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21 pages, 3431 KiB  
Article
Synthesis and Antibacterial Evaluation of an Indole Triazole Conjugate with In Silico Evidence of Allosteric Binding to Penicillin-Binding Protein 2a
by Vidyasrilekha Sanapalli, Bharat Kumar Reddy Sanapalli and Afzal Azam Mohammed
Pharmaceutics 2025, 17(8), 1013; https://doi.org/10.3390/pharmaceutics17081013 (registering DOI) - 3 Aug 2025
Abstract
Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial [...] Read more.
Background: Antibacterial resistance (ABR) poses a major challenge to global health, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the prominent multidrug-resistant strains. MRSA has developed resistance through the expression of Penicillin-Binding Protein 2a (PBP2a), a key transpeptidase enzyme involved in bacterial cell wall biosynthesis. Objectives: The objective was to design and characterize a novel small-molecule inhibitor targeting PBP2a as a strategy to combat MRSA. Methods: We synthesized a new indole triazole conjugate (ITC) using eco-friendly and click chemistry approaches. In vitro antibacterial tests were performed against a panel of strains to evaluate the ITC antibacterial potential. Further, a series of in silico evaluations like molecular docking, MD simulations, free energy landscape (FEL), and principal component analysis (PCA) using the crystal structure of PBP2a (PDB ID: 4CJN), in order to predict the mechanism of action, binding mode, structural stability, and energetic profile of the 4CJN-ITC complex. Results: The compound ITC exhibited noteworthy antibacterial activity, which effectively inhibited the selected strains. Binding score and energy calculations demonstrated high affinity of ITC for the allosteric site of PBP2a and significant interactions responsible for complex stability during MD simulations. Further, FEL and PCA provided insights into the conformational behavior of ITC. These results gave the structural clues for the inhibitory action of ITC on the PBP2a. Conclusions: The integrated in vitro and in silico studies corroborate the potential of ITC as a promising developmental lead targeting PBP2a in MRSA. This study demonstrates the potential usage of rational drug design approaches in addressing therapeutic needs related to ABR. Full article
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17 pages, 1724 KiB  
Article
Effects of Eriobotrya japonica (Thunb.) Lindl. Leaf Extract on Zebrafish Embryogenesis, Behavior, and Biochemical Pathways
by Jorge Barros, Irene Gouvinhas, Carlos Venâncio, Daniel Granato, Ana Novo Barros and Luís Félix
Molecules 2025, 30(15), 3252; https://doi.org/10.3390/molecules30153252 (registering DOI) - 3 Aug 2025
Abstract
Eriobotrya japonica (Thunb.) Lindl. leaves are rich in polyphenolic compounds, yet their toxicological effects in aquatic models remain poorly understood. This study evaluated the impact of a hydroethanolic E. japonica leaf extract on zebrafish embryos through the use of morphological, behavioral, and biochemical [...] Read more.
Eriobotrya japonica (Thunb.) Lindl. leaves are rich in polyphenolic compounds, yet their toxicological effects in aquatic models remain poorly understood. This study evaluated the impact of a hydroethanolic E. japonica leaf extract on zebrafish embryos through the use of morphological, behavioral, and biochemical parameters. The 96 h LC50 was determined as 189.8 ± 4.5 mg/L, classifying the extract as practically non-toxic, according to OECD guidelines. Thereby, embryos were exposed for 90 h to 75 and 150 mg/L concentrations of the E. japonica leaf extract. While no significant effects were noted at the lowest concentration of 150 mg/L, significant developmental effects were observed, including reduced survival, delayed hatching, underdevelopment of the swim bladder, and retention of the yolk sac. These malformations were accompanied by marked behavioral impairments. Biochemical analysis revealed a concentration-dependent increase in superoxide dismutase (SOD) and catalase (CAT) activity, suggesting the activation of antioxidant defenses, despite no significant change in reactive oxygen species (ROS) levels. This indicates a potential compensatory redox response to a pro-oxidant signal. Additionally, the acetylcholinesterase (AChE) activity was significantly reduced at the highest concentration, which may have contributed to the observed neurobehavioral changes. While AChE inhibition is commonly associated with neurotoxicity, it is also a known therapeutic target in neurodegenerative diseases, suggesting concentration-dependent dual effects. In summary, the E. japonica leaf extract induced concentration-dependent developmental and behavioral effects in zebrafish embryos, while activating antioxidant responses without triggering oxidative damage. These findings highlight the extract’s potential bioactivity and underscore the need for further studies to explore its safety and therapeutic relevance. Full article
(This article belongs to the Special Issue Biological Activities of Traditional Medicinal Plants, 2nd Edition)
18 pages, 4468 KiB  
Article
Proteomic and Functional Analysis Reveals Temperature-Driven Immune Evasion Strategies of Streptococcus iniae in Yellowfin Seabream (Acanthopagrus latus)
by Yanjian Yang, Guanrong Zhang, Ruilong Xu, Yiyang Deng, Zequan Mo, Yanwei Li and Xueming Dan
Biology 2025, 14(8), 986; https://doi.org/10.3390/biology14080986 (registering DOI) - 2 Aug 2025
Abstract
Streptococcus iniae (S. iniae) is a globally significant aquatic pathogen responsible for severe economic losses in aquaculture. While the S. iniae infection often exhibits distinct seasonal patterns strongly correlated with water temperature, there is limited knowledge regarding the temperature-dependent immune evasion [...] Read more.
Streptococcus iniae (S. iniae) is a globally significant aquatic pathogen responsible for severe economic losses in aquaculture. While the S. iniae infection often exhibits distinct seasonal patterns strongly correlated with water temperature, there is limited knowledge regarding the temperature-dependent immune evasion strategies of S. iniae. Our results demonstrated a striking temperature-dependent virulence phenotype, with significantly higher A. latus mortality rates observed at high temperature (HT, 33 °C) compared to low temperature (LT, 23 °C). Proteomic analysis revealed temperature-dependent upregulation of key virulence factors, including streptolysin S-related proteins (SagG, SagH), antioxidant-related proteins (SodA), and multiple capsular polysaccharide (cps) synthesis proteins (cpsD, cpsH, cpsL, cpsY). Flow cytometry analysis showed that HT infection significantly reduced the percentage of lymphocyte and myeloid cell populations in the head kidney leukocytes of A. latus, which was associated with elevated caspase-3/7 expression and increased apoptosis. In addition, HT infection significantly inhibited the release of reactive oxygen species (ROS) but not nitric oxide (NO) production. Using S. iniae cps-deficient mutant, Δcps, we demonstrated that the cps is essential for temperature-dependent phagocytosis resistance in S. iniae, as phagocytic activity against Δcps remained unchanged across temperatures, while NS-1 showed significantly reduced uptake at HT. These findings provide new insights into the immune evasion of S. iniae under thermal regulation, deepening our understanding of the thermal adaptation of aquatic bacterial pathogens. Full article
(This article belongs to the Special Issue Aquatic Economic Animal Breeding and Healthy Farming)
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17 pages, 2547 KiB  
Article
A Host Cell Vector Model for Analyzing Viral Protective Antigens and Host Immunity
by Sun-Min Ahn, Jin-Ha Song, Seung-Eun Son, Ho-Won Kim, Gun Kim, Seung-Min Hong, Kang-Seuk Choi and Hyuk-Joon Kwon
Int. J. Mol. Sci. 2025, 26(15), 7492; https://doi.org/10.3390/ijms26157492 (registering DOI) - 2 Aug 2025
Abstract
Avian influenza A viruses (IAVs) pose a persistent threat to the poultry industry, causing substantial economic losses. Although traditional vaccines have helped reduce the disease burden, they typically rely on multivalent antigens, emphasize humoral immunity, and require intensive production. This study aimed to [...] Read more.
Avian influenza A viruses (IAVs) pose a persistent threat to the poultry industry, causing substantial economic losses. Although traditional vaccines have helped reduce the disease burden, they typically rely on multivalent antigens, emphasize humoral immunity, and require intensive production. This study aimed to establish a genetically matched host–cell system to evaluate antigen-specific immune responses and identify conserved CD8+ T cell epitopes in avian influenza viruses. To this end, we developed an MHC class I genotype (B21)-matched host (Lohmann VALO SPF chicken) and cell vector (DF-1 cell line) model. DF-1 cells were engineered to express the hemagglutinin (HA) gene of clade 2.3.4.4b H5N1 either transiently or stably, and to stably express the matrix 1 (M1) and nucleoprotein (NP) genes of A/chicken/South Korea/SL20/2020 (H9N2, Y280-lineage). Following prime-boost immunization with HA-expressing DF-1 cells, only live cells induced strong hemagglutination inhibition (HI) and virus-neutralizing (VN) antibody titers in haplotype-matched chickens. Importantly, immunization with DF-1 cells transiently expressing NP induced stronger IFN-γ production than those expressing M1, demonstrating the platform’s potential for differentiating antigen-specific cellular responses. CD8+ T cell epitope mapping by mass spectrometry identified one distinct MHC class I-bound peptide from each of the HA-, M1-, and NP-expressing DF-1 cell lines. Notably, the identified HA epitope was conserved in 97.6% of H5-subtype IAVs, and the NP epitope in 98.5% of pan-subtype IAVs. These findings highlight the platform’s utility for antigen dissection and rational vaccine design. While limited by MHC compatibility, this approach enables identification of naturally presented epitopes and provides insight into conserved, functionally constrained viral targets. Full article
(This article belongs to the Special Issue Molecular Research on Immune Response to Virus Infection and Vaccines)
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33 pages, 4098 KiB  
Systematic Review
Pharmacological Inhibition of the PI3K/AKT/mTOR Pathway in Rheumatoid Arthritis Synoviocytes: A Systematic Review and Meta-Analysis (Preclinical)
by Tatiana Bobkova, Artem Bobkov and Yang Li
Pharmaceuticals 2025, 18(8), 1152; https://doi.org/10.3390/ph18081152 (registering DOI) - 2 Aug 2025
Abstract
Background/Objectives: Constitutive activation of the PI3K/AKT/mTOR signaling cascade underlies the aggressive phenotype of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA); however, a quantitative synthesis of in vitro data on pathway inhibition remains lacking. This systematic review and meta-analysis aimed to (i) aggregate [...] Read more.
Background/Objectives: Constitutive activation of the PI3K/AKT/mTOR signaling cascade underlies the aggressive phenotype of fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA); however, a quantitative synthesis of in vitro data on pathway inhibition remains lacking. This systematic review and meta-analysis aimed to (i) aggregate standardized effects of pathway inhibitors on proliferation, apoptosis, migration/invasion, IL-6/IL-8 secretion, p-AKT, and LC3; (ii) assess heterogeneity and identify key moderators of variability, including stimulus type, cell source, and inhibitor class. Methods: PubMed, Europe PMC, and the Cochrane Library were searched up to 18 May 2025 (PROSPERO CRD420251058185). Twenty of 2684 screened records met eligibility. Two reviewers independently extracted data and assessed study quality with SciRAP. Standardized mean differences (Hedges g) were pooled using a Sidik–Jonkman random-effects model with Hartung–Knapp confidence intervals. Heterogeneity (τ2, I2), 95% prediction intervals, and meta-regression by cell type were calculated; robustness was tested with REML-HK, leave-one-out, and Baujat diagnostics. Results: PI3K/AKT/mTOR inhibition markedly reduced proliferation (to –5.1 SD), IL-6 (–11.1 SD), and IL-8 (–6.5 SD) while increasing apoptosis (+2.7 SD). Fourteen of seventeen outcome clusters showed large effects (|g| ≥ 0.8), with low–moderate heterogeneity (I2 ≤ 35% in 11 clusters). Prediction intervals crossed zero only in small k-groups; sensitivity analyses shifted pooled estimates by ≤0.05 SD. p-AKT and p-mTOR consistently reflected functional changes and emerged as reliable pharmacodynamic markers. Conclusions: Targeted blockade of PI3K/AKT/mTOR robustly suppresses the proliferative and inflammatory phenotype of RA-FLSs, reaffirming this axis as a therapeutic target. The stability of estimates across multiple analytic scenarios enhances confidence in these findings and highlights p-AKT and p-mTOR as translational response markers. The present synthesis provides a quantitative basis for personalized dual-PI3K/mTOR strategies and supports the adoption of standardized long-term preclinical protocols. Full article
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14 pages, 2030 KiB  
Article
In Vitro Assessment of the Antimicrobial and Antibiofilm Activities of Commercial Toothpastes Against Streptococcus mutans
by Yun Ju Lee and Jeong Nam Kim
Appl. Biosci. 2025, 4(3), 38; https://doi.org/10.3390/applbiosci4030038 (registering DOI) - 2 Aug 2025
Abstract
Toothpaste is an essential oral hygiene product commonly used to sustain oral health due to its incorporation of antimicrobial agents. Numerous functional toothpastes enriched with antimicrobial agents have been developed and are available to consumers. This study evaluates the antimicrobial and antibiofilm efficacy [...] Read more.
Toothpaste is an essential oral hygiene product commonly used to sustain oral health due to its incorporation of antimicrobial agents. Numerous functional toothpastes enriched with antimicrobial agents have been developed and are available to consumers. This study evaluates the antimicrobial and antibiofilm efficacy of 12 commercially available toothpaste products, including those with specialized functions. Statistical significance was assessed to validate the differences observed among the toothpaste samples. Their effects on Streptococcus mutans, the primary pathogen responsible for dental caries, were evaluated. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined, and bacterial growth was measured to compare antimicrobial activities. Toothpaste containing 1000 μg/mL fluoride and whitening toothpaste exhibited the strongest antimicrobial effects, effectively inhibiting S. mutans growth. Additionally, bamboo salt-enriched and tartar-control toothpaste demonstrated inhibitory effects on bacterial growth. Assays to evaluate the ability of cells to form biofilms and the expression of genes involved in biofilm formation revealed a partial correlation between biofilm formation and spaP, gtfB, gtfC, and gtfD expression, although some showed opposite trends. Collectively, this study provides valuable insights into the antimicrobial and biofilm inhibition capabilities of commercial toothpastes against S. mutans, offering a foundation for evaluating the efficacy of functional toothpaste products. Full article
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21 pages, 2600 KiB  
Article
Bamboo Biochar and Sodium Silicate Alleviate Oxybenzone-Induced Phytotoxicity via Distinct Mechanisms for Sustainable Plant Protection
by Chuantong Cui, Wenhai Yang, Weiru Dang, Ruiya Chen, Pedro García-Caparrós, Guoqun Yang, Jianhua Huang and Li-Jun Huang
Plants 2025, 14(15), 2382; https://doi.org/10.3390/plants14152382 (registering DOI) - 2 Aug 2025
Abstract
Oxybenzone (OBZ), an organic ultraviolet filter, is an emerging contaminant posing severe threats to ecosystem health. Using tobacco (Nicotiana tabacum) as a model plant, this study investigated the alleviation mechanisms of exogenous silicon (Na2SiO3, Si) and bamboo-based [...] Read more.
Oxybenzone (OBZ), an organic ultraviolet filter, is an emerging contaminant posing severe threats to ecosystem health. Using tobacco (Nicotiana tabacum) as a model plant, this study investigated the alleviation mechanisms of exogenous silicon (Na2SiO3, Si) and bamboo-based biochar (Bc) under OBZ stress. We systematically analyzed physiological and biochemical responses, including phenotypic parameters, reactive oxygen species metabolism, photosynthetic function, chlorophyll synthesis, and endogenous hormone levels. Results reveal that OBZ significantly inhibited tobacco growth and triggered a reactive oxygen species (ROS) burst. Additionally, OBZ disrupted antioxidant enzyme activities and hormonal balance. Exogenous Bc mitigated OBZ toxicity by adsorbing OBZ, directly scavenging ROS, and restoring the ascorbate-glutathione (AsA-GSH) cycle, thereby enhancing photosynthetic efficiency, while Si alleviated stress via cell wall silicification, preferential regulation of root development and hormonal signaling, and repair of chlorophyll biosynthesis precursor metabolism and PSII function. The mechanisms of the two stress mitigators were complementary, Bc primarily relied on physical adsorption and ROS scavenging, whereas Si emphasized metabolic regulation and structural reinforcement. These findings provide practical strategies for simultaneously mitigating organic UV filter pollution and enhancing plant resilience in contaminated soils. Full article
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23 pages, 1985 KiB  
Article
Photobiomodulation of 450 nm Blue Light on Human Keratinocytes, Fibroblasts, and Endothelial Cells: An In Vitro and Transcriptomic Study on Cells Involved in Wound Healing and Angiogenesis
by Jingbo Shao, Sophie Clément, Christoph Reissfelder, Patrick Téoule, Norbert Gretz, Feng Guo, Sabina Hajizada, Stefanie Uhlig, Katharina Mößinger, Carolina de la Torre, Carsten Sticht, Vugar Yagublu and Michael Keese
Biomedicines 2025, 13(8), 1876; https://doi.org/10.3390/biomedicines13081876 (registering DOI) - 1 Aug 2025
Abstract
Background: Blue light (BL) irradiation has been shown to induce photobiomodulation (PBM) in cells. Here, we investigate its influence on cell types involved in wound healing. Methods: Cellular responses of immortalized human keratinocytes (HaCaTs), normal human dermal fibroblasts (NHDFs), and human umbilical [...] Read more.
Background: Blue light (BL) irradiation has been shown to induce photobiomodulation (PBM) in cells. Here, we investigate its influence on cell types involved in wound healing. Methods: Cellular responses of immortalized human keratinocytes (HaCaTs), normal human dermal fibroblasts (NHDFs), and human umbilical vein endothelial cells (HUVECs) after light treatment at 450 nm were analyzed by kinetic assays on cell viability, proliferation, ATP quantification, migration assay, and apoptosis assay. Gene expression was evaluated by transcriptome analysis. Results: A biphasic effect was observed on HaCaTs, NHDFs, and HUVECs. Low-fluence (4.5 J/cm2) irradiation stimulated cell viability, proliferation, and migration. mRNA sequencing indicated involvement of transforming growth factor beta (TGF-β), ErbB, and vascular endothelial growth factor (VEGF) pathways. High-fluence (18 J/cm2) irradiation inhibited these cellular activities by downregulating DNA replication, the cell cycle, and mismatch repair pathways. Conclusions: HaCaTs, NHDFs, and HUVECs exhibited a dose-dependent pattern after BL irradiation. These findings broaden the view of PBM following BL irradiation of these three cell types, thereby promoting their potential application in wound healing and angiogenesis. Our data on low-fluence BL at 450 nm indicates clinical potential for a novel modality in wound therapy. Full article
(This article belongs to the Section Cell Biology and Pathology)
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
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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22 pages, 486 KiB  
Review
Unraveling NETs in Sepsis: From Cellular Mechanisms to Clinical Relevance
by Giulia Pignataro, Stefania Gemma, Martina Petrucci, Fabiana Barone, Andrea Piccioni, Francesco Franceschi and Marcello Candelli
Int. J. Mol. Sci. 2025, 26(15), 7464; https://doi.org/10.3390/ijms26157464 (registering DOI) - 1 Aug 2025
Abstract
Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, frequently resulting in septic shock and multi-organ failure. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in the pathophysiology of sepsis. NETs are extracellular structures composed of [...] Read more.
Sepsis is a clinical syndrome characterized by a dysregulated host response to infection, frequently resulting in septic shock and multi-organ failure. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in the pathophysiology of sepsis. NETs are extracellular structures composed of chromatin DNA, histones, and granular proteins released by neutrophils through a specialized form of cell death known as NETosis. While NETs contribute to the containment of pathogens, their excessive or dysregulated production in sepsis is associated with endothelial damage, immunothrombosis, and organ dysfunction. Several NET-associated biomarkers have been identified, including circulating cell-free DNA (cfDNA), histones, MPO-DNA complexes, and neutrophil elastase–DNA complexes, which correlate with the disease severity and prognosis. Therapeutic strategies targeting NETs are currently under investigation. Inhibition of NET formation using PAD4 inhibitors or ROS scavengers has shown protective effects in preclinical models. Conversely, DNase I therapy facilitates the degradation of extracellular DNA, reducing the NET-related cytotoxicity and thrombotic potential. Additionally, heparin and its derivatives have demonstrated the ability to neutralize NET-associated histones and mitigate coagulopathy. Novel approaches include targeting upstream signaling pathways, such as TLR9 and IL-8/CXCR2, offering further therapeutic promise. Full article
(This article belongs to the Collection Advances in Cell and Molecular Biology)
23 pages, 1139 KiB  
Article
A Critical Appraisal of Off-Label Use and Repurposing of Statins for Non-Cardiovascular Indications: A Systematic Mini-Update and Regulatory Analysis
by Anna Artner, Irem Diler, Balázs Hankó, Szilvia Sebők and Romána Zelkó
J. Clin. Med. 2025, 14(15), 5436; https://doi.org/10.3390/jcm14155436 (registering DOI) - 1 Aug 2025
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Abstract
Background: Statins exhibit pleiotropic anti-inflammatory, antioxidant, and immunomodulatory effects, suggesting their potential in non-cardiovascular conditions. However, evidence supporting their repurposing remains limited, and off-label prescribing policies vary globally. Objective: To systematically review evidence on statin repurposing in oncology and infectious diseases, and to [...] Read more.
Background: Statins exhibit pleiotropic anti-inflammatory, antioxidant, and immunomodulatory effects, suggesting their potential in non-cardiovascular conditions. However, evidence supporting their repurposing remains limited, and off-label prescribing policies vary globally. Objective: To systematically review evidence on statin repurposing in oncology and infectious diseases, and to assess Hungarian regulatory practices regarding off-label statin use. Methods: A systematic literature search (PubMed, Web of Science, Scopus, ScienceDirect; 2010–May 2025) was conducted using the terms “drug repositioning” OR “off-label prescription” AND “statin” NOT “cardiovascular,” following PRISMA guidelines. Hungarian off-label usage data from the NNGYK (2008–2025) were also analyzed. Results: Out of 205 publications, 12 met the inclusion criteria—75% were oncology-focused, and 25% focused on infectious diseases. Most were preclinical (58%); only 25% offered strong clinical evidence. Applications included hematologic malignancies, solid tumors, Cryptococcus neoformans, SARS-CoV-2, and dengue virus. Mechanisms involved mevalonate pathway inhibition and modulation of host immune responses. Hungarian data revealed five approved off-label statin uses—three dermatologic and two pediatric metabolic—supported by the literature and requiring post-treatment reporting. Conclusions: While preclinical findings are promising, clinical validation of off-label statin use remains limited. Statins should be continued in cancer patients with cardiovascular indications, but initiation for other purposes should be trial-based. Future directions include biomarker-based personalization, regulatory harmonization, and cost-effectiveness studies. Full article
(This article belongs to the Section Pharmacology)
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35 pages, 7970 KiB  
Article
Heteroaryl-Capped Hydroxamic Acid Derivatives with Varied Linkers: Synthesis and Anticancer Evaluation with Various Apoptosis Analyses in Breast Cancer Cells, Including Docking, Simulation, DFT, and ADMET Studies
by Ekta Shirbhate, Biplob Koch, Vaibhav Singh, Akanksha Dubey, Haya Khader Ahmad Yasin and Harish Rajak
Pharmaceuticals 2025, 18(8), 1148; https://doi.org/10.3390/ph18081148 (registering DOI) - 1 Aug 2025
Viewed by 23
Abstract
Background/Objectives: Cancer suffers from unresolved therapeutic challenges owing to the lack of targeted therapies and heightened recurrence risk. This study aimed to investigate the new series of hydroxamate by structurally modifying the pharmacophore of vorinostat. Methods: The present work involves the synthesis [...] Read more.
Background/Objectives: Cancer suffers from unresolved therapeutic challenges owing to the lack of targeted therapies and heightened recurrence risk. This study aimed to investigate the new series of hydroxamate by structurally modifying the pharmacophore of vorinostat. Methods: The present work involves the synthesis of 15 differently substituted 2H-1,2,3-triazole-based hydroxamide analogs by employing triazole ring as a cap with varied linker fragments. The compounds were evaluated for their anticancer effect, especially their anti-breast cancer response. Molecular docking and molecular dynamics simulations were conducted to examine binding interactions. Results: Results indicated that among all synthesized hybrids, the molecule VI(i) inhibits the growth of MCF-7 and A-549 cells (GI50 < 10 μg/mL) in an antiproliferative assay. Compound VI(i) was also tested for cytotoxic activity by employing an MTT assay against A549, MCF-7, and MDA-MB-231 cell lines, and the findings indicate its potent anticancer response, especially against MCF-7 cells with IC50 of 60 µg/mL. However, it experiences minimal toxicity towards the normal cell line (HEK-293). Mechanistic studies revealed a dual-pathway activation: first, apoptosis (17.18% of early and 10.22% of late apoptotic cells by annexin V/PI analysis); second, cell cycle arrest at the S and G2/M phases. It also promotes ROS generation in a concentration-dependent manner. The HDAC–inhibitory assay, extended in silico molecular docking, and MD simulation experiments further validated its significant binding affinity towards HDAC 1 and 6 isoforms. DFT and ADMET screening further support the biological proclivity of the title compounds. The notable biological contribution of VI(i) highlights it as a potential candidate, especially against breast cancer cells. Full article
(This article belongs to the Section Medicinal Chemistry)
20 pages, 1876 KiB  
Article
Evaluation of Clean-Label Additives to Inhibit Molds and Extend the Shelf Life of Preservative-Free Bread
by Ricardo H. Hernández-Figueroa, Aurelio López-Malo, Beatriz Mejía-Garibay, Nelly Ramírez-Corona and Emma Mani-López
Microbiol. Res. 2025, 16(8), 179; https://doi.org/10.3390/microbiolres16080179 (registering DOI) - 1 Aug 2025
Viewed by 41
Abstract
This study evaluates the efficacy of commercial clean-label additives, specifically fermentates, in inhibiting mold growth in vitro and extending the shelf life of preservative-free bread. The mold growth on selected bread was modeled using the time-to-growth approach. The pH, aw, and [...] Read more.
This study evaluates the efficacy of commercial clean-label additives, specifically fermentates, in inhibiting mold growth in vitro and extending the shelf life of preservative-free bread. The mold growth on selected bread was modeled using the time-to-growth approach. The pH, aw, and moisture content of fresh bread were determined. In addition, selected fermentates were characterized physicochemically. Fermentates, defined as liquid or powdered preparations containing microorganisms, their metabolites, and culture supernatants, were tested at varying concentrations (1% to 12%) to assess their antimicrobial performance and impact on bread quality parameters, including moisture content, water activity, and pH. The results showed significant differences in fermentate efficacy, with Product A as the best mold growth inhibitor in vitro and a clear dose-dependent response. For Penicillium corylophilum, inhibition increased from 51.90% at 1% to 62.60% at 4%, while P. chrysogenum had an inhibition ranging from 32.26% to 34.49%. Product F exhibited moderate activity on both molds at 4%, inhibiting between 28.48% and 46.27%. The two molds exhibited differing sensitivities to the fermentates, with P. corylophilum consistently more susceptible to inhibition. Product A displayed a low pH (2.61) and high levels of lactic acid (1053.6 mmol/L) and acetic acid (1061.3 mmol/L). Product F presented a similar pH but lower levels of lactic and acetic acid. A time-to-growth model, validated by significant coefficients (p < 0.05) and high predictive accuracy (R2 > 0.95), was employed to predict the appearance of mold on bread loaves. The model revealed that higher concentrations of fermentates A and F delayed mold growth, with fermentate A demonstrating superior efficacy. At 2% concentration, fermentate A delayed mold growth for 8 days, compared to 6 days for fermentate F. At 8% concentration, fermentate A prevented mold growth for over 25 days, significantly outperforming the control (4 days). Additionally, fermentates influenced bread quality parameters, with fermentate A improving crust moisture retention and reducing water activity at higher concentrations. These findings highlight the potential of fermentates as sustainable, consumer-friendly alternatives to synthetic preservatives, offering a viable solution to the challenge of bread spoilage while maintaining product quality. Full article
(This article belongs to the Collection Microbiology and Technology of Fermented Foods)
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30 pages, 955 KiB  
Review
Breaking Barriers with Sound: The Implementation of Histotripsy in Cancer
by Ashutosh P. Raman, Parker L. Kotlarz, Alexis E. Giff, Katherine A. Goundry, Paul Laeseke, Erica M. Knavel Koepsel, Mosa Alhamami and Dania Daye
Cancers 2025, 17(15), 2548; https://doi.org/10.3390/cancers17152548 (registering DOI) - 1 Aug 2025
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Abstract
Histotripsy is a novel, noninvasive, non-thermal technology invented in 2004 for the precise destruction of biologic tissue. It offers a powerful alternative to more conventional thermal or surgical interventions. Using short-pulse, low-duty cycle ultrasonic waves, histotripsy creates cavitation bubble clouds that selectively and [...] Read more.
Histotripsy is a novel, noninvasive, non-thermal technology invented in 2004 for the precise destruction of biologic tissue. It offers a powerful alternative to more conventional thermal or surgical interventions. Using short-pulse, low-duty cycle ultrasonic waves, histotripsy creates cavitation bubble clouds that selectively and precisely destroy targeted tissue in a predefined volume while sparing critical structures like bile ducts, ureters, and blood vessels. Such precision is of value when treating tumors near vital structures. The FDA has cleared histotripsy for the treatment of all liver tumors. Major medical centers are currently spearheading clinical trials, and some institutions have already integrated the technology into patient care. Histotripsy is now being studied for a host of other cancers, including primary kidney and pancreatic tumors. Preclinical murine and porcine models have already revealed promising outcomes. One of histotripsy’s primary advantages is its non-thermal mechanical actuation. This feature allows it to circumvent the limitations of heat-based techniques, including the heat sink effect and unpredictable treatment margins near sensitive tissues. In addition to its non-invasive ablative capacities, it is being preliminarily explored for its potential to induce immunomodulation and promote abscopal inhibition of distant, untreated tumors through CD8+ T cell responses. Thus, it may provide a multilayered therapeutic effect in the treatment of cancer. Histotripsy has the potential to improve precision and outcomes across a multitude of specialties, from oncology to cardiovascular medicine. Continued trials are crucial to further expand its applications and validate its long-term efficacy. Due to the speed of recent developments, the goal of this review is to provide a comprehensive and updated overview of histotripsy. It will explore its physics-based mechanisms, differentiating it from similar technologies, discuss its clinical applications, and examine its advantages, limitations, and future. Full article
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Article
Comparative Analysis of the Long-Term Real-World Efficacy of Interleukin-17 Inhibitors in a Cohort of Patients with Moderate-to-Severe Psoriasis Treated in Poland
by Wiktor Kruczek, Aleksandra Frątczak, Iga Litwińska-Inglot, Karina Polak, Zuzanna Pawlus, Paulina Rutecka, Beata Bergler-Czop and Bartosz Miziołek
J. Clin. Med. 2025, 14(15), 5421; https://doi.org/10.3390/jcm14155421 (registering DOI) - 1 Aug 2025
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Abstract
Background: Bimekizumab, secukinumab, and ixekizumab are IL-17-targeting biologics approved for the treatment of moderate-to-severe plaque psoriasis. While secukinumab and ixekizumab selectively inhibit IL-17A, bimekizumab targets both IL-17A and IL-17F, potentially providing greater anti-inflammatory efficacy. This study aimed to compare the real-world effectiveness, [...] Read more.
Background: Bimekizumab, secukinumab, and ixekizumab are IL-17-targeting biologics approved for the treatment of moderate-to-severe plaque psoriasis. While secukinumab and ixekizumab selectively inhibit IL-17A, bimekizumab targets both IL-17A and IL-17F, potentially providing greater anti-inflammatory efficacy. This study aimed to compare the real-world effectiveness, safety, and tolerability of these agents in a Polish dermatology center between 2019 and 2024. Methods: We conducted a retrospective analysis of 98 patients meeting at least one of the following criteria: PASI ≥ 10, BSA ≥ 10, DLQI ≥ 10, or involvement of special areas with inadequate response or contraindications to ≥2 systemic therapies. Patients with prior exposure only to IL-17 inhibitors were excluded. PASI, BSA, and DLQI scores were recorded at baseline, week 4, and week 12. Due to differences in dosing schedules, outcomes were aligned using standardized timepoints and exponential modeling of continuous response trajectories. Mixed-effects ANOVA was used to assess the influence of baseline factors (age, BMI, PsA status) on treatment outcomes. Adverse events were documented at each monthly follow-up visit. Results: Bimekizumab showed the greatest effect size for PASI reduction (Hedges’ g = 3.662), followed by secukinumab (2.813) and ixekizumab (1.986). Exponential modeling revealed a steeper response trajectory with bimekizumab (intercept = 0.289), suggesting a more rapid PASI improvement. The efficacy of bimekizumab was particularly notable in patients who were previously treated with IL-23 inhibitors. All three agents demonstrated favorable safety profiles, with no serious adverse events or discontinuations. The most frequent adverse events were mild and included upper respiratory tract infections and oral candidiasis. Conclusions: This real-world analysis confirmed that IL-17 inhibitors effectively improved PASI, BSA, and DLQI scores in moderate-to-severe psoriasis. Bimekizumab demonstrated the most rapid early improvements and a higher modeled likelihood of complete clearance, without significant differences at week 12. All agents were well tolerated, underscoring the need for further individualized, large-scale studies. Full article
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