Search Results (34)

Background/Objectives: Symmetrical dual-site acetylcholinesterase (AChE) inhibitors offer a compelling strategy to mitigate mutational drug resistance, yet static modeling fails to capture induced-fit dynamics under mutational stress. Methods: Here, a 100,000-compound virtual library was filtered using a machine learning-based QSAR classification pipeline. A strict, empirically calibrated Jaccard applicability domain filter (AD = 0.823) eliminated topological anomalies, yielding a robust cross-validation accuracy (ROC-AUC: 0.80 ± 0.05; independent test MCC: 0.61). Multi-parameter ADMET and shape screening prioritized unique chemotypes to probe the 20 Å enzyme gorge. All-atom explicit-solvent molecular dynamics simulations were coupled with 150 ns enhanced-sampling Metadynamics along two orthogonal collective variables (gorge depth and ligand orientation) to map out the free energy surfaces under mutational stress. Results: Symmetrical probes suffered catastrophic unbinding upon anchor loss. Conversely, the symmetrical core of Lead Compound 1631 demonstrated extraordinary structural resilience. In silico site-directed mutagenesis (W86A and W286A) triggered a thermodynamic locking effect; the W86A mutant forced the complex into a deeper energetic well (ΔG_min = 9.23 ± 1.98 kJ/mol) than the wild-type state (5.26 ± 1.69 kJ/mol). MM/GBSA decomposition confirmed an active electrostatic-solvation compensation mechanism along a “solvation see-saw” diagonal (ΔΔG_total = +1.59 kcal/mol). Finally, Dynamic Cross-Correlation Matrix analysis quantified a mechanical inversion of the CAS-PAS axis into an anti-correlated clamping mode (−0.04) that locked the ligand bridge in place. Conclusions: These results demonstrate that symmetrical dual-site targeting, combined with dynamic thermodynamic locking, provides a resilient framework to overcome mutational resistance in AChE inhibitors. Full article

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and its role in promoting the degradation of the low-density lipoprotein receptor (LDLR) has revolutionized lipid-lowering therapy, offering new therapy for patients with hypercholesterolemia. Notably, PCSK9 is now being explored for functions beyond lipid regulation. Emerging evidence implicates PCSK9 in vascular pathology by influencing endothelial dysfunction, inflammatory signaling, oxidative stress, and vascular homeostasis—potentially through LDLR-independent mechanisms. This review critically evaluates PCSK9’s potential as a regulator of endothelial dysfunction, synthesizing findings from in vitro, in vivo, and clinical studies. While current PCSK9-targeted therapies, including monoclonal antibodies and siRNA-based agents, have demonstrated robust efficacy in lowering lipid levels and reducing cardiovascular risk, their direct effects on endothelial PCSK9 signaling remain unclear. On the other hand, novel approaches—such as peptide-based inhibitors, intracellular modulation, and natural compounds—resulted in new insights into endothelial-specific PCSK9 pathways. Overall, this review highlights the need to bridge experimental and clinical evidence by applying endothelial-focused models, multi-omics analyses, and functional vascular assessments to clarify the role of PCSK9 in endothelial dysfunction and to propose future strategies for cardiovascular interventions targeting PCSK9-mediated endothelial dysfunction. Full article

Sodium-ion batteries (SIBs) have emerged as one of the most promising alternatives to lithium-ion systems, driven by the abundance and low cost of sodium resources as well as the urgent demand for sustainable large-scale energy storage. In recent years, remarkable advances have been achieved in electrode materials, electrolytes, and interfacial engineering, which have significantly improved the electrochemical performance of SIBs. Hard carbons and alloy-type anodes have shown encouraging progress in balancing capacity and stability, while layered oxides, polyanionic compounds, and Prussian blue analogues are leading candidates for cathodes due to their structural diversity and tunable redox properties. Concurrently, the development of advanced liquid and solid electrolytes, together with strategies to control the solid–electrolyte interphase (SEI) and cathode–electrolyte interphase (CEI), is enhancing safety and long-term cycling. Despite these achievements, critical challenges remain, including limited energy density, volumetric expansion in alloying anodes, interfacial instability, and scalability issues. This review provides a comprehensive overview of the fundamental principles, recent material innovations, and failure mechanisms of SIBs, and highlights the current status of industrial progress led by companies such as Faradion, HiNa Battery, CATL, and Tiamat. Finally, future perspectives are discussed, emphasizing the role of sodium-ion technology in grid-scale storage, renewable energy integration, and sustainable battery recycling. By bridging academic advances and industrial development, this article outlines the roadmap toward the commercialization of sodium-ion batteries. Full article

Aqueous zinc-ion batteries (AZIBs) are promising for large-scale grid storage due to inherent safety, low cost, environmental compatibility, high theoretical capacity (820 mAhg⁻¹), and suitable redox potential (−0.763 V vs. SHE). However, practical deployment is hindered by coupled challenges at the zinc anode–hydrogen evolution, dendrite growth, and corrosion/passivation, which severely limit cycle life and coulombic efficiency. This review systematically summarizes key advances in AZIB research. It first elucidates working principles and four cathode energy storage mechanisms: Zn²⁺ insertion/extraction, H⁺/Zn²⁺ co-insertion, chemical conversion, and dissolution/deposition. Second, it examines four mainstream cathodes (manganese-based, vanadium-based, Prussian blue analogs, and organic compounds), analyzing performance bottlenecks and corresponding optimization via structural modification. Third, it explores functional mechanisms of advanced separators (polymer, inorganic/ceramic composite, MOF-based, and cellulose-based) in regulating uniform Zn²⁺ deposition and suppressing dendrites. Fourth, it summarizes anode optimization strategies: artificial protective layers for interface stabilization, electrolyte additives to modulate Zn²⁺ solvation/deposition, and 3D porous structures to reduce local current density and provide nucleation sites. Finally, key scientific challenges and future directions are discussed—multi-strategy synergy, in situ characterization, practical battery construction, and sustainable technological development, offering theoretical guidance for advancing AZIBs toward large-scale applications. This review aims to provide a comprehensive perspective spanning from materials to systems, and from mechanisms to applications. Its core objective is not merely to list the types of cathode materials, but to establish a logical bridge directly connecting “key challenges” to “optimization strategies,” with a particular emphasis on the issues and solutions related to the cathode side. Full article

Dysglycemia represents an early and progressive stage of cardiometabolic disease, characterized by IR, metabolic inflammation, and increased cardiovascular risk. Its high prevalence and largely asymptomatic course often lead to diagnostic and therapeutic inertia, resulting in missed opportunities for early intervention. Recognizing dysglycemia as a disease continuum rather than a transitional condition supports the need for anticipatory and integrated preventive strategies. Within this framework, nutraceuticals are emerging as valuable supportive tools in the management of dysglycemia, particularly in individuals with increased metabolic risk who are not yet candidates for pharmacological therapy. Nutraceutical compounds can target key pathophysiological mechanisms underlying dysglycemia, including impaired insulin sensitivity, oxidative stress, chronic low-grade inflammation, and altered postprandial glucose metabolism. Clinical evidence supports the use of selected micronutrients, polyphenols, and standardized plant extracts in improving fasting and postprandial glycemic control. Phytocomplexes derived from plants such as Mangifera indica, Momordica charantia, and Malus domestica exert complementary and multitarget actions, including modulation of carbohydrate absorption, activation of AMPK-related pathways, enhancement of peripheral glucose uptake, stimulation of incretin secretion, and improvement of endothelial function. When integrated with lifestyle and dietary interventions, nutraceuticals may reduce glycemic variability, improve metabolic resilience, and delay progression toward type 2 diabetes. Overall, nutraceuticals represent a rational bridge between lifestyle measures and pharmacological treatment in the personalized management of dysglycemia. Full article

Frequent drilling fluid lost circulation in the Kuqa foreland area of the Tarim Oilfield severely constrains drilling efficiency and safety. The complex formation structures and diverse lost circulation types in this region are compounded by a lack of systematic classification in existing studies and weak correlation between mechanism analysis and field plugging measures, leading to a deficiency in quantitative decision-making for lost circulation prevention and control. Based on lithology analysis, loss zone pressure differential calculation, well log interpretation, and core observations, this study establishes an integrated “formation–lithology–pressure” diagnostic and classification method for lost circulation. A systematic classification framework comprising five types of lost circulation channels and mechanisms was developed. Based on this, the dominant lost circulation types and characteristics of three typical vertical formations in the Kuqa foreland were clarified: ① The supra-salt sandy conglomerate formations (e.g., Q1x, N2k) are dominated by permeability loss, where the loss rate (V) and bottomhole pressure differential (ΔP) exhibit a strong positive correlation (V ∝ ΔP). On-site application of graded bridging plugging formulations achieved a first-attempt success rate of ≥90%. ② The salt–gypsum formations (E1-2km) are primarily characterized by induced fracture loss, with a weak correlation between V and ΔP and dynamic fracture opening/closing behavior. Conventional rigid plugging materials showed limited effectiveness, resulting in a first-attempt success rate of <50%. ③ The K1bs formation is dominated by vertically developed natural fracture loss, where V and ΔP also demonstrate a strong positive correlation. In a specific Keshen block, a power-law relationship between the fracture aperture (W) and loss rate was established (W = 0.26·V^0.62, R² = 0.98), providing a basis for predicting fracture aperture and optimizing plugging formulations, with a plugging success rate of ≥80%. The classification system and quantitative criteria developed in this study effectively link lost circulation mechanisms, dynamic characteristics, and engineering countermeasures, offering theoretical support and a decision-making framework for optimizing lost circulation prevention and control measures and improving success rates in the Kuqa foreland area. Full article

Nature has long served as a prolific source of bioactive compounds, offering structurally diverse scaffolds for the development of therapeutics. In recent years, increasing attention has been given to nature-inspired covalent inhibitors, molecules that form covalent bonds with pathogen- or cancer-specific targets, due to their potential selectivity and sustained biological activity. This review explores the landscape of covalent inhibitors derived from natural sources, with a focus on compounds from fungi, marine organisms, bacteria and plants. In particular, emphasis is placed on the molecular mechanisms through which these compounds exert their activity against different types of pathogens and other biomedically relevant targets, highlighting key structural motifs that facilitate covalent interactions. Furthermore, the review discusses recent advances in synthetic modification, target identification, and optimization strategies that bridge natural compound discovery with modern drug development. By drawing insights from nature’s chemical repertoire, this work ultimately displays the potential of natural covalent inhibitors as a promising foundation for next-generation anti-infective and anticancer therapeutics. Full article

Objectives: Shen-Ling-Bai-Zhu-San (SLBZS) is a classical traditional Chinese herbal formula with spleen-invigorating and dampness-resolving properties. Recent pharmacological studies suggest its potential to regulate immune and metabolic disorders. Type 2 diabetes mellitus (T2D) and ulcerative colitis (UC) often coexist as comorbidities characterized by chronic inflammation, microbial imbalance, and insulin dysregulation, yet effective therapies remain limited. This study aimed to investigate the molecular mechanisms through which SLBZS may benefit T2D–UC comorbidity. Methods: An integrative multi-omics strategy was applied, combining network pharmacology, structural bioinformatics, and ensemble molecular docking–dynamics simulations. These complementary approaches were used to identify SLBZS bioactive compounds, predict their putative targets, and examine their interactions with disease-related biological networks. Results: The analyses revealed that flavonoids in SLBZS act on the SLC6A14/PI3K–AKT signaling axis, thereby modulating immune responses and improving insulin sensitivity. In addition, SLBZS was predicted to regulate the NF-$\kappa$B/MAPK signaling pathways, key hubs linking inflammation and metabolic dysfunction in T2D–UC. These dual actions suggest that SLBZS can intervene in both inflammatory and metabolic processes. Conclusions: SLBZS demonstrates promising therapeutic potential for T2D–UC by targeting interconnected immune–metabolic networks. These findings not only provide mechanistic insights bridging traditional therapeutic concepts with modern pharmacology but also establish a theoretical basis for future experimental validation and clinical application. Full article

Background/Objectives: Carotenoids in citrus are vital nutritional compounds and precursors of the stress hormone abscisic acid (ABA). SNF1-related kinases (SnRKs)—key regulators of plant stress signaling that phosphorylate is targeting proteins for post-transcriptional regulation—mediate ABA signaling through its subfamily SnRK2-phosphatase type-2C (PP2C)-PYR1-LIKE (PYL) cascades. This study aims to identify the SnRK-PP2C-PYL family members and decipher their underlying post-transcriptional regulatory mechanisms which control carotenoid metabolism in Citrus sinensis for improved nutrition and stress resilience. Methods: SnRK, PP2C, and PYL were identified by integrated HMMER-blastp-CDD pipeline in the Citrus genome. Using two carotenoid-divergent cultivars, ‘Newhall’ (yellow) and ‘Cara Cara’ (red, hyperaccumulating linear carotenoids), we conducted spatiotemporal expression profiling and integrated transcriptomic and metabolomic data via Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules correlated with accumulation. Results: We identified 26 CsSnRKs (1 SnRK1, 7 SnRK2, 18 SnRK3), 57 CsPP2Cs, and 7 CsPYLs in Citrus sinensis. Despite a >26-fold difference in linear carotenoids, structural gene expression was similar among cultivars, strongly implicating post-transcriptional control. WGCNA identified a key turquoise module highly correlated with linear carotenoid content. This module contained phosphorylation-related genes (CsSnRK1/3.5/3.6/3.16, CsPP2C14/15/33/35/38/40/43/56, and CsPYL6), biosynthetic genes (CsPSY1, CsZISO, and CsZDS), and candidate transcription factors. Network analysis predicted that CsSnRKs, CsPP2Cs, and CsPYLs regulate phytoene-derived carotenoid biosynthesis. Conclusions: We propose a novel phosphorylation-mediated post-transcriptional regulatory network in carotenoid accumulation. This mechanism bridges ABA signaling and metabolic adaptation, providing crucial molecular targets for engineering nutrient-dense and climate-resilient citrus varieties. Full article

Background/Objectives: The integration of natural compounds in cancer research marked a crucial shift in the modern medical landscape, through a growing acknowledgment of their potential as efficient, less toxic, and cost-effective alternatives to contemporary chemotherapeutics. Liquiritigenin (LIQ) is a compound obtained from different plants, the most important being the Glycyrrhiza species, commonly known as licorice. Methods: This review compiles findings from previously published preclinical studies and experimental research articles focusing on LIQ’s pharmacological effects, with particular attention to its anticancer potential. The relevant literature was identified using established scientific databases and selected based on relevance to cancer biology and LIQ-associated signaling pathways. Results: LIQ demonstrates anti-oxidant, anti-inflammatory, and anti-proliferative effects. It exerts its potential anticancer activities by inducing apoptosis, preventing cell proliferation, and modulating various signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), and so on. Conclusions: LIQ represents a promising natural agent for cancer therapy, with evidence supporting its multifunctional role in targeting tumor growth and survival mechanisms. By providing a detailed analysis of LIQ, this review aims to highlight its therapeutic efficacy across various cancer types and emphasize its importance as a promising compound in cancer research. In addition, this review seeks to bridge the gap between traditional medicine and modern pharmacology and paves the way for LIQ’s clinical application in cancer therapy. Full article

Climate change significantly impacts agricultural infrastructure, particularly in communal land farming systems, where socio-economic vulnerabilities intersect with environmental stressors. This study examined the effects of extreme weather events (floods, droughts, strong winds, frost, and hail) on various agricultural infrastructures—including bridges, arable land, soil erosion control structures, dipping tanks, roads, and fences—using an ordered probit model. A survey was conducted using structured questionnaires between August and September 2023, collecting data from communal farmers (n = 60) in oKhahlamba Municipality, Bergville. Key results from respondents showed that roads (87%), bridges (85%), and both arable land and erosion structures were reported as highly affected by extreme weather events, especially flooding and frost. Gender, the type of farmer, access to climate information, and exposure to extreme weather significantly influenced perceived impact severity. The ordered probit regression model results reveal that drought (p = 0.05), floods (p = 0.1), strong winds (p = 0.05), and frost (p = 0.1) significantly influence the perceived impacts on infrastructure. Extreme weather events, including flooding (p = 0.012) and frost (p = 0.018), are critical drivers of infrastructure damage, particularly for smallholder farmers. Cumulative impacts—such as repeated infrastructure failure, access disruptions, and increased repair burdens—compound over time, further weakening resilience. The results underscore the urgent need for investments in flood-resilient roads and bridges, improved erosion control systems, and livestock water infrastructure. Support should also include gender-sensitive adaptation strategies, education on climate risk, and dedicated financial mechanisms for smallholder farmers. These findings contribute to global policy discourses on climate adaptation, aligning with SDGs 2 (Zero Hunger), 9 (Industry, Innovation, and Infrastructure), and 13 (Climate Action), and offer actionable insights for building infrastructure resilience in vulnerable rural contexts. Full article

Piezo-driven compliant actuators capable of out-of-plane displacement from the substrate are urgently required in the fields of micro/nano manipulations and active optics, where compact size and low-profile configurations are often critical. In this paper, a two-stage amplification mechanism is developed by orthogonal series connection of a bridge-type mechanism and a Scott-Russell mechanism, for the sake of a large amplification ratio and high stiffness. The low-profile configuration is realized by horizontally mounting the piezoelectric actuator within the planar bridge-type amplification mechanism. The bridge-type mechanism initially amplifies the output displacement of the piezoelectric actuator. A compound guiding mechanism at the output end significantly enhances the equivalent stiffness and constrains parasitic displacements of the bridge-type mechanism. The second-stage Scott–Russell mechanism, further amplifies and converts the in-plane displacement into out-of-plane motion. The kinematic and static model of the developed mechanism is established using the compliance matrix method, enabling precise prediction of the amplification ratio and input/equivalent stiffness. Finite element simulations and experimental tests on the prototype validate the modeling accuracy and mechanical performance of the proposed low-profile amplification mechanism, demonstrating a large amplification ratio of 15.70, a high resonant frequency of 312.50 Hz, and a load-bearing capacity up to 20 N. Full article

Eczema is a complex autoimmune condition characterised mainly by inflammation and skin lesions along with physical and psychological comorbidities. Although there have been significant advances in understanding the mechanisms behind atopic dermatitis, conventionally available treatments yield inconsistent results and have some unintended consequences. In today’s digital age, where knowledge is just a click away, natural-based supplements have been on the rise for a more “natural” treatment towards any type of disease. Natural compounds, particularly derived from medicinal plants, have piqued significant interest in the development of herbal remedies for chronic inflammatory skin conditions. Among many compounds, flavonoids have shown promise in treating eczema due to their strong anti-inflammatory, antioxidant, and anti-allergic properties, making them helpful in preventing allergic reactions, inflammation, and skin irritation. This review highlights the therapeutic potential of flavonoid-based bioactive compounds to manage eczema, emphasising the mechanisms of action. Additionally, providing a comprehensive analysis of the potential of emerging and established compounds, while bridging a gap between traditional and modern medicine. Flavonoids offer a variety of opportunities for further research and innovative formulations that can maximise its full benefits. Further combination of flavonoids with various approaches such as nanoencapsulation for enhanced bioavailability, hydrogel-based delivery systems for a controlled release, and additive manufacturing for personalised topical formulations, could align with future precision medicine needs. Full article

ROS (i.e., reactive oxygen species) scavenging is a key function of various Mn-based enzymes, including superoxide dismutases (SODs) and catalases, which are actively linked to oxidative stress-related diseases. In this study, we synthesized and characterized two novel Mn(III)-based synzymes (i.e., synthetic enzymes), designated C1 ([MnL1Cl(H₂O)]Cl·3H₂O) and C2 ([MnL2Cl₂]·2H₂O), which differ in the presence of a bridging aliphatic or aromatic group in the chelator. Using a range of analytical techniques, we found that the aromatic C2 bridge significantly influences the Mn(III) center’s cis-β configuration, unlike C1, which adopts a trans configuration. We then thoroughly evaluated the oxidation-reduction properties of C1 and C2, including their redox potentials (by cyclic voltammetry) and capacity to consume various ROS species (using DPPH, hydroxyl radical, hydrogen peroxide, and superoxide UV–visible spectrophotometric assays). The specific kinetics of the H₂O₂ dismutation process, as measured by a Clark-type electrode and time-resolved ESI-MS, revealed that both synzymes possess catalytic activity. Toxicological experiments using the Galleria mellonella larval model demonstrated the compounds’ innocuous nature towards higher eukaryotic organisms, while cytotoxicity assays confirmed their selective efficacy against lung cancer cells. Additional cytological assays, such as the thiobarbituric acid reactive substances assay and caspase-3 activity and p53 expression analysis, reported that C1 and C2 induce cytotoxicity against cancer cells via apoptosis rather than necrosis and behave very differently towards redox substances and ROS-regulating enzymes in vivo. These findings suggest that the structural differences between C1 and C2 lead to distinct redox properties and biological activities, highlighting the potential of these novel Mn(III)-based synzymes as therapeutic agents for the treatment of oxidative stress-related diseases, particularly lung cancer. Further studies are warranted to elucidate the underlying mechanisms of action and explore their clinical applications. Full article

Dissolved organic matter (DOM) is widely present in soil environments and plays a crucial role in controlling the morphology, environmental behavior, and hazards of arsenic (As) in soil. In the Fe-rich red soil of tea plantations, the decomposition of tea tree litter complicates DOM properties, leading to more uncertain interactions between DOM, Fe, and As. This study focused on three tea plantations in Huangshan City to investigate the contents of DOM, Fe, and As in surface red soils (Ferralsols) and establish their correlations. Three-dimensional fluorescence spectroscopy and PARAFAC analysis methods were used to analyze the DOM components and fluorescence signatures. Additionally, the process and mechanism of the binding of DOM-Fe with As were explored through laboratory experiments on the morphological transformation of As by DOM-Fe. The results showed that the pH values of the soils in the three tea plantations ranged from 3.9 to 5.2, and the entire sample was strongly acidic. The DOM exhibited strong intrinsic properties and low humification, containing three types of humic acid components and one intermediate protein component. The DOC content in the Fe-rich red soil did not have a direct correlation with Fe and As, but the interaction of DOM fractions with Fe significantly influenced the As content. Specifically, the interaction of protein-like fractions with Fe had a more pronounced effect on the As content. The maximum sorption rate of As by DOM was 15.45%, and this rate increased by 49 to 75% with the participation of Fe. In the configuration of the metal electron bridge, Fe acts as a cation, forming a connecting channel between the negatively charged DOM and As, thus enhancing the DOM’s binding capacity to As. DOM-Fe compounds bind As through surface pores and functional groups. These findings provide deeper insights into the influence of DOM on As behavior in Fe-rich soil environments and offer theoretical support for controlling As pollution in red soil. Full article