Search Results (2,130)

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

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

Several natural products have been shown to display antiviral activity against the hepatitis B virus (HBV), among a number of other viruses. In a previous study, the hydro-alcoholic extracts (n = 66) of 31 species from the Venezuelan Amazonian rain forest were tested on the hepatoma cell line HepG2.2.15, which constitutively produces HBV. One of the species that exerted inhibitory activity on HBV replication was Senna silvestris. The aim of this study was the bioassay-guided purification of the ethanol fraction of leaves of S. silvestris, which displayed the most significant inhibitory activity against HBV. After solvent extraction and two rounds of reverse-phase HPLC purification, NMR analysis identified salsolinol as the compound that may exert the desired antiviral activity. The purified compound exerted inhibition of both HBV DNA and core HBV DNA. Pure salsolinol obtained from a commercial source also displayed anti-HBV DNA inhibition, with an approximate MIC value of 12 µM. Although salsolinol is widely used in Chinese traditional medicine to treat congestive heart failure, it has also been associated with Parkinson’s disease. More studies are warranted to analyze the effect of changes in its chemical conformation, searching for potent antiviral, perhaps dual agents against HBV and HIV, with reduced toxicity. Full article

This study explores the potential of biodegradable Bioglass 45S5 formulations as a dual-function approach for preventing and treating Staphylococcus aureus infections in orthopaedic surgery while addressing the growing concern of antimicrobial resistance (AMR). The research focuses on the development and characterisation of antibiotic-loaded BG45S5 formulations, assessing parameters such as drug loading efficiency, release kinetics, antimicrobial efficacy, and dissolution behaviour. Key findings indicate that the F2l-BG45S5-T-T-1.5 and F2l-BG45S5-T-V-1.5 formulations demonstrated controlled antibiotic release for up to seven days, with size distributions of D(10): 7.11 ± 0.806 µm, 4.96 ± 0.007 µm; D(50): 25.34 ± 1.730 µm, 25.20.7 ± 0.425 µm; and D(90): 53.7 ± 7.95 µm, 56.10 ± 0.579 µm, respectively. These formulations facilitated hydroxyapatite formation on their surfaces, indicative of osteogenic potential. The antimicrobial assessments revealed zones of inhibition against methicillin-susceptible Staphylococcus aureus (MSSA, ATCC-6538) measuring 20.3 ± 1.44 mm and 24.6 ± 1.32 mm, while for methicillin-resistant Staphylococcus aureus (MRSA, ATCC-43300), the inhibition zones were 21.6 ± 1.89 mm and 22 ± 0.28 mm, respectively. Time-kill assay results showed complete bacterial eradication within eight hours. Additionally, biocompatibility testing via MTT assay confirmed cell viability of >75%. In conclusion, these findings highlight the promise of antibiotic-loaded BG45S5 as a multifunctional biomaterial capable of both combating bone infections and supporting bone regeneration. These promising results suggest that in vivo studies should be undertaken to expedite these materials into clinical applications. Full article

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly targets host cytoskeletal proteins for metabolic–immune regulation. Using an innovative GST pull-down/mass spectrometry approach, we made the seminal discovery of β-actin (ACTB) as the primary host target of ENO1—the first reported bacterial effector–cytoskeleton interaction mediating metabolic reprogramming. ENO1–ACTB binding depends on a hydrogen bond network involving ACTB’s 117Glu and 372Arg residues. This interaction triggers (1) glycolytic activation via Glut1 upregulation, establishing Warburg effect characteristics (lactic acid accumulation/ATP inhibition), and (2) ROS-mediated activation of dual inflammatory axes (HIF-1α/IL-1β and IL-6/TNF-α). This work establishes three groundbreaking concepts: (1) the first evidence of a pathogen effector hijacking host ACTB for metabolic manipulation, (2) a novel ‘glycolysis–ACTB–ROS-inflammation’ axis, and (3) the first demonstration of bacterial proteins coordinating a Warburg effect with cytokine storms. These findings provide new targets for anti-infection therapies against Mycoplasma bovis. Full article

Developing multifunctional wound dressings with excellent mechanical properties, strong tissue adhesion, and efficient antibacterial activity is crucial for promoting wound healing. This study prepared a novel nanocomposite hydrogel dressing based on sodium alginate-polyacrylic acid dual crosslinking networks, incorporating tannic acid-coated cellulose nanocrystals (TA@CNC) and in-situ reduced silver nanoparticles for multifunctional enhancement. The rigid CNC framework significantly improved mechanical properties (elastic modulus of 146 kPa at 1 wt%), while TA catechol groups provided excellent adhesion (36.4 kPa to pigskin, 122% improvement over pure system) through dynamic hydrogen bonding and coordination interactions. TA served as a green reducing agent for uniform AgNPs loading, with CNC negative charges preventing particle aggregation. Antibacterial studies revealed synergistic effects between TA-induced membrane disruption and Ag⁺-triggered reactive oxygen species generation, achieving >99.5% inhibition against Staphylococcus aureus and Escherichia coli. The TA@CNC-regulated porous structure balanced swelling performance and water vapor transmission, facilitating wound exudate management and moist healing. This composite hydrogel successfully integrates mechanical toughness, tissue adhesion, antibacterial activity, and biocompatibility, providing a novel strategy for advanced wound dressing development. Full article

Background: Localized scleroderma (LoS) is a chronic autoimmune condition marked by cutaneous fibrosis and persistent inflammation. Modulating the activation of inflammatory cells and fibroblasts remains a central strategy in LoS treatment. We investigate the anti-fibrotic effects of Annexin A5 (AnxA5), identified as a key inflammatory component in fat extract, and assess its therapeutic efficacy. Methods: In vitro experiments were performed using TGF-β-stimulated primary human dermal fibroblasts treated with recombinant AnxA5. The anti-fibrotic effects and underlying mechanisms were assessed using CCK-8 assays, quantitative real-time PCR, Western blotting, and immunocytochemistry. In vivo, AnxA5 was administered via both preventative and therapeutic protocols in bleomycin-induced LoS mouse models. Treatment outcomes were evaluated by histological staining, collagen quantification, immunostaining, and measurement of pro-inflammatory cytokines. Results: TGF-β stimulation induced myofibroblast differentiation and extracellular matrix (ECM) production in dermal fibroblasts, both of which were significantly attenuated by AnxA5 treatment through the inhibition of phosphorylation of Smad2. In vivo, both preventative and therapeutic administration of AnxA5 effectively reduced dermal thickness, collagen deposition, ECM accumulation, M1 macrophage infiltration, and levels of pro-inflammatory cytokines. Conclusions: Through both preventative and therapeutic administration, AnxA5 ameliorates LoS by exerting dual anti-fibrotic and anti-inflammatory effects, underscoring its potential for treating fibrotic diseases. Full article

The rise of multidrug-resistant Pseudomonas aeruginosa underscores the need for novel therapeutic targets beyond conventional peptidoglycan biosynthesis. Some bacterial strains bypass MurA inhibition by fosfomycin via a cell wall salvage pathway. This study targeted P. aeruginosa AmgK (PaAmgK) and MurU (PaMurU) to identify inhibitors that could complement fosfomycin therapy. A malachite-green-based dual-enzyme assay enabled efficient activity measurements and high-throughput chemical screening. Screening 232 compounds identified Congo red and CTAB as potent PaMurU inhibitors. A targeted mass spectrometric analysis confirmed the selective inhibition of PaMurU relative to that of PaAmgK. Molecular docking simulations indicate that Congo red preferentially interacts with PaMurU through electrostatic contacts, primarily involving the residues Arg28 and Arg202. The binding of Congo red to PaMurU was corroborated further using SUPR-differential scanning fluorimetry (SUPR-DSF), which revealed ligand-induced thermal destabilization. Ongoing X-ray crystallographic studies, in conjunction with site-directed mutagenesis and enzyme kinetic analyses, aim to elucidate the binding mode at an atomic resolution. Full article

Preeclampsia (PE) is a multifactorial hypertensive disorder unique to pregnancy and a leading cause of maternal and fetal morbidity and mortality worldwide. Its pathogenesis involves placental dysfunction and an exaggerated maternal inflammatory response. Uric acid (UA), traditionally regarded as a marker of renal impairment, is increasingly recognized as an active contributor to the development of PE. Elevated UA levels are associated with oxidative stress, endothelial dysfunction, immune activation, and reduced renal clearance. Clinically, UA is measured in the second and third trimesters to assess disease severity and guide obstetric management, with higher levels correlating with early-onset PE and adverse perinatal outcomes. Its predictive accuracy improves when combined with other clinical and biochemical markers, particularly in low-resource settings. Mechanistically, UA and its monosodium urate crystals can activate the NLRP3 inflammasome, a cytosolic multiprotein complex of the innate immune system. This activation promotes the release of IL-1β and IL-18, exacerbating placental, vascular, and renal inflammation. NLRP3 inflammasome activation has been documented in placental tissues, immune cells, and kidneys of women with PE and is associated with hypertension, proteinuria, and endothelial injury. Experimental studies indicate that targeting UA metabolism or inhibiting NLRP3 activation, using agents such as allopurinol, metformin, or MCC950, can mitigate the clinical and histopathological features of PE. These findings support the dual role of UA as both a biomarker and a potential therapeutic target in the management of the disease. Full article

The interleukin-20 (IL-20) cytokine subfamily, a subset of the IL-10 superfamily, includes IL-19, IL-20, IL-22, IL-24, and IL-26. Recently, their involvement in cancer biology has gained attention, particularly due to their impact on the tumor microenvironment (TME). Notably, IL-20 subfamily cytokines can exert both pro-tumorigenic and anti-tumorigenic effects, depending on the context. For example, IL-22 promotes tumor growth by enhancing cancer cell proliferation and protecting against apoptosis, whereas IL-24 demonstrates anti-tumor activity by inducing cancer cell death and inhibiting metastasis. Additionally, these cytokines influence macrophage polarization—an essential factor in the immune landscape of tumors—thereby modulating the inflammatory environment and immune evasion strategies. Understanding the dual role of IL-20 subfamily cytokines within the TME and their interactions with cancer cell hallmarks presents a promising avenue for therapeutic development. Interleukin-20 receptor antagonists are being researched for their role in cancer therapy, since they potentially inhibit tumor growth and progression. This review explores the relationship between IL-20 cytokines and key cancer-related processes, including growth and proliferative advantages, angiogenesis, invasion, metastasis, and TME support. Further research is necessary to unravel the specific mechanisms underlying their contributions to tumor progression and to determine their potential for targeted therapeutic strategies. Full article

Water supply and sewage drainage pipes have a critical role to play in the provision of clean water and sanitation, and pipe material selection influences infrastructure life, water quality, and microbial communities. Zinc-containing compounds are highly valued due to their mechanical properties, anticorrosion behavior, and antimicrobial properties. However, the effect of zinc salts, such as zinc sulfate heptahydrate and zinc chloride, on biofilm-forming bacteria, including Escherichia coli and Enterococcus faecalis, is not well established. This study investigates the antibacterial properties of these zinc salts under simulated pipeline conditions using minimum inhibitory concentration assays, biofilm production assays, and antibiotic sensitivity tests. Findings indicate that zinc chloride is more antimicrobial due to its higher solubility and bioavailability of Zn²⁺ ions. At higher concentrations, zinc salts inhibit the development of a biofilm, whereas sub-inhibitory concentrations enhance the growth of biofilm, suggesting a stress response in bacteria. zinc chloride also enhances antibiotic efficacy against E. coli but induces resistance in E. faecalis. These findings highlight the dual role of zinc salts in preventing biofilm formation and modulating antimicrobial resistance, necessitating further research to optimize material selection for water distribution networks and mitigate biofilm-associated risks in pipeline systems. Full article

Background: Protein kinase R (PKR) inhibits general mRNA translation by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). PKR also modulates NF-κB signaling during viral infections, but comparative studies of PKR-mediated NF-κB responses across mammalian species and their regulation by viral inhibitors remain largely unexplored. This study aimed to characterize the conserved antiviral and inflammatory roles of mammalian PKR orthologs and investigate their modulation by poxviral inhibitors. Methods: Using reporter gene assays and quantitative RT-PCR, we assessed the impact of 17 mammalian PKR orthologs on general translation inhibition, stress-responsive translation, and NF-κB-dependent induction of target genes. Congenic human and rabbit cell lines infected with a myxoma virus strain lacking PKR inhibitors were used to compare the effects of human and rabbit PKR on viral replication and inflammatory responses. Site-directed mutagenesis was employed to determine key residues responsible for differential sensitivity to the viral inhibitor M156. Results: All 17 mammalian PKR orthologs significantly inhibited general translation, strongly activated stress-responsive ATF4 translation, and robustly induced NF-κB target genes. Inhibition of these responses was specifically mediated by poxviral K3 orthologs that effectively suppressed PKR activation. Comparative analyses showed human and rabbit PKRs similarly inhibited virus replication and induced cytokine transcripts. Amino acid swaps between rabbit PKRs reversed their sensitivity to viral inhibitor M156 and NF-κB activation. Conclusions: Our data show that the tested PKR orthologs exhibit conserved dual antiviral and inflammatory regulatory roles, which can be antagonized by poxviral K3 orthologs that exploit eIF2α mimicry to modulate the PKR-NF-κB axis. Full article

Burkholderia gladioli is a multifaceted bacterium with both pathogenic and beneficial strains, and nonpathogenic Burkholderia species have shown potential as plant growth-promoting rhizobacteria (PGPRs) and biocontrol agents. However, the molecular mechanisms underlying their beneficial functions remain poorly characterized. This study systematically investigated the antimicrobial mechanisms and plant growth-promoting properties of B. gladioli strain ZBSF BH07, isolated from the grape rhizosphere, by combining genomic and functional analyses, including whole-genome sequencing, gene annotation, phylogenetic and comparative genomics, in vitro antifungal assays, and plant growth promotion evaluations. The results showed that ZBSF BH07 exhibited broad-spectrum antifungal activity, inhibiting 14 grape pathogens with an average inhibition rate of 56.58% and showing dual preventive/curative effects against grape white rot, while also significantly promoting grape seedling growth with increases of 54.9% in plant height, 172.9% in root fresh weight, and 231.34% in root dry weight. Genomic analysis revealed an 8.56-Mb genome (two chromosomes and one plasmid) encoding 7431 genes and 26 secondary metabolite biosynthesis clusters (predominantly nonribosomal peptide synthetases), supporting its capacity for antifungal metabolite secretion, and functional analysis confirmed genes for indole-3-acetic acid (IAA) synthesis, phosphate solubilization, and siderophore production. These results demonstrate that ZBSF BH07 suppresses pathogens via antifungal metabolites and enhances grape growth through phytohormone regulation and nutrient acquisition, providing novel insights into the dual mechanisms of B. gladioli as a biocontrol and growth-promoting agent and laying a scientific foundation for developing sustainable grapevine disease management strategies. Full article

Hydrazine, a highly toxic and reactive compound widely used as rocket fuel, poses significant environmental and health risks, particularly in long-term space missions. This study investigates the cometabolic capacity of Chlorella vulgaris and seven extremophilic Bacillus spp. strains—isolated from the arid Dead Sea region—to tolerate and degrade hydrazine at concentrations up to 25 ppm. The microalga C. vulgaris reduced hydrazine levels by 81% within 24 h at 20 ppm, while the Bacillus isolates achieved an average reduction of 45% over 120 h. Identified strains included B. licheniformis, B. cereus, and B. atrophaeus. Co-culture experiments demonstrated that C. vulgaris and B. cereus (isolate ISO-36) stably coexisted without antagonistic effects, suggesting a synergistic detoxification interaction. Flow cytometry revealed that most bacteria transitioned into spores under stress, highlighting a survival adaptation. Titanium, representing a biocompatible material common in aerospace hardware, did not inhibit microbial growth or hydrazine degradation. These findings underscore the potential of Dead Sea-derived microbial consortia for cometabolic hydrazine detoxification and support the feasibility of converting spacecraft components into functional photobioreactors. This approach offers dual-use benefits for space missions and industrial wastewater treatment. Future studies should investigate degradation pathways, stress resilience, and bioreactor scale-up. Full article

In wet flue gas desulfurization and denitrification processes, nitrite accumulation inhibits denitrification efficiency and induces secondary pollution due to its acidic disproportionation. This study developed a Mn-modified ZSM-5 zeolite catalyst, achieving efficient resource conversion of nitrite in nitrogen-containing wastewater through an O₃ + Mn/ZSM-5 catalytic system. Mn/ZSM-5 catalysts with varying SiO₂/Al₂O₃ ratios (prepared by wet impregnation) were characterized by BET, XRD, and XPS. Experimental results demonstrated that Mn/ZSM-5 (SiO₂/Al₂O₃ = 400) exhibited a larger specific surface area, enhanced adsorption capacity, abundant surface Mn³⁺/Mn⁴⁺ species, hydroxyl oxygen species, and chemisorbed oxygen, leading to superior oxidation capability and catalytic activity. Under the optimized conditions of reaction temperature = 40 °C, initial pH = 4, Mn/ZSM-5 dosage = 1 g/L, and O₃ concentration = 100 ppm, the $\mathrm{N}{\mathrm{O}}_2^{-}$ oxidation efficiency reached 94.33%. Repeated tests confirmed that the Mn/ZSM-5 catalyst exhibited excellent stability and wide operational adaptability. The synergistic effect between Mn species and the zeolite support significantly improved ozone utilization efficiency. The O₃ + Mn/ZSM-5 system required less ozone while maintaining high oxidation efficiency, demonstrating better cost-effectiveness. Mechanism studies revealed that the conversion pathway of $\mathrm{N}{\mathrm{O}}_2^{-}$ followed a dual-path catalytic mechanism combining direct ozonation and free radical chain reactions. Practical spray tests confirmed that coupling the Mn/ZSM-5 system with ozone oxidation flue gas denitrification achieved over 95% removal of liquid-phase $\mathrm{N}{\mathrm{O}}_2^{-}$ byproducts without compromising the synergistic removal efficiency of NO_x/SO₂. This study provided an efficient catalytic solution for industrial wastewater treatment and the resource utilization of flue gas denitrification byproducts. Full article