Multifunctional Agents Research Articles

Multi-Functional AIE Phototheranostic Agent Enhancing αPD-L1 Response for Oral Squamous Cell Carcinoma Immunotherapy.

Oral squamous cell carcinoma (OSCC) represents a prevalent head and neck malignancy with surgical intervention as the primary clinical option. Immunotherapy, particularly immune checkpoint blockade (ICB) targeting PD-1/PD-L1 shows great promise but is impeded by the immunosuppressive tumor microenvironment and low PD-L1 expression in OSCC. Herein, the "all-in-one" phototherapeutic nanoparticles (TSD NPs) are reported with balanced reactive oxygen species and photothermal conversion capacity for combined photoimmunotherapy and ICB immunotherapy against OSCC. A novel electron acceptor, 3-(dicyanomethylene)-2,3-dihydrobenzothiophene-1,1-dioxide (DTM), is introduced to develop the phototherapeutic agent with aggregation-induced emission (AIE) feature and NIR-II fluorescence centered at 1000nm. Benefiting from the AIE feature and the DTM acceptor, the resultant TSD NPs also exhibit strong type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency (45.3%), which can profoundly induce immunogenic cell death (ICD), activate cytotoxic T lymphocytes, and convert the immunosuppressive tumor microenvironment into an immune-supportive one. Additionally, TSD NPs upregulate the PD-L1 expression on OSCC cells, thus enhancing the efficacy of combined treatment with αPD-L1 ICB immunotherapy. This results show that the synergistic treatment of TSD NPs and αPD-L1 effectively eradicates solid OSCC tumors without adverse effects on normal tissues, proving a novel and promising strategy for OSCC management.

Fabrication of a novel macrophage-targeted biomimetic delivery composite hydrogel with multiple-sensitive properties for tri-modal combination therapy of rheumatoid arthritis

In this study, a porous polydopamine (PDA) nanoparticle-decorated β-glucan microcapsules (GMs) nanoplatform (PDA/GMs) were developed with macrophage-targeted biomimetic features and a carriers-within-carriers structure. Indocyanine green (ICG) and catalase (CAT) were subsequently co-encapsulated within the PDA/GMs to create a multifunctional nanotherapeutic agent, termed CIPGs. Furthermore, CIPGs and sinomenine (SIN) were co-loaded within a thermo-sensitive hydrogel to design an injectable delivery system, termed CIPG/SH, with potential for multi-modal therapy of rheumatoid arthritis (RA). Photothermal studies indicated that the CIPGs hold excellent photothermal conversion ability and thermal stability, as they combined the photothermal performance of both PDA and ICG. Meanwhile, the CIPGs displayed favorable oxygen self-supplying and photodynamic performance. The CIPGs showed near-infrared (NIR)-induced phototoxicity, effectively inhibiting macrophage proliferation and displaying remarkable antibacterial activity. In vitro drug release from the prepared CIPG/SH showed a controlled release pattern. Animal experiments conducted on an RA mice model confirmed that the formulated CIPG/SH exhibited significant therapeutic effects. By integrating the biological advantages, photothermal/photodynamic performance of the CIPGs, and controlled drug release performance of the thermo-sensitive hydrogels in a single delivery system, the prepared injectable CIPG/SH represents a novel versatile delivery system with great potential for multi-modal combination targeting therapy in RA.

Ga2Se3 nanosheets: Broad-spectrum antibacterial and antioxidant agents with low drug resistance

The efficient treatment of many infectious diseases is hindered by uncontrolled bacterial infections and inflammation induced by reactive oxygen species (ROS). Thus, there is an urgent need for the development of multifunctional therapeutic agents that possessing both antibacterial and antioxidant features. In this study, a novel antibacterial and antioxidant agent, Ga2Se3 nanosheets (NSs), were firstly prepared by the liquid-phase exfoliation method. The Ga2Se3 NSs exhibited broad-spectrum sterilization capabilities, even including multidrug-resistant strains. Noteworthily, Ga2Se3 NSs showed a remarkable 800-fold enhancement in antibacterial efficacy compared to the bulk materials, while also demonstrating low drug resistance compared to the traditional antibiotics. Their superior antibacterial performance is primarily attributed to the disruption of basic bacterial metabolism induced by gallium and selenium components, as well as the dimensional engineering of Ga2Se3 NSs. Cellular studies further confirmed the protective effects of pluronic F127 modified Ga2Se3 NSs against oxidative stress damage, preserving cellular functions through ROS scavenging. This study highlights the superior antibacterial and antioxidant properties of Ga2Se3 NSs, which offers an alternative opportunity for addressing the drug resistance issue in treatment of certain special diseases.

Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads

Multi-functional cysteine-targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Herein, we present novel unsaturated and asymmetric ketone (oxazolinosene) scaffolds that selectively conjugate cysteine residues of peptides and bovine serum albumin under normal physiological conditions. This unsaturated saccharide depletes GSH in NCI-H1299 cells, leading to anti-tumor effects in vitro. The acetyl group of the ketal moiety on the saccharide ring can be converted to other carboxylic acids in a one-pot synthesis. In this way, the loaded acid can be click-released during cysteine conjugation, making the oxazolinosene a potential multifunctional therapeutic agent. The reaction kinetic model for oxazolinosene conjugation to GSH is well established and was used to evaluate oxazolinosene reactivity. The aforementioned oxazolinosenes were stereoselectively synthesized via a one-step reaction of nitriles with saccharides and conveniently converted into a series of α, β-unsaturated ketone N-glycosides as prevalent synthetic building blocks. The reaction mechanisms of oxazolinosene synthesis were investigated through calculations and validated with control experiments. Overall, these oxazolinosenes can be easily synthesized and developed as cysteine-targeted covalent warheads carrying useful click-releasing groups.

A Versatile Reversible, Degenerative Chain Transfer Mechanism for the Catalytic Living Ring-Opening Metathesis Polymerization.

Most metathesis polymers based on norbornene derivatives carry a vinyl end group. Here we show that these vinyl end groups readily undergo a degenerative exchange of the terminal methylene unit in the presence of sub-stoichiometric amounts of a propagating metathesis polymer carrying a Grubbs ruthenium complex. We show that this degenerative exchange can be exploited in synthesizing ROMP polymers in a catalytic living fashion. Chain transfer agents based on styrene, or monosubstituted conjugated 1,3 diene derivatives are used as initiating sites for the catalytic living polymerization. Suitable derivatives of these chain transfer agents not only allow the linear living growth of polymers but also the synthesis of block copolymers from macro-initiators or star polymers from multi-functional chain transfer agents. This reversible exchange mechanism offers a cheaper, greener, and more sustainable alternative for the synthesis of living ROMP polymers compared to the classical synthetic route.

Design, Synthesis, and Invitro Pharmacological Evaluation of Novel Resveratrol Surrogate Molecules against Alzheimer's Disease.

A series of resveratrol surrogate molecules were designed, synthesized and biologically evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) along with anti-oxidant activity as potential novel multifunctional agents against Alzheimer's disease (AD). Six novel compounds were synthesized by reacting (E)-4-(3,5-Dimethoxystyryl) aniline with benzaldehyde and some selected derivatives of benzaldehyde in the presence of ethanol and a few drops of glacial acetic acid which followed the general scheme involved in the formation of Schiff bases. The spectral analysis data including FT-IR, 1H-NMR, 13C-NMR, and Mass spectroscopy results were found to be in good agreement with the newly synthesized compounds (Resveratrol Surrogate Molecules 1-6). The synthesized compounds were evaluated for their dual cholinesterase inhibitory activities, cytotoxic effect, and anti-oxidant potential. The results showed that compound RSM5 showed potent inhibitory activity against AChE and BChE. In, addition the cytotoxicity of the compound RSM5 is less and found to be within the desirable limit indicating the potential safety of RSM5. Also, it possesses substantial anti-oxidant activity which qualifies RSM5 as an anti-AD agent. Taken together, these findings demonstrate that the molecule RSM5 had the most multifunctional properties and could be a promising lead molecule for the future development of drugs for Alzheimer's treatments.

Psidium guajav-mediated zinc oxide nanoparticles as a multifunctional, microbicidal, antioxidant and antiproliferative agent against destructive pathogens.

Bio-inspired zinc oxide nanoparticles are gaining immense interest due to their safety, low cost, biocompatibility, and broad biological properties. In recent years, much research has been focused on plant-based nanoparticles, mainly for their eco-friendly, facile, and non-toxic character. Hence, the current study emphasized a bottom-up synthesis of zinc oxide nanoparticles (ZnO NPs) from Psidium guajava aqueous leaf extract and evaluation of its biological properties. The structural characteristic features of biosynthesized ZnO NPs were confirmed using various analytical methods, such as UV-Vis spectroscopy, X-ray diffraction (XRD), energy-dispersive X-ray analysis (EDX), Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), Scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HR-TEM). The synthesized ZnO NPs exhibited ahydrodynamic shape with an average particle size of 11.6-80.2nm. A significant antimicrobial efficiency with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 40 and 27µg/ml for Enterococcus faecalis, followed by 30 and 40µg/ml for Staphylococcus aureus, 20 and 30µg/ml for Staphylococcus mutans, 30µg/ml for Candida albicans was observed by ZnO NPs. Additionally, they showed significant breakdown of biofilms of Streptococcus mutans and Candida albicans indicating their future value in drug-resistance research. Furthermore, an excellent dose-dependent activity of antioxidant property was noticed with an IC50 of 9.89µg/ml. The antiproliferative potential of the ZnO NPs was indicated by the viability of MDA MB 231 cells, which showed adrastic decrease in response to increased concentrations of biosynthesized ZnO NPs. Thus, the present results open up vistas to explore their pharmaceutical potential for the development of targeted anticancer drugs in the future.

Design, synthesis, and biological evaluation of imidazolylacetophenone oxime derivatives as novel brain-penetrant agents for Alzheimer's disease treatment

Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1−8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9−30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 μM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aβ42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

Photothermal therapy and cell imaging tracking of porous silicon nanoparticle by magnesiothermic reduction and surface modification

The synthesis of silicon nanoparticles (PSi NPs) from silica nanoparticles (SiO₂) via magnesium (Mg) reduction is a promising technique due to its simplicity and cost-effectiveness. In this study, silica is utilized as the primary precursor and is subjected to a reduction process using magnesium powder as the reducing agent. By covalently attaching Fluorescein Isothiocyanate (FITC) to the surface of PSi NPs, we aim to enhance their fluorescence intensity and stability while also improving their surface reactivity and biocompatibility. The modified PSi NPs system was characterized using various microscopic techniques, Raman spectra, porosity and morphology analysis, Zeta potential, and analysis of organic functional groups to confirm successful conjugation and to evaluate changes in surface morphology, fluorescence properties, and colloidal stability. By leveraging the inherent photothermal conversion efficiency of PSi NPs, we explore their capacity to generate localized heat upon near-infrared (NIR) light irradiation, effectively inducing cancer cell apoptosis. Concurrently, the natural fluorescence of PSi NPs is harnessed to enable high-resolution imaging, facilitating real-time tracking and monitoring of therapeutic processes. The PSi NPs were subjected to a series of in vitro experiments to assess their photothermal efficiency, cytotoxicity, and imaging capabilities. Results demonstrate that PSi NPs exhibit excellent photothermal effects, leading to significant cell death in targeted cancer cells upon NIR exposure, while their fluorescence properties provide clear and detailed imaging. These findings highlight the potential of PSi NPs as multifunctional agents in cancer therapy, combining effective photothermal treatment with non-invasive imaging, thereby enhancing the precision and efficacy of therapeutic interventions.

Crocus sativus (Saffron): A potential multifunctional therapeutic agent for neurodegenerative disorders.

Crocus sativus (Saffron): A potential multifunctional therapeutic agent for neurodegenerative disorders.

Cholesterol Depletion-Enhanced Ferroptosis and Immunotherapy via Engineered Nanozyme.

Ferroptosis, an iron- and reactive oxygen species (ROS)-dependent cell death, holds significant promise for tumor therapy due to its ability to induce lipid peroxidation (LPO) and trigger antitumor immune responses. However, elevated cholesterol levels in cancer cells impede ferroptosis and compromise immune function. Here, a novel nanozyme, Fe-MOF/CP, composed of iron metal-organic framework (Fe-MOF) nanoparticles loaded with cholesterol oxidase and PEGylation for integrated ferroptosis and immunotherapy is introduced. Fe-MOF/CP depletes cholesterol and generates hydrogen peroxide, enhancing ROS levels and inducing LPO, thereby promoting ferroptosis. This process disrupts lipid raft integrity and downregulates glutathione peroxidase 4 and ferroptosis suppressor protein 1, further facilitating ferroptosis. Concurrently, Fe-MOF/CP augments immunogenic cell death, reduces programmed death-ligand 1 expression, and revitalizes exhausted CD8+ T cells. In vivo studies demonstrate significant therapeutic efficacy in abscopal, metastasis, and recurrent tumor models, highlighting the robust antitumor immune responses elicited by Fe-MOF/CP. This study underscores the potential of Fe-MOF/CP as a multifunctional therapeutic agent that combines ferroptosis and immunotherapy, offering a promising strategy for effective and durable cancer treatment.

Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer’s disease therapy

A series of scutellarein 7-l-amino acid carbamate-4′-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer’s disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, l-Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC50 values of 7.04 μM and 9.73 μM, respectively. Moreover, 11l exhibited more potent H3R antagonistic activities than clobenpropit, with an IC50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu2+-induced Aβ1–42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu2+-induced Aβ fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aβ25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood–brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.

Triple effective water treatment agent: P(AA/AMPS) capped sulfur quantum dots boast remarkable antiscale, antibacterial, and real-time tracking capabilities

Recent research has explored nanomaterials as sustainable scale inhibitors for water treatment. This research specifically delved into the development of environmentally benign antimicrobial sulfur quantum dot scale inhibitors (P(AA/AMPS)-SQDs) by capping P(AA/AMPS) with varying molecular weights. The synthesized P(AA/AMPS)-SQDs underwent thorough characterization employing high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy, and zeta potential analysis. The inhibitory efficacy of P(AA/AMPS)-SQDs on calcium carbonate (CaCO3) and calcium sulfate (CaSO4) scale formation was conducted under diverse conditions, including scale inhibitor concentration, reaction time, temperature, and pH using scanning electron microscopy and X-ray powder diffraction techniques. Remarkably, the water agent P(AA/AMPS)-SQDs showcased exceptional fluorescence, water solubility, and resilience to high temperatures. At specified concentrations, P(AA/AMPS)-SQDs demonstrated remarkable inhibition efficiencies, with over 98 % inhibition against the CaCO3 scale at 20 mg/L and over 97 % inhibition against the CaSO4 scale at 0.5 mg/L, significantly outperforming traditional scale inhibitors. Furthermore, P(AA/AMPS)-SQDs exhibited almost 100 % inhibition efficiency against Bacillus subtilis at a dosage of 150 mg/L. Furthermore, molecular dynamics simulation and quantum chemical calculations were employed to clarify the scale inhibition mechanisms of P(AA/AMPS)-SQDs. This multifunctional water treatment agent, integrating scale inhibition, antimicrobial properties, and online monitoring capabilities, lays a solid foundation for potential applications in engineering domains.

Edaravone N-benzyl pyridinium derivatives: BACE-1 inhibition, kinetics and in silico binding pose determination

BACE-1 plays a pivotal role in the production of β-amyloid (Aβ) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC50 = 44.10 µM - 123.70 µM) and obtained IC50 values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC50 = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC50 of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

Discovery of Multi-functional Lead Compounds Originating from Traditional Chinese Medicine for Developing Anti-depressive Agents via Virtual Screening

Background: The increasing prevalence of depression has become a global health issue. Currently approved anti-depressive including 5-hydroxytryptamine (5-HT), dopamine (DA), norepinephrine (NE), triple reuptake inhibitors (TRIs) and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists have limited effects because of their insufficient efficacy and/or slow onset of action. Developing multifunctional antidepressants that can modulate 5-HT, DA, NE, and NMDA simultaneously can potentially overcome the current drug defects. Objective: This study aimed to explore leads for the development of multi-functional anti-depressive agents that simultaneous triple reuptake inhibitory and NMDA-GluN2B receptor antagonistic activities. Methods: Potential leads were screened virtually from the TCMSP database based on the 3DPharmacophore model of TRIs followed by the molecular docking into NMDA-GluN2B receptor, BBB score, and the in silico toxicity evaluation. The biological activities of discovered leads on 5-HT, NE, and DA reuptake and their effect on the NMDA-GluN2B receptor were evaluated via radio-labeled neurotransmitters and competition radio-ligand binding experiment with [3H] ifenprodil, respectively. Lastly, the antidepressant effect of these potential leads was determined in vivo through the forced swim test in mice. Results: Two compounds were attained as potential leads after the aforementioned experiments. Further in vitro biological evaluation identified Hit-2 as a promising lead that exerted favorable triple 5- HT/DA/NE reuptake inhibitory activity (66.98% inhibition rate at 10 μM against hNET, 73.01% inhibition rate at 1 μM against hDAT and 86.27% inhibition rate at 1 μM against hSERT), as well as potent NMDA-GluN2B receptor antagonistic activity (Ki=115.73 ± 3.54 nM). The antidepressant activity of Hit- 2 was confirmed through in vivo experiments Conclusion: Hit-2 not only simultaneously inhibited the reuptake of 5-HT, DA, and NE, and acted as an NMDA-GluN2B receptor antagonist in vitro but also showed in vivo antidepressant activity. These findings may serve as a structural basis for the further development of multi-functional anti-depressive agents.

Engineered extracellular vesicles coated with an antimicrobial peptide for advanced control of bacterial sepsis.

Alarming sepsis-related mortality rates present significant challenges to healthcare services globally. Despite advances made in the field, there is still an urgent need to develop innovative approaches that could improve survival rates and reduce the overall cost of treatment for sepsis patients. Therefore, this study aimed to develop a novel multifunctional therapeutic agent for advanced control of bacterial sepsis. Extracellular vesicles (EVs) isolated from lipopolysaccharide (LPS) induced HepG2 (hepatocellular carcinoma cells) (iEV) displayed an average particle size of 171.63±2.77nm, a poly dispersion index (PDI) of 0.32±0.0, and a zeta potential (ZP) of -11.87±0.18mV. Compared to HepG2 EV, LPS induction significantly increases the EV protein concentration, PDI and ZP, reduces the average size and promotes cell proliferation and cytoprotective effects of the isolated EVs (iEVs) against LPS-induced cytotoxicity. Coating of iEV with a cationic antimicrobial peptide (AMP) to form PC-iEV slightly changed their physical properties and shifted their surface charge toward neutral values. This modification improved the antibacterial activity (2-fold lower minimum bactericidal concentration [MBC] values) and biocompatibility of the conjugated peptide while maintaining iEV cytoprotective and anti-inflammatory activities. Our findings indicate the superior anti-inflammatory and antibacterial dual activity of PC-iEV against pathogens associated with sepsis.

Dendrobium nobile alkaloids modulate calcium dysregulation and neuroinflammation in Alzheimer's disease: A bioinformatic analysis

IntroductionDendrobium nobile Lindl alkaloids, or DNLA for short, are the most active ingredients found in D.nobile, a top grade plant in Shen Nong Ben Cao Jing, with an extensive history of medicinal use in Chinese traditional medicine (TCM) as a multifunctional therapeutic agent. Recent evidence has emerged linking the neuroprotective and anti-aging effects of DNLA to their involvement in promoting autophagy of toxic amyloid-β (Aβ) plaques and modulation of key enzymes involved in the hyperphosphorylation of Tau proteins. Although amyloid buildup and the aggregation of Tau proteins are central to the onset of Alzheimer's disease (AD), evidence on how DNLA relate to other overlooked dysregulated AD-associated pathways is still lacking. MethodsWe intend on deciphering the underlying mechanisms driving the anti-AD effect of DNLA, using a combination of network analysis based on differentially expressed genes found in AD patients, target fishing, centrality analysis, enrichment analysis and hub genes identification. ResultsIn total, 2069 genes were found differentially expressed in SRP181886 and a PPI network constructed with common targets between DNLA and AD. Five hub genes were identified having a discriminatory power greater than 0.7; HTR2A, GRIN2B, GABRA1, HTR2C, GRIN2A, with the former being the top bottleneck node in the network. Enrichment analysis found that DNLA exert an anti-AD effect through the regulation of the calcium signaling pathway and the serotonergic system, by modulating key receptors implicated in excitatory/inhibitory neurotransmission. Additionally, DNLA were found to modulate two subunits of NMDA receptor involved in the release of pro-inflammatory cytokines, underlying the possible involvement of DNLA in neuroinflammation. DiscussionThis further emphasizes the therapeutic value of D.nobile and the multi-target, multi-pathway potential of DNLA to counteract the deleterious effects of calcium dysregulation and excitatory toxicity in AD, while providing evidence-based rationale behind the traditional use of D. nobile in TCM.

Development of manganese cobalt oxide (MnCo2O4) nanoparticle as multifunctional agents for antibacterial, anticancer and dye degradation applications

This study addresses the pressing concern of dye effluent contamination in water bodies and proposes a multifaceted solution through the synthesis and application of Manganese cobalt oxide (MnCo2O4) nanoparticles. The nanoparticles were prepared hydrothermally using acetate precursors, and their composition was carefully confirmed by XRD, FTIR, UV-DRS, FESEM, and EDX studies. The prepared MnCo2O4 nanoparticles, when exposed to the best-suited conditions (20 mL of dye solution containing 2.5 mg of MnCo2O4 NP kept at direct sunlight for 24 h, reaction time), exhibited remarkable efficiency in completely breaking down inorganic dyes, with removal percentages of 78.8 % for Methyl blue (MB) and 97.6 % for Congo red (CR). Notably, the synthesized MnCo2O4 nanoparticles display strong antibacterial capabilities against multidrug-resistant bacteria and considerable anticancer effects on the cervical cancer cell line (HeLa), as verified by the MTT assay. This comprehensive investigation positions the MnCo2O4 nanoparticle as a promising candidate for efficient wastewater treatment, a robust antibacterial agent, and a potential therapeutic agent against cervical cancer, highlighting its diverse and impactful applications.

New 1,2,4-oxadiazole derivatives as potential multifunctional agents for the treatment of Alzheimer’s disease: design, synthesis, and biological evaluation

A series of new 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their anti-AD potential. The results revealed that eleven compounds (1b, 2a-c, 3b, 4a-c, and 5a-c) exhibited excellent inhibitory potential against AChE, with IC50 values ranging from 0.00098 to 0.07920 µM. Their potency was 1.55 to 125.47 times higher than that of donepezil (IC50 = 0.12297 µM). In contrast, the newly synthesized oxadiazole derivatives with IC50 values in the range of 16.64–70.82 µM exhibited less selectivity towards BuChE when compared to rivastigmine (IC50 = 5.88 µM). Moreover, oxadiazole derivative 2c (IC50 = 463.85 µM) was more potent antioxidant than quercetin (IC50 = 491.23 µM). Compounds 3b (IC50 = 536.83 µM) and 3c (IC50 = 582.44 µM) exhibited comparable antioxidant activity to that of quercetin. Oxadiazole derivatives 3b (IC50 = 140.02 µM) and 4c (IC50 = 117.43 µM) showed prominent MAO-B inhibitory potential. They were more potent than biperiden (IC50 = 237.59 µM). Compounds 1a, 1b, 3a, 3c, and 4b exhibited remarkable MAO-A inhibitory potential, with IC50 values ranging from 47.25 to 129.7 µM. Their potency was 1.1 to 3.03 times higher than that of methylene blue (IC50 = 143.6 µM). Most of the synthesized oxadiazole derivatives provided significant protection against induced HRBCs lysis, revealing the nontoxic effect of the synthesized compounds, thus making them safe drug candidates. The results unveiled oxadiazole derivatives 2b, 2c, 3b, 4a, 4c, and 5a as multitarget anti-AD agents. The high AChE inhibitory potential can be computationally explained by the synthesized oxadiazole derivatives’ significant interactions with the AChE active site. Compound 2b showed good physicochemical properties. All these data suggest that 2b could be considered as a promising candidate for future development.

Thiolated chitosan nanoparticles encapsulated nisin and selenium: antimicrobial/antibiofilm/anti-attachment/immunomodulatory multi-functional agent

BackgroundThe increase in the resistance of bacterial strains to antibiotics has led to research into the bactericidal potential of non-antibiotic compounds. This study aimed to evaluate in vitro antibacterial/ antibiofilm properties of nisin and selenium encapsulated in thiolated chitosan nanoparticles (N/Se@TCsNPs) against prevalent enteric pathogens including standard isolates of Vibrio (V.) cholerae O1 El Tor ATCC 14,035, Campylobacter (C.) jejuni ATCC 29,428, Salmonella (S.) enterica subsp. enterica ATCC 19,430, Shigella (S.) dysenteriae PTCC 1188, Escherichia (E.) coli O157:H7 ATCC 25,922, Listeria (L.) monocytogenes ATCC 19,115, and Staphylococcus (S.) aureus ATCC 29,733.MethodsThe synthesis and comprehensive analysis of N/Se@TCsNPs have been completed. Antibacterial and antibiofilm capabilities of N/Se@TCsNPs were evaluated through broth microdilution and crystal violet assays. Furthermore, the study included examining the cytotoxic effects on Caco-2 cells and exploring the immunomodulatory effects of N/Se@TCsNPs. This included assessing the levels of both pro-inflammatory (IL-6 and TNFα) and anti-inflammatory (IL-10 and TGFβ) cytokines and determining the gene expression of TLR2 and TLR4.ResultsThe N/Se@TCsNPs showed an average diameter of 136.26 ± 43.17 nm and a zeta potential of 0.27 ± 0.07 mV. FTIR spectroscopy validated the structural features of N/Se@TCsNPs. Scanning electron microscopy (SEM) images confirmed their spherical shape and uniform distribution. Thermogravimetric Analysis (TGA)/Differential Scanning Calorimetry (DSC) tests demonstrated the thermal stability of N/Se@TCsNPs, showing minimal weight loss of 0.03%±0.06 up to 80 °C. The prepared N/Se@TCsNPs showed a thiol content of 512.66 ± 7.33 µmol/g (p < 0.05), an encapsulation efficiency (EE) of 69.83%±0.04 (p ≤ 0.001), and a drug release rate of 74.32%±3.45 at pH = 7.2 (p ≤ 0.004). The synthesized nanostructure demonstrated potent antibacterial activity against various isolates, with effective concentrations ranging from 1.5 ± 0.08 to 25 ± 4.04 mg/mL. The ability of N/Se@TCsNPs to reduce bacterial adhesion and internalization in Caco-2 cells underscored their antibiofilm properties (p ≤ 0.0001). Immunological studies indicated that treatment with N/Se@TCsNPs led to decreased levels of inflammatory cytokines IL-6 (14.33 ± 2.33 pg/mL) and TNFα (25 ± 0.5 pg/mL) (p ≤ 0.0001), alongside increased levels of anti-inflammatory cytokines IL-10 (46.00 ± 0.57 pg/mL) and TGFβ (42.58 ± 2.10 pg/mL) in infected Caco-2 cells (p ≤ 0.0001). Moreover, N/Se@TCsNPs significantly reduced the expression of TLR2 (0.22 ± 0.09) and TLR4 (0.16 ± 0.05) (p < 0.0001).ConclusionIn conclusion, N/Se@TCsNPs exhibited significant antibacterial/antibiofilm/anti-attachment/immunomodulatory effectiveness against selected Gram-positive and Gram-negative enteric pathogens. However, additional ex-vivo and in-vivo investigations are needed to fully assess the performance of nanostructured N/Se@TCsNPs.