Search Results (904)

Eminium rauwolffii (Blume) Schott var. rauwolffii is a member of the Araceae a large and mainly tropical family distributed worldwide. The Eminium species are utilized for various purposes including therapeutic uses in traditional medicine and as food. To analyze the antioxidant properties of water extract of E. rauwolffii (WEER) and ethanol extract of E. rauwolffii (EEER), 2,2’-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS^•+) radical and 1,1-diphenyl-2-picrylhydrazyl (DPPH^.) free radical scavenging, Fe³⁺-2,4,6-tris(2-pyridyl)-S-triazine (TPTZ) and Cu²⁺ reducing assays were studied. Antioxidant activities and reducing properties of both extracts were compared to standard antioxidants: BHT, BHA, α-Tocopherol, and Trolox. The IC₅₀ values of EEER for radical scavenging were higher than those of standard antioxidants (25.35 ± 1.42 μg/mL for ABTS^•+ and 106.80 ± 1.88 μg/mL for DPPH^•). The total phenolic and flavonoid quantities in WEER and EEER were measured in the range of 189.78 ± 0.01 to 298.54 ± 0.01 mg GAE/g and 89.37 ± 0.01 to 178.95 ± 0.01 mg QE/g, respectively. The IC₅₀ values for EEER and WEER against α-glycosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carbonic anhydrase I and II (hCA I and II) enzymes were 10.79 ± 5.61 to 13.18 ± 5.77, 36.14 ± 4.61 to 62.63 ± 1.67, 69.37 ± 7.36 to 37.48 ± 0.27, 81.30 ± 5.95 to 62.35 ± 8.03, and 29.34 ± 1.38 to 115.90 ± 3.3 µg/mL respectively. The antioxidant activity and enzymes inhibitory capacity of WEER were close, and comparable to the capacity demonstrated by the standards. The amount of sixteen compounds was identified from EEER. Numerous phytochemicals, including cynaroside, p-coumaric acid, cosmosiin, caffeic acid, and quinic acid, were quantitatively determined using the LC-MS/MS method. This clearly indicates that phenolic- and flavonoid-rich E. rauwolffii may have potential in the management of glaucoma, Alzheimer’s disease, diabetes, cardiovascular, and cancer disorders. Full article

This study presents a comprehensive geochemical and isotopic investigation of urban stream sediments draining into the Keban Dam Lake in Eastern Türkiye. A total of 15 sediment samples were collected along a ~35 km transect, spanning rural-to-urban transition zones. PAAS-normalised REE patterns revealed coherent light REE behaviour and positive Eu anomalies (Eu/Eu* = 1.57–2.01), except sample K8 (Eu/Eu* = 0.91), indicating contributions from plagioclase-bearing lithologies. Enrichment Factor (EF) calculations based on scandium normalisation showed notable enrichment in Li, Zr, Nb, and REEs, reflecting felsic source rocks and mineralogical sorting. Multivariate statistical analyses (PCA and HCA) revealed distinct groupings of elements associated with lithogenic sources (Be, Sc, and Y) and anthropogenic inputs (Li, Sn, and Rb). Spatial clustering of samples into rural, transitional, and urban zones supported this differentiation, suggesting increasing anthropogenic influence downstream. Sr isotopic data (⁸⁷Sr/⁸⁶Sr = 0.7045–0.7057) and Pb isotope ratios (²⁰⁶Pb/²⁰⁴Pb = 18.914–18.947) suggest dominantly geogenic control, with slightly more radiogenic signatures in urban sediments. These integrated geochemical and isotopic results provide the provenance model for the Keban catchment, highlighting how natural lithological sources and urbanisation jointly shape sediment composition and metal distribution. The findings also provide a useful geochemical baseline for environmental monitoring, sediment quality assessment, and sustainable watershed management in the Keban Dam Lake basin. Full article

Coumarins represent a distinctive class of non-classical carbonic anhydrase inhibitors that interact with the entrance region of the catalytic pocket rather than directly coordinating the catalytic Zn²⁺ ion. In this study, a series of glycosylated coumarins was synthesized through a copper-catalyzed multicomponent reaction involving propargyl glycosides, salicylaldehyde, and tosyl azide, providing efficient access to iminocoumarin-based glycosides derived from natural carbohydrates. The inhibitory activity of the synthesized compounds was evaluated against human carbonic anhydrase isoforms I, II, IX, and XII using a stopped-flow CO₂ hydrase assay. The compounds showed negligible inhibition of the cytosolic isoforms hCA I and hCA II, while displaying moderate activity toward the tumor-associated isoforms hCA IX and hCA XII, with Ki values ranging from 12.9 to 41.8 μM. Among the series, 6-O-(2H-chromene-2-one-3-yl-methyl)-D-galactopyranose (10a) emerged as the most potent inhibitor of hCA IX and XII. Structure–activity relationship analysis indicated that deprotected glycosyl derivatives exhibit improved inhibitory activity compared to protected analogues. To rationalize these observations, molecular docking followed by molecular dynamics simulations and MM-GBSA binding free energy calculations were performed for both anomeric forms of compound 10a. The computational results revealed a clear preference for the β-anomer, particularly in hCA IX and XII, where favorable interactions with catalytic threonine residues and isoform-specific aromatic residues stabilize the ligand within the active-site entrance. These findings provide a molecular explanation for the experimentally observed selectivity and highlight glycosyl coumarins as potential starting points for further optimization toward selective inhibitors of tumor-associated carbonic anhydrases. Full article

Severe accidental hypothermia represents a unique and potentially reversible cause of cardiac arrest in which prolonged resuscitation may still result in favorable neurological recovery. Unlike normothermic cardiac arrest, hypothermic cardiac arrest (HCA) is characterized by profound metabolic suppression and temperature-mediated myocardial instability, requiring a fundamentally different therapeutic paradigm. Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) provides not only circulatory support but also controlled reperfusion and rewarming, positioning it as the cornerstone of modern management. Recent international guidelines have clarified indications for extracorporeal life support (ECLS) in HCA and have contributed to improved standardization of care. Building upon these recommendations, this narrative review focuses on physiological principles underlying extracorporeal rewarming and their implications for bedside management. We examine mechanisms of ischemia–reperfusion injury, rewarming-associated hemodynamic instability and myocardial stunning, discuss dynamic risk assessment beyond statistical thresholds such as the HOPE score and summarize practical considerations regarding cannulation strategies, differential hypoxia, left ventricular unloading and neurologic evaluation. By integrating current evidence with pathophysiological insight and organizational considerations, this review proposes a clinically oriented framework to support decision-making in hypothermic cardiac arrest and to optimize meaningful neurological recovery. Full article

Chronic oxidative stress and lipid imbalance drive metabolic disorders such as obesity and non-alcoholic fatty liver disease, yet few therapies target the upstream redox imbalance in key tissues. Human carbonic anhydrase III (hCA III), a redox-associated enzyme enriched in liver and adipose tissue, has long remained pharmacologically elusive due to its low catalytic activity and lack of modulators. Here, we identify fragment-like nicotinic acid derivatives as non-sulfonamide hCA III modulators and evaluate their associated cellular effects. Using an esterase activity assay, we screened 25 analogues and identified two fragment-like hits, compound 17 (2-thioethyl) and compound 22 (6-morpholino), with IC₅₀ values of 487 and 361 µM, respectively. Orthogonal thermal shift analysis supported compound-protein interaction, and selected hits were subsequently evaluated in HepG2 cells. Both compounds were associated with reduced CA3 mRNA expression after treatment at 1 µM, while their cellular phenotypes diverged, with compound 22 increasing ROS under oxidative stress conditions and compound 17 affecting mitochondrial membrane potential. Taken together, these findings identify tractable nicotinic acid-derived fragment hits and associated cellular phenotypes that warrant further mechanistic investigation. These fragment-like hits provide a practical starting point for studying the redox-linked biology of hCA III. Full article

Background/Objectives: A robust and scalable manufacturing framework for lipid-based nanocarriers remains a critical challenge, particularly for labile phytochemicals such as curcuminoids in turmeric. This study presents an integrated Quality by Design (QbD)-driven and Outcome-Based Design (ObD) strategy to establish a scalable, resource-efficient manufacturing process for curcuminoids-loaded nanostructured lipid carriers (NLCs). Methods: To overcome the limitations of conventional multivariate design of experiments (DOE), which require extensive experimental runs, a risk-based, knowledge-driven single-factor screening approach was employed. Guided by risk assessment tools, including Ishikawa diagrams and failure mode considerations, 12 representative processing conditions were selected to define the design space. Critical quality attributes (CQAs), namely, particle size, polydispersity index (PDI), and zeta potential, were predefined to establish a robust control strategy. A two-step homogenization process—high-shear homogenization (HSH) for pre-emulsification followed by high-pressure homogenization (HPH) for nanoscale refinement—was systematically optimized. Results: Multivariate data analysis using principal component analysis (PCA) and hierarchical cluster analysis (HCA) identified key critical process parameters (CPPs), particularly HSH speed, processing time, and HPH cycles, as dominant factors influencing nanoparticle characteristics. The optimized 1-h process enabled successful scale-up of NLCs from 100 g to 5000 g, demonstrating the capability to generate nanosized particles within 100–500 nm. The combined HSH–HPH approach produced smaller, more uniform nanoparticles with high encapsulation efficiency and physical stability, outperforming HSH alone. Conclusions: Overall, this study establishes a practical and industrially viable framework that integrates QbD principles with data-driven optimization tools, for enabling reliable translation from laboratories to semi-industrial production. Full article

This study presents the first watershed-scale assessment of the impact of thermal spring discharges on the hydrochemistry and water quality of the Soummam basin (northeastern Algeria). Fourteen stations were monitored during three campaigns (October 2024, December 2024 and March 2025), combining physicochemical analyses, hydrochemical diagrams, and water quality indices (WQI and IWQI). The results reveal a clear spatial gradient in water composition, from low-mineral Ca-HCO₃/Ca-SO₄ facies in upstream areas to highly mineralized Na-Cl facies associated with thermal springs (Sidi Yahia and Sillal). Electrical conductivity reaches up to 27,359 µS/cm, reflecting intense mineralization driven by evaporite dissolution and deep water–rock interaction. This thermomineral signature propagates downstream through mixing and ion exchange processes, leading to progressive salinity enrichment. Water quality indices highlight significant degradation in thermally influenced zones, with approximately 50% of samples unsuitable for drinking (WQI > 300) and more than 60% classified as highly restricted for irrigation (IWQI < 40). Cluster analysis further confirms the distinction between severely impacted, moderately affected, and relatively preserved waters. Overall, the findings demonstrate that thermal discharges represent a major and persistent driver of salinization, emphasizing the need to incorporate geothermal influences into water resource management strategies in semi-arid environments. Full article

Background: B7-H3, a type I transmembrane glycoprotein belonging to the B7 superfamily, is an attractive target for antitumor therapies. B7-H3 demonstrates aberrant overexpression in various types of solid tumors while showing limited and low expression in normal human organs. Various types of treatment targeting B7-H3 have been reported. Among these treatments, antibody–drug conjugates (ADCs) have shown potent activity, and several clinical trials, including DS7300a and MGC018, are currently ongoing. Methods: Here, we constructed CD276-8 ADC, composed of the anti-B7-H3 antibody CD276-8 with moderate affinity, an enzymatically cleavable tetra-peptide-based linker and DXd. Characteristics, including in vitro binding affinity and internalization activity, were assessed by bio-layer interferometry (BLI), flow cytometry and high content analysis (HCA). The cytotoxicity of CD276-8 ADC was evaluated in cell lines expressing B7-H3. Pharmacokinetic profiles and antitumor activity were evaluated in mouse models in vivo. Finally, the developability of CD276-8 ADC was assessed with plasma stability, accelerated stability and freeze–thaw studies using LC-MS and HPLC. Results: Characterization in vitro demonstrated the moderate affinity and acceptable internalization activity of CD276-8 ADC. In addition, CD276-8 ADC exhibited potent antitumor activities in B7-H3-positive cell line-derived xenograft (CDX) models with acceptable pharmacokinetic profiles, although it showed less potent cytotoxicity in various cell lines in vitro, indicating acceptable developability. Conclusions: We developed CD276-8 ADC, a B7-H3-targeting ADC with moderate affinity, which delivers the TOP1 inhibitor DXd. This design combined moderate affinity and acceptable pharmacokinetics, resulting in potent antitumor efficacy in vivo. Our study suggests that affinity optimization could be a useful consideration for enhancing ADC efficacy, positioning CD276-8 ADC as a promising therapeutic for B7-H3-expressing solid tumors. Full article

This study establishes a facies-based framework for characterizing reservoir quality in the Upper Pannonian geothermal reservoirs of the Szentes field (Hungary). To evaluate vertical heterogeneity and optimize the selection of geothermal reinjection zones, an integrated core–log–statistical workflow was applied to data from boreholes SZT-1 and SZSZT-IX. The methodology combined petrophysical measurements, petrographic observations, and multivariate statistical analyses, including Hierarchical Cluster Analysis (HCA) and Linear Discriminant Analysis (LDA). The siliciclastic succession was classified into four distinct facies clusters representing a continuum of depositional energy regimes: Rolling, Graded Suspension with Rolling, fine-grained Suspension, and Uniform Suspension. The results demonstrate a dual control on reservoir quality: the primary pore framework is determined by depositional grain-size architecture and sediment transport processes, while mechanical compaction and diagenetic alteration subsequently modify pore connectivity and flow efficiency. Among the identified facies, deposits formed from Graded Suspension with Rolling represent the most favorable reservoir units, combining high porosity (up to 33%) with exceptionally high permeability (>1500 mD). In contrast, suspension-dominated facies deposited from Graded and Uniform Suspension exhibit significantly reduced permeability due to higher matrix content, cementation, and compaction. The results demonstrate that reservoir performance in the Szentes geothermal system is primarily controlled by facies-scale heterogeneity rather than by depth-based stratigraphic divisions alone. This integrated facies-based approach provides a predictive framework for extrapolating reservoir properties to uncored intervals and offers practical guidance for optimizing reinjection strategies and sustainable geothermal reservoir management. Full article

This study investigates the antioxidant, enzyme inhibitory, and antimicrobial activities of water (WEHL) and ethanol (EEHL) extracts of hop (Humulus lupulus) cones. Phytochemical analyses revealed higher total phenolic content in EEHL (271.52 ± 0.13 mg GAE/g) than in WEHL (251.84 ± 0.06 mg GAE/g), as well as higher total flavonoid content (182.56 ± 0.45 mg QE/g for EEHL versus 179.39 ± 0.46 mg QE/g for WEHL). Antioxidant activity, determined by DPPH and ABTS assays, showed that EEHL had stronger radical scavenging capacity with IC₅₀ values of 19.13 ± 4.66 μg/mL (DPPH) and 12.66 ± 1.94 μg/mL (ABTS), compared to WEHL (DPPH: 20.90 ± 2.39 μg/mL; ABTS: 32.41 ± 4.29 μg/mL). In reducing assays, EEHL also showed better absorbance values in FRAP (0.77 ± 0.01), CUPRAC (2.09 ± 0.05), and Fe³⁺ reducing (1.95 ± 0.01) tests. EEHL likely outperformed WEHL due to solvent polarity and extraction efficiency. Moderately polar ethanol extracts a broader range of phenolics and flavonoids, including fewer polar bioactive compounds that contribute to antioxidant capacity and enzyme inhibition. This matches higher TPC/TFC in EEHL and explains stronger radical scavenging, reducing power, and multi-enzyme inhibition. Enzyme inhibition studies revealed that EEHL inhibited acetylcholinesterase (IC₅₀: 26.06 μg/mL), butyrylcholinesterase (IC₅₀: 44.00 μg/mL), α-glycosidase (IC₅₀: 119.31 μg/mL), and carbonic anhydrase isoenzymes hCA I (IC₅₀: 59.78 μg/mL) and hCA II (IC₅₀: 21.19 μg/mL). LC–MS/MS analysis identified major phenolic compounds such as isoquercitrin (3.14 ng/mL), rutin (0.60 ng/mL), and hesperidin (0.43 ng/mL) in EEHL. Antimicrobial screening showed selective activity against Staphylococcus aureus with an inhibition zone of 18.50 ± 0.58 mm, while no inhibition was observed against Escherichia coli and Candida albicans. These findings provide a solvent-dependent in vitro profile that can guide extraction strategies, support antioxidant and multi-enzyme screening (including hCA I and II), and identify candidates for selective antimicrobial evaluation and further preclinical investigation. Despite extensive use of hop extracts, comparative solvent-dependent profiling that links LC–MS/MS phenolic composition with a broad multi-enzyme inhibition panel, including the less frequently evaluated hCA I/II isoenzymes, remains limited. Therefore, the objective of this study was to systematically compare WEHL and EEHL in terms of phytochemical content and in vitro antioxidant, enzyme inhibitory, and antimicrobial activities. Overall, these results provide a solvent-dependent, comparative in vitro profile of WEHL vs. EEHL that can support antioxidant, multi-enzyme screening (including hCA I and II), and selective antimicrobial assays. Full article

Background/Objectives: Malignant transformation of hepatocellular adenoma (HCA) represents a clinically significant yet incompletely understood process. Although the pathological and clinical characteristics of HCA have been extensively described, its spatial molecular heterogeneity and spatially organized molecular variation at the tissue level remain insufficiently characterized. This study aimed to establish a spatially integrated multi-omics workflow and to delineate spatially organized molecular variation across histologically defined regions from adenoma to carcinoma. Methods: A sequential dual-layer matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) workflow was developed to acquire small-molecule metabolomic and N-glycan spatial data from the same formalin-fixed paraffin-embedded (FFPE) tissue section. Four rare HCA specimens containing focal carcinoma transformation were included in this study. Pixel-level clustering, region-based co-localization analysis, and diffusion pseudotime modeling were applied to characterize spatial metabolic and N-glycan patterns across normal liver tissue (NL), hepatocellular adenoma (HCA), and carcinoma-transformed regions within adenoma (HCA-HCC). Results: Small-molecule MSI revealed spatial metabolic stratification within HCA, with variation observed in nucleotide-related, lipid-related, sulfur-related, and sugar nucleotide–associated metabolites. Pseudotime analysis revealed a spatial ordering of samples across NL, HCA, and HCA-HCC regions, showing differences in antioxidant-associated metabolites, lipid-related features, and bile acid-related metabolites across regions. N-glycan MSI identified independent glycosylation niches, with increasing structural complexity and enrichment of highly branched glycans in carcinoma-transformed regions. Integration of metabolomic and glycomic data suggested spatially associated patterns between metabolite features and glycan structures across regions. Conclusions: This study provides spatially resolved evidence of spatially organized patterns of molecular variation across histologically defined regions of HCA. The identified metabolic and N-glycan gradients provide insights into spatial molecular organization during malignant transformation of hepatocellular adenoma. Full article

Objective: Based on previous findings on the Lingguizhugan (LGZG)-mediated gut–liver axis, this study clarifies the therapeutic mechanisms of LGZG in metabolic dysfunction-associated steatotic liver disease (MASLD), with a focus on the gut microbiota–bile acid–TGR5 (GPBAR1) axis. Methods: C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce MASLD, followed by 4-week LGZG intervention (21.57 g/kg/day, oral gavage). Metabolic phenotypes, gut microbiota (16S rRNA sequencing), serum/hepatic bile acids (targeted metabolomics), and molecular targets (qPCR/Western blot) were analyzed. Results: LGZG significantly alleviated HFD-induced obesity, insulin resistance, and hepatic steatosis, while enhancing whole-body energy expenditure (increased oxygen consumption (VO₂), and heat production (p < 0.05). It also reduced serum ALT (p < 0.001) and AST levels (p < 0.01). Mechanistically, LGZG remodeled the gut microbiota, specifically increasing Akkermansia, Bifidobacterium and Lachnospiraceae_NK4A236_group while decreasing Lactobacillus. This shift inhibited the intestinal FXR-Fgf15 axis, concurrently activating the hepatic alternative bile acid synthesis pathway (upregulating CYP27A1 and CYP7B1 protein expression; p < 0.001 and p < 0.01, respectively). Consequently, systemic accumulation of non-12α-hydroxylated bile acids (non-12-OH BAs) such as hyocholic acid (HCA) and 7-ketolithocholic acid (7-ketoLCA) occurred—known TGR5 agonists and intestinal FXR antagonists. These changes elevated serum GLP-1 levels (p < 0.05) and activated adipose TGR5-cAMP/PKA/CREB signaling. The metabolic benefits primarily originated from non-12-OH BAs enrichment and TGR5-mediated adipose browning, not hepatic FXR activation. Conclusions: Our findings show that LGZG ameliorates MASLD by remodeling bile acid profiles via intestinal FXR-Fgf15 axis inhibition and hepatic alternative synthesis pathway activation. This study highlights the TGR5-targeting properties of LGZG, providing a mechanistic basis for its therapeutic use in metabolic disorders. Full article

This study introduces a novel risk detection and control system to enhance social stability in major construction projects. Utilizing a heterogeneous cellular automaton model, the system simulates complex interactions among project stakeholders to identify and mitigate Social Stability Risks (SSR). Integrating the Ignorant–Latent–Malcontent–Recovered (ILMR) framework, the model applies principles from epidemiology to predict and manage the spread of social stability risks. Simulation results demonstrate the model’s effectiveness in reducing the number of malcontent and ignorant individuals while increasing the recovered category, stabilizing the social environment around large projects. This approach helps manage immediate risks and improves long-term social acceptance and sustainability of engineering projects. By bridging risk management with advanced simulation techniques, this research contributes to major construction projects by providing a robust framework for managing complex social dynamics, thereby enhancing project success and stakeholder satisfaction. The findings underscore the potential of integrating innovative technological tools with traditional risk management strategies to address the socio-technical challenges of large-scale engineering projects. Full article

China’s rapid urbanization has accelerated the transition of residential development toward high-density models. As a critical interface between architecture and the urban environment, residential facades reflect evolving design strategies, living demands, and technological conditions. However, due to the complexity and diversity of facade components, the underlying influencing factors of facade evolution remain insufficiently explored. This study focuses on Shenzhen, a typical high-density city in southern China, and quantitatively analyzes 225 residential facades from 1980 to 2024 using HCA (Hierarchical Cluster Analysis). The results show that the development of residential facades in Shenzhen presents continuous and staged evolutionary characteristics, with a transition from simplified, function-oriented configurations to diversified and technology-integrated forms. Six clusters of facade types are identified, and the analysis reveals that this evolution is driven by the combined effects of policies and design standards (external factors), resident demand (internal factors), and technological development (technical support), rather than merely stylistic changes. This study establishes a quantitative classification framework to identify the evolutionary patterns and influencing factors of residential facades, enriches the research system of high-density residential facades, provides methodological support for facade analysis, and offers both theoretical and practical guidance for facade design in subtropical high-density cities. Full article

The essential reaction of CO₂ hydration, fundamental to all living organisms, is facilitated by the enzyme carbonic anhydrase (CA, EC 4.2.1.1). This enzyme plays a crucial role in regulating various physiological and pathological processes. A series of heterocyclic benzenesulfonamide derivatives (19 compounds) were evaluated as possible inhibitors of human CAs. Their inhibitory properties were tested against several isoforms such as the cytosolic hCA I and hCA II, as well as the transmembrane isoforms hCA IV, hCA IX and hCA XII. The tested molecules demonstrated notable inhibitory potential, particularly toward hCA II and hCA IV, where five and four compounds, respectively, exhibited greater potency than the reference inhibitor, acetazolamide. Molecular docking simulations were further performed to elucidate the binding interactions of the most active compounds with the human CA II, IV IX and XII isoforms Full article