Search Results (477)

Multidrug resistance (MDR) is a central cause of chemotherapy failure and tumor recurrence and metastasis, and its mechanism involves enhanced drug efflux, target mutation, upregulation of DNA repair and remodeling of the tumor microenvironment. ABC transporter protein (P-gp, MRP, and BCRP)-mediated efflux of drugs is the most intensively researched aspect of the study, but the first three generations of small-molecule reversal agents were stopped in the clinic because of toxicity or pharmacokinetic defects. Natural products are considered as the fourth generation of MDR reversal agents due to their structural diversity, multi-targeting and low toxicity. In this paper, we systematically summarize the inhibitory activities of monoterpenes, sesquiterpenes, diterpenes and triterpenes against ABC transporter proteins in in vitro and in vivo models and focus on the new mechanism of reversing drug resistance by blocking efflux pumps, modulating signaling pathways such as PI3K-AKT, Nrf2, NF-κB and remodeling the tumor microenvironment. For example, Terpenoids possess irreplaceable core advantages over traditional multidrug resistance (MDR) reversers: Compared with the first three generations of synthetic reversers, natural/semisynthetic terpenoids integrate low toxicity (mostly derived from edible medicinal plants, half-maximal inhibitory concentration IC₅₀ > 50 μM), high target specificity (e.g., oleanolic acid specifically inhibits the ATP-binding cassette (ABC) transporter subtype ABCC1 without cross-reactivity with ABCB1), and multi-mechanistic synergistic effects (e.g., β-caryophyllene simultaneously mediates the dual effects of “ABCB1 efflux inhibition + apoptotic pathway activation”). These unique characteristics enable terpenoids to effectively circumvent key limitations of traditional synthetic reversers, such as high toxicity and severe drug–drug interactions. Among them, lupane-type derivative BBA and euphane-type sooneuphanone D (triterpenoids), as well as dihydro-β-agarofuran-type compounds and sesquiterpene lactone Conferone (sesquiterpenoids), have emerged as the core lead compounds with the greatest translational potential in current MDR reverser research, attributed to their potent in vitro and in vivo MDR reversal activity, low toxicity, and excellent druggable modifiability. At the same time, we point out bottlenecks, such as low bioavailability, insufficient in vivo evidence, and unclear structure–activity relationship and put forward a proposal to address these bottlenecks. At the same time, the bottlenecks of low bioavailability, insufficient vivo evidence and unclear structure–activity relationship have been pointed out, and future research directions such as nano-delivery, structural optimization and combination strategies have been proposed to provide theoretical foundations and potential practical pathways for the clinical translation research of terpenoid compounds, whose clinical application still requires further in vivo validation and translational research support. Full article

Type 2 diabetes mellitus (T2DM) involves chronic hyperglycemia, insulin resistance, low-grade inflammation, and oxidative stress that drive cardiometabolic and renal damage despite current therapies. Sodium–glucose cotransporter (SGLT) inhibitors have reshaped the treatment landscape, but residual risk and safety concerns highlight the need for new agents that combine glucose-lowering efficacy with redox–inflammatory modulation. LASSBio-1986 is a synthetic N-acylhydrazone (NAH) derivative designed as a gliflozin-like scaffold with the potential to interact with SGLT1/2 while also influencing oxidative and inflammatory pathways. Here, we integrated in silico and in vivo approaches to characterize LASSBio-1986 as a multifunctional antidiabetic lead in murine models of glucose dysregulation. PASS and target class prediction suggested a broad activity spectrum and highlighted transporter- and stress-related pathways. Molecular docking indicated high-affinity binding to both SGLT1 and SGLT2, with a modest energetic preference for SGLT2, and ADME/Tox predictions supported favorable oral drug-likeness. In vivo, intraperitoneal LASSBio-1986 improved oral glucose tolerance and reduced glycemic excursions in an acute glucose challenge model in C57BL/6 mice, while enhancing hepatic and skeletal muscle glycogen stores. In a dexamethasone-induced insulin-resistance model, LASSBio-1986 improved insulin sensitivity, favorably modulated serum lipids, attenuated thiobarbituric acid-reactive substances (TBARS), restored reduced glutathione (GSH) levels, and rebalanced pro- and anti-inflammatory cytokines in metabolic tissues, with efficacy broadly comparable to dapagliflozin. These convergent findings support LASSBio-1986 as a preclinical, multimodal lead that targets SGLT-dependent glucose handling while mitigating oxidative and inflammatory stress in models relevant to T2DM. Chronic disease models, formal toxicology, and pharmacokinetic studies, particularly with oral dosing, will be essential to define its translational potential. Full article

Heat threatens male fertility in crops, yet the regulatory basis of anther dehiscence under high temperatures remains unclear. We compared a heat-sensitive pepper cultivar (DL) with a heat-tolerant landrace (B021) across two anther stages using integrated transcriptome, small-RNA, degradome, co-expression, and enzymatic assays. DL showed a collapse of anther dehiscence above 34–38 °C, whereas B021 retained normal dehiscence at 39 °C, and histology revealed tapetal enlargement, premature degeneration, and locule contraction only in DL. RNA-seq indicated genotype- and stage-dependent reprogramming, with DL suppressing phenylpropanoid/cell-wall, transport, and proteostasis pathways, while B021 maintained reproductive and stress-integration programs. Small-RNA profiling and degradome sequencing identified conserved miRNA families with in vivo target cleavage, and notably, miR397 targeting a laccase gene showed stronger evidence in B021, which is consistent with controlled lignification. Functional organization of differentially expressed miRNA targets highlighted modules in respiration/redox, hormone and terpenoid metabolism, vascular–cell-wall programs, and proteostasis/osmotic buffering. WGCNA modules correlated with heat-tolerance traits converged on the same processes. Enzyme assays corroborated multi-omics predictions, with SOD, CAT, and POD activities consistently induced in B021 and limited MDA accumulation. Together, the data supports a model in which tolerant anthers sustain dehiscence under heat by coordinating secondary-wall formation, auxin/jasmonate/gibberellin crosstalk, respiratory and reactive oxygen species buffering, and protein/membrane quality control, providing tractable targets for breeding heat-resilient peppers. Full article

Time delays are intrinsic to mitotic regulation, particularly within the spindle assembly checkpoint (SAC) and the spindle position checkpoint (SPOC). These delays emerge from multi-step protein activation, molecular transport, force-dependent conformational transitions, and spatial redistribution of regulatory complexes. They span seconds to minutes and strongly influence checkpoint activation, maintenance, and silencing. Increasing evidence shows that such delayed processes shape mitotic timing, checkpoint robustness, and cell-fate decisions. While classical ordinary differential equation (ODE) models assume instantaneous biochemical responses, delay differential equations (DDEs) provide a natural framework for representing these finite timescales by explicitly incorporating system history. Recent DDE-based studies have revealed how delayed signaling contributes to bistability, oscillatory responses, prolonged mitotic arrest, and variability in checkpoint outputs. This review summarizes the biological origins of delays in SAC and SPOC, including Mad2 activation, MCC assembly and turnover, APC/C reactivation, tension maturation at kinetochores, and Bfa1–Bub2 regulation of Tem1. The article further discusses how mechanistic models with explicit delays improve our understanding of SAC–SPOC ordering, error-correction dynamics, and mitotic exit control. Finally, open challenges and future directions are outlined for integrative delay-aware modeling that unifies biochemical, mechanical, and spatial processes to better explain checkpoint function and chromosomal stability. Full article

Per- and polyfluoroalkyl substances (PFAS) are emerging contaminants that persist in soil environments, necessitating reliable models to predict their fate and transport. This study evaluates the performance of three theoretical models in estimating the maximum adsorption capacity (Qmax) of perfluorooctanoic acid (PFOA) on kaolinite and montmorillonite clay minerals. The models assessed include a van der Waals interaction-based approach, a monolayer adsorption capacity model, and a surface site density model emphasizing reactive hydroxyl groups at mineral edges. Benzene, nitrogen, and glyphosate molecules were used as reference compounds for model validation. Results indicated that the van der Waals model significantly underestimated Qmax (0.0007 mg·g⁻¹ for kaolinite), while the monolayer capacity model produced substantial overestimations (17.51 mg·g⁻¹) compared to the experimental range (0.10–10.0 mg·g⁻¹). The surface site density model provided the most accurate predictions (3.39 mg·g⁻¹ for kaolinite), although it slightly underestimated values for montmorillonite (0.20 mg·g⁻¹) by excluding interlayer adsorption. These discrepancies demonstrate that simplified models cannot adequately capture the complex adsorption behavior of PFAS. Accurate prediction requires site-specific approaches incorporating electrostatic forces, hydrogen bonding, and steric effects. As PFAS accumulation in soil directly contributes to groundwater contamination, improving adsorption models is essential for accurate risk assessment and the development of effective remediation strategies. Full article

The study underpins the geothermal energy potential of Cambrian reservoirs in Lithuania, which utilizes the use of reactive transport modelling to examine how different reinjection temperatures and flow rates affect mineral changes. The results are then applied to design field development plans, using petroleum engineering methods such as horizontal wells and induced fracturing. The research study indicates that there are some changes in porosity and permeability over time due to mineral dissolution and precipitation because of injection rates, but no adverse effect of re-injection temperature was observed. Hence, a reinjection temperature of 40 °C is geochemically stable and suitable for long-term operation, with no significant effect on mineral behavior. Moreover, application of horizontal wells proves that there is a significant increase in water production and power (thermal) output due to improved reservoir exposure. Hydraulic fracturing further enhanced the performance and flow rates, concluding that, among all the sites studied, Nausodis demonstrated the highest thermal output, while Genciai showed the lowest potential due to limited reservoir temperature and productivity. Thus, research aims to improve power output by studying how well design, reinjection methods, and chemical reactions affect the reservoir, and it shows that using horizontal wells, fracturing, and proper reinjection temperature can help increase geothermal energy recovery in Lithuania. Full article

Building on our previous study on batch pervaporation membrane reactors for isoamyl acetate synthesis, this work evaluates a two-step continuous process integrating a slurry reactor and a commercial pervaporator module based on a hybrid silica membrane. The system combines catalytic esterification of acetic acid with isoamyl alcohol with simultaneous water removal to enhance conversion and product selectivity. Operating conditions were defined using experimentally validated thermodynamic, kinetic, and mass-transport models. A hydrodynamic assessment confirmed turbulent flow within the membrane module, and model predictions were compared with experimental data for validation. The results confirmed the occurrence of reactive pervaporation and demonstrated that both the membrane area-to-reactor volume ratio and catalyst loading significantly influence the equilibrium shift. Although conversion remained limited by the available membrane area, the commercial pervaporation unit exhibited stable operation, consistent flux behavior, and effective water selectivity. These findings demonstrate the technical feasibility of the continuous slurry reactor–pervaporator configuration and establish a framework for further optimization and scale-up of isoamyl acetate production via reactive pervaporation. Full article

Metabolic reprogramming is a fundamental hallmark and a key driver of malignant tumors. By reshaping glucose, lipid, and amino acid metabolism, as well as mitochondrial function, it sustains the abnormal proliferation and survival of tumor cells, making it a crucial target for anti-tumor therapy. Curcumin, a natural multi-target compound, exhibits unique advantages in intervening in tumor metabolic reprogramming due to its low toxicity and broad-spectrum regulatory properties. In various tumor models, it can directly modulate the activity of key glycolytic enzymes, such as hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2, as well as transporters like glucose transporter 1. Furthermore, it inhibits the expression of proteins related to lipid metabolism, including fatty acid synthase and stearoyl-CoA desaturase 1, while also intervening in amino acid metabolic networks, such as glutaminase and branched-chain amino acid transaminase. Additionally, curcumin targets mitochondrial function and reactive oxygen species balance, creating multi-dimensional intervention effects through various pathways, including the induction of ferroptosis by regulating the SLC7A11/GPX4 axis and modulating gut microbiota metabolism. Its mechanism of action involves the synergistic regulation of key signaling pathways, including phosphoinositide 3-kinase/Akt, NF-κB, AMP-activated protein kinase, and hypoxia-inducible factor-1alpha. Furthermore, its specific effect profile demonstrates significant dependency on cell type and tumor model. This article systematically reviews the regulatory effects of curcumin on these critical metabolic processes and pathways in tumor metabolic reprogramming, revealing its molecular mechanisms in disrupting tumor growth and progression by targeting energy and biosynthetic metabolism. These findings provide a significant theoretical foundation and a preclinical research perspective for the development of natural antitumor drugs based on metabolic regulation, as well as for optimizing combination therapy strategies. Full article

Background: The reintroduction of colistin has led to the rapid emergence of colistin-resistant strains, significantly diminishing its therapeutic efficacy. This presents a need for effective adjuvants to restore colistin efficacy. Approach: We screened the colistin adjuvants through a high-throughput method and then evaluated their synergistic effects and underlying mechanisms. Results: We identified β,β-dimethylacrylalkannin (β,β-Dim), a naphthoquinone compound derived from Lithospermum erythrorhizon, as a potent colistin adjuvant (fractional inhibitory concentration index (FICI) < 0.5). β,β-Dim enhanced colistin activity against 4 of 6 susceptible strains and all 18 colistin-resistant strains carrying either plasmid-borne mcr genes (mcr-1, mcr-3, mcr-8, and mcr-9) or chromosomal two-component system (TCS) mutations (pmrA/B, phoP, and mgrB). These strains included Klebsiella pneumoniae, Escherichia coli, Salmonella Typhimurium, Pseudomonas aeruginosa, and Acinetobacter baumannii. The combination reduced the minimum inhibitory concentrations (MICs) of colistin by 4–1024-fold (from 512 to ≤2 µg/mL). Mechanistically, colistin-mediated outer membrane permeabilization facilitates β,β-Dim entry. Once internalized, β,β-Dim interacts with cytoplasmic membrane phospholipids and disrupts membrane biofunction. Further analysis showed that LPS transport and efflux pump activity were impaired, leading to LPS accumulation in the cytoplasmic membrane and increased intracellular colistin content. These processes elevated reactive oxygen species (ROS) production and markedly reduced ATP levels. In a murine infection model, β,β-Dim (2 mg/kg) combined with colistin (0.2 mg/kg) markedly increased survival from 20% (colistin alone) to 80%. Conclusions: These findings highlight that β,β-Dim combined with colistin is a promising therapeutic strategy for infections caused by colistin-resistant pathogens. Full article

Advection–diffusion–reaction-type interface models have wide-ranging applications in environmental science, chemical engineering, and biological systems, particularly in modeling pollutant transport in groundwater, reactive flows, and drug diffusion across biological membranes. This paper presents a novel numerical method for the solution of these models. The proposed method integrates the meshless collocation technique with the finite difference method. The temporal derivative is approximated using a finite difference scheme, while spatial derivatives are approximated using radial basis functions. The interface across the fixed boundary is treated with discontinuous diffusion, advection, and reaction coefficients. The proposed numerical scheme is applied to both linear and non-linear models. The Gauss elimination method is used for the linear models, while the quasi-Newton linearization method is employed to address the non-linearity in non-linear cases. The $L_{\infty }$ error is computed for varying numbers of collocation points to assess the method’s accuracy. Furthermore, the performance of the method is compared with the Haar wavelet collocation method and the immersed interface method. Numerical results demonstrate that the proposed approach is more efficient, accurate, and easier to implement than existing methods. The technique is implemented in MATLAB R2024b software. Full article

Compressed air energy storage in aquifers presents a promising approach for large-scale energy storage, yet its implementation is complicated by geochemical reactions, such as pyrite oxidation, which can impact reservoir integrity and operational efficiency. This study numerically investigates the evolution of reservoir characteristics and geochemical processes during CAESA operations to address these challenges. Using the TOUGHREACT simulator, we developed one-dimensional and two-dimensional reactive transport models based on the Pittsfield aquifer field test parameters to simulate coupled thermal-hydrological–chemical processes under varying injection rates, temperatures, reservoir depths, and operational cycles. The results demonstrate that higher injection rates induce greater near-well pressure buildup and extended thermal zones, while deeper reservoirs exhibit abrupt declines in pressure and gas saturation due to formation constraints. Geochemical analyses reveal that pyrite oxidation dominates, leading to oxygen depletion, groundwater acidification (pH reduction), and secondary mineral precipitation, such as goethite and hematite. These findings underscore the critical interplay between operational parameters and geochemical reactions, highlighting the need for optimized design to ensure long-term stability and efficiency of aquifer-based energy storage systems. Full article

The study evaluates the long-term environmental performance of natural filtration dams for leachate treatment at a municipal solid waste landfill. Field measurements of a system operating for 24 years, equipped with natural clay-loam filtration barriers, provide empirical validation for assessing the effectiveness and durability of natural material-based treatment approaches. Hydrogeological studies, including well drilling, water sampling, and comprehensive chemical analysis, demonstrate that the cascade filtration system achieves pollutant removal efficiencies of 80–95% for major contaminants. Physical property measurements reveal progressive density reduction from 1005 to 994 kg/m³ and viscosity decreases from 1.048 to 1.011 cSt across the treatment system. Numerical simulations demonstrate that contaminant transport under actual site conditions remains diffusion-dominated over multi-decadal timescales, with aquifer concentrations remaining below 1% of source values after 50 years. Parametric studies reveal that density-driven convective fingering develops only at source concentrations exceeding 100 g/L. The findings validate the long-term viability of natural geological barriers combined with cascade filtration systems for cost-effective leachate treatment, demonstrating that preliminary treatment through natural filtration effectively suppresses gravitational instabilities and protects underlying aquifers. Full article

Anemia, characterized by reduced hemoglobin (Hb), remains a major health concern. Although iron and erythropoietin (EPO) therapies are effective, limitations in safety and accessibility have prompted interest in nutritional alternatives. Hydrolyzed milk-derived peptides (H-MDPs) contain bioactive sequences with diverse physiological effects, yet their role in erythropoiesis remains poorly defined. This study investigated the hematopoietic actions of H-MDP using zebrafish and mouse models. Adult zebrafish underwent phlebotomy-induced anemia and received oral H-MDP for 3 weeks. Hb levels, erythrocyte morphology, and expression of erythropoiesis- and iron-metabolism genes were assessed. In healthy mice, renal Epo expression, circulating EPO, and serum cytokines were measured after 2 weeks of H-MDP administration. H-MDP significantly accelerated Hb recovery in anemic zebrafish (4.6 ± 0.64 g/dL vs. 3.4 ± 0.66 g/dL in untreated fish at week 1) and markedly improved erythrocyte maturation. These effects coincided with strong induction of epo, hif1aa/b, igf1, csf1a, and csf3b in the heart and liver, as well as normalization of anemia-induced hepatic iron-transport genes (tfa, fpn1, tfr2) and reactivation of hamp. In mice, H-MDP elevated renal Epo mRNA and circulating EPO (approximately 2.3-fold) without altering steady-state Hb, and cytokine profiling with IPA-predicted activation of the erythropoietin signaling pathway. Collectively, these findings indicate that H-MDPs modulate erythropoiesis by coordinating the activation of EPO-related and iron-regulatory networks, supporting their potential as functional food ingredients for hematologic recovery and anemia management. Full article

Arsenic (As) in groundwater often fluctuates around the 10 µg/L health-based guideline, complicating compliance assessment and risk-based management. This study investigates the short-term temporal behavior of As and its implications for compliance at three supply wells in the Caplina aquifer (La Yarada Los Palos, Tacna, Peru), based on a one-year fortnightly time series. At each visit, in situ electrical conductivity (EC), total dissolved solids (TDS), pH, and temperature were measured, and total As was determined by inductively coupled plasma–mass spectrometry (ICP–MS). The dataset was evaluated using robust descriptive statistics, exceedance proportions with Wilson 95% confidence intervals, Spearman rank correlations, simple time-series diagnostics, and comparisons of deterministic monthly schemes against the fortnightly reference. Exceedances were widespread—100% at Point 1 and 91.7% at Points 2 and 3—yielding 94.4% at the network scale, with no consistent seasonal signal. Relative variability was low yet operationally decisive (coefficient of variation (CV) ≈ 7–10%; interquartile range ≈ 1.3–1.6 µg/L), and typical fortnightly oscillations of ~0.5–1.5 µg/L were sufficient to flip compliance labels under monthly sampling. Point-wise associations were generally weak, except for a moderate As–TDS correlation at Point 1, supporting an interpretation dominated by geogenic As under arid, alkaline, and saline conditions, modulated by redox processes, anion competition, and mixing/pumping dynamics. The findings support risk-based monitoring with a fortnightly baseline and adaptive escalation when predefined activation criteria and action thresholds are met, using EC/TDS, pH, and simple redox indicators as operational early warnings. To reduce exposure in such settings, priority should be given to source management, pre-oxidation of As(III) to As(V), and adsorption onto iron media (or membranes where appropriate), while future work should integrate high-frequency sensing, in situ or inline speciation, reactive-transport modeling, and locally trained risk mapping to strengthen contributions to Sustainable Development Goals 3 (Good Health and Well-Being) and 6 (Clean Water and Sanitation). Full article

The transition to sustainable aviation fuel (SAF) is critical for reducing the carbon footprint of the aviation sector while ensuring compatibility with current engines and infrastructure. Regulatory constraints, such as ASTM D7566, currently limit SAF blending to 50% in commercial flights, emphasizing the need for accurate evaluation of SAF properties to enable broader adoption. This review presents an updated overview of fuel studies evaluating key thermophysical and transport properties of hydrocarbon-based SAFs—including density, viscosity, specific energy, flash point, and thermal stability—with particular emphasis on molecular dynamics (MD) simulations. Among the MD simulations, the OPLS-AA force field demonstrates high accuracy in modeling liquid-phase hydrocarbons and shows strong agreement with experimental data. Coupled with MD engines like LAMMPS and GROMACS, it enables scalable and efficient simulations of SAF blends. Emerging research trends highlight integrative approaches that combine classical MD and machine learning (ML) in fuel property prediction, and force-field optimization to improve predictive capability. Future research in fuel is moving toward multi-force-field coupling using reactive frameworks such as ReaxFF for studying pyrolysis and oxidation, and data-driven experiments with in situ simulation feedback loops to accelerate SAF design and facilitate wider implementation in aviation. Full article