Biomolecules

43 pages, 2332 KiB

Open AccessReview

Application of Microorganisms for the Valorization of Side-Products of Rapeseed De-Oiling

by Michal Jacek Binczarski, Justyna Zuberek, Justyna Fraczyk, Beata Kolesinska, Milivoj Radojčin, Ivan Pavkov, Ewa Wiktorowska-Sowa, Jan Piotrowski, Zbigniew Jerzy Kaminski and Izabela Alina Witonska

Biomolecules 2025, 15(7), 917; https://doi.org/10.3390/biom15070917 (registering DOI) - 22 Jun 2025

Abstract

The increasing demand for sustainable agriculture and environmental protection has prompted the exploration of innovative methods to valorize byproducts from rapeseed oil production. This review focuses on the application of microorganisms as a promising approach to transforming rapeseed de-oiling residues, such as cake [...] Read more.

The increasing demand for sustainable agriculture and environmental protection has prompted the exploration of innovative methods to valorize byproducts from rapeseed oil production. This review focuses on the application of microorganisms as a promising approach to transforming rapeseed de-oiling residues, such as cake and meal, into valuable products. This review discusses traditional and modern methods of rapeseed oil extraction, the composition and challenges posed by rapeseed byproducts, and the presence of antinutritional components such as glucosinolates, erucic acid, and phytic acid. Microbial applications, including the production of industrial enzymes, enhanced digestibility, and the neutralization of antinutritional factors, are examined as key solutions for waste valorization. Additionally, the role of microbial consortia and genetic modification in optimizing transformation processes is discussed. This review underscores the potential of microorganisms in creating eco-friendly, scalable technologies that contribute to resource efficiency and environmental sustainability in the agricultural and biotechnology sectors. Full article

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

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Graphical abstract

33 pages, 1601 KiB

Open AccessReview

Emerging Insights into the Relationship Between Amino Acid Metabolism and Diabetic Cardiomyopathy

by Yi Wen, Xiaozhu Ma, Shuai Mei, Qidamugai Wuyun and Jiangtao Yan

Biomolecules 2025, 15(7), 916; https://doi.org/10.3390/biom15070916 (registering DOI) - 22 Jun 2025

Abstract

Diabetes mellitus (DM) is a complex global pandemic that frequently leads to multiple complications. Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with type 1 and 2 diabetes and is fundamentally characterized by abnormalities in myocardial structure and function. [...] Read more.

Diabetes mellitus (DM) is a complex global pandemic that frequently leads to multiple complications. Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with type 1 and 2 diabetes and is fundamentally characterized by abnormalities in myocardial structure and function. Metabolic disorders occupy a leading role in the pathogenesis of DCM, manifesting as disrupted substrate metabolism, dysregulated signaling pathways, and energy imbalance. Given the limited benefits of conventional therapeutic strategies targeting glucolipid metabolism, increasing research efforts have focused on amino acid metabolism. Amino acids are involved in the synthesis of nitrogen-containing compounds and serve as an energy source under specific conditions. Moreover, emerging studies demonstrate that metabolic disturbances of specific amino acids—such as branched-chain amino acids (BCAAs), glutamine, and arginine—exacerbate mitochondrial dysfunction and oxidative stress, thereby promoting myocardial fibrosis and cardiomyocyte injury. Therefore, this review aims to summarize the general characteristics and regulatory pathways of amino acid metabolism, as well as the specific mechanisms by which metabolic alterations of amino acids contribute to the pathogenesis and progression of diabetic cardiomyopathy, with the hope of advancing more effective translational therapeutic approaches. Full article

(This article belongs to the Section Molecular Medicine)

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28 pages, 2595 KiB

Open AccessReview

Autophagy: Shedding Light on the Mechanisms and Multifaceted Roles in Cancers

by Hongmei You, Ling Wang, Hongwu Meng, Jun Li and Guoying Fang

Biomolecules 2025, 15(7), 915; https://doi.org/10.3390/biom15070915 (registering DOI) - 22 Jun 2025

Abstract

Autophagy, an evolutionarily conserved self-degradation catabolic mechanism, is crucial for recycling breakdown products and degrading intracellular components such as cytoplasmic organelles, macromolecules, and proteins in eukaryotes. The process, which can be selective or non-selective, involves the removal of specific ribosomes, protein aggregates, and [...] Read more.

Autophagy, an evolutionarily conserved self-degradation catabolic mechanism, is crucial for recycling breakdown products and degrading intracellular components such as cytoplasmic organelles, macromolecules, and proteins in eukaryotes. The process, which can be selective or non-selective, involves the removal of specific ribosomes, protein aggregates, and organelles. Although the specific mechanisms governing various aspects of selective autophagy have not been fully understood, numerous studies have revealed that the dysregulation of autophagy-related genes significantly influences cellular homeostasis and contributes to a wide range of human diseases, particularly cancers, neurodegenerative disorders and inflammatory diseases. Notably, accumulating evidence highlights the complex, dual role of autophagy in cancer development. Thus, this review systematically summarizes the molecular mechanisms of autophagy and presents the latest research on its involvement in both pro- and anti-tumor progression. Furthermore, we discuss the role of autophagy in cancer development and summarize advancement in tumor therapies targeting autophagy. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 523 KiB

Open AccessArticle

Inflammatory Drug-Resistant Epilepsy Index (IDREI) as a Molecular Compound Biomarker in Focal Epilepsies

by Maria José Aguilar-Castillo, Guillermo Estivill-Torrús, Guillermina García-Martín, Pablo Cabezudo-García, Yolanda López-Moreno, Jesús Ortega-Pinazo, Teresa Ramírez-García, Nicolas Lundahl Ciano-Petersen and Pedro Jesus Serrano-Castro

Biomolecules 2025, 15(7), 914; https://doi.org/10.3390/biom15070914 (registering DOI) - 22 Jun 2025

Abstract

Background: There is growing evidence that neuroinflammation is involved in epileptogenesis. Identifying its biomarkers can be important for distinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from drug-resistant epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved [...] Read more.

Background: There is growing evidence that neuroinflammation is involved in epileptogenesis. Identifying its biomarkers can be important for distinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from drug-resistant epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved epilepsy patients divided into three groups: healthy controls (HC), seizure-free epilepsy (SFE), and DRE. Demographic and clinical data and plasmatic and/or CSF levels of 24 different inflammation-related molecules were collected for each patient and were analyzed through univariate and multivariate analysis. Results: The study included 68 patients: 38 in the DRE group, 14 in the SFE group, and 16 in the HC group. A new Inflammatory Drug-Resistant Epilepsy Index (IDREI) was created using key variables with significant or trending significance. This index combined pro-inflammatory mediators (ICAM-1 and NfL) and anti-inflammatory factors (IL-10 and IL-4), showing statistical significance (p = 0.002). ROC curve analysis for the IDREI gave an AUC of 0.731 (95% CI: 0.608–0.854). A multivariate logistic regression model’s ROC analysis resulted in a higher AUC of 0.891 (95% CI: 0.791–0.991). Conclusions: The IDREI molecular index shows promise in predicting epilepsy and drug-resistant epilepsy (DRE). Additional prospective studies are required to assess its clinical utility. Full article

(This article belongs to the Special Issue Molecular Biomarkers of Epileptogenesis)

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16 pages, 1489 KiB

Open AccessReview

Caspase-14-like Proteases: An Epidermal Caspase and Its Evolutionarily Ancient Relatives

by Leopold Eckhart, Attila Placido Sachslehner, Julia Steinbinder and Heinz Fischer

Biomolecules 2025, 15(7), 913; https://doi.org/10.3390/biom15070913 (registering DOI) - 22 Jun 2025

Abstract

Caspases are a family of cysteine-dependent aspartate-directed proteases implicated in programmed cell death. Humans have eleven proteolytically active caspases, namely caspase-1 through -10 and caspase-14. The latter is expressed exclusively in epithelial cells and constitutively resides in its active form in the cornified [...] Read more.

Caspases are a family of cysteine-dependent aspartate-directed proteases implicated in programmed cell death. Humans have eleven proteolytically active caspases, namely caspase-1 through -10 and caspase-14. The latter is expressed exclusively in epithelial cells and constitutively resides in its active form in the cornified layer of the human epidermis. Molecular phylogenetics has revealed that caspase-14 belongs to a subfamily of caspases, which also includes caspase-15 and -16. The latter are evolutionarily more ancient than caspase-14 and have been lost in the phylogenetic lineage leading to humans. Here, we review the molecular properties, the species distributions, and the biological roles of caspase-14-like proteases in amniotes. In contrast to the prodomain-less caspase-14, caspase-15 contains a prodomain that is predicted to assume a pyrin fold, and caspase-16 features a prodomain with unique sequence similarity to the catalytic domain. Gene knockout in mice, evolutionary gene loss in aquatic mammals and the association of human CASP14 mutations with ichthyosis indicate that caspase-14 is associated with the barrier function of mammalian skin. Caspase-15 is able to induce apoptosis in cell culture, but its role in vivo and the role of caspase-16 are currently unknown. We propose directions for research to further characterize caspase-14-like proteases. Full article

(This article belongs to the Section Molecular Biophysics: Structure, Dynamics, and Function)

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27 pages, 3386 KiB

Open AccessReview

The Multifaceted Role of VIRMA, a Core Component of the Methyltransferase Complex, in Cancer and Cancer Therapy

by Jinmeng Lu, Chengyu Zhang, Mengshuang Yin, Huili You, Chao Xiong, Jing Wu, Ying Gong, Zhangang Xiao and Jing Shen

Biomolecules 2025, 15(7), 912; https://doi.org/10.3390/biom15070912 (registering DOI) - 22 Jun 2025

Abstract

VIRMA (also known as KIAA1429), as a core regulatory subunit of the m6A methyltransferase complex, plays a key role in tumorigenesis and progression by dynamically regulating RNA methylation modifications. Studies have shown that VIRMA is aberrantly overexpressed in more than 20 types of [...] Read more.

VIRMA (also known as KIAA1429), as a core regulatory subunit of the m6A methyltransferase complex, plays a key role in tumorigenesis and progression by dynamically regulating RNA methylation modifications. Studies have shown that VIRMA is aberrantly overexpressed in more than 20 types of malignant tumors, including liver cancer, breast cancer, and lung cancer, and is significantly associated with chromosome 8q amplification and poor prognosis. Its mechanism of action involves regulating the expression of tumor-associated genes through both m6A-dependent and m6A-independent pathways, thereby promoting tumor proliferation, metastasis, and drug resistance. These findings suggest that VIRMA has the potential to serve as a pan-cancer diagnostic and prognostic biomarker. This review summarizes the role of VIRMA in malignant tumors from multiple perspectives and explores its potential applications in clinical diagnosis and treatment. Full article

(This article belongs to the Section Molecular Biology)

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16 pages, 3263 KiB

Open AccessReview

Targeting Programmed Cell Death in Flap Ischemia/Reperfusion Injury

by Shengyue Liu, Xiaohe Xiong, Lei Chen, Jiaqi Hu, Ping Luo, Zhanpeng Ou and Fugui Zhang

Biomolecules 2025, 15(7), 911; https://doi.org/10.3390/biom15070911 - 20 Jun 2025

Abstract

A skin flap is a composite tissue unit comprising skin and subcutaneous fat with an intact vascular supply. Skin flaps are commonly employed for wound reconstruction, transplantation of damaged tissues, and cosmetic procedures. However, flap necrosis resulting from ischemia/reperfusion injury (IRI) is a [...] Read more.

A skin flap is a composite tissue unit comprising skin and subcutaneous fat with an intact vascular supply. Skin flaps are commonly employed for wound reconstruction, transplantation of damaged tissues, and cosmetic procedures. However, flap necrosis resulting from ischemia/reperfusion injury (IRI) is a frequent complication, leading to surgical failure. Therefore, This review systematically summarizes the mechanisms and therapeutic interventions targeting specific modalities of programmed cell death (PCD) in the context of IRI compromising flap survival. These interventions encompass a range of strategies, including preconditioning, systemic administration, and local drug delivery. Furthermore, we summarize key therapeutic targets for various types of PCD, along with shared pathways and therapies applicable across multiple PCD modalities. The findings presented in this review validate the feasibility of targeted therapies against PCD to prevent post-reconstructive flap necrosis. These findings provide novel strategies, such as targeting common pathways in PCD and leveraging diverse biomaterials, to enhance therapeutic outcomes. Further clinical investigations are warranted to target PCD pathways for the treatment of flap necrosis. Full article

(This article belongs to the Special Issue Necrotic Cell Death Mechanisms and Therapies)

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25 pages, 1445 KiB

Open AccessReview

The Role of Astrocytes in Synaptic Dysfunction and Memory Deficits in Alzheimer’s Disease

by Cristina A. Muñoz de León-López, Irene Navarro-Lobato and Zafar U. Khan

Biomolecules 2025, 15(7), 910; https://doi.org/10.3390/biom15070910 - 20 Jun 2025

Abstract

Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes [...] Read more.

Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes express various receptors, transporters, gliotransmitters, and other molecules that enable them to sense and respond to external signals. They are also implicated in amyloid-β clearance. In Alzheimer’s disease, excessive accumulation of amyloid-β induces the polarization of astrocytes into the A1 phenotype, promoting the release of inflammatory cytokines and mitochondrial reactive oxygen species, leading to alterations in astrocytic functions. Under such conditions, gliotransmitter release, glutamate neurotransmission, AMPA receptor trafficking, and both Hebbian and non-Hebbian forms of synaptic plasticity—biological activities essential for synaptic functions—are compromised. Moreover, astrocytes are essential for learning, memory, and synaptic plasticity, and alterations in their function are associated with memory deficits in Alzheimer’s disease. This review provides an overview of the current understanding of the defects in astrocytes that lead to altered synaptic functions, neuronal structural plasticity, and memory deficits in Alzheimer’s disease. Full article

(This article belongs to the Special Issue The Role of Astrocytes in Neurodegenerative Diseases)

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16 pages, 1041 KiB

Open AccessReview

The Role of SLPI Gene-Mediated Inflammation in Osteoarthritis

by Mahmuda Siddika Shefa and Wanil Kim

Biomolecules 2025, 15(7), 909; https://doi.org/10.3390/biom15070909 - 20 Jun 2025

Abstract

Osteoarthritis (OA) is a degenerative disease of joint tissue characterized by the breaking down of cartilage and resulting changes in synovium and bone. Mechanics and biology interact in a feed-forward manner in that imbalanced joint loading leads to tissue degeneration and vice versa. [...] Read more.

Osteoarthritis (OA) is a degenerative disease of joint tissue characterized by the breaking down of cartilage and resulting changes in synovium and bone. Mechanics and biology interact in a feed-forward manner in that imbalanced joint loading leads to tissue degeneration and vice versa. Amid numerous genetic factors, the Secretory Leukocyte Protease Inhibitor (SLPI) gene encodes a protein that plays a crucial role in inhibiting proteases, modulating inflammation, promoting tissue repair, and regulating immune responses. In the context of OA, SLPI has been identified as a key regulator in joint homeostasis. The release of SLPI in human tissues is augmented by pro-inflammatory factors. Such factors include cytokines released during infection or inflammatory processes, such as interleukins-1 and 6 (IL-1 and IL-6), and tumor necrosis factor alpha (TNF-α) released in many inflammatory rheumatic diseases. In this work, a comprehensive review of SLPI-mediated inflammation in OA, its biological functions, and its association with OA is described, providing a foundation for future investigations into its potential therapeutic use. As there is no effective strategy to treat or prevent OA in clinic, further investigation is encouraged to explore the translational possibility of SLPI for drug development. Full article

(This article belongs to the Section Molecular Biomarkers)

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15 pages, 5419 KiB

Open AccessArticle

Exploring the Antimicrobial and Immunomodulatory Potential of Gecko-Derived Cathelicidin Gj-CATH5

by Shasha Cai, Ningyang Gao, Junhan Wang and Jing Li

Biomolecules 2025, 15(7), 908; https://doi.org/10.3390/biom15070908 - 20 Jun 2025

Abstract

Regulating the innate immune response against infections, particularly drug-resistant bacteria, is a key focus in anti-infection therapy. Cathelicidins, found in vertebrates, are crucial for pathogen resistance. Few studies have explored gecko cathelicidins’ anti-infection properties. Recently, five new cathelicidins (Gj-CATH1-5) were identified in Gekko [...] Read more.

Regulating the innate immune response against infections, particularly drug-resistant bacteria, is a key focus in anti-infection therapy. Cathelicidins, found in vertebrates, are crucial for pathogen resistance. Few studies have explored gecko cathelicidins’ anti-infection properties. Recently, five new cathelicidins (Gj-CATH1-5) were identified in Gekko japonicus. The peptide Gj-CATH5, from G. japonicus, shows promise against Pseudomonas aeruginosa through various mechanisms. This study examined Gj-CATH5’s protective effects using in vitro and in vivo models, finding that it significantly reduced bacterial load in a mouse infection model when administered before or shortly after infection. Flow cytometry and the plate counting method showed that Gj-CATH5 boosts neutrophil and macrophage activity, enhancing chemotaxis, phagocytosis, and bactericidal functions. Gj-CATH5 increases ROS production, MPO activity, and NET formation, aiding pathogen clearance. Its amphipathic α-helical structure supports broad-spectrum bactericidal activity (MBC: 4–8 μg/mL) against Gram-negative and antibiotic-resistant bacteria. Gj-CATH5 is minimally cytotoxic (<8% hemolysis at 200 μg/mL) and preserves cell viability at therapeutic levels. These results highlight Gj-CATH5’s dual role in pathogen elimination and immune modulation, offering a promising approach to combat multidrug-resistant infections while reducing inflammation. This study enhances the understanding of reptilian cathelicidins and lays the groundwork for peptide-based immune therapies against difficult bacterial infections. Full article

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

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15 pages, 2142 KiB

Open AccessArticle

DNA Damage Response Regulation Alleviates Neuroinflammation in a Mouse Model of α-Synucleinopathy

by Sazzad Khan, Himanshi Singh, Jianfeng Xiao and Mohammad Moshahid Khan

Biomolecules 2025, 15(7), 907; https://doi.org/10.3390/biom15070907 - 20 Jun 2025

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression [...] Read more.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach. Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks. In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapeutic Approaches of Neurodegenerative Diseases)

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21 pages, 6109 KiB

Open AccessArticle

Transcriptome Analysis Reveals PpMYB1 and PpbHLH1 Promote Anthocyanin Accumulation in Phalaenopsis pulcherrima Flowers

by Jianqiang Wen, Ji Li, Kunlin Wu, Jingjue Zeng, Lin Li, Lin Fang and Songjun Zeng

Biomolecules 2025, 15(7), 906; https://doi.org/10.3390/biom15070906 - 20 Jun 2025

Abstract

Phalaenopsis pulcherrima are known for their captivating floral morphology and diverse colors, demonstrate exceptional resilience to adverse environmental conditions, and exhibit significant potential for hybrid breeding. However, current research on flower coloration is still limited. The data from this study indicates that variations [...] Read more.

Phalaenopsis pulcherrima are known for their captivating floral morphology and diverse colors, demonstrate exceptional resilience to adverse environmental conditions, and exhibit significant potential for hybrid breeding. However, current research on flower coloration is still limited. The data from this study indicates that variations in anthocyanin levels are the primary determinants of the difference between white and purple colors. Through RNA-seq, we identified 469 genes that were differentially expressed. Furthermore, our bioinformatics exploration uncovered two potential transcription factors, PpMYB1 and PpbHLH1, which play regulatory roles in anthocyanin accumulation. Y2H assays demonstrated that these two TFs could form heterodimers and interact with each other. Afterwards, transient expression assays were conducted for the first time in P. pulcherrima flowers, revealing that overexpression of PpMYB1 alone or in combination with PpbHLH1 resulted in purple petal pigmentation. Overexpressing PpMYB1 in tobacco resulted in more purple-colored corollas, stamens, pistils, and pods compared to control plants. Y1H and dual-luciferase assays provided further evidence that PpMYB1 and PpbHLH1 interact with the promoters of the structural genes PpF3H, PpDFR, and PpANS in the anthocyanin biosynthesis pathway, thereby driving their robust expression. This study not only enhances our understanding of the molecular mechanisms underlying anthocyanin synthesis but also holds significant practical implications for advancing plant hybrid breeding and genetic engineering applications in flower color regulation. Full article

(This article belongs to the Section Molecular Biology)

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13 pages, 1444 KiB

Open AccessArticle

Cycloadditions as a Sweet Route to ‘Double C-Glycosylation’

by Kevin P. P. Mahoney, Rosemary Lynch, Rhea T. Bown, Sunil V. Sharma, Piyasiri Chueakwon, G. Richard Stephenson, David B. Cordes, Alexandra M. Z. Slawin and Rebecca J. M. Goss

Biomolecules 2025, 15(6), 905; https://doi.org/10.3390/biom15060905 - 19 Jun 2025

Abstract

Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and, in natural products, glycosylation [...] Read more.

Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and, in natural products, glycosylation often confers improved bioactivity and bioavailability. Whilst a single C-glycoside link between a sugar moiety and its aglycone core is a common feature in natural products isolated to date, only a small number, including the antibiotics granaticin and sarubicin, are covalently bonded twice to a single sugar moiety. The way in which this “double C-glycosylation” is naturally mediated is not yet known, yet has been speculated on. Here, we report the exploration and development of a potentially biomimetic procedure that utilises intermolecular cycloaddition chemistry to access new “double C-glycosylated” products and enables the creation of bridged polycyclic ethers from a common maltol-derived oxidopyrylium salt precursor. Full article

(This article belongs to the Section Chemical Biology)

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15 pages, 1207 KiB

Open AccessReview

Gene Fusions as Potential Therapeutic Targets in Soft Tissue Sarcomas

by Qiongdan Zheng, Tong Wang, Zijian Zou, Wenjie Ma, Zirui Dong, Jingqin Zhong, Wanlin Liu, Yu Xu, Tu Hu, Wei Sun and Yong Chen

Biomolecules 2025, 15(6), 904; https://doi.org/10.3390/biom15060904 - 19 Jun 2025

Abstract

Though having been discovered in one third of sarcomas, gene fusions are less studied in their roles as potential therapeutic targets, making conventional modalities the mainstream treatment options for sarcoma patients. Recent decades have witnessed encouraging progress in basic research delving into mechanisms [...] Read more.

Though having been discovered in one third of sarcomas, gene fusions are less studied in their roles as potential therapeutic targets, making conventional modalities the mainstream treatment options for sarcoma patients. Recent decades have witnessed encouraging progress in basic research delving into mechanisms underlying how gene fusions drive sarcomas; nevertheless, further translation to clinical application fails to keep abreast with the advances achieved in basic science. In this review, we will focus on key chromosomal translocation-driven sarcomas defined by characteristic hallmark fusion oncoproteins, including Ewing sarcoma with EWSR1–FLI1/ERG fusion, epithelioid hemangioendothelioma with WWTR1–CAMTA1/YAP1–TFE1 fusion, and others, to discuss the potential of directly targeting these fusion proteins as therapeutic targets in preclinical and clinical contexts. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Genetics of Human Disease)

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21 pages, 842 KiB

Open AccessReview

Advances in Local Drug Delivery for Periodontal Treatment: Present Strategies and Future Directions

by Mayuka Nakajima, Mayuko Yanagawa, Honoka Takikawa, Truong Tran Thien, Lorena Zegarra-Caceres, Chunyang Yan and Koichi Tabeta

Biomolecules 2025, 15(6), 903; https://doi.org/10.3390/biom15060903 - 19 Jun 2025

Abstract

Periodontitis is a highly prevalent, irreversible inflammatory disease characterized by the destruction of tooth-supporting tissues, eventually leading to tooth loss. Conventional treatment involves the mechanical removal of the subgingival biofilm, which is a major cause of gingival inflammation. However, the inaccessibility of deep-seated [...] Read more.

Periodontitis is a highly prevalent, irreversible inflammatory disease characterized by the destruction of tooth-supporting tissues, eventually leading to tooth loss. Conventional treatment involves the mechanical removal of the subgingival biofilm, which is a major cause of gingival inflammation. However, the inaccessibility of deep-seated polymicrobial biofilms limits its effectiveness. Despite the adjunct use of systemic antimicrobials, their low site-specific bioavailability and systemic side effects remain concerns. Local drug administration offers a targeted alternative. However, the dynamic oral environment, which is characterized by continuous salivary and gingival crevicular fluid flow, poses challenges in maintaining therapeutic drug levels. Drug delivery systems (DDSs) provide technical solutions to overcome these limitations. With advancements in materials science and nanotechnology, diverse local DDS (LDDS) formulations tailored for periodontal applications have been developed. While traditionally focused on infection control, the application of LDDSs has expanded beyond antimicrobial therapy. Increasing attention has been paid to LDDS-based regenerative strategies, which aim to overcome the limitations of conventional regenerative therapies. This review aims to provide a comprehensive overview of the current and emerging DDS strategies in periodontal therapy, focusing on their applications in infection management and bone regeneration and discussing their limitations and prospects for clinical translation. Full article

(This article belongs to the Special Issue Biologics and Biomaterials for Periodontal Treatment: Current and Future Challenges)

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29 pages, 10703 KiB

Open AccessArticle

Enhanced Therapeutic Efficacy of Omeprazole Nanosuspension in Ethanol-Induced Gastric Ulcer: A Focus on Oxidative Stress and Inflammatory Pathways

by Mody Albalawi and Sahar Khateeb

Biomolecules 2025, 15(6), 902; https://doi.org/10.3390/biom15060902 - 19 Jun 2025

Abstract

Gastric ulcer is a concerning condition that affects numerous individuals globally. Omeprazole (OMP), a well-known drug for treating stomach ulcers, has been associated with several adverse effects and limited solubility. The study aimed to create an omeprazole nanosuspension (OMP-NS) with improved solubility and [...] Read more.

Gastric ulcer is a concerning condition that affects numerous individuals globally. Omeprazole (OMP), a well-known drug for treating stomach ulcers, has been associated with several adverse effects and limited solubility. The study aimed to create an omeprazole nanosuspension (OMP-NS) with improved solubility and bioavailability. Additionally, the study investigated the potential therapeutic effects of OMP-NS on ethanol-induced gastric injury in rats, comparing it to traditional OMP therapy to identify novel therapeutic alternatives. The characterization of the OMP-NS was assessed using DLS, TEM, XRD, FTIR, UV spectrophotometric analysis, in vitro release studies, and entrapment efficiency (EE) assays. A total of 24 male Wistar albino rats (weighing 150–200 g, aged 8–10 weeks) were randomly divided into four groups (six rats/group). Gastric injury was induced using absolute ethanol (5 mL/kg), followed by oral administration of either OMP or OMP-NS (20 mg/kg) for 7 days. Data were analyzed using one-way ANOVA accompanied by the Bonferroni post hoc test or the Kruskal–Wallis test, based on data distribution, with significance set at p < 0.05. The OMP-NS demonstrated a Z-average diameter of 216.1 nm, a polydispersity index of 0.2, and a zeta potential of −19.6 mV. The particles were predominantly spherical with an average size of 67.28 nm. In vitro release studies showed 97.78% release at 8 h, with an EE% of 96.97%. Ethanol-induced gastric ulcers were associated with oxidative stress, characterized by elevated levels of NADPH, ROS, MDA, and NO, while the level of SOD was reduced. It was accompanied by increased inflammatory markers HMGB1, which subsequently increased TLR-2, MyD88, NF-κBp56, NLRP3, TNF-α, IL-1β, and IL-6 levels; conversely, a significant decrease in Nrf2/PPAR-γ/SIRT1 levels was observed. In contrast, OMP-NS administration significantly reduced oxidative stress and inflammatory markers, restored SOD activity, and upregulated protective pathways Nrf2/PPAR-γ/SIRT1 more effectively than conventional OMP therapy. In conclusion, OMP-NS represents a promising therapeutic strategy with notable anti-inflammatory and anti-ulcerogenic effects in ethanol-induced gastric ulcers. Full article

(This article belongs to the Section Cellular Biochemistry)

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17 pages, 1642 KiB

Open AccessReview

Ankyrin-G and Its Binding Partners in Neurons: Orchestrating the Molecular Structure of the Axon Initial Segment

by Xiaowei Zhu, Yanyan Yu, Zhuqian Jiang, Yoshinori Otani and Masashi Fujitani

Biomolecules 2025, 15(6), 901; https://doi.org/10.3390/biom15060901 - 19 Jun 2025

Abstract

The axon initial segment (AIS) is a specialized subcellular domain that plays an essential role in action potential initiation and the diffusion barrier. A key organizer of the AIS is Ankyrin-G, a scaffolding protein responsible for clustering voltage-gated ion channels, cell adhesion molecules [...] Read more.

The axon initial segment (AIS) is a specialized subcellular domain that plays an essential role in action potential initiation and the diffusion barrier. A key organizer of the AIS is Ankyrin-G, a scaffolding protein responsible for clustering voltage-gated ion channels, cell adhesion molecules (CAMs), and cytoskeletal components at this critical neuronal domain. Recent proteomic analyses have revealed a complex network of proteins in the AIS, emphasizing Ankyrin-G’s central role in its molecular architecture. This review discusses new findings in the study of AIS-associated proteins. It explains how Ankyrin-G and its binding partners (such as ion channels, CAMs, spectrins, actin, and microtubule-associated proteins including end-binding protein 3, tripartite motif-containing protein 46, and calmodulin-regulated spectrin-associated protein 2) organize their structure. Understanding the dynamic regulation and molecular interactions within the AIS offers insights into neuronal excitability and reveals potential therapeutic targets for axonal dysfunction–related diseases. Through these dynamic interactions, Ankyrin-G ensures the proper alignment and dense clustering of key channel complexes, thereby maintaining the AIS’s distinctive molecular and functional identity. By further unraveling the complexity of Ankyrin-G’s interactome, our understanding of AIS formation, maintenance, and plasticity will be considerably enhanced, contributing to the elucidation of the pathogenesis of neurological and neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology of Neurodevelopment)

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20 pages, 3130 KiB

Open AccessArticle

Adaptation to Arginine Deprivation Leads to a More Aggressive, Therapy-Resistant Phenotype in HNSCC Cells

by Oleg Chen, Olena Vovk, Nikita Polishchuk, Oksana Mayevska, Galyna Shuvayeva, Melike Demir, Vasyl Lukiyanchuk, Leoni A. Kunz-Schughart, Anna Dubrovska and Oleh Stasyk

Biomolecules 2025, 15(6), 900; https://doi.org/10.3390/biom15060900 - 19 Jun 2025

Abstract

Purpose: The development of acquired resistance to arginine deprivation therapy (ADT) is a major barrier to its efficacy. This study aimed to elucidate the possible mechanisms underlying the resistance to ADT. Methods: We applied repeated ADT and established a subline SAS-R9 of the [...] Read more.

Purpose: The development of acquired resistance to arginine deprivation therapy (ADT) is a major barrier to its efficacy. This study aimed to elucidate the possible mechanisms underlying the resistance to ADT. Methods: We applied repeated ADT and established a subline SAS-R9 of the human head and neck squamous cell carcinoma (HNSCC) cells semi-resistant to arginine (Arg) deprivation in vitro. This subline was compared to the parental SAS cell lines for its relative clonogenic proliferation, aggregation, adhesion, and migration capacities. The transcriptomic changes were assessed by RNA sequencing. Signaling pathway alterations were confirmed by RT-PCR and Western blotting. Relative cell radioresistance was analyzed by radiobiological clonogenic survival assay. DNA double-strand break (DSB) repair was assessed by γH2A.X foci analysis. Results: SAS-R9 cells showed higher survival in response to ADT and radiotherapy, elevated clonogenic proliferation rate, cell–cell aggregation, and cell–matrix adhesion, along with increased epithelial–mesenchymal transition (EMT) markers and enhanced DNA DSB repair, potentially related to a more aggressive and therapy-resistant phenotype. Conclusions: While acute ADT has radiosensitizing potential, this new study suggests that long-term, repeated ADT is associated with cell selection and reprogramming, resulting in resistance to radiotherapy-induced DNA damage and higher tumor cell aggressiveness. Full article

(This article belongs to the Special Issue DNA Damage, Mutagenesis, and Repair Mechanisms)

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20 pages, 2917 KiB

Open AccessReview

HIF-1α: A Key Factor Mediating Tumor Cells from Digestive System to Evade NK Cell Killing via Activating Metalloproteinases to Hydrolyze MICA/B

by Quan Zhu, Shuyi Tang, Ting Huang, Chunjing Chen, Biyuan Liu, Chuyu Xiao, Liugu Chen, Wang Wang and Fangguo Lu

Biomolecules 2025, 15(6), 899; https://doi.org/10.3390/biom15060899 - 19 Jun 2025

Abstract

Malignant tumors of the digestive system are widespread and pose a serious threat to humans. Immune escape is an important factor promoting the deterioration of malignant tumors in the digestive system. Natural killer cells (NK cells) are key members of the anti-tumor and [...] Read more.

Malignant tumors of the digestive system are widespread and pose a serious threat to humans. Immune escape is an important factor promoting the deterioration of malignant tumors in the digestive system. Natural killer cells (NK cells) are key members of the anti-tumor and immune surveillance system, mainly exerting cytotoxic effects by binding to the activating receptor natural killer cell group 2D (NKG2D) on their cell surface with the corresponding ligands (major histocompatibility complex class I chain-related protein A/B, MICA/B) on the surface of tumor cells. Malignant tumors of epithelial origin usually highly express NKG2D ligands such as MICA, which can attract NK cells to kill tumor cells and also serve as an important basis for NK cell-based immunotherapy. Tumor cells highly express hypoxia-inducible factor-1α (HIF-1α), which promotes the expression of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). These metalloproteinases hydrolyze MICA and other ligands on the surface of tumor cells to generate soluble molecules. These soluble ligands, when binding to NKG2D, cannot activate NK cells and also block the binding of NKG2D to MICA on the surface of tumor cells, enabling tumor cells to evade the killing effect of NK cells. Almost all organs in the digestive system originate from epithelial tissue, so the soluble ligands generated by the HIF-1α/MMPs or HIF-1α/ADAMs signaling pathways play a crucial role in evading NK cell killing. A comprehensive understanding of this immune escape process is helpful for a deeper understanding of the molecular mechanism of NK cell anti-tumor activity. This article reviews the molecular mechanisms of common digestive system malignancies evading NK cell killing, providing new insights into the mechanism of tumor immune escape. Full article

(This article belongs to the Section Molecular Medicine)

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