Hydrogen-bonding Interactions Research Articles

Esculetin improves inflammation of the kidney via gene expression against doxorubicin-induced nephrotoxicity in rats: In vivo and in silico studies

Examining the preventive potential and underlying mechanisms of Esculetin (E) in mitigating kidney damage induced by doxorubicin (DOX) in rats, this study also assessed the nephrotoxic effects when DOX was administered in combination with E. The experimental protocol involved a two-week treatment period with cumulative DOX doses (5 mg/kg), daily administration of E (50 mg/kg and 100 mg/kg), and the combined treatment of DOX with E50 and E100. The study delved into the gene expression levels of key regulatory factors associated with inflammation and apoptosis. Molecular analyses revealed that E effectively ameliorated the dysregulations induced by DOX at gene levels in the kidneys. Notably, the concurrent administration of E was observed to counteract the alterations in gene expressions induced by DOX significantly. E treatment decreased serum creatinine, albumin, and urea nitrogen levels in DOX-induced kidney damage. Furthermore, the docking analysis revealed that pi–cation, pi–pi stacking, and hydrogen bond interactions were the predominant molecular interactions within the binding pockets of these genes. This suggests that the nephroprotection provided by E involves the remodeling of inflammation and apoptosis pathways affected by DOX.

“Three birds with one stone” strategy for building easily reprocessable cellulosic thermosetting resins

Cellulose is the most abundant natural polypolysaccharide and is an ideal raw material to replace petroleum-based plastics. However, natural cellulose is difficult to be thermo-processed like conventional plastics because of the rich and strong hydrogen bonds interactions. In this study, a series of dialdehyde derivatives of cellulose (DACs) were prepared by periodate oxidation of cellulose, and cellulose covalent adaptive networks based on acetal dynamic covalent bonds (ACCs) were prepared using dipentaerythritol as a crosslinker for DAC. This strategy can introduce acetal bonds, weaken hydrogen bonds, and reduce rigidity to kill three birds with one stone. The excellent reprocessing performance of ACCs is attributed to the reconstruction of the cellulose hydrogen bond network by acetal bonds, and the reversible exchange reaction of the acetal bonds at high temperatures endows the cellulose chains with mobility, allowing ACCs to be remodeled by hot pressing at 90°C for 15 min. The excellent stability and reprocessability of ACCs hold the promise of replacing current non-renewable petroleum-based plastics and provide inspiration for the development of other types of biomass plastics.

Tunable protic ionic liquid catalysts for the efficient one-step synthesis of isosorbide-based polycarbonates

Using CO2-derived dimethyl carbonate (DMC) instead of diphenyl carbonate (DPC) as a carbonyl source for synthesizing bio-based polycarbonates is a green and cost-effective route. However, the synthesis of high-performance polycarbonates via the DMC route remains challenging due to the poor reactivity and selectivity of DMC compared to DPC. Herein, we designed a series of highly active protic ionic liquid (PIL) catalysts for the synthesis of poly(isosorbide carbonate) (PIC) from DMC with ISB. The influences of the structures of anion and cation on the catalytic activity of PILs were systematically studied. Compared with the reported aprotic IL catalysts, the unique reactive hydrogen of the cation in PILs could form a strong hydrogen bond interaction with the carbonyl group of DMC, resulting in higher reactivity of the carbonyl carbon of DMC. Moreover, the nucleophilicity of the anion could be easily tuned by adjusting the pKa value, which effectively realized the balance of the reactivity difference between exo-OH and endo-OH in ISB. Among them, [DBUH][Im] showed the highest catalytic activity, and the weight-average molecular weight (Mw) and glass transition temperature of PIC reached 55,700 g/mol and 160 °C, respectively. Combined with NMR analyses and DFT calculations, the mechanism that exhibited the synergetic catalytic effect of anion-cation for the polymerization of DMC and ISB was presented.

Optimized Second-Generation IL-4Rα Inhibition: Structural and Molecular Dynamics Properties of Rademikibart Fab-IL-4Rα Complex

Introduction: Global Burden of Disease studies showed atopic dermatitis (AD) and asthma are the top two immune-mediated inflammatory diseases at younger age [1]. Dupilumab was the initial first-generation interleukin-4 receptor alpha (IL-4Rα) inhibitor for treating both type I and type II IL-4Rα-dependent inflammatory disorders. Following recent clinical trials, rademikibart (previously, CBP-201) emerges as an optimized next-generation human monoclonal antibody with higher binding affinity to IL-4Rα compared to dupilumab [2]. It demonstrated better effect in inhibiting STAT6 intracellular signaling in vitro and provided similar potency inhibiting both IL-4 induced TARC release and IL-4 induced B cell activation [2]. Materials & Methods: X-ray crystallography was used to determine the atomic resolution 3D structure of rademikibart fragment antigen binding (Fab) bound to IL-4Rα. This structure was analyzed and compared computationally with the 2.82 Å resolution crystal structure of dupilumab Fab bound to IL-4Rα (Protein Data Bank Code 6WGL). Molecular dynamics studies on rademikibart and dupilumab bound to IL-4Rα examined the stability of the complexes and effects of amino acid mutations on complex formation. Results: The x-ray crystal structure of rademikibart Fab bound to IL-4Rα was determined at 2.71Å and compared to the complex of dupilumab Fab and IL-4Rα. The rotation angle between dupilumab and rademikibart bound to IL- 4Rα is 59.17°. This rotation enables the epitope of rademikibart, but not dupilumab, on IL-4Rα to overlap more closely with the conserved binding interface utilized by IL-4 and IL-13 cytokines. Molecular dynamics simulations of rademikibart Fab and dupilumab Fab complexed with IL-4Rα showed the third interface loop (residues 148 to 152 in domain 2) of IL-4Rα interacts directly with rademikibart, which is absent in dupilumab/IL- 4Rα complex. This finding is confirmed by analysis of the hydrogen bond interactions at the interface between the antibodies and IL-4Rα, demonstrating superior binding energy for rademikibart. Through single amino acid mutation analysis on rademikibart, we identified residue Y50 on rademikibart as the key residue interacting with IL- 4Rα’s third interface loop. Conclusion: Our data provide a molecular and structural rationale for the enhanced IL-4Rα inhibition by rademikibart over dupilumab, confirming rademikibart as an optimized second-generation IL-4Rα inhibitor.

The Improved Redispersibility of Cellulose Nanocrystals Using Hydroxypropyl Cellulose and Structure Color from Redispersed Cellulose Nanocrystals.

Cellulose nanocrystals (CNC) have been significantly developed as a building block material for the design of novel functional materials in many fields such as biomedicine, nanotechnology, and materials science due to their excellent optical properties, biocompatibility, and sustainability. Improving the redispersibility of CNC in the sustainable processing of nanocellulose has been a challenge because intense hydrogen bond interaction leads to irreversible aggregation, making CNC difficult to redisperse and increasing the cost of storage and transportation of CNC. Hydroxypropyl cellulose (HPC) is an important hydroxy propylated cellulose ether. As a water-soluble cellulose derivative, HPC has a polyhydroxy structure similar to that of CNC, which leads to good compatibility and high affinity between HPC and CNC. In this work, HPC of different molecular weights was comixed with CNC of different contents, which was then dried using different methods, and the dried samples were redispersed in water. The addition of HPC improved the redispersibility of the CNC. Finally, the redispersed suspension was also redried to form a film, which was found to retain its structure color. These results provide an important avenue for the redispersion of dried CNC and for the development of functional materials from redispersed CNC.

Palladium catalyzed ortho-C(sp2)-H activation/cyclization of aryl amines assisted by imine and vinylacetic acid.

Palladium-catalyzed directed C - H functionalization/cyclization is an effective approach for synthesizing nitrogen heterocycles. Imine, known for its ease of installation/removal, has been extensively used in the C-H activation of aldehydes, ketones, and alkylamines. Nevertheless, it has been rarely explored in the C(sp2)-H activation of aryl amines because of the generation of a strained four-membered palladacycle. Herein, an imine directed palladium catalyzed C(sp2)-H functionalization of aryl amines assisted by vinylacetic acid is established, providing access to a variety of γ-lactone fused tetrahydroquinolines under mild reaction conditions. The methodology demonstrates broad substrate scope and good functional group tolerance, representing notable advancement in organic synthesis. Mechanistic experiments are performed to clarify how the C(sp2)-H activation occurs, indicating the crucial role of vinylacetic acid. DFT calculations supports the observations, elucidating the strained four-membered ring C-H activation barrier is overcome via coordination and hydrogen bond interaction of vinylacetic acid.

Design and Evaluation of Peptide Inhibitors Targeting the Dimerization of SARS-CoV-2 Main Protease.

The severe acute respiratory syndrome virus 2 (SARS-CoV-2) seriously impacted public health. The evolutionarily conserved viral chymotrypsin-like main protease (Mpro) is an important target for anti-SARS-CoV-2 drug development. Previous studies have shown that the eight N-terminal amino acids (N8) of SARS-CoV Mpro are essential for its dimerization, and are used to design inhibitors against SARS-CoV Mpro dimerization. Here, we established a simple readout assay using SDS-PAGE and Coomassie blue staining to measure inhibitory activity of N8 peptide derived from SARS-CoV-2 Mpro. To optimize its inhibitory effect, we then modified the side-chain length, charge, and hydrophilicity of the N8 peptide, and introduced a mutated Mpro recognition sequence. As a result, we obtained a series of potent peptide inhibitors against SARS-CoV-2 Mpro, with N8-A24 being the most efficient with an IC50 value of 1.44 mM. We observed that N8-A24 reduced Mpro dimerization with an IC50 value of 0.86 mM. Molecular docking revealed that N8-A24 formed hydrogen bond interactions with critical dimeric interface residues, thus inhibiting its dimerization and activity. In conclusion, our study not only discovers a series of peptide inhibitors targeting the SARS-CoV-2 Mpro dimerization, but also provides a promising strategy for the rational design of new inhibitors against COVID-19.

Promoting Water Activation via Molecular Engineering Enables Efficient Asymmetric C-C Coupling during CO2 Electroreduction.

Water activation plays a crucial role in CO2 reduction, but improving the electrocatalytic performance through controlled water activation presents a significant challenge. Herein, we achieved electrochemical CO2 reduction to ethene and ethanol with high selectivity by promoting water dissociation and asymmetric C-C coupling by engineering Cu surfaces with N-H-rich molecules. Direct spectroscopic evidence, coupled with density functional theory calculations, demonstrates that the N-H-rich molecules accelerate interfacial water dissociation via hydrogen-bond interactions, and the generated hydrogen species facilitate the conversion of *CO to *CHO. This enables the efficient asymmetric *CHO-*CO coupling to C2 products with a faradaic efficiency (FE) ∼ 30% higher than that of the unmodified catalyst. Moreover, by adjustment of the relative *CHO/*CO coverage via Cu surface facet regulation, the selectivity can be entirely switched between C2 products and CH4. These mechanistic insights further guided the development of a more efficient catalyst by directly modifying Cu2O nanocubes with the N-H-rich molecule, achieving remarkable C2 product (mainly ethene and ethanol) FEs of 85.7% at a current density of 800 mA cm-2 and excellent stability under nearing industrial conditions. This study advances our understanding of the CO2 reduction mechanisms and offers an effective and general strategy for enhancing electrocatalytic performance by accelerating water dissociation.

From Gas to Solution: The Changing Neutral Structure of Proline upon Solvation.

Liquid-jet photoelectron spectroscopy (LJ-PES) and electronic-structure theory were employed to investigate the chemical and structural properties of the amino acid l-proline in aqueous solution for its three ionized states (protonated, zwitterionic, and deprotonated). This is the first PES study of this amino acid in its biologically relevant environment. Proline's structure in the aqueous phase under neutral conditions is zwitterionic, distinctly different from the nonionic neutral form in the gas phase. By analyzing the carbon 1s and nitrogen 1s core levels as well as the valence spectra of aqueous-phase proline, we found that the electronic structure is dominated by the protonation state of each constituent molecular site (the carboxyl and amine groups) with small yet noticeable interference across the molecule. The site-specific nature of the core-level spectra enables the probing of individual molecular constituents. The valence photoelectron spectra are more difficult to interpret because of the overlapping signals of proline with the solvent and pH-adjusting agents (HCl and NaOH). Yet, we are able to reveal subtle effects of specific (hydrogen-bonding) interaction with the solvent on the electronic structure. We also demonstrate that the relevant conformational space is much smaller for aqueous-phase proline than for its gas-phase analogue. This study suggests that caution must be taken when comparing photoelectron spectra for gaseous- and aqueous-phase molecules, particularly if those molecules are readily protonated/deprotonated in solution.

Skeletal Editing of Energetic Materials: Acid-Catalyzed One-Step Synthesis of Bridged Triazoles as High-Energy-Density Materials via the Nef Reaction.

Thermally stable insensitive energetic materials have captivated significant attention from the global research community due to their potential impact. In this study, a series of symmetric and asymmetric nitromethyl-bridged triazole compounds were synthesized from pyrimidine moieties via a skeletal editing approach. Additionally, carbonyl-bridged compounds were synthesized in a single step by using acid-catalyzed Nef reactions from their nitromethyl precursors. Peripheral modifications of pyrimidine resulted in fused energetic moieties. All synthesized compounds were fully characterized by using infrared spectroscopy, high-resolution mass spectrometry, multinuclear magnetic resonance spectroscopy, elemental analysis, and differential scanning calorimetry. Single-crystal X-ray diffraction analysis confirmed the structures of compounds 4 and 10. The newly synthesized moieties exhibit densities ranging from 1.75 to 1.86 g cm-3, detonation velocities between 8044 and 8608 m s-1, and detonation pressures between 23.10 and 30.31 GPa. Notably, compounds 9 and 10 demonstrate exceptional heat resistance, with decomposition temperatures of 315 and 335 °C, respectively. Computational studies, including density functional theory, quantum theory of atoms in molecules, noncovalent interactions, and electrostatic surface potential analysis, account for hydrogen-bonding and noncovalent interactions. This work highlights the potential of skeletal editing in the development of high-performing, thermally stable energetic materials.

In Silico Efficacy of Oleic Acid, n-Hexanoic acid, and Epiglobulol Obtained from Conocarpus Lancifolius against Class D β-lactamases

Introduction: Antimicrobial resistance poses an escalating global challenge, compounded by the sluggish pace of new antibiotic discovery. Objectives: This study undertook an in silico analysis of phytochemicals derived from Conocarpus lancifolius, a local plant in the Jazan region of Saudi Arabia, to investigate potential antibacterial agents. Methods: The 3D crystallographic structure of OXA-48 was sourced from the RCSB protein databank (PDBID: 3HBR) and pre-processed. The Lib Dock algorithm facilitated the analysis of optimal binding orientations and potential interactions between compounds and the 3HBR. Results: The docking analysis outcome revealed Oleic acid as the most active compound and the binding mode exhibited that the -OH group of the terminal carboxylic acid moiety formed hydrogen bonds with Thr197 and Ala207, and the oxygen atom showed bonding with Lys116. Moreover, N-hexanoic acid also demonstrated promising binding interactions with the 3HBR, displaying hydrogen bond interactions with Lys208, Tyr211, and Ser70, along with hydrophobic alkyl interactions with Lys208 and Met115 at the protein's active sites. Unfavourable donor-donor and acceptor-acceptor bindings were also observed with Ser70 and Arg250 residues. Conclusions: The OXA-48 and NDM-1 predominate in countries of the Arabian Peninsula. Our findings suggest oleic acid as a promising candidate for combating OXA-48 β-lactamase, pending further assessment of its atomic structure via X-ray crystallography.

Quenching Rate Constants of Lewis Base-Boryl Radical by Substrates: a Laser Flash Photolysis Study.

The advanced strategy using Lewis base-boryl radicals (LBRs) has recently been proposed for the addition of alkyl substituents to the full-carbon quaternary center of an organic molecule. However, as the rate-determining step in the whole route, reaction rate constants of LBRs with substrates are extremely lacking. In this paper, 4-dimethylaminopyridine (DMAP)-BH2• was selected as a representative of LBRs, and its reactions with six monochloro-substituted substrates, including three methyl chlorobenzoates and three chlorinated acetanilides were studied in experiments and theoretical calculations. The bimolecular reaction rate constants, kq, were determined using laser flash photolysis approach. By comparing activation energies along the two addition pathways, we have clarified the rate-determining step as the attacking to carbonyl oxygen instead of chlorine atom. Furthermore, noncovalent interaction (NCI) analyses on these substrates indicate that weak interactions, such as hydrogen-bonding and van der Waals interactions, have significant influence on the reactivity of these substrates. Our study provides concrete clues to extend this synthetic strategy.

Oral administration of tannic acid attenuates dyslipidemia, hyperglycemia, and oxidative stress in high‐fat and fructose diet‐induced obesity in rats

AbstractObesity and diabetes are considered life‐threatening conditions, characterized by increased oxidative stress, insulin resistance, hepatotoxicity, hyperglycemia, and hypercholesterolemia. Therefore, we studied the effects of tannic acid in a high‐fat and fructose‐diet‐induced rat model of obesity. Administration of tannic acid at doses of 200 and 400 mg/kg significantly reduced fasting blood glucose concentration, reversed disoriented lipid profile, decreased liver enzyme activities, and inhibited oxidative stress compared to the high‐fat, high‐sugar group. Histopathological examination showed preserved pancreas and liver architecture in the tannic acid‐administered groups. The in vitro inhibitory activity of tannic acid against alpha‐amylase, alpha‐glucosidase, and pancreatic lipase showed good inhibitory potential. Molecular docking studies showed high binding affinity and more hydrogen bond interactions between tannic acid and receptor proteins (alpha‐amylase, alpha‐glucosidase, and pancreatic lipase) implicated in obesity and diabetes. In conclusion, tannic acid prevented the onset of oxidative stress, preserved the liver, and restored the disoriented lipid profile in high‐fat and fructose diet‐induced obesity in rats.

Characteristics of whey protein concentrate/egg white protein composite film modified by transglutaminase and its application on cherry tomatoes.

In order to obtain food packaging film with better performance, whey protein concentrate (WPC) and egg white protein (EWP) were used as film-forming substrates, and its film properties weremodified by transglutaminase (TG). Then the effect of TG on the mechanical, physical, barrier, and microstructural properties of the WPC/EWP composite biodegradable film was investigated, and its preliminary application potential was explored. Compared toWPC and EWP films, WPC/EWP composite film had higher transmittance, tensile strength (TS), and thermal stability. Fluorescence results showed that the film experienced fluorescence quenching after TG treatment. Fourier transform infrared and x-ray diffraction results showed that WPC and EWP had good compatibility in the biodegradable film, the hydrogen bond interaction of film was increased due to TG, resulting in an increase in TS. Meanwhile, the water vapor permeability and contact angle of WPC/EWP film treated with TG at 5U/g protein increased by 28% and 76.1%, respectively. Besides, the WPC/EWP biodegradable film modified by TG (TG-W/E) was applied as a coating film on cherry tomatoes, effectively reducing the weight loss rate during storage from 14.2% to 10.8%. Furthermore, indexes, such as solid content, spoilage rate, hardness, pH, and lycopene, showed that the film had a good preservation effect on cherry tomatoes. To conclude, the appropriate addition of TG has a positive effect on the film properties of the WPC/EWP biodegradable film, which is beneficial to the development and utilization of protein-based film. WPC/EWP biodegradable film modified by TG has a great application prospect in extending the shelf life of fruit and vegetable.

Molecular mechanism underlying effect of D93 and D289 protonation states on inhibitor-BACE1 binding: exploration from multiple independent Gaussian accelerated molecular dynamics and deep learning

ABSTRACT BACE1 has been regarded as an essential drug design target for treating Alzheimer’s disease (AD). Multiple independent Gaussian accelerated molecular dynamics simulations (GaMD), deep learning (DL), and molecular mechanics general Born surface area (MM-GBSA) method are integrated to elucidate the molecular mechanism underlying the effect of D93 and D289 protonation on binding of inhibitors OV6 and 4B2 to BACE1. The GaMD trajectory-based DL successfully identifies significant function domains. Dynamic analysis shows that the protonation of D93 and D289 strongly affects the structural flexibility and dynamic behaviour of BACE1. Free energy landscapes indicate that inhibitor-bound BACE1s have more conformational states in the protonated states than the wild-type (WT) BACE1, and show more binding poses of inhibitors. Binding affinities calculated using the MM-GBSA method indicate that the protonation of D93 and D289 highly disturbs the binding ability of inhibitors to BACE1. In addition, the protonation of two residues significantly affects the hydrogen bonding interactions (HBIs) of OV6 and 4B2 with BACE1, altering their binding activity to BACE1. The binding hot spots of BACE1 recognized by residue-based free energy estimations provide rational targeting sites for drug design towards BACE1. This study is anticipated to provide theoretical aids for drug development towards treatment of AD.

Study of the effect of N, N-diethyl hydroxyl amine/multi-layered graphene oxide hybrid on reducing cathodic delamination and increasing corrosion resistance of epoxy coating on steel substrate

In this study, a hybrid of multi-layered graphene oxide (MLGO) and oxygen absorbent corrosion inhibitor N, N-diethyl hydroxylamine (DEHA) was investigated. The nano hybrid was prepared in order to reduce the amount of cathodic delamination and increase the corrosion resistance of the epoxy coating. Epoxy coatings were prepared using the optimal percentage of 0.75 wt. % of the nano hybrid with different ratios between MLGO and DEHA like (1:2), (1:1) and (2:1). Mapping energy-dispersive X-ray spectroscopy, thermo gravimetry analysis and Fourier transform infrared (FT-IR) analysis indicated the uniform distribution of the inhibitor throughout the MLGO structure and the hydrogen bond interactions between them. The results of FT-IR spectroscopy: attenuated total reflectance test after six months confirmed the presence and stability of the inhibitor in the coating. Also, the results of 800 h of salt spray test and the long-term electrochemical impedance test after 7 months showed that the epoxy coating, containing MLGO-DEHA (1:2) had the highest corrosion resistance (2.54 × 107 Ω cm2) and the lowest cathodic delamination (15.9%). The results were also confirmed by cathodic delamination and pull-off adhesion tests.

PH-Independent Selective Formation of VO2+ Motif Incorporating a Family of Hydrazone Ligands: Synthesis, Structure, and Luminescence-Based Sensing Studies toward Selective Metal Ions.

Two new dioxidovanadium(V) compounds with the general formula [VVO2(L)] (L = hydrazone ligand) were synthesized using three different methods (acidic, neutral, and basic media) with either VIVOSO4. 5H2O, [VIVO(acac)2], or NH4VVO3 as the starting material and hydrazone ligands. In both cases, five coordinated V5+ ions adopted distorted square pyramidal geometry through the coordination of two oxido ligands and one hydrazone ligand. In compound 1, the presence of free hydroxyl groups stabilized the molecular species through intramolecular O-H•••N type hydrogen bond interactions. In compound 2, the free amino groups are involved in both intramolecular N-H•••N type and intermolecular N-H•••O type hydrogen bond interactions. Compound 1 showed highly selective luminescence turn-on behavior, along with a 33-nm blue shift in the presence of Al3+ ions in an aqueous medium. The experimental limit of detection (LOD) was found to be 66 nM. Whereas compound 2 showed luminescence quenching behavior in the presence of Fe3+, Al3+, and Cr3+ ions. The LODs were observed to be 312, 408, and 280 nM for Fe3+, Al3+, and Cr3+ ions, respectively. The luminescence response mechanisms of both compounds in the presence of metal ions have been correlated with molecular-level interactions.

High Proton Conductivity of Sulfonate-amine Ionic HOFs and Enhancement of SPEEK Composite Membranes.

Hydrogen-bonded organic frameworks (HOFs) are crystalline materials assembled by intermolecular hydrogen-bonding interactions, and their hydrogen-bonding structures are effective pathways for proton transport. Herein, we synthesize iHOF-45 using 4,4'-diaminodiphenylmethane and 1,3,6,8-pyrenetetrasulfonicacid sodium salt with 2D hydrogen-bonding networks. The stability of ionic HOFs (iHOFs) can be enhanced by introducing ionic bonds in addition to hydrogen-bonding forces. Thermal analyses demonstrated that iHOF-45 exhibited excellent thermal stability up to 332 °C. The proton conductivity of iHOF-45 was evaluated, demonstrating a notable increase with rising temperature and RH. At 100 °C and 98 % RH, the conductivity reached 5.25×10-3 S cm-1. The activation energy (Ea) of iHOF-45 was calculated to be 0.281 eV for 98 % RH, and the proton conduction was attributed to the Grotthuss mechanism, whereby the protons were transported in 2D hydrogen-bonding networks. Moreover, iHOF-45 was doped into SPEEK to prepare composite membranes, the proton conductivity of the 15 % iHOF-45/SPEEK membrane reached 9.52×10-2 S cm-1 at 80 °C and 98 % RH, representing a 45.1 % increase over that of the SPEEK. This suggests that doping enhances the proton conductivity of SPEEK and providing a reference for the development of high proton conductivity materials.

Boosting mRNA-Engineered Monocytes via Prodrug-Like Microspheres forBone Microenvironment Multi-Phase Remodeling.

Monocytes, as progenitors of macrophages and osteoclasts, play critical roles in various stages of bone repair, necessitating phase-specific regulatory mechanisms. Here, icariin (ICA) prodrug-like microspheres (ICA@GM) are developed, as lipid nanoparticle (LNP) transfection boosters, to construct mRNA-engineered monocytes for remodeling the bone microenvironment across multiple stages, including the acute inflammatory and repair phases. Initially, ICA@GM is prepared from ICA-conjugated gelatin methacryloyl via a microfluidics system. Then, monocyte-targeting IL-4 mRNA-LNPs are then prepared and integrated into injectable microspheres (mRNA-ICA@GM) via electrostatic and hydrogen bond interactions. After bone-defect injection, LNPs are controlled released from mRNA-ICA@GM within 3 days, rapidly transfecting monocytes for monocyte IL-4 mRNA-engineering, which effectively suppressed acute inflammatory responses via polarization programming and paracrine signaling. Afterwards, ICA is sustainably released as well via cleavable boronate esters across multiple stages, cooperatively boosting the mRNA-engineered monocytes to inhibit coenocytic fusion and osteoclastic function. Both in vitro and in vivo data indicated that mRNA-ICA@GM can not only reverse the inflammatory environment but also suppress monocyte-derived osteoclast formation to accelerate bone repair. In summary, mRNA-engineered monocytes and ICA prodrug-like microspheres are combined to achieve long-lasting multi-stage bone microenvironment regulation, offering a promising repair strategy.

Systematic analysis of natural topoisomerase I inhibitors from Forsythiae Fructus by ultrafiltration-UPLC-ESI-MS/MS, pharmacophore modelling, and molecular dynamics simulation

This study conducted a systematic analysis to explore natural DNA topoisomerase I (topo I) inhibitors from Forsythiae Fructus (FF). Crude extract of FF exhibited notable toxic and anti-proliferative effects on A549 cells. A total of 36 components were identified using bioaffinity ultrafiltration UPLC-ESI-MS/MS. Pinoresinol, 1,8-dihydrox­yanthraquinone, quercetin, and lariciresinol were screened as topo I inhibitors. Their ESI fragmentation patterns were analysed. An obvious repair effect on damaged DNA strands was observed by topo I inhibitory binding assay. Moreover, a common feature-based pharmacophore model was constructed and another 7 topo I inhibitors were screened. Molecular docking indicated that hydrogen bond, π-anion, and π-alkyl interaction were major interactions. Molecular dynamics simulation revealed important residues determining the binding of amentoflavone, forsythoside B and topo I. The results improved current understanding of natural topo I inhibitors from FF. Moreover, the combination of multi-disciplinary approaches provided a new tool to investigate natural antitumor products.