The toxicity for the human body of non-steroidal anti-inflammatory drugs (NSAIDs) overdoses is a consequence of their low water solubility, high doses, and facile accessibility to the population. New drug delivery systems (DDS) are necessary to overcome the bioavailability and toxicity related to NSAIDs. In this context, UiO-66(Zr) metal-organic framework (MOF) shows high porosity, stability, and load capacity, thus being a promising DDS. However, the adsorption and release capability for different NSAIDs is scarcely described. In this work, the biocompatible UiO-66(Zr) MOF was used to study the adsorption and release conditions of ibuprofen, naproxen, and diclofenac using a theoretical and experimental approximation. DFT results showed that the MOF-drug interaction was due to an intermolecular hydrogen bond between protons of the groups in the defect sites, (μ3 - OH, and - OH2) and a lone pair of oxygen carboxyl functional group of the NSAIDs. Also, the experimental results suggest that the solvent where the drug is dissolved affects the adsorption process. The adsorption kinetics are similar between the drugs, but the maximum load capacity differs for each drug. The release kinetics assay showed a solvent dependence kinetics whose maximum liberation capacity is affected by the interaction between the drug and the material. Finally, the biological assays show that none of the systems studied are cytotoxic for HMVEC. Additionally, the wound healing assay suggests that the UiO-66(Zr) material has potential application on the wound healing process. However, further studies should be done.

The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation. This study utilizes a novel integration of computational techniques, including multiscale biomolecular and molecular dynamics simulations, physicochemical and medicinal chemistry predictions, quantum computations and virtual screening from the ZINC and Chembridge databases, to elucidate the resistance mechanism and identify lead compounds that have the potential to improve treatment outcomes for PZA-resistant MTB, namely ZINC15913786, ZINC20735155, Chem10269711, Chem10279789 and Chem10295790. These computational methods offer a cost-effective, rapid alternative to traditional drug trials by bypassing the need for organic subjects while providing highly accurate insight into the binding sites and efficacy of new drug candidates. The need for rapid and appropriate drug development emphasizes the need for robust computational analysis to justify further validation through in vitro and in vivo experiments.

Cyclodextrin-based metal-organic framework (CD-MOF) has been widely used in various delivery systems due to its excellent edibility and high drug loading capacity. However, its typically bulky size and high brittleness in aqueous solutions pose significant challenges for practical applications. Here, we proposed an ultrasonic-assisted method for rapid synthesis of uniformly-sized nanoscale CD-MOF, followed by its hydrophobic modification through ester bond cross-linking (Nano-CMOF). Proper ultrasound treatment effectively reduced particle size to nanoscale (393.14 nm). Notably, carbonate ester cross-linking method significantly improved water stability without altering its cubic shape and high porosity (1.3 cm3/g), resulting in a retention rate exceeding 90% in various media. Furthermore, the loading of quercetin did not disrupt cubic structure and showcased remarkable storage stability. Nano-CMOF achieved controlled release of quercetin in both aqueous environments and digestion. Additionally, Nano-CMOF demonstrated exceptional antioxidant (free radical scavenging 82.27%) and biocompatibility, indicating its significant potential as novel nutritional delivery systems in food and biomedical fields.

A novel method for chiral identification of glutamine enantiomers based on chiral carbon quantum dots (cCQDs) fluorescent probes. cCQDs were prepared using a one-step hydrothermal method with L-tryptophan as the carbon source and chiral source, producing spherical nanoparticles exhibiting a blue colour luminescence. The fluorescence intensity (F) of cCQDs was enhanced or quenched following the addition of chiral enantiomeric glutamine (L/D-Gln), and therefore cCQDs, as a fluorescence probe, could be used for enantioselective sensing of the L/D-Gln. The fluorescence enhancement value (∆FE ) exhibited good linearity with L-Gln concentration in the range 0.23-10.00 mM, and the limit of detection was 0.14 mM. The fluorescence quenching value (∆FQ ) showed a good linear relationship with D-Gln concentration in the range 0.29-10.00 mM, and the detection limit was 0.18 mM. The mechanism of fluorescence enhancement/quenching was explored by molecular modelling and the type of quenching. The method was applied to the determination of L-Gln content in real samples, and the recovery rate was satisfactory. This study provided a novel approach for the synthesis of cCQDs and the recognition of amino acid enantiomers.

An innovative and universal imprinted sensor design for sandwich type detection of gemcitabine (GMT) in human serum samples is described. GMT is widely used in the treatment of different tumors, such as lung, ovarian, pancreatic, and breast cancer. The serum albumin-drug interaction was translated to design a multifunctional, ratiometric and dual mode silver nanoparticle based probe (BSA-Ag nanoprobe), as a read out system. Subsequently, polypyrrol imprinted drug receptor sites was engineered to selectively capture the GMT on the transducer surface. The GMT was sandwiched between imprinted receptor surface and BSA-Ag nanoprobe to generate the spectro-electrochemical signals. The formation of nanoprobe was confirmed through various characterization techniques, including X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, micro-Raman spectroscopy, Dynamic light scattering (DLS), and UV-Visible (UV-Vis) analysis, while each step of sensor fabrication was characterized via field emission scanning electron microscope (FE-SEM), Static water Contact angle measurements, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). Different variable parameters were optimized to improve the analytical performance of the sensor design. Under optimal conditions, spectro-electrochemical sensor permitted linear ranges between 1 and 200 μmol L-1 and 0.5-200 μmol L-1, with limits of detection (LOD) of 0.4 μmol L-1 and 0.15 μmol L-1 respectively. Furthermore, the designed sensor successfully differentiated the serum samples of lung cancer patients and healthy volunteers. The obtained results were validated with standard Liquid chromatography-mass spectrometry (LC/MS) analysis of the patients and healthy volunteer\'s serum samples. Lastly, density functional theory (DFT) and molecular docking calculations revealed the enhanced GMT binding capability of molecularly imprinted polypyrrole and molecular level interaction between the GMT and BSA, to validate the sandwich sensor design.

Ionic diodes constructed with asymmetric channel geometry and/or charge layout have shown outstanding performance in ion transport manipulation and reverse electrodialysis (RED) energy collection, but the working mechanism is still indistinct. Herein, we systematically investigated RED energy conversion of straight nanochannel-based bipolar ionic diode by coupling the Poisson-Nernst-Planck and Navier-Strokes equations. The effects of nanochannel structure, charging polarity, and symmetricity as well as properties of working fluids on the output voltage and output power were investigated. The results show that as high-concentration feeding solution is applied, the bipolar ionic diode-based RED system gives higher output voltage and output power compared to the unipolar channel RED system. Under optimal conditions, the voltage output of the bipolar channel is increased by ∼100% and the power output is increased by ∼260%. This work opens a new route for the design and optimization of high-performance salinity energy harvester as well as for water desalination.

Patient-derived tumor organoids (PDTOs) have the potential to be used to predict the patient response to chemotherapy. However, the cutoff value of the half-maximal inhibition concentration (IC50) for PDTO drug sensitivity has not been validated with clinical cohort data. We established PDTOs and performed a drug test in 277 samples from 242 CRC patients who received FOLFOX or XELOX chemotherapy. After follow-up and comparison of the PDTO drug test and final clinical outcome results, the optimal IC50 cutoff value for PDTO drug sensitivity was 43.26 μmol/L. This PDTO drug test-defined cutoff value could predict patient response with 75.36% sensitivity, 74.68% specificity, and 75% accuracy. Moreover, this value distinguished groups of patients with significant differences in survival benefit. Our study is the first to define the IC50 cutoff value for the PDTO drug test to effectively distinguish CRC patients with chemosensitivity or nonsensitivity and predict survival benefits.

The design, synthesis, and biological evaluation of a novel series of HIV-1 protease inhibitors containing pyrrolidines with diverse linkers as the P2 ligands and various aromatic derivatives as the P2\' ligands were described. A number of inhibitors demonstrated potent efficacy in both enzyme and cellular assays, as well as relatively low cytotoxicity. In particular, inhibitor 34b with a (R)-pyrrolidine-3-carboxamide P2 ligand and a 4-hydroxyphenyl P2\' ligand displayed exceptional enzyme inhibitory activity with an IC50 value of 0.32 nM. Furthermore, 34b also exhibited robust antiviral activity against both wild-type HIV-1 and drug-resistant variant with low micromolar EC50 values. In addition, the molecular modelling studies revealed the extensive interactions between inhibitor 34b and the backbone residues of both wild-type and drug-resistant HIV-1 protease. These results suggested the feasibility of utilizing pyrrolidine derivatives as the P2 ligands and provided valuable information for further design and optimization of highly potent HIV-1 protease inhibitors.

Here, an ethanol-mediated method was introduced to fabricate γ-cyclodextrin-based metal-organic frameworks (γ-CD-MOFs) as microcarriers for epigallocatechin-3-gallate (EGCG). Through adjusting ethanol gas diffusion temperature and ethanol liquid feed speed, we achieved control of crystallization efficiency and crystals size without extra surfactants. Under the sequential regulatory by ethanol in two phases, the obtained γ-CD-MOFs with cubic shape exhibited excellent crystallinity, high surface area, and uniform size distribution. Through the interplay of hydrogen bonding, hydrophobic interactions and π stacking, EGCG molecules could be stored efficiently within cavities and tunnels of the γ-CD-MOFs with high load capability of 334 mg g-1. More importantly, the incorporation of EGCG within frameworks wouldn\'t disintegrate the unique body-centered cubic structure of γ-CD-MOFs, in turn, would improve the thermostability and antioxidative activity of EGCG. Significantly, all food-grade materials ensured the γ-CD-MOFs high acceptance and applicability for food and biomedical applications.

The ongoing antibiotic-resistance crisis is becoming a global problem affecting public health. Urgent efforts are required to design novel therapeutics against pathogenic bacterial species. Brucella melitensis is an etiological agent of brucellosis, which mostly affects sheep and goats but several cases have also been reported in cattle, water buffalo, yaks and dogs. Infected animals also represent the major source of infection for humans. Development of safer and effective vaccines for brucellosis remains a priority to support disease control and eradication in animals and to prevent infection to humans. In this research study, we designed an in-silico multi-epitopes vaccine for B. melitensis using computational approaches. The pathogen core proteome was screened for good vaccine candidates using subtractive proteomics, reverse vaccinology and immunoinformatic tools. In total, 10 proteins: catalase; siderophore ABC transporter substrate-binding protein; pyridoxamine 5\'-phosphate oxidase; superoxide dismutase; peptidylprolyl isomerase; superoxide dismutase family protein; septation protein A; hypothetical protein; binding-protein-dependent transport systems inner membrane component; and 4-hydroxy-2-oxoheptanedioate aldolase were selected for epitopes prediction. To induce cellular and antibody base immune responses, the vaccine must comprise both B and T-cells epitopes. The epitopes were next screened for antigenicity, allergic nature and water solubility and the probable antigenic, non-allergic, water-soluble and non-toxic nine epitopes were shortlisted for multi-epitopes vaccine construction. The designed vaccine construct comprises 274 amino acid long sequences having a molecular weight of 28.14 kDa and instability index of 27.62. The vaccine construct was further assessed for binding efficacy with immune cell receptors. Docking results revealed that the designed vaccine had good binding potency with selected immune cell receptors. Furthermore, vaccine-MHC-I, vaccine-MHC-II and vaccine-TLR-4 complexes were opted based on a least-binding energy score of -5.48 kcal/mol, 0.64 kcal/mol and -2.69 kcal/mol. Those selected were then energy refined and subjected to simulation studies to understand dynamic movements of the docked complexes. The docking results were further validated through MMPBSA and MMGBSA analyses. The MMPBSA calculated -235.18 kcal/mol, -206.79 kcal/mol, and -215.73 kcal/mol net binding free energy, while MMGBSA estimated -259.48 kcal/mol, -206.79 kcal/mol and -215.73 kcal/mol for TLR-4, MHC-I and MHC-II complexes, respectively. These findings were validated by water-swap and entropy calculations. Overall, the designed vaccine construct can evoke proper immune responses and the construct could be helpful for experimental researchers in formulation of a protective vaccine against the targeted pathogen for both animal and human use.