Affinity Interaction Research Articles

Molecular docking and invitro evaluation of glucosamine sulfate targeting MMP-3, MMP-9, and IL-4 for potential osteoarthritis treatment.

This study intended to investigate the potential of glucosamine sulfate (GS) as an inhibitor of genes involved in osteoarthritis (OA) development. Despite GS is often used for OA treatment due to its cartilage preservation and minimum side effects, the molecular mechanism behind its interactions remains unknown. Molecular docking was conducted to analyze the interactions between glucosamine sulfate and genes associated with OA such as matrix metalloproteinase-3 (MMP-3), MMP-9, and interleukin-4 (IL-4). Additionally, a cell viability assay using RAW 264.7 cells was performed to evaluate the toxicity of glucosamine sulfate at various concentrations. Molecular docking results revealed that glucosamine sulfate has a good binding affinity and stable interactions with MMP-3, MMP-9, and IL-4, indicating that it may have inhibitory effects on targeted genes. Nevertheless, the cell viability assay analysis demonstrated that glucosamine sulfate had considerable toxic effects in RAW 264.7 cells at highest concentrations. Glucosamine sulfate exhibited stable molecular interactions with genes associated to OA development. However, GS toxicity at high concentrations necessitates future research studies to optimize dosing and assess its therapeutic safety in OA treatment.

Tumor-Expressed SPPL3 Supports Innate Antitumor Immune Responses.

The development of an effective antitumor response relies on the synergistic actions of various immune cells that recognize tumor cells via distinct receptors. Tumors, however, often manipulate receptor-ligand interactions to evade recognition by the immune system. Recently, we highlighted the role of neolacto-series glycosphingolipids (nsGSLs), produced by the enzyme β1,3-N-acetylglucosaminyltransferase 5 (B3GNT5), in tumor immune escape. We previously demonstrated that loss of signal peptide peptidase like 3 (SPPL3), an inhibitor of B3GNT5, results in elevated levels of nsGSLs and impairs CD8 T cell activation. The impact of loss of SPPL3 and an elevated nsGSL profile in tumor cells on innate immune recognition remains to be elucidated. This study investigates the antitumor efficacy of neutrophils, NK cells, and γδ T cells on tumor cells lacking SPPL3. Our findings demonstrate that SPPL3-deficient target cells are less susceptible to trogocytosis by neutrophils and killing by NK cells and γδ T cells. Mechanistically, SPPL3 influences trogocytosis and γδ T cell-instigated killing through modulation of nsGSL expression, whereas SPPL3-mediated reduced killing by NK cells is nsGSL-independent. The nsGSL-dependent SPPL3 sensitivity depends on the proximity of surface receptor domains to the cell membrane and the affinity of receptor-ligand interactions as shown with various sets of defined antibodies. Thus, SPPL3 expression by tumor cells alters crosstalk with immune cells through the receptor-ligand interactome thereby driving escape not only from adaptive but also from innate immunity. These data underline the importance of investigating a potential synergism of GSL synthesis inhibitors with current immune cell-activating immunotherapies.

Identification of novel tau positron emission tomography tracers for chronic traumatic encephalopathy by comprehensive in silico screening and molecular dynamics simulation.

Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive mild traumatic brain injury, is characterized neuropathologically by abnormal hyperphosphorylated tau accumulation. Early detection of tau deposition in the brain is crucial for the prevention and evaluation of CTE. Positron emission tomography (PET) tracers can image specific proteins, while the optimal PET tracer for CTE tau fibrils remains unidentified. In this study, structure-based virtual screening and CNS PET MPO algorithms were utilized to identify candidates for novel tau PET tracers from 23 000 compounds in the ChemDiv CNS BBB library. A total of 8 μs molecular dynamics simulations were then employed to evaluate their binding affinity and atomic-level interaction with CTE tau protofibrils. The results indicate that V017-7820 (CNS-4), S776-0061 (CNS-12), S567-0465 (CNS-18), and T828-0465 (CNS-25) exhibit higher docking scores and binding free energies with CTE tau protofibrils while also satisfying the fundamental physicochemical properties of PET tracers. Further simulation analyses reveal that CNS-4 has the strongest binding affinity to tau protofibrils among the four compounds. Hydrophobic, π-π stacking, and hydrogen bonding interactions are the primary driving forces for the binding of these compounds to CTE tau protofibrils. In particular, CNS-12 and CNS-25 exhibit more intense hydrophobic and π-π stacking interactions, whereas CNS-4 and CNS-25 exhibit stronger hydrogen bonding interactions. This study identifies promising lead compounds for tau PET tracers and highlights their mechanism of binding to CTE tau protofibrils, which provides new insights for further screening and development of novel PET tracers for CTE diagnosis.

Integrative Machine Learning, Virtual Screening, and Molecular Modeling for BacA-Targeted Anti-Biofilm Drug Discovery Against Staphylococcal Infections

The rise in antibiotic-resistant Staphylococcal infections necessitates innovative approaches to identify new therapeutic agents. This study investigates the application of machine learning models to identify potential phytochemical inhibitors against BacA, a target related to Staphylococcal infections. Active compounds were retrieved from BindingDB while the decoy was generated from DUDE. The RDKit was utilized for feature engineering. Machine learning models such as k-nearest neighbors (KNN), the support vector machine (SVM), random forest (RF), and naive Bayes (NB) were trained on an initial dataset consisting of 226 active chemicals and 2550 inert compounds. Accompanied by an MCC of 0.93 and an accuracy of 96%, the RF performed better. Utilizing the RF model, a library of 9000 phytochemicals was screened, identifying 300 potentially active compounds, of which 192 exhibited drug-like properties and were further analyzed through molecular docking studies. Molecular docking results identified Ergotamine, Withanolide E, and DOPPA as top inhibitors of the BacA protein, accompanied by interaction affinities of −8.8, −8.1, and −7.9 kcal/mol, respectively. Molecular dynamics (MD) was applied for 100 ns to these top hits to evaluate their stability and dynamic behavior. RMSD, RMSF, SASA, and Rg analyses showed that all complexes remained stable throughout the simulation period. Binding energy calculations using MMGBSA analysis revealed that the BacA_Withanolide E complex exhibited the most favorable binding energy profile with significant van der Waals interactions and a substantial reduction in gas-phase energy. It also revealed that van der Waals interactions contributed significantly to the binding stability of Withanolide E, while electrostatic interactions played a secondary role. The integration of machine learning models with molecular docking and MD simulations proved effective in identifying promising phytochemical inhibitors, with Withanolide E emerging as a potent candidate. These findings provide a pathway for developing new antibacterial agents against Staphylococcal infections, pending further experimental validation and optimization.

Unveiling the potential of bioactive compounds from Linum usitatissimum L. to target Hepatocellular carcinoma: an in silico based approach

Bioactive metabolites from Linum usitatissimum L. have been extensively explored for their anti-cancer and antioxidant potential in several cancer cell lines. The bioactive chemicals that have been reported are being assessed using in silico methods to create a new antagonist that may effectively target hepatocellular carcinoma by inhibiting c-Kit (stem cell factor receptor) and HBXIP (hepatitis B X-interacting protein). Dysregulation in function or overexpression of c-Kit and HBXIP shows the development of hepatocellular carcinoma. The objective of this study is to use computational approaches to choose the most suitable candidate that interacts with our chosen target proteins, c-Kit and HBXIP, derived from flaxseed. From the online resources, namely RCSB and PubChem, the 3D structures of the proteins and bioactive compounds are obtained. The drug likeness study and ADMET profiling of these bioactive compounds were performed, and the selected fourteen compounds were considered for docking analysis. The molecular docking study revealed that secoisolariciresinol (SECO) has a comparable interaction affinity of −5.5 kcal/mol and −7.5 kcal/mol with HBXIP and c-KIT, respectively, when compared to the redock co-crystal complex (-3.5 kcal/mol and −12.4 kcal/mol, respectively). The results of the molecular dynamics simulation study demonstrate the constancy of the SECO_HBXIP and SECO_c-Kit complexes when compared to the redock complex. The average root-mean-square fluctuation (RMSF), root-mean-square deviation (RMSD) values, gyration (Rg) and hydrogen bonding provide additional evidence of the significant binding and stability of the complexes. Moreover, in vitro cell viability assay on HepG2 also showed a significant reduction in the cell proliferation after the treatment with SECO.

Dynamic O-GlcNAcylation governs long-range chromatin interactions in V(D)J recombination during early B-cell development.

V(D)J recombination secures the production of functional immunoglobulin (Ig) genes and antibody diversity during the early stages of B-cell development through long-distance interactions mediated by cis-regulatory elements and trans-acting factors. O-GlcNAcylation is a dynamic and reversible posttranslational modification of nuclear and cytoplasmic proteins that regulates various protein functions, including DNA-binding affinity and protein-protein interactions. However, the effects of O-GlcNAcylation on proteins involved in V(D)J recombination remain largely unknown. To elucidate this relationship, we downregulated O-GlcNAcylation in a mouse model by administering an O-GlcNAc inhibitor or restricting the consumption of a regular diet. Interestingly, the inhibition of O-GlcNAcylation in mice severely impaired Ig heavy-chain (IgH) gene rearrangement. We identified several factors crucial for V(D)J recombination, including YY1, CTCF, SMC1, and SMC3, as direct targets of O-GlcNAc modification. Importantly, O-GlcNAcylation regulates the physical interaction between SMC1 and SMC3 and the DNA-binding patterns of YY1 at the IgH gene locus. Moreover, O-GlcNAc inhibition downregulated DDX5 protein expression, affecting the functional association of CTCF with its DNA-binding sites at the IgH locus. Our results showed that locus contraction and long-range interactions throughout the IgH locus are disrupted in a manner dependent on the cellular O-GlcNAc level. In this study, we established that V(D)J recombination relies on the O-GlcNAc status of stage-specific proteins during early B-cell development and identified O-GlcNAc-dependent mechanisms as new regulatory components for the development of a diverse antibody repertoire.

The Docking and Dynamics Simulation of Natural Compounds from Abrus precatorius L. for Investigating the Possibility of GluR3 Inhibition to Treat Depression

Background The rising incidence of Major Depressive Disorder (MDD), in conjunction with the inadequate effectiveness and resistance observed in existing therapeutic approaches, emphasizes the urgent need to investigate novel therapeutics that provide enhanced efficacy with reduced adverse effects. Abrus precatorius L., an herb that is readily available and frequently utilized in traditional medicine, is frequently prescribed to patients suffering from neurological disorders. Purpose The goal of this study is to discover novel active compounds from the A. precatorius plant that can specifically target the GluR3 receptor using in silico techniques, to develop a safe and efficient treatment for MDD. Methods Homology modeling, molecular docking, molecular dynamics simulation, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were employed in this investigation to screen compounds derived from A. precatorius. Their potential to inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activity, specifically glutamate receptor 3 (GluR3), which is associated with MDD, was the objective of this study. Results Among 31 compounds derived from A. precatorius, 15 successfully cleared the ADMET filter criteria. Subsequently, the best homology model of GluR3 was constructed using Phyre2. This facilitated an investigation into the intramolecular interactions exhibited by the filtered compounds. Notably, the four compounds with the most pronounced binding affinities are identified by their PubChem compound IDs (CIDs): 160511, 44257585, 1983, and 145857. The binding affinity and internal molecular interactions of the top-ranking compound, PubChem CID 160511, were subjected to further validation through MD simulations, affirming its sustained stability in binding. Conclusion CIDs: The compound 160511 cleared ADMET analysis with no notable side effects and high binding affinity and stability, making it a potential drug candidate for MDD. To ascertain the precise efficacy of medications, additional in vitro, in vivo, and clinical studies are required.

A hydrogel film microarray stabilizes very short structure switching aptamer duplexes to achieve enhanced sensing of small molecules

The reduction of affinity associated with the modifications required to create FRET- aptamer constructs represents a key challenge hindering the practical adaptation of such systems for small molecule detection. While the use of shorter and rationally positioned quencher stems is desirable to enhance target-induced fluorescence recovery, the weak hybridization potential of such stems results in high levels of background fluorescence and poor sensitivity. Herein, we introduce a hydrogel microarray sensor able to thermally stabilize very short aptamer duplexes (i.e., quencher stems ≤10-bp), resulting in improved FRET efficiency and reduced background levels across a broad range of conditions. The optimal hydrogel microarray can physically entrap >75 % of loaded aptamer reporters while maintaining high accessibility to the target molecules, enabling accurate quantification of dose-responsive affinity interactions. Using an ATP aptamer reporter, the hydrogel sensor can achieve a binding affinity as low as 14.7 µm − comparable to the native aptamer – and very low limits of detection (LOD) of 1.2 µm in a pure buffer and 4.6 µm in 50 % serum. Moreover, the developed hydrogel microarray is reusable, amenable to printing fabrication, and provides protection against nuclease-based degradation. This simple approach thus holds promise for advancing microarray aptamer technology in critical biosensing applications.

Anti-ulcerogenic activity of Citrus medica var. sarcodactylis fruit extract nano-emulsion in gastric ulcer rat model through modulating HMBG1/TLR4/NF-κB and Nrf2/HSP70/PGE2 signaling pathways

One of the most prevalent gastrointestinal multi-etiological diseases is gastric ulcer, with several consequences and serious side influences. Nowadays, nanotechnology is one of the advanced tools to enhance drug delivery and bioavailability. Hence, the prime goal of this study was to create safe gastro-protective therapy using methanol fruit extract of Citrus medica var. sarcodactylis (CMF) and its prepared nano formula (Nano-CMF). CMF or its nano form was given to rats at dose 600 mg/kg/day for a week along with a single oral administration of ethanol (5 ml/kg) at the 7th day. The particle size distribution of formulated CMF reflected the successful preparation of nano form, with average size 65 nm. Pretreatment with CMF or its nano formula to ethanol challenged rats significantly controlled the inflammatory response through down-regulated gastric HMBG1/TLR4/NF-κB signaling pathway and its downstream mediators at p<0.001. Moreover, CMF or nano-CMF lessened oxidative stress incidence via modulating Nrf2 signaling pathway, sustaining prostaglandin content, and reducing gastric juice acidity with a significant p value less than 0.001, as compared to the EtOH-intoxicated rats. In addition, nano form effectively preserved the gastric mucosal integrity and alleviated apoptosis in gastric cells as validated by ulcer index (p<0.001), and the histological and immunohistochemical findings, when matched to the EtOH-treated group. The metabolomics analysis revealed the characterization of 36 compounds. GC/MS of CH2Cl2 fraction led to the identification of 34 compounds, the major category was fatty acid esters amounting 43.92%. The TLC technique for methanol extract led to isolation of 8 compounds: (4,5-O-Dicaffeoylquinic acid, ferulic acid, hesperidin, limettin, 5-demethylsinensetin, brassicasterol, campesterol and β-sitosterol). Brassicasterol is newly reported from species while 5-demethylsinensetin was newly reported from the Citrus genus. Furthermore, the docking experiments revealed strong binding affinity interactions of these compounds with TLR-4, Nrf2-Keap1 complex, and pNF-κBp65. In conclusion, mechanism of action of CMF or its nano formula exerting anti-ulcer effect was postulated based on the synergistic action of its reported compounds which possesses anti-inflammatory, antioxidant, and anti-apoptotic activities. To be noted, nano CMF showed a superior potent anti-ulcer activity than CMF and conventional therapy, omeprazole.

Suppression of NNK Metabolism by Anthocyanin-Rich Haskap Berry Supplementation Through Modulation of P450 Enzymes

Oral supplementation of anthocyanins-rich haskap (Lonicera caerulea) berry (HB) reduces 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis, cytotoxicity, DNA damage, and modulated inflammation in vitro and in vivo. The procarcinogen NNK is metabolically activated by cytochrome P450 (P450) enzymes, producing reactive metabolites that induce lung carcinogenesis. Hypothesis: Therefore, we hypothesized that the HB-modulated protective effect against NNK could be due to its ability to suppress P450 enzymes. Methods: HB (6 mg of cyanidin-3-O-glucoside [C3G] in 0.2 g of HB/mouse/day) was given to A/J mice as a dietary supplement following subsequent administration of NNK (100 mg/kg body weight). The liver tissues of mice were analyzed to determine the expression of P450s and metabolites. Results: HB upregulated the expression of cyp2a4 and cyp2a5 mRNA and nuclear receptor/transcription factor (PPARα) in NNK-deprived hepatic tissues. With NNK, HB downregulated the expression of cyp2a4 and cyp2a5 and facilitated the formation of non-carcinogenic NNK metabolites. Molecular docking indicated a high binding affinity and strong hydrophobic interactions between C3G and its major metabolites, peonidin-3-O-glucoside, petunidin-3-O-glucoside, peonidin and cyanidin with Cyp2a5 and with human P450 homologue CYP2A13. Conclusions: HB could be a potential dietary supplement to inhibit the P450 activated NNK carcinogenic metabolites formation. Hence, inhibiting the activation of NNK by lung CYP2A13 through dietary HB supplementation could be a strategy to reduce lung carcinogenesis among smokers. Understanding the effect of HB on the activity of CYP2A13 in human studies is necessary before recommending these natural compounds as therapeutics.

Veratric Acid as a Potential Antidiabetic Agent: Molecular Docking and In vivo Enzyme Inhibition Studies with Insights from STz-NA Induced Diabetic Rat Model

Streptozotocin-nicotinamide (STz-NA) has proven to be an effective agent in inducing type 2 diabetes (T2DM) in experimental models due to its genotoxic impact on pancreatic β-cells. STz reduces nicotinamide adenine dinucleotide (NAD+) through the glucose transporter GLUT2, leading to cellular damage, DNA strand breaks, and cell death. Nicotinamide (NA), a biochemical precursor of NAD+ and poly-ADP-ribose-polymerase-1 (PARP-1) inhibitor, plays a crucial protective role by modulating NAD+ levels, which are essential in ATP production and other metabolic processes. Excessive DNA damage, however, triggers PARP-1 over-activation, depleting cellular reserves and resulting in cell necrosis. This study further investigates the antidiabetic and hepatoprotective effects of Veratric Acid (VA) by comparing it to Glibenclamide. Utilizing Computer-Aided Drug Design (CADD), VA was identified as a structurally similar compound with potential antidiabetic properties. Molecular docking studies targeting proteins, such as GLUT-1 (PDB ID: 4PYP) and 1BSI, along with in vivo assays in STz-NA-induced diabetic Wistar rats, were conducted. VA demonstrated significant binding affinity and molecular interactions comparable to standard antidiabetic agents, showing inhibitory effects on liver enzymes SGOT and SGPT, and supporting its potential role in diabetes management. Docking and histopathology results revealed that VA effectively reduced blood glucose, improved insulin levels, and enhanced liver function in diabetic rats. Additionally, VA promoted insulin secretion from pancreatic β-cells and upregulated insulin-related markers, with minimal hepatotoxicity compared to Glibenclamide. VA treatment significantly improved enzymatic and non-enzymatic antioxidant levels, lowered lipid peroxidation, and improved lipid profiles, which were confirmed by histopathological liver observations. Veratric Acid at low doses effectively modulates blood glucose and diabetes-related biochemical parameters, highlighting its promise as a safer, natural therapeutic alternative for diabetes treatment.

Novel Hydrazide-Hydrazones Bearing a Benzimidazole Ring: Design, Synthesis, and Evaluation of Inhibitor Properties Against CA I and CA II Isozymes.

In this study, we propose identifying potential novel compounds targeting carbonic anhydrase I and II. Herein, we have designed and synthesized new benzimidazole-hydrazide-hydrazones derivatives (4a-4r) to investigate the effects of these synthesized compounds on CA isoenzymes. The compounds' 1H NMR, 13C NMR, and HRMS spectra were used to confirm their chemical structures. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by invitro assay. These compounds have IC50 values of 3.727-1.493 μM (hCA I) and 3.892-1.547 μM (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 3.006 ± 0.17 μM-0.356 ± 0.0 μM (hCA I) and 2.923 ± 0.15 μM-0.346 ± 0.0 μM (hCA II). Acetazolamide (AAZ) was used as the reference in the study. The most potent derivatives, a 4-methoxy derivative (compound 4k) and 4-(trifluoromethyl) derivative (compound 4g), than AAZ (IC50 = 2.26 μM) and their IC50 values were found as 1.493 μM and 1.675 μM, respectively. Compared to AAZ, the other derivatives having more effect on hCA I were compounds 4b, 4e, 4l, 4m, 4n, and 4o. The compounds gave IC50 values of 1.743, 1.789, 1.933, 1.966, 1.983, and 1.986 μM, respectively. Compounds 4a-4r found no more effective inhibitory activity against hCA II isozyme than AAZ (IC50 = 1.17 μM). According to the invitro test results, detailed protein-ligand interactions of the compounds 4b and 4k exhibited considerably low binding energies, suggesting strong interaction affinities against hCA I. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.

Carotenoids Interaction with PCSK9: Exploring Novel Cholesterol-Lowering Strategies

Background/Objectives: This study investigated the potential of green algae-derived carotenoids as natural inhibitors of the proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of cholesterol metabolism. PCSK9 promotes the degradation of low-density lipoprotein receptors (LDLR), thereby increasing blood cholesterol levels and elevating the risk of cardiovascular diseases. Methods/Results: We screened the pharmacophore fit score of 27 carotenoids with PCSK9 and identified 14 that were analyzed for binding affinity and molecular interactions. Astaxanthin, siphonaxanthin, and prasinoxanthin were identified as the top candidates, demonstrating strong binding affinity (−10.5, −10.3, and −9.4 Kcal/mol, respectively) and stable interactions with several known key residues within the active site of PCSK9, including Pro-331, Arg-357, Cys-358, Val-359, Asp-360, Ile-416, Leu-436, Thr-437, Pro-438, Leu-440, Arg-458, Val-460, Trp-461, Arg-476, Cys-477, Ala-478, Ala-649, Val-650, and Asp-651. Density functional theory analysis confirmed the stability of astaxanthin and its favorable electronic properties, suggesting its potential as an effective inhibitor. Molecular dynamics simulations of the PCSK9–astaxanthin complex revealed sustained structural stability and key interactions critical for maintaining the functional integrity of the protein. Conclusions: These findings provide evidence that specific carotenoids, particularly astaxanthin, may offer a cost-effective alternative to existing PCSK9 inhibitors, providing a potential approach for managing cholesterol levels and reducing cardiovascular risk. Pre-clinical and clinical validations are required to confirm the therapeutic potential of these compounds.

From nature’s pharmacy: harnessing bioactive phytoconstituents as fibroblast growth factor receptor 3 inhibitors for anti-cancer therapeutics

Fibroblast growth factor receptor 3 (FGFR3) is a key protein involved in regulating cell growth and development. Aberrant activation of FGFR3 has been linked to several diseases, including cancer and skeletal disorders. Therefore, identifying potential inhibitors of FGFR3 is of great interest in developing targeted therapies. In this study, we employed a combined docking and molecular dynamics simulation (MDS) approach to investigate the inhibitory potential of plant-based compounds against FGFR3. Here, we utilized structure-based virtual screening to identify potential phytoconstituents from the IMPPAT library with the ability to inhibit FGFR3 activity. The initial screening process involved molecular docking to assess the binding potential of the compounds towards FGFR3. Afterward, we employed various filters to determine physicochemical properties, ADMET, and PASS evaluation to identify potential hits against FGFR3. This process discovered two phytoconstituents, Cycloartobiloxanthone and Desoxylimonin, as promising candidates against FGFR3. These compounds exhibited favorable binding affinity, efficiency, and specific interaction towards the FGFR3 binding pocket. They preferred binding to the active site of FGFR3 and possessed desirable drug-like properties. To gain a deeper understanding of their interaction mechanism, conformational dynamics, and stability, we conducted all-atom MDS lasting 200 nanoseconds (ns) on the FGFR3-Cycloartobiloxanthone and FGFR3-Desoxylimonin complexes. The MDS consistently demonstrated the formation of stable protein-ligand complexes between FGFR3 and Cycloartobiloxanthone/Desoxylimonin throughout the trajectory. Based on these results, it can be inferred that Cycloartobiloxanthone and Desoxylimonin can potentially serve as valuable scaffolds in developing drugs targeting FGFR3 for cancer therapeutic after required validation.

Lipopolysaccharide Imprinted Polymers for Specific Recognition of Bacterial Outer Membrane Vesicles.

Outer membrane vesicles (OMVs) secreted by bacteria are emerging diagnostic markers for bacterial infection or disease detection due to their carriage of various signaling molecules. However, actual biological samples of patients are extremely complex, and applying OMVs to clinical diagnosis remains a major challenge. One of the major challenges is that there are still great difficulties in the enrichment of OMVs including tedious steps and lower concentration. And some commonly used exosome enrichment methods, such as ultracentrifugation, still have some shortcomings. Herein, we introduce lipopolysaccharide (LPS) molecularly imprinted polymer (MIP) for efficient capturing and analyzing OMVs, enabling a novel approach to bacterial disease diagnosis based on biorecognition materials. LPS, as a unique structure of Gram-negative bacteria, also widely expressed on the surface of OMVs, which will form cyclic hydrogen bonds with functional monomers of MIP with affinity interactions. The prepared MIP efficiently can isolate OMVs from 100 μL of culture broth via specific affinity LPS in less than 40 min with a recovery rate of over 95%. Moreover, MIP exhibits good reusability, with almost identical enrichment performance after 5 repeated cycles, contributing to reducing experimental costs in both time and economy. The captured OMVs can be detected using Western blotting with target protein antibodies or in combination with proteomic analysis, providing a proteomic biomarker platform for early bacteria disease diagnosis.

Fluorescent Sensing for the Detection and Quantification of Sulfur-Containing Gases.

Sulfur-containing gases, such as H2S and SO2, play significant roles in a multitude of biological processes affecting human life and health. Precise and efficient detection of these gases is therefore crucial for advancing one's understanding of their biological roles and developing effective diagnostic strategies. Fluorescent sensing offers a highly sensitive and versatile approach for detecting these gases. This Review examines the recent advances in the fluorescent detection of H2S and SO2, highlighting the key mechanisms involved in fluorescence signal transduction, including changes in intensity and wavelength shifts. The diverse array of probe molecules employed for this purpose, including those utilizing mechanisms such as nucleophilic reactions, Förster resonance energy transfer (FRET), and sulfur affinity interactions are explored. In additional to organic sensors, the focus of the Review is particularly directed toward quantum dot (QD) systems, emphasizing their tunable optical properties that hold immense potential for fluorescence sensing. Beyond the traditional III-V QDs, we delve into the emerging fluorescence sensors based on halide perovskite QDs, upconversion nanocrystals, and other novel materials. These advanced QD systems hold promise for the development of highly sensitive and cost-effective gas detectors, paving the way for significant advances in biomedical and environmental monitoring. This Review provides a comprehensive overview of the current state-of-the-art in QD-based fluorescence sensing of sulfur-containing gases and provides a multifaceted discussion comparing organic fluorescent sensors with QD sensors, highlighting the key challenges and opportunities for the integration of fluorescence sensing as it evolves. The Review aims to facilitate further research and development of innovative sensing platforms to enable more accurate and sensitive detection of these important gases.

Ultrasound-Assisted Synthesis of Pyrazoline Derivatives as Potential Antagonists of RAGE-Mediated Pathologies: Insights from SAR Studies and Biological Evaluations.

In the context of age-related disorders, the receptor of advanced glycation end products (RAGE), plays a pivotal role in the pathogenesis of these conditions by triggering downstream signaling pathways associated with chronic inflammation and oxidative stress. Targeting this inflammaging phenomenon with RAGE antagonists holds promise for interventions with broad implications in healthy aging and the management of age-related conditions. This study explores the structure-activity relationship (SAR) of pyrazoline-based RAGE antagonists synthesized using an ultrasound-assisted green one-pot two-steps methodology. Our investigation identifies phenylurenyl-pyrazoline 2 g as a promising candidate, demonstrating superior efficiency compared to the reference antagonist Azeliragon (IC50=13 μM). Compound 2 g exhibits potent inhibition of the AGE2-BSA/sRAGE interaction (IC50=22 μM) and favorable affinity in Microscale Thermophoresis (MST) assays (Kd=17.1 μM), along with a favorable safety profile, with no apparent cytotoxicity observed in vitro in the MTS assay. These findings underscore the potential of pyrazoline-derived RAGE antagonists as therapeutic agents for addressing age-related disorders.

Crotalaria madurensis flavonol glycosides’ antibacterial activity against Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) infections are prevalent in hospitals and often lead to significant health complications. This study aimed to explore the chemical composition of the aerial part of Crotalaria madurensis and evaluate its antioxidant and antibacterial properties. The impact of gamma irradiation on the antibacterial properties of the plant extract and metabolite 1 against MRSA was also examined. Fourier-transform infrared (FTIR) analysis was conducted on the filtrates of untreated MRSA and MRSA treated with the plant extract and metabolite 1. Four flavonol glycosides were identified as gossypetin 8-methoxy, 3-O-β-D-xylopyranoside (metabolite 1), gossypetin 8-O-β-D-glucopyranoside (metabolite 2), kaempferol 3-O-β-D-glucpyranoside (Astragalin, metabolite 3), and herbacetin 7-methoxy-3-O-β-D-glucopyranoside (metabolite 4). All metabolites exhibited significant antioxidant properties using different assays. The antibacterial efficacy of the extract and metabolite 1, which showed substantial antioxidant properties compared to the other isolated metabolites, was evaluated. Both the plant extract and metabolite 1 significantly reduced the viability and cell count of MRSA at concentrations of 1.0 and 0.5 mg/ml. The antibacterial activity of the plant extract and metabolite 1 was assessed after gamma irradiation at 50 and 100 Gy, which did not significantly affect the antibacterial efficiency. FTIR analysis indicated that the plant extract and metabolite 1 significantly altered the band frequency values, bandwidth, and peak intensity % of the treated MRSA filtrate. Molecular docking studies suggested that metabolite 1 exhibited the highest antioxidant and anti-MRSA activity, with strong binding scores like the ligand, indicating an effective interaction and high affinity between metabolite 1 and the target molecule.

Magnetic 3D macroporous MOF oriented urinary exosome metabolomics for early diagnosis of bladder cancer

Bladder cancer (BCa) exhibits the escalating incidence and mortality due to the untimely and inaccurate early diagnosis. Urinary exosome metabolites, carrying critical tumor cell information and directly related to bladder, emerge as promising non-invasive diagnostic biomarkers of BCa. Herein, the magnetic 3D ordered macroporous zeolitic imidazolate framework-8 (magMZIF-8) is synthesized and used for efficient urinary exosome isolation. Notably, beyond retaining the single crystals and micropores of conventional ZIF-8, MZIF-8 is further enhanced with highly oriented and ordered macropores (150 nm) and the large specific surface area (973 m2·g–1), which could enable the high purity and yield separation of exosomes via leveraging the combination of size exclusion, affinity, and electrostatic interactions between magMZIF-8 and the surfaces of exosome. Furthermore, the magnetic and hydrophilic properties of magMZIF-8 will further simplify the process and enhance the efficiency of separation. After conditional optimization, a 50 mL of urine is sufficient for exosome metabolomics analysis, and the time for isolating exosomes from 42 urine samples was 2 hours only. Incorporating machine learning algorithms with LC-MS/MS analysis of the metabolic patterns obtained from isolated exosomes, early-stage BCa patients were differentiated from healthy controls, with area under the curve (AUC) value of 0.844–0.9970 in the training set and 0.875-1.00 in the test set, signifying its potential as a reliable diagnostic tool. This study offers a promising approach for the non-invasive and efficient diagnosis of BCa on a large scale via exosome metabolomics.Graphical

A deep eutectic solvent with bifunctional acid sites treatment to upgrade a bamboo kraft pulp into a cellulose-acetate grade dissolving pulp

Valorization of non-wood pulp, such as bamboo bleached kraft pulp into high-purity cellulose acetate (CA)-grade dissolving pulp is crucial but challenging in China. Herein, a series of metal salt-based deep eutectic solvents (MSDESs) involving various ZnCl2-urea (U), ZnCl2-glycerol (G), and ZnCl2-lactic acid (LA) are comparatively investigated for this purpose. Thanks to the bifunctional acid sites of Lewis acid ZnCl2 and Brønsted acid LA, the ZnCl2-LA MSDES has the highest acidity (2.62) and interaction affinity to bamboo fibers, leading to the highest efficiency in simultaneous pulp purification and activation. As a result, the resultant upgraded pulp from ZnCl2-LA (DES3-F) features remarkable improvements in purity (from 80.8 % to 93.1 %), intrinsic viscosity (from 897 to 419 mg/L), and reactivity (from 18.1 % to 80.8 %). Moreover, the modified acetate product has a high degree of substitution of 2.84 and a yield of 75.5 %. In short, such a proposed MSDES treatment can offer a promising and alternative approach for the manufacture of high-quality dissolving pulp and its derivatives.