Cytoprotective effects of antioxidant supplementation on mesenchymal stem cell therapy.

Mesenchymal stem cells (MSCs) are earmarked as perfect candidates for cell therapy and tissue engineering due to their capacity to differentiate into different cell types. However, their potential for application in regenerative medicine declines when the levels of the reactive oxygen and nitrogen species (RONS) increase from the physiological levels, a phenomenon which is at least inevitable in ex vivo cultures and air-exposed damaged tissues. Increased levels of RONS can alter the patterns of osteogenic and adipogenic differentiation and inhibit proliferation, as well. Besides, oxidative stress enhances senescence and cell death, thus lowering the success rates of the MSC engraftment. Hence, in this review, we have selected some representatives of antioxidants and newly emerged nano antioxidants in three main categories, including chemical compounds, biometabolites, and protein precursors/proteins, which are proved to be effective in the treatment of MSCs. We will focus on how antioxidants can be applied to optimize the clinical usage of the MSCs and their associated signaling pathways. We have also reviewed several paralleled properties of some antioxidants and nano antioxidants which can be simultaneously used in real-time imaging, scaffolding techniques, and other applications in addition to their primary antioxidative function.

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.

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.

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.

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.