Alzheimer's disease (AD) is characterized by the appearance of brain pathology decades prior to clinical symptoms. The pre-symptomatic phase of AD provides opportunity for early detection and intervention. One early intervention that has been proposed is the use of non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen. However, evidence suggests that effects of naproxen intervention differ with stage of the disease, and the optimal intervention time is not clear. Accordingly, in this study, we investigated the impact of the timing of naproxen treatment in a rat model of AD. We used the TgF344-AD rat model of AD which develops characteristic pathological features of human AD, including abundant amyloid plaque pathology, astrogliosis, and microgliosis by 6 months of age, and neurofibrillary tangles and neuronal loss by 16 months of age. We examined the effects of naproxen treatment beginning at 1, 4, and 10 months of age in transgenic (Tg) animals and their wild-type (WT) littermates. We used longitudinal in vivo magnetic resonance spectroscopy (MRS) to study the impact of naproxen treatment on hippocampus neurochemistry. Previous studies have used MRS to non-invasively characterize the trajectory of altered hippocampal neurochemistry across the lifespan in the TgF344-AD rat model. In the current study, we employed MRS at 4, 10, and 16 months, i.e. prior to or after the appearance of amyloidosis and gliosis (6 months) and tau pathology (16 months), respectively, in Tg animals. Naproxen treatment altered neurochemistry in Tg animals only if administered beginning at 1 or 4 months of age, mitigating an otherwise observed increase in total choline and decrease in taurine. A more subtle effect was observed on the otherwise-expected increase in myo-inositol. These results highlight the possibility that earlier naproxen intervention could have distinct neurochemical effects compared to delayed treatment, though mechanistic implications remain to be clarified. Moreover, these findings support the use of MRS as a useful non-invasive method of monitoring treatment-related changes in neurochemistry in transgenic animal models.

Humic acid (HA) may inhibit the degradation of contaminants by quenching reactive species in some traditional advanced oxidation processes (AOPs). However, our study found that HA can remarkably enhance the degradation of contaminants by the sunlight-activated periodate (PI) system in practical applications. Herein, a HA-boosted sunlight-activated PI system for contaminant degradation was systematically investigated. The results showed that 2 mgC/L HA increased the degradation efficiency of naproxen (NAP) by about 2.4-fold in the sunlight/PI system. Increased HA or PI concentration enhanced NAP degradation by the sunlight/PI/HA system. Quencher, fluorescence and nitrogen experiments proved that hydroxyl radical (HO·) and ozone (O3) were the main reactive species for the degradation of NAP. Radical probe and O3 experiments confirmed that the increase of pH decreased the quantum yield of PI photolysis, resulting in the decrease of average O3 concentration and the steady-state concentration of HO·, thereby lowering the degradation of NAP. The contributions of HO· and O3 to NAP degradation were determined to be from 65.4% to 81.1% and from 19.3% to 28.1% at pH 4.0-9.0, respectively. The situation of PI decline in different systems proved that the triplet excited state of HA (3HA*) rather than HA·- was the key intermediate species for the accelerated activation of PI, and PI was eventually converted into iodate. The accelerated activation of PI with increasing HA concentration was attributed to the elevated steady-state concentration of 3HA*. Additionally, the applicability of the sunlight/PI/HA system was verified by the degradation of seven different micropollutants. Suwannee River natural organic matter (SRNOM) was also demonstrated to exhibit similar enhancing effects on PI activation as HA under sunlight exposure. Cl- and HCO3- inhibited the degradation of NAP in view of the conversion of HO· into chlorine-containing and carbonate radicals. This work provides a novel insight into improving the solar-photoactivated PI process for water treatment.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and indomethacin, have reduced amyloid beta (Aβ) levels and improved cognitive function in mouse models of Alzheimer's disease (AD). The objective of the current research is to evaluate different NSAIDs using computer-aided drug design (CADD) to explore their potential as new treatments for AD. CADD is an advanced technique for designing biologically active molecules and involves two primary approaches: structure-based virtual screening and ligand-based virtual screening. After identifying the NSAID with the highest affinity for amyloid Aβ1-42 fibrils (PDB 2BEG), we designed analogs through bioisosteric modifications. Twenty derivatives were created, and two carprofen analogs with the most promising properties were synthesized, yielding 75% success with compound A-1 and 70% with compound A-2. These analogs exhibited lower predicted IC50 values (1.57 μM) and more negative interaction energies (-6.43 and -6.67 kcal/mol for A-1 and A-2, respectively) compared to carprofen. Safety evaluations in L929 cells indicated that these compounds were safe at concentrations of 40 µM. In conclusion, two carprofen analogs were successfully designed and synthesized, demonstrating higher affinity for the amyloid Aβ1-42 fibrils, better-predicted IC50 values than carprofen, and safety in the L929 in vitro assay.

Naproxen is a widely used nonsteroidal anti-inflammatory drug, and previous studies have shown that its administration in mice influenced antral follicle growth and ovulation. Therefore, the present study aimed to investigate the reversibility of these effects following treatment interruption and to evaluate their impact across different mouse backgrounds. For Experiment I, C57BL/6 females (n = 20, 6 weeks of age) were treated with 10 mg/kg (low, n = 7) or 50 mg/kg (high, n = 7) of naproxen, while animals of the vehicle group received PBS + DMSO 5% (n = 6), followed by 21 days of rest. After euthanasia, the ovaries were histologically analysed. For Experiment II (C57BL/6) and Experiment III (Swiss and BALB/c), animals were treated for eight days with the same protocol, receiving 20 IU of eCG and 20 IU of hCG for ovulation induction. Recovered oocytes were collected and quantified. Results demonstrated that the treatment affected the percentage of primary follicles, which increased in the high-dose group compared with the vehicle group. Additionally, the rate of antral follicles was higher in the high group than in the vehicle and low-dose groups. The number of ovulated oocytes was not altered in BALB/c and Swiss females, as well as the number of corpora haemorrhagica and corpus luteum (p > 0.05). Overall, our findings indicate that naproxen treatment may have transient effects on folliculogenesis in C57BL/6 mice, with no impact in BALB/c or Swiss mice.

Human serum albumin (HSA) is critical for treating liver cirrhosis with ascites. However, plasma-derived HSA (pHSA) faces limitations in supply and carries potential infection risks. To address the urgent need for a therapeutically equivalent alternative, we established an efficient expression system for recombinant HSA (rHSA) in Pichia pastoris. We purified rHSA via a three-step chromatography purification process, yielding approximately 260 mg per 1.5 L of culture. Comprehensive analyses confirmed its structural equivalence to pHSA. Mass spectrometry revealed a molecular weight of 66,530.8 Da, while circular dichroism showed a 36.9% α-helical content. Furthermore, isothermal titration calorimetry demonstrated comparable drug-binding affinities for naproxen and warfarin. In a CCl4-induced rat model of liver cirrhosis with ascites, rHSA displayed significant, dose-dependent therapeutic effects. Notably, high-dose rHSA achieved efficacy statistically equivalent to pHSA. It reduced ascites volume by 50.1%, improved liver index by 33.5% and restored colloid osmotic pressure along with liver function markers (ALT, AST, and bilirubin). This study provides the first in vivo evidence confirming the therapeutic equivalence and dose-effect relationship of P. pastoris-derived rHSA compared with pHSA. These findings establish a scalable, cost-effective, and safe platform for rHSA production, supporting its potential as a viable clinical substitute for plasma-derived albumin.

Organic micropollutants (OMPs) in wastewater treatment plant (WWTP) effluent pose persistent risks to aquatic ecosystems and drinking water sources. Riverbank filtration (RBF) is a nature-based treatment process, yet the compartment-specific roles of riverbed sediment and downstream soil in OMP attenuation remain poorly resolved under wastewater-impacted conditions. Here, we combined targeted chemical analysis, OMP property compilation, shotgun metagenomics, EnviPath-based biotransformation annotation, and exploratory network analysis to investigate OMP attenuation in a laboratory-scale RBF system treating real WWTP effluent for 10 months. Nineteen OMPs were monitored along a sequential sediment-soil filtration pathway. Sediment preferentially attenuated hydrophilic or charged compounds, including lidocaine, amantadine, and sotalol, whereas soil contributed more strongly to the attenuation of naproxen, atenolol, and losartan. Metagenomic profiling revealed distinct microbial communities and functional gene repertoires between sediment and soil after long-term operation. Sediment harbored higher relative abundances of genes associated with oxidative xenobiotic transformation, including cytochrome P450-related enzymes, demethylases, dehydrogenases, oxidases, and aromatic compound degradation pathways. An exploratory Spearman network further identified associations among microbial genera, EnviPath-annotated candidate biotransformation genes, and OMP removal rates, including 17 KO-OMP links supported by both correlation and pathway annotation. These findings indicate that sediment and soil develop complementary microbial functional potentials that may support compound-specific OMP attenuation. This study provides a mechanistic basis for optimizing sediment-soil configurations in wastewater-impacted RBF systems and for improving nature-based barriers against diverse OMP mixtures.

Au(I) complexes are widely investigated as therapeutic agents due to their high affinity for biological nucleophiles and protein targets. Here, the reactivity of an Auranofin (AF) derivative bearing naproxen as a ligand toward hen egg white lysozyme (HEWL) was investigated by a combined crystallographic and computational approach. Notably, the first observation of lysine metalation in HEWL by an Au complex is reported. The results highlight how ligand substitution can significantly affect Au(I) reactivity toward biomacromolecules, enabling noncanonical targeting and potentially impacting biological activity.

Reliable discrimination of diastereomeric pharmaceutical cocrystals remains a significant analytical challenge, particularly when structural differences are subtle or when monocrystals suitable for X-ray diffraction are not available or difficult to prepare. Here, we compare the performance of four spectroscopic techniques, solid-state nuclear magnetic resonance (ssNMR), Raman spectroscopy, infrared (IR) absorption, and solid-state vibrational circular dichroism (ssVCD), in terms of the resolution of model diastereomeric cocrystals. The first pair of diastereomeric cocrystals, (S)-naproxen with (R)- and (S)-alanine, represents an example of systems with pronounced packing differences, whereas the cocrystals of (R)-ivabradine hydrochloride with (R)- and (S)-mandelic acid are nearly isostructural diastereomers. The NMR and vibrational spectra were interpreted based on density functional theory (DFT) simulations, allowing for a detailed spectra-structure assignment and analysis. Although all techniques detected cocrystal formation, their practical discriminatory power toward diastereomers varied. VCD spectroscopy provided reliable differentiation, even for nearly isostructural systems, although the data were hampered by the experimental noise. Raman spectroscopy, especially in the low-frequency region, was effective for a rapid detection of distinct packing motifs but less sensitive for the closely related structures. ssNMR provides a complementary localized insight. The results indicate the advantages and drawbacks of using Raman spectroscopy, ssNMR, and VCD for screening, structural studies, and chiral identification of pharmaceutical cocrystals and other chiral complex solid-state systems.

The conventional 4-aminoantipyrine (4-AAP) method for volatile phenols (VPs) fails to detect certain substituted phenols, leading to an underestimation of VPs in water. To overcome this "selectivity blind spot", we developed an integrated flow-injection analysis chemiluminescence (FIA-CL) platform that quantifies VPs as phenol-equivalent concentrations, providing a more inclusive readout than the 4-AAP method and enabling rapid and reliable monitoring. This sensing mechanism utilizes a competitive reaction where VPs compete with the CL probe (naproxen, NAP) for reactive iron species (Fe(IV)) generated by Fe(II)-activated periodate, resulting in concentration-dependent signal attenuation. Moreover, to address signal loss due to separation between mixing and detection units in conventional FIA-CL systems, we designed a Y-shaped flow-through cell that synchronizes mixing and detection within the same microzone for real-time signal capture. The optimized platform yielded a detection limit of 3.47 μg L[-1] with a linear range of 0.011-20 mg L[-1], outperforming the 4-AAP method with a 3-fold lower LOD and an 8-fold wider range. Analysis of real water samples showed that VPs concentrations measured by the platform exceeded those obtained by the 4-AAP method, with mass spectrometry confirming that this discrepancy arises from 4-AAP's failure to respond to certain substituted phenols. Thus, our platform provides a sensitive, broad-spectrum tool for VPs monitoring.

The choline-based monomeric ionic liquid (MIL), that is, [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA), was modified by ion exchange to introduce a pharmaceutical anion (aspartic acid (APT), diclofenac (DIC), cholic acid (CHA), ibuprofen (IBU), nalidixic acid (NAL), naproxen (NAP), piperacillin (PIP), tazobactam (TAZ), and valproic acid (VPA)). The TMAMA MILs with satisfactory exchange efficiency containing DIC, IBU, TAZ, or VPA anions were polymerized by "grafting from" multifunctional macroinitiators. The reactions yielded successful synthesis of PIP-anion-based ionic graft polymer conjugates with a tunable ionic fraction, with drug contents reaching 74-92%. These single-drug delivery systems (DDSs) were developed into co-delivery systems by conjugating ionic TAZ into PIP-polymer carriers, achieving drug contents of 48-68% for PIP and 31-41% for TAZ. Under physiological dialysis conditions, the conjugates demonstrated similar release efficiencies (51-84% for PIP and 66-81% for TAZ). Surface analysis by water contact angle (WCA) indicated increased hydrophilicity in dual systems (36-52°) compared to the single systems (48-59°). In aqueous solutions, the conjugates formed nanosized self-assemblies with diameters of 180-330 nm. Biomodification of TMAMA-based MILs with pharmaceutical anions faces limitations; nevertheless, the successful incorporation of selected substances, such as PIP, enables the formation of ionic conjugates. The hybrid sequential ion exchange strategy provides a versatile platform for controlled co-delivery of PIP and TAZ.

The occurrence of persistent pharmaceutical residues, such as nonsteroidal anti-inflammatory drugs (NSAIDs), in aquatic environments requires treatment strategies that combine high removal efficiency with operational practicality. Herein, a hybrid lignin-based cationic hydrogel incorporating the iron-based metal-organic framework MIL-100-(Fe) (LS-pAAm-DAC/MIL-100-(Fe)) is reported as a multifunctional material for the integrated adsorption and heterogeneous photo-Fenton degradation of naproxen sodium (NPX-Na) in water. The composite is synthesized via in situ radical polymerization, leading to the uniform immobilization of crystalline MIL-100-(Fe) within a sustainable, lignin-derived polymer network. Structural and morphological analyses (XRD, ATR-FTIR, SEM/EDS) confirm the preservation of the MOF structure and its homogeneous dispersion throughout the hydrogel matrix. The composite exhibits rapid NPX-Na uptake and enhanced adsorption capacity (39 mg/g) compared with the pristine hydrogel, attributable to combined electrostatic interactions in the cationic network and additional adsorption sites on MIL-100-(Fe). Under UVA irradiation in the presence of H2O2, the material promotes complete NPX-Na degradation via a heterogeneous photo-Fenton process, with HPLC/MS evidence of progressive transformation into oxidized phthalic acid-type by-products. Importantly, ICP-OES analysis reveals no detectable iron leaching, demonstrating robust immobilization of MIL-100-(Fe) and operational stability. The composite retains substantial adsorption performance over multiple regeneration cycles, highlighting its reusability. Overall, LS-pAAm-DAC/MIL-100-(Fe) represents a recoverable and sustainable platform that integrates capture and oxidative degradation of anionic pharmaceuticals, offering promising prospects for advanced water treatment applications.

The purpose of the present study was to evaluate whether dissolution testing in biorelevant bicarbonate buffer (BCB) can predict the solubility-limited oral absorption of high-dose free acid drugs. Valsartan and naproxen were selected as model compounds exhibiting solubility-limited absorption at high doses. A biorelevant BCB solution (concentration: 10 mM, initial pH (pHini) = 6.5, buffer capacity (β) = 4.4 mM/pH) (BCB), a phosphate buffer solution with the same pH and β (PPB), and a USP phosphate buffer solution (β = 27 mM/pH, modified to pHini 6.5) were employed for dissolution tests. The dose-to-fluid volume ratio (Dose/FV) was set to reflect the clinical or compendial conditions. The fraction of a dose absorbed in humans (Fa) predicted using a simple theoretical framework was compared with the clinical Fa calculated from pharmacokinetic data in the literature. When using BCB or PPB with the same β and the clinical Dose/FV, the bulk-phase pH after 4 h (pHbulk, 4 h) was markedly lower than pHini (< pH 6.0 for naproxen, < pH 5.0 for valsartan). Consequently, the dissolved drug concentration at 4 h (Cdissolv, 4 h) was markedly lower than the solubility at pH 6.5. Using Cdissolv, 4 h, the dose dependency of Fa was appropriately predicted. In contrast, when using USP or the compendial Dose/FV, the pHbulk, 4 h and Cdissolv, 4 h were less reduced, leading to an overestimation of Fa. Overall, the use of BCB or PPB and a clinical Dose/FV improved the in vivo predictability for high-dose free acid drugs.