Search Results (25,482)

Ferroptosis of mesenchymal stem cells (MSCs) is a critical bottleneck restricting the efficiency of ruminant biological breeding. Phloretin, a natural bioactive polyphenol, exhibits potential ferroptosis-inhibitory activity. However, the regulatory effects and underlying mechanisms of phloretin on ruminant MSCs remain poorly understood. This study aimed to investigate the effects of phloretin on ferroptosis and elucidate its underlying molecular mechanisms. Herein, we isolated and cultured adipose-derived mesenchymal stem cells (AD-MSCs) from adipose tissue of a 9-day-old Leizhou goat and established a ferroptosis model in these cells using RSL3. We detected cell viability, proliferation, migration, ferroptosis-related indexes and key protein expression. The results showed that phloretin (25 and 50 μM) dose-dependently inhibited ferroptosis in goat AD-MSCs, reducing intracellular ferrous ion (Fe²⁺), reactive oxygen species (ROS) and lipid peroxidation levels, restoring glutathione content, and ameliorating mitochondrial structural damage. Mechanistically, phloretin exerted its anti-ferroptosis effects through direct antioxidant activity, activation of the Nrf2/HO-1/GPX4 signaling pathway and Fe²⁺ chelation. Nrf2 and GPX4 were key targets in this process. These results provide preliminary in vitro evidence and a theoretical basis for the potential application of phloretin in future research related to meat goat production and ruminant breeding. Full article

The chemical composition of basil essential oil is influenced by plant developmental stage, which alters the relative distribution of volatile constituents and their functional properties. In this study, we investigated developmental-stage-dependent changes in the essential oil composition of Ocimum basilicum and evaluated their relationship with nitric oxide (NO) inhibitory activity and estragole exposure. Essential oils were obtained by hydrodistillation and analyzed by gas chromatography–tandem mass spectrometry (GC–MS/MS), resulting in the identification of 54 volatile compounds representing 98.13–98.97% of the total composition. Estragole remained the dominant constituent, ranging from 70.58% to 85.55%, with the lowest proportion at the flowering stage (Day 85). In contrast, minor constituents, including eucalyptol (2.41–3.77%), β-ocimene (0.52–1.98%), and methyleugenol (~2.00%), increased during flowering. NO inhibitory activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages was strongest at Day 85. Estimated Daily Intake (EDI) ranged from 0.4215 to 1.1005 µg kg⁻¹ bw day⁻¹, and Margin of Exposure (MOE) ranged from 2999 to 7830. These findings indicate that developmental stage influences composition, activity, and exposure. From a compositional perspective, the observed redistribution among major chemical groups reflects a structured balance that can be interpreted within a symmetry-related framework in multicomponent systems. Full article

Licania tomentosa leaf extract was used to synthesize zinc oxide nanoparticles (ZnO NPs) which were systematically analyzed by X-ray diffraction (XRD), scanning electron microscopy (SEM), UV-Visible (UV-Vis) and Fourier transform infrared (FT-IR) spectroscopies and energy-dispersion X-ray spectroscopy (EDS) methods. Based on XRD scans, the green NPs have an average crystallite size of 15.9 nm as estimated using the Scherrer equation and have a roughly spherical shape with an average diameter of 25.15 ± 1.2 nm as calculated from SEM data. As estimated from the Tauc plot based on UV-Vis absorption spectra, ZnO NPs have a small band gap of 3.0 eV. The biosynthesized ZnO NPs were effectively utilized for the photodegradation of methylene blue (MB) and crystal violet (CV) dyes under UV illumination with resulting MB and CV degradation efficiencies of ~94% and ~81% after 60 min and 70 min, with pH = 12 and pH = 10, respectively. Different experimental parameters such as NPs quantity, experimental pH, light intensity and initial concentration of dyes were varied to test the performance of the catalyst. Furthermore, efficient recycling of the catalyst was demonstrated. We also undertook antimicrobial studies of the green ZnO NPs. The ZnO NPs demonstrated broad-spectrum antimicrobial efficacy against Escherichia coli ATCC 35218, Enterococcus faecalis ATCC 29737, Klebsiella pneumoniae ATCC 700603, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa B3, Staphylococcus aureus ATCC 29213, and S. aureus SA01, with the minimum inhibitory concentration (MIC) and the inhibitory concentrations associated with 50% effect (IC50) values ranging from 250 to 2000 µg/mL and 7.74 to 283.14 µg/mL, respectively. The nanoparticles also significantly inhibited biofilm formation by E. faecalis ATCC 29737, P. aeruginosa ATCC 27856, and S. aureus SA03. The antimicrobial efficiency of the ZnO NPs against Escherichia coli ATCC 25922 and Staphylococcus aureus SA03 isolates was also assessed using the disk diffusion assays. Taken together, our results reveal that the biosynthesized ZnO NPs are promising multifunctional materials with potential applications in antimicrobial treatments, biofilm control, and photocatalytic remediation. Full article

The roots of Acridocarpus smeathmannii were identified as a natural source of the benzyl-terpene 2-(5-isopropyl-4-methoxy-2-methylbenzyl)phenol (FAH-01, chamanen), which was isolated and structurally characterized by chromatographic and spectroscopic techniques, including two-dimensional NMR analysis. Functionally, FAH-01 exerted pronounced inhibitory effects on human prostate smooth muscle contractility. In organ bath experiments, it reduced noradrenaline-induced contractions by up to 72% and phenylephrine-induced contractions by up to 63%, without affecting agonist potency (pEC₅₀). During electrical field stimulation (2–32 Hz), FAH-01 suppressed neurogenic contractile responses, indicating interference with adrenergic and nerve-mediated signaling pathways. Beyond smooth muscle modulation, FAH-01 showed antioxidant activity in the DPPH radical-scavenging assay and exhibited early-stage toxicity in the Artemia salina cysts. Collectively, these findings identify FAH-01 as a bioactive natural product with potent inhibitory effects on adrenergic and neurogenic contraction in human prostate smooth muscle, supporting its therapeutic potential in conditions associated with increased smooth muscle tone. Further preclinical studies are needed to elucidate its mechanisms of action, toxicity, and in vivo efficacy. Full article

Background: Prostate cancer (PCa) is the leading male urinary malignancy globally. Our previous article demonstrated the anti-PCa activity of Euphorbia humifusa Willd water extract (EHW) and some of its compounds via downregulating AR expression, but the anti-PCa active compounds from Euphorbia humifusa Willd (EH) and their mechanisms of action are yet to be clarified. Thus, the current article studied the in vitro anti-PCa effects of 3,3′-di-O-methylellagic acid (3,3′-di-O-Me-EA) derived from EHW and the related mechanism involved. Methods: 3,3’-di-O-Me-EA was isolated from EHW applying bioassay-guided fractionation. The spectroscopic methods were used to determining the structure of 3,3′-di-O-Me-EA. The drug-likeness and ADMET properties (absorption, distribution, metabolism, excretion, and toxicity) of 3,3′-di-O-Me-EA were analyzed in silico. Molecular docking and real-time surface plasmon resonance (SPR) analysis were performed to measure the interaction of 3,3′-di-O-Me-EA and VDAC1 protein. The viability and apoptosis of 22RV-1 and DU145 PCa cells were determined using MTT and Annexin V-FITC staining assay, respectively. q-PCR and Western blot experiments were used to analyzing the gene and protein expressions of VDAC1. Results: 3,3′-di-O-Me-EA was isolated and purified from EHW with a purity of ≥90.06%, and its structure was identified by HRTOF mass, NMR, and an authentic standard. In silico ADMET analysis indicated its favorable drug-like and pharmacokinetic properties. Molecular docking and SPR results confirmed that 3,3′-di-O-Me-EA could bind with the VDAC1 protein. Moreover, 3,3′-di-O-Me-EA dose- and time-dependently inhibited 22RV-1 and DU145 PCa cell viability, and induced apoptosis in a dose-dependent manner (p < 0.05). RT-qPCR and Western blot results showed that 3,3′-di-O-Me-EA dose-dependently up-regulated VDAC1 gene and protein expression levels in 22RV-1 and DU145 cells (p < 0.05). Meanwhile, in VDAC1-depleted 22RV-1 and DU145 cells, 3,3′-di-O-Me-EA down-regulated VDAC1 gene and protein expression levels, increased cell viability, and inhibited apoptosis compared to 22RV-1 and DU145 cells (p < 0.05). Furthermore, 3,3′-di-O-Me-EA enhanced VDAC1 gene and protein expression levels, inhibited cell viability, and induced apoptosis in VDAC1-overexpressed 22RV-1 and DU145 cells compared with 22RV-1 and DU145 cells (p < 0.05). Overall, EH active compound 3,3′-di-O-Me-EA may inhibit viability and induce apoptosis of 22RV-1 and DU145 PCa cells via up-regulating VDAC1 gene and protein expression levels. Conclusion: The results indicated that the 22RV1 and DU145 PCa cell viability inhibitory effects of 3,3′-di-O-Me-EA isolated from EH may be mediated by induction of apoptosis through up-regulation of VDAC1 gene and protein expression levels. Full article

We examined neocortical pathology and interneuron degeneration in neonatal hypoxia-ischemic encephalopathy (HIE). Piglets in two age groups (2–3 or 7–10 days old, n = 4–12/group) underwent global cerebral hypoxia–ischemia (HI) or sham treatment. Piglets (2–3 days old) had epidural electrodes for continuous electroencephalography (cEEG) and were treated with hypothermia (HT) or remained at normothermia (NT). Older piglets, all NT, had scalp EEG. Piglets at both ages had seizures and survived for 1–7 days. Cortical damage was assessed by hematoxylin & eosin staining and immunohistochemistry; calretinin (CR), parvalbumin (PV), and vasoactive intestinal peptide (VIP) interneurons (INs) were counted. Cell injury was assessed by DNA fragmentation and protein nitration. TAR DNA binding protein-43 (TDP43) and the DNA repair scaffold protein X-ray repair cross complementing-1 (XRCC1) were examined for degeneration mechanisms. Cortical layers 3 and 4 showed high vulnerability; damage emerged as isolated cells, focal and laminar, and distributed as panlaminar throughout different cortical regions that correlated with seizure burden. HT protected strongly against cortical damage. CR- and PV-INs were severely depleted in HI-NT piglets compared to sham. VIP INs appeared invulnerable. HT partially rescued the loss of INs. CR and PV formed nuclear and cytoplasmic inclusions that colocalized with TDP43 and XRCC1; co-immunoprecipitation identified interactions among these proteins, and tyrosine nitration of CR. CR and PV INs accumulated DNA single- and double-strand breaks and appeared as attritional apoptosis variants with proteinopathy. This cell death is identified as aggreosis. IN loss correlated with seizure presence. Postmortem human neonatal HIE cases had a similar loss of CR and PV INs and nuclear depletion of TDP43 in the neocortex. Thus, neonatal HIE causes the loss of neocortical inhibitory IN subtypes with vulnerabilities instructed by their intrinsic calcium-binding protein signature and by mechanisms consistent with toxic sequestration and the nuclear depletion of XRCC1 and TDP43 underlying DNA damage accumulation. Early inhibitory IN deletion could drive seizure evolution in HIE; TDP43 and XRCC1 could be therapeutic targets for neonatal HIE. Full article

Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Isorhamnetin (ISO), a natural dietary flavonoid, has demonstrated potent anti-lung cancer activity in cell models. However, its precise mechanism of action within the complex landscape of NSCLC remains to be fully elucidated. Methods: The effects of ISO on NSCLC cell viability, apoptosis, and cell cycle distribution were assessed in A549 and H1650 cells using the MTT assay, Annexin V-FITC/PI staining, and flow cytometry. Wound healing and Transwell assays were employed to evaluate the isorhamnetin impact on cell migration, invasion, and adhesion. To investigate the underlying molecular mechanisms, RNA sequencing (RNA-seq) was performed, followed by validation of key target genes and proteins using qRT-PCR and Western blot analysis. Results: ISO treatment elicited a significant, dose- and time-dependent inhibition of NSCLC cell viability, which coincided with a marked induction of apoptosis. Cell cycle analysis revealed that ISO triggered an S-phase arrest. Transcriptomic profiling identified ELFN1 and TMEM186 as significantly upregulated genes, while SETDB1 was downregulated in a concentration-dependent manner; this was accompanied by a concomitant upregulation of FGFBP1 protein expression. Functionally, ISO effectively suppressed the migratory, invasive, and adhesive capabilities of both cell lines. Conclusions: Our findings demonstrate that ISO exerts a potent anti-proliferative and anti-metastatic effect on NSCLC cells. The underlying mechanism is multifaceted, involving the induction of apoptosis and cell cycle arrest, coupled with the modulation of a novel regulatory network centered on ELFN1, TMEM186, SETDB1, and FGFBP1. These results provide new mechanistic insights into the anti-tumor pharmacology of isorhamnetin and highlight its potential as a therapeutic agent targeting both cancer cells and their supporting microenvironments. Full article

Cadmium (Cd), a common environmental and occupational toxicant, is an important risk factor for neurodegenerative diseases. Metformin has been found to have neuroprotective effect, in addition to antidiabetic function. Our recent studies have identified that metformin ameliorates Cd neurotoxicity via blocking ROS-dependent PP5/AMPK-JNK signaling pathway. Here we further show that metformin protected PC12 cells and primary neurons from Cd-poisoning by mitigating Cd-induced increases in ATG5/LC3-II/p62 levels and autophagosomes. Knockdown of ATG5 dramatically potentiated the inhibitory effects of metformin on Cd-induced LC3-II, cleavage of caspase-3, accumulation of autophagosomes and apoptosis in PC12 cells. Addition of chloroquine (CQ) strengthened the basic and Cd-elevated ATG5/LC3-II/p62 levels, autophagosome accumulation and cell apoptosis, whereas metformin powerfully blocked the events, implying a metformin-promoted autophagic flux-dependent mechanism involved. Further research revealed that metformin prevented Cd-induced autophagic flux impairment and cell apoptosis, which was attributed to restraining Cd inactivation of AMPK. This is supported by the findings that activation of AMPK with AICAR or ectopic expression of constitutively active AMPKα (AMPKα-ca) reinforced the inhibitory effects of metformin on Cd-evoked ATG5/LC3-II/p62/autophagosomes and apoptosis in PC12 cells and/or primary neurons. Taken together, the results indicate that metformin protects neuronal cells from Cd-induced autophagic flux impairment-dependent apoptosis by activating AMPK. Our studies highlight that metformin has a great potential for prevention of Cd toxicity related to neurodegenerative diseases. Full article

Transcriptional and translational inhibition are fundamental regulatory mechanisms in gene networks, governing diverse processes from viral replication to neuroplasticity. Two-component genetic oscillators based on the “activator–repressor” motif serve as ideal models for studying biological rhythms due to their simplicity and rich dynamics. However, systematic theoretical comparisons of distinct inhibitory mechanisms—particularly using inhibition strength as a control variable—remain lacking. Addressing this gap, we present a comprehensive bifurcation analysis of the post-translational repression model, proving the existence and uniqueness of its positive equilibrium, deriving Hopf bifurcation conditions, and identifying critical parameter ranges for sustained oscillations. Using inhibition strength as a key comparator, we systematically contrast transcriptional and post-translational repression, elucidating how different inhibitory mechanisms modulate oscillation initiation and amplitude. We further reveal distinct symmetry–asymmetry patterns in their bifurcation dynamics: transcriptional repression exhibits asymmetric bistable regimes, while post-translational repression manifests narrow, nearly symmetric oscillatory intervals. This unified analytical framework not only advances the theoretical understanding of two-component genetic oscillators but also provides a generalizable paradigm for dissecting complex gene regulatory dynamics. Full article

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a key enzyme for the repair of stalled topoi-somerase 1 (TOP1)-DNA complexes. We have previously developed a TDP1 inhibitor, compound OL9-116, which is capable of enhancing the action of the anticancer drug topotecan (TPC), a TOP1 poison, in vitro and in vivo. In this study, the inhibition mode of OL9-116 (uncompetitive) was investigated. We have shown that N-terminal domain of TDP1, which is important for the cell function of TDP1 but is not involved in catalysis directly, reduced the inhibitory potency of OL9-116 probably by influencing the conformation of the enzyme. OL9-116 did not reduce cell viability and did not affect mitochondrial membrane potential. OL9-116 enhanced the cytotoxic/antiproliferative effect of TPC on the panel of tumor cells. This effect was not observed on nontumor cells or TDP1-deficient cells. OL9-116 and TPC had different effects on TDP1 and TOP1 gene expression detected by PCR depending on the cell type and the presence of functional TDP1. The direct relation between the effects of the compounds on the gene expression and cell survival was not found. The obtained data indicated a synergistic effect of OL9-116 and TPC, which appeared to be mediated by TDP1 inhibition rather than by an effect on TDP1 gene expression. Full article

Background: Autonomic side effects are a major determinant of tolerability for many psychotherapeutic drugs. While often attributed to receptor-mediated mechanisms, the potential contribution of direct modulation of smooth muscle excitability remains poorly characterized at a comparative pharmacological level. Methods: A systematic comparative pharmacological profiling of a broad panel of psychotherapeutic drugs (antidepressants, antipsychotics, and anxiolytics) was conducted using a standardized ex vivo model. Potassium chloride (KCl, 105 mM) was used to induce depolarization-dependent contraction in three isolated smooth muscle preparations (rat uterus, rat vas deferens, and guinea-pig ileum). Inhibitory potency (IC₅₀), dose-dependency, and tissue consistency were integrated to define functional inhibitory profiles. Results: Psychotherapeutic drugs exhibited marked heterogeneity in their ability to inhibit K⁺-induced smooth muscle contraction. Integrative analysis stratified compounds into four distinct functional profiles: (i) High Inhibitory Liability (e.g., nortriptyline, paroxetine), characterized by low micromolar IC₅₀ values and dose-dependent inhibition across multiple tissues; (ii) Non-Selective Inhibition (e.g., flunarizine, cinnarizine), showing consistent but dose-independent inhibition; (iii) Tissue-Dependent Inhibition (e.g., risperidone, reboxetine); and (iv) Minimal Inhibition (e.g., moclobemide). Agents classified within the High Inhibitory Liability profile correspond to drugs known to carry a higher clinical burden of autonomic adverse effects. Conclusions: This study reveals a previously underrecognized pharmacodynamic dimension of psychotherapeutic drugs and establishes a comparative functional taxonomy based on their direct, non-receptor-mediated inhibition of smooth muscle excitability. The identified profiles provide a mechanism-informed framework for contextualizing autonomic side-effect liability and may support improved safety evaluation in psychotherapeutic drug development. Full article

Background: Cognitive and psychiatric disorders are caused by a complex interplay between genetic predisposition, environmental exposures, and dynamic molecular regulation in the brain. Animal models provide a controlled environment for examining these mechanisms, and advances in transcriptome and epigenomic technologies have greatly expanded our knowledge of disease-relevant pathways. Objective: This scoping review systematically maps and synthesizes the epigenetic and transcriptomic findings from the established animal models of four neuropsychiatric conditions—autism spectrum disorder (ASD), schizophrenia, depression, and Rett syndrome—drawing on a PRISMA-ScR-guided literature search. The review characterizes the breadth of evidence, identifies convergent and divergent molecular pathways, and highlights the translational gaps and therapeutic implications. Methods: Research employing chromatin accessibility testing, genome-wide DNA methylation mapping, single-cell and bulk RNA sequencing, histone modification profiling, and multi-omics integration in mouse and other validated animal models was thoroughly reviewed. A quality appraisal of the primary experimental studies (n = 63) was performed using a modified CAMARADES checklist. Results: Beyond generalized cellular stress responses, multi-omics analysis emphasizes the cell-type- and context-dependent nature of epigenetic changes in animal models, including isoform-specific histone modifications and model-dependent binding of HDAC/MeCP2 complexes to genes involved in synaptic plasticity. Single-cell RNA sequencing analyses have uniformly shown transcriptional changes in parvalbumin-positive (PV+) interneurons. Conclusions: The specific convergence of epigenetic disruptions in neural circuits involved in synaptic structure and inhibitory function could play a role in the generation of neuropsychiatric phenotypes in animal models, highlighting the importance of circuit- and cell-type-specific epigenetics while pointing to potential therapeutic avenues. Full article

Fusarium oxysporum f. sp. lycopersici (FOL) is one of the most destructive soil-borne pathogens affecting tomato production worldwide, causing substantial yield losses and persisting in soil for extended periods. The increasing regulatory restrictions on chemical fungicides and the emergence of resistant pathogen strains have intensified the search for sustainable and environmentally friendly alternatives. This systematic review synthesizes studies published between 2000 and 2025 that evaluated the antifungal efficacy of essential oils (EOs), their bioactive constituents, and EO-based nanoformulations against FOL in tomato. A total of 40 studies were included, following the PRISMA 2020 guidelines, encompassing in vitro, greenhouse, and limited field evaluations. Many EOs rich in phenolic compounds and oxygenated monoterpenes, such as thymol, carvacrol, eugenol, citral, and menthol, consistently inhibited FOL growth and spore germination, with reported mycelial growth inhibition ranging from 60 to 100% and minimum inhibitory concentrations (MICs) between 0.05 and 1.5 µL ml⁻¹. However, the use of EOs is often limited because they evaporate quickly, do not mix well with water, can harm plants, and do not persist under field conditions. Nano-delivery systems, including nanoemulsions, polymeric nanoparticles, chitosan-based carriers, and lipid-based nanostructures, have been shown to enhance the stability, bioavailability, and antifungal efficacy of EOs. This has led to improved disease management and reduced pesticide application rates. In addition, several EO-based treatments have been reported to activate plant defense responses, including the induction of defense-related genes, antioxidant enzymes, and epigenetic modifications. Overall, EO-based nanoformulations show promise as next-generation biopesticides for the sustainable management of tomato Fusarium wilt. Nevertheless, large-scale field validation, standardized formulation protocols, and regulatory assessments are required before these technologies can be widely implemented in agriculture. Full article

Three novel alkaloids, penicitrioids A–C (1–3), and two known compounds (4–5) were isolated from the ethyl acetate (EtOAc) extract of the solid fermentation of Penicillium citrinum VDL118, an endophytic fungus harbored in the leaves of Vaccinium dunalianum Wight (Ericaceae), a perennial evergreen shrub native to the southwestern regions of China, Myanmar, and Vietnam. Compounds 1 and 2 are novel pyridine alkaloids characterized by an unprecedented dihydrofuro[3,4-c]pyridine core, while 3 features a distinct pyrrolo[3,4-c]pyridine framework. Their structures were unambiguously established by comprehensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. In vitro antifungal assays revealed that compounds 1–5 exhibited moderate to potent inhibitory effects against five tested phytopathogenic fungi, with minimum inhibitory concentrations (MICs) ranging from 3.1 to 100 μg/mL. Notably, four of them (1–4) displayed broad-spectrum and potent activity against Gloeophyllum trabeum, Coriolus versicolor, Fusarium solani, and Botrytis cinerea, with MIC values as low as 3.1–12.5 μg/mL. Furthermore, a plausible biosynthetic pathway for compounds 1–3 was proposed. Full article

The objective of this study is to develop and assess the feasibility of utilizing lotus (Nelumbo nucifera Gaertn.) leaf extract as a green corrosion inhibitor for copper in a sulfuric acid environment. The inhibitory efficacy was comprehensively evaluated using a multi-technique approach, incorporating electrochemical measurements, weight loss analysis, theoretical analysis, and surface morphological characterization. The experimental results demonstrate that the lotus leaf extract functions as an efficient corrosion inhibitor for copper, achieving an inhibition efficiency of 88.07% at 700 mg/L by effectively suppressing both cathodic and anodic corrosion processes. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) confirmed the protective effect, whereas X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared spectroscopy (FTIR) identified functional groups and surface interaction between metal and inhibitor. Theoretical calculations further confirmed the involvement of nitrogen (N) and oxygen (O) as the key active sites. Adsorption behavior adheres to the Langmuir isotherm model, involving both physical and chemical adsorption processes that inhibit the Cu⁺→Cu²⁺ oxidation reaction. This study demonstrates acid-resistant protection of copper using lotus leaf extract. Full article