certain regions of the dHipp. It is noteworthy that young adult rats demonstrated the highest degree of vulnerability to inflammation associated with the loss of melatonin as a hormone. In contrast, middle-aged rats with pinealectomy exhibited a complex and partial adaptive response. These findings emphasize the dynamic and age-dependent nature of neuroinflammation following pinealectomy, underscoring the developmental stage as a critical determinant of inflammatory susceptibility. Full article

(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases—4th Edition)

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20 pages, 2007 KB

Open AccessReview

Vertebrate and Invertebrate Animal Models for the Study of Down Syndrome

by Ann-Charlotte Granholm

Int. J. Mol. Sci. 2025, 26(16), 8092; https://doi.org/10.3390/ijms26168092 - 21 Aug 2025

Viewed by 363

Abstract

Down syndrome (DS) is the most common survivable chromosome trisomy, with an incidence of about 1 in 600–700 births. Consequences of chromosome 21 trisomy include developmental delays, congenital cardiac abnormalities, skeletal abnormalities, and age-related dementia of the Alzheimer’s disease (AD) type. Up to [...] Read more.

Down syndrome (DS) is the most common survivable chromosome trisomy, with an incidence of about 1 in 600–700 births. Consequences of chromosome 21 trisomy include developmental delays, congenital cardiac abnormalities, skeletal abnormalities, and age-related dementia of the Alzheimer’s disease (AD) type. Up to 90% of individuals with DS develop dementia symptoms in their 40s or 50s. Because the biological mechanisms involved in DS-related developmental and age-related pathology are less known, animal models consisting of both lower-order and higher-order animals have been developed. We here review the most pertinent and well-studied DS animal models including models developed in C. elegans, Drosophila, zebrafish, and mice. Molecular pathways involved in DS morbidity that were discovered in animal models will also be discussed. Full article

(This article belongs to the Special Issue Using Model Organisms to Study Complex Human Diseases)

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17 pages, 2471 KB

Open AccessArticle

Canine Endometrial Mesenchymal Stem Cells: Characterization and Functional Assessment for Cartilage Repair

by Zuzana Vikartovska, Marcela Maloveska, Natalia Nosalova, Lubica Hornakova, Mykhailo Huniadi, Nikola Hudakova, Slavomir Hornak, Blazej Kalinaj, Peter Kubatka and Dasa Cizkova

Int. J. Mol. Sci. 2025, 26(16), 8091; https://doi.org/10.3390/ijms26168091 - 21 Aug 2025

Viewed by 236

Abstract

Endometrial mesenchymal stem cells (eMSCs) are a novel and biologically potent source of multipotent stromal cells with potential beyond reproductive medicine. This study explored their phenotypic profile, trilineage differentiation, and the cytoprotective effects of their conditioned media (eMSCCM) on oxidatively stressed neonatal and [...] Read more.

Endometrial mesenchymal stem cells (eMSCs) are a novel and biologically potent source of multipotent stromal cells with potential beyond reproductive medicine. This study explored their phenotypic profile, trilineage differentiation, and the cytoprotective effects of their conditioned media (eMSCCM) on oxidatively stressed neonatal and adult chondrocytes. Canine eMSCs displayed typical fibroblast-like morphology and expressed high levels of mesenchymal surface markers CD29 and CD44, low hematopoietic markers CD34/CD45, and variable CD90, confirming a mesenchymal identity. Differentiation assays revealed osteogenic and chondrogenic differentiation, whereas adipogenic activity was limited. Using eMSCCM at 25% and 50% concentrations, chondrocyte viability was assessed after exposure to 200 µM H₂O₂. eMSCCM significantly enhanced the viability of H₂O₂-stressed chondrocytes in a dose-dependent manner, particularly at 50%, with marked effects at 24 and 48 h. Although metabolic activity declined at 72 h, the treated cells remained more metabolically active than untreated controls. These findings suggest that eMSCCM offers promising cytoprotective effects for cartilage-related oxidative stress conditions. Full article

(This article belongs to the Special Issue The Role of Mesenchymal Stem Cells in Organ Repair and Tissue Regeneration)

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28 pages, 7062 KB

Open AccessArticle

Cervicovaginal Microbiome and HPV: A Standardized Approach to 16S/ITS NGS and Microbial Community Profiling for Viral Association

by Jane Shen-Gunther, Qingqing Xia, Hong Cai and Yufeng Wang

Int. J. Mol. Sci. 2025, 26(16), 8090; https://doi.org/10.3390/ijms26168090 - 21 Aug 2025

Viewed by 296

Abstract

16S rRNA next-generation sequencing (NGS) has significantly advanced cervicovaginal microbiome profiling, offering insights into the relationship between vaginal dysbiosis and HPV-associated carcinogenesis. However, reliance on a limited set of 16S hypervariable regions introduces inherent biases that impact results. This study developed standardized workflows [...] Read more.

16S rRNA next-generation sequencing (NGS) has significantly advanced cervicovaginal microbiome profiling, offering insights into the relationship between vaginal dysbiosis and HPV-associated carcinogenesis. However, reliance on a limited set of 16S hypervariable regions introduces inherent biases that impact results. This study developed standardized workflows for 16S/ITS NGS, with a focus on identifying methodological biases that influence microbial abundance and taxonomic specificity. Commercial NGS tools were employed, including the 16S/ITS QIAseq V1–V9 screening panel, ATCC vaginal microbial standard, and CLC Genomics Workbench integrated with a customized database (VAGIBIOTA) for analysis. The microbial communities of 66 cervical cytology samples were characterized. Among the regions tested, V3V4 exhibited the least quantitative bias, while V1V2 offered the highest specificity. Microbial profiles and Community State Types (CST) (I–V) were broadly consistent with prior studies, with Lactobacillus abundance clustering into three states: L.-dominant (CST I–III, V), L.-diminished (CST IV-A), and L.-depleted (CST IV-B). Differential abundance analysis revealed that anaerobic opportunistic pathogens dominant in CST IV-B (dysbiosis) were also enriched in HSIL and HPV-16 positive samples. Our findings revealed distinct differences in species identification across 16S rRNA hypervariable regions, emphasizing the importance of region selection in clarifying microbial contributions to HPV-associated carcinogenesis. Full article

(This article belongs to the Special Issue Recent Advances in Human Papillomavirus (HPV) Research)

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19 pages, 2307 KB

Open AccessArticle

SERS- and SEIRA-Based Characterization and Sensing of Highly Selective Bradykinin B2 Receptor Antagonists

by Edyta Proniewicz and Adam Prahl

Int. J. Mol. Sci. 2025, 26(16), 8089; https://doi.org/10.3390/ijms26168089 - 21 Aug 2025

Viewed by 217

Abstract

One of the major challenges in diagnosing various diseases, including neurological and neurodegenerative disorders, as well as carcinogenesis, is detecting unlabeled neurotransmitters. Surface-enhanced Raman spectroscopy (SERS) and surface-enhanced infrared spectroscopy (SEIRA) are promising methods for neurotransmitter biosensing and bioimaging. These methods are unique [...] Read more.

One of the major challenges in diagnosing various diseases, including neurological and neurodegenerative disorders, as well as carcinogenesis, is detecting unlabeled neurotransmitters. Surface-enhanced Raman spectroscopy (SERS) and surface-enhanced infrared spectroscopy (SEIRA) are promising methods for neurotransmitter biosensing and bioimaging. These methods are unique in that they are non-destructive and can identify molecular fingerprints. In this study, these methods were used to detect the following potent bradykinin (BK) antagonists: [D-Arg⁰,Hyp³,Thi⁵,D-Tic⁷,Oic⁸]BK, [D-Arg⁰,Hyp³,Thi⁵,D-Phe⁷,Thi⁸]BK, [D-Arg⁰,Hyp³,Igl⁵,D-Phe(5F)⁷,Oic⁸]BK, and [D-Arg⁰,Hyp³,Igl⁵,D-Igl⁷,Oic⁸]BK. The peptides were immobilized on a sensor surface consisting of silver (AgNPs) and gold (AuNPs) nanoparticles. These sensors have uniform particle sizes and small size distributions. Thanks to fast synthesis, easy handling, and reproducible results, these sensors enable routine testing. The vibrational structure of these peptides could not be determined using classical vibrational methods (Raman and IR) or surface-enhanced methods (SERS and SEIRA). This work presents the results of that research. Additionally, the SEIRA spectrum for BK or its analogs has not yet been published. This study presents research using SERS and SEIRA that shows that AgNP and AuNP sensors can detect the peptides under investigation. SERS is a more selective method than SEIRA because it allows for the differentiation of peptides based on the enhancement of certain bands in the SERS spectra. Furthermore, each peptide uniquely interacts with AuNPs, whereas all peptides bind to AgNPs via the C-terminus in different orientations. Consequently, the AuNP sensor is more selective than the AgNP sensor. Some bands were selected as markers for the sensing of specific peptides. Full article

(This article belongs to the Special Issue Nanoparticle-Based Biosensors and Their Applications)

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42 pages, 3184 KB

Open AccessReview

The β-1,4 GalT-V Interactome—Potential Therapeutic Targets and a Network of Pathways Driving Cancer and Cardiovascular and Inflammatory Diseases

by Subroto Chatterjee, Dhruv Kapila, Priya Dubey, Swathi Pasunooti, Sruthi Tatavarthi, Claire Park and Caitlyn Ramdat

Int. J. Mol. Sci. 2025, 26(16), 8088; https://doi.org/10.3390/ijms26168088 - 21 Aug 2025

Viewed by 385

Abstract

UDP-Gal-β-1,4 galactosyltransferase-V (GalT-V) is a member of a large family of galactosyltransferases whose function is to transfer galactose from the nucleotide sugar UDP-galactose to a glycosphingolipid glucosylceramide, to generate lactosylceramide (LacCer). It also causes the N and O glycosylation of proteins in the [...] Read more.

UDP-Gal-β-1,4 galactosyltransferase-V (GalT-V) is a member of a large family of galactosyltransferases whose function is to transfer galactose from the nucleotide sugar UDP-galactose to a glycosphingolipid glucosylceramide, to generate lactosylceramide (LacCer). It also causes the N and O glycosylation of proteins in the Trans Golgi area. LacCer is a bioactive lipid second messenger that activates an “oxidative stress pathway”, leading to critical phenotypes, e.g., cell proliferation, migration angiogenesis, autophagy, and apoptosis. It also activates an “inflammatory pathway” that contributes to the progression of disease pathology. β-1,4-GalT-V gene expression is regulated by the binding of the transcription factor Sp-1, one of the most O-GlcNAcylated nuclear factors. This review elaborates the role of the Sp-1/GalT-V axis in disease phenotypes and therapeutic approaches targeting not only Sp-1 but also Notch-1, Wnt-1 frizzled, hedgehog, and β-catenin. Recent evidence suggests that β-1,4GalT-V may glycosylate Notch-1 and, thus, regulate a VEGF-independent angiogenic pathway, promoting glioma-like stem cell differentiation into endothelial cells, thus contributing to angiogenesis. These findings have significant implications for cancer and cardiovascular disease, as tumor vascularization often resumes aggressively following anti-VEGF therapy. Moreover, LacCer can induce angiogenesis independent of VEGF and its level are reported to be high in tumor tissues. Thus, targeting both VEGF-dependent and VEGF-independent pathways may offer novel therapeutic strategies. This review also presents an up-to-date therapeutic approach targeting the β-1,4-GalT-V interactome. In summary, the β-1,4-GalT-V interactome orchestrates a broad network of signaling pathways essential for maintaining cellular homeostasis. Conversely, its dysregulation can promote unchecked proliferation, angiogenesis, and inflammation, contributing to the initiation and progression of multiple diseases. Environmental factors and smoking can influence β-1,4-GalT-V expression and its interactome, whereas elevated β-1,4-GalT-V expression may serve as a diagnostic biomarker of colorectal cancer, inflammation—exacerbated by factors that may worsen pre-existing cancer malignancies, such as smoking and a Western diet—and atherosclerosis, amplifying disease progression. Increased β-1,4-GalT-V expression is frequently associated with tumor aggressiveness and chronic inflammation, underscoring its potential as both a biomarker and therapeutic target in colorectal and other β-1,4-GalT-V-driven cancers, as well as in cardiovascular and inflammatory diseases. Full article

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

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15 pages, 11641 KB

Open AccessArticle

Cell-Free DNA Based Next-Generation Sequencing Does Not Differentiate Between Oligoprogression and Systemic Progression in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors—An Explorative Study

by Pim Rozendal, Hanneke Kievit, Paul van der Leest, Idris Bahce, Michiel Pegtel, Harry J. M. Groen, Léon C. van Kempen, T. Jeroen N. Hiltermann and Ed Schuuring

Int. J. Mol. Sci. 2025, 26(16), 8087; https://doi.org/10.3390/ijms26168087 - 21 Aug 2025

Viewed by 276

Abstract

Immune checkpoint inhibitors (ICIs) are a key treatment for advanced non-small cell lung cancer (NSCLC), but most patients will ultimately experience disease progression due to acquired resistance to ICI. Clinically, it is relevant to differentiate between systemic progression (SP) and oligoprogression (OP). Following [...] Read more.

Immune checkpoint inhibitors (ICIs) are a key treatment for advanced non-small cell lung cancer (NSCLC), but most patients will ultimately experience disease progression due to acquired resistance to ICI. Clinically, it is relevant to differentiate between systemic progression (SP) and oligoprogression (OP). Following SP, ICI treatment is usually discontinued, while in OP, patients are preferably treated with local ablative treatment with continuation of the ICI treatment. However, with progressive disease, it remains difficult to differentiate between true OP or SP. Circulating tumor DNA (ctDNA) analysis provides an accurate real-time reflection of the tumor burden. It remains elusive if ctDNA abundance and/or dynamics can discriminate between OP and SP. Therefore, the aim of this exploratory cohort study is to evaluate whether the sequential molecular tumor profiling of ctDNA is suitable for discriminating between true OP and SP in advanced NSCLC. Patients with stage III/IV NSCLC showing progression after ≥3 months of ICI were included. OP was defined retrospectively by RECIST response ≥ 6 months after local treatment and continued ICIs. Serial plasma samples were analyzed using the AVENIO ctDNA Expanded NGS assay targeting 77 cancer-related genes. Twenty patients (6 OP, 14 SP) were included. Somatic alterations were detected in 16 patients (median 4 mutations). No significant differences in baseline ctDNA levels, changes at progression, or mutation patterns were observed between OP and SP. Although ctDNA levels generally decreased early after the start of ICI treatment, and were increased at disease progression, mutational profiles of the 77 genes using the AVENIO Expanded ctDNA panel did not distinguish OP from SP. Full article

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

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16 pages, 690 KB

Open AccessArticle

Upregulation of HOTTIP and Its Potential Role in Monitoring Exercise Adaptation

by Agnieszka Mołoń, Dominika Podgórska, Artur Płonka, Wojciech Bajorek, Wojciech Czarny, Paweł Król, Rafał Podgórski and Marek Cieśla

Int. J. Mol. Sci. 2025, 26(16), 8086; https://doi.org/10.3390/ijms26168086 - 21 Aug 2025

Viewed by 239

Abstract

Athletic performance is modulated by a complex interaction of physiological, environmental, and genetic factors, with regular exercise triggering molecular changes that influence gene expression and tissue adaptation. Despite growing knowledge, the underlying molecular mechanisms remain only partially understood, highlighting the need for precise [...] Read more.

Athletic performance is modulated by a complex interaction of physiological, environmental, and genetic factors, with regular exercise triggering molecular changes that influence gene expression and tissue adaptation. Despite growing knowledge, the underlying molecular mechanisms remain only partially understood, highlighting the need for precise biomarkers to monitor training-induced physiological adaptations. Long non-coding RNAs (lncRNAs) regulate cellular processes, including adaptation to physical exercise. Twelve healthy elite female volleyball players (mean age 27 ± 5.4 years) participated in the study. This study evaluated the expression of selected lncRNAs (SNHG4, SNHG5, PACERR, NEAT1, HIX003209, and HOTTIP) during a 10-week training program and evaluated their potential as biomarkers of training adaptation. Blood samples were collected before and after the training period. LncRNA expression was measured by quantitative polymerase chain reaction. HOTTIP exhibited an increase in expression after training (over sixfold change, p = 0.009, adjusted p = 0.024) and demonstrated high diagnostic accuracy (AUC = 0.917), which improved to 0.97 when combined with creatine kinase. Other lncRNAs showed no significant changes, although a correlation between HOTTIP and SNHG4 was noted. HOTTIP is markedly upregulated following chronic exercise and, especially when combined with creatine kinase, shows promise as a molecular biomarker for monitoring training adaptation in elite female volleyball players. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Influences on Personality Traits and Athletic Performance)

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20 pages, 3667 KB

Open AccessArticle

Formation of the Vasculogenic Mimicry Phenotype in Melanoma Mel Z Cells Is Coupled with Changes in Inter-Chromosomal Contacts of Developmental Genes with rDNA Clusters

by Nickolai A. Tchurikov, Elena S. Klushevskaya, Viktoriya N. Lukicheva, Antonina N. Kretova, Elizaveta N. Poperekova, Vladimir R. Chechetkin, Galina I. Kravatskaya, Amalia A. Vartanian, Vyacheslav S. Kosorukov, Ildar R. Alembekov and Yuri V. Kravatsky

Int. J. Mol. Sci. 2025, 26(16), 8085; https://doi.org/10.3390/ijms26168085 - 21 Aug 2025

Viewed by 262

Abstract

Upon transferal from plastic to Matrigel, melanoma cells demonstrate growth in three dimensions and form de novo vascular networks—known as vasculogenic mimicry—that are characteristic of the stemness phenotype of aggressive tumors. It has been reported that during malignant transformation, stress, or differentiation, the [...] Read more.

Upon transferal from plastic to Matrigel, melanoma cells demonstrate growth in three dimensions and form de novo vascular networks—known as vasculogenic mimicry—that are characteristic of the stemness phenotype of aggressive tumors. It has been reported that during malignant transformation, stress, or differentiation, the long-range inter-chromosomal interactions between numerous developmental genes and nucleoli are changed. The aim of this work was to study the potential mechanisms behind the development of the vasculogenic mimicry phenotype in melanoma cells and whether the formation of these 3D structures is connected with the reorganization of inter-chromosomal contacts of rDNA clusters. Here, we show that after 15 h of growth on Matrigel, and following the formation of the vasculogenic mimicry phenotype, dramatic changes occur in Mel Z cells in rDNA contacts with different genomic regions that possess mainly developmental genes. Approximately 400 genes that retained stable contacts with nucleoli were co-expressed with different lincRNAs and were highly associated with H3K27me3 marks and simultaneously regulated by different transcription factors. These genes are involved in development and cell adhesion and may control the basic stage of differentiation. The genes that acquired or increased contacts with rDNA clusters during growth on Matrigel are associated with cell morphogenesis, cell junctions, and the cytoskeleton. Here, we present the first evidence that nucleoli may be involved in both the activation and repression of particular groups of developmental rDNA-contacting genes in melanoma cells forming the vasculogenic mimicry phenotype. We conclude that the inter-chromosomal interactions between developmental genes and rDNA clusters are dynamic, and that nucleoli play an important role in the development of vasculogenic mimicry and stemness phenotypes in aggressive tumor genes. Full article

(This article belongs to the Special Issue Molecular Diagnostics and Genomics of Tumors)

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21 pages, 4158 KB

Open AccessArticle

Insight into the Sporulation Physiology of Elkhorn Fern: Metabolic, Hormonal, and Pigment Changes Within a Single Leaf of Platycerium bifurcatum

by Jakub Oliwa, Iwona Stawoska, Violetta Katarzyna Macioszek, Michał Dziurka, Magdalena Rys, Diana Saja-Garbarz, Anna Maksymowicz, Andrzej Kornaś and Andrzej Skoczowski

Int. J. Mol. Sci. 2025, 26(16), 8084; https://doi.org/10.3390/ijms26168084 - 21 Aug 2025

Viewed by 281

Abstract

Platycerium bifurcatum is one of the most widely cultivated ornamental fern species worldwide and a valuable component of the biodiversity of pantropical forests. In addition to its photosynthetic function, the sporotrophophyll leaves of this species periodically develop a large, clearly demarcated sporangium at [...] Read more.

Platycerium bifurcatum is one of the most widely cultivated ornamental fern species worldwide and a valuable component of the biodiversity of pantropical forests. In addition to its photosynthetic function, the sporotrophophyll leaves of this species periodically develop a large, clearly demarcated sporangium at the leaf tips, enabling physiological and biochemical measurements both in the active sporulation part and in the non-sporulating leaf area. The aim of this study was to assess anatomical changes, determine thermal effects and the content of selected phytohormones, and analyze the spatial distribution of pigments in the sporophilic and trophophylic part of the same leaf during spore formation. The study utilized fluorescence microscopy, isothermal microcalorimetry, Raman mapping, and ultra-high-performance liquid chromatography coupled with a Triple Quad LC/MS analyzer. The results revealed significant physiological differences between the sporulating and non-sporulating leaf areas. For the first time, differences in thermogenesis within the two leaf regions accompanying sporulation and linked to the sporangium development stage have been demonstrated in ferns. Increases in gibberellins (GA3, GA4, and GA6), auxin (indole-3-butyric acid), (±)-cis, trans-abscisic acid, and abscisic acid glucose ester were observed in the sporophilic part of the leaf, as well as fluctuations in phytohormones in the trophophilic part, indicating internal metabolite relocation within the leaf. Raman analysis and 2D mapping revealed local lignin accumulation and fluctuations in carotenoid levels during spore maturation. The results of this study demonstrate physiological variation within a single leaf and the mechanisms accompanying sporulation, which provide a better understanding of fern adaptive strategies. Full article

(This article belongs to the Special Issue Plant Hormone Signaling)

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12 pages, 424 KB

Open AccessArticle

CACNA1A Genetic Variants and Their Potential Involvement in Migraine Pathogenesis

by Oliwia Szymanowicz, Bartosz Słowikowski, Joanna Poszwa, Ulyana Goutor, Małgorzata Wiszniewska, Paweł P. Jagodziński, Wojciech Kozubski and Jolanta Dorszewska

Int. J. Mol. Sci. 2025, 26(16), 8083; https://doi.org/10.3390/ijms26168083 - 21 Aug 2025

Viewed by 226

Abstract

Migraine is a prevalent neurological disorder that affects over 1 billion individuals worldwide. The pathogenesis of migraine remains incompletely understood, though evidence suggests a multifactorial etiology involving genetic factors. The CACNA1A gene has been implicated in rare forms of Familial Hemiplegic Migraine (FHM). [...] Read more.

Migraine is a prevalent neurological disorder that affects over 1 billion individuals worldwide. The pathogenesis of migraine remains incompletely understood, though evidence suggests a multifactorial etiology involving genetic factors. The CACNA1A gene has been implicated in rare forms of Familial Hemiplegic Migraine (FHM). This study aimed to investigate the role of CACNA1A variants in individuals with and without a family history of migraine. We genotyped 150 subjects (100 migraine patients: 50 with migraine without aura (MO), 50 with migraine with aura (MA) and 50 controls) for six CACNA1A variants using Sanger sequencing. Statistical analyses were performed in Statistica (p < 0.05). The CADD v1.7 model was used to assess the potential pathogenicity of novel variants. Three variants described in databases (rs10405121, rs894252513, and rs1012663275) and three novel variants (ch19:13228374 G > C, ch19:13228428 G > C, and ch19:13228348 A > T) were identified. The rs10405121 variant was associated with both migraine types, with the homozygous AA genotype exclusively found in familial cases. Abnormal genotype of rs894252513 and rs1012663275 were detected only in familial cases with MO. The novel variants were observed exclusively in patients with a family history of migraine, suggesting their potential relevance to inherited migraine pathogenesis. Novel variants may contribute to migraine pathogenesis by altering calcium channel function and lowering the threshold for cortical spreading depression (CSD). Full article

(This article belongs to the Special Issue Molecular Diagnosis and Treatment of Migraine)

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17 pages, 860 KB

Open AccessReview

Neurophysiological Basis of Short-Chain Fatty Acid Action in Pain Modulation: Therapeutic Implications

by Mamoru Takeda, Yukito Sashide and Syogo Utugi

Int. J. Mol. Sci. 2025, 26(16), 8082; https://doi.org/10.3390/ijms26168082 - 21 Aug 2025

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Abstract

The gut microbiota influences both energy metabolism and central nervous system (CNS) functions. This influence is mediated by humoral factors, including various metabolites, neurotransmitters, cytokines, and hormones, in addition to neural pathways such as the vagus nerve. Notably, short-chain fatty acids (SCFAs)—comprising acetic, [...] Read more.

The gut microbiota influences both energy metabolism and central nervous system (CNS) functions. This influence is mediated by humoral factors, including various metabolites, neurotransmitters, cytokines, and hormones, in addition to neural pathways such as the vagus nerve. Notably, short-chain fatty acids (SCFAs)—comprising acetic, propionic, and butyric acids—merit specific attention. These compounds originate from the anaerobic fermentation of dietary fibers by the gut microbiota. Growing evidence indicates that SCFAs confer beneficial effects on diverse pain conditions. Although previous review articles have summarized animal studies suggesting the possibility that SCFAs can alleviate pathological pain, there are few reviews on the neurophysiological mechanisms by which SCFAs modulate the excitability of nociceptive neurons in the pain pathway under nociceptive and pathological conditions. Extending previous in vitro findings, our laboratory recently conducted in vivo neurophysiological studies using animal models to explore the pain-relieving properties of SCFAs. Our published results demonstrate two significant effects: (i) an intravenous anesthetic action against nociceptive pain and (ii) an anti-inflammatory contribution to chronic pain alleviation. This review synthesizes the current understanding of the mechanisms by which SCFAs modulate pain and explores their contribution to the attenuation of nociceptive and/or pathological pain. Furthermore, we discuss their prospective clinical application Full article

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

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Int. J. Mol. Sci., Volume 26, Issue 16 (August-2 2025) – 451 articles

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