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Search Results (3,415)

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13 pages, 3790 KiB  
Article
Anti-CD26 Antibody Suppresses Epithelial-Mesenchymal Transition in Colorectal Cancer Stem Cells
by Takumi Iwasawa, Ryo Hatano, Satoshi Takeda, Ayumi Kurusu, Chikako Okamoto, Kazunori Kato, Chikao Morimoto and Noriaki Iwao
Int. J. Mol. Sci. 2025, 26(15), 7620; https://doi.org/10.3390/ijms26157620 - 6 Aug 2025
Abstract
CD26 (dipeptidyl peptidase-4) is a marker of colorectal cancer stem cells with high metastatic potential and resistance to therapy. Although CD26 expression is known to be associated with tumor progression, its functional involvement in epithelial-mesenchymal transition (EMT) and metastasis remains to be fully [...] Read more.
CD26 (dipeptidyl peptidase-4) is a marker of colorectal cancer stem cells with high metastatic potential and resistance to therapy. Although CD26 expression is known to be associated with tumor progression, its functional involvement in epithelial-mesenchymal transition (EMT) and metastasis remains to be fully elucidated. In this study, we aimed to investigate the effects of a monoclonal anti-CD26 antibody on EMT-related phenotypes and metastatic behavior in colorectal cancer cells. We evaluated changes in EMT markers by quantitative PCR and Western blotting, assessed cell motility and invasion using scratch wound-healing and Transwell assays, and examined metastatic potential in vivo using a splenic injection mouse model. Treatment with the anti-CD26 antibody significantly increased the expression of the epithelial marker E-cadherin and reduced levels of EMT-inducing transcription factors, including ZEB1, Twist1, and Snail1, at the mRNA and protein levels. Functional assays revealed that the antibody markedly inhibited cell migration and invasion in vitro without exerting cytotoxic effects. Furthermore, systemic administration of the anti-CD26 antibody significantly suppressed the formation of liver metastases in vivo. These findings suggest that CD26 may contribute to the regulation of EMT and metastatic behavior in colorectal cancer. Our data highlight the potential therapeutic utility of CD26-targeted antibody therapy for suppressing EMT-associated phenotypes and metastatic progression. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer: 4th Edition)
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21 pages, 3451 KiB  
Article
Transcriptional Repression of CCL2 by KCa3.1 K+ Channel Activation and LRRC8A Anion Channel Inhibition in THP-1-Differentiated M2 Macrophages
by Miki Matsui, Junko Kajikuri, Hiroaki Kito, Yohei Yamaguchi and Susumu Ohya
Int. J. Mol. Sci. 2025, 26(15), 7624; https://doi.org/10.3390/ijms26157624 - 6 Aug 2025
Abstract
We investigated the role of the intermediate-conductance, Ca2+-activated K+ channel KCa3.1 and volume-regulatory anion channel LRRC8A in regulating C-C motif chemokine ligand 2 (CCL2) expression in THP-1-differentiated M2 macrophages (M2-MACs), which serve as a useful [...] Read more.
We investigated the role of the intermediate-conductance, Ca2+-activated K+ channel KCa3.1 and volume-regulatory anion channel LRRC8A in regulating C-C motif chemokine ligand 2 (CCL2) expression in THP-1-differentiated M2 macrophages (M2-MACs), which serve as a useful model for studying tumor-associated macrophages (TAMs). CCL2 is a potent chemoattractant involved in the recruitment of immunosuppressive cells and its expression is regulated through intracellular signaling pathways such as ERK, JNK, and Nrf2 in various types of cells including macrophages. The transcriptional expression of CCL2 was suppressed in M2-MACs following treatment with a KCa3.1 activator or an LRRC8A inhibitor via distinct signaling pathways: ERK–CREB2 and JNK–c-Jun pathways for KCa3.1, and the NOX2–Nrf2–CEBPB pathway for LRRC8A. Under in vitro conditions mimicking the elevated extracellular K+ concentration ([K+]e) characteristic of the tumor microenvironment (TME), CCL2 expression was markedly upregulated, and this increase was reversed by treatment with them in M2-MACs. Additionally, the WNK1–AMPK pathway was, at least in part, involved in the high [K+]e-induced upregulation of CCL2. Collectively, modulating KCa3.1 and LRRC8A activities offers a promising strategy to suppress CCL2 secretion in TAMs, potentially limiting the CCL2-induced infiltration of immunosuppressive cells (TAMs, Tregs, and MDSCs) in the TME. Full article
(This article belongs to the Special Issue Regulation of Ion Channels and Transporters)
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25 pages, 2042 KiB  
Article
Transcriptomic Profiling of Mouse Mesenchymal Stem Cells Exposed to Metal-Based Nanoparticles
by Michal Sima, Helena Libalova, Zuzana Simova, Barbora Echalar, Katerina Palacka, Tereza Cervena, Jiri Klema, Zdenek Krejcik, Vladimir Holan and Pavel Rossner
Int. J. Mol. Sci. 2025, 26(15), 7583; https://doi.org/10.3390/ijms26157583 - 5 Aug 2025
Abstract
Mesenchymal stem cells (MSCs), i.e., adult stem cells with immunomodulatory and secretory properties, contribute to tissue growth and regeneration, including healing processes. Some metal nanoparticles (NPs) are known to exhibit antimicrobial activity and may further potentiate tissue healing. We studied the effect of [...] Read more.
Mesenchymal stem cells (MSCs), i.e., adult stem cells with immunomodulatory and secretory properties, contribute to tissue growth and regeneration, including healing processes. Some metal nanoparticles (NPs) are known to exhibit antimicrobial activity and may further potentiate tissue healing. We studied the effect of Ag, CuO, and ZnO NPs after in vitro exposure of mouse MSCs at the transcriptional level in order to reveal the potential toxicity as well as modulation of other processes that may modify the activity of MSCs. mRNA–miRNA interactions were further investigated to explore the epigenetic regulation of gene expression. All the tested NPs mediated immunomodulatory effects on MSCs, generation of extracellular vesicles, inhibition of osteogenesis, and enhancement of adipogenesis. Ag NPs exhibited the most pronounced response; they impacted the expression of the highest number of mRNAs, including those encoding interferon-γ-stimulated genes and genes involved in drug metabolism/cytochrome P450 activity, suggesting a response to the potential toxicity of Ag NPs (oxidative stress). Highly interacting MiR-126 was upregulated by all NPs, while downregulation of MiR-92a was observed after the ZnO NP treatment only, and both effects might be associated with the improvement of MSCs’ healing potency. Overall, our results demonstrate positive effects of NPs on MSCs, although increased oxidative stress caused by Ag NPs may limit the therapeutical potential of the combined MSC+NP treatment. Full article
(This article belongs to the Section Molecular Nanoscience)
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24 pages, 2475 KiB  
Article
An Immunomodulating Peptide with Potential to Promote Anticancer Immunity Without Compromising Immune Tolerance
by Michael Agrez, Christopher Chandler, Amanda L. Johnson, Marlena Sorensen, Kirstin Cho, Stephen Parker, Benjamin Blyth, Darryl Turner, Justyna Rzepecka, Gavin Knox, Anastasia Nika, Andrew M. Hall, Hayley Gooding and Laura Gallagher
Biomedicines 2025, 13(8), 1908; https://doi.org/10.3390/biomedicines13081908 - 5 Aug 2025
Abstract
Background: Immune checkpoint inhibitor therapy in patients with lung cancer and metastatic melanoma is associated with exacerbation of autoimmune-related diseases. The efficacy of treatment targeting the programmed cell death receptor-1 (PD-1) checkpoint relies upon a feedback loop between interferon gamma (IFN-γ) and the [...] Read more.
Background: Immune checkpoint inhibitor therapy in patients with lung cancer and metastatic melanoma is associated with exacerbation of autoimmune-related diseases. The efficacy of treatment targeting the programmed cell death receptor-1 (PD-1) checkpoint relies upon a feedback loop between interferon gamma (IFN-γ) and the interleukin-12 isoform, IL-12p40. Paradoxically, both cytokines and the anti-PD-1 antibody worsen psoriasis. We previously reported an immunomodulating peptide, designated IK14004, that inhibits progression of Lewis lung cancer in mice yet uncouples IFN-γ from IL-12p40 production in human immune cells. Methods: Immune cells obtained from healthy donors were exposed to IK14004 in vitro to further characterise the signalling pathways affected by this peptide. Using C57BL/6 immunocompetent mice, the effect of IK14004 was tested in models of lung melanoma and psoriatic skin. Results: Differential effects of IK14004 on the expression of IFN-α/β, the interleukin-15 (IL-15) receptor and signal transducers and activators of transcription were consistent with immune responses relevant to both cancer surveillance and immune tolerance. Moreover, both melanoma and psoriasis were inhibited by the peptide. Conclusions: Taken together, these findings suggest mechanisms underlying immune homeostasis that could be exploited in the setting of cancer and autoimmune pathologies. Peptide administered together with checkpoint blockers in relevant models of autoimmunity and cancer may offer an opportunity to gain further insight into how immune tolerance can be retained in patients receiving cancer immunotherapy. Full article
(This article belongs to the Special Issue Peptides and Amino Acids in Drug Development: Here and Now)
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18 pages, 3891 KiB  
Review
Navigating Brain Organoid Maturation: From Benchmarking Frameworks to Multimodal Bioengineering Strategies
by Jingxiu Huang, Yingli Zhu, Jiong Tang, Yang Liu, Ming Lu, Rongxin Zhang and Alfred Xuyang Sun
Biomolecules 2025, 15(8), 1118; https://doi.org/10.3390/biom15081118 - 4 Aug 2025
Viewed by 119
Abstract
Brain organoid technology has revolutionized in vitro modeling of human neurodevelopment and disease, providing unprecedented insights into cortical patterning, neural circuit assembly, and pathogenic mechanisms of neurological disorders. Critically, human brain organoids uniquely recapitulate human-specific developmental processes—such as the expansion of outer radial [...] Read more.
Brain organoid technology has revolutionized in vitro modeling of human neurodevelopment and disease, providing unprecedented insights into cortical patterning, neural circuit assembly, and pathogenic mechanisms of neurological disorders. Critically, human brain organoids uniquely recapitulate human-specific developmental processes—such as the expansion of outer radial glia and neuromelanin—that are absent in rodent models, making them indispensable for studying human brain evolution and dysfunction. However, a major bottleneck persists: Extended culture periods (≥6 months) are empirically required to achieve late-stage maturation markers like synaptic refinement, functional network plasticity, and gliogenesis. Yet prolonged conventional 3D culture exacerbates metabolic stress, hypoxia-induced necrosis, and microenvironmental instability, leading to asynchronous tissue maturation—electrophysiologically active superficial layers juxtaposed with degenerating cores. This immaturity/heterogeneity severely limits their utility in modeling adult-onset disorders (e.g., Alzheimer’s disease) and high-fidelity drug screening, as organoids fail to recapitulate postnatal transcriptional signatures or neurovascular interactions without bioengineering interventions. We summarize emerging strategies to decouple maturation milestones from rigid temporal frameworks, emphasizing the synergistic integration of chronological optimization (e.g., vascularized co-cultures) and active bioengineering accelerators (e.g., electrical stimulation and microfluidics). By bridging biological timelines with scalable engineering, this review charts a roadmap to generate translationally relevant, functionally mature brain organoids. Full article
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16 pages, 1632 KiB  
Article
Meloidogyne incognita Significantly Alters the Cucumber Root Metabolome and Enriches Differential Accumulated Metabolites Regulating Nematode Chemotaxis and Infection
by Naicun Chen, Qianqian Sun, Zhiqun Chen and Xu Zhang
Horticulturae 2025, 11(8), 892; https://doi.org/10.3390/horticulturae11080892 (registering DOI) - 1 Aug 2025
Viewed by 178
Abstract
Root-knot nematode (Meloidogyne incognita) is a globally destructive plant-parasitic nematode that severely impedes the sustainable production of horticultural crops. Metabolic reprogramming in plant roots represents the host response to M. incognita infection that can also be exploited by the nematode to [...] Read more.
Root-knot nematode (Meloidogyne incognita) is a globally destructive plant-parasitic nematode that severely impedes the sustainable production of horticultural crops. Metabolic reprogramming in plant roots represents the host response to M. incognita infection that can also be exploited by the nematode to facilitate its parasitism. In this study, untargeted metabolomics was employed to analyze metabolic changes in cucumber roots following nematode inoculation, with the goal of identifying differentially accumulated metabolites that may influence M. incognita behavior. Metabolomic analysis revealed that M. incognita significantly altered the cucumber root metabolome, triggering an accumulation of lipids and organic acids and enriching biotic stress-related pathways such as alkaloid biosynthesis and linoleic acid metabolism. Among differentially accumulated metabolites, myristic acid and hexadecanal were selected for further study due to their potential roles in nematode inhibition. In vitro assays demonstrated that both metabolites suppressed egg hatching and reduced infectivity of M. incognita, while pot experiments indicated a correlation between their application and reduced root gall formation. Chemotaxis assays further revealed that both metabolites exerted repellent effects on the chemotactic migration of M. incognita J2 and suppressed the transcriptional expression of two motility-and feeding-related neuropeptides, Mi-flp-1 and Mi-flp-18. In conclusion, this study demonstrates the significant potential of differentially accumulated metabolites induced by M. incognita infection for nematode disease control, achieved by interfering with nematode chemotaxis and subsequent infection. This work also provides deeper insights into the metabolomic mechanisms underlying the cucumber-M. incognita interaction. Full article
(This article belongs to the Special Issue 10th Anniversary of Horticulturae—Recent Outcomes and Perspectives)
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14 pages, 3198 KiB  
Article
Small Nucleolar RNA from S. cerevisiae Binds to Phosphatidylinositol 4,5-Bisphosphate
by Irma A. Jiménez-Ramírez, Miguel A. Uc-Chuc, Luis Carlos Rodríguez Zapata and Enrique Castaño
Non-Coding RNA 2025, 11(4), 55; https://doi.org/10.3390/ncrna11040055 - 28 Jul 2025
Cited by 1 | Viewed by 229
Abstract
Background: snoRNAs have traditionally been known for their role as guides in post-transcriptional rRNA modifications. Previously, our research group identified several RNAs that may bind to PIP2 with LIPRNA-seq. Among them, snR191 stood out due to its potential specific interaction with this [...] Read more.
Background: snoRNAs have traditionally been known for their role as guides in post-transcriptional rRNA modifications. Previously, our research group identified several RNAs that may bind to PIP2 with LIPRNA-seq. Among them, snR191 stood out due to its potential specific interaction with this lipid, distinguishing itself from other snoRNAs. However, a detailed study is needed to define the molecular interactions between RNA and lipids, which remain unknown but may serve as a mechanism for transport or liquid–liquid phase separation. This study aimed to determine the interaction between a snoRNA called snR191 and PIP2. Method: A novel methodology for RNA-PIP2 interaction was carried out. Total RNA from Saccharomyces cerevisiae was incubated with PIP2-bound nitrocellulose membranes and RT-PCR reactions. We performed the prediction of snR191-PIP2 interaction by molecular docking and in silico mutations of snoR191. Results: From LIPRNA-seq analysis, we identified that PIP2-bound RNAs were significantly enriched in diverse biological processes, including transmembrane transport and redox functions. Our RNA-PIP2 interaction approach was successful. We demonstrated that snR191 specifically interacts with PIP2 in vitro. The elimination of DNA ensured that the interaction assay was RNA-specific, strengthening the robustness of the experiment. PIP2 was docked to snR191 in a stem–loop–stem motif. Six hydrogen bonds across four nucleotides mediated the PIP2-snR191 interaction. Finally, mutations in snR191 affected the structural folding. Conclusions: In this study, we demonstrate the effectiveness of a new methodology for determining RNA–lipid interactions, providing strong evidence for the specific interaction between snR191 and PIP2. Integrating biochemical and computational approaches has allowed us to understand the binding of these biomolecules. Therefore, this work significantly broadens our understanding of snR191-PIP2 interactions and opens new perspectives for further research. Full article
(This article belongs to the Section Long Non-Coding RNA)
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31 pages, 3024 KiB  
Review
Synthetic and Functional Engineering of Bacteriophages: Approaches for Tailored Bactericidal, Diagnostic, and Delivery Platforms
by Ola Alessa, Yoshifumi Aiba, Mahmoud Arbaah, Yuya Hidaka, Shinya Watanabe, Kazuhiko Miyanaga, Dhammika Leshan Wannigama and Longzhu Cui
Molecules 2025, 30(15), 3132; https://doi.org/10.3390/molecules30153132 - 25 Jul 2025
Viewed by 393
Abstract
Bacteriophages (phages), the most abundant biological entities on Earth, have long served as both model systems and therapeutic tools. Recent advances in synthetic biology and genetic engineering have revolutionized the capacity to tailor phages with enhanced functionality beyond their natural capabilities. This review [...] Read more.
Bacteriophages (phages), the most abundant biological entities on Earth, have long served as both model systems and therapeutic tools. Recent advances in synthetic biology and genetic engineering have revolutionized the capacity to tailor phages with enhanced functionality beyond their natural capabilities. This review outlines the current landscape of synthetic and functional engineering of phages, encompassing both in-vivo and in-vitro strategies. We describe in-vivo approaches such as phage recombineering systems, CRISPR-Cas-assisted editing, and bacterial retron-based methods, as well as synthetic assembly platforms including yeast-based artificial chromosomes, Gibson, Golden Gate, and iPac assemblies. In addition, we explore in-vitro rebooting using TXTL (transcription–translation) systems, which offer a flexible alternative to cell-based rebooting but are less effective for large genomes or structurally complex phages. Special focus is given to the design of customized phages for targeted applications, including host range expansion via receptor-binding protein modifications, delivery of antimicrobial proteins or CRISPR payloads, and the construction of biocontained, non-replicative capsid systems for safe clinical use. Through illustrative examples, we highlight how these technologies enable the transformation of phages into programmable bactericidal agents, precision diagnostic tools, and drug delivery vehicles. Together, these advances establish a powerful foundation for next-generation antimicrobial platforms and synthetic microbiology. Full article
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18 pages, 6289 KiB  
Article
Antagonistic Interactions Between Dickeya solani and Bacillus subtilis
by Roberta Gatta, Adam Iwanicki, Robert Czajkowski and Michał Obuchowski
Int. J. Mol. Sci. 2025, 26(15), 7193; https://doi.org/10.3390/ijms26157193 - 25 Jul 2025
Viewed by 182
Abstract
Microorganisms in their natural ecological niches are constantly challenged by other inhabitants. Antagonisms exhibited by interacting microbial species are directed towards survival and increasing of their fitness. The Soft Rot Pectobacteriaceae (SRP) is a good model to study these complex microbial interactions. Along [...] Read more.
Microorganisms in their natural ecological niches are constantly challenged by other inhabitants. Antagonisms exhibited by interacting microbial species are directed towards survival and increasing of their fitness. The Soft Rot Pectobacteriaceae (SRP) is a good model to study these complex microbial interactions. Along with being present in various environments, SRPs are often transferred between environments, allowing the bacteria to encounter members of other species. In this study, we investigated interactions between Dickeya solani, a representative of SRPs and a causative agent of potato soft rot, and Bacillus subtilis, which is known to be a potent producer of secondary metabolites mediating antibiosis. We have found that the soil isolate B. subtilis MB73/2 not only suppresses in vitro soft-rotting of infected potato tubers but is also able to cause directional, coordinated escape of natural isolates D. solani IFB0102 and IPO2222. While this coordinated movement of D. solani depends on surfactin produced by B. subtilis MB73/2, we show that both Dickeya strains exhibit different antagonistic interaction phenotypes toward the competing Bacillus. We prove that this antagonism depends on a single nucleotide polymorphism in one of transcriptional regulators of D. solani belonging to the LysR family. Full article
(This article belongs to the Section Molecular Microbiology)
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11 pages, 1161 KiB  
Article
In Vivo Emergence of Podovirus Resistance via tarS Mutation During Phage-Antibiotic Treatment of Experimental MSSA Endocarditis
by Jérémy Cherbuin, Jonathan Save, Emma Osswald and Grégory Resch
Viruses 2025, 17(8), 1039; https://doi.org/10.3390/v17081039 - 25 Jul 2025
Viewed by 435
Abstract
Phage therapy shows promise as an adjunct to antibiotics for treating Staphylococcus aureus infections. We previously reported a combined flucloxacillin/two-phage cocktail treatment selected for resistance to podovirus phage 66 in a rodent model of methicillin-susceptible S. aureus (MSSA) endocarditis. Here we show that [...] Read more.
Phage therapy shows promise as an adjunct to antibiotics for treating Staphylococcus aureus infections. We previously reported a combined flucloxacillin/two-phage cocktail treatment selected for resistance to podovirus phage 66 in a rodent model of methicillin-susceptible S. aureus (MSSA) endocarditis. Here we show that resistant clones harbor mutations in tarS, which encodes a glycosyltransferase essential for β-GlcNAcylation of wall teichoic acid (WTA). This WTA modification has been described in vitro as critical for podoviruses adsorption. Transcriptomics confirmed continued tarS expression in resistant clones, supporting a loss-of-function mechanism. Accordingly, phage 66 binding and killing were restored by WT tarS complementation. In addition, we investigated the counterintuitive innate susceptibility to phage 66 of the tarM + Laus102 strain used in the endocarditis model. We show that it likely results from a significant lower tarM expression, in contrast to the innate resistant strain RN4220. Our findings demonstrate that tarS-mediated WTA β-GlcNAcylation is critical for podovirus infection also in vivo and identify tarM transcriptional defect as a new mechanism of podoviruses susceptibility in S. aureus. Moreover, and since tarS disruption has been previously shown to enhance β-lactam susceptibility, our results support the development of combined podovirus/antibiotic strategies for the management of MRSA infections. Full article
(This article belongs to the Special Issue Phage–Antibiotic Combination Therapy)
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11 pages, 3264 KiB  
Article
An Oncolytic Vaccinia Virus Expressing Aphrocallistes Vastus Lectin Modulates Hepatocellular Carcinoma Metabolism via ACSS2/TFEB-Mediated Autophagy and Lipid Accumulation
by Qiang Wang, Simeng Zhou, Yin Wang, Yajun Gao, Yanrong Zhou, Ting Ye, Gongchu Li and Kan Chen
Mar. Drugs 2025, 23(8), 297; https://doi.org/10.3390/md23080297 - 24 Jul 2025
Viewed by 353
Abstract
Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we [...] Read more.
Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we engineered an oncoVV-expressing Aphrocallistes vastus lectin (oncoVV-AVL) and uncovered its unique ability to exploit the ACSS2/TFEB axis, driving metabolic competition in HCC. In vitro, oncoVV-AVL triggered cell autophagy and lipid accumulation (3.4–5.7-fold upregulation of FASN and ACC1) while suppressing glucose uptake (41–63% higher extracellular glucose and 33–34% reduced lactate). Mechanistically, oncoVV-AVL upregulated acetyl-CoA synthetase 2 (ACSS2), promoting its nuclear translocation and interaction with transcription factor EB (TFEB) to concurrently activate lipogenesis and autophagic flux. The pharmacological inhibition of ACSS2 abolished these effects, confirming its central role. In vivo, oncoVV-AVL suppressed tumor growth while inducing lipid deposition (2-fold triglyceride increase), systemic hypoglycemia (42% glucose reduction), and autophagy activation (elevated LC3B-II/I ratios). This study establishes ACSS2 as a metabolic checkpoint in OV therapy, providing a rationale for combining oncolytic virotherapy with metabolic modulators in HCC. Full article
(This article belongs to the Special Issue Marine Glycobiology)
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19 pages, 9109 KiB  
Article
Metformin Enhances Doxycycline Efficacy Against Pasteurella multocida: Evidence from In Vitro, In Vivo, and Morphological Studies
by Nansong Jiang, Weiwei Wang, Qizhang Liang, Qiuling Fu, Rongchang Liu, Guanghua Fu, Chunhe Wan, Longfei Cheng, Yu Huang and Hongmei Chen
Microorganisms 2025, 13(8), 1724; https://doi.org/10.3390/microorganisms13081724 - 23 Jul 2025
Viewed by 259
Abstract
Pasteurella multocida (Pm) is a zoonotic pathogen that poses a significant threat to animal health and causes substantial economic losses, further aggravated by rising tetracycline resistance. To restore the efficacy of tetracyclines to Pm, we evaluated the synergistic antibacterial activity [...] Read more.
Pasteurella multocida (Pm) is a zoonotic pathogen that poses a significant threat to animal health and causes substantial economic losses, further aggravated by rising tetracycline resistance. To restore the efficacy of tetracyclines to Pm, we evaluated the synergistic antibacterial activity of doxycycline combined with metformin, an FDA-approved antidiabetic agent. Among several non-antibiotic adjuvant candidates, metformin exhibited the most potent in vitro synergy with doxycycline, especially against capsular serogroup A strain (PmA). The combination demonstrated minimal cytotoxicity and hemolysis in both mammalian and avian cells and effectively inhibited resistance development under doxycycline pressure. At 50 mg/kg each, the combination of metformin and doxycycline significantly reduced mortality in mice and ducks acutely infected with PmA (from 100% to 60%), decreased pulmonary bacterial burdens, and alleviated tissue inflammation and damage. Mechanistic validation confirmed that metformin enhances membrane permeability in Pm without compromising membrane integrity, dissipates membrane potential, increases intracellular doxycycline accumulation, and downregulates the transcription of the tetracycline efflux gene tet(B). Morphological analyses further revealed pronounced membrane deformation and possible leakage of intracellular contents. These findings highlight metformin as a potent, low-toxicity tetracycline adjuvant with cross-species efficacy, offering a promising therapeutic approach for managing tetracycline-resistant Pm infections. Full article
(This article belongs to the Section Veterinary Microbiology)
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31 pages, 4221 KiB  
Article
Estradiol Downregulates MicroRNA-193a to Mediate Its Angiogenic Actions
by Lisa Rigassi, Mirel Adrian Popa, Ruth Stiller, Brigitte Leeners, Marinella Rosselli and Raghvendra Krishna Dubey
Cells 2025, 14(15), 1134; https://doi.org/10.3390/cells14151134 - 23 Jul 2025
Cited by 1 | Viewed by 342
Abstract
Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play [...] Read more.
Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth. Full article
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18 pages, 3760 KiB  
Article
Transcriptomic Meta-Analysis Unveils Shared Neurodevelopmental Toxicity Pathways and Sex-Specific Transcriptional Signatures of Established Neurotoxicants and Polystyrene Nanoplastics as an Emerging Contaminant
by Wenhao Wang, Yutong Liu, Nanxin Ma, Rui Wang, Lifan Fan, Chen Chen, Qiqi Yan, Zhihua Ren, Xia Ning, Shuting Wei and Tingting Ku
Toxics 2025, 13(8), 613; https://doi.org/10.3390/toxics13080613 - 22 Jul 2025
Viewed by 288
Abstract
Environmental contaminants exhibit heterogeneous neurotoxicity profiles, yet systematic comparisons between legacy neurotoxicants and emerging pollutants remain scarce. To address this gap, we implemented an integrative transcriptome meta-analysis framework that harmonized eight transcriptomic datasets spanning in vivo and in vitro neural models exposed to [...] Read more.
Environmental contaminants exhibit heterogeneous neurotoxicity profiles, yet systematic comparisons between legacy neurotoxicants and emerging pollutants remain scarce. To address this gap, we implemented an integrative transcriptome meta-analysis framework that harmonized eight transcriptomic datasets spanning in vivo and in vitro neural models exposed to two legacy neurotoxicants (bisphenol A [BPA], 2, 2′, 4, 4′-tetrabromodiphenyl ether [BDE-47]) and polystyrene nanoplastics (PSNPs) as an emerging contaminant. Our analysis revealed a substantial overlap (68% consistency) in differentially expressed genes (DEGs) between BPA and PSNPs, with shared enrichment in extracellular matrix disruption pathways (e.g., “fibronectin binding” and “collagen binding”, p < 0.05). Network-based toxicogenomic mapping linked all three contaminants to six neurological disorders, with BPA showing the strongest associations with Hepatolenticular Degeneration. Crucially, a sex-stratified analysis uncovered male-specific transcriptional responses to BPA (e.g., lipid metabolism and immune response dysregulation), whereas female models showed no equivalent enrichment. This highlights the sex-specific transcriptional characteristics of BPA exposure. This study establishes a novel computational toxicology workflow that bridges legacy and emerging contaminant research, providing mechanistic insights for chemical prioritization and gender-specific risk assessment. Full article
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18 pages, 5443 KiB  
Article
Toosendanin Induces Hepatotoxicity by Facilitating ALOX5-Mediated Lipid Peroxidation and Sensitizing Cells to Ferroptosis
by Jiajie Ni, Liru Huang, Yifan Tian, Changxin Zhao, Ziyi Zhou, Feihai Shen and Zhiying Huang
Pharmaceuticals 2025, 18(7), 1078; https://doi.org/10.3390/ph18071078 - 21 Jul 2025
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Abstract
Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying [...] Read more.
Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. Methods: HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb/c and C57BL/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. Results: TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. Conclusions: Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis. Full article
(This article belongs to the Section Pharmacology)
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