Current Issues in Molecular Biology

23 pages, 1140 KiB

Open AccessReview

Hypersensitivity to Folic Acid and/or Folinic Acid—A Review of Clinical Cases, Potential Mechanism, Possible Cross-Allergies and Current Diagnostic Options

by Kinga Lis

Curr. Issues Mol. Biol. 2025, 47(8), 654; https://doi.org/10.3390/cimb47080654 (registering DOI) - 14 Aug 2025

Abstract

Folic acid and its derivatives (e.g., folinic acid) are a group of water-soluble compounds collectively known as vitamin B9. Synthetic folic acid is a component of dietary supplements, medications and other pharmaceuticals and fortified foods. Folinic acid (5-formyltetrahydrofolic acid) is the active metabolite [...] Read more.

Folic acid and its derivatives (e.g., folinic acid) are a group of water-soluble compounds collectively known as vitamin B9. Synthetic folic acid is a component of dietary supplements, medications and other pharmaceuticals and fortified foods. Folinic acid (5-formyltetrahydrofolic acid) is the active metabolite of folic acid. It is used to treat vitamin B9 deficiency and as an adjunct to various combination therapies. Hypersensitivity reactions to folic acid or folinic acid are rare and occur following exposure to synthetic folic acid or its derivatives but not on natural folates. In people allergic to folates, cross-reactions are possible following exposure to folic acid analogues (including antifolates, e.g., methotrexate). The mechanism of hypersensitivity to folic acid and/or folinic acid has not been clearly established. Both IgE-dependent and non-IgE-dependent hypersensitivity reactions are likely. It is possible that folic or folinic acid is either an immunogen or a hapten. Diagnosing hypersensitivity to folic/folinic acid is difficult. There are no validated in vitro or in vivo diagnostic tests. The basophil activation test (BAT) appears to be a promising tool for diagnosing folate allergy. The aims of the manuscript were to review published clinical cases of hypersensitivity reactions to folic or folinic acid, potential mechanisms of these reactions and possible cross-allergies, and current diagnostic possibilities of folate hypersensitivity. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Regulation in Allergy and Immune Diseases, Immunodeficiencies, 2nd Edition)

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27 pages, 1370 KiB

Open AccessReview

Immune Organoids: A Review of Their Applications in Cancer and Autoimmune Disease Immunotherapy

by David B. Olawade, Emmanuel O. Oisakede, Eghosasere Egbon, Saak V. Ovsepian and Stergios Boussios

Curr. Issues Mol. Biol. 2025, 47(8), 653; https://doi.org/10.3390/cimb47080653 - 13 Aug 2025

Abstract

Immune organoids have emerged as a ground-breaking platform in immunology, offering a physiologically relevant and controllable environment to model human immune responses and evaluate immunotherapeutic strategies. Derived from stem cells or primary tissues, these three-dimensional constructs recapitulate key aspects of lymphoid tissue architecture, [...] Read more.

Immune organoids have emerged as a ground-breaking platform in immunology, offering a physiologically relevant and controllable environment to model human immune responses and evaluate immunotherapeutic strategies. Derived from stem cells or primary tissues, these three-dimensional constructs recapitulate key aspects of lymphoid tissue architecture, cellular diversity, and functional dynamics, providing a more accurate alternative to traditional two-dimensional cultures and animal models. Their ability to mimic complex immune microenvironments has positioned immune organoids at the forefront of cancer immunotherapy development, autoimmune disease modeling, and personalized medicine. This narrative review highlights the advances in immune organoid technology, with a focus on their applications in testing immunotherapies, such as checkpoint inhibitors, CAR-T cells, and cancer vaccines. It also explores how immune organoids facilitate the study of autoimmune disease pathogenesis with insights into their molecular basis and support in high-throughput drug screening. Despite their transformative potential, immune organoids face significant challenges, including the replication of systemic immune interactions, standardization of fabrication protocols, scalability limitations, biological heterogeneity, and the absence of vascularization, which restricts organoid size and maturation. Future directions emphasize the integration of immune organoids with multi-organ systems to better replicate systemic physiology, the development of advanced biomaterials that closely mimic lymphoid extracellular matrices, the incorporation of artificial intelligence (AI) to optimize organoid production and data analysis, and the rigorous clinical validation of organoid-derived findings. Continued innovation and interdisciplinary collaboration will be essential to overcome existing barriers, enabling the widespread adoption of immune organoids as indispensable tools for advancing immunotherapy, vaccine development, and precision medicine. Full article

(This article belongs to the Section Molecular Medicine)

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24 pages, 11598 KiB

Open AccessArticle

Integrating Primary and Metastatic scRNA–Seq and Bulk Data to Develop an Immune–Based Prognosis Signature for Colorectal Cancer

by Kaiyuan Xing, Liangshuang Li, Yingnan Ma and Jiang Zhu

Curr. Issues Mol. Biol. 2025, 47(8), 652; https://doi.org/10.3390/cimb47080652 - 13 Aug 2025

Abstract

Colorectal cancer (CRC) is a highly aggressive cancer, with its treatment and prognosis particularly challenging due to metastasis. The immune response is involved in the whole process of CRC development, and immunotherapy has increasingly become a part of CRC patients’ treatment. However, comprehensive [...] Read more.

Colorectal cancer (CRC) is a highly aggressive cancer, with its treatment and prognosis particularly challenging due to metastasis. The immune response is involved in the whole process of CRC development, and immunotherapy has increasingly become a part of CRC patients’ treatment. However, comprehensive research on the immune microenvironment driving CRC metastasis remains limited. Given this limitation, we proposed a bioinformatics method to construct a metastasis–based immune prognostic model (MIPM) by integrating CRC single–cell RNA sequencing (scRNA–seq) and bulk data. Our study identified several MIPM genes significantly associated with CRC metastasis and progression. MIPM reliably predicted overall survival (OS) and tumor recurrence in CRC across eleven bulk validation datasets. Notably, MIPM could independently predict outcomes beyond traditional clinical factors such as age, sex, and stage. It showed high predictive accuracy in CRC patients treated with chemotherapy. Drug sensitivity and multifaceted immune analyses further underscored the importance of MIPM in therapeutic and immunotherapy response modulation. In conclusion, our findings have profound implications for the illustration of MIPM, which could serve as a new plausible prognostic marker for CRC patients and provide new insights for treatment strategies. The further evaluation and investigation of MIPM will enhance the prognosis and precision therapy of CRC patients. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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17 pages, 1885 KiB

Open AccessArticle

BCG Impact on PD-1/PD-L1 Expression in Peripheral Immunocytes of Cancer Patients—A Potential Explanation for Its Activity in Preventing Alzheimer’s Disease

by Benjamin Y. Klein, Ofer N. Gofrit and Charles L. Greenblatt

Curr. Issues Mol. Biol. 2025, 47(8), 651; https://doi.org/10.3390/cimb47080651 - 13 Aug 2025

Abstract

We found, retrospectively, that BCG therapy in non-muscle invasive bladder cancer (NMIBC) reduces the rate of Alzheimer’s disease. Blockade of the ligand PD-L1 or its checkpoint receptor PD-1 has been shown to improve cognitive function and reduce brain pathology features in a mouse [...] Read more.

We found, retrospectively, that BCG therapy in non-muscle invasive bladder cancer (NMIBC) reduces the rate of Alzheimer’s disease. Blockade of the ligand PD-L1 or its checkpoint receptor PD-1 has been shown to improve cognitive function and reduce brain pathology features in a mouse model of Alzheimer’s disease (AD). Given that peripheral blood mononuclear cells (PBMCs) are involved in aging brain pathology and thus represent a potential AD therapeutic target, we analyzed the impact of BCG on the expression of PD-1, PD-L1, and inflammation modulators in PBMCs. Cryopreserved PBMCs pre- and post-BCG-treated six melanoma and six NMIBC patients were repurposed for immunoelectrophoretic analysis of PBMC-extracted proteins. PBMCs, post-BCG treatment in melanoma patients, were harvested only 4 months after the start of treatment (short BCG period), whereas the PBMCs of NMIBC patients were harvested 24 to 52 months after starting the BCG treatment. In melanoma PBMCs, BCG upregulated PD-L1 (p = 0.052) while downregulating PD-1 (insignificantly, p = 0.16). In contrast, in NMIBC patients, BCG downregulated PD-L1 (insignificantly, p = 0.67), while upregulating PD-1 (p = 0.0082). PD-L1 positive correlation with p-IkB (r = 0.7228) under BCG is inverted to that of PD-L1 against IkB (p = −0.9491). The difference between these opposite correlations is significant (p = 0.011), indicating that PD-L1 is upregulated early after BCG treatment, in association with p-IKB, which enables inflammation. This association subsided later, and for PD-1, did not occur at the short or long BCG periods. Experiments with a larger number of patients may substantiate the hypothesis that an increase in PD-1 by BCG relative to PD-L1 may protect against AD. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology Insights into Neurodegenerative Diseases: From Pathogenesis to Therapeutic Targets)

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17 pages, 2011 KiB

Open AccessReview

A Narrative Review of Heavy Metals and Sperm Quality: The Interplay with Antioxidant Imbalance and Reactive Oxygen Species

by Soukaina Azil, Khaoula Errafii, Moncef Benkhalifa, Noureddine Louanjli, Bouchra Ghazi and Salsabil Hamdi

Curr. Issues Mol. Biol. 2025, 47(8), 650; https://doi.org/10.3390/cimb47080650 - 13 Aug 2025

Abstract

Reproductive infertility is characterized by the inability to achieve pregnancy after a year or more of unprotected sexual intercourse. This review highlights the significant impact of exposure to both types of heavy metals (essential and non-essential) on the reproductive performance of various species, [...] Read more.

Reproductive infertility is characterized by the inability to achieve pregnancy after a year or more of unprotected sexual intercourse. This review highlights the significant impact of exposure to both types of heavy metals (essential and non-essential) on the reproductive performance of various species, particularly humans. Heavy metals present a high atomic density and weight, including lead, mercury, cadmium, nickel, chromium, and arsenic, and are delivered into the environment through natural and human activities, posing a threat to ecological systems and human reproductive health. These heavy metals have the potential for bioaccumulation and can adversely affect male fertility and sperm quality due to their role in disrupting endocrine functions, altering hormone levels responsible for sperm production, and inducing oxidative stress. The elevated production of reactive oxygen species (ROS) exceeds the capability of antioxidants and can lead to the alteration of sperm quality. Seminal fluid contains antioxidants like vitamin C, vitamin E, zinc, and selenium to counteract the impacts of ROS and also to preserve the sperm function. This review aims also to explore the impact of heavy metals on sperm quality and their relationship with antioxidant imbalance and ROS. The exposure to heavy metals whether through occupational or environmental means increases the production of ROS and therefore leads to an imbalance of antioxidants production. All these factors have no doubt an impact on male reproductive health. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)

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21 pages, 3063 KiB

Open AccessArticle

Evaluation of the Safety and Antiproliferative Activity of Bulgarian Rose Essential Oil: An In Vitro and In Silico Model of Colorectal Adenocarcinoma

by Rayna Nenova, Kalin Kalinov, Deyana Nedeva, Ana Dobreva, Neli Vilhelmova-Ilieva, Ani Georgieva and Ivan Iliev

Curr. Issues Mol. Biol. 2025, 47(8), 649; https://doi.org/10.3390/cimb47080649 - 13 Aug 2025

Abstract

The side effects of conventional cancer treatments, such as chemotherapy, radiotherapy, etc., worsen the quality of life of patients. Therefore, it is necessary to explore the possibilities of creating new drugs containing natural products with low toxicity. The experimental scientific pharmacological research of [...] Read more.

The side effects of conventional cancer treatments, such as chemotherapy, radiotherapy, etc., worsen the quality of life of patients. Therefore, it is necessary to explore the possibilities of creating new drugs containing natural products with low toxicity. The experimental scientific pharmacological research of rose preparations in Bulgaria began in the first half of the 20th century. Bulgarian rose essential oil (BREO) is qualified by GC FID analysis. To study the effect of the BREO, we used HCT-8 and HT-29 tumor cell lines. As a model of healthy tissue, we used the non-tumorigenic cells MCF-12F. Cells were treated with twofold increasing concentrations of BREO from 7.5 µg/mL to 1000 µg/mL. The NRU test and MTT assay were used for evaluation of the safety, antiproliferative activity and colony formation assay. Our results showed low cytotoxicity (CC₅₀ = 629.72 ± 22.38 μg/mL) and high level of photosafety (PIF = 0.92) of BREO. The antiproliferative activity test shows that the BREO has an IC₅₀ = 290.45 ± 10.79 μg/mL for the HT-29 cells. In the normal cell line MCF-12F, this effect is lower (IC₅₀ = 383.90 ± 34.75 μg/mL). Furthermore, colony forming assay showed a significant reduction in IC₅₀ value (IC₅₀ = 163.79 ± 10.25 μg/mL) in HT-29 cells. The in silico experiments confirmed the potential of the BREO for antiproliferative effect and further activation of different pathways leading to apoptosis. Full article

(This article belongs to the Special Issue The Green Revolution in Cancer Research: Bioactive Substances from Plants as Promising Therapeutics)

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17 pages, 1715 KiB

Open AccessArticle

Biochemical Changes in Prostate Cancer: FMNL1 and PAK1 in Plasma and Urine

by Elif Bilgin Doğru, Selçuk Erdem, Hilal Oğuz Soydinç, Ayça İribaş and Derya Duranyıldız

Curr. Issues Mol. Biol. 2025, 47(8), 648; https://doi.org/10.3390/cimb47080648 - 13 Aug 2025

Abstract

Prostate cancer is a clinically heterogeneous disease. Since PSA is not cancer-specific, and due to the bone metastases seen in the advanced stage and bone deformations caused by hormone therapy, it is necessary to use new biomarkers. Formin-like-protein 1 (FMNL1), a member of [...] Read more.

Prostate cancer is a clinically heterogeneous disease. Since PSA is not cancer-specific, and due to the bone metastases seen in the advanced stage and bone deformations caused by hormone therapy, it is necessary to use new biomarkers. Formin-like-protein 1 (FMNL1), a member of the formin protein family, is of great importance in actin polymerization, cell attachment, and migration processes. p21-activated kinase 1 (PAK1) proteins, members of the PAK protein kinases, play a role in cytoskeletal organization, as well as regulating other cellular activities such as cell survival, mitosis, and transcription. In our study, plasma and urine samples of 60 prostate cancer patients and 20 healthy controls were studied using RT-PCR and ELISA methods. No statistical difference was found between FMNL1 mRNA and protein expression levels of patients and controls in both plasma and urine samples (p > 0.05). There was no statistical difference between PAK1 mRNA expression levels of patients and controls in plasma and urine samples (p > 0.05). While no significant difference was found in PAK1 protein levels in plasma samples (p > 0.05), it was found to be lower in urine samples of patients compared to the control group (p = 0.00). Both marker molecules have low expression levels in early-stage PCa. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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21 pages, 1316 KiB

Open AccessReview

Can Salivary Biomarkers Serve as Diagnostic and Prognostic Tools for Early Detection in Patients with Colorectal Cancer? A Systematic Review

by Stanisław Krokosz, Maria Obrycka and Anna Zalewska

Curr. Issues Mol. Biol. 2025, 47(8), 647; https://doi.org/10.3390/cimb47080647 - 12 Aug 2025

Abstract

Colorectal cancer (CRC) stands as one of the most prevalent and lethal forms of cancer worldwide with early detection playing a crucial role in improving the survival rate. Salivary biomarkers have emerged as a promising non-invasive alternative for CRC early detection. A comprehensive [...] Read more.

Colorectal cancer (CRC) stands as one of the most prevalent and lethal forms of cancer worldwide with early detection playing a crucial role in improving the survival rate. Salivary biomarkers have emerged as a promising non-invasive alternative for CRC early detection. A comprehensive search of the Web of Science, Scopus, and PubMed databases was performed to identify relevant studies published between 2018 and April 2025. Inclusion criteria focused on studies analyzing salivary biomarkers in adult CRC patients, while pediatric studies, non-diagnostic applications, and studies with insufficient statistical power were excluded. A total of 12 studies were included in this review, identifying various salivary biomarkers associated with CRC. Salivary microbiota, including Fusobacterium nucleatum and other bacterial species, demonstrated potential as diagnostic markers. Metabolomic profiling revealed elevated levels of lactate and pyruvate, reflecting metabolic alterations in CRC. Several microRNAs, such as miR-92a and miR-29a, exhibited high sensitivity and specificity for CRC detection. Additionally, protein-based biomarkers, including chemerin and sHLA-G, were found to be significantly elevated in CRC patients. Salivary biomarkers show great promise as a non-invasive, cost-effective approach for CRC detection and prognosis. Their ability to reflect systemic disease processes makes them a valuable complement to existing screening methods. Full article

(This article belongs to the Section Molecular Medicine)

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12 pages, 2441 KiB

Open AccessArticle

Linolenic Acid Inhibits Cancer Stemness and Induces Apoptosis by Regulating Nrf2 Expression in Gastric Cancer Cells

by Jen-Lung Chen, Yi-Shih Ma, Kuen-Jang Tsai, Hsin-Yi Tsai, Li-Jen Yeh, Hung-Wen Tsai, Judy Yen, Hong-Wen Tsai and Ming-Wei Lin

Curr. Issues Mol. Biol. 2025, 47(8), 646; https://doi.org/10.3390/cimb47080646 - 12 Aug 2025

Abstract

Although chemotherapy is the preferred treatment for gastric cancer, the therapeutic drugs currently available have limited efficacy and severe side effects. Cancer stem cells within tumor masses have the distinctive properties of self-renewal, maintenance, and resistance to chemotherapy. Hence, agents capable of targeting [...] Read more.

Although chemotherapy is the preferred treatment for gastric cancer, the therapeutic drugs currently available have limited efficacy and severe side effects. Cancer stem cells within tumor masses have the distinctive properties of self-renewal, maintenance, and resistance to chemotherapy. Hence, agents capable of targeting stemness in gastric tumors with minimal side effects are urgently required. Enzymes that generate reactive oxygen species contribute to the high oxidation levels observed in tumors. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidant transcription factor, regulates cancer stemness. Increasing evidence highlights the potential of nutritional supplementation to treat cancer stemness. ω-3 polyunsaturated fatty acids support human health and offer benefits for cancer treatment. Linolenic acid (LA), an ω-3 polyunsaturated fatty acid, inhibits the expression of proteins associated with stemness and promotes apoptosis in gastric cancer cells. Our findings indicated that LA treatment substantially inhibited key characteristics of gastric cancer stemness and induced oxidative stress and caspase-3-mediated apoptosis by downregulating Nrf2-mediated expression. These results suggest that LA is a promising nutritional supplement for targeting cancer stemness in the treatment of gastric cancer. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 3rd Edition)

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14 pages, 4774 KiB

Open AccessReview

Biochemical Battle: Influence of Omega-6 Fatty Acids on the Formation of DNA Adducts with 4-HNE

by Edyta Błaszczyk and Bolesław T. Karwowski

Curr. Issues Mol. Biol. 2025, 47(8), 645; https://doi.org/10.3390/cimb47080645 - 12 Aug 2025

Abstract

While omega-6 fatty acids play an important role in normal cell function, their excess in the diet is associated with an increased risk of developing diseases such as obesity, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and Alzheimer’s disease. Furthermore, excessive [...] Read more.

While omega-6 fatty acids play an important role in normal cell function, their excess in the diet is associated with an increased risk of developing diseases such as obesity, non-alcoholic fatty liver disease (NAFLD), inflammatory bowel disease (IBD) and Alzheimer’s disease. Furthermore, excessive intake has been shown to lead to chronic inflammation, which is related to increased production of reactive oxygen species (ROS). This conditioncan initiate lipid peroxidation in cell membranes, leading to the degradation of their fatty acids. One of the main products of omega-6 peroxidation is the α,β-unsaturated aldehyde, i.e., 4-hydroxynonenal (4-HNE), which is able to form four diastereoisomeric adducts with guanine. These 4-HNE adducts have been identified in the DNA of humans and rodents. Depending on their stereochemistry, they are able to influence double helix stability and cause DNA–DNA or DNA–Protein cross-links. Moreover, studies have shown that 4-HNE adducts formed in the human genome are considered mutation hotspots in hepatocellular carcinoma. Although the cell possesses defence mechanisms, without a well-balanced diet allowing correct cell function, they may not be sufficient to protect the genetic code. This review provides an overview of the molecular mechanisms underlying oxidative stress, lipid peroxidation, and the formation of DNA adducts. Particular emphasis is placed on the role of an omega-6-rich diet in inflammatory diseases, and on the formation of 4-HNE, which is a major product of lipid peroxidation, and its broader implications for genome stability, ageing, and disease progression. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2025)

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16 pages, 8770 KiB

Open AccessArticle

Integrated Transcriptomic and Metabolomic Analyses Shed Light on the Regulation of Aromatic Amino Acid Biosynthesis in a Novel Albino Tea (Camellia sinensis) Mutation

by Ying Gao, Suimei Li, Xiaojia Zhang, Shuwei Yu, Xinyu Liu, Changbo Yuan, Yuantao Yao, Fan’an Zhang and Lubin Song

Curr. Issues Mol. Biol. 2025, 47(8), 644; https://doi.org/10.3390/cimb47080644 - 12 Aug 2025

Abstract

Off-white or yellowish shoots are common in tea plants (Camellia sinensis L.), and such albino variations are often accompanied by metabolic reprogramming, including increased contents of amino acids and lower levels of polyphenols. Nonetheless, the molecular mechanisms that underlie these albino variations [...] Read more.

Off-white or yellowish shoots are common in tea plants (Camellia sinensis L.), and such albino variations are often accompanied by metabolic reprogramming, including increased contents of amino acids and lower levels of polyphenols. Nonetheless, the molecular mechanisms that underlie these albino variations remain to be fully clarified. Here, we examined the ultrastructural characteristics of novel, naturally occurring, yellowish mutated tea leaves and performed metabolomic analyses on green and albino leaves and stems. Then, transcriptomic analyses were also conducted on green and albino leaves to investigate the mechanistic basis of the albino variation. As expected, the cells of albino tea leaves contained fewer and smaller chloroplasts with disorganized thylakoids and smaller starch granules. Widely targeted metabolomics analysis revealed 561 differentially abundant metabolites between green and albino leaves and stems, but there was little difference between green and albino stems. Then, RNA sequencing of green and albino leaves revealed downregulation of genes associated with light harvesting and photosynthesis, and integration of the metabolomic and transcriptomic results indicated that biosynthesis of aromatic amino acids (AAAs) was strongly upregulated in albino leaves. To gain additional insight into the molecular basis of the increased AAA levels, Oxford Nanopore long-read sequencing was performed on green and albino leaves, which enabled us to identify differences in long non-coding RNAs (lncRNAs) and alternatively spliced transcripts between green and albino leaves. Interestingly, the amino acid biosynthesis genes arogenate dehydratase/prephenate dehydratase (ADT) and serine hydroxymethyltransferase (SHMT) were highlighted in the lncRNA and alternative splicing analyses, and the transcription factor genes PLATZ, B3 Os04g0386900, and LRR RLK At1g56140 showed significant changes in both expression and alternative splicing in albino leaves. Together, our data suggest that biosynthesis of AAAs might be crucial for albino mutations in tea plants and could be coordinated with the regulation of lncRNAs and alternative splicing. This is a complex regulatory network, and further exploration of the extensive metabolic reprogramming of albino tea leaves will be beneficial. Full article

(This article belongs to the Special Issue Genetics and Natural Bioactive Components in Beverage Plants)

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29 pages, 12966 KiB

Open AccessArticle

Integrative Analysis of Differentially Expressed miRNAs and Noncoding RNA Networks Reveals Molecular Mechanisms Underlying Metritis in Postpartum Dairy Cows

by Ramanathan Kasimanickam, Joao Ferreira and Vanmathy Kasimanickam

Curr. Issues Mol. Biol. 2025, 47(8), 643; https://doi.org/10.3390/cimb47080643 - 11 Aug 2025

Abstract

Postpartum metritis in dairy cows compromises reproductive performance and leads to substantial economic losses. This study investigated the molecular mechanisms underlying metritis by integrating high-throughput circulating microRNA (miRNA) profiling with systems-level bioinformatics. Previously, 30 differentially expressed miRNAs, 16 upregulated and 14 downregulated, were [...] Read more.

Postpartum metritis in dairy cows compromises reproductive performance and leads to substantial economic losses. This study investigated the molecular mechanisms underlying metritis by integrating high-throughput circulating microRNA (miRNA) profiling with systems-level bioinformatics. Previously, 30 differentially expressed miRNAs, 16 upregulated and 14 downregulated, were identified in metritis-affected cows compared to healthy controls. Building on these findings, this study predicted miRNA target genes and constructed regulatory networks involving miRNAs, mRNAs, circRNAs, lncRNAs, and snRNAs, alongside protein–protein interaction networks. Functional annotation and KEGG pathway analysis revealed that upregulated miRNAs influenced genes involved in immune activation, apoptosis, and metabolism, while downregulated miRNAs were associated with angiogenesis, immune suppression, and tissue repair. Hub genes such as AKT3, VEGFA, and HIF1A were central to immune and angiogenic signaling, whereas UBE3A and ZEB1 were linked to immune inhibition. Interferon-stimulated genes (e.g., ISG15, RSAD2, CXCL chemokines) were shown to regulate solute carriers, contributing to immune dysregulation. Key pathways included PI3K-Akt, NF-κB, JAK-STAT, insulin resistance, and T cell receptor signaling. Noncoding RNAs such as NEAT1, KCNQ1OT1, and XIST, along with miRNAs like bta-miR-15b and bta-miR-148a, emerged as pro-inflammatory regulators, while bta-miR-199a-3p appeared to exert immunosuppressive effects. These findings offer new insights into the complex regulatory networks driving metritis and suggest potential targets for improving fertility in dairy cows. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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16 pages, 2155 KiB

Open AccessArticle

Molecular Insights into Tumor Immunogenicity

by Irini Doytchinova, Stanislav Sotirov and Ivan Dimitrov

Curr. Issues Mol. Biol. 2025, 47(8), 641; https://doi.org/10.3390/cimb47080641 - 11 Aug 2025

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Abstract

Tumor immunogenicity depends on the ability of peptides to form stable and specific interactions with both HLA molecules and T-cell receptors (TCRs). While HLA binding is essential, not all HLA-binding peptides elicit T-cell responses. This study investigates the molecular features distinguishing immunogenic T-cell [...] Read more.

Tumor immunogenicity depends on the ability of peptides to form stable and specific interactions with both HLA molecules and T-cell receptors (TCRs). While HLA binding is essential, not all HLA-binding peptides elicit T-cell responses. This study investigates the molecular features distinguishing immunogenic T-cell epitopes from non-immunogenic HLA binders. Two datasets of nonamer peptides—38 T-cell epitopes and 144 non-epitopes—were compiled and analyzed using sequence logo models and molecular dynamics (MD) simulations of TCR–peptide–HLA complexes. A comparative logo analysis revealed strong amino acid preferences at central positions (p4–p8) in T-cell epitopes and absences in non-epitopes. A representative epitope–non-epitope pair was selected for structural modeling and 100 ns MD simulations. The T-cell epitope formed a more stable complex with the TCR and exhibited greater flexibility, supporting an induced-fit recognition mechanism. It also established a broader and longer-lasting network of hydrogen bonds and π interactions across the residues at positions p4–p8. In contrast, the non-epitope engaged TCR at only two positions. These findings highlight the critical role of the peptide’s central region in TCR engagement and provide structural insights useful for neoantigen prediction, vaccine design, and TCR-based immunotherapies. Full article

(This article belongs to the Special Issue Molecular Biology in Drug Design and Precision Therapy)

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14 pages, 1050 KiB

Open AccessArticle

Harringtonine Attenuates Extracellular Matrix Degradation, Skin Barrier Dysfunction, and Inflammation in an In Vitro Skin Aging Model

by Sullim Lee and Sanghyun Lee

Curr. Issues Mol. Biol. 2025, 47(8), 642; https://doi.org/10.3390/cimb47080642 - 10 Aug 2025

Viewed by 120

Abstract

With the growing interest in natural strategies for preventing skin aging, plant-derived compounds are being actively investigated for their potential protective effects against skin inflammation and extracellular matrix (ECM) degradation. In this study, we explored the anti-aging and anti-inflammatory effects of harringtonine, an [...] Read more.

With the growing interest in natural strategies for preventing skin aging, plant-derived compounds are being actively investigated for their potential protective effects against skin inflammation and extracellular matrix (ECM) degradation. In this study, we explored the anti-aging and anti-inflammatory effects of harringtonine, an alkaloid isolated from Cephalotaxus harringtonia, in normal human epidermal keratinocytes (NHEKs) under inflammatory stress induced by tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Harringtonine significantly suppressed the expression of matrix metalloproteinases (MMP)-1, MMP-2, and MMP-9 and restored the expression of collagen synthesis-related genes [collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), and collagen type IV alpha 1 chain COL4A1)], indicating its protective role in ECM degradation. Additionally, harringtonine improved the expression of skin barrier-related genes, such as serine peptidase inhibitor kazal type 5 (SPINK5), loricrin (LOR), quaporin-3 (AQP3), filaggrin (FLG), and keratin 1 (KRT1) although it had no significant effect on involucrin (IVL). Harringtonine also markedly reduced the production of pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, and IL-8] and inflammatory mediators, including prostaglandin E₂ (PGE₂), cyclooxygenase-2 (COX-2), and nitric oxide (NO). Our findings suggest that harringtonine may serve as a promising natural compound for mitigating skin aging and inflammation through multi-targeted modulation of ECM remodeling, skin barrier function, and inflammatory response. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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12 pages, 419 KiB

Open AccessArticle

Serum Immunoglobulin Changes in Multiple Myeloma Patients Treated with CAR T-Cell Therapy

by Alexa Burger, Ulrike Bacher, Michele Hoffmann, Katja Seipel, Christof Schild, Inna Shaforostova and Thomas Pabst

Curr. Issues Mol. Biol. 2025, 47(8), 640; https://doi.org/10.3390/cimb47080640 - 9 Aug 2025

Viewed by 153

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for relapsed or refractory multiple myeloma (RRMM), with high response rates of 80–95%. Serum immunoglobulin changes have been observed throughout conventional multiple myeloma treatment, including after immunomodulatory drugs, proteasome inhibitors, and [...] Read more.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for relapsed or refractory multiple myeloma (RRMM), with high response rates of 80–95%. Serum immunoglobulin changes have been observed throughout conventional multiple myeloma treatment, including after immunomodulatory drugs, proteasome inhibitors, and autologous stem cell transplantation. However, the clinical significance of new abnormal protein bands (APBs) following CAR T-cell therapy is largely unexplored. We retrospectively analyzed consecutive multiple myeloma (MM) patients who received CAR T-cell therapy at the University Hospital Bern between May 2021 and February 2024. Serum paraprotein (M-protein) patterns were assessed using immuno-fixation electrophoresis (IFE) before and after CAR T-cell treatment. Patients were grouped based on serum immunoglobulin changes. Among 46 patients, 9 (19.6%) developed new APBs following CAR T-cell therapy. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed between patients with and without APBs. Immunoglobulin changes occurred in both relapsed and non-relapsed patients, suggesting that the appearance of new APBs does not indicate disease progression. This observation aligns with previous reports of paraprotein changes following conventional MM therapies. This report suggests that new APBs following CAR T-cell therapy are a relatively common finding but do not correlate with inferior clinical outcomes. Our results highlight the need for larger, multi-center studies to further investigate this phenomenon in MM patients undergoing CAR T-cell therapy. Full article

(This article belongs to the Special Issue Multiple Myeloma: From Molecular Mechanism to Diagnosis and Therapy)

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21 pages, 2548 KiB

Open AccessArticle

Protective Effects of Inula japonica Leaf Extract Against PM₁₀-Induced Oxidative Stress in Human Keratinocytes

by Yea Jung Choi, So-Ri Son, Sullim Lee and Dae Sik Jang

Curr. Issues Mol. Biol. 2025, 47(8), 639; https://doi.org/10.3390/cimb47080639 - 9 Aug 2025

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Abstract

This study aimed to evaluate the protective effects of Inula japonica leaf extract against PM₁₀-induced oxidative stress in normal human keratinocytes. Keratinocytes were pretreated with various concentrations of Inula japonica leaf extract and subsequently exposed to PM10. Cell viability, ROS production, [...] Read more.

This study aimed to evaluate the protective effects of Inula japonica leaf extract against PM₁₀-induced oxidative stress in normal human keratinocytes. Keratinocytes were pretreated with various concentrations of Inula japonica leaf extract and subsequently exposed to PM10. Cell viability, ROS production, gene and protein expression (qRT-PCR and Western blot), and UHPLC-MS profiling were assessed. Network pharmacology analysis was conducted using database-predicted compounds of Inulae Flos. The extract significantly reduced PM₁₀-induced ROS generation and restored the expression of epidermal barrier-related genes such as loricrin. It also inhibited phosphorylation of MAPKs (ERK, p38) and modulated apoptotic and inflammatory markers including Bax, p53, MMP-9, and COX-2. UHPLC-MS analysis identified eight compounds not previously reported in our earlier study, which may contribute to the extract’s protective effects. Inula japonica leaf extract exerts protective effects against PM₁₀-induced skin damage by reducing oxidative stress and inflammation in keratinocytes. These findings support its potential as a therapeutic candidate for pollution-related skin disorders. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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36 pages, 543 KiB

Open AccessReview

Homologous Recombination Deficiency in Ovarian and Breast Cancers: Biomarkers, Diagnosis, and Treatment

by Bhaumik Shah, Muhammad Hussain and Anjali Seth

Curr. Issues Mol. Biol. 2025, 47(8), 638; https://doi.org/10.3390/cimb47080638 - 8 Aug 2025

Viewed by 648

Abstract

Homologous recombination deficiency (HRD) is a pivotal biomarker in precision oncology, driving therapeutic strategies for ovarian and breast cancers through impaired DNA double-strand break repair. This narrative review synthesizes recent advances (2021–2025) in HRD’s biological basis, prevalence, detection methods, and clinical implications, focusing [...] Read more.

Homologous recombination deficiency (HRD) is a pivotal biomarker in precision oncology, driving therapeutic strategies for ovarian and breast cancers through impaired DNA double-strand break repair. This narrative review synthesizes recent advances (2021–2025) in HRD’s biological basis, prevalence, detection methods, and clinical implications, focusing on high-grade serous ovarian carcinoma (HGSOC; ~50% HRD prevalence) and triple-negative breast cancer (TNBC; 50–70% prevalence). HRD arises from genetic (BRCA1/2, RAD51C/D, PALB2) and epigenetic alterations (e.g., BRCA1 methylation), leading to genomic instability detectable via scars (LOH, TAI, LST) and mutational signatures (e.g., COSMIC SBS3). Advanced detection integrates genomic assays (Myriad myChoice CDx, Caris HRD, FoundationOne CDx), functional assays (RAD51 foci), and epigenetic profiling, with tools like HRProfiler and GIScar achieving >90% sensitivity. HRD predicts robust responses to PARP inhibitors (PARPi) and platinum therapies, extending progression-free survival by 12–36 months in HGSOC. However, resistance mechanisms (BRCA reversion, SETD1A/EME1, SOX5) and assay variability (60–70% non-BRCA concordance) pose challenges. We propose a conceptual framework in ^{Section 10}, integrating multi-omics, methylation analysis, and biallelic reporting to enhance detection and therapeutic stratification. Regional variations (e.g., Asian cohorts) and disparities in access underscore the need for standardized, cost-effective diagnostics. Future priorities include validating novel biomarkers (SBS39, miR-622) and combination therapies (PARPi with ATR inhibitors) to overcome resistance and broaden HRD’s applicability across cancers. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Health and Diseases)

23 pages, 864 KiB

Open AccessReview

Physiological Mechanisms of and Therapeutic Approaches to the Gut Microbiome and Low-Grade Inflammation in Obesity

by Agnieszka Pelc, Weronika Fic, Tymoteusz Typrowicz and Ewelina Polak-Szczybyło

Curr. Issues Mol. Biol. 2025, 47(8), 637; https://doi.org/10.3390/cimb47080637 - 8 Aug 2025

Viewed by 342

Abstract

Obesity is a growing global health challenge, closely linked to chronic low-grade inflammation. This persistent, low-intensity immune response contributes to the development of metabolic, cardiovascular, and cancer-related diseases. A key player in this process is the gut microbiota. Dysbiosis, an imbalance in gut [...] Read more.

Obesity is a growing global health challenge, closely linked to chronic low-grade inflammation. This persistent, low-intensity immune response contributes to the development of metabolic, cardiovascular, and cancer-related diseases. A key player in this process is the gut microbiota. Dysbiosis, an imbalance in gut bacterial composition, disrupts metabolic function, weakens the intestinal barrier, and promotes the production of pro-inflammatory cytokines. In people with obesity, gut microbial diversity is reduced, and the ratio of beneficial to harmful bacteria shifts, affecting lipid metabolism and immune balance. Short-chain fatty acids, produced by gut bacteria, help maintain gut integrity and reduce inflammation. Butyrate, a major SCFA, also improves insulin sensitivity and may support obesity treatment. Diet plays a central role in shaping the gut microbiome. Western diets tend to promote dysbiosis and inflammation, while Mediterranean-style diets encourage the growth of beneficial bacteria. Targeted modulation of the microbiota through diet, probiotics, or medication emerges as a promising strategy for preventing and managing obesity. Full article

(This article belongs to the Special Issue Insights from Genetics, Epigenetics, and Microbiome Research in Obesity: Integrative Approaches to Understand Metabolic Disorders)

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33 pages, 5037 KiB

Open AccessArticle

Convergent and Divergent Mitochondrial Pathways as Causal Drivers and Therapeutic Targets in Neurological Disorders

by Yanan Du, Sha-Sha Fan, Hao Wu, Junwen He, Yang He, Xiang-Yu Meng and Xuan Xu

Curr. Issues Mol. Biol. 2025, 47(8), 636; https://doi.org/10.3390/cimb47080636 - 8 Aug 2025

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Abstract

Mitochondrial dysfunction is implicated across a spectrum of neurological diseases, yet its causal role and mechanistic specificity remain unclear. This study employed a multi-modal integrative analysis of mitochondrial gene expression in Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson’s [...] Read more.

Mitochondrial dysfunction is implicated across a spectrum of neurological diseases, yet its causal role and mechanistic specificity remain unclear. This study employed a multi-modal integrative analysis of mitochondrial gene expression in Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Parkinson’s Disease (PD) to address these gaps. We combined machine learning for predictive modeling with genetic causal inference methods (Mendelian Randomization, colocalization, PheWAS), followed by drug enrichment analysis and molecular docking. Our machine learning models, particularly Support Vector Machine and Multi-layer Perceptron, effectively classified these conditions, with MS exhibiting the highest predictability (mean Accuracy: 0.758). Causal inference analyses identified specific gene–disease links; for instance, genetically predicted increased expression of PDK1 was causally associated with an elevated risk for both AD (OR = 1.041) and ALS (OR = 1.037), identifying pyruvate metabolism as a shared vulnerability. In contrast, genes like SLC25A38 emerged as highly predictive specifically for PD. We also observed evidence of potential brain–periphery interaction, such as a bidirectional causal relationship between red blood cell indices and MS risk. Finally, drug enrichment analysis highlighted Celecoxib, and subsequent molecular docking predicted a strong binding affinity to PDK1 (docking score S = −6.522 kcal/mol), generating hypotheses for potential metabolic modulation. Taken together, this study provides a computational hypothesis framework suggesting mitochondrial pathways and targets that warrant future biological validation. This study provides specific, genetically supported evidence for the causal role of mitochondrial pathways in neurological diseases and identifies tangible targets for future therapeutic development. Full article

(This article belongs to the Collection Bioinformatics Approaches to Biomedicine)

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20 pages, 1575 KiB

Open AccessReview

Neuroprotective Potential of Phytocompounds in the Treatment of Dementia: The State of Knowledge from the Scopolamine-Induced Animal Model of Alzheimer’s Disease

by Joanna Szala-Rycaj, Mirosław Zagaja, Aleksandra Szewczyk, Jolanta Polak and Marta Andres-Mach

Curr. Issues Mol. Biol. 2025, 47(8), 635; https://doi.org/10.3390/cimb47080635 - 8 Aug 2025

Viewed by 203

Abstract

Dementia is a broad category of neurodegenerative pathologies characterized by a progressive decline in two or more cognitive domains, including memory, language, executive and visuospatial functions, personality, and behavior, resulting in the loss of the ability to perform instrumental and/or basic daily activities. [...] Read more.

Dementia is a broad category of neurodegenerative pathologies characterized by a progressive decline in two or more cognitive domains, including memory, language, executive and visuospatial functions, personality, and behavior, resulting in the loss of the ability to perform instrumental and/or basic daily activities. One of the most common types of dementia is Alzheimer’s disease. Current approved treatments for Alzheimer’s disease are mainly limited to alleviating cognitive, behavioral, and psychological deficits. To date, four drugs belonging to two families have been approved for the treatment of Alzheimer’s disease: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and antiglutamatergic drugs (memantine). Drugs delay the progression of the disease, but they cause a number of side effects. Many scientific studies have focused on finding natural products with potential neuroprotective properties and no or minimal cytotoxicity that can support current drug therapy. The main objective of this review is to analyze and describe the neuroprotective potential of selected groups of natural substances (polyphenols, alkaloids, terpenoids) in one of the commonly performed in vivo studies, the scopolamine-induced animal model of Alzheimer’s disease. The article is a review of literature reports from the last 5 years, and the information collected indicates that the neuroprotective activity of natural compounds may prove to be a potential alternative or add-on for Alzheimer’s disease therapy. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology Insights into Neurodegenerative Diseases: From Pathogenesis to Therapeutic Targets)

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28 pages, 3589 KiB

Open AccessArticle

Computational Exploration of Bacterial Compounds Targeting Arginine-Specific Mono-Adp-Ribosyl-Transferase 1 (Art1): A Pathway to Novel Therapeutic Anticancer Strategies

by Nedjwa Mansouri, Ouided Benslama, Sabrina Lekmine, Hichem Tahraoui, Mohammad Shamsul Ola, Jie Zhang and Abdeltif Amrane

Curr. Issues Mol. Biol. 2025, 47(8), 634; https://doi.org/10.3390/cimb47080634 - 8 Aug 2025

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Abstract

Cancer is a multifaceted and life-threatening disease characterized by the unregulated proliferation of malignant cells. Developing new therapies and diagnostic methods for cancer remains a critical focus of research. Proteins involved in cancer progression are being targeted to facilitate the discovery of effective [...] Read more.

Cancer is a multifaceted and life-threatening disease characterized by the unregulated proliferation of malignant cells. Developing new therapies and diagnostic methods for cancer remains a critical focus of research. Proteins involved in cancer progression are being targeted to facilitate the discovery of effective biological treatments. Among these, the ART1 protein plays a critical role in promoting cancer progression, establishing it as a key target for drug therapy. Actinomycetes, known for their anticancer activity, were explored in this study for their potential to inhibit ART1. One hundred bioactive secondary metabolites derived from actinomycetes were subjected to in silico screening to evaluate their potential anticancer activity through inhibition of ART1. The three-dimensional structure of ART1 was generated using the SWISS-MODEL tool and validated through the Save server 6.0 and ProSa web. The structural stability of the ART1 protein was evaluated through molecular dynamics analysis using the iMod server. The potential active sites within the ART1 structure were mapped using the Computed Atlas of Surface Topography of Proteins (CASTp). Molecular docking and protein–ligand interaction studies were performed using AutoDock Vina. Additionally, pharmacophore modeling was conducted using the Pharmit server to identify promising compounds. Toxicity predictions and in silico drug-likeness assessments were carried out using Swiss-ADME and ADMET Lab which evaluate Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Molecular dynamics simulations results for the ART1 protein demonstrated high stability over time. Additionally, resistomycin, borrelidin, tetracycline, and oxytetracycline were identified as the top-ranking ligands, exhibiting binding energies between −8.9 kcal/mol and −9.3 kcal/mol. These ligands exhibited favorable pharmacophore profiles, drug-likeness, and ADMET properties, indicating their potential safety and efficacy in humans. In conclusion, the selected actinomycete-derived ligands show promise for further research and development as potential anticancer agents targeting ART1. Full article

(This article belongs to the Special Issue Molecular Keys to Bioactivity: Pharmacophore and SAR Exploration in Organic Compounds)

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21 pages, 5866 KiB

Open AccessArticle

Genome-Wide Identification and Expression Analysis of the GH19 Chitinase Gene Family in Sea Island Cotton

by Jingjing Ma, Yilei Long, Jincheng Fu, Nengshuang Shen, Le Wang, Shuaijun Wu, Jing Li, Quanjia Chen, Qianli Zu and Xiaojuan Deng

Curr. Issues Mol. Biol. 2025, 47(8), 633; https://doi.org/10.3390/cimb47080633 - 7 Aug 2025

Viewed by 156

Abstract

In this study, GH19 chitinase (Chi) gene family was systematically identified and characterized using genomic assemblies from four cotton species: Gossypium barbadense, G. hirsutum, G. arboreum, and G. raimondii. A suite of analyses was performed, including genome-wide gene identification, [...] Read more.

In this study, GH19 chitinase (Chi) gene family was systematically identified and characterized using genomic assemblies from four cotton species: Gossypium barbadense, G. hirsutum, G. arboreum, and G. raimondii. A suite of analyses was performed, including genome-wide gene identification, physicochemical property characterization of the encoded proteins, subcellular localization prediction, phylogenetic reconstruction, chromosomal mapping, promoter cis-element analysis, and comprehensive expression profiling using transcriptomic data and qRT-PCR (including tissue-specific expression, hormone treatments, and Fusarium oxysporum infection assays). A total of 107 GH19 genes were identified across the four species (35 in G. barbadense, 37 in G. hirsutum, 19 in G. arboreum, and 16 in G. raimondii). The molecular weights of GH19 proteins ranged from 9.9 to 97.3 kDa, and they were predominantly predicted to localize to the extracellular space. Phylogenetic analysis revealed three well-conserved clades within this family. In tetraploid cotton, GH19 genes were unevenly distributed across 12 chromosomes, often clustering in certain regions, whereas in diploid species, they were confined to five chromosomes. Promoter analysis indicated that GH19 gene promoters contain numerous stress- and hormone-responsive motifs, including those for abscisic acid (ABA), ethylene (ET), and gibberellin (GA), as well as abundant light-responsive elements. The expression patterns of GH19 genes were largely tissue-specific; for instance, GbChi23 was predominantly expressed in the calyx, whereas GbChi19/21/22 were primarily expressed in the roots and stems. Overall, this study provides the first comprehensive genomic and functional characterization of the GH19 family in G. barbadense, laying a foundation for understanding its role in disease resistance mechanisms and aiding in the identification of candidate genes to enhance plant defense against biotic stress. Full article

(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants, 3rd Edition)

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43 pages, 2840 KiB

Open AccessReview

Oxytocin, Vasopressin and Stress: A Hormetic Perspective

by Hans P. Nazarloo, Marcy A. Kingsbury, Hannah Lamont, Caitlin V. Dale, Parmida Nazarloo, John M. Davis, Eric C. Porges, Steven P. Cuffe and C. Sue Carter

Curr. Issues Mol. Biol. 2025, 47(8), 632; https://doi.org/10.3390/cimb47080632 - 7 Aug 2025

Viewed by 197

Abstract

The purpose of this article is to examine a previously unrecognized role for the vasopressin–oxytocin (VP-OT) system in mammalian “stress-response hormesis.” The current review adds hormesis to the long list of beneficial effects of OT. Hormesis, a biphasic adaptive response to low-level stressors, [...] Read more.

The purpose of this article is to examine a previously unrecognized role for the vasopressin–oxytocin (VP-OT) system in mammalian “stress-response hormesis.” The current review adds hormesis to the long list of beneficial effects of OT. Hormesis, a biphasic adaptive response to low-level stressors, is introduced here to contextualize the dynamic roles of oxytocin and vasopressin. As with hormesis, the properties of the VP-OT system are context-, time-, and dose-sensitive. Here we suggest that one key to understanding hormesis is the fact that VP and OT and their receptors function as an integrated system. The VP-OT system is capable of changing and adapting to challenges over time, including challenges necessary for survival, reproduction and sociality. Prior research suggests that many beneficial effects of OT are most apparent only following stressful experiences, possibly reflecting interactions with VP, its receptors and other components of the hypothalamic–pituitary–adrenal axis. The release of OT is documented following various kinds of hormetic experiences such as birth, vigorous exercise, ischemic events and the ingestion of emetics, including psychedelics. The phasic or cyclic modulation of VP and related “stress” hormones, accompanied or followed by the release of OT, creates conditions that conform to the core principles of hormesis. This concept is reviewed here in the context of other hormones including corticotropin releasing hormone (CRH) and urocortin, as well as cytokines. In general, VP and classic “stress hormones” support an active response, helping to quickly mobilize body systems. OT interacts with all of these, and may subsequently re-establish homeostasis and precondition the organism to deal with future stressors. However, the individual history of an organism, including epigenetic modifications of classical stress hormones such as VP, can moderate the effects of OT. Oxytocin’s effects also help to explain the important role of sociality in mammalian resilience and longevity. A hormetic perspective, focusing on a dynamic VP-OT system, offers new insights into emotional and physical disorders, especially those associated with the management of chronic stress, and helps us to understand the healing power of social behavior and perceived safety. Full article

(This article belongs to the Special Issue Current Advances in Oxytocin Research)

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18 pages, 2972 KiB

Open AccessArticle

Flavonoids from Cercidiphyllum japonicum Exhibit Bioactive Potential Against Skin Aging and Inflammation in Human Dermal Fibroblasts

by Minseo Kang, Sanghyun Lee, Dae Sik Jang, Sullim Lee and Daeyoung Kim

Curr. Issues Mol. Biol. 2025, 47(8), 631; https://doi.org/10.3390/cimb47080631 - 7 Aug 2025

Viewed by 175

Abstract

With increasing interest in natural therapeutic strategies for skin aging, plant-derived compounds have gained attention for their potential to protect against oxidative stress and inflammation. In this study, we investigated the anti-aging and anti-inflammatory effects of flavonoids isolated from Cercidiphyllum japonicum using a [...] Read more.

With increasing interest in natural therapeutic strategies for skin aging, plant-derived compounds have gained attention for their potential to protect against oxidative stress and inflammation. In this study, we investigated the anti-aging and anti-inflammatory effects of flavonoids isolated from Cercidiphyllum japonicum using a tumor necrosis factor-alpha (TNF-α)-stimulated normal human dermal fibroblast (NHDF) model. The aerial parts of C. japonicum were extracted and analyzed by high-performance liquid chromatography (HPLC), leading to the identification of four major compounds: maltol, chlorogenic acid, ellagic acid, and quercitrin. Each compound was evaluated for its antioxidant and anti-aging activities in TNF-α-stimulated NHDFs. Among them, ellagic acid exhibited the most potent biological activity and was selected for further mechanistic analysis. Ellagic acid significantly suppressed intracellular reactive oxygen species (ROS) generation and matrix metalloproteinase-1 (MMP-1) secretion (both p < 0.001), while markedly increasing type I procollagen production (p < 0.01). Mechanistic studies demonstrated that ellagic acid inhibited TNF-α-induced phosphorylation of mitogen-activated protein kinases (MAPKs), downregulated cyclooxygenase-2 (COX-2), and upregulated heme oxygenase-1 (HO-1), a key antioxidant enzyme. Additionally, ellagic acid attenuated the mRNA expression of inflammatory cytokines, including interleukin-6 (IL-6) and interleukin-8 (IL-8), indicating its broad modulatory effects on oxidative and inflammatory pathways. Collectively, these findings suggest that ellagic acid is a promising plant-derived bioactive compound with strong antioxidant and anti-inflammatory properties, offering potential as a therapeutic agent for the prevention and treatment of skin aging. Full article

(This article belongs to the Section Bioorganic Chemistry and Medicinal Chemistry)

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21 pages, 1426 KiB

Open AccessReview

Physical Activity and Metabolic Disorders—What Does Gut Microbiota Have to Do with It?

by Aneta Sokal-Dembowska, Ewelina Polak-Szczybyło, Kacper Helma, Patrycja Musz, Maciej Setlik, Weronika Fic, Dawid Wachowiak and Sara Jarmakiewicz-Czaja

Curr. Issues Mol. Biol. 2025, 47(8), 630; https://doi.org/10.3390/cimb47080630 - 7 Aug 2025

Viewed by 267

Abstract

Obesity, type 2 diabetes mellitus (T2DM) and steatohepatitis associated with metabolic dysfunction (MASLD) are on the rise and pose serious health challenges worldwide. In recent years, researchers have gained a better understanding of the important role of the gut microbiota in the development [...] Read more.

Obesity, type 2 diabetes mellitus (T2DM) and steatohepatitis associated with metabolic dysfunction (MASLD) are on the rise and pose serious health challenges worldwide. In recent years, researchers have gained a better understanding of the important role of the gut microbiota in the development and progression of these diseases. Intestinal dysbiosis can contribute to the occurrence of increased intestinal permeability, inflammation and reduced numbers of commensal bacteria. In obesity, these changes contribute to chronic low-grade inflammation and deregulated metabolism. In MASLD, gut microbiota dysbiosis can promote liver fibrosis and impair bile acid metabolism, while in T2DM, they are associated with impaired glycemic control and insulin resistance. Regular physical activity has a positive effect on the composition of the gut microbiota, increasing its diversity, modulating its metabolic functions, strengthening the intestinal barrier and reducing inflammation. These findings suggest that exercise and microbiota-targeted interventions may play an important role in the prevention and treatment of metabolic diseases. Full article

(This article belongs to the Special Issue Metabolic Interactions Between the Gut Microbiome and Organism)

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18 pages, 435 KiB

Open AccessReview

Molecular and Glycosylation Pathways in Osteosarcoma: Tumor Microenvironment and Emerging Strategies Toward Personalized Oncology

by Georgian Longin Iacobescu, Antonio-Daniel Corlatescu, Horia Petre Costin, Razvan Spiridonica, Mihnea-Ioan-Gabriel Popa and Catalin Cirstoiu

Curr. Issues Mol. Biol. 2025, 47(8), 629; https://doi.org/10.3390/cimb47080629 - 7 Aug 2025

Viewed by 299

Abstract

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical [...] Read more.

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical and chemotherapeutic approaches, the presence of metastatic or recurrent disease is still detrimental to the patient’s outcome. Major advances in understanding the molecular mechanisms of OS are needed to substantially improve outcomes for patients being treated for OS. This review integrates new data on the molecular biology, pathophysiology, and immune landscape of OS, as well as introducing salient areas of tumorigenesis underpinning these findings, such as chromothripsis; kataegis; cancer stem cell dynamics; and updated genetic, epigenetic, and glycosylation modifiers. In addition, we review promising biomarkers, diagnostic platforms, and treatments, including immunotherapy, targeted small molecule inhibitors, and nanomedicine. Using genomic techniques, we have defined OS for its significant genomic instability due to TP53 and RB1 mutations, chromosomal rearrangements, and aberrant glycosylation. The TME is also characterized as immunosuppressive and populated by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately inhibiting immune checkpoint inhibitors. Emerging fields such as glycomics and epigenetics, as well as stem cell biology, have defined promising biomarkers and targets. Preclinical studies have identified that glycan-directed CAR therapies could be possible, as well as metabolic inhibitors and 3D tumor models, which presented some preclinical success and could allow for tumoral specificity and enhanced efficacy. OS is a biologically and clinically complex disease; however, advances in exploring the molecular and immunologic landscape of OS present new opportunities in biomarkers and the development of new treatment options with adjunctive care. Successful treatments in the future will require personalized, multi-targeted approaches to account for tumor heterogeneity and immune evasion. This will help us turn the corner in providing improved outcomes for patients with this resilient malignancy. Full article

(This article belongs to the Special Issue Tumor Microenvironment: Crosstalk Between Epigenetics, Metabolism and Immunity)

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18 pages, 2279 KiB

Open AccessArticle

MvAl-MFP: A Multi-Label Classification Method on the Functions of Peptides with Multi-View Active Learning

by Yuxuan Peng, Jicong Duan, Yuanyuan Dan and Hualong Yu

Curr. Issues Mol. Biol. 2025, 47(8), 628; https://doi.org/10.3390/cimb47080628 - 6 Aug 2025

Viewed by 237

Abstract

The rapid expansion of peptide libraries and the increasing functional diversity of peptides have highlighted the significance of predicting the multifunctional properties of peptides in bioinformatics research. Although supervised learning methods have made advancements, they typically necessitate substantial amounts of labeled data for [...] Read more.

The rapid expansion of peptide libraries and the increasing functional diversity of peptides have highlighted the significance of predicting the multifunctional properties of peptides in bioinformatics research. Although supervised learning methods have made advancements, they typically necessitate substantial amounts of labeled data for yielding accurate prediction. This study presents MvAl-MFP, a multi-label active learning approach that incorporates multiple feature views of peptides. This method takes advantage of the natural properties of multi-view representation for amino acid sequences, meets the requirement of the query-by-committee (QBC) active learning paradigm, and further significantly diminishes the requirement for labeled samples while training high-performing models. First, MvAl-MFP generates nine distinct feature views for a few labeled peptide amino acid sequences by considering various peptide characteristics, including amino acid composition, physicochemical properties, evolutionary information, etc. Then, on each independent view, a multi-label classifier is trained based on the labeled samples. Next, a QBC strategy based on the average entropy of predictions across all trained classifiers is adopted to select a specific number of most valuable unlabeled samples to submit them to human experts for labeling by wet-lab experiments. Finally, the aforementioned procedure is iteratively conducted with a constantly expanding labeled set and updating classifiers until it meets the default stopping criterion. The experiments are conducted on a dataset of multifunctional therapeutic peptides annotated with eight functional labels, including anti-bacterial properties, anti-inflammatory properties, anti-cancer properties, etc. The results clearly demonstrate the superiority of the proposed MvAl-MFP method, as it can rapidly improve prediction performance while only labeling a small number of samples. It provides an effective tool for more precise multifunctional peptide prediction while lowering the cost of wet-lab experiments. Full article

(This article belongs to the Special Issue Challenges and Advances in Bioinformatics and Computational Biology)

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17 pages, 10110 KiB

Open AccessArticle

An Integrated Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and Experimental Validation Study to Investigate the Potential Mechanism of Isoliquiritigenin in the Treatment of Ischemic Stroke

by Hang Yuan, Yuting Hou, Yuan Jiao, Xin Lu and Liang Liu

Curr. Issues Mol. Biol. 2025, 47(8), 627; https://doi.org/10.3390/cimb47080627 - 6 Aug 2025

Viewed by 343

Abstract

Isoliquiritigenin (ISL) is a type of chalcone that widely exists in medicinal plants of the Leguminosae family and exhibits a remarkable anti-ischemic stroke (IS) effect. However, the anti-IS mechanisms of ISL remain to be systematically elucidated. In this study, network pharmacology was used [...] Read more.

Isoliquiritigenin (ISL) is a type of chalcone that widely exists in medicinal plants of the Leguminosae family and exhibits a remarkable anti-ischemic stroke (IS) effect. However, the anti-IS mechanisms of ISL remain to be systematically elucidated. In this study, network pharmacology was used to predict potential targets related to the anti-IS effect of ISL. The binding ability of ISL to potential core targets was further analyzed by molecular docking and molecular dynamics (MD) simulations. By establishing an oxygen–glucose deprivation/reoxygenation (OGD/R)-induced HT22 cell model, the anti-IS mechanisms of ISL were investigated via RT-qPCR and Western Blot (WB). As a result, network pharmacology analysis revealed that APP, ESR1, MAO-A, PTGS2, and EGFR may be potential core targets of ISL for anti-IS treatment. Molecular docking and molecular dynamics simulation results revealed that ISL can stably bind to the five potential core targets and form stable complex systems with them. The results of the cell experiments revealed a significant anti-IS effect of ISL. Additionally, mRNA and protein expression levels of APP, MAO-A and PTGS2 or ESR1 in the ISL treatment group were significantly lower or higher than those in the OGD/R group In conclusion, ISL may improve IS by regulating the protein expression levels of APP, ESR1, MAO-A, and PTGS2. Full article

(This article belongs to the Special Issue Cerebrovascular Diseases: From Pathogenesis to Treatment)

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13 pages, 3991 KiB

Open AccessCommunication

Feminization of the Blood–Brain Barrier Changes the Brain Transcriptome of Drosophila melanogaster Males

by Danyel S. Davis, Warda Hashem, Chamala Lama, Joseph L. Reeve and Brigitte Dauwalder

Curr. Issues Mol. Biol. 2025, 47(8), 626; https://doi.org/10.3390/cimb47080626 - 6 Aug 2025

Viewed by 189

Abstract

Beyond its crucial role as a tight barrier to protect the nervous system, the Blood–Brain Barrier (BBB) is increasingly being recognized for its physiological processes that affect brain function and behavior. In Drosophila melanogaster, the BBB expresses sex-specific transcripts, and a change [...] Read more.

Beyond its crucial role as a tight barrier to protect the nervous system, the Blood–Brain Barrier (BBB) is increasingly being recognized for its physiological processes that affect brain function and behavior. In Drosophila melanogaster, the BBB expresses sex-specific transcripts, and a change in the sexual identity of adult BBB cells results in a significant reduction in male courtship behavior. The molecular nature of this BBB/brain interaction and the molecules that mediate it are unknown. Here we feminize BBB cells by targeted expression of the Drosophila female-specific master regulator TraF in otherwise normal males. We examined the effect on RNA expression in dissected brains by RNA sequencing. We find that 283 transcripts change in comparison to normal control males. Transcripts representing cell signaling processes and synaptic communication are enriched, as are hormonal mediators. These transcripts provide a valuable resource for addressing questions about BBB and brain interaction. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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15 pages, 329 KiB

Open AccessArticle

Genetic Risk Profiles for Atherosclerosis and Venous Thromboembolism in Azorean and Mainland Portuguese Populations: A Comparative Analysis

by Luisa Mota-Vieira, Joana Duarte, Xavier Catena, Jaime Gonzalez, Andrea Capocci and Cláudia C. Branco

Curr. Issues Mol. Biol. 2025, 47(8), 625; https://doi.org/10.3390/cimb47080625 - 6 Aug 2025

Viewed by 548

Abstract

The frequency of specific variants associated with the risk of developing cardiovascular diseases has been extensively studied through genome-wide association studies (GWASs). Differences between populations may be caused by the interaction of several factors, such as environmental and genetic backgrounds. Here, we studied [...] Read more.

The frequency of specific variants associated with the risk of developing cardiovascular diseases has been extensively studied through genome-wide association studies (GWASs). Differences between populations may be caused by the interaction of several factors, such as environmental and genetic backgrounds. Here, we studied 19 SNPs involved in atherosclerosis (AT) and venous thromboembolism (VTE) risk in the Azorean and mainland Portuguese populations and compared their frequencies with other European, Asian, and African populations. Results revealed that, although there was no difference between Azorean and mainland populations, eight SNPs in ADAMTS7, PCSK9, APOE, and LDLR genes showed significant statistical differences (χ², p < 0.05) when compared with the European population. The multilocus genetic profile (MGP) analysis demonstrated that 7.4% of mainlanders and 11.2% of Azoreans have a high-risk of developing atherosclerosis. The opposite tendency was observed for venous thromboembolism risk, where the mainland population presented a higher risk (6.5%) than the Azorean population (4.1%). Significant differences in VTE-MGP distribution were found among the Azorean geographic groups (p < 0.05), with the Eastern group showing the highest VTE risk. Conversely, for the risk AT-MGP, the Central group shows the highest risk (12.9%). Taken together, the data suggest a risk of developing a cardiovascular disease consistent with the European population. However, the Azorean-specific genetic background and socio-cultural habits (dietary and sedentary) may explain the differences observed, validating the need to assess the allelic and genotypic frequencies between different populations, especially in small geographical locations, such as the Azores archipelago. In conclusion, these findings can improve the prevention, diagnosis, and treatment of high-risk individuals, and contribute to reducing the lifelong burden of cardiovascular diseases in the Azorean population. Full article

(This article belongs to the Section Molecular Medicine)

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Curr. Issues Mol. Biol., Volume 47, Issue 8 (August 2025) – 77 articles

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