International Journal of Molecular Sciences最新文献

Curcumin, a compound known for its antioxidant and neuroprotective properties, faces challenges due to its low water solubility, which can limit its effectiveness. One effective method to address this issue is through amorphization. Incorporating curcumin into a polymeric matrix to form amorphous solid dispersions is a common approach. Another strategy involves co-amorphous systems, where low-molecular-weight components act as co-formers. A recent innovative approach combines these strategies. This study used tryptophan as a co-former and prepared systems using supercritical fluid technology. The amorphous nature of two systems was confirmed through X-ray powder diffraction: one with 10% curcumin and a polymer, and another with 10% curcumin, a polymer, and tryptophan. Fourier-transform infrared analysis demonstrated molecular interactions among all components in the systems. Scanning electron microscopy revealed that the amorphization process significantly modified the morphology of the powder particles. The ternary system with tryptophan notably increased curcumin solubility by over 300-fold. The amorphous form of curcumin in both systems exhibited significantly higher dissolution rates compared to its crystalline form. The system with tryptophan showed more than a threefold improvement in permeability according to the PAMPA test. The enhanced solubility led to over a sixfold increase in antioxidant activity and a 25-fold improvement in the inhibition of the enzyme butyrylcholinesterase.

Cancer remains a leading cause of morbidity and mortality worldwide, highlighting the urgent need for novel therapeutic agents. This study investigated the synthesis and biological evaluation of O-alkyl (E)-chalcone derivatives (4a-4v) as potential anticancer agents. The compounds were synthesized via aldol condensation of substituted aldehydes and acetophenones, with structures confirmed by IR, NMR, and mass spectrometry. In vitro cytotoxicity assays revealed varying effectiveness, with compounds 4a, 4b, 4q, and 4v exhibiting potent activity against MDA-MB-231 and MCF-7, showing IC₅₀ values between 2.08 and 13.58 µM, besides HCT-116 and HeLa cancer cell lines (IC₅₀ values between 6.59 and 22.64 µM). Notably, compound 4b displayed remarkable selectivity, with an IC₅₀ of 54.59 µM against the non-cancerous WI-38 cell line. Additionally, protein kinase inhibition assays indicated that compounds 4b and 4q effectively inhibited EGFR and VEGFR-2, with 4b outperforming the standard inhibitor erlotinib. Molecular docking studies of compound 4q showed strong binding affinities in the ATP-binding pockets of EGFR, HER2, VEGFR2, and CDK2. In silico analyses further highlighted the favorable pharmacokinetic properties of compound 4q, underscoring its potential as a selective tyrosine kinase inhibitor. These findings suggest the therapeutic promise of O-alkyl (E)-chalcone derivatives in cancer treatment.

The dynamic nature of human endometrial tissue presents unique challenges in analysis. Despite extensive research into endometrial disorders such as endometriosis and infertility, recent systematic reviews have highlighted concerning issues with the reproducibility of omics studies attempting to identify biomarkers. This review examines factors contributing to poor reproducibility in endometrial omics research. Hormonal fluctuations in the menstrual cycle lead to widespread molecular changes in the endometrium, most notably in gene expression profiles. In this review, we examine the variability in omics data due to the menstrual cycle and highlight the importance of accurate menstrual cycle dating for effective statistical modelling. The current standards of endometrial dating lack precision and we make the case for using molecular-based modelling methods to estimate menstrual cycle time for endometrium tissue samples. Additionally, we discuss statistical considerations such as confounding and interaction effects, as well as the importance of recording the detailed and accurate clinical information of patients. By addressing these methodological challenges, we aim to establish more robust and reproducible research practises, increasing the reliability of endometrial omics research and biomarker discovery.

This study presents an efficient and environmentally sustainable synthesis of ZnO nanoparticles using a starch-mediated sol-gel approach. This method yields crystalline mesoporous ZnO NPs with a hexagonal wurtzite structure. The synthesized nanoparticles demonstrated remarkable multifunctionality across three critical applications. In photocatalysis, the ZnO NPs exhibited exceptional efficiency, achieving complete degradation of methylene blue within 15 min at pH 11, significantly surpassing the performance of commercial ZnO. Under neutral pH conditions, the nanoparticles effectively degraded various organic dyes, including methylene blue, rhodamine B, and methyl orange, following pseudo-first-order kinetics. The methylene blue degradation process was aligned with the Langmuir-Hinshelwood model, emphasizing their advanced catalytic properties. For supercapacitor applications, the ZnO NPs attained a high specific capacitance of 550 F/g at 1 A/g, underscoring their potential as energy storage solutions. Additionally, the nanoparticles demonstrated strong UV-induced antiradical activity, with an EC₅₀ of 32.2 μg/mL in DPPH assays. Notably, the cytotoxicity evaluation revealed an LC₅₀ of 1648 μg/mL, indicating excellent biocompatibility. This study highlights a sustainable approach for the synthesis of multifunctional ZnO NPs that offers effective solutions for environmental remediation, energy storage, and biomedical applications.

Particulate matter (PM) is a major component of ambient air pollution. PM exposure is linked to numerous adverse health effects, including chronic lung diseases. Air quality guidelines designed to regulate levels of ambient PM are currently based on the mass concentration of different particle sizes, independent of their origin and chemical composition. The objective of this study was to assess the relative hazardous effects of carbonaceous particles (soot), ammonium nitrate, ammonium sulfate, and copper oxide (CuO), which are standard components of ambient air, reflecting contributions from primary combustion, secondary inorganic constituents, and non-exhaust emissions (NEE) from vehicular traffic. Human epithelial cells representing bronchial (BEAS-2B) and alveolar locations (H441 and A549) in the airways, human lung fibroblasts (HFL-1), and rat precision-cut lung slices (PCLS) were exposed in submerged cultures to different concentrations of particles for 5-72 h. Following exposure, cell viability, metabolic activity, reactive oxygen species (ROS) formation, and inflammatory responses were analyzed. CuO and, to a lesser extent, soot reduced cell viability in a dose-dependent manner, increased ROS formation, and induced inflammatory responses. Ammonium nitrate and ammonium sulfate did not elicit any significant cytotoxic responses but induced immunomodulatory alterations at very high concentrations. Our findings demonstrate that secondary inorganic components of PM have a lower hazard cytotoxicity compared with combustion-derived and indicative NEE components, and alveolar epithelial cells are more sensitive to PM exposure. This information should help to inform which sources of PM to target and feed into improved, targeted air quality guidelines.

Precise binding free-energy predictions for ligands targeting metalloproteins, especially zinc-containing histone deacetylase (HDAC) enzymes, require specialized computational approaches due to the unique interactions at metal-binding sites. This study evaluates a docking algorithm optimized for zinc coordination to determine whether it could accurately differentiate between protonated and deprotonated states of hydroxamic acid ligands, a key functional group in HDAC inhibitors (HDACi). By systematically analyzing both protonation states, we sought to identify which state produces docking poses and binding energy estimates most closely aligned with experimental values. The docking algorithm was applied across HDAC 2, 4, and 8, comparing protonated and deprotonated ligand correlations to experimental data. The results demonstrate that the deprotonated state consistently yielded stronger correlations with experimental data, with R² values for deprotonated ligands outperforming protonated counterparts in all HDAC targets (average R² = 0.80 compared to the protonated form where R² = 0.67). These findings emphasize the significance of proper ligand protonation in molecular docking studies of zinc-binding enzymes, particularly HDACs, and suggest that deprotonation enhances predictive accuracy. The study's methodology provides a robust foundation for improved virtual screening protocols to evaluate large ligand libraries efficiently. This approach supports the streamlined discovery of high-affinity, zinc-binding HDACi, advancing therapeutic exploration of metalloprotein targets. A comprehensive, step-by-step tutorial is provided to facilitate a thorough understanding of the methodology and enable reproducibility of the results.

Soil salinization poses a significant challenge to global agriculture, particularly in arid and semi-arid regions like Xinjiang. Kalidium schrenkianum, a halophytic plant adapted to saline-alkaline conditions, harbors endophytic microorganisms with potential plant growth-promoting properties. In this study, 177 endophytic bacterial strains were isolated from K. schrenkianum, and 11 key strains were identified through functional screening based on salt tolerance, nutrient solubilization, and growth-promoting traits. Synthetic microbial communities (SMCs) were then constructed using these strains and optimized to enhance wheat growth under salt stress. The SMCs significantly improved seed germination, root length, and seedling vigor in both spring and winter wheat in hydroponic and pot experiments. Furthermore, the SMCs enhanced the activities of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and levels of malondialdehyde (MDA) and proline (PRO). They also reduced oxidative stress and improved chlorophyll content in wheat seedlings. These results demonstrate the potential of microbial consortia derived from extreme environments as eco-friendly biofertilizers for improving crop performance in saline soils, offering a sustainable alternative to chemical fertilizers and contributing to agricultural resilience and productivity.

Nimodipine is the current gold standard in the treatment of subarachnoid hemorrhage, as it is the only known calcium channel blocker that has been proven to improve neurological outcomes. In addition, nimodipine exhibits neuroprotective properties in vitro under various stress conditions. Furthermore, clinical studies have demonstrated a neuroprotective effect of nimodipine after vestibular schwannoma surgery. However, the molecular mode of action of nimodipine pre-treatment has not been well investigated. In the present study, using real-time cell death assays, we demonstrated that nimodipine not only reduces cell death induced by osmotic and oxidative stress but also protects cells directly at the time of stress induction in Schwann cells. Nimodipine counteracts stress-induced calcium overload and the overexpression of the Cav1.2 calcium channel. In addition, we found nimodipine-dependent upregulation of sarcoplasmic/endoplasmic reticulum calcium ATPase 3 (SERCA3) and LIM domain only 4 (LMO4) protein. Analysis of anti-apoptotic cell signaling showed an inhibition of the pro-apoptotic protein glycogen synthase kinase 3 beta (GSK3β). Nimodipine-treated Schwann cells exhibited higher levels of phosphorylated GSK3β at serine residue 9 during osmotic and oxidative stress. In conclusion, nimodipine prevents cell death by protecting cells from calcium overload by fine-tuning intracellular calcium signaling and gene expression.

Tanshinones, biologically active diterpene compounds derived from Salvia miltiorrhiza, interact with specific proteins and DNA sequences, influencing signaling pathways in animals and humans. This study highlights tanshinone-protein interactions observed at concentrations achievable in vivo, ensuring greater physiological relevance compared to in vitro studies that often employ supraphysiological ligand levels. Experimental data suggest that while tanshinones interact with multiple proteomic targets, only a few enzymes are significantly affected at biologically relevant concentrations. This apparent paradox may be resolved by tanshinones' ability to bind DNA and influence enzymes involved in gene expression or mRNA stability, such as RNA polymerase II and human antigen R protein. These interactions trigger secondary, widespread changes in gene expression, leading to complex proteomic alterations. Although the current understanding of tanshinone-protein interactions remains incomplete, this study provides a foundation for deciphering the molecular mechanisms underlying the therapeutic effects of S. miltiorrhiza diterpenes. Additionally, numerous tanshinone derivatives have been developed to enhance pharmacokinetic properties and biological activity. However, their safety profiles remain poorly characterized, limiting comprehensive insights into their medicinal potential. Further investigation is essential to fully elucidate the therapeutic and toxicological properties of both native and modified tanshinones.

Oxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer's disease (AD). AD is a multifactorial chronic neurodegenerative syndrome indicated by a form of progressive dementia associated with aging. While one-target drugs only soften its symptoms while generating drug resistance, multi-target polyphenols from fruits and vegetables, such as ellagitannins (ETs), ellagic acid (EA), and urolithins (UROs), having potent antioxidant and radical scavenging effects capable of counteracting OS, could be new green options to treat human degenerative diseases, thus representing hopeful alternatives and/or adjuvants to one-target drugs to ameliorate AD. Unfortunately, in vivo ETs are not absorbed, while providing mainly ellagic acid (EA), which, due to its trivial water-solubility and first-pass effect, metabolizes in the intestine to yield UROs, or irreversible binding to cellular DNA and proteins, which have very low bioavailability, thus failing as a therapeutic in vivo. Currently, only UROs have confirmed the beneficial effect demonstrated in vitro by reaching tissues to the extent necessary for therapeutic outcomes. Unfortunately, upon the administration of food rich in ETs or ETs and EA, URO formation is affected by extreme interindividual variability that renders them unreliable as novel clinically usable drugs. Significant attention has therefore been paid specifically to multitarget EA, which is incessantly investigated as such or nanotechnologically manipulated to be a potential "lead compound" with protective action toward AD. An overview of the multi-factorial and multi-target aspects that characterize AD and polyphenol activity, respectively, as well as the traditional and/or innovative clinical treatments available to treat AD, constitutes the opening of this work. Upon focus on the pathophysiology of OS and on EA's chemical features and mechanisms leading to its antioxidant activity, an all-around updated analysis of the current EA-rich foods and EA involvement in the field of AD is provided. The possible clinical usage of EA to treat AD is discussed, reporting results of its applications in vitro, in vivo, and during clinical trials. A critical view of the need for more extensive use of the most rapid diagnostic methods to detect AD from its early symptoms is also included in this work.