Search Results (458)

Zinc deficiency is increasingly recognized as a risk factor for neurodegenerative diseases, yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the impact of intracellular zinc depletion on oxidative stress and inflammasome activation in microglial (SIM-A9) and neuronal (SH-SY5Y) cell models, and evaluated the protective effects of polyphenolic compounds. Intracellular zinc chelation with the membrane-permeable chelator TPEN markedly increased reactive oxygen species (ROS) production, reduced cell viability, and upregulated the mRNA expression of NLRP3 inflammasome-related genes and pro-inflammatory cytokines. In contrast, extracellular zinc chelation had no effect, highlighting the critical role of intracellular zinc homeostasis in maintaining redox balance. Zinc supplementation significantly attenuated these responses. Among 32 polyphenols screened by DPPH radical scavenging assay, caffeic acid derivatives—chicoric acid (ChA), rosmarinic acid (RA), and caffeic acid phenethyl ester (CAPE)—exhibited the most potent antioxidant activity, surpassing that of edaravone. These compounds suppressed ROS production and differentially protected against zinc deficiency-induced cellular damage. ChA showed the strongest ROS inhibitory activity (IC50: 1.9 µM in SIM-A9), RA provided robust cytoprotection even at low concentrations, and CAPE most effectively suppressed inflammasome-related gene expression and inhibited aggregation of both Aβ1–42 and the highly neurotoxic pyroglutamate-modified variant pEAβ3–42. These findings demonstrate that intracellular zinc deficiency drives ROS-dependent upregulation of NLRP3 inflammasome-related genes, and suggest that caffeic acid derivative polyphenols may serve as complementary agents for mitigating neuroinflammatory and amyloidogenic processes relevant to Alzheimer’s disease. Full article

Background/Objectives: This review describes the advantages of new photonic-based approaches for assessing the activity of caries lesions. Many lesions have been arrested or are non-carious developmental defects, such as fluorosis, which do not require intervention. New methods are needed to assess lesion activity and avoid unnecessary removal of the tooth structure. Methods: At present, there are no reliable methods for assessing lesion activity in vivo. Nondestructive optical monitoring of lesion structure and the changes in light scattering that occur during drying offer the potential for lesion activity assessment during a single examination. Since optical diagnostic instruments exploit changes in the porosity and the permeability of the lesion, they have the potential to assess whether lesions are active and expanding or arrested and undergoing remineralization. Optical coherence tomography (OCT), Raman imaging and fluorescence loss, thermal and short-wavelength infrared (SWIR) reflectance measurements during lesion dehydration with forced air are presented. Results: Clinical studies have shown that optical coherence tomography is capable of showing distinct structural differences between active and arrested lesions on coronal and root surfaces. Differences in the kinetics of dehydration measured using reflectance measurements at SWIR wavelengths coincident with water absorption bands also show great potential. Conclusions: OCT and dehydration imaging at SWIR wavelengths have great potential for assessing lesion activity since they can also be used for caries screening, are safe for frequent monitoring and do not require the application of external agents. Full article

This review examines the emerging role of machine learning (ML) in pharmaceutical chemistry, with emphasis on molecular design, synthetic feasibility, and structure–property–performance (SPP) relationships. By enabling pre-synthesis prediction of physicochemical properties, reaction pathways, and pharmaceutical performance, ML can reduce empirical trial-and-error experimentation and support more efficient exploration of chemical space. A structured narrative review design with PRISMA-aligned systematic search elements was used to evaluate 101 studies, enabling transparent literature identification, eligibility screening, and thematic synthesis across heterogeneous ML applications in pharmaceutical chemistry. This review examines structure–property relationships (SPRs) and property–performance relationships (PPRs), with emphasis on key pharmaceutical endpoints such as solubility, permeability, stability, dissolution, and bioavailability. An integrated SPP framework is proposed to connect molecular structure, intermediate properties, and final performance outcomes while incorporating retrosynthetic analysis and experimental feedback and closed-loop optimization. Recent frontier developments are also discussed, including molecular foundation models, multimodal language–graph models, diffusion-based molecular generation, E(3)-equivariant models, and MolMIM-like latent-space optimization. This review also covers co-folding and joint ligand–protein modeling, Boltz-2-like affinity prediction, AlphaFold 3-related biomolecular interaction modeling, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction. Key limitations include dataset leakage, benchmark inconsistency, assay variability, conformational and protonation-state effects, reproducibility challenges, regulatory constraints, and the gap between computational prediction and prospective experimental validation. Future progress is expected to depend on hybrid physics–ML models, uncertainty-aware prospective validation, autonomous experimentation, explainable artificial intelligence, and sustainability-aware molecular design. Overall, ML is evolving from a predictive tool into a chemically informed decision-support framework for rational, synthesis-aware, and experimentally validated pharmaceutical development. Full article

Increasing pressure on surface water resources in intensive agricultural regions has driven the search for sustainable alternatives for irrigation supply, especially in areas where water quality limits crop safety and export opportunities. In this context, riverbank filtration (RBF) systems offer a nature-based solution by utilizing physical, chemical, and biological processes associated with river–aquifer exchange. However, their implementation depends on suitable site selection supported by hydrogeological, geomorphological, and hydraulic criteria. This study developed an integrated methodology to identify zones with potential for implementing RBF systems in the Roldanillo–Unión–Toro irrigation district, located in northern Valle del Cauca, Colombia. This region requires irrigation water over 10,256 ha of agricultural land (mainly sugarcane, maize, grapes, and guava). We combined geophysical methods (vertical electrical soundings, 2D electrical resistivity tomography, and passive seismic), geotechnical methods (CPTu tests), and hydraulic characterization of the river reach to evaluate subsurface stratigraphy, preliminary hydrogeological suitability, inferred river–aquifer connectivity conditions, and channel stability. The evaluation covered four sectors along an approximately 21 km stretch of the Cauca River’s left-bank alluvial valley. The results revealed pronounced lateral and vertical heterogeneity of alluvial materials. However, the “El Palmar” sector was identified as the best-supported priority sector for future RBF validation, due to the presence of profile-scale evidence of potentially permeable sandy and gravelly units with intermediate resistivity values (52–61 Ω·m), favorable stratigraphic organization, and stable river-reach conditions during the field campaign. In contrast, the other three sectors (La Esperanza, Candelaria, and Cayetana) showed more fine-grained sediments with deeper permeable strata. River-flow measurements during the July 2025 field campaign indicated high discharge conditions at the evaluated reach, while river-channel observations showed active fine-sediment transport; these findings provide hydraulic and sedimentary context for the future evaluation of induced infiltration and potential clogging, but do not constitute direct evidence of river–aquifer exchange. This study highlights the value of integrated screening approaches for prioritizing candidate RBF sites in agricultural alluvial settings, while indicating that pumping tests, piezometric monitoring, hydraulic-gradient analysis, and water-quality validation remain necessary before engineering implementation. Full article

Volcanic gas and isotope time series are indirect observables of coupled magmatic and hydrothermal dynamics. We formulate a reduced integer–fractional model in which ordinary differential equations describe deep recharge, pressure, gas-phase volatile inventory, and source mixing, whereas Caputo equations describe shallow hydrothermal pressure, thermal excess, gas pathway effectiveness, permeability, and scrubbing. Under explicit local regularity and admissibility assumptions, the mixed-order Volterra problem is locally well-posed and the physically admissible state set is positively invariant. We derive componentwise dissipative estimates and state conditions for global continuation under bounded trajectories and analyze finite-interval consistency with the integer-order limit and local stability of a frozen commensurate hydrothermal linearization. Conservative observation equations link hidden states to gas ratios, fluxes, and isotope ratios. The inverse problem is treated diagnostically; global identifiability is not claimed. Local sensitivity screening, Fisher information concepts, and scalar recovery tests are used only as preliminary local diagnostics of information content under known or misspecified forcing. Synthetic demonstrations and a reference forward solver illustrate how hydrothermal memory and sulfur scrubbing can reshape carbon dioxide/sulfur dioxide (CO₂/SO₂) anomalies before site-specific calibration. Full article

This work evaluated the effect of enriched gas flood maturity and mobile water on transient foam behavior and oil recovery under high-pressure (2000 psi), moderate-temperature (38 °C) and salinity (20,000 ppm NaCl) conditions in high-permeability Bentheimer sandstone. A synthetic gas mixture containing relatively high contents of CO₂ (20%) and propane (26%) was used to simulate the enriched field gas. Screening of foaming surfactants including alpha olefin sulfonates and a betaine for good foamability and stability as well as low adsorption on the sandstone indicates that the alpha olefin sulfonate with a longer chain length was the best candidate for foaming the enriched gas in the presence of oil. Core flooding experiments conducted with this surfactant showed a strong impact of gas flood maturity and injection foam quality on both the transient foam behavior and oil displacement efficiency. Foam injection at residual oil saturation (about 14%) to a gas–brine flood exhibited robust foam propagation. The presence of mobile oil before foam injection due to the immaturity of the gas–brine flood (e.g., oil saturations above 50%) posed a detrimental effect on the rate of foam viscosity buildup. However, water injection during the pre-foam flood strongly supported foam generation even at relatively high oil saturations. A further evaluation of water contribution to enhancing foam propagation by adjusting foam quality showed that the water injection strategy before and during foam flooding should be optimized to improve both transient foam behavior and gas–oil contact for enhanced oil sweep efficiency. Full article

Natural gas hydrate is an important emerging strategic resource, but low permeability makes the horizontal well length a key factor limiting productivity. A prediction model for friction torque of deepwater riserless drilling strings was established, and the segmented friction coefficient of hydrate horizontal wells was inverted and applied to the Shenhu hydrate reservoir. The results show that the main limiting factor for the extreme extension length of natural gas hydrate horizontal wells is the mechanical extreme extension length. The main affecting factor of the mechanical extreme extension length is the running limit of the screen pipe. The friction coefficient is the most significant factor affecting the mechanical extreme extension of horizontal wells, with the friction coefficient inside the casing in the high-build-rate section being the largest. The research identifies the primary factors governing the limit extension during horizontal well construction. The findings provide theoretical guidance for reservoir selection, well site determination, and wellbore configuration optimization in hydrate development. Ultimately, this contributes to maximizing single-well productivity and advancing the commercialization of hydrate resources. Full article

Background and Objectives: This study aims to evaluate the recent literature on the oral–gut connection in the context of periodontal disease, emphasizing the significance of systemic risk associated with chronic inflammation. This review explores whether chronic inflammation resulting from periodontal disease can induce systemic conditions through alterations in the gut microbiome and whether periodontal treatment may contribute to overall health improvement. Materials and Methods: A systematic database search was performed using pre-established search strategies. Searches were conducted in three databases between 1 and 20 October 2025. A total of 578 articles were screened for eligibility based on inclusion and exclusion criteria. Two authors agreed on the selection process used. The methodological quality of the included studies was assessed using the Newcastle–Ottawa scale and the Risk of Bias 2 Tool. Results: Eleven studies were considered eligible for inclusion in the review. The gut microbiome is similar to the oral microbiome in patients with periodontitis. Gut microbial shifts may drive systemic inflammation and metabolic dysfunction. Tooth loss and gum disease are linked to alterations in the gut bacteria, potentially compromising the intestinal barrier permeability. In contrast, the presence of natural teeth may prevent oral–gut bacterial transmission. Changes in the gut microbiota are correlated with improvements in periodontal status after non-surgical periodontal therapy. Conclusions: The evidence presented in this review supports an association between periodontitis, oral–gut microbial alterations, and systemic inflammatory conditions. However, most available studies are observational, limiting causal inference. Targeted modulation of the gut microbiome may represent a promising area for future research, but its clinical applicability remains inconclusive. Full article

Nogo (RTN4) proteins and their receptors have emerged as candidate mediators of metabolic regulation and vascular pathology relevant to type 2 diabetes (T2D). The primary objective of this PRISMA-guided systematic review was to evaluate the clinical and cohort evidence for RTN4/RTN4R as potential biomarkers of T2D progression and vascular complications. A secondary objective was to synthesize preclinical mechanistic evidence on the effects of Nogo axis modulation on pathways relevant to the pathogenesis of T2D. We performed a PRISMA-guided systematic review. The protocol was not prospectively registered in PROSPERO. To ensure reproducibility, we provide complete search keywords, the screening log and the full-text exclusion table. PubMed/MEDLINE, EMBASE and Web of Science were searched for studies published 2000–2025; full search keywords are provided in the main text. The search strategy combined and free-text terms with Boolean operators. We included original preclinical and clinical studies, cohort/proteomic analyses, meta-analyses, and mechanistic papers reporting expression, function, signaling, or clinical associations of Nogo proteins/receptors in metabolic or vascular outcomes. Exclusion criteria: non-English articles, unclear methods, studies outside 2000–2025, and studies lacking primary data. Two reviewers independently screened records; conflicts were resolved by consensus. Study quality was appraised using established tools (SYRCLE for animal studies, Newcastle–Ottawa Scale for cohort/case-control studies). Preclinical evidence supports tissue-specific roles for RTN4 isoforms and receptors in the regulation of insulin secretion, proGCG → GLP-1 processing, ER homeostasis, and vascular permeability through the Src/PI3K/Akt and RhoA/ROCK axes. Cohort and proteomic analyses report associations between RTN4/RTN4R or serum NogoB and faster progression of T2D or vascular complications, but genetic assessment of causality (Mendelian randomization) has so far provided limited support in available data sets. Findings are heterogeneous with respect to directionality and tissue localization. RTN4 signaling exhibits tissue-specific mechanisms relevant to glucose regulation and vascular biology and warrants further translational study. However, heterogeneity across studies and limited genetic support for causality indicate that isoform-specific quantitative validation, longitudinal cohorts and integrated genetic–functional analyses are required before RTN4/RTN4R can be considered as clinical biomarkers. Full article

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a highly prevalent multisystem disorder and is strongly associated with increased cardiovascular risk. Cardiovascular diseases represent the leading cause of mortality in this population. As the hepatic manifestation of systemic metabolic dysfunction, MASLD is initiated by excess lipid accumulation driven by increased dietary fatty acid intake and accelerated de novo lipogenesis. This triglyceride overload induces lipotoxicity, triggering hepatocellular injury, immune activation, and mitochondrial dysfunction. Excessive mitochondrial reactive oxygen species (ROS) generation acts as a critical second hit, promoting inflammatory cytokine production and disease progression. Beyond lipid dysregulation, impaired hepatic insulin signaling leads to hyperglycemia and compensatory hyperinsulinemia, further stimulating lipogenesis and reinforcing a self-perpetuating metabolic cycle. Persistent ROS production overwhelms antioxidant defenses and depletes hepatic glutathione (GSH), resulting in systemic redox imbalance. These disturbances extend beyond the liver, contributing to atherogenic dyslipidemia and chronic inflammation. In parallel, gut dysbiosis and increased intestinal permeability amplify immune activation. Reduced circulating GSH further weakens systemic antioxidant capacity; oxidative stress may represent a central mechanistic link between MASLD and CVD. In concert with metabolic and inflammatory mediators, ROS disrupt pathways governing vascular and myocardial homeostasis, leading to coronary atherosclerosis, microvascular dysfunction, left ventricular remodeling, hypertrophy, and impaired relaxation. Clinically, this translates into an increased burden of coronary artery disease and heart failure, particularly heart failure with preserved ejection fraction. Given this integrated pathophysiology, early identification of subclinical cardiovascular involvement is essential. We highlight emerging biomarkers, advocate for multidisciplinary screening strategies, and discuss integrated pharmacological approaches targeting shared metabolic pathways. Recognizing MASLD as a cardiovascular risk amplifier is critical for improving risk stratification and enabling the development of effective, co-targeted therapeutic strategies. Full article

A critical challenge in coalbed methane (CBM) extraction is the severe formation damage induced by conventional foam fracturing fluids, primarily through polymer retention and hydrogen bond disruption within the microporous matrix. This study presents a molecularly engineered, low-damage foam fracturing fluid that leverages synergistic nanoparticle–surfactant interactions to construct a robust interfacial pseudo-gel network, thereby decoupling effective fracture stimulation from adverse geochemical damage. The primary novelties of this work are threefold: (i) establishing a direct, quantitative cause-and-effect relationship between molecular interfacial architecture and reservoir protection, (ii) proposing a comprehensive “interfacial control” design paradigm that engineers viscoelasticity at the gas–liquid interface rather than through bulk polymer gelation, and (iii) demonstrating the complete decoupling of foam stability from formation damage in a polymer-free system. A systematic optimization methodology was employed: initial foaming agents were screened via the Waring Blender method, evaluating foam volume, half-life, and a derived comprehensive index; subsequently, synergistic binary surfactant mixtures and foam stabilizers were assessed to formulate the final systems. An optimized formulation, designated Foam System I (0.5 wt.% fluorosurfactant FK + 0.5 wt.% nano-silica RX + 2.0 wt.% KCl), demonstrated exceptional foam quality (Γ = 77.1 ± 1.5%) and kinetic stability (T₁/₂ > 350 s). Rheological characterization confirmed shear-thinning behavior conforming to the Herschel–Bulkley model (n = 0.38–0.42, R² > 0.98) and a structural recovery of 92.5 ± 2.1%—comparable to crosslinked polymer gels but achieved without any bulk viscosifier. Core flood analyses revealed that Foam System I induced a permeability damage of only 12.75 ± 1.8%, representing a 55–75% reduction compared to polyethylene glycol (PEG)-stabilized reference fluids (28.36–51.91%). X-ray photoelectron spectroscopy (XPS) correlated this enhanced reservoir compatibility with an 18.0 ± 2.0% suppression of oxygen-containing functional group adsorption, attributed to the steric hindrance conferred by the fluorinated hydrophobic moieties. This work establishes an “interfacial control” paradigm wherein gel-like stabilization for proppant transport is achieved via interfacial viscoelasticity rather than bulk polymer gelation, thereby directly addressing the critical imperative to harmonize fracture conductivity with reservoir protection in unconventional energy development. The findings are validated for shallow CBM reservoir conditions (25–35 °C), with extension to higher-temperature formations identified as a priority for future investigation. Full article

Background: The blood–brain barrier (BBB), which restricts the brain penetration of most small molecules and almost all biologics, continues to be a significant hurdle in the development of drugs for the central nervous system (CNS). During early-stage screening, a reliable computational prediction of BBB permeability, typically expressed as log BB, can help reduce the experimental load. Methods: We provide a well-validated machine learning system created solely using the B3DB experimental database, which includes 7807 chemicals with BBB⁺/BBB⁻ annotations and 1058 compounds with in vivo log BB values. Using the Mordred library, a carefully selected set of 40 two-dimensional chemical descriptors was calculated from SMILES notation without the use of artificial data augmentation. Stratified five-fold cross-validation was used to comprehensively benchmark the nine methods used in this study. Results: On a held-out test set (n = 212), gradient boosting produced the greatest regression performance, with R² = 0.6043, RMSE = 0.4740 log units, and MAE = 0.3326, which is in line with the upper range recorded for experimental BBB datasets. On an internal test set (n = 1562), the corresponding classifier obtained an AUC-ROC of 0.9476 and a balanced accuracy of 0.8568; on an independent external validation set (n = 175), it achieved an AUC-ROC of 0.9137. Topological polar surface area was found by SHAP analysis to be the primary factor influencing BBB permeability, with lipophilicity and ionization-related characteristics being the second and third most important factors, respectively. Nonlinear relationships in accordance with accepted pharmacokinetic principles were validated using partial dependence analysis. Conclusion: This study provides a reliable technique for predicting BBB permeability in CNS drug discovery. Full article

Major depressive disorder (MDD) is a mental illness with high mortality, suicide, and relapse rates that could become the leading cause of health problems worldwide by 2030. The microbiota–gut–brain axis involves bidirectional communication between the human gut microbiota and the central nervous system (CNS). The gut microbiome is a complex ecosystem of approximately 100 trillion microorganisms, including viruses, bacteria, and fungi. The gut microbiota has recently been recognized for its impact on various diseases and health concerns. Several factors influence the composition and structure of gut microbes, ultimately affecting human physiology, with the nervous system being particularly vulnerable. The gut–brain–microbiota axis influences several important brain functions through numerous pathways, including vagus nerve signaling, gut microbial synthesis of metabolites, and immune-related chemicals. These factors can influence neurotransmitter activity, neuroinflammation, behavior, and mental health. Despite increased interest, the possibility of modifying the gut microbiota as a therapeutic approach remains unclear. Although numerous studies suggest that microbiota play an important role in many illnesses, the precise mechanisms are yet to be elucidated, and there are currently no evidence-based, microbiota-focused treatments for these illnesses. Recent research indicates that gut dysbiosis (GD) causes increased intestinal permeability (leaky gut), initiates systemic inflammation, and contaminates the blood. Opportunistic microbial metabolites cross the blood–brain barrier, triggering a neuroinflammatory cascade and apoptotic pathways while affecting neurogenesis and neurotransmitters, ultimately resulting in the development of MDD and anxiety. This review examined the factors influencing normal gut microbiota and GD-mediated MDD, as well as possible therapeutic options. The study outlines its objectives and methodological approaches, including the screening and filtering of research on GD-induced depression. Furthermore, it explored the daily use of dietary supplements, revealing new paths for clinical and preclinical research. Full article

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory condition, with therapy-resistant patients undergoing surgery and a high risk of developing colorectal cancer. Novel therapeutic approaches have shown limited efficacy in IBD treatment, highlighting the need for safer and more personalized strategies. The potential of natural compounds to modulate inflammation suggests their use as a potential adjunct therapy for IBD patients. Methods: Intestinal epithelial cells organoids (IECOs) were derived from IBD and non-IBD tissues from IBD patients, and levels of inflammation markers and epithelial barrier permeability were assayed using qRT-PCR, WB, IF and leaking assays in the presence of Ozoile, an extra virgin olive oil enriched in ozonides. The Luciferase-based IBD-like organoid platform was generated for preliminary screening of anti-inflammatory drugs. Results: In this study, we showed that IBD-ECOs recapitulate tissue architecture and pathological state. We showed that Ozoile has anti-inflammatory and epithelial barrier modulatory effects and that the Luciferase IBD-like organoid model is sensitive to anti-inflammatory compounds. Conclusions: Using IECOs, the specific anti-inflammatory and regenerative properties of Ozoile were assessed. Notably, our study highlights the potential of an IBD-like organoid platform to use in high-throughput screenings for rapid selection of anti-inflammatory drugs. Full article

Background: Neglected diseases caused by protozoan parasites remain a major public health burden, particularly in low- and middle-income countries. Among the chemical motifs explored in antiparasitic drug discovery, guanidine-containing compounds have attracted considerable attention due to their strong cationic character, high capacity for hydrogen bonding, and versatility in interacting with biological targets. Methodology: This review summarizes advances reported in the last decade regarding guanidine derivatives with activity against pathogens associated with Chagas disease, human African trypanosomiasis, Leishmaniasis, tuberculosis, toxoplasmosis, dengue and schistosomiasis. Results: Evidence gathered from synthetic, natural, and drug-repurposing studies indicates that the guanidine, guanidine-containing and guanidine-related compounds contribute to modulating biological activity by changing electrostatic interactions, hydrogen-bonding networks, and physicochemical properties, with enzymes, nucleic acids, and membrane-associated targets essential for parasite survival. Across the analyzed studies, several emerging structure–activity relationship trends were identified, including the contribution of polycationic or dicationic architectures, the influence of halogenated or lipophilic substituents, and the dependence of biological activity on the complete molecular framework, including heterocyclic systems, macrocycles, peptide conjugates, hybrid scaffolds, and repurposed drugs. In addition to direct antiparasitic effects, certain guanidine-containing and guanidine-related compounds demonstrate immunomodulatory or host-protective properties, expanding the therapeutic relevance of this class. Despite promising in vitro results, protonation trapping, efflux pump susceptibility, and pharmacokinetic limitations such as poor oral absorption, high polarity, plasma protein binding and limited membrane permeability remain significant challenges for clinical translation. Nonetheless, the integration of medicinal chemistry, computational modeling, and biological screening continues to accelerate the identification of optimized scaffolds. Conclusions: Overall, guanidine-based compounds constitute a promising scaffold for the development of new therapeutic strategies targeting neglected parasitic diseases, and further structural optimization may enable the emergence of candidates with improved efficacy, selectivity, and drug-like properties. Full article