Acid-Resistant Nano-antioxidants Based on Epigallocatechin Gallate Alleviate Acute Intestinal and Kidney Inflammation.

Epigallocatechin gallate (EGCG)-based nanosystems have garnered significant attention for their ability to alleviate inflammation due to their excellent anti-inflammatory properties and enhanced drug delivery capabilities. However, the degradation of EGCG in strongly acidic environments poses a challenge for potential administration, particularly in oral formulations, where gastric resistance is essential. In this study, we develop a "disintegration and reorganization" strategy to create acid-resistant antioxidant nanoparticles (EGA NPs) based on EGCG and 5-aminosalicylic acid (5-ASA) for mitigating inflammation in colitis and acute kidney injury. At acidic pH, the ester bond in EGCG breaks down, producing two building blocks. These, together with 5-ASA and formaldehyde, form oligomers through a combination of phenol-aldehyde condensation and the Mannich reaction. The resulting oligomers self-assemble into EGA NPs, which exhibit significant stability under both acidic and neutral pH conditions. This stability makes them suitable for oral administration, allowing them to withstand harsh gastric conditions, as well as for intravenous injection. Importantly, these oligomers retain the antioxidant and anti-inflammatory properties of EGCG, effectively scavenging reactive oxygen species and reducing intracellular oxidative stress. Additionally, EGA shows potential as a drug carrier, efficiently loading the anti-inflammatory agent curcumin (Cur) to form Cur@EGA NPs. In vivo studies demonstrate the efficacy of Cur@EGA and EGA in alleviating acute colitis and kidney injury following oral and intravenous administration, respectively. These nanoparticulate formulations exhibit superior inflammation reduction compared to free Cur in vivo. Overall, our findings introduce a novel acid-resistant nanoplatform based on EGCG for the treatment of acute inflammation.

Layer-by-layer reinforced-mediated sustained-release nanoantioxidants for long-lasting prevention against drug-induced liver injury.

Drug-induced liver injury (DILI) is a commonly encountered and diagnostically complex etiology of acute liver failure, characterized by early indications of hepatic oxidative stress. The most economical approach for DILI treatment is effective and durable oxidative stress prevention. Herein, we propose a long-lasting nanoantioxidant called PDA-Zn-BAI NPs characterized by sustained-release of baicalein (a natural antioxidant) for the long-lasting prevention of DILI. It is constructed using dopamine as an intermediate and layer-by-layer reinforcement strategy based on Zn2+-mediated coordination bonding, π-π stacking, and steric hindrance made of polydopamine network. Optimized PDA-Zn-BAI NPs performed a satisfactory sustained-release effect (36.67% ± 6.67 in normal condition and 60.32% ± 3.19 in acid condition of cumulative release within 5 days). Furthermore, it's been found that PDA-Zn-BAI NPs could continuously be accumulated in the liver with negligible hepatotoxicity and were activated to effectively scavenge reactive oxygen species to break off the damage of acetaminophen to the liver within 5 days (ALT as an indicator, > 70% prevention effect lasts for 5 days), which was vital for the long-lasting prevention of DILI. The long-lasting detoxification by PDA-Zn-BAI NPs in patients with DILI suggested a potential clinical application, especially for those patients who need prolonged administration of hepatotoxic drugs.

Nanoantioxidant Materials: Nanoengineering Inspired by Nature.

Oxidants are very active compounds that can cause damage to biological systems under specific environmental conditions. One effective way to counterbalance these adverse effects is the use of anti-oxidants. At low concentrations, an antioxidant is defined as a compound that can delay, control, or prevent an oxidative process. Antioxidants exist in plants, soil, and minerals; therefore, nature is a rich source of natural antioxidants, such as tocopherols and polyphenols. In nature, antioxidants perform in tandem with their bio-environment, which may tune their activity and protect them from degradation. In vitro use of antioxidants, i.e., out of their biomatrix, may encounter several drawbacks, such as auto-oxidation and polymerization. Artificial nanoantioxidants can be developed via surface modification of a nanoparticle with an antioxidant that can be either natural or synthetic, directly mimicking a natural antioxidant system. In this direction, state-of-the-art nanotechnology has been extensively incorporated to overcome inherent drawbacks encountered in vitro use of antioxidants, i.e., out of their biomatrix, and facilitate the production and use of antioxidants on a larger scale. Biomimetic nanoengineering has been adopted to optimize bio-medical antioxidant systems to improve stability, control release, enhance targeted administration, and overcome toxicity and biocompatibility issues. Focusing on biotechnological sciences, this review highlights the importance of nanoengineering in developing effective antioxidant structures and comparing the effectiveness of different nanoengineering methods. Additionally, this study gathers and clarifies the different antioxidant mechanisms reported in the literature and provides a clear picture of the existing evaluation methods, which can provide vital insights into bio-medical applications.

Architecture of Nanoantioxidant Based on Mesoporous Organosilica Trp-Met-PMO with Dipeptide Skeleton.

A nanoantioxidant of mesoporous organosilica (Trp-Met-PMO) based on the framework of tryptophan-methionine dipeptide was first designed and constructed by condensation between self-created dipeptide organosilica precursor (Trp-Met-Si) and tetraethyl orthosilicate (TEOS) in alkaline conditions under the template hexadecyl trimethyl ammonium bromide (CTAB). Trp-Met-Si was prepared by the reaction between dipeptide Trp-Met and conventional organosilicon coupling agent isocyanatopropyltriethoxysilane (IPTES) via a multiple-step reaction method. The material Trp-Met-PMO was confirmed by XRD, FT-IR and N2 adsorption-desorption analysis. The material Trp-Met-5-PMO with low amounts of organosilica precursor remained a mesoporous material with well-ordered 2D hexagonal (P6mm) structure. With increasing amounts of organosilica precursor, a mesoporous structure was still formed, as shown in the material Trp-Met-100-PMO with the highest amounts of organosilica precursor. Moreover, pore size distribution, surface area and porosity of Trp-Met-PMO are regulated with different amounts of organosilica precursor Trp-Met-Si. The antioxidant activity of Trp-Met-PMO was evaluated by ABTS free radical-scavenging assay. The results showed that antioxidant activity was largely enhanced with increasing contents of organosilica precusor Trp-Met-Si in the skeleton. The material Trp-Met-40-PMO exhibited maximum scavenging capacity of ABTS free radicals, the inhibition percent was 5.88%. This study provides a design strategy for nanoantioxidant by immobilizing short peptides within the porous framework of mesoporous material.

Design of Diselenide-Bridged Hyaluronic Acid Nano-antioxidant for Efficient ROS Scavenging to Relieve Colitis.

Overproduction of reactive oxygen species (ROS), a key characteristic of inflammatory bowel disease (IBD), is responsible for dysregulation of signal transduction, inflammatory response, and DNA damage, which ultimately leads to disease progression and deterioration. Thus, ROS scavenging has become a promising strategy to navigate IBD. Inspired by the targeting capability of hyaluronic acid (HA) to CD44-overexpressed inflammatory cells together with the redox regulation capacity of diselenide compounds, we developed an oral nanoformulation, i.e., diselenide-bridged hyaluronic acid nanogel (SeNG), with a view to treat colitis through a ROS scavenging mechanism. Our data demonstrated that SeNG specifically accumulated in colitis tissue that was mediated by highly efficient CD44-HA interaction. This has allowed us to demonstrate a significant anti-inflammatory effect in an acute colitis mouse model induced by dextran sulfate sodium and trinitrobenzenesulfonic acid. Mechanistically, we continued to show SeNG reduced the ROS level via both direct elimination and up-regulation of the Nrf2/HO-1 signal pathway. Collectively, our work provides proof-of-principle evidence for a SeNG-mediated nano-antioxidant strategy, by which colitis could be effectively managed.

Chain-Breaking Antioxidant and Peroxyl Radical Trapping Activity of Phenol-Coated Magnetic Iron Oxide Nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPION) are important materials for biomedical applications, and phenol capping is a common procedure to passivate their surface. As phenol capped SPION have been reported to behave as antioxidants, herein, we investigate the mechanism underlying this activity by studying the reaction with alkyl peroxyl (ROO•) radicals. SPION were prepared by coprecipitation of Fe(II) and Fe(III), using phenolic antioxidants (gallic acid, Trolox and nordihydroguaiaretic acid) as post-synthesis capping agents and by different purification procedures. The reactivity of ROO• was investigated by inhibited autoxidation studies, using styrene as an oxidizable substrate (solvent MeCN, 30 °C) and azo-bis(isobutyronitrile) as a radical initiator. While unprotected, bare SPION behaved as prooxidant, accelerating the O2 consumption of styrene autoxidation, phenol capping provided a variable antioxidant effect that was dependent upon the purification degree of the material. Thoroughly washed SPION, containing from 7% to 14% (w/w) of phenols, had a low reactivity toward peroxyl radicals, while SPION with a higher phenol content (46% to 55%) showed a strong radical trapping activity. Our results indicate that the antioxidant activity of phenol-capped SPION can be caused by its release in a solution of weakly bound phenols, and that purification plays a major role in determining the properties of these materials.

Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH.

Kupffer cells are a key source of reactive oxygen species (ROS) and are implicated in the development of steatohepatitis and fibrosis in nonalcoholic steatohepatitis (NASH). We recently developed a polythiolated and mannosylated human serum albumin (SH-Man-HSA), a nano-antioxidant that targets Kupffer cells, in which the mannosyl units on albumin allows their specific uptake by Kupffer cells via the mannose receptor C type 1 (MRC1), and in which the polythiolation confers antioxidant activity. The aim of this study was to investigate the therapeutic potential of SH-Man-HSA in NASH model mice. In livers from mice and/or patients with NASH, we observed a reduced blood flow in the liver lobes and the down-regulation in MRC1 expression in Kupffer cells, and SH-Man-HSA alone failed to improve the pathological phenotype in NASH. However, the administration of a nitric oxide (NO) donor restored hepatic blood flow and increased the expression of the mannose receptor C type 2 (MRC2) instead of MRC1. Consequently, treatment with a combination of SH-Man-HSA and an NO donor improved oxidative stress-associated pathology. Finally, we developed a hybrid type of nano-antioxidant (SNO-Man-HSA) via the S-nitrosation of SH-Man-HSA. This nanomedicine efficiently delivered both NO and thiol groups to the liver, with a hepatoprotective effect that was comparable to the combination therapy of SH-Man-HSA and an NO donor. These findings suggest that SNO-Man-HSA has the potential for functioning as a novel nano-therapy for the treatment of NASH.

Improvement of morpho-physiological, ultrastructural and nutritional profiles in wheat seedlings through astaxanthin nanoparticles alleviating the cadmium toxicity.

Heavy metal accumulation in arable lands and water bodies has become one of the serious global issues among multitude of food security challenges. In particular, cadmium (Cd) concentration has been increasing substantially in the environment that negatively affects the growth and yield of important agricultural crops, especially wheat (Triticum aestivum L.). No doubt, nanotechnology is a revolutionary science but the comprehension of nanoparticle-plants interaction and its potential alleviatory role against metal stress is still elusive. Here, we investigated the mechanistic role of astaxanthin nanoparticles (AstNPs) in Cd stress amelioration and their interaction with wheat under Cd-spiked conditions. The AstNPs fabrication was confirmed through ultraviolet visible spectroscopy, where the particles showed characteristic peak at 423 nm. However, Fourier transform infrared, X-ray diffraction, scanning electron microscopy and transmission electron microscopy analyses confirmed the presence of stabilized spherical-shaped nanocrystals of AstNPs within the size range of 12.03-30.37 nm. The hydroponic application of AstNPs (100 mg L-1) to Cd-affected wheat plants increased shoot height (59%), shoot dry weight (31%), nitrogen concentration (42%), and phosphorus concentration (26%) as compared to non-treated Cd affected seedlings. Moreover, AstNPs-treated plants showed reduction in acropetal Cd translocation (29%) in contrast to plants treated with Cd only. Under Cd-spiked conditions, AstNPs-treated plants displayed an improved nutrient profile (P, N, K+ and Ca2+) with a relative decrease in Na+ content in comparison with non-treated plants. Interestingly, it was found that AstNPs restricted the translocation of Cd to aerial plant parts by negatively regulating Cd transporter genes (TaHMA2 and TaHMA3), and relieved plants from oxidative burst by activating antioxidant machinery via triggering expressions of TaSOD and TaPOD genes. Consequently, it was observed that the application of AstNPs helped in maintaining the nutrient acquisition and ionic homeostasis in Cd-affected wheat plants, which subsequently improved the physiochemical profiles of plants under Cd-stress. This study suggests that AstNPs plausibly serve as stress stabilizers for plants under heavy metal-polluted environment.

New Nanomaterials with Intrinsic Antioxidant Activity by Surface Functionalization of Niosomes with Natural Phenolic Acids.

Nanoantioxidants have emerged as smart devices able to provide improved stability and biocompatibility and sustained and targeted release of conventional antioxidants. In the current research, a new family of nanoantioxidants has been developed by covalently grafting gallic (GA), caffeic (CF) and ferulic (FR) acid on the surfaces of Tween 80 niosomes. First, empty and curcumin (CUR)-loaded vesicles were prepared using a thin-layer evaporation technique and then functionalized with phenolic acids using carbodiimide chemistry. Nanoantioxidants obtained were characterized in terms of size, polydispersity index, zeta potential, and loading efficiency. Their antioxidant activity was studied by ABTS and DPPH assays. Surface functionalization of empty and CUR-loaded vesicles provided stable vesicles with intrinsic antioxidant properties. In vitro antioxidant assays highlighted that vesicles functionalized with FR or GA exhibited better antioxidant activity compared to CF-grafted niosomes. Furthermore, vesicles loaded with CUR and functionalized with GA and CF showed an enhanced scavenging ability of ABTS and DPPH radicals, compared to the single antioxidant-loaded formulations, highlighting an important synergic effect of CUR when used in combination with GA ad CF.

Prevention of Hepatic Ischemia-Reperfusion Injury by Carbohydrate-Derived Nanoantioxidants.

Hepatic ischemia-reperfusion injury (IRI), which mainly results from excessive reactive oxygen species (ROS) generated by a reperfusion burst of oxygen, has long been a major cause of liver dysfunction and failure after surgical procedures. Here, a monodispersed hydrophilic carbohydrate-derived nanoparticle (C-NP) was synthesized as a nanoantioxidant that could effectively prevent hepatic IRI. The spherical C-NPs had a size of ∼78 ± 11.3 nm covered with polar surface groups. They were well dispersible in water with good colloidal stability, nontoxicity, and good ROS scavenging capability. The C-NPs also exhibited good circulation lifetime, effective delivery to liver, and gradual degradability with an ability to assist the IRI group maintaining a normal and healthy liver status. The pathology mechanism of C-NPs in hepatic IRI was confirmed to be scavenging of excessive ROS by C-NPs. The effective therapeutic treatment of C-NPs in living animals revealed a great potential in clinical prevention for hepatic IRI.

Nanoantioxidant-Based Silica Particles as Flavonoid Carrier for Drug Delivery Applications.

Nanosystems used in pharmaceutical formulations have shown promising results in enhancing the administration of drugs of difficult formulations. In particular, porous silica nanoparticles have demonstrated excellent properties for application in biological systems; however, there are still several challenges related to the development of more effective and biocompatible materials. An interesting approach to enhance these nanomaterials has been the development of nanoantioxidant carriers. In this work, a hybrid nanoantioxidant carrier based on porous silica nanoplatform with rosmarinic acid antioxidant immobilized on its surface were developed and characterized. Techniques such as dynamic light scattering (DLS), zeta potential, transmission electron microscopy (TEM), N2 adsorption-desorption measurements, differential scanning calorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and 2,2-diphenyl-1-picrylhydrazyl (DPPH●) assay were used to characterize and evaluate the antioxidant activity of nanocarriers. In addition, drug release profile was evaluated using two biorelevant media. The antioxidant activity of rosmarinic acid was maintained, suggesting the correct disposition of the moiety. Kinetic studies reveal that more morin is released in the simulated intestinal fluid than in the gastric one, while an anomalous non-Fickian release mechanism was observed. These results suggest a promising antioxidant nanocarrier suitable for future application in drug delivery.

Magnetically directed antioxidant and antimicrobial agent: synthesis and surface functionalization of magnetite with quercetin.

Oxidative stress can be reduced substantially using nanoantioxidant materials by tuning its surface morphological features up to a greater extent. The physiochemical, biological and optical properties of the nanoantioxidants can be altered by controlling their size and shape. In view of that, an appropriate synthesis technique should be adopted with optimization of the process variables. Properties of magnetite nanoparticles (IONP) can be tailored to upgrade the performance of biomedicine. Present research deals with the functionalization IONP using a hydrophobic agent of quercetin (Q). The application of quercetin will control its size using both the functionalization method including in-situ and post-synthesis technique. In in-situ techniques, the functionalized magnetite nanoparticles (IONP@Q) have average particles size 6 nm which are smaller than the magnetite (IONP) without functionalization. After post functionalization technique, the average particle size of magnetite IONP@Q2 determined was 11 nm. The nanoparticles also showed high saturation magnetization of about 51-59 emu/g. Before starting the experimental lab work, Prediction Activity Spectra of Substances (PASS) software was used to have a preliminary idea about the biological activities of Q. The antioxidant activity was carried out using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. The antibacterial studies were carried out using well diffusion method. The results obtained were well supported by the simulated results. Furthermore, the values of the half maximal inhibitory concentration (IC50) of the DPPH antioxidant assay were decreased using the functionalized one and it exhibited a 2-3 fold decreasing tendency than the unfunctionalized IONP. This exhibited that the functionalization process can easily enhance the free radical scavenging properties of IONPs up to three times. MIC values confirms that functionalized IONP have excellent antibacterial properties against the strains used (Staphylococcus aureus, Bacillus subtilis and Escherichia coli) and fungal strains (Aspergillus niger, Candida albicans, Trichoderma sp. and Saccharomyces cerevisiae). The findings of this research showed that the synthesized nanocomposite has combinatorial properties (magnetic, antioxidant and antimicrobial) which can be considered as a promising candidate for biomedical applications. It can be successfully used for the development of biomedicines which can be subsequently applied as antioxidant, anti-inflammatory, antimicrobial and anticancer agents.

Enhanced Antioxidant Activity under Biomimetic Settings of Ascorbic Acid Included in Halloysite Nanotubes.

Antioxidant activity of native vitamin C (ascorbic acid, AH2) is hampered by instability in solution. Selective loading of AH2 into the inner lumen of natural halloysite nanotubes (HNT) yields a composite nanoantioxidant (HNT/AH2), which was characterized and investigated for its reactivity with the persistent 1,1-diphenyl-2-picrylhydrazyl (DPPH•) radical and with transient peroxyl radicals in the inhibited autoxidation of organic substrates, both in organic solution (acetonitrile) and in buffered (pH 7.4) water in comparison with native AH2. HNT/AH2 showed excellent antioxidant performance being more effective than native ascorbic acid by 131% in acetonitrile and 290% (three-fold) in aqueous solution, under identical settings. Reaction with peroxyl radicals has a rate constant of 1.4 × 106 M-1 s-1 and 5.1 × 104 M-1 s-1, respectively, in buffered water (pH 7.4) and acetonitrile, at 30 °C. Results offer physical understanding of the factors governing HNT/AH2 reactivity. Improved performance of HNT/AH2 is unprecedented among forms of stabilized ascorbic acid and its relevance is discussed on kinetic grounds.

Nanoantioxidants: Recent Trends in Antioxidant Delivery Applications.

Antioxidants interact with free radicals, terminating the adverse chain reactions and converting them to harmless products. Antioxidants thus minimize the oxidative stress and play a crucial role in the treatment of free radicals-induced diseases. However, the effectiveness of natural and/or synthetic antioxidants is limited due to their poor absorption, difficulties to cross the cell membranes, and degradation during delivery, hence contributing to their limited bioavailability. To address these issues, antioxidants covalently linked with nanoparticles, entrapped in nanogel, hollow particles, or encapsulated into nanoparticles of diverse origin have been used to provide better stability, gradual and sustained release, biocompatibility, and targeted delivery of the antioxidants with superior antioxidant profiles. This review aims to critically evaluate the recent scientific evaluations of nanoparticles as the antioxidant delivery vehicles, as well as their contribution in efficient and enhanced antioxidant activities.

Catechin-conjugated mesoporous hydroxyapatite nanoparticle: A novel nano-antioxidant with enhanced osteogenic property.

Hydroxyapatite is the main component of mineral phase of bone which is widely employed for coating metal implants and scaffold materials in synthetic bone grafts owing to its osteoinductive property. In order to improve the bioactivity of hydroxyapatite, mesoporous hydroxyapatite nanoparticles (MHAP) were synthesized and chemically functionalized with 3-aminopropyltriethoxysilane. The amine-functionalized nanoparticles were conjugated with a natural antioxidant, catechin (Cat), through a stable amide linkage. The true structure of the bioconstruct was confirmed by calculating condensed Fukui indices. The functionalized-hydroxyapatite nanoparticles (Cat@MHAP) showed an outstanding antioxidant activity, having reactivity toward hydroxyl and superoxide radicals larger than that of free catechin. To explore the bone cell responses to this material, multilayer nanoparticle films were prepared by MHAP and Cat@MHAP on a glass substrate. Afterward, the short- and long-term responses of cultured mesenchymal stem cells (MSCs), osteosarcoma cells (Saos-2), and doxorubicin-resistant cells (RSaos-2/Dox) on the surface of the prepared films were investigated. Both the MSCs and bone tumor cells selectively adhered onto Cat@MHAP surface as compared with glass and MHAP at initial culture time. Moreover, it was found that Cat@MHAP decreases the proliferation of Saos-2 and RSaos-2/Dox cells in a time-dependent manner, while it supports the growth of MSCs, indicating the ability of Cat@MHAP to distinguish tumor cells from normal ones. Further, Cat@MHAP promotes the osteogenic differentiation in both the MSCs and tumor cells, accompanied by the attenuation of intracellular ROS. From these results, Cat@MHAP is a novel "nano-antioxidant," which could be considered as a promising biomaterial in treating bone defects, particularly after surgery in osteosarcoma patients.

Surface Functionalization of Iron Oxide Nanoparticles with Gallic Acid as Potential Antioxidant and Antimicrobial Agents.

In this research, we report the size-controlled synthesis and surface-functionalization of magnetite with the natural antioxidant gallic acid (GA) as a ligand, using in situ and post-synthesis methods. GA functionalization provided narrow size distribution, with an average particle size of 5 and 8 nm for in situ synthesis of gallic acid functionalized magnetite IONP@GA1 and IONP@GA2, respectively, which are ultra-small particles as compared to unfunctionalized magnetite (IONP) and post functionalized magnetite IONP@GA3 with average size of 10 and 11 nm respectively. All the IONPs@GA samples were found hydrophilic with stable aggregation state. Prior to commencement of experimental lab work, PASS software was used to predict the biological activities of GA and it is found that experimental antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and antimicrobial studies using well diffusion method are in good agreement with the simulated results. Furthermore, the half maximal inhibitory concentration (IC50) values of DPPH antioxidant assay revealed a 2-4 fold decrease as compared to unfunctionalized IONP. In addition to antioxidant activity, all the three IONP@GA proved outstanding antimicrobial activity while testing on different bacterial and fungal strains. The results collectively indicate the successful fabrication of novel antioxidant, antimicrobial IONP@GA composite, which are magnetically separable, efficient, and low cost, with potential applications in polymers, cosmetics, and biomedical and food industries.