Search Results (15,882)

Prostate cancer (PCa) remains lethal at advanced stages, partly due to stem-like subpopulations known as prostate cancer stem cells (PCSCs) that sustain tumor growth and therapeutic resistance. Imipridones are small-molecule anticancer agents, with next-generation derivatives ONC206 and ONC212 designed for enhanced potency and broader activity. This study compared their antitumor efficacy and mechanisms in advanced androgen-independent PCa (AIPC) models, namely DU145 and PC3 cells, using two- and three-dimensional systems encompassing bulk cancer cells and PCSCs. DU145 and PC3 AIPC cells were treated with ONC201 (parent compound), ONC206, or ONC212. Functional assays assessed proliferation, viability, migration, invasion, PCa spheroids formation, cell cycle distribution, and mitochondrial membrane potential and mass, while RNA sequencing defined transcriptional responses. ONC212 was the most potent derivative, inhibiting proliferation and migration and abolishing PCa spheroids at nanomolar doses, whereas ONC201 and ONC206 required higher concentrations. Transcriptomic analyses revealed shared repression of DNA replication and cell-cycle transition programs, with activation of integrated stress and unfolded protein responses (ISR/UPR) and FOXO signaling. ONC206 favored PERK–ATF4-mediated apoptosis with reduced DNA repair, while ONC212 more strongly impacted oxidative phosphorylation-related pathways and mitochondrial RNA processing. Imipridones induced a time-dependent cell-cycle redistribution with increased sub-G1 accumulation and modulated mitochondrial membrane potential and mass in a context-dependent manner. Collectively, these findings position ONC212 as a leading imipridone candidate in AIPC models, combining potent inhibition of tumor and stem-like cell functions with a coherent stress-response signature that supports further translational evaluation. Full article

Autophagy is a self-degradative homeostatic mechanism that plays an important role in tumor viability, metabolic reprogramming, and drug resistance. Circulating tumor DNA (ctDNA) is fragmented DNA that comes from dying tumor cells and leaks out into the blood stream. ctDNA can now be measured through blood tests and is a non-invasive way to identify cancer. ctDNA has shown promise for early detection of cancer, prognosis, and monitoring treatment response in real time. There is emerging mechanistic evidence suggesting a potential relationship between autophagy and ctDNA dynamics which has been discussed as a new autophagy–ctDNA axis. Autophagy can affect ctDNA levels by promoting or suppressing apoptosis and necrosis of tumor cells. When autophagy is cytoprotective, less DNA would be shed into the bloodstream. When autophagy is inhibited or defective, more DNA would be released because of increased genomic instability. Stressors found within the tumor microenvironment (TME) like hypoxia, oxidative stress, and nutrient depletion can also induce autophagy and indirectly affect ctDNA. Targeting autophagy therapeutically with drugs that induce or inhibit autophagy such as chloroquine (CQ) or mechanistic target of rapamycin (mTOR) inhibitors can affect ctDNA concentrations. Although emerging mechanistic evidence suggests a potential relationship between autophagy and ctDNA dynamics, direct clinical studies validating this interaction remain lacking. Therefore, this review presents the autophagy–ctDNA relationship as a hypothetical and exploratory model that warrants further mechanistic and translational investigation in cancer development, therapeutic resistance, and clinical applications. Full article

This study presents a rapid, eukaryotic impedimetric biosensor that applies the yeast Saccharomyces cerevisiae as a robust, cost-effective biorecognition element for monitoring the acute toxicity of two representative pharmaceuticals, naproxen and isoniazid, in aquatic systems. The biosensor utilizes a previously developed three-electrode system made from type 316 stainless steel. Yeast cells seeded onto these electrodes serve as the biosensing element. By monitoring changes in electrical impedance, the system quantifies the cellular stress induced by pharmaceutical exposure. Electrochemical Impedance Spectroscopy (EIS) revealed a concentration-dependent decrease in both resistance and capacitance, attributed to cell death and subsequent desorption from the working electrode surface. These findings were validated through optical density at 600 nm (OD₆₀₀) growth curve analysis and methylene blue viability staining, which confirmed metabolic inhibition and membrane damage. Results indicate a linear response for naproxen within the 2.5 mM to 20 mM range, with a LOD of 0.509 mM, and for isoniazid within the 10 mM to 100 mM range, with a LOD of 0.684 mM. Naproxen demonstrated a more pronounced cytotoxic effect, with cell viability dropping to 41.08% at 10 mM compared to 68.79% for isoniazid. While conventional analytical methods focus on chemical quantification, this proof-of-concept biosensor provides a rapid toxic/non-toxic signal, offering a biologically relevant tool for real-time monitoring of industrial waste streams and acute environmental contamination. Full article

Background: Acetification is a complex process driven by acetic acid bacteria (AAB), in which high ethanol and acidity levels require strong microbial metabolic adaptation. Although the microbiota involved in vinegar production has been described, the functional mechanisms that enable these bacteria to maintain metabolic activity remain poorly understood. In this study, the functional dynamics of AAB during Verdejo vinegar acetification were analyzed using a quantitative metaproteomic approach. Methods: Acetification was performed in submerged culture under semi-continuous conditions, and samples were collected at four stages of the cycle (S1–S4). Results: LC-MS/MS analysis led to the identification of 1626 proteins, of which 1409 were assigned to the Acetobacteraceae family. Komagataeibacter europaeus was the dominant species (73.7%). Hierarchical clustering revealed four protein abundance patterns, and differential analysis identified 350 proteins with increased abundance and 169 with decreased abundance, with the greatest changes observed between S1 and S4. Functional annotation and protein–protein interaction analyses indicated that the main metabolic adaptations involve pathways related to energy metabolism, amino acid biosynthesis, membrane-associated functions, cellular homeostasis, and acid stress response. Conclusions: Overall, the results show that K. europaeus concentrates most of the metabolic activity during acetification and that proteome reorganization reflects key molecular strategies for adaptation and survival under high-acidity conditions. Full article

Traditional Chinese brick-and-stone archways are not merely architectural products shaped by geographical constraints; they also embody a highly rational structural logic. Drawing on the unique earthen environment of the Loess Plateau and the region’s traditions of brick-and-stone construction, the Jinzhong region of China has developed a distinct system of archways. Consequently, to deconstruct the mechanical wisdom inherent in the traditional building techniques of the Jinzhong region, this study selected residential buildings in Qi County and Pingyao, as well as Qing Dynasty (1636–1912 AD) official architecture, as case studies. Through field investigations into the masonry techniques of three typical vault forms—the single-centre arch, the double-centre arch, and the four-centre arch—the study revealed their evolutionary characteristics in terms of geometric form. Static numerical simulation analysis was conducted using the Abaqus CAE 2025 (Dassault Systèmes, Vélizy-Villacoublay, France) platform. The study found that, under a simulated surface load of 0.027 N/mm², different arch profiles exhibited significant quantitative mechanical differences, and their stress distributions and deformation thresholds showed distinct scenario-specific tendencies. The results show that, compared to a semicircular arch, the official double-centred arch reduces maximum displacement by approximately 20%, and the maximum principal stress decreased from 1.35 MPa to 1.215 MPa, effectively mitigating the risk of cracking at the arch crown. With this high sectional stiffness and displacement-constraining capability, it supports the high load requirements of defensive city fortifications. Compared to the Pingyao gentle-type four-centre arch, its maximum displacement increased by only about 10%, and the maximum principal stress rose by only about 8%. Therefore, given similar mechanical performance but considering construction feasibility, the official double-centred arch was selected for the construction of defensive city fortifications. Furthermore, although the stress concentration at the corners (arch feet) of the Pingyao gentle-curved four-centred arch is approximately 4.8% higher than that of the pointed four-centred arch, its spatial utilization is improved by 15–20%; This geometric trade-off achieved through composite curvature maximizes interior clear space while maintaining structural stability, aligning with the functional requirements of guyao architecture for large-span living spaces. Meanwhile, the semicircular vaults of Qi County demonstrate universal value in low-load residential door and window components due to their low construction threshold. These quantitative data and qualitative observations indicate that the evolution of traditional forms is not merely an esthetic pursuit, but rather a precise optimization of structural performance within the constraints of material strength. This coupled relationship between “geometric form, load-bearing mechanism and usage context” confirms the inherent principles of resource efficiency and performance balance within traditional building systems. The quantitative assessment framework established in this study provides scientific guidance, grounded in construction logic, for the preventive conservation and precise reinforcement strategies of historic masonry structures. Full article

Heat pump technology can efficiently recover waste heat from oil and gas gathering, processing, and transportation. However, the energy transfer mechanism of high-speed rotating internal flow in the scroll compressor remains unclear under unbalanced load conditions, leading to low equipment energy efficiency and high operation and maintenance costs. This study adopted dynamic grid technology, finite element analysis and one-way thermal–fluid–solid coupling method to quantitatively study the flow field characteristics and mechanical response of four characteristic phases. The results showed that the internal pressure and temperature fields of the compressor presented a non-uniform distribution. The deformation of the scroll wraps was mainly concentrated in the compression chamber, and the maximum stress was concentrated at the wraps’ root. Further analysis revealed that temperature loading played a dominant role in the structural responses. At a spindle rotation angle of 0°, under temperature loading alone, the maximum deformation and maximum stress were 28.605 μm and 521.81 MPa, respectively, while the corresponding values under pressure loading alone were small. In addition, the deformation and stress under coupled loading were not a linear superposition of the individual loading effects, with a deformation deviation of 0.938 μm and a stress deviation of 7.18 MPa at a spindle rotation angle of 0°. In this study, a numerical model of the scroll compressor was established and experimentally verified, which provided a theoretical basis for optimizing scroll profile design, suppressing wrap tip wear and improving the energy efficiency of heat pump systems. Full article

Salinity stress adversely affects plant growth, yield, and productivity. It requires an investigation of ameliorative techniques, for example, spraying synthesized nanoparticles such as zinc oxide nanoparticles (ZnOnps). This current research studied the impact of sodium chloride as a stressor (150 mM NaCl) and the application of ZnOnps (2 g L⁻¹) on some biochemical properties of maize (Zea mays) leaves. The experiment involved examining some mineral concentrations (Na, K, Mg, Zn, Cu, Mn), fatty acid profile, and the antimicrobial (antibacterial and antifungal) properties of aqueous and diethyl ether maize leaf extracts, supported by molecular docking studies of the 17 previously determined phenolic compounds against DNA gyrase and alpha-L-fucosidase enzymes. Applying ZnOnps markedly decreased sodium concentrations from 5.8 to 1.9 mg g⁻¹ dry weight (DW) and established ion balance. ZnOnps also reduced γ-linolenic acid levels to 60% under stress, returning them to normal (34%), while increasing palmitic acid to 30%. Determining the antimicrobial activities indicated that extracts from plants sprayed with ZnOnps exhibited enhanced antimicrobial activity, as evidenced by the lowest minimum inhibitory concentrations against bacterial and fungal strains, including Salmonella typhi and Aspergillus flavus. The computational molecular docking confirmed the antimicrobial findings, with the compound apigenin-7-glucoside, which exhibited the highest binding affinity scores for antibacterial (−7.4 kcal/mol), and the compound chlorogenic acid as antifungal (−7.2 kcal/mol) against the enzyme targets. Thus, ZnOnps can be considered an efficient strategy for mitigating salinity stress in maize plants while elevating the antimicrobial activity and stability of variant secondary compounds. Full article

In vitro methods rely on costly chemical inputs, such as synthetic nutrients, prompting us to search for sustainable alternatives. This study evaluated wastewater generated from the cigarette butt (CB) recycling process as a potential growth stimulant additive for in vitro plant cultivation. Seeds of Brachiaria ruziziensis Germain & Evrard were sown on agar media containing increasing CB wastewater concentrations from 0 to 25% v/v (CB0 to CB25, respectively) under controlled conditions. Germination was monitored over 10 days, and functional and physiological traits of shoot and root systems were assessed at the end. Responses were concentration-dependent and consistent with hormesis. Low concentrations, particularly CB2, enhanced germination (92.2% vs. ~67% in CB0), shoot elongation (~6 vs. 3.4 cm), and total biomass (~47 vs. ~33 mg fresh weight), while maintaining total chlorophyll and increasing carotenoids (147.8 vs. 103.3 µg g⁻¹ FW) and chlorophyll a/b ratio (2.1 vs. 1.5). Contrarily, higher concentrations (≥CB10) reduced germination (47.6% at CB25), strongly inhibited root growth (0.5 cm at CB25), decreased total biomass (~19 mg at CB25), led to growth disorders, and reduced pigment stability. These inhibitory effects were associated with the accumulation of CB-derived compounds, including high nicotine levels and unbalanced nutrients. At low concentrations, coordinated root aerenchyma formation and modulation of stomatal density indicated anatomical plasticity under mild stress conditions, although their physiological significance remains to be clarified. Overall, CB recycling-derived wastewater can act as an effective growth stimulant for B. ruziziensis in vitro when applied at low concentrations, offering a potential alternative for plant biotechnology while contributing to waste valorization. Full article

Marine invertebrates are characterized by high species diversity, a wide distribution, ease of culture, low cost, short life cycles and high sensitivity to pollutants, which makes them excellent models for observing toxic effects and elucidating underlying mechanisms. This paper reviews representative species from three phyla—Arthropoda, Mollusca, and Echinodermata—under both single emerging contaminant exposure and combined exposure scenarios, and analyzes the reproductive and neurotoxic impacts of these contaminants on marine invertebrates. Neurotoxicity is mediated by several key mechanisms: inhibition of acetylcholinesterase activity; disruption of neurotransmitter balance, oxidative stress; and cellular damage, interference with embryonic neural development and axis specification, and impairment of neural cell differentiation and migration. Reproductive toxicity impairs reproductive development by disrupting endocrine signaling, inducing oxidative stress, downregulating reproduction-related genes and damaging gonadal structure. Studies have shown that, besides environmental factors, contaminant concentration is closely correlated with toxic potency and differing concentration ratios can lead to either antagonistic or synergistic effects in combined toxicity. Current research has largely focused on single or binary contaminant systems, whereas studies on multi-contaminant mixtures and their interactions with multiple environmental factors remain limited. Future research should prioritize combined exposure to multiple contaminants, long-term multigenerational observations and the development of comprehensive ecological risk assessment models and monitoring standards, thereby providing a scientific basis for marine ecological conservation. Full article

Caffeine (CAF) is a widely consumed psychostimulant known to modulate adenosine receptors and neurotransmitter systems, although its effects in invertebrates remain poorly understood. Environmentally relevant concentrations (5, 30, and 50 µg/L) are associated with altered behavior, including locomotion, exploration, and feeding, in the freshwater gastropod Physella acuta. This study examined molecular responses underlying these effects. Adult snails were exposed to CAF for 24 h and 7 days. Gene expression related to the nervous system and stress pathways was analyzed by RT-PCR, including A1AR, ADORA2B, AChE, GLRA2, DRD2, RYR, HSD11β, HSP70, SLC6A2, and SLC6A1. After 24 h, exposure to 50 µg/L CAF altered A1AR expression and caused downregulation of AChE, GLRA2, and DRD2, associated with observed behavioral changes. A1AR upregulation may indicate compensatory adjustment in adenosine signaling. After 7 days, A1AR remained upregulated, while genes linked to inhibitory neurotransmission showed partial recovery. Increased expression of genes involved in dopamine regulation and steroid metabolism suggested physiological adaptation. Overall, CAF induced dose- and time-dependent molecular responses in P. acuta, linking neurochemical disruption with behavioral changes and highlighting its ecological risk as an emerging freshwater contaminant. Full article

Galaxolide (HHCB), a synthetic polycyclic musk widely used as a fragrance ingredient in numerous personal care and household products, has raised increasing environmental concern due to its persistence, bioaccumulation potential, and widespread occurrence in aquatic environments. In this context, the need to establish a concrete ecotoxicological risk profile, defining both the toxicity levels and the mechanisms of action, is fundamental. For this reason, in the current study, we selected the freshwater leech Hirudo verbana as a suitable in vivo model to assess the HHCB ability in inducing inflammatory response and oxidative stress. By means of morphological, immunofluorescence, and molecular analyses, HHCB was shown not only to affect the leech innate immune response by modulating angiogenesis and macrophage-like cells recruitment, but also to promote the expression of enzymes involved in the antioxidant response, such as superoxide dismutase (SOD), glutathione S-transferase (GST) and catalase (CAT). Overall, these findings indicate that HHCB could induce significant physiological alterations, with sub-lethal concentrations able to affect immune homeostasis. Furthermore, this study supports the use of alternative invertebrate models to better understand the possible harmful effects of emerging contaminants. Full article

Germination of fenugreek (Trigonella foenum-graecum L.) seeds causes degradation of some antinutritional compounds. At the same time, the content of dietary important compounds, including some carbohydrates, in the sprouts increases. The aim of this study was to investigate changes in the soluble carbohydrate profile during germination and growth of fenugreek sprouts in the roots, hypocotyl and cotyledons. Furthermore, we assessed the effect of cold stress and desiccation on the carbohydrate profile in the main parts of the sprouts. Gas chromatography analyses of soluble carbohydrates showed that fenugreek seeds and sprouts contained sixteen soluble carbohydrates. In dry seeds, the main saccharides were raffinose family oligosaccharides (RFOs), sucrose and d-pinitol. During fenugreek germination, the drastic decomposition of RFOs and galactosides of cyclitols occurred faster in the embryonic axis than in the cotyledons. This was accompanied by an increase in the concentrations of monosaccharides and sucrose, as well as d-pinitol and myo-inositol in the developing hypocotyl and roots. Both examined stresses increased sucrose and raffinose concentration in cotyledons and roots, but in the hypocotyl similar changes were observed only under desiccation. The process of desiccation did not affect the d-pinitol content in the cotyledons of fenugreek sprouts, slightly reduced the content in the hypocotyl, but increased its level in the roots. Applied cold stress did not affect the content of d-pinitol and myo-inositol in the cotyledons and hypocotyl of fenugreek sprouts and only slightly reduced their level in the roots. The obtained results indicate different responses of fenugreek sprout organs to vegetation conditions caused by cold and/or desiccation stress. The practically insignificant effect of cold storage and desiccation on the level of d-pinitol and myo-inositol in fenugreek sprouts is new information that will probably be important for consumers. Full article

Background: Coenzyme Q₁₀ and Alpha-lipoic acid are two essential antioxidants involved in numerous physiological processes, including cellular energy production and the mitigation of oxidative stress. Their accurate quantification is critical for understanding their biological roles and therapeutic potential. Herein, an RPLC-MS/MS method for the rapid and simultaneous determination of ubiquinone-10 (CoQ₁₀), the reduced form ubiquinol-10 (CoQ₁₀H₂), and Alpha-lipoic acid (ALA) in human serum was developed and validated. Methods: Chromatographic separation was performed on a Waters ACQUITY UPLC HSS T3 column (2.1 mm × 150 mm, i.d. 1.7 μm). Detection was performed on a SCIEX Triple Quad 6500+ system, applying multiple reaction monitoring (MRM). Single-phase protein precipitation was selected as the sample preparation protocol, providing satisfactory recovery for the analytes. Results: The method was linear over the concentration of 53.8–613 ng/mL for CoQ₁₀H₂, 23.1–263 ng/mL for CoQ₁₀ and 7.7–87.6 ng/mL for ALA. Intra- and inter-day accuracy was found to be between 81.8 and 109% and 84.4 to 106%, respectively, for all analytes, while intra- and inter-day precision was found to vary from 0.8% to 9.9% %RSD and 2.0% to 7.7% %RSD, respectively. A limit of quantitation (LOQ) of 4.2 ng/mL was found for CoQ₁₀H₂, 1.7 ng/mL for CoQ₁₀ and 0.7 ng/mL for ALA. Conclusions: The developed LC-MS/MS method enables rapid, sensitive and simultaneous quantification of CoQ₁₀H₂, CoQ_10, and ALA in human serum with satisfactory accuracy, precision and sensitivity. The method is suitable for bioanalytical applications and was successfully applied to the analysis of 10 real samples obtained from healthy volunteers. Full article

The rehabilitation of the loggerhead sea turtle, Caretta caretta, involves stressors like handling and confinement. To assess physiological stress responses during rehabilitation, twenty-five C. caretta hospitalized at C.Re.Ta.M. were monitored over a two-month period at three time points (T0, T1, and T2). The cohort included 12 juveniles (CCL: 30.6 ± 5.7 cm) and 13 subadults (CCL: 52.5 ± 10.4 cm). Heterophil/lymphocyte ratios (H/L), corticosterone (CORT), glucose (Glu), creatine kinase (CK), and uric acid (UA) plasma concentrations were assessed. Two-way repeated-measure ANOVA revealed significant time effects on H/L ratio (p < 0.0001), CORT (p < 0.0001), Glu (p = 0.0002), CK (p < 0.0001), and UA (p < 0.05), with a significative group x time interaction observed for CK (p = 0.016), CORT (p = 0.006) and UA (p = 0.035). No group effect was observed in any of the data. In the juvenile group, H/L (p < 0.01) and CORT (p < 0.001) were significantly lower at T2 compared to T0. At the T0 point, CORT levels were significantly higher in juveniles compared to the subadult group. In subadults, significant decreases in H/L ratio (p < 0.001), Glu (p < 0.01), CK (p < 0.001), and UA (p < 0.05) were observed at both T1 and T2 relative to T0. At T0, CK levels were significantly higher in subadults compared to juveniles. No significant correlations were found between CORT and the other measured parameters. Our results suggest that the rehabilitation period is a safety period during which the animals reestablish their homeostasis despite captivity conditions. However, further studies are needed to define other causes of variations in stress levels in rehabilitating C. caretta. Full article

The hydrogen embrittlement (HE) behavior of an Fe–18Mn–8Al–1C–5Ni lightweight steel containing a fine and uniformly distributed B2 phase and κ-carbide was investigated by slow strain rate tensile testing with in situ hydrogen charging. Hydrogen charging reduces the elongation from 28.2% to 11.2%, while preserving an ultimate tensile strength above 1100 MPa and yielding an HE index of 60.2%. A thermal desorption analysis reveals a multi-peak desorption curve corresponding to diffusible hydrogen, hydrogen reversibly trapped at κ-carbides, and hydrogen strongly bound at the B2/γ interfaces, revealing a hierarchical hydrogen trapping behavior. Electron backscatter diffraction and electron channeling contrast imaging analyses near the fracture head region further reveal that localized hydrogen enrichment at the B2/γ boundaries induces severe stress concentration and interfacial weakening, shifting the fracture mode from ductile micro-void coalescence in air to hydrogen assisted intergranular and interphase cracking. This study clarifies the distinct roles of coherent κ-carbide and B2/γ interfaces in hydrogen trapping and crack initiation, offering a microstructure-based perspective for designing high-strength, HE resistant lightweight steels. Full article