Biomolecules

19 pages, 8263 KiB

Open AccessArticle

Dissecting the tRNA Fragment tRF3E–Nucleolin Interaction: Implications in Breast Cancer

by Maurizio Falconi, Junbiao Wang, Andrea Costamagna, Mara Giangrossi, Sunday Segun Alimi, Emilia Turco, Massimo Bramucci, Luana Quassinti, Rossana Petrilli, Michela Buccioni, Gabriella Marucci, Augusto Amici, Paola Defilippi, Roberta Galeazzi and Cristina Marchini

Biomolecules 2025, 15(7), 1054; https://doi.org/10.3390/biom15071054 - 21 Jul 2025

Viewed by 725

Abstract

Nucleolin (NCL), an RNA-binding protein which regulates critical cellular processes, is frequently dysregulated in human cancers, including breast cancer, making it an attractive therapeutic target. However, molecular details of the RNA-NCL interaction have not been investigated yet. A tRNA fragment named tRF3E, displaying [...] Read more.

Nucleolin (NCL), an RNA-binding protein which regulates critical cellular processes, is frequently dysregulated in human cancers, including breast cancer, making it an attractive therapeutic target. However, molecular details of the RNA-NCL interaction have not been investigated yet. A tRNA fragment named tRF3E, displaying tumor suppressor roles in breast cancer, was found to bind NCL with high affinity displacing NCL-controlled transcripts. Here, we investigated the determinants and cooperativity of tRF3E-NCL interaction by Electrophoretic Mobility Shift Assays and in silico docking analysis, using wild-type or mutated tRF3E. We found that NCL, through its RNA-binding domains (RBD1–2 and RBD3–4), binds simultaneously two tRF3E molecules, giving rise to an energetically favored complex. Instead, a mutant form of tRF3E (M19–24), in which the NCL recognition element in position 19–24 has been disrupted, contacts NCL exclusively at RBD3–4, causing the loss of cooperativity among RBDs. Importantly, when expressed in MCF7 breast cancer cells, tRF3E significantly reduced cell proliferation and colony formation, confirming its role as tumor suppressor, but tRF3E functional properties were lost when the 19–24 motif was mutated, suggesting that cooperativity among multiple domains is required for the NCL-mediated tRF3E antitumor function. This study sheds light on the dynamic of RNA-NCL interaction and lays the foundations for using tRF3E as a promising NCL-targeted biodrug candidate. Full article

(This article belongs to the Special Issue Bioactive Molecules: Structures, Functions and Potential Uses for Cancer Prevention and Targeted Therapies (2nd Edition))

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25 pages, 4337 KiB

Open AccessArticle

Cullin-3 and Regulatory Biomolecules Profiling in Vitiligo: Integrated Docking, Clinical, and In Silico Insights

by Hidi A. A. Abdellatif, Mohamed Azab, Eman Hassan El-Sayed, Rwan M. M. M. Halim, Ahmad J. Milebary, Dhaifallah A. Alenizi, Manal S. Fawzy and Noha M. Abd El-Fadeal

Biomolecules 2025, 15(7), 1053; https://doi.org/10.3390/biom15071053 - 21 Jul 2025

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Abstract

Background: Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 [...] Read more.

Background: Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 degradation, and its interplay with inflammatory mediators in vitiligo pathogenesis are underexplored. This study investigates CUL3, NRF2, and the associated regulatory networks in vitiligo, integrating clinical profiling and computational docking to identify therapeutic targets. Methods: A case-control study compared non-segmental vitiligo patients with age-/sex-matched controls. Lesional skin biopsies were analyzed by qRT-PCR for the expression of CUL3, NRF2, miRNA-146a, FOXP3, NF-κB, IL-6, TNF-α, and P53. Molecular docking was used to evaluate vitexin’s binding affinity to Keap1, validated by root mean square deviation (RMSD) calculations. Results: Patients with vitiligo exhibited significant downregulation of CUL3 (0.27 ± 0.03 vs. 1 ± 0.58; p = 0.013), NRF2 (0.37 ± 0.26 vs. 1 ± 0.8; p = 0.001), and FOXP3 (0.09 ± 0.2 vs. 1 ± 0.3; p = 0.001), alongside the upregulation of miRNA-146a (4.7 ± 1.9 vs. 1 ± 0.8; p = 0.001), NF-κB (4.7 ± 1.9 vs. 1 ± 0.5; p = 0.001), IL-6 (2.8 ± 1.5 vs. 1 ± 0.4; p = 0.001), and TNF-α (2.2 ± 1.1 vs. 1 ± 0.3; p = 0.001). P53 showed no differential expression (p > 0.05). Docking revealed a strong binding of vitexin to Keap1 (RMSD: 0.23 Å), mirroring the binding of the control ligand CDDO-Im. Conclusions: Dysregulation of the CUL3/Keap1/NRF2 axis and elevated miRNA-146a levels correlate with vitiligo progression, suggesting a role for oxidative stress and immune imbalance. Vitexin’s high-affinity docking to Keap1 positions it as a potential modulator of the NRF2 pathway, offering novel therapeutic avenues. This study highlights the translational potential of targeting the ubiquitin–proteasome and antioxidant pathways in the management of vitiligo. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Skin Disorders)

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14 pages, 7022 KiB

Open AccessArticle

Sensitive and Facile Detection of Aloin via N,F-CD-Coated Test Strips Coupled with a Miniaturized Fluorimeter

by Guo Wei, Chuanliang Wang, Rui Wang, Peng Zhang, Xuhui Geng, Jinhua Li, Abbas Ostovan, Lingxin Chen and Zhihua Song

Biomolecules 2025, 15(7), 1052; https://doi.org/10.3390/biom15071052 - 21 Jul 2025

Viewed by 263

Abstract

Aloin, a kind of active phenolic component, is sourced from Aloe vera. Recently, the determination of aloin has received enormous attention, owing to its positive performance (including anti-tumor, antibacterial, detoxification, liver protection, anti-stomach damage, and skin protection activities) and painful side effects [...] Read more.

Aloin, a kind of active phenolic component, is sourced from Aloe vera. Recently, the determination of aloin has received enormous attention, owing to its positive performance (including anti-tumor, antibacterial, detoxification, liver protection, anti-stomach damage, and skin protection activities) and painful side effects (increased carcinogenicity caused by excessive use of aloin) impacting human health. This investigation was inspired by the good fluorescence properties of carbon dots (CDs); CD-based sensors have aroused a great deal of interest due to their excellent sensitivity and selectivity. Thus, it is of great significance to develop novel CD-based sensors for aloin determination. Herein, N,F-CDs were designed and synthesized through a convenient hydrothermal strategy; the synthesized N,F-CDs possessed good fluorescence performance and a small particle size (near 4.3 nm), which demonstrated the successful preparation of N,F-CDs. The resulting N,F-CDs possessed a large Stokes shift and could emit a highly stable green fluorescence. The fluorescence of the N,F-CDs could be effectively quenched by aloin through the inner filter effect. Furthermore, the synthesis procedure was easy to operate. Finally, the N,F-CD-coated test strips were fabricated and combined with a miniaturized fluorimeter for the fluorescence detection of aloin via the inner filter effect for the first time. The N,F-CD-coated test strips were fabricated and used for the fluorescence sensing of aloin, and the results were compared with a typical ultraviolet (UV) method. The N,F-CD-coated test strips exhibited high recovery (96.9~106.1%) and sensitivity (31.8 nM, n = 3), good selectivity, low sample consumption (1 μL), high speed (5 min), good stability, and anti-interference properties. The results indicate that N,F-CD-coated test strips are applicable for the quantitative determination of aloin in bovine serum, orange juice, and urine samples. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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13 pages, 1988 KiB

Open AccessArticle

Genetic Diversity in the Suppressyn Gene Sequence: From Polymorphisms to Loss-of-Function Mutations

by Jun Sugimoto, Danny J. Schust, Takeshi Nagamatsu, Yoshihiro Jinno and Yoshiki Kudo

Biomolecules 2025, 15(7), 1051; https://doi.org/10.3390/biom15071051 - 21 Jul 2025

Viewed by 340

Abstract

The suppressive regulator of cell fusion, suppressyn, is specifically expressed in the human placenta and is thought to play a crucial role in trophoblast fusion or syncytialization. Previous studies have suggested that alterations in its expression are associated with aberrant placental development, [...] Read more.

The suppressive regulator of cell fusion, suppressyn, is specifically expressed in the human placenta and is thought to play a crucial role in trophoblast fusion or syncytialization. Previous studies have suggested that alterations in its expression are associated with aberrant placental development, such as the immature placental morphology observed in Down syndrome, and may contribute to the pathogenesis of fetal growth restriction. While syncytialization in trophoblasts is an essential process for normal placental development, the precise molecular causes of its dysregulation remain poorly understood. In the present study, we aimed to elucidate the potential contribution of genomic variation to the loss of suppressyn function, extending previous analyses of expression abnormalities in perinatal disorders. Through sequence analysis, (1) we identified six polymorphisms within the coding region of the suppressyn gene, and (2) discovered that certain deletions and specific amino acid substitutions result in a complete loss of suppressyn-mediated inhibition of cell fusion. Although these mutations have not yet been reported in disease-associated genomic databases, our findings suggest that comprehensive genomic studies of perinatal and other disorders may reveal pathogenic variants of suppressyn, thereby uncovering novel genetic contributions to placental dysfunction. It is also anticipated that these findings might direct the development of therapeutic strategies targeting loss-of-function mutations. Full article

(This article belongs to the Special Issue Recent Advances in Retroviruses and Endogenous Retroviruses (ERVs) in Mammalian Placenta and Beyond 2025)

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19 pages, 6597 KiB

Open AccessArticle

GSR Deficiency Exacerbates Oxidative Stress and Promotes Pulmonary Fibrosis

by Wenyu Zhao, Hehe Cao, Wenbo Xu, Yudi Duan, Yulong Gan, Shuang Huang, Ying Cao, Siqi Long, Yingying Zhang, Guoying Yu and Lan Wang

Biomolecules 2025, 15(7), 1050; https://doi.org/10.3390/biom15071050 - 20 Jul 2025

Viewed by 359

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder characterized by excessive scarring of lung tissue, predominantly affecting middle-aged and elderly populations. Oxidative stress plays a pivotal role in the pathogenesis of pulmonary fibrosis, disrupting redox homeostasis and driving fibrotic progression. Glutathione reductase (GSR), a key antioxidant enzyme, is essential for maintaining cellular glutathione (GSH) levels and mitigating oxidative damage. However, the specific involvement of GSR in IPF remains poorly understood. This study found that GSR levels were downregulated in IPF patients and mice treated with bleomycin (BLM). GSR knockdown enhanced epithelial-to-mesenchymal transition (EMT) in A549 cells and promoted the activation of MRC5 cells. Additionally, GSR depletion promoted cellular migration and senescence in both A549 and MRC5 cells. Mechanistically, silencing GSR in A549 and MRC5 cells led to a marked reduction in intracellular GSH levels, resulting in elevated reactive oxygen species (ROS) accumulation, thereby promoting the activation of the TGF-β/Smad2 signaling pathway. In conclusion, our findings demonstrate that GSR deficiency aggravates pulmonary fibrosis by impairing antioxidant defense mechanisms, promoting EMT, and activating fibroblasts through the TGF-β/Smad2 signaling. These findings suggest that GSR may be essential in reducing the fibrotic progression of IPF. Full article

(This article belongs to the Section Molecular Biology)

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11 pages, 520 KiB

Open AccessArticle

Hemodynamic and Morpho-Biochemical Parameters of Rabbit Blood After Injection of Enzyme Preparations

by V. G. Vertiprakhov, N. A. Sergeenkova, S. V. Karamushkina and B. Sh. Dashieva

Biomolecules 2025, 15(7), 1049; https://doi.org/10.3390/biom15071049 - 18 Jul 2025

Viewed by 357

Abstract

The anti-inflammatory effect of trypsin in animals and humans is the basis for the development of new veterinary and medical drugs and alternatives to antibiotics. The current experiment analyzed the effect of pig pancreatic tissue lyophilizate and crystalline trypsin on the hemodynamic and [...] Read more.

The anti-inflammatory effect of trypsin in animals and humans is the basis for the development of new veterinary and medical drugs and alternatives to antibiotics. The current experiment analyzed the effect of pig pancreatic tissue lyophilizate and crystalline trypsin on the hemodynamic and morpho-biochemical parameters of rabbit blood. The experiments were carried out on 20 rabbits of the Soviet chinchilla breed of 6–8 months of age. Animals were intramuscularly injected with sterile solution of 0.9% NaCl in 0.5 mL (group 1, n = 5), sterile solution of crystalline trypsin in 0.9% NaCl at a concentration of 0.25 mg/kg body weight (group 2, n = 5), sterile solution of crystalline trypsin in 0, 9% NaCl at a concentration of 0.5 mg/kg body weight (group 3, n = 5), or sterile suspension of pig pancreas lyophilizate at a concentration of 1 mg/kg body weight (group 4, n = 5). Animals were injected once daily for five consecutive days. Significant changes in arterial blood pressure, serum enzymes activity, and the count of various blood cellular components were induced by the administration of different trypsin preparations. All data obtained indicate the presence of a biologically active substance in the lyophilizate, the effect of which requires further animal studies to create a prototype for the development of new drugs for human and animal use. Full article

(This article belongs to the Special Issue Digestive Enzymes in Health and Disease)

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19 pages, 2093 KiB

Open AccessReview

PHF20L1: An Epigenetic Regulator in Cancer and Beyond

by Yishan Wang, Qin Hu, Haixia Zhao, Lulu Zeng, Zhongwei Zhao, Xia Li, Qiaoyou Weng, Yang Yang, Minjiang Chen, Jiansong Ji and Rongfang Qiu

Biomolecules 2025, 15(7), 1048; https://doi.org/10.3390/biom15071048 - 18 Jul 2025

Viewed by 285

Abstract

Plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) is a novel epigenetic “reader” that specifically recognises histone post-translational modifications (PTMs) via its Tudor and PHD finger domains, thereby regulating chromatin remodelling, DNA damage repair, and oncogene transcriptional activation. This review comprehensively summarises the [...] Read more.

Plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) is a novel epigenetic “reader” that specifically recognises histone post-translational modifications (PTMs) via its Tudor and PHD finger domains, thereby regulating chromatin remodelling, DNA damage repair, and oncogene transcriptional activation. This review comprehensively summarises the role of PHF20L1 in various cancers, including breast, ovarian, and colorectal cancers, as well as retinoblastomas, and elucidates its molecular mechanisms of action in cancer pathogenesis. Accumulating evidence indicates that PHF20L1 is upregulated in these malignancies and drives tumour progression by promoting proliferation, metastasis, and immune evasion. Furthermore, PHF20L1 orchestrates tumour-related gene expression by interacting with key epigenetic complexes. Given its unique structural features, we propose novel strategies for developing small-molecule inhibitors and combinatorial therapies, providing a theoretical basis for targeted epigenetic regulation for precision treatment. Future research should further investigate the molecular regulatory networks of PHF20L1 in different cancers and other human diseases and focus on developing specific small-molecule inhibitors to enable precision-targeted therapies. Full article

(This article belongs to the Special Issue Tumor Genomics and Liquid Biopsy in Cancer Biology)

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15 pages, 1142 KiB

Open AccessArticle

The Estimated Intake of S100B Relates to Microbiota Biodiversity in Different Diets

by Tehreema Ghaffar, Veronica Volpini, Serena Platania, Olga Vassioukovitch, Alessandra Valle, Federica Valeriani, Fabrizio Michetti and Vincenzo Romano Spica

Biomolecules 2025, 15(7), 1047; https://doi.org/10.3390/biom15071047 - 18 Jul 2025

Viewed by 342

Abstract

The S100B protein, known for its role in the central and enteric nervous systems, has recently been identified in dietary sources such as milk, dairy products, fruits, and vegetables. Given its potential interaction with the gut microbiota, this study explores the relationship between [...] Read more.

The S100B protein, known for its role in the central and enteric nervous systems, has recently been identified in dietary sources such as milk, dairy products, fruits, and vegetables. Given its potential interaction with the gut microbiota, this study explores the relationship between dietary intake of S100B and microbiota biodiversity across different diets. A comprehensive study was conducted, estimating S100B concentrations in 13 dietary patterns recommended in different countries. This is the first study to provide a comparative estimation of S100B exposure from the diet and to explore its potential ecological and epidemiological relevance. The association between S100B levels and microbiota biodiversity was statistically analyzed, showing a direct correlation. Microbial diversity was assessed using the Shannon index, based on data extracted from studies reporting microbiota composition across dietary patterns. Additionally, the relative risk of Crohn’s disease was assessed in different populations to examine potential links between dietary patterns, S100B, and chronic disease prevention. A moderate positive correlation (R² = 0.537) was found between S100B concentration and Shannon index, suggesting that diets higher in S100B (e.g., Mediterranean diet) were associated with higher microbial alpha-diversity. Furthermore, Western-style diets, with the lowest S100B levels, exhibited a higher relative risk for Crohn’s disease (R² = 0.780). These findings highlight the potential role of dietary S100B content in modulating gut microbiota diversity and reducing chronic disease risk. Full article

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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16 pages, 2363 KiB

Open AccessArticle

BUB1 an Overexpressed Kinase in Sarcoma: Finding New Target Therapy for Osteosarcoma, Liposarcoma, Synovial Sarcoma, and Leiomyosarcoma

by Mercedes Olvera-Valencia, Fernando Luna-Maldonado, Joselyn Juarez-Reyes, Alejandro Lopez-Saavedra, Jossimar Coronel-Hernandez, Oliver Millan-Catalan, Daniel Guzman-Gomez, Frida Rodríguez-Izquierdo, Luis A. Herrera, David Francisco Cantú-De León, Carlos Perez-Plasencia and Eloy-Andres Pérez-Yepez

Biomolecules 2025, 15(7), 1046; https://doi.org/10.3390/biom15071046 - 18 Jul 2025

Viewed by 720

Abstract

Sarcomas are heterogeneous mesenchymal tumors, and their pharmacological treatment remains challenging due to the high toxicity and poor efficacy of current therapies. This study aimed to identify common overexpressed kinases in the four most frequent sarcoma subtypes to establish novel therapeutic targets. A [...] Read more.

Sarcomas are heterogeneous mesenchymal tumors, and their pharmacological treatment remains challenging due to the high toxicity and poor efficacy of current therapies. This study aimed to identify common overexpressed kinases in the four most frequent sarcoma subtypes to establish novel therapeutic targets. A bioinformatics approach using patient-derived gene expression data sets identified overexpressed kinases shared across these sarcoma types. Later, BUB1 was determined as the kinase consistently overexpressed across the osteosarcoma, liposarcoma, leiomyosarcoma, and synovial sarcoma. Moreover, the role of this kinase was further validated through molecular and functional assays, including pharmacological inhibition in cell lines derived from the four sarcoma subtypes. BUB1 inhibition reduced the phosphorylation of AKT and H2A proteins, precluded cell proliferation, and inhibited colony formation in sarcoma cells. Finally, overall survival analysis highlighted a strong correlation between high BUB1 expression and poorer survival rates in sarcoma patients. Altogether, these findings underscore the potential of BUB1 as a therapeutic target and prognostic marker in sarcomas. Targeted inhibition of BUB1 may provide a novel strategy to reduce tumor growth and improve outcomes for patients with bone and soft tissue sarcomas. Full article

(This article belongs to the Special Issue Signaling Pathways as Therapeutic Targets for Cancer)

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29 pages, 3654 KiB

Open AccessReview

A Mechanistic Approach to Replacing Antibiotics with Natural Products in the Treatment of Bacterial Diarrhea

by Mingbang Wei, Huaizhi Liu, Zhefan Hu, Peixiao Wen, Yourong Ye, Yangzom Chamba, Hongliang Zhang and Peng Shang

Biomolecules 2025, 15(7), 1045; https://doi.org/10.3390/biom15071045 - 18 Jul 2025

Viewed by 388

Abstract

Natural products have emerged as potential alternatives to antibiotics in the treatment of bacterial diarrhea, due to their multi-targeting effects, low potential for inducing resistance, and favorable safety profiles. Currently, the search for natural product-based therapies has become an emerging focus in medical [...] Read more.

Natural products have emerged as potential alternatives to antibiotics in the treatment of bacterial diarrhea, due to their multi-targeting effects, low potential for inducing resistance, and favorable safety profiles. Currently, the search for natural product-based therapies has become an emerging focus in medical research. This growing interest is driven by the increasing awareness that the widespread and irrational use of antibiotics has contributed to the alarming rise in antibiotic-resistant bacterial strains, which in turn diminishes the efficacy of conventional drugs. Among these concerns, the limitations of antibiotics in managing bacterial diarrhea and the potential mechanisms by which natural products exert therapeutic effects are the main focus of this paper. Natural products, containing a wide array of bioactive compounds, can not only directly inhibit the growth of pathogenic bacteria, disrupt bacterial membrane synthesis, and reduce toxin production, but also modulate inflammatory responses, enhance immune function, repair intestinal barriers, and restore gut microbial ecology—highlighting their systemic and multi-targeted therapeutic potential. Therefore, this paper will elaborate on how natural products combat bacterial diarrhea from three aspects: the pathogen and pathogenesis of bacterial diarrhea, natural product-based therapeutic studies, and the underlying mechanisms of action, thereby proposing natural products as viable alternatives to antibiotics. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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17 pages, 1772 KiB

Open AccessArticle

Exploration of the Possible Relationships Between Gut and Hypothalamic Inflammation and Allopregnanolone: Preclinical Findings in a Post-Finasteride Rat Model

by Silvia Diviccaro, Roberto Oleari, Federica Amoruso, Fabrizio Fontana, Lucia Cioffi, Gabriela Chrostek, Vera Abenante, Jacopo Troisi, Anna Cariboni, Silvia Giatti and Roberto Cosimo Melcangi

Biomolecules 2025, 15(7), 1044; https://doi.org/10.3390/biom15071044 - 18 Jul 2025

Viewed by 1814

Abstract

Background: Finasteride, a 5α-reductase inhibitor commonly prescribed for androgenetic alopecia, has been linked to persistent adverse effects after discontinuation, known as post-finasteride syndrome (PFS). Symptoms include neurological, psychiatric, sexual, and gastrointestinal disturbances. Emerging evidence suggests that PFS may involve disruption of sex steroid [...] Read more.

Background: Finasteride, a 5α-reductase inhibitor commonly prescribed for androgenetic alopecia, has been linked to persistent adverse effects after discontinuation, known as post-finasteride syndrome (PFS). Symptoms include neurological, psychiatric, sexual, and gastrointestinal disturbances. Emerging evidence suggests that PFS may involve disruption of sex steroid homeostasis, neuroactive steroid deficiency (notably allopregnanolone, ALLO), and gut–brain axis alterations. Objective: This study aimed to investigate the effects of finasteride withdrawal (FW) in a rat model and evaluate the potential protective effects of ALLO on gut and hypothalamic inflammation. Methods: Adult male Sprague Dawley rats were treated with finasteride for 20 days, followed by one month of drug withdrawal. A subgroup received ALLO treatment during the withdrawal. Histological, molecular, and biochemical analyses were performed on the colon and hypothalamus. Gut microbiota-derived metabolites and markers of neuroinflammation and blood–brain barrier (BBB) integrity were also assessed. Results: At FW, rats exhibited significant colonic inflammation, including a 4.3-fold increase in Mφ1 levels (p < 0.001), a 2.31-fold decrease in butyrate concentration (p < 0.01), and elevated hypothalamic GFAP and Iba-1 protein expression (+360%, p < 0.01 and +100%, p < 0.01, respectively). ALLO treatment rescued these parameters in both the colon and hypothalamus but only partially restored mucosal and BBB structural integrity, as well as the NF-κB/PPARγ pathway. Conclusions: This preclinical study shows that FW causes inflammation in both the gut and hypothalamus in rats. ALLO treatment helped reduce several of these effects. These results suggest ALLO could have a protective role and have potential as a treatment for PFS patients. Full article

(This article belongs to the Section Molecular Medicine)

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28 pages, 1119 KiB

Open AccessReview

β-Catenin: A Key Molecule in Osteoblast Differentiation

by Edyta Wróbel, Piotr Wojdasiewicz, Agnieszka Mikulska and Dariusz Szukiewicz

Biomolecules 2025, 15(7), 1043; https://doi.org/10.3390/biom15071043 - 18 Jul 2025

Viewed by 423

Abstract

β-catenin is a key regulator of osteoblast differentiation, proliferation, and bone homeostasis. Through its interaction with transcription factors such as TCF/LEF, Runx2, and Osx, it coordinates gene expression essential for osteogenesis. The aim of this review is to demonstrate how β-catenin signaling is [...] Read more.

β-catenin is a key regulator of osteoblast differentiation, proliferation, and bone homeostasis. Through its interaction with transcription factors such as TCF/LEF, Runx2, and Osx, it coordinates gene expression essential for osteogenesis. The aim of this review is to demonstrate how β-catenin signaling is modulated by various physiological and pathological factors, including mechanical loading, oxidative stress, HIV-1 gp120, fluoride, implant topography, and microRNAs. These factors influence Wnt/β-catenin signaling through different mechanisms, often exerting opposing effects on osteoblast function. By integrating these modulators, we provide a comprehensive view of the dynamic regulation of β-catenin in bone biology. Understanding this complexity may provide insight into novel therapeutic strategies targeting β-catenin in bone regeneration, metabolic bone diseases, and pathologies such as HIV-associated bone loss or osteosarcoma. Full article

(This article belongs to the Section Molecular Biology)

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13 pages, 726 KiB

Open AccessArticle

Bilirubin Metabolism and Thyroid Cancer: Insights from ALBI and PALBI Indices

by Jong Won Shin, Jae Woong Sull, Nguyen Thien Minh and Sun Ha Jee

Biomolecules 2025, 15(7), 1042; https://doi.org/10.3390/biom15071042 - 18 Jul 2025

Viewed by 354

Abstract

Background: This study evaluated the association between bilirubin subtypes (total, indirect, and direct bilirubin) and thyroid cancer risk, with a particular focus on stratified analyses using the ALBI (Albumin-Bilirubin) and PALBI (Platelet-Albumin-Bilirubin) indices by sex, smoking and drinking status, and age under 50 [...] Read more.

Background: This study evaluated the association between bilirubin subtypes (total, indirect, and direct bilirubin) and thyroid cancer risk, with a particular focus on stratified analyses using the ALBI (Albumin-Bilirubin) and PALBI (Platelet-Albumin-Bilirubin) indices by sex, smoking and drinking status, and age under 50 years. Methods: Data were obtained from 133,596 participants in the Korean Cancer Prevention Study-II (KCPS-II) cohort. During a mean follow-up period of 13.55 years, 2314 cases of thyroid cancer (ICD-10: C73) were identified. Serum bilirubin levels and ALBI and PALBI indices were analyzed using Cox proportional hazards regression models stratified by age, sex, smoking, and alcohol consumption status to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: In women, indirect bilirubin showed the strongest inverse association with thyroid cancer risk. ALBI and PALBI indices based on indirect bilirubin also demonstrated significant associations. A 1 standard deviation (SD) increase in indirect bilirubin was associated with a decreased risk of thyroid cancer (HR: 0.92, 95% CI: 0.84–0.99), and the ALBI index similarly showed an inverse association (HR: 0.92, 95% CI: 0.87–0.99). In contrast, the PALBI index was positively associated with thyroid cancer risk (HR: 1.11, 95% CI: 1.03–1.20). Among women who had never smoked, significant associations were observed for indirect bilirubin (HR: 0.91, 95% CI: 0.83–1.00), ALBI (HR: 0.93, 95% CI: 0.86–1.00), and PALBI (HR: 1.14, 95% CI: 1.05–1.23). In analyses stratified by alcohol consumption, the PALBI index was associated with increased thyroid cancer risk in non-drinkers, former drinkers, and ever drinkers, with respective risk increases of 15%, 18%, and 9%. Conclusions: In women, indirect bilirubin was significantly and inversely associated with thyroid cancer risk, and the ALBI and PALBI indices incorporating indirect bilirubin showed consistent results. These findings suggest that indirect bilirubin may play a critical role in the metabolic pathways underlying thyroid cancer in women. Full article

(This article belongs to the Special Issue Molecular Basis and Oxidative Stress of Thyroid Diseases)

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16 pages, 810 KiB

Open AccessReview

Synergizing Liquid Biopsy and Hybrid PET Imaging for Prognostic Assessment in Prostate Cancer: A Focus Review

by Federica Stracuzzi, Sara Dall’ Armellina, Gayane Aghakhanyan, Salvatore C. Fanni, Giacomo Aringhieri, Lorenzo Faggioni, Emanuele Neri, Duccio Volterrani and Dania Cioni

Biomolecules 2025, 15(7), 1041; https://doi.org/10.3390/biom15071041 - 18 Jul 2025

Viewed by 350

Abstract

Positron emission tomography (PET) and liquid biopsy have independently transformed prostate cancer management. This review explores the complementary roles of PET imaging and liquid biopsy in prostate cancer, focusing on their combined diagnostic, monitoring, and prognostic potential. A systematic search of PubMed, Scopus, [...] Read more.

Positron emission tomography (PET) and liquid biopsy have independently transformed prostate cancer management. This review explores the complementary roles of PET imaging and liquid biopsy in prostate cancer, focusing on their combined diagnostic, monitoring, and prognostic potential. A systematic search of PubMed, Scopus, and Cochrane Library databases was conducted to identify human studies published in English up to January 2025. Seventeen studies met the inclusion criteria and were analyzed according to PRISMA guidelines. Across the included studies, PET-derived imaging metrics, such as metabolic activity and radiotracer uptake, correlated consistently with liquid biopsy biomarkers, including circulating tumor cells and cell-free DNA. Their joint application demonstrated added value in early detection, treatment monitoring, and outcome prediction, particularly in castration-resistant prostate cancer. Independent and synergistic prognostic value was noted for both modalities, including survival outcomes such as overall survival and progression-free survival. Combining PET imaging and liquid biopsy emerges as a promising, non-invasive strategy for improving prostate cancer diagnosis, monitoring, and therapeutic stratification. While preliminary findings are encouraging, large-scale prospective studies are essential to validate their integrated clinical utility. Full article

(This article belongs to the Special Issue Spotlight on Hot Cancer Biological Biomarkers)

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14 pages, 4042 KiB

Open AccessArticle

Conditional Deletion of Translin/Trax in Dopaminergic Neurons Reveals No Impact on Psychostimulant Behaviors or Adiposity

by Yunlong Liu, Renkun Wu, Gaiyuan Geng, Helian Yang, Chunmiao Wang, Mengtian Ren and Xiuping Fu

Biomolecules 2025, 15(7), 1040; https://doi.org/10.3390/biom15071040 - 17 Jul 2025

Viewed by 305

Abstract

Despite the abundant expression of the microRNA-degrading Translin (TN)/Trax (TX) complex in midbrain dopaminergic (DA) neurons and its implication in neuropsychiatric disorders, its cell-autonomous roles in metabolic and behavioral responses remain unclear. To address this, we generated DA neuron-specific conditional knockout (cKO) mice [...] Read more.

Despite the abundant expression of the microRNA-degrading Translin (TN)/Trax (TX) complex in midbrain dopaminergic (DA) neurons and its implication in neuropsychiatric disorders, its cell-autonomous roles in metabolic and behavioral responses remain unclear. To address this, we generated DA neuron-specific conditional knockout (cKO) mice for Tsn (TN) or Tsnax (TX) using DAT-Cre. Immunostaining confirmed efficient TX loss in Tsnax cKO DA neurons without affecting TN, while Tsn deletion abolished TX expression, revealing asymmetric protein dependency. Body composition analysis showed no alterations in adiposity in either cKO model. Locomotor responses to acute or repeated administration of cocaine (20 mg/kg) or amphetamine (2.5 mg/kg) were unchanged in Tsn or Tsnax cKO mice. Furthermore, amphetamine-induced conditioned place preference (1 mg/kg) was unaffected. These results demonstrate that the TN/TX complex within DA neurons is dispensable for regulating adiposity, psychostimulant-induced locomotion (both acute and sensitized), or amphetamine reward-related behavior, suggesting its critical functions may lie outside these specific domains. Full article

(This article belongs to the Section Molecular Genetics)

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14 pages, 3379 KiB

Open AccessArticle

Effects of Isaria cateniannulata and Beauveria bassiana on Buckwheat Growth and Associated Insect Pest

by Xiaona Zhang, Lingdi Gu, Can Liu, Guimin Yang, Xue Yang, Kaifeng Huang and Qingfu Chen

Biomolecules 2025, 15(7), 1039; https://doi.org/10.3390/biom15071039 - 17 Jul 2025

Viewed by 253

Abstract

The Tetranychus urticae Koch (Acari: Tetranychidae) is one of the primary pests affecting buckwheat, and its management has become increasingly critical. Entomopathogenic fungi offer a promising way to solve this problem by providing both pest control and disease resistance, as well as promoting [...] Read more.

The Tetranychus urticae Koch (Acari: Tetranychidae) is one of the primary pests affecting buckwheat, and its management has become increasingly critical. Entomopathogenic fungi offer a promising way to solve this problem by providing both pest control and disease resistance, as well as promoting plant growth through endophytic colonization. This study investigated the effects of applying Isaria cateniannulata (Liang) Samson & Hywel-Jones and Beauveria bassiana (Bals.-Criv.) Vuill. on different buckwheat varieties, and analyzed the physiological indices of buckwheat, the population of T. urticae and Euseius nicholsi (Ehara & Lee). Results showed that the optimum concentration for fungal colonization on buckwheat was 1 × 10⁷ spores/mL. The combined application of I. cateniannulata and B. bassiana significantly enhanced buckwheat growth, with root length, plant height, main stem diameter, fresh weight, and dry weight reaching 63.3 mm, 24.1 cm, 2.1 mm, 2.0 g, and 0.1 g, respectively. The highest escape rate of T. urticae was 76.33%. Furthermore, the combined application of mixed fungal suspension and E. nicholsi had the best control effect on T. urticae, with pest suppression exceeding 97.83% and an oviposition as low as 0.25 eggs per female. This study is the first to demonstrate that the joint application of I. cateniannulata and B. bassiana can promote buckwheat growth and, when combined with predatory mites, effectively control T. urticae. These findings provide a theoretical basis for the development of integrated biocontrol strategies combining entomopathogenic fungi and predatory mites. Full article

(This article belongs to the Special Issue Microbial Biocontrol and Plant-Microbe Interactions)

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30 pages, 1348 KiB

Open AccessReview

Emerging Molecular Mechanisms in Malaria Pathogenesis and Novel Therapeutic Approaches: A Focus on P. falciparum Malaria

by Adekunle Sanyaolu, Aleksandra Marinkovic, Stephanie Prakash, Vyshnavy Balendra, Omar Shazley, Tatiana Gardellini, Abdul Jan, Kokab Younis, Chuku Okorie and Ricardo Izurieta

Biomolecules 2025, 15(7), 1038; https://doi.org/10.3390/biom15071038 - 17 Jul 2025

Viewed by 853

Abstract

Malaria is still one of the biggest global health problems, especially in parts of the world, such as sub-Saharan Africa, which remains most heavily affected. Despite significant advancements in testing, treatment, and prevention, malaria continues to seriously impact millions, primarily young children and [...] Read more.

Malaria is still one of the biggest global health problems, especially in parts of the world, such as sub-Saharan Africa, which remains most heavily affected. Despite significant advancements in testing, treatment, and prevention, malaria continues to seriously impact millions, primarily young children and populations in rural and impoverished areas. This paper looks at how the malaria parasite works inside the body, how it avoids the immune system, and how it becomes resistant to current drugs. Thanks to new advances in genetic and biochemical research, scientists are discovering new weak points in the parasite that could lead to better treatments. New vaccines, like RTS, S and R21, along with antibody-based therapies, offer renewed hope; however, extending the duration of the immunity they induce and ensuring effectiveness across diverse parasite strains remain significant challenges. Solving the malaria crisis will require more than science—it also necessitates equitable and timely access to treatments, robust health systems, and international collaboration. Continued research and global cooperation bring the world closer to ending malaria for good. Full article

(This article belongs to the Special Issue New Insights into Molecular Mechanisms and Therapeutics for Malaria)

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27 pages, 7011 KiB

Open AccessReview

Conceptus Elongation, Implantation, and Early Placental Development in Species with Central Implantation: Pigs, Sheep, and Cows

by Gregory A. Johnson, Thainá Minela, Heewon Seo, Fuller W. Bazer, Robert C. Burghardt, Guoyao Wu, Ky G. Pohler, Claire Stenhouse, Joe W. Cain, Zachary K. Seekford and Dallas R. Soffa

Biomolecules 2025, 15(7), 1037; https://doi.org/10.3390/biom15071037 - 17 Jul 2025

Viewed by 502

Abstract

Species have different strategies for implantation and placentation. Much can be learned about general molecular and cellular biology through the examination and comparison of these differences. To varying degrees, implantation in all species includes alterations in epithelial polarity, the transformation of the endometrial [...] Read more.

Species have different strategies for implantation and placentation. Much can be learned about general molecular and cellular biology through the examination and comparison of these differences. To varying degrees, implantation in all species includes alterations in epithelial polarity, the transformation of the endometrial stroma, the differentiation of the trophoblast, cell-to-cell and tissue-to-tissue signaling through hormones, cytokines, and extracellular vesicles, and the alteration of the maternal immune system. This review focuses on implantation in pigs, sheep, and cows. These species share with mice/rats and humans/primates the key events of early embryonic development, pregnancy recognition, and the establishment of functional placentation. However, there are differences between the pregnancies of livestock and other species that make livestock unique biomedical models for the study of pregnancy and cell biology in general. Pig, sheep, and cow conceptuses (embryo/fetus and associated placental membranes) elongate prior to implantation, displaying central implantation, extended periods of conceptus attachment to the uterus, and epitheliochorial (pigs) and synepitheliochorial (sheep and cows) placentation. This review will discuss what is understood about how the trophoblast and extraembryonic endoderm of pig, sheep, and cow conceptuses elongate, and how a major goal of current in vitro models is to achieve conceptus elongation. It will then examine the adhesion cascade for conceptus implantation that initiates early placental development in pigs, sheep, and cows. Finally, it will conclude with a brief overview of early placental development in pigs, sheep, and cows, with a listing of some important “omics” studies that have been published. Full article

(This article belongs to the Special Issue Embryo Implantation: New Molecular Insights in Endometrial Receptivity, Trophoblast Invasion and Signaling)

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19 pages, 2563 KiB

Open AccessReview

The Intricate Process of Calcification in Granuloma Formation and the Complications Following M. tuberculosis Infection

by Nickolas Yedgarian, Jacqueline Agopian, Brandon Flaig, Fouad Hajjar, Arshavir Karapetyan, Kannan Murthy, Ani Patrikyan, Kirakos Tomas, Kevin Tumanyan, Mohammad J. Nasiri, Selvakumar Subbian and Vishwanath Venketaraman

Biomolecules 2025, 15(7), 1036; https://doi.org/10.3390/biom15071036 - 17 Jul 2025

Viewed by 466

Abstract

Mycobacterium tuberculosis—an acid-fast staining bacterium—is a serious global health challenge that can have both short-term and long-term complications. Although the immune response helps trap the infection, it can also cause necrosis and calcification, leading to lung tissue damage. Calcification is a known [...] Read more.

Mycobacterium tuberculosis—an acid-fast staining bacterium—is a serious global health challenge that can have both short-term and long-term complications. Although the immune response helps trap the infection, it can also cause necrosis and calcification, leading to lung tissue damage. Calcification is a known outcome of chronic granuloma evolution in TB. Multiple pathways contribute to fibrosis and calcification; some examples are IL-1β, TGF-β, and TNF-α. Current antifibrotic drugs, such as nintedanib and pirfenidone, are effective but may increase the risk of latent tuberculosis reactivation in certain patients. Experimental therapies such as artemisinin derivatives have shown promise in preclinical TB fibrosis models, while cell-based therapies like bone marrow-derived mononuclear cells are also under early investigation for dual antifibrotic and immunomodulatory effects. This literature review will explore recent studies on the pathogenesis of M. tuberculosis, the mechanisms underlying calcification in granuloma formation, and subsequent complications of the disease process. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Infectious Pathogen Adaptation, Emergence, and Re-emergence)

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18 pages, 7149 KiB

Open AccessArticle

Co-Inhibition of PARP and STAT3 as a Promising Approach for Triple-Negative Breast Cancer

by Changyou Shi, Li Pan, Satomi Amano, Mei-Yi Wu, Chenglong Li and Jiayuh Lin

Biomolecules 2025, 15(7), 1035; https://doi.org/10.3390/biom15071035 - 17 Jul 2025

Viewed by 386

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk [...] Read more.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk early-stage settings. However, acquired resistance to PARP inhibitors and their limited applicability in non-BRCA TNBCs are now two major growing clinical problems. Activation of the IL-6/STAT3 signaling cascade has been implicated in therapeutic resistance. In this study, we evaluated the combined effects of the PARP inhibitor olaparib and the STAT3 inhibitor LLL12B in human TNBC cell lines with both BRCA mutations and wild-type BRCA status. Our results demonstrate that the PARP inhibitor olaparib can induce increased interleukin-6 (IL-6) in TNBC cells, with ELISA showing a 2- to 39-fold increase across five cell lines. MTT assays revealed that knocking down or inhibiting STAT3, a key downstream effector of the IL-6/GP130 pathway, sensitizes TNBC cells to olaparib. Treatment with either olaparib or LLL12B alone reduced TNBC cell viability, migration, and invasion. Notably, their combined administration produced a markedly enhanced inhibitory effect compared to individual treatments, regardless of BRCA mutation status. These findings highlight the potential of dual PARP and STAT3 inhibition as a novel targeted therapeutic strategy for both BRCA-mutant and BRCA-proficient TNBC. Full article

(This article belongs to the Special Issue PARPs in Cell Death and PARP Inhibitors in Cancers: 2nd Edition)

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16 pages, 805 KiB

Open AccessReview

Heparin, Heparin-like Molecules, and Heparin Mimetics in Breast Cancer: A Concise Review

by Diego R. Gatica Portillo, Yishu Li, Navneet Goyal, Brian G. Rowan, Rami A. Al-Horani and Muralidharan Anbalagan

Biomolecules 2025, 15(7), 1034; https://doi.org/10.3390/biom15071034 - 17 Jul 2025

Viewed by 354

Abstract

Heparin and heparan sulfate are essential in various biological processes relevant to cancer biology and pathology. Given the clinical importance of breast cancer, it is of high interest to seek more effective and safer treatment. The application of heparins (UFH, LMWH, ULMWH, fondaparinux) [...] Read more.

Heparin and heparan sulfate are essential in various biological processes relevant to cancer biology and pathology. Given the clinical importance of breast cancer, it is of high interest to seek more effective and safer treatment. The application of heparins (UFH, LMWH, ULMWH, fondaparinux) and heparin mimetics as potential treatments is particularly interesting. Their use led to promising results in various breast cancer models by exhibiting anti-angiogenic and anti-metastatic properties. This article concisely reviews studies involving heparins and mimetics in both in vitro and in vivo breast cancer settings. We highlight molecules, conjugates, delivery systems, and combinations involving heparin or its mimetics. We also survey several potential biological targets such as VEGF, FGF-2, TGFβ-1, PDGF-B, NPP-1, CXCL12-CXCR4 axis, and CCR7-CCL21 axis. Overall, heparins and their mimetics, conjugates, and combinations represent a powerful strategy to effectively and safely treat breast cancer, which is the most common cancer diagnosed in women worldwide and the fifth leading cause of cancer-related deaths worldwide. Full article

(This article belongs to the Special Issue Advances in Glycosaminoglycans (GAGs) and Mimetics)

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13 pages, 2208 KiB

Open AccessArticle

Electrophysiological Characterization of Sex-Dependent Hypnosis by an Endogenous Neuroactive Steroid Epipregnanolone

by Tamara Timic Stamenic, Ian Coulter, Douglas F. Covey and Slobodan M. Todorovic

Biomolecules 2025, 15(7), 1033; https://doi.org/10.3390/biom15071033 - 17 Jul 2025

Viewed by 407

Abstract

Neuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone [...] Read more.

Neuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone (EpiP) in wild-type mice using behavioral assessment of hypnosis (loss of righting reflex, LORR) and in vivo electrophysiological recordings. Specifically, local field potentials (LFPs) were recorded from the central medial thalamus (CMT) and electroencephalogram (EEG) signals were recorded from the barrel cortex. We found that EpiP-induced LORR exhibited clear sex differences, with females showing increased sensitivity. Spectral power analysis and thalamocortical (TC) and corticocortical (CC) phase synchronization further supported enhanced hypnotic susceptibility in female mice. Our findings reveal characteristic sex-dependent effects of EpiP on the synchronized electrical activity in both thalamus and cortex. These results support renewed exploration of endogenous NAS as clinically relevant anesthetic agents. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease: 2nd Edition)

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21 pages, 4209 KiB

Open AccessArticle

The Upregulation of L1CAM by SVHRSP Mitigates Neuron Damage, Spontaneous Seizures, and Cognitive Dysfunction in a Kainic Acid-Induced Rat Model of Epilepsy

by Zhen Li, Biying Ge, Haoqi Li, Chunyao Huang, Yunhan Ji, Melitta Schachner, Shengming Yin, Sheng Li and Jie Zhao

Biomolecules 2025, 15(7), 1032; https://doi.org/10.3390/biom15071032 - 17 Jul 2025

Viewed by 415

Abstract

Temporal lobe epilepsy (TLE) is a common drug-resistant form of epilepsy, often accompanied by cognitive and emotional disturbances, highlighting the urgent need for novel therapies. Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP), isolated and synthetically derived from scorpion venom, has shown anti-epileptic and neuroprotective [...] Read more.

Temporal lobe epilepsy (TLE) is a common drug-resistant form of epilepsy, often accompanied by cognitive and emotional disturbances, highlighting the urgent need for novel therapies. Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP), isolated and synthetically derived from scorpion venom, has shown anti-epileptic and neuroprotective potential. This study evaluated the anti-epileptic effects of SVHRSP in a kainic acid (KA)-induced TLE rat model. Our results demonstrated that SVHRSP (0.81 mg/kg/day) reduced the frequency and severity of spontaneous seizures. Behavioral tests showed improved cognitive performance in the novel object recognition, object location, and T-maze tasks, as well as reduced anxiety-like behavior in the open-field test. Moreover, SVHRSP mitigated hippocampal neuronal loss and glial activation. Transcriptomic analysis indicated that SVHRSP upregulates genes involved in adhesion molecule-triggered and axon guidance pathways. Western blotting and immunofluorescence further confirmed that SVHRSP restored dendritic (MAP2), axonal (NFL), and synaptic (PSD95) marker expression, elevated the functionally important L1CAM fragment (L1-70), and increased myelin basic protein-induced serine protease activity responsible for L1-70 generation. Blockade of L1CAM expression diminished the neuroprotective effects of SVHRSP, suggesting a critical role for L1CAM-mediated synapse functions. This study is the first to reveal the therapeutic potential of SVHRSP in TLE via L1CAM-associated mechanisms. Full article

(This article belongs to the Section Molecular Medicine)

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23 pages, 1935 KiB

Open AccessReview

Heterologous Caseins: The Role of Phosphorylation in Their Functionality and How to Achieve It

by Soledad Mora Vásquez, Santiago García-Jacobo, Guy A. Cardineau and Silverio García-Lara

Biomolecules 2025, 15(7), 1031; https://doi.org/10.3390/biom15071031 - 17 Jul 2025

Viewed by 340

Abstract

Heterologous expression of caseins in non-mammalian systems offers a sustainable and scalable alternative for producing milk proteins, with potential applications in the food and biopharmaceutical industries. However, a significant challenge in these systems is achieving proper phosphorylation, a critical post-translational modification required for [...] Read more.

Heterologous expression of caseins in non-mammalian systems offers a sustainable and scalable alternative for producing milk proteins, with potential applications in the food and biopharmaceutical industries. However, a significant challenge in these systems is achieving proper phosphorylation, a critical post-translational modification required for casein functionality and stability. This review explores the current state of research on heterologous casein production, with a particular focus on the biological and technical hurdles associated with phosphorylation. Specifically, we examine the absence of the mammalian-specific kinase Fam20C in plant and yeast systems and the broader lack of secretory kinase machinery in bacteria, which collectively contribute to impaired phosphorylation fidelity. While some endogenous kinases may partially compensate, they are typically insufficient to replicate the phosphorylation pattern required for functionality. We evaluate potential strategies to address these limitations, analyze the role of phosphorylation in casein functionality, provide insights into existing patents and experimental approaches, and highlight ongoing research efforts. By synthesizing current knowledge and proposing new avenues for innovation, this review aims to provide a roadmap for the successful production of functional heterologous caseins. Full article

(This article belongs to the Section Molecular Biology)

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10 pages, 1970 KiB

Open AccessCorrection

Correction: Lambert et al. Cytochalasans and Their Impact on Actin Filament Remodeling. Biomolecules 2023, 13, 1247

by Christopher Lambert, Katharina Schmidt, Marius Karger, Marc Stadler, Theresia E. B. Stradal and Klemens Rottner

Biomolecules 2025, 15(7), 1030; https://doi.org/10.3390/biom15071030 - 16 Jul 2025

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Abstract

In the original publication [...] Full article

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16 pages, 1415 KiB

Open AccessArticle

Targeted Overexpression of Mitochondrial ALDH2 in Coronary Endothelial Cells Mitigates HFpEF in a Diabetic Mouse Model

by Guodong Pan, Bipradas Roy, Emmanuel Oppong Yeboah, Thomas Lanigan, Roland Hilgarth, Rajarajan A. Thandavarayan, Michael C. Petriello, Shailendra Giri and Suresh Selvaraj Palaniyandi

Biomolecules 2025, 15(7), 1029; https://doi.org/10.3390/biom15071029 - 16 Jul 2025

Viewed by 398

Abstract

Heart failure (HF) has become an epidemic, with a prevalence of ~7 million cases in the USA. Despite accounting for nearly 50% of all HF cases, heart failure with a preserved ejection fraction (HFpEF) remains challenging to treat. Common pathophysiological mechanisms in HFpEF [...] Read more.

Heart failure (HF) has become an epidemic, with a prevalence of ~7 million cases in the USA. Despite accounting for nearly 50% of all HF cases, heart failure with a preserved ejection fraction (HFpEF) remains challenging to treat. Common pathophysiological mechanisms in HFpEF include oxidative stress, microvascular dysfunction, and chronic unresolved inflammation. Our lab focuses on oxidative stress-mediated cellular dysfunction, particularly the toxic effects of lipid peroxidation products like 4-hydroxy-2-nonenal (4HNE). Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, plays a vital role in detoxifying 4HNE and thereby protecting the heart against pathological stress. ALDH2 activity is reduced in various metabolic stress-mediated cardiac pathologies. The dysfunction of coronary vascular endothelial cells (CVECs) is critical in initiating HFpEF development. Thus, we hypothesized that ectopic overexpression of ALDH2 in CVECs could mitigate metabolic stress-induced HFpEF pathogenesis. In this study, we tested the efficacy of intracardiac injections of the ALDH2 gene into CVECs in db/db mice—a model of obesity-induced type 2 diabetes mellitus (T2DM)—and their controls, db/m mice, by injection with ALDH2 constructs (AAV9-VE-cadherin-hALDH2-HA tag-P2A) or control constructs (AAV9-VE-cadherin-HA tag-P2A-eGFP). We found that intracardiac ALDH2 gene transfer increased ALDH2 levels specifically in CVECs compared to other myocardial cells. Additionally, we observed increased ALDH2 levels and activity, along with decreased 4HNE adducts, in the hearts of mice receiving ALDH2 gene transfer compared to control GFP transfer. Furthermore, ALDH2 gene transfer to CVECs improved diastolic function compared to GFP control alone. In conclusion, ectopic ALDH2 expression in CVECs can contribute, at least partially, to the amelioration of HFpEF. Full article

(This article belongs to the Special Issue Mitochondrial Proteins: From Import and Biogenesis to Complex Functional Network)

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21 pages, 3177 KiB

Open AccessReview

Galectin-3: Integrator of Signaling via Hexosamine Flux

by Mana Mohan Mukherjee, Devin Biesbrock and John Allan Hanover

Biomolecules 2025, 15(7), 1028; https://doi.org/10.3390/biom15071028 - 16 Jul 2025

Viewed by 254

Abstract

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a prognostic indicator for multiple clinically important disorders, including cardiovascular disease. Gal-3 binds to cell surface glycans to form lattices that modulate [...] Read more.

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a prognostic indicator for multiple clinically important disorders, including cardiovascular disease. Gal-3 binds to cell surface glycans to form lattices that modulate surface receptor signaling and internalization. However, the tissue-specific regulation of Gal-3 surface expression remains poorly understood. Here, we review evidence for the involvement of Gal-3 in cell surface signaling, intranuclear events, and intracellular trafficking. Our focus will be on the O-GlcNAc modification as a regulator of Gal-3 biosynthesis, non-canonical secretion, and recycling. We argue that the nutrient-driven cytoplasmic hexosamine biosynthetic pathway (HBP) and endomembrane transport mechanisms generate unique pools of nucleotide sugars. The differing levels of nucleotide sugars in the cytosol, endoplasmic reticulum (ER), and Golgi apparatus generate differential thresholds for the responsiveness of O-GlcNAc cycling, N- and O-linked glycan synthesis/branching, and glycolipid synthesis. By regulating Gal-3 synthesis and non-canonical secretion, O-GlcNAc cycling may serve as a nexus constraining Gal-3 cell surface expression and lattice formation. This homeostatic feedback mechanism would be critical under conditions where extensive glycan synthesis and branching in the endomembrane system and on the cell surface are maintained by elevated hexosamine synthesis. Thus, O-GlcNAc cycling and Gal-3 synergize to regulate Gal-3 secretion and influence cellular signaling. In humans, Gal-3 serves as an early-stage prognostic indicator for heart disease, kidney disease, viral infection, autoimmune disease, and neurodegenerative disorders. Since O-GlcNAc cycling has also been linked to these pathologic states, exploring the interconnections between O-GlcNAc cycling and Gal-3 expression and synthesis is likely to emerge as an exciting area of research. Full article

(This article belongs to the Special Issue Cell Biology and Biomedical Application of Galectins)

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53 pages, 2310 KiB

Open AccessReview

Metabolic Reprogramming in Respiratory Viral Infections: A Focus on SARS-CoV-2, Influenza, and Respiratory Syncytial Virus

by Jordi Camps, Simona Iftimie, Andrea Jiménez-Franco, Antoni Castro and Jorge Joven

Biomolecules 2025, 15(7), 1027; https://doi.org/10.3390/biom15071027 - 16 Jul 2025

Viewed by 442

Abstract

Respiratory infections caused by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus pose significant global health challenges, leading to high morbidity and mortality, particularly in vulnerable populations. Despite their distinct virological characteristics, these viruses exploit host cellular metabolism to [...] Read more.

Respiratory infections caused by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus pose significant global health challenges, leading to high morbidity and mortality, particularly in vulnerable populations. Despite their distinct virological characteristics, these viruses exploit host cellular metabolism to support replication, modulate immune responses, and promote disease progression. Emerging evidence shows that they induce metabolic reprogramming, shifting cellular energy production toward glycolysis to meet the bioenergetic demands of viral replication. Additionally, alterations in lipid metabolism, including enhanced fatty acid synthesis and disrupted cholesterol homeostasis, facilitate viral entry, replication, and immune evasion. The dysregulation of mitochondrial function and oxidative stress pathways also contributes to disease severity and long-term complications, such as persistent inflammation and immune exhaustion. Understanding these metabolic shifts is crucial for identifying new therapeutic targets and novel biomarkers for early disease detection, prognosis, and patient stratification. This review provides an overview of the metabolic alterations induced by severe acute respiratory syndrome coronavirus 2, influenza virus, and respiratory syncytial virus, highlighting shared and virus-specific mechanisms and potential therapeutic interventions. Full article

(This article belongs to the Special Issue Metabolic Pathways, COVID-19 and Other Viral Acute Respiratory Infections: Mechanisms and Clinical Implications: 2nd Edition)

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30 pages, 1106 KiB

Open AccessReview

Transcription-Coupled Nucleotide Excision Repair: A Faster Solution or the Only Option?

by Andriy Khobta and Leen Sarmini

Biomolecules 2025, 15(7), 1026; https://doi.org/10.3390/biom15071026 - 16 Jul 2025

Viewed by 471

Abstract

A branch of the nucleotide excision repair (NER) pathway, transcription-coupled repair (TCR or TC-NER) specifically operates on the template DNA strand of actively transcribed genes. Initiated by stalling of elongating RNA polymerase complexes at damaged sites, TC-NER has historically been viewed as “accelerated [...] Read more.

A branch of the nucleotide excision repair (NER) pathway, transcription-coupled repair (TCR or TC-NER) specifically operates on the template DNA strand of actively transcribed genes. Initiated by stalling of elongating RNA polymerase complexes at damaged sites, TC-NER has historically been viewed as “accelerated repair”, arguably necessary for the maintenance of vital transcription function. Conversely, the conventional “global genome” (GG-NER) mechanism, operating throughout the genome, is usually regarded as a much slower process, even though it has long been found that differences in repair kinetics between transcribed DNA and the rest of the genome are not manifested for all structural types of DNA damage. Considering that damage detection is the rate-limiting step of overall repair reactions in most cases and that the mechanisms of the initial recognition of modified DNA structure are fundamentally different between TC-NER and GG-NER, it is suggestive to attribute the observed kinetic differences to different damage spectra recognized by the two pathways. This review summarizes current knowledge on the differential requirements of TC-NER and GG-NER towards specific damage types, based on their structural rather than spatial characteristics, and highlights some common features of DNA modifications repaired preferentially or exclusively by TC-NER, while evading other repair mechanisms. Full article

(This article belongs to the Special Issue Molecular Mechanisms in DNA and RNA Damage and Repair)

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17 pages, 9983 KiB

Open AccessArticle

Integrated Multi-Omics of the Longissimus Dorsal Muscle Transcriptomics and Metabolomics Reveals Intramuscular Fat Accumulation Mechanism with Diet Energy Differences in Yaks

by Jingying Deng, Pengjia Bao, Ning Li, Siyuan Kong, Tong Wang, Minghao Zhang, Qinran Yu, Xinyu Cao, Jianlei Jia and Ping Yan

Biomolecules 2025, 15(7), 1025; https://doi.org/10.3390/biom15071025 - 16 Jul 2025

Viewed by 221

Abstract

IMF (intramuscular fat, IMF), as a key index for evaluating meat quality traits (shear force and cooking loss, etc.), and its deposition process are jointly regulated by nutritional and genetic factors. In this study, we analyzed the molecular regulation mechanism of IMF deposition [...] Read more.

IMF (intramuscular fat, IMF), as a key index for evaluating meat quality traits (shear force and cooking loss, etc.), and its deposition process are jointly regulated by nutritional and genetic factors. In this study, we analyzed the molecular regulation mechanism of IMF deposition in the LD (longissimus dorsal muscle, LD) by dietary energy level in Pamir yaks. Meat quality assessment showed that the meat quality of the High-energy diet group (1.53 MJ/Kg, G) and the Medium-energy diet group (1.38 MJ/Kg, Z) were significantly improved compared with that of the Low-energy diet group (0.75 MJ/Kg, C), in which IMF content in the LD of yaks in G group was significantly higher (p < 0.05) compared with Z and C groups. Further analysis by combined transcriptomics and lipid metabolomics revealed that the differences in IMF deposition mainly originated from the metabolism of lipids, such as TG (triglycerides, TG), PS (phosphatidylserine, PS), and LPC (lysophosphatidylcholine, LPC), and were influenced by SFRP4, FABP4, GADD45A, PDGFRA, RBP4, and DGAT2 genes, further confirming the importance of lipid–gene interactions in IMF deposition. This study reveals the energy-dependent epigenetic regulatory mechanism of IMF deposition in plateau ruminants, which provides molecular targets for optimizing yak nutritional strategies and quality meat production, while having important theoretical and practical value for the sustainable development of livestock husbandry on the Tibetan Plateau. Full article

(This article belongs to the Section Molecular Genetics)

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