International Journal of Molecular Sciences

29 pages, 4767 KiB

Open AccessArticle

Advancing Measurable Residual Disease Detection in Pediatric BCP-ALL: Insights from Novel Immunophenotypic Markers

by Alexandra Baldzhieva, Hasan Burnusuzov, Hristina Andreeva, Teodora Kalfova, Steliyan Petrov, Dobrina Dudova, Katya Vaseva, Marianna Murdjeva and Hristo Taskov

Int. J. Mol. Sci. 2025, 26(9), 4282; https://doi.org/10.3390/ijms26094282 (registering DOI) - 30 Apr 2025

Abstract

Measurable Residual Disease (MRD) assessment in pediatric acute lymphoblastic leukemia (ALL) is crucial for relapse prediction and treatment guidance. Multiparameter flow cytometry (MFC) enhances detection but faces limitations due to insufficient leukemia-associated immunophenotypes (LAIPs) and antigen modulation. This study explores new markers to [...] Read more.

Measurable Residual Disease (MRD) assessment in pediatric acute lymphoblastic leukemia (ALL) is crucial for relapse prediction and treatment guidance. Multiparameter flow cytometry (MFC) enhances detection but faces limitations due to insufficient leukemia-associated immunophenotypes (LAIPs) and antigen modulation. This study explores new markers to improve MFC-based MRD detection in B-cell precursor ALL (BCP-ALL). Expression-patterns of seven aberrancy markers, i.e., CD44, CD304, CD73, CD86, CD123, CD99, CD58, and one B-cell maturation marker, CD22, were studied in 143 samples with leukemic-blasts from sixty-one childhood BCP-ALL patients and in hematogones of 20 non-leukemic bone marrow (BM) samples using fourteen-color MFC. The highest relative frequences of LAIPs amounted to 82.50%, reported for CD99 and CD58, followed by CD44 (81.10%), CD73 (76.20%), CD22 (73.40%), CD304 and CD86 (68.50%), while the lowest relative frequence was CD123 (44.40%). Differential expression of CD58, CD304, and CD73 in diagnostic samples was highly significant (p < 0.01) between pre-B-I, pre-B-II, immature B cells, and BCP-ALL blasts. In MRD-positive samples CD73 showed significantly high (p < 0.01) differential expression between all stages of hematogones and residual blasts, followed by CD304, CD58, and CD22. CD73 and CD304 were identified as the most reliable among the tested markers for distinguishing both diagnostic and MRD blasts from normal B cell precursors. Full article

(This article belongs to the Special Issue Trends and Prospects of Flow Cytometry in Cell and Molecular Biology)

20 pages, 12622 KiB

Open AccessArticle

Paw Skin as a Translational Model for Investigating Fibrotic and Inflammatory Wound Healing Defects in Recessive Dystrophic Epidermolysis Bullosa

by Cristian De Gregorio, Giselle Ramos-Gonzalez, Bernardo Morales-Catalán, Fernando Ezquer and Marcelo Ezquer

Int. J. Mol. Sci. 2025, 26(9), 4281; https://doi.org/10.3390/ijms26094281 (registering DOI) - 30 Apr 2025

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disease caused by COL7A1 mutations. It leads to skin fragility, chronic inflammation, and impaired wound healing. The condition often results in fibrotic scarring, pseudosyndactyly, and cutaneous squamous cell carcinoma (SCC). However, current animal models [...] Read more.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic disease caused by COL7A1 mutations. It leads to skin fragility, chronic inflammation, and impaired wound healing. The condition often results in fibrotic scarring, pseudosyndactyly, and cutaneous squamous cell carcinoma (SCC). However, current animal models fail to fully replicate chronic RDEB wounds. In this study, we used Collagen VII-hypomorphic mice (Col7a1^flNeo/flNeo) and created full-thickness wounds on their paw skin, an area prone to fibrosis due to mechanical stress. We analyzed the healing process using histology, immunofluorescence, and electron microscopy. The RDEB mice showed delayed wound closure, increased inflammation, and poor granulation tissue formation. At 30 days post-injury, we observed persistent fibrosis, with elevated levels of Collagen I, α-SMA+ myofibroblasts, and tenascin-C. These mice also had fewer intraepidermal nerve fibers, which may help explain the neuropathic pain associated with RDEB. Our model reproduces the main features of chronic RDEB wounds. It offers a useful tool for evaluating therapies aimed at reducing inflammation, fibrosis, and tumor risk in these patients. Full article

(This article belongs to the Special Issue New Insights into the Use of Mouse Models for the Study of Skin Disorders)

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18 pages, 8554 KiB

Open AccessArticle

Low-Temperature and Light Pretreatment Interactively Promote Rapid Flowering, Early Ripening, and Yield Accumulation of Winter Wheat

by Yuanlong Wu, Runnan Shuai, Xiaoxu Zhan, Qiangui Wang, Si Tang, Tingting Gao, Yanyan Zhao, Qichang Yang and Zhonghua Bian

Int. J. Mol. Sci. 2025, 26(9), 4280; https://doi.org/10.3390/ijms26094280 (registering DOI) - 30 Apr 2025

Abstract

Exposing wheat (Triticum aestivum L.) seeds to a combination of light and low temperatures for 4–6 weeks, followed by transferring to speed breeding (SB) conditions, has been demonstrated to effectively reduce generation time in winter wheat. To reveal the underlying mechanisms of [...] Read more.

Exposing wheat (Triticum aestivum L.) seeds to a combination of light and low temperatures for 4–6 weeks, followed by transferring to speed breeding (SB) conditions, has been demonstrated to effectively reduce generation time in winter wheat. To reveal the underlying mechanisms of accelerated generation advancement in winter wheat, we investigated changes in transcriptome and the subsequent responses in plant growth, flowering of germinated seeds vernalized at 4 °C with white exposure (VL) or under dark conditions (VD) for 4 weeks before sowing, and subsequent growth under SB conditions. Germinated seeds without vernalization were directly sown under SB conditions and served as controls (Control). The results showed that, compared with Control and VD, VL significantly expedited vernalization, resulting in early flowering for around 6 days and accelerated ripening of progeny seeds for 13 days with a higher germination index and vigor index. The transcriptomic analysis revealed that the differently expressed genes (DEGs) involved in GA synthesis and its signal transduction both participated in the light-induced speed vernalization and the subsequent rapid growth and development of winter wheat. The MADS-box transcription factors, especially VRN-A1 and MADS55, might play a vital role in the light- and low-temperature-induced early flowering. Our results stress the importance of light in vernalization and lay the groundwork for further elucidating the mechanisms underlying the light-induced speed vernalization of winter wheat. Full article

(This article belongs to the Section Molecular Plant Sciences)

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14 pages, 2266 KiB

Open AccessFeature PaperArticle

Non-Oxidised Parathyroid Hormone and a Panel of Markers of Calcium–Phosphate Metabolism for Analysis of Secondary Hyperparathyroidism in Selected Patient Groups—A Quality Assurance Project

by Ursula Huber-Schoenauer, Janne Cadamuro, Ulrike Kipman, Emma Stoellinger, Michael Lichtenauer, Vera Paar, Ludmilla Kedenko, Kathrin Guggenbichler, Bernhard Paulweber, Christian Pirich and Hermann Salmhofer

Int. J. Mol. Sci. 2025, 26(9), 4279; https://doi.org/10.3390/ijms26094279 (registering DOI) - 30 Apr 2025

Abstract

Intact parathyroid hormone (PTHi) plays a central role in the regulation of mineral and bone metabolism. Due to post-translational modifications of the hormone, the interpretation of elevated PTHi values is challenging and may benefit from an expanded analytical panel. Within this project, additional [...] Read more.

Intact parathyroid hormone (PTHi) plays a central role in the regulation of mineral and bone metabolism. Due to post-translational modifications of the hormone, the interpretation of elevated PTHi values is challenging and may benefit from an expanded analytical panel. Within this project, additional parameters of calcium–phosphate metabolism, such as non-oxidised parathyroid hormone (noxPTH), calcidiol, vitamin D binding protein (VDBP), and fibroblast growth factor 23 (FGF23) were evaluated in a control population of 177 individuals as well as 182 patients with renal, gastroenterological, and liver diseases. While PTHi and noxPTH levels were up to 10-fold higher in dialysis patients, the proportion of noxPTH on PTHi was significantly higher for all patient groups showing signs of inflammation. However, no strong confounders for PTHi could be identified. The correlation between CRP and the proportion of oxidised PTHi in total PTHi suggests an influence of inflammatory oxidative stress on the proportion of active noxPTH. Apart from the established role of vitamin D, the addition of noxPTH and its proportion of total PTHi in the assessment of unclear PTHi elevations seems reasonable, whereas there is no evidence for the standardised analysis of further parameters such as FGF23 and VDBP. Full article

(This article belongs to the Special Issue Calcium Metabolism and Regulation)

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23 pages, 7506 KiB

Open AccessArticle

Biocompatibility Research of Magnetosomes Synthesized by Acidithiobacillus ferrooxidans

by Bai-Qiang Wu, Jun Wang, Yang Liu, Bao-Jun Yang, Hui-Ying Li, Chun-Xiao Zhao and Guan-Zhou Qiu

Int. J. Mol. Sci. 2025, 26(9), 4278; https://doi.org/10.3390/ijms26094278 (registering DOI) - 30 Apr 2025

Abstract

Magnetosomes are magnetic nanocrystals synthesized by bacteria that have important application value in biomedicine. Therefore, it is very important to evaluate their biocompatibility. It has been reported that the extremophilic acidophilic bacterium Acidithiobacillus ferrooxidans, which is aerobic, can synthesize intracellular Fe₃O [...] Read more.

Magnetosomes are magnetic nanocrystals synthesized by bacteria that have important application value in biomedicine. Therefore, it is very important to evaluate their biocompatibility. It has been reported that the extremophilic acidophilic bacterium Acidithiobacillus ferrooxidans, which is aerobic, can synthesize intracellular Fe₃O₄ magnetosomes. In this paper, we performed a comprehensive and systematic evaluation of the biocompatibility of magnetosomes with an average particle size of 53.66 nm from Acidithiobacillus ferrooxidans, including pharmacokinetics, degradation pathways, acute systemic toxicity, cytotoxicity, genotoxicity, blood index and immunotoxicity. The phase composition of the magnetosomes was identified as Fe3O4 through XRD and HRTEM analyses. Biocompatibility evaluation results showed that magnetosomes metabolized rapidly in rats and degraded thoroughly in major organs, with almost no residue. When the injection concentration was low (40 mg/kg, 60 mg/kg), magnetosomes would not cause pathological changes in the major organs of mice, basically. At the same time, magnetosomes had low cytotoxicity, genotoxicity, immunotoxicity and hemolysis rate, which proved that the magnetosomes synthesized by Acidithiobacillus ferrooxidans are magnetic nanomaterials with good biocompatibility. This research provides an important theoretical basis for the large-scale application of bacterial magnetosomes as functional magnetic nanomaterials. Full article

(This article belongs to the Section Molecular Nanoscience)

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23 pages, 2502 KiB

Open AccessReview

Advancements in Plant-Derived sRNAs Therapeutics: Classification, Delivery Strategies, and Therapeutic Applications

by Qianru Rao, Hua Hua and Junning Zhao

Int. J. Mol. Sci. 2025, 26(9), 4277; https://doi.org/10.3390/ijms26094277 (registering DOI) - 30 Apr 2025

Abstract

Plant-derived small RNAs (sRNAs) have garnered significant attention in nucleic acid therapeutics, driven by their distinctive cross-kingdom regulatory capabilities and extensive therapeutic promise. These sRNAs exhibit a wide range of pharmacological effects, including pulmonary protection, antiviral, anti-inflammatory, and antitumor activities, underscoring their substantial [...] Read more.

Plant-derived small RNAs (sRNAs) have garnered significant attention in nucleic acid therapeutics, driven by their distinctive cross-kingdom regulatory capabilities and extensive therapeutic promise. These sRNAs exhibit a wide range of pharmacological effects, including pulmonary protection, antiviral, anti-inflammatory, and antitumor activities, underscoring their substantial potential for clinical translation. A key advantage lies in their delivery, facilitated by plant-specific nanovesicular carriers—such as plant exosomes, herbal decoctosomes, and bencaosomes—which protect sRNAs from gastrointestinal degradation and enable precise, tissue-specific targeting. This review provides a comprehensive analysis of plant-derived sRNAs, detailing their classification, gene-silencing mechanisms, and nanovesicle-mediated cross-kingdom delivery strategies. It further explores their therapeutic potential and underlying molecular mechanisms in major human diseases. Additionally, we critically evaluate current technical challenges and propose future directions to advance the development of plant-derived sRNAs for precision therapeutics. This work aims to offer a robust theoretical framework and practical guidance for the clinical advancement of plant-derived sRNA-based therapies. Full article

(This article belongs to the Section Molecular Plant Sciences)

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20 pages, 1858 KiB

Open AccessReview

Targeting Gene C9orf72 Pathogenesis for Amyotrophic Lateral Sclerosis

by Zhao Zhong Chong and Nizar Souayah

Int. J. Mol. Sci. 2025, 26(9), 4276; https://doi.org/10.3390/ijms26094276 (registering DOI) - 30 Apr 2025

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult neurodegenerative disorder. Since no cure has been found, finding effective therapeutic targets for ALS remains a major challenge. Gene C9orf72 mutations with the formation of hexanucleotide repeat (GGGGCC) expansion (HRE) have been considered the most [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a fatal adult neurodegenerative disorder. Since no cure has been found, finding effective therapeutic targets for ALS remains a major challenge. Gene C9orf72 mutations with the formation of hexanucleotide repeat (GGGGCC) expansion (HRE) have been considered the most common genetic pathogenesis of ALS. The literature review indicates that the C9orf72 HRE causes both the gain-of-function toxicity and loss of function of C9ORF72. The formation of RNA foci and dipeptide repeats (DPRs) resulting from HRE is responsible for toxic function gain. The RNA foci can interfere with RNA processing, while DPRs directly bind to and sequester associated proteins to disrupt processes of rRNA synthesis, mRNA translation, autophagy, and nucleocytoplasmic transport. The mutations of C9orf72 and HRE result in the loss of functional C9ORF72. Under physiological conditions, C9ORF72 binds to Smith–Magenis chromosome region 8 and WD repeat-containing protein and forms a protein complex. Loss of C9ORF72 leads to autophagic impairment, increased oxidative stress, nucleocytoplasmic transport impairment, and inflammatory response. The attempted treatments for ALS have been tried by targeting C9orf72 HRE; however, the outcomes are far from satisfactory yet. More studies should be performed on pharmacological and molecular modulators against C9orf72 HRE to evaluate their efficacy by targeting HRE. Full article

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

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31 pages, 1349 KiB

Open AccessReview

Biotechnological Applications of Biogenic Nanomaterials from Red Seaweed: A Systematic Review (2014–2024)

by Aline Nunes, Graziano Rilievo, Massimiliano Magro, Marcelo Maraschin, Fabio Vianello and Giuseppina Pace Pereira Lima

Int. J. Mol. Sci. 2025, 26(9), 4275; https://doi.org/10.3390/ijms26094275 - 30 Apr 2025

Abstract

Green synthesized nanoparticles (NPs) are arousing constantly increasing attention due to inherent advantages such as biocompatibility, nontoxicity, and cost-effectiveness. As the state of the art of this rapidly evolving topic demands a punctual update, the present study was focused on reviewing the novelty, [...] Read more.

Green synthesized nanoparticles (NPs) are arousing constantly increasing attention due to inherent advantages such as biocompatibility, nontoxicity, and cost-effectiveness. As the state of the art of this rapidly evolving topic demands a punctual update, the present study was focused on reviewing the novelty, feasibility, and effectiveness related to the specific category of red seaweed-derived NPs. Among algae, red seaweeds have already gained consideration in the global market due to their high content of primary and secondary metabolites, supporting multifunctional applications across various industries. This scoping review reveals how this interest has also driven their investigation as a natural source for the sustainable NP fabrication. The fragmentary body of studies was synthesized, identifying red seaweed NPs as a flourishing nanotechnological subgroup and meriting their own space in the scientific literature. Noteworthy, the great majority of the reviewed papers feature efficient controlled release, enhanced bioavailability, and reduced toxicity, making red seaweed NPs elective candidates for the medical sector as anticancer, antimicrobial, and antioxidant agents. Moreover, their parent natural counterparts seem to endow NPs with unexpected specificity toward biological targets such as prokaryotic and tumor cells. Nanotechnological solutions based on red seaweeds pave the way to a new avenue of opportunities and challenges. Full article

(This article belongs to the Section Molecular Biophysics)

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14 pages, 22281 KiB

Open AccessArticle

USO1 Coordinates Centriolar Satellites to Regulate Male Germ Cell Proliferation and Cell Cycle Progression

by Xinyi Li, Peiyi Lin, Zaikuan Zhang, Runzhi Wang, Jing Cai, Xiaosong Feng, Zhihong Jiang, Shengming Xu and Yajun Xie

Int. J. Mol. Sci. 2025, 26(9), 4274; https://doi.org/10.3390/ijms26094274 (registering DOI) - 30 Apr 2025

Abstract

The endoplasmic reticulum–Golgi apparatus system is an important organelle regulating male reproduction. USO1 vesicle transport factor (USO1), as an important molecule in this system, is a general vesicular transport factor and regulates various biological processes in vivo. However, the potential role of USO1 [...] Read more.

The endoplasmic reticulum–Golgi apparatus system is an important organelle regulating male reproduction. USO1 vesicle transport factor (USO1), as an important molecule in this system, is a general vesicular transport factor and regulates various biological processes in vivo. However, the potential role of USO1 in mammalian testis development and spermatogenesis has not been investigated. We documented the presence of USO1 in mouse germ cells and its functional roles by generating Uso1-knockout germ cell lines. Uso1 depletion suppressed cell proliferation and growth while stimulating apoptosis in GC1 and GC2 cells. In addition, the Uso1 knockout blocked cell cycle progression and weakened DNA damage repair. Mechanistically, USO1 is associated with male reproduction by regulating the expression of genes involved in spermatogenesis, and we found evidence that USO1 is closely linked to centriolar satellites (CSs), which may play an important biological role. Overall, our findings reveal a vital role for USO1 in male fertility and offer a significant understanding of the functions of golgin proteins in reproductive biology. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 5703 KiB

Open AccessReview

The Regulatory Role of Long Non-Coding RNAs in the Development and Progression of Osteoporosis

by Rogelio F. Jiménez-Ortega, Diana I. Aparicio-Bautista, Adriana Becerra-Cervera, Alejandra I. Ortega-Meléndez, Nelly Patiño, Berenice Rivera-Paredez, Alberto Hidalgo-Bravo and Rafael Velázquez-Cruz

Int. J. Mol. Sci. 2025, 26(9), 4273; https://doi.org/10.3390/ijms26094273 - 30 Apr 2025

Abstract

Osteoporosis (OP) is a disease affecting bone metabolism, characterized by low bone mineral density and the deterioration of the bone microarchitecture, leading to increased bone fragility and risk of fracture. OP mainly results from alterations in the balance between osteoclast-mediated bone resorption and [...] Read more.

Osteoporosis (OP) is a disease affecting bone metabolism, characterized by low bone mineral density and the deterioration of the bone microarchitecture, leading to increased bone fragility and risk of fracture. OP mainly results from alterations in the balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Currently, there are several molecular mechanisms underlying the development of OP that are not entirely clear. One such mechanism is the role of long non-coding RNAs, which are key regulators of gene expression through various mechanisms. In the last decade, it has been shown that these molecules participate in multiple biological processes and play essential roles in the pathogenesis of different diseases. In this review, we address recent advances on the relationship of long non-coding RNAs with OP, mainly over their regulatory functions during osteoclastogenesis and osteogenesis. Furthermore, we analyze their potential application as clinical or therapeutic resources focused on OP. Full article

(This article belongs to the Special Issue Molecular Insights into RNA Diseases)

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31 pages, 5408 KiB

Open AccessReview

Drought Stress in Roses: A Comprehensive Review of Morphophysiological, Biochemical, and Molecular Responses

by Hmmam Zarif, Chunguo Fan, Guozhen Yuan, Rui Zhou, Yufei Chang, Jingjing Sun, Jun Lu, Jinyi Liu and Changquan Wang

Int. J. Mol. Sci. 2025, 26(9), 4272; https://doi.org/10.3390/ijms26094272 - 30 Apr 2025

Abstract

Climate change poses significant threats to agriculture globally, particularly in arid and semi-arid regions where drought stress (DS) is most severe, disrupting ecosystems and constraining progress in agriculture and horticulture. Roses, valued for their aesthetic appeal, are highly susceptible to abiotic stresses, especially [...] Read more.

Climate change poses significant threats to agriculture globally, particularly in arid and semi-arid regions where drought stress (DS) is most severe, disrupting ecosystems and constraining progress in agriculture and horticulture. Roses, valued for their aesthetic appeal, are highly susceptible to abiotic stresses, especially DS, which markedly reduces flower quantity and quality. Under DS conditions, roses exhibit diverse morphological, physiological, biochemical, and molecular adaptations that vary across species. This review examines the effects of DS on rose growth, yield, and physiological traits, including gas exchange, photosynthesis, phytohormone dynamics, and water and nutrient relationships, alongside their biochemical and molecular responses. Furthermore, DS impacts the biosynthesis of secondary metabolites, notably reducing the yield and quality of essential oils in roses, which are critical for their commercial value in perfumery and aromatherapy. Additionally, the impact of DS on rose flower quality and post-harvest longevity is assessed. By elucidating these diverse responses, this review provides a framework for understanding DS effects on roses and offers insights to develop strategies for mitigating its adverse impacts. Full article

(This article belongs to the Special Issue Advanced Plant Molecular Responses to Abiotic Stresses)

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53 pages, 1615 KiB

Open AccessReview

From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine

by Corneliu Toader, Matei Serban, Octavian Munteanu, Razvan-Adrian Covache-Busuioc, Mihaly Enyedi, Alexandru Vlad Ciurea and Calin Petru Tataru

Int. J. Mol. Sci. 2025, 26(9), 4271; https://doi.org/10.3390/ijms26094271 - 30 Apr 2025

Abstract

The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones of neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches for [...] Read more.

The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones of neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches for neurodegenerative and psychiatric diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). Nevertheless, clinical applicability is obstructed by hurdles in delivery, patient-specific diversity, and pleiotropic signaling. Here, we summarize findings in BDNF research, including its regulatory pathways and diagnostic/prognostic biomarkers and integrative therapeutic approaches. We describe innovative delivery systems, such as lipid nanoparticle-based mRNA therapies and CRISPR-dCas9-based epigenetic editing that bypass obstacles such as BBB (blood–brain barrier) and enzymatic degradation. The recent implementation of multiplex panels combining BDNF biodynamic indicators with tau and amyloid-β signaling markers showcases novel levels of specificity for both early detection and potential therapeutic monitoring. Humanized preclinical models like iPSC-derived neurons and organoids point to the key role of BDNF in neurodeveloping and neurodegenerative processes, paralleling advances in bridging preclinical observation and clinical environments. Moreover, novel therapeutic tools delivering TrkB activators or the implementation of AI-based dynamic care platforms enable tailored and scalable treatments. This review also aims to extend a framework used in the understanding of BDNF’s relevance to traditional neurodegenerative models by situating more recent work detailing BDNF’s actions in ischemic tissues and the gut–brain axis in the context of systemic health. Finally, we outline a roadmap for the incorporation of BDNF-centered therapies into worldwide healthcare, highlighting ethical issues, equity, and interdisciplinary decomposition. The therapeutic potential of BDNF heralds a new era in neuroscience and medicine, revolutionizing brain health and paving the way for the advancement of precision medicine. Full article

(This article belongs to the Special Issue Molecular Research on the Neurodegenerative Diseases)

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14 pages, 1987 KiB

Open AccessArticle

Transmembrane Homodimers Interface Identification: Predicting Interface Residues in Alpha-Helical Transmembrane Protein Homodimers Using Sequential and Structural Features

by Bander Almalki and Li Liao

Int. J. Mol. Sci. 2025, 26(9), 4270; https://doi.org/10.3390/ijms26094270 - 30 Apr 2025

Abstract

Most bitopic transmembrane proteins associate with one another through interface residues to form dimers, which facilitate or activate specific cellular functions. Therefore, accurately identifying interface residues in a given dimer is crucial for understanding its function and has been a challenging pursuit for [...] Read more.

Most bitopic transmembrane proteins associate with one another through interface residues to form dimers, which facilitate or activate specific cellular functions. Therefore, accurately identifying interface residues in a given dimer is crucial for understanding its function and has been a challenging pursuit for many computational methods. These methods can be broadly categorized into two approaches: general-purpose ones for dimerization and specialized ones for interface residues. In this study, we develop a machine learning method that integrates both approaches by integrating sequential and structural features extracted from predicted structures and various domains. The results from cross-validation on a benchmark dataset show that our method, despite utilizing significantly fewer features, outperforms the state-of-the-art methods by more than three percentage points in performance, as measured by the F1 score. Furthermore, we evaluated the performance of the proposed model on a benchmark dataset as compared to the state-of-the-art multimeric structure predictors, including RoseTTAFold2, AlphaFold2Multimer, and PREDDIMER. The results show the superiority of the proposed model by outperforming all the other models, highlighting the effectiveness of integrating both structural and sequential features within the proposed framework. Full article

(This article belongs to the Special Issue Molecular Modeling: Latest Advances and Applications)

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22 pages, 5259 KiB

Open AccessArticle

Genome-Wide Identification and Evolution-Profiling Analysis of Heat Shock Protein Gene Family in Poaceae Barnhart

by Xiaoyi Huang, Yue Liu, Xiao Yu, Yajun Cai, Lingyu Hou, Jingyuan Zhang and Hongchun Yang

Int. J. Mol. Sci. 2025, 26(9), 4269; https://doi.org/10.3390/ijms26094269 (registering DOI) - 30 Apr 2025

Abstract

Heat shock proteins (HSPs) function as molecular chaperones to maintain protein homeostasis and repair denatured proteins, counteracting abiotic stresses. Despite their functional importance, a systematic bioinformatics analysis of the HSP gene family was lacking in Poaceae. In this study, we revealed that [...] Read more.

Heat shock proteins (HSPs) function as molecular chaperones to maintain protein homeostasis and repair denatured proteins, counteracting abiotic stresses. Despite their functional importance, a systematic bioinformatics analysis of the HSP gene family was lacking in Poaceae. In this study, we revealed that HSPs are widely distributed from algae to eudicots, with varying numbers in Poaceae including Oryza, Triticum, and Panicum. Gene duplication events, particularly dispersed duplication (DSD), tandem duplication (TD), and genome polyploidization, have probably driven the increased number of HSP genes and the expansion of HSP family proteins. Gene Ontology (GO) annotation analyses suggested their conserved functions. Promoter cis-acting element analyses indicated that their expression levels were tightly regulated by abiotic stresses. We validated that many collinear HSP genes are indeed regulated by the cold stress by analyzing the published RNA-seq data in rice, maize, and wheat, and performing RT-qPCR in rice. Our findings shed light on the role of HSPs in the abiotic stress response, laying the groundwork for further exploration of HSP functions in Poaceae. Full article

(This article belongs to the Special Issue Plant Responses to Biotic and Abiotic Stresses)

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17 pages, 3703 KiB

Open AccessArticle

EMitool: Explainable Multi-Omics Integration for Disease Subtyping

by Yong Xu, Jun Wu, Chen Chen, Jian Ouyang, Dawei Li and Tieliu Shi

Int. J. Mol. Sci. 2025, 26(9), 4268; https://doi.org/10.3390/ijms26094268 - 30 Apr 2025

Abstract

Disease subtyping is essential for personalized medicine, enabling tailored treatment strategies based on disease heterogeneity. Advances in high-throughput technologies have led to the rapid accumulation of multi-omics data, driving the development of integration methods for comprehensive disease subtyping. However, existing approaches often lack [...] Read more.

Disease subtyping is essential for personalized medicine, enabling tailored treatment strategies based on disease heterogeneity. Advances in high-throughput technologies have led to the rapid accumulation of multi-omics data, driving the development of integration methods for comprehensive disease subtyping. However, existing approaches often lack explainability and fail to establish clear links between subtypes and clinical outcomes. To address these challenges, we developed EMitool, an explainable multi-omics integration tool that leverages a network-based fusion strategy to achieve biologically and clinically relevant disease subtyping without requiring prior clinical information. Using data from 31 cancer types in The Cancer Genome Atlas (TCGA), EMitool demonstrated superior subtyping accuracy compared to eight state-of-the-art methods. It also provides contribution scores for different omics data types, enhancing interpretability. EMitool-derived subtypes exhibited significant associations with the overall survival, pathological stage, tumor mutational burden, immune microenvironment characteristics, and therapeutic responses. Specifically, in kidney renal clear cell carcinoma (KIRC), EMitool identified three distinct subtypes with varying prognoses, immune cell compositions, and drug sensitivities. These findings highlight its potential for biomarker discovery and precision oncology. Full article

(This article belongs to the Section Molecular Informatics)

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17 pages, 1320 KiB

Open AccessArticle

Electrochemically Reduced Graphene Oxide Covalently Bound Sensor for Paracetamol Voltammetric Determination

by Amaya Paz de la vega, Fabiana Liendo, Bryan Pichún, Johisner Penagos, Rodrigo Segura and María Jesús Aguirre

Int. J. Mol. Sci. 2025, 26(9), 4267; https://doi.org/10.3390/ijms26094267 - 30 Apr 2025

Abstract

Designing a highly sensitive and efficient functionalized electrode for precise drug analysis remains a significant challenge. In this work, an electrochemical sensor based on a glassy carbon electrode (GCE) modified with phenyl diazonium salts (ph) and electrochemically reduced graphene oxide (ERGO), labeled GCE/ph/ERGO, [...] Read more.

Designing a highly sensitive and efficient functionalized electrode for precise drug analysis remains a significant challenge. In this work, an electrochemical sensor based on a glassy carbon electrode (GCE) modified with phenyl diazonium salts (ph) and electrochemically reduced graphene oxide (ERGO), labeled GCE/ph/ERGO, was developed for the detection of paracetamol (PAR) in pharmaceutical matrices using square wave voltammetry (SWV). The modified electrode was characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV). Compared to the bare GCE, the GCE/ph/ERGO sensor demonstrated significantly improved conductivity and anodic current peak for PAR over two orders of magnitude higher, indicating a substantial enhancement in electrochemical performance. Under optimized conditions, the developed sensor exhibited a low detection limit of 18.2 nM and a quantification limit of 60.6 nM. Precision studies yielded relative standard deviations (RSDs) below 8%. The sensor demonstrated excellent selectivity in the presence of common pharmaceutical excipients and high accuracy in the analysis of generic pharmaceutical formulations, with results comparable to those obtained by the HPLC technique. These findings confirm the sensor’s reliability, stability, robustness, and suitability for routine analysis of PAR in pharmaceutical samples. Full article

(This article belongs to the Special Issue Advanced Electrode and Electrolyte Materials: Molecular Scale Design, Synthesis, Mechanisms and Applications)

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17 pages, 4288 KiB

Open AccessArticle

A Novel Supramolecular Salt of Hypoxanthine with Maleic Acid as a Potential Weight-Loss Drug

by Fumin Xue, Xinyue Yuan, Xingyi Li, Shimin Fang and Yan Cheng

Int. J. Mol. Sci. 2025, 26(9), 4266; https://doi.org/10.3390/ijms26094266 - 30 Apr 2025

Abstract

Improving the stability of drugs in the solid state, as well as improving their solubility and poor bioavailability, is highly physiologically relevant. In this study, we focused on enhancing the solubility of hypoxanthine (HYP) through salt formation resulting from the preparation of hypoxanthine–maleic [...] Read more.

Improving the stability of drugs in the solid state, as well as improving their solubility and poor bioavailability, is highly physiologically relevant. In this study, we focused on enhancing the solubility of hypoxanthine (HYP) through salt formation resulting from the preparation of hypoxanthine–maleic acid salt (HYP-MAL). Single crystals were obtained through solvent evaporation methods, and DSC, TGA, PXRD, FT-IR, and ¹H NMR spectra were used to characterize the samples. The salt system had higher solubility properties than HYP, with an equilibrium solubility in water that was roughly 2.4 times greater than that of HYP, but the salt’s equilibrium solubility increased when the pH shifted from 7.4 to 1.2; additionally, from 0 to 10 min, the powder dissolution rate was 1.8 times that of HYP, resulting in increased bioavailability. The anti-obesity impact of HYP-MAL salt on obese mice was investigated, providing important insights for the development of future weight-loss medications. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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26 pages, 1321 KiB

Open AccessReview

Vascular Remodeling: The Multicellular Mechanisms of Pulmonary Hypertension

by Jinjin Dai, Hongyang Chen, Jindong Fang, Shiguo Wu and Zhuangzhuang Jia

Int. J. Mol. Sci. 2025, 26(9), 4265; https://doi.org/10.3390/ijms26094265 - 30 Apr 2025

Abstract

Pulmonary hypertension (PH) is a serious cardiovascular disease caused by a variety of pathogenic factors, which is characterized by increased pulmonary vascular resistance (PVR) and progressive elevation of mean pulmonary artery pressure (mPAP). This disease can lead to right ventricular hypertrophy and, in [...] Read more.

Pulmonary hypertension (PH) is a serious cardiovascular disease caused by a variety of pathogenic factors, which is characterized by increased pulmonary vascular resistance (PVR) and progressive elevation of mean pulmonary artery pressure (mPAP). This disease can lead to right ventricular hypertrophy and, in severe cases, right heart failure and even death. Vascular remodeling—a pathological modification involving aberrant vasoconstriction, cell proliferation, apoptosis resistance, and inflammation in the pulmonary vascular system—is a significant pathological hallmark of PH and a critical process in its progression. Recent studies have found that vascular remodeling involves the participation of a diversity of cellular pathological alterations, such as the dysfunction of pulmonary artery endothelial cells (PAECs), the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), the phenotypic differentiation of pulmonary artery fibroblasts, the inflammatory response of immune cells, and pericyte proliferation. This review focuses on the mechanisms and the intercellular crosstalk of these cells in the PH process, emphasizing recent advances in knowledge regarding cellular signaling pathways, inflammatory responses, apoptosis, and proliferation. To develop better treatments, a list of possible therapeutic approaches meant to slow down certain biological functions is provided, with the aim of providing new insights into the treatment of PH by simplifying the intricacies of these complex connections. In this review, comprehensive academic databases such as PubMed, Embase, Web of Science, and Google Scholar were systematically searched to discuss studies relevant to human and animal PH, with a focus on vascular remodeling in PH. Full article

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

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34 pages, 2039 KiB

Open AccessReview

Gut Microbiota and Cardiovascular Diseases: Unraveling the Role of Dysbiosis and Microbial Metabolites

by Barathan Muttiah and Alfizah Hanafiah

Int. J. Mol. Sci. 2025, 26(9), 4264; https://doi.org/10.3390/ijms26094264 - 30 Apr 2025

Abstract

Cardiovascular diseases (CVDs), including heart failure (HF), hypertension, myocardial infarction (MI), and atherosclerosis, are increasingly linked to gut microbiota dysbiosis and its metabolic byproducts. HF, affecting over 64 million individuals globally, is associated with systemic inflammation and gut barrier dysfunction, exacerbating disease progression. [...] Read more.

Cardiovascular diseases (CVDs), including heart failure (HF), hypertension, myocardial infarction (MI), and atherosclerosis, are increasingly linked to gut microbiota dysbiosis and its metabolic byproducts. HF, affecting over 64 million individuals globally, is associated with systemic inflammation and gut barrier dysfunction, exacerbating disease progression. Similarly, hypertension and MI correlate with reduced microbial diversity and an abundance of pro-inflammatory bacteria, contributing to vascular inflammation and increased cardiovascular risk. Atherosclerosis is also influenced by gut dysbiosis, with key microbial metabolites such as trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs) playing crucial roles in disease pathogenesis. Emerging evidence highlights the therapeutic potential of natural compounds, including flavonoids, omega-3 fatty acids, resveratrol, curcumin, and marine-derived bioactives, which modulate the gut microbiota and confer cardioprotective effects. These insights underscore the gut microbiota as a critical regulator of cardiovascular health, suggesting that targeting dysbiosis may offer novel preventive and therapeutic strategies. Further research is needed to elucidate underlying mechanisms and optimize microbiome-based interventions for improved cardiovascular outcomes. Full article

(This article belongs to the Special Issue Interplay Between the Human Microbiome and Diseases)

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