Targeting Inflammation and Oxidative Stress to Improve Outcomes in a TNBS Murine Crohn's Colitis Model.

Inflammation and oxidative stress are implicated in the pathogenesis of Crohn's disease. Cerium oxide nanoparticle (CNP) conjugated to microRNA 146a (miR146a) (CNP-miR146a) is a novel compound with anti-inflammatory and antioxidative properties. We hypothesized that local administration of CNP-miR146a would improve colitis in a 2,4,6-Trinitrobenzenesulfonic acid (TNBS) mouse model for Crohn's disease by decreasing colonic inflammation. Balb/c mice were instilled with TNBS enemas to induce colitis. Two days later, the mice received cellulose gel enema, cellulose gel with CNP-miR146a enema, or no treatment. Control mice received initial enemas of 50% ethanol and PBS enemas on day two. The mice were monitored daily for weight loss and clinical disease activity. The mice were euthanized on days two or five to evaluate their miR146a expression, inflammation on histology, and colonic IL-6 and TNF gene expressions and protein concentrations. CNP-miR146a enema successfully increased colonic miR146a expression at 12 h following delivery. At the end of five days from TNBS instillation, the mice treated with CNP-miR146a demonstrated reduced weight loss, improved inflammation scores on histology, and reduced gene expressions and protein concentrations of IL-6 and TNF. The local delivery of CNP-miR146a in a TNBS mouse model of acute Crohn's colitis dramatically decreased inflammatory signaling, resulting in improved clinical disease.

A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma.

Recent studies suggest that long non-coding RNAs (lncRNAs) contribute to medulloblastoma (MB) formation and progression. We have identified an lncRNA, lnc-HLX-2-7, as a potential therapeutic target in group 3 (G3) MBs. lnc-HLX-2-7 RNA specifically accumulates in the promoter region of HLX, a sense-overlapping gene of lnc-HLX-2-7, which activates HLX expression by recruiting multiple factors, including enhancer elements. RNA sequencing and chromatin immunoprecipitation reveal that HLX binds to and activates the promoters of several oncogenes, including TBX2, LIN9, HOXM1, and MYC. Intravenous treatment with cerium-oxide-nanoparticle-coated antisense oligonucleotides targeting lnc-HLX-2-7 (CNP-lnc-HLX-2-7) inhibits tumor growth by 40%-50% in an intracranial MB xenograft mouse model. Combining CNP-lnc-HLX-2-7 with standard-of-care cisplatin further inhibits tumor growth and significantly prolongs mouse survival compared with CNP-lnc-HLX-2-7 monotherapy. Thus, the lnc-HLX-2-7-HLX-MYC axis is important for regulating G3 MB progression, providing a strong rationale for using lnc-HLX-2-7 as a therapeutic target for G3 MBs.

A Multifunctional Therapeutic Strategy Using P7C3 as A Countermeasure Against Bone Loss and Fragility in An Ovariectomized Rat Model of Postmenopausal Osteoporosis.

By 2060, an estimated one in four Americans will be elderly. Consequently, the prevalence of osteoporosis and fragility fractures will also increase. Presently, no available intervention definitively prevents or manages osteoporosis. This study explores whether Pool 7 Compound 3 (P7C3) reduces progressive bone loss and fragility following the onset of ovariectomy (OVX)-induced osteoporosis. Results confirm OVX-induced weakened, osteoporotic bone together with a significant gain in adipogenic body weight. Treatment with P7C3 significantly reduced osteoclastic activity, bone marrow adiposity, whole-body weight gain, and preserved bone area, architecture, and mechanical strength. Analyses reveal significantly upregulated platelet derived growth factor-BB and leukemia inhibitory factor, with downregulation of interleukin-1 R6, and receptor activator of nuclear factor kappa-B (RANK). Together, proteomic data suggest the targeting of several key regulators of inflammation, bone, and adipose turnover, via transforming growth factor-beta/SMAD, and Wingless-related integration site/be-catenin signaling pathways. To the best of the knowledge, this is first evidence of an intervention that drives against bone loss via RANK. Metatranscriptomic analyses of the gut microbiota show P7C3 increased Porphyromonadaceae bacterium, Candidatus Melainabacteria, and Ruminococcaceae bacterium abundance, potentially contributing to the favorable inflammatory, and adipo-osteogenic metabolic regulation observed. The results reveal an undiscovered, and multifunctional therapeutic strategy to prevent the pathological progression of OVX-induced bone loss.

A neoteric antibacterial ceria-silver nanozyme for abiotic surfaces.

Community-associated and hospital-acquired infections caused by bacteria continue to yield major global challenges to human health. Bacterial contamination on abiotic surfaces is largely spread via high-touch surfaces and contemporary standard disinfection practices show limited efficacy, resulting in unsatisfactory therapeutic outcomes. New strategies that offer non-specific and broad protection are urgently needed. Herein, we report our novel ceria-silver nanozyme engineered at a molar ratio of 5:1 and with a higher trivalent (Ce3+) surface fraction. Our results reveal potent levels of surface catalytic activity on both wet and dry surfaces, with rapid, and complete eradication of Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin resistant S. aureus, in both planktonic and biofilm form. Preferential electrostatic adherence of anionic bacteria to the cationic nanozyme surface leads to a catastrophic loss in both aerobic and anaerobic respiration, DNA damage, osmodysregulation, and finally, programmed bacterial lysis. Our data reveal several unique mechanistic avenues of synergistic ceria-Ag efficacy. Ag potentially increases the presence of Ce3+ sites at the ceria-Ag interface, thereby facilitating the formation of harmful H2O2, followed by likely permeation across the cell wall. Further, a weakened Ag-induced Ce-O bond may drive electron transfer from the Ec band to O2, thereby further facilitating the selective reduction of O2 toward H2O2 formation. Ag destabilizes the surface adsorption of molecular H2O2, potentially leading to higher concentrations of free H2O2 adjacent to bacteria. To this end, our results show that H2O2 and/or NO/NO2-/NO3- are the key liberators of antibacterial activity, with a limited immediate role being offered by nanozyme-induced ROS including O2•- and OH•, and likely other light-activated radicals. A mini-pilot proof-of-concept study performed in a pediatric dental clinic setting confirms residual, and continual nanozyme antibacterial efficacy over a 28-day period. These findings open a new approach to alleviate infections caused by bacteria for use on high-touch hard surfaces.

3D printed bioabsorbable composite scaffolds of poly (lactic acid)-tricalcium phosphate-ceria with osteogenic property for bone regeneration.

The fabrication of customized implants by additive manufacturing has allowed continued development of the personalized medicine field. Herein, a 3D-printed bioabsorbable poly (lactic acid) (PLA)- ß-tricalcium phosphate (TCP) (10 wt %) composite has been modified with CeO2 nanoparticles (CeNPs) (1, 5 and 10 wt %) for bone repair. The filaments were prepared by melt extrusion and used to print porous scaffolds. The nanocomposite scaffolds possessed precise structure with fine print resolution, a homogenous distribution of TCP and CeNP components, and mechanical properties appropriate for bone tissue engineering applications. Cell proliferation assays using osteoblast cultures confirmed the cytocompatibility of the composites. In addition, the presence of CeNPs enhanced the proliferation and differentiation of mesenchymal stem cells; thereby, increasing alkaline phosphatase (ALP) activity, calcium deposition and bone-related gene expression. Results from this study have shown that the 3D printed PLA-TCP-10%CeO2 composite scaffold could be used as an alternative polymeric implant for bone tissue engineering applications: avoiding additional/revision surgeries and accelerating the regenerative process.

Surface Chemistry of Biologically Active Reducible Oxide Nanozymes.

Reducible metal oxide nanozymes (rNZs) are a subject of intense recent interest due to their catalytic nature, ease of synthesis, and complex surface character. Such materials contain surface sites which facilitate enzyme-mimetic reactions via substrate coordination and redox cycling. Further, these surface reactive sites are shown to be highly sensitive to stresses within the nanomaterial lattice, the physicochemical environment, and to processing conditions occurring as part of their syntheses. When administered in vivo, a complex protein corona binds to the surface, redefining its biological identity and subsequent interactions within the biological system. Catalytic activities of rNZs each deliver a differing impact on protein corona formation, its composition, and in turn, their recognition, and internalization by host cells. Improving the understanding of the precise principles that dominate rNZ surface-biomolecule adsorption raises the question of whether designer rNZs can be engineered to prevent corona formation, or indeed to produce "custom" protein coronas applied either in vitro, and preadministration, or formed immediately upon their exposure to body fluids. Here, fundamental surface chemistry processes and their implications in rNZ material performance are considered. In particular, material structures which inform component adsorption from the application environment, including substrates for enzyme-mimetic reactions are discussed.

Effect of Silicon Dioxide and Magnesium Oxide on the Printability, Degradability, Mechanical Strength and Bioactivity of 3D Printed Poly (Lactic Acid)-Tricalcium Phosphate Composite Scaffolds.

BACKGROUND: Poly (lactic acid) (PLA) is a biodegradable polyester that has been exploited for a variety of biomedical applications, including tissue engineering. The incorporation of ß-tricalcium phosphate (TCP) into PLA has imparted bioactivity to the polymeric matrix. METHODS: We have modified a 90%PLA-10%TCP composite with SiO2 and MgO (1, 5 and 10 wt%), separately, to further enhance the material bioactivity. Filaments were prepared by extrusion, and scaffolds were fabricated using 3D printing technology associated with fused filament fabrication. RESULTS: The PLA-TCP-SiO2 composites presented similar structural, thermal, and rheological properties to control PLA and PLA-TCP. In contrast, the PLA-TCP-MgO composites displayed absence of crystallinity, lower polymeric molecular weight, accelerated degradation ratio, and decreased viscosity within the 3D printing shear rate range. SiO2 and MgO particles were homogeneously dispersed within the PLA and their incorporation increased the roughness and protein adsorption of the scaffold, compared to a PLA-TCP scaffold. This favorable surface modification promoted cell proliferation, suggesting that SiO2 and MgO may have potential for enhancing the bio-integration of scaffolds in tissue engineering applications. However, high loads of MgO accelerated the polymeric degradation, leading to an acid environment that imparted the composite biocompatibility. The presence of SiO2 stimulated mesenchymal stem cells differentiation towards osteoblast; enhancing extracellular matrix mineralization, alkaline phosphatase (ALP) activity, and bone-related genes expression. CONCLUSION: The PLA-10%TCP-10%SiO2 composite presented the most promising results, especially for bone tissue regeneration, due to its intense osteogenic behavior. PLA-10%TCP-10%SiO2 could be used as an alternative implant for bone tissue engineering application.

miRNA-211 maintains metabolic homeostasis in medulloblastoma through its target gene long-chain acyl-CoA synthetase 4.

The prognosis of childhood medulloblastoma (MB) is often poor, and it usually requires aggressive therapy that adversely affects quality of life. microRNA-211 (miR-211) was previously identified as an important regulator of cells that descend from neural cells. Since medulloblastomas primarily affect cells with similar ontogeny, we investigated the role and mechanism of miR-211 in MB. Here we showed that miR-211 expression was highly downregulated in cell lines, PDXs, and clinical samples of different MB subgroups (SHH, Group 3, and Group 4) compared to normal cerebellum. miR-211 gene was ectopically expressed in transgenic cells from MB subgroups, and they were subjected to molecular and phenotypic investigations. Monoclonal cells stably expressing miR-211 were injected into the mouse cerebellum. miR-211 forced expression acts as a tumor suppressor in MB both in vitro and in vivo, attenuating growth, promoting apoptosis, and inhibiting invasion. In support of emerging regulatory roles of metabolism in various forms of cancer, we identified the acyl-CoA synthetase long-chain family member (ACSL4) as a direct miR-211 target. Furthermore, lipid nanoparticle-coated, dendrimer-coated, and cerium oxide-coated miR-211 nanoparticles were applied to deliver synthetic miR-211 into MB cell lines and cellular responses were assayed. Synthesizing nanoparticle-miR-211 conjugates can suppress MB cell viability and invasion in vitro. Our findings reveal miR-211 as a tumor suppressor and a potential therapeutic agent in MB. This proof-of-concept paves the way for further pre-clinical and clinical development.

Inorganic Nanoparticles as Radiosensitizers for Cancer Treatment.

Nanotechnology has expanded what can be achieved in our approach to cancer treatment. The ability to produce and engineer functional nanoparticle formulations to elicit higher incidences of tumor cell radiolysis has resulted in substantial improvements in cancer cell eradication while also permitting multi-modal biomedical functionalities. These radiosensitive nanomaterials utilize material characteristics, such as radio-blocking/absorbing high-Z atomic number elements, to mediate localized effects from therapeutic irradiation. These materials thereby allow subsequent scattered or emitted radiation to produce direct (e.g., damage to genetic materials) or indirect (e.g., protein oxidation, reactive oxygen species formation) damage to tumor cells. Using nanomaterials that activate under certain physiologic conditions, such as the tumor microenvironment, can selectively target tumor cells. These characteristics, combined with biological interactions that can target the tumor environment, allow for localized radio-sensitization while mitigating damage to healthy cells. This review explores the various nanomaterial formulations utilized in cancer radiosensitivity research. Emphasis on inorganic nanomaterials showcases the specific material characteristics that enable higher incidences of radiation while ensuring localized cancer targeting based on tumor microenvironment activation. The aim of this review is to guide future research in cancer radiosensitization using nanomaterial formulations and to detail common approaches to its treatment, as well as their relations to commonly implemented radiotherapy techniques.

Infrared and Raman Diagnostic Modeling of Phosphate Adsorption on Ceria Nanoparticles.

Cerium dioxide (CeO2; ceria) nanoparticles (CeNPs) are promising nanozymes that show a variety of biological activity. Effective nanozymes need to retain their activity in the face of surface speciation in biological environments, and characterizing surface speciation is therefore critical to understanding and controlling the therapeutic capabilities of CeNPs. In particular, adsorbed phosphates can impact the enzymatic activity exploited to convert phosphate prodrugs into therapeutics in vivo and also define the early stages of the phosphate-scavenging processes that lead to the transformation of active CeO2 into inactive CePO4. In this work, we utilize ab initio lattice-dynamics calculations to study the interaction of phosphates with the three major surfaces of ceria and to predict the infrared (IR) and Raman spectral signatures of adsorbed phosphate species. We find that phosphates adsorb strongly to CeO2 surfaces in a range of stable binding configurations, of which 5-fold coordinated P species in a trigonal bipyramidal coordination may represent a stable intermediate in the early stages of phosphate scavenging. We find that the phosphate species show characteristic spectral fingerprints between 500 and 1500 cm-1, whereas the bare CeO2 surfaces show no active modes above 600 cm-1, and the 5-fold coordinated P species in particular show potential diagnostic P-O stretching modes between 650 and 700 cm-1 in both IR and Raman spectra. This comprehensive exploration of different binding modes for phosphates on CeO2 and the set of reference spectra provides an important step toward the experimental characterization of phosphate speciation and, ultimately, control of its impact on the performance of ceria nanozymes.

Ultrasound-Responsive Nanobubbles for Combined siRNA-Cerium Oxide Nanoparticle Delivery to Bone Cells.

This study aims to present an ultrasound-mediated nanobubble (NB)-based gene delivery system that could potentially be applied in the future to treat bone disorders such as osteoporosis. NBs are sensitive to ultrasound (US) and serve as a controlled-released carrier to deliver a mixture of Cathepsin K (CTSK) siRNA and cerium oxide nanoparticles (CeNPs). This platform aimed to reduce bone resorption via downregulating CTSK expression in osteoclasts and enhance bone formation via the antioxidant and osteogenic properties of CeNPs. CeNPs were synthesized and characterized using transmission electron microscopy and X-ray photoelectron spectroscopy. The mixture of CTSK siRNA and CeNPs was adsorbed to the surface of NBs using a sonication method. The release profiles of CTSK siRNA and CeNPs labeled with a fluorescent tag molecule were measured after low-intensity pulsed ultrasound (LIPUS) stimulation using fluorescent spectroscopy. The maximum release of CTSK siRNA and the CeNPs for 1 mg/mL of NB-(CTSK siRNA + CeNPs) was obtained at 2.5 nM and 1 µg/mL, respectively, 3 days after LIPUS stimulation. Then, Alizarin Red Staining (ARS) was applied to human bone marrow-derived mesenchymal stem cells (hMSC) and tartrate-resistant acid phosphatase (TRAP) staining was applied to human osteoclast precursors (OCP) to evaluate osteogenic promotion and osteoclastogenic inhibition effects. A higher mineralization and a lower number of osteoclasts were quantified for NB-(CTSK siRNA + CeNPs) versus control +RANKL with ARS (p < 0.001) and TRAP-positive staining (p < 0.01). This study provides a method for the delivery of gene silencing siRNA and CeNPs using a US-sensitive NB system that could potentially be used in vivo and in the treatment of bone fractures and disorders such as osteoporosis.

Examining sialic acid derivatives as potential inhibitors of SARS-CoV-2 spike protein receptor binding domain.

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has been the primary reason behind the COVID-19 global pandemic which has affected millions of lives worldwide. The fundamental cause of the infection is the molecular binding of the viral spike protein receptor binding domain (SP-RBD) with the human cell angiotensin-converting enzyme 2 (ACE2) receptor. The infection can be prevented if the binding of RBD-ACE2 is resisted by utilizing certain inhibitors or drugs that demonstrate strong binding affinity towards the SP RBD. Sialic acid based glycans found widely in human cells and tissues have notable propensity of binding to viral proteins of the coronaviridae family. Recent experimental literature have used N-acetyl neuraminic acid (Sialic acid) to create diagnostic sensors for SARS-CoV-2, but a detailed interrogation of the underlying molecular mechanisms is warranted. Here, we perform all atom molecular dynamics (MD) simulations for the complexes of certain Sialic acid-based molecules with that of SP RBD of SARS CoV-2. Our results indicate that Sialic acid not only reproduces a binding affinity comparable to the RBD-ACE2 interactions, it also assumes the longest time to dissociate completely from the protein binding pocket of SP RBD. Our predictions corroborate that a combination of electrostatic and van der Waals energies as well the polar hydrogen bond interactions between the RBD residues and the inhibitors influence free energy of binding.Communicated by Ramaswamy H. Sarma.

Broad-Spectrum, Potent, and Durable Ceria Nanoparticles Inactivate RNA Virus Infectivity by Targeting Virion Surfaces and Disrupting Virus-Receptor Interactions.

There is intense interest in developing long-lasting, potent, and broad-spectrum antiviral disinfectants. Ceria nanoparticles (CNPs) can undergo surface redox reactions (Ce3+ ↔ Ce4+) to generate ROS without requiring an external driving force. Here, we tested the mechanism behind our prior finding of potent inactivation of enveloped and non-enveloped RNA viruses by silver-modified CNPs, AgCNP1 and AgCNP2. Treatment of human respiratory viruses, coronavirus OC43 and parainfluenza virus type 5 (PIV5) with AgCNP1 and 2, respectively, prevented virus interactions with host cell receptors and resulted in virion aggregation. Rhinovirus 14 (RV14) mutants were selected to be resistant to inactivation by AgCNP2. Sequence analysis of the resistant virus genomes predicted two amino acid changes in surface-located residues D91V and F177L within capsid protein VP1. Consistent with the regenerative properties of CNPs, surface-applied AgCNP1 and 2 inactivated a wide range of structurally diverse viruses, including enveloped (OC43, SARS-CoV-2, and PIV5) and non-enveloped RNA viruses (RV14 and feline calicivirus; FCV). Remarkably, a single application of AgCNP1 and 2 potently inactivated up to four sequential rounds of virus challenge. Our results show broad-spectrum and long-lasting anti-viral activity of AgCNP nanoparticles, due to targeting of viral surface proteins to disrupt interactions with cellular receptors.

Nanotechnology enabled radioprotectants to reduce space radiation-induced reactive oxidative species.

Interest in space exploration has seen substantial growth following recent launch and operation of modern space technologies. In particular, the possibility of travel beyond low earth orbit is seeing sustained support. However, future deep space travel requires addressing health concerns for crews under continuous, longer-term exposure to adverse environmental conditions. Among these challenges, radiation-induced health issues are a major concern. Their potential to induce chronic illness is further potentiated by the microgravity environment. While investigations into the physiological effects of space radiation are still under investigation, studies on model ionizing radiation conditions, in earth and micro-gravity conditions, can provide needed insight into relevant processes. Substantial formation of high, sustained reactive oxygen species (ROS) evolution during radiation exposure is a clear threat to physiological health of space travelers, producing indirect damage to various cell structures and requiring therapeutic address. Radioprotection toward the skeletal system components is essential to astronaut health, due to the high radio-absorption cross-section of bone mineral and local hematopoiesis. Nanotechnology can potentially function as radioprotectant and radiomitigating agents toward ROS and direct radiation damage. Nanoparticle compositions such as gold, silver, platinum, carbon-based materials, silica, transition metal dichalcogenides, and ceria have all shown potential as viable radioprotectants to mitigate space radiation effects with nanoceria further showing the ability to protect genetic material from oxidative damage in several studies. As research into space radiation-induced health problems develops, this review intends to provide insights into the nanomaterial design to ameliorate pathological effects from ionizing radiation exposure. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Nanotechnology Approaches to Biology > Cells at the Nanoscale Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

CNP-miR146a improves outcomes in a two-hit acute- and ventilator-induced lung injury model.

Acute respiratory distress syndrome (ARDS) has high mortality (~40 %) and requires the lifesaving intervention of mechanical ventilation. A variety of systemic inflammatory insults can progress to ARDS, and the inflamed and injured lung is susceptible to ventilator-induced lung injury (VILI). Strategies to mitigate the inflammatory response while restoring pulmonary function are limited, thus we sought to determine if treatment with CNP-miR146a, a conjugate of novel free radical scavenging cerium oxide nanoparticles (CNP) to the anti-inflammatory microRNA (miR)-146a, would protect murine lungs from acute lung injury (ALI) induced with intratracheal endotoxin and subsequent VILI. Lung injury severity and treatment efficacy were evaluated via lung mechanical function, relative gene expression of inflammatory biomarkers, and lung morphometry (stereology). CNP-miR146a reduced the severity of ALI and slowed the progression of VILI, evidenced by improvements in inflammatory biomarkers, atelectasis, gas volumes in the parenchymal airspaces, and the stiffness of the pulmonary system.

BindingSite-AugmentedDTA: enabling a next-generation pipeline for interpretable prediction models in drug repurposing.

While research into drug-target interaction (DTI) prediction is fairly mature, generalizability and interpretability are not always addressed in the existing works in this field. In this paper, we propose a deep learning (DL)-based framework, called BindingSite-AugmentedDTA, which improves drug-target affinity (DTA) predictions by reducing the search space of potential-binding sites of the protein, thus making the binding affinity prediction more efficient and accurate. Our BindingSite-AugmentedDTA is highly generalizable as it can be integrated with any DL-based regression model, while it significantly improves their prediction performance. Also, unlike many existing models, our model is highly interpretable due to its architecture and self-attention mechanism, which can provide a deeper understanding of its underlying prediction mechanism by mapping attention weights back to protein-binding sites. The computational results confirm that our framework can enhance the prediction performance of seven state-of-the-art DTA prediction algorithms in terms of four widely used evaluation metrics, including concordance index, mean squared error, modified squared correlation coefficient ($r^2_m$) and the area under the precision curve. We also contribute to three benchmark drug-traget interaction datasets by including additional information on 3D structure of all proteins contained in those datasets, which include the two most commonly used datasets, namely Kiba and Davis, as well as the data from IDG-DREAM drug-kinase binding prediction challenge. Furthermore, we experimentally validate the practical potential of our proposed framework through in-lab experiments. The relatively high agreement between computationally predicted and experimentally observed binding interactions supports the potential of our framework as the next-generation pipeline for prediction models in drug repurposing.

Cerium Oxide Nanoparticles Conjugated with Tannic Acid Prevent UVB-Induced Oxidative Stress in Fibroblasts: Evidence of a Promising Anti-Photodamage Agent.

Exposure to ultraviolet radiation induces photodamage towards cellular macromolecules that can progress to photoaging and photocarcinogenesis. The topical administration of compounds that maintain the redox balance in cells presents an alternative approach to combat skin oxidative damage. Cerium oxide nanoparticles (CNPs) can act as antioxidants due to their enzyme-like activity. In addition, a recent study from our group has demonstrated the photoprotective potential of tannic acid (TA). Therefore, this work aimed to synthesize CNPs associated with TA (CNP-TA) and investigate its photoprotective activity in L929 fibroblasts exposed to UVB radiation. CNP conjugation with TA was confirmed by UV-Vis spectra and X-ray photoelectron spectroscopy. Bare CNPs and CNP-TA exhibited particle sizes of ~5 and ~10 nm, superoxide dismutase activity of 3724 and 2021 unit/mg, and a zeta potential of 23 and -19 mV, respectively. CNP-TA showed lower cytotoxicity than free TA and the capacity to reduce the oxidative stress caused by UVB; supported by the scavenging of reactive oxygen species, the prevention of endogenous antioxidant system depletion, and the reduction in oxidative damage in lipids and DNA. Additionally, CNP-TA improved cell proliferation and decreased TGF-ß, metalloproteinase-1, and cyclooxygenase-2. Based on these results, CNP-TA shows therapeutic potential for protection against photodamage, decreasing molecular markers of photoaging and UVB-induced inflammation.

An osteogenic magnesium alloy with improved corrosion resistance, antibacterial, and mechanical properties for orthopedic applications.

The aim of this study was to develop a novel biodegradable magnesium (Mg) alloy for bone implant applications. We used scandium (Sc; 2 wt %) and strontium (Sr; 2 wt %) as alloying elements due to their high biocompatibility, antibacterial efficacy, osteogenesis, and protective effects against corrosion. In the present work, we also examined the effect of a heat treatment process on the properties of the Mg-Sc-Sr alloy. Alloys were manufactured using a metal casting process followed by heat treatment. The microstructure, corrosion, mechanical properties, antibacterial activity, and osteogenic activity of the alloy were assessed in vitro. The results showed that the incorporation of Sc and Sr elements controlled the corrosion, reduced the hydrogen generation, and enhanced mechanical properties. Furthermore, alloying with Sc and Sr demonstrated a significantly enhanced antibacterial activity and decreased biofilm formation compared to control Mg. Also, culturing Mg-Sc-Sr alloy with human bone marrow-derived mesenchymal stromal cells showed a high degree of biocompatibility (>90% live cells) and a significant increase in osteoblastic differentiation in vitro shown by Alizarin red staining and alkaline phosphatase activity. Based on these results, the Mg-Sc-Sr alloy heat-treated at 400°C displayed optimal mechanical properties, corrosion rate, antibacterial efficacy, and osteoinductivity. These characteristics make the Mg-Sc-Sr alloy a promising candidate for biodegradable orthopedic implants in the fixation of bone fractures such as bone plate-screws or intramedullary nails.

A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme.

The disability, mortality and costs due to ionizing radiation (IR)-induced osteoporotic bone fractures are substantial and no effective therapy exists. Ionizing radiation increases cellular oxidative damage, causing an imbalance in bone turnover that is primarily driven via heightened activity of the bone-resorbing osteoclast. We demonstrate that rats exposed to sublethal levels of IR develop fragile, osteoporotic bone. At reactive surface sites, cerium ions have the ability to easily undergo redox cycling: drastically adjusting their electronic configurations and versatile catalytic activities. These properties make cerium oxide nanomaterials fascinating. We show that an engineered artificial nanozyme composed of cerium oxide, and designed to possess a higher fraction of trivalent (Ce3+) surface sites, mitigates the IR-induced loss in bone area, bone architecture, and strength. These investigations also demonstrate that our nanozyme furnishes several mechanistic avenues of protection and selectively targets highly damaging reactive oxygen species, protecting the rats against IR-induced DNA damage, cellular senescence, and elevated osteoclastic activity in vitro and in vivo. Further, we reveal that our nanozyme is a previously unreported key regulator of osteoclast formation derived from macrophages while also directly targeting bone progenitor cells, favoring new bone formation despite its exposure to harmful levels of IR in vitro. These findings open a new approach for the specific prevention of IR-induced bone loss using synthesis-mediated designer multifunctional nanomaterials.

Engineered Faceted Cerium Oxide Nanoparticles for Therapeutic miRNA Delivery.

In general, wound healing is a highly ordered process, with distinct phases of inflammation, proliferation, and remodeling. However, among diabetic patients, the progression through these phases is often impeded by increased level of oxidative stress and persistent inflammation. Our previous studies demonstrated that cerium oxide nanoparticles (CNPs) conjugated with therapeutic microRNA146a (miR146a) could effectively enhance wound healing by targeting the NFκB pathway, reducing oxidative stress and inflammation. In the present study, we consider the potential effects of nanomaterial surface-faceting and morphology on the efficacy of miRNA delivery. Compared with octahedral-CNPs and cubic-CNPs, rod-CNPs exhibited higher loading capacity. In addition, in comparing the influence of particle morphology on wound healing efficacy, several markers for bioactivity were evaluated and ascribed to the combined effects of the gene delivery and reactive oxygen species (ROS) scavenging properties. In the cellular treatment study, rod-CNP-miR146a displayed the greatest miR146a delivery into cells. However, the reduction of IL-6 was only observed in the octahedral-CNP-miR146a, suggesting that the efficacy of the miRNA delivery is a result of the combination of various factors. Overall, our results give enlightenments into the relative delivery efficiency of the CNPs with different morphology enhancing miRNA delivery efficacy.