RESUMEN
Myocardial infarction (MI) has a 5-year mortality rate of more than 50% due to the lack of effective treatments. Interactions between cardiomyocytes and the MI microenvironment (MIM) can determine the progression and fate of infarcted myocardial tissue. Here, a specially designed Melanin-based composite nanomedicines (MCN) is developed to effectively treat MI by reprogramming the MIM. MCN is a nanocomposite composed of polydopamine (P), Prussian blue (PB) and cerium oxide (CexOy) with a Mayuan-like structure, which reprogramming the MIM by the efficient conversion of detrimental substances (H+, reactive oxygen species, and hypoxia) into beneficial status (O2 and H2O). In coronary artery ligation and ischemia reperfusion models of male mice, intravenously injecting MCN specifically targets the damaged area, resulting in restoration of cardiac function. With its promising therapeutic effects, MCN constitutes a new agent for MI treatment and demonstrates potential for clinical application.
Asunto(s)
Cerio , Indoles , Melaninas , Infarto del Miocardio , Nanomedicina , Polímeros , Animales , Melaninas/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Masculino , Ratones , Nanomedicina/métodos , Indoles/química , Polímeros/química , Cerio/química , Cerio/farmacología , Cerio/administración & dosificación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Nanocompuestos/química , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Microambiente Celular/efectos de los fármacos , FerrocianurosRESUMEN
Chronic wound healing is a common clinical challenge, characterized by bacterial infection, protracted inflammatory response, oxidative stress, and insufficient neovascularization. Nanozymes have emerged as a promising solution for treating skin wounds due to their antioxidant, antibacterial, and angiogenic properties. In recent years, combining nanozymes with hydrogels to jointly promote wound healing has attracted increasing research interest. However, most of the current nanocomposite hydrogels are still not effective in simultaneously controlling inflammatory, oxidative stress and bacterial invasion in wound healing. Improving the therapeutic functional diversity and efficacy of nanocomposite hydrogels remains a problem that needs to be addressed. In this study, we prepared nanocomposite hydrogels (GelMD-Cur@ZHMCe) by combining methylacrylated gelatin modified with dopamine (GelMD) with Zinc-doped hollow mesoporous cerium oxide nanoparticles loaded with curcumin (Cur@ZHMCe). The resulting hydrogels exhibited excellent water absorption, adhesion, and biocompatibility. In vitro and in vivo studies have demonstrated that GelMD-Cur@ZHMCe has excellent antioxidant, antibacterial, anti-inflammatory and vasculature-promoting properties, which enable it to rapidly promote wound repair. The wound healing rate of the rat total skin defect infection model treated with GelMD-Cur@ZHMCe reached 98.5±4.9 % after 14 days of treatment. It was demonstrated that this multifunctional nanocomposite hydrogel provides a promising therapeutic strategy for skin repair.
Asunto(s)
Antibacterianos , Antioxidantes , Cerio , Curcumina , Dopamina , Gelatina , Hidrogeles , Nanocompuestos , Ratas Sprague-Dawley , Cicatrización de Heridas , Zinc , Hidrogeles/química , Hidrogeles/administración & dosificación , Cerio/química , Cerio/administración & dosificación , Cerio/farmacología , Cicatrización de Heridas/efectos de los fármacos , Animales , Gelatina/química , Curcumina/administración & dosificación , Curcumina/química , Curcumina/farmacología , Nanocompuestos/química , Nanocompuestos/administración & dosificación , Dopamina/química , Dopamina/administración & dosificación , Zinc/química , Zinc/administración & dosificación , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/química , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Antioxidantes/química , Masculino , Ratas , Ratones , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antiinflamatorios/química , Piel/efectos de los fármacos , Piel/metabolismo , HumanosRESUMEN
Acute myocardial infarction (AMI) resulting from coronary artery occlusion stands as the predominant cause of cardiovascular disability and mortality worldwide. An all-encompassing treatment strategy targeting pathological processes of oxidative stress, inflammation, proliferation and fibrotic remodeling post-AMI is anticipated to enhance therapeutic outcomes. Herein, an up-down-structured bilayer microneedle (Ce-CLMs-BMN) with reactive oxygen species (ROS) and ultrasound (US) dual-responsiveness is proposed for AMI in-situ sequential therapy. The upper-layer microneedle is formulated by crosslinking ROS-sensitive linker with polyvinyl alcohol loaded with cerium dioxide nanoparticles (CeNPs) featuring versatile enzyme-mimetic activities. During AMI acute phase, prompted by ischemia-induced microenvironmental redox imbalance, this layer swiftly releases CeNPs, which aid in eliminating excessive ROS and catalyzing oxygen gas (O2) production through multiple enzymatic pathways, thereby alleviating oxidative stress-induced damage and modulating inflammation. In AMI chronic repair phase, micro-nano reactors (CLMs) situated in the lower-layer microneedle undergo cascade reactions with the assistance of US irradiation to generate nitric oxide (NO). As a bioactive molecule with pro-angiogenic and anti-fibrotic effects, NO expedites cardiac repair while attenuating adverse remodeling. Additionally, its antiplatelet-aggregating properties contribute to thromboprophylaxis. In-vitro and in-vivo results substantiate the efficacy of this integrated healing approach in AMI management, showcasing promising prospects for advancing infarcted heart repair.
Asunto(s)
Infarto del Miocardio , Agujas , Especies Reactivas de Oxígeno , Infarto del Miocardio/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Animales , Nanopartículas/uso terapéutico , Cerio/administración & dosificación , Cerio/química , Cerio/farmacología , Estrés Oxidativo/efectos de los fármacos , Humanos , Óxido Nítrico/administración & dosificación , Óxido Nítrico/metabolismo , Ratas , Masculino , Alcohol Polivinílico/química , Alcohol Polivinílico/administración & dosificaciónRESUMEN
Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile antioxidant, anti-inflammatory, anti-tumor, anti-HIV, and anti-infection properties. Nonetheless, the major problem related to its use is its poor oral bioavailability, which can be overcome by encapsulating it into small particles, such as hydrogel beads containing mesoporous silica. In this work, various systems have been synthesized: starting from mesoporous silica glasses (MGs), cerium-containing MGs have been produced; then, these systems have been loaded with 4 to 6% of curcumin. Finally, various MGs at different compositions have been included in alginate beads. In vitro studies showed that these hybrid materials enable the stabilization and effective delivery of curcumin and that a synergic effect can be achieved if Ce3+/Ce4+ and curcumin are both part of the beads. From swelling tests, it is possible to confirm a controlled curcumin release compartmentalized into the gastrointestinal tract. For all beads obtained, a curcumin release sufficient to achieve the antioxidant threshold has been reached, and a synergic effect of cerium and curcumin is observed. Moreover, from catalase mimetic activity tests, we confirm the well-known catalytic activity of the couple Ce3+/Ce4+. In addition, an extremely good radical scavenging effect of curcumin has been demonstrated. In conclusion, these systems, able to promote an enzymatic-like activity, can be used as drug delivery systems for curcumin-targeted dosing.
Asunto(s)
Alginatos , Antineoplásicos , Antioxidantes , Cerio , Curcumina , Alginatos/química , Antioxidantes/administración & dosificación , Cerio/administración & dosificación , Curcumina/administración & dosificación , Dióxido de Silicio/química , Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos , HumanosRESUMEN
In recent years, nanozymes based on two-dimensional (2D) nanomaterials have been receiving great interest for cancer photothermal therapy. 2D materials decorated with nanoparticles (NPs) on their surface are advantageous over conventional NPs and 2D material based systems because of their ability to synergistically improve the unique properties of both NPs and 2D materials. In this work, we report a nanozyme based on flower-like MoS2nanoflakes (NFs) by decorating their flower petals with NCeO2using polyethylenimine (PEI) as a linker molecule. A detailed investigation on toxicity, biocompatibility and degradation behavior of fabricated nanozymes in wild-typeDrosophila melanogastermodel revealed that there were no significant effects on the larval size, morphology, larval length, breadth and no time delay in changing larvae to the third instar stage at 7-10 d for MoS2NFs before and after NCeO2decoration. The muscle contraction and locomotion behavior of third instar larvae exhibited high distance coverage for NCeO2decorated MoS2NFs when compared to bare MoS2NFs and control groups. Notably, the MoS2and NCeO2-PEI-MoS2NFs treated groups at 100µg ml-1covered a distance of 38.2 mm (19.4% increase when compared with control) and 49.88 mm (no change when compared with control), respectively. High-resolution transmission electron microscopy investigations on the new born fly gut showed that the NCeO2decoration improved the degradation rate of MoS2NFs. Hence, nanozymes reported here have huge potential in various fields ranging from biosensing, cancer therapy and theranostics to tissue engineering and the treatment of Alzheimer's disease and retinal therapy.
Asunto(s)
Materiales Biocompatibles/toxicidad , Cerio/toxicidad , Disulfuros/toxicidad , Molibdeno/toxicidad , Nanoestructuras/toxicidad , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacocinética , Cerio/administración & dosificación , Cerio/química , Cerio/farmacocinética , Disulfuros/administración & dosificación , Disulfuros/química , Disulfuros/farmacocinética , Drosophila melanogaster , Tracto Gastrointestinal/metabolismo , Larva/efectos de los fármacos , Larva/crecimiento & desarrollo , Larva/metabolismo , Locomoción/efectos de los fármacos , Ensayo de Materiales , Tasa de Depuración Metabólica , Molibdeno/administración & dosificación , Molibdeno/química , Molibdeno/farmacocinética , Contracción Muscular/efectos de los fármacos , Nanoestructuras/administración & dosificación , Nanoestructuras/química , Polietileneimina/administración & dosificación , Polietileneimina/química , Polietileneimina/farmacocinética , Polietileneimina/toxicidad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: The main goal of our study was to explore the wound-healing property of a novel cerium-containing N-acethyl-6-aminohexanoate acid compound and determine key molecular targets of the compound mode of action in diabetic animals. METHODS: Cerium N-acetyl-6-aminohexanoate (laboratory name LHT-8-17) as a 10 mg/mL aquatic spray was used as wound experimental topical therapy. LHT-8-17 toxicity was assessed in human skin epidermal cell culture using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. A linear wound was reproduced in 18 outbred white rats with streptozotocin-induced (60 mg/kg i.p.) diabetes; planar cutaneous defect was modelled in 60 C57Bl6 mice with streptozotocin-induced (200 mg/kg i.p.) diabetes and 90 diabetic db/db mice. Firmness of the forming scar was assessed mechanically. Skin defect covering was histologically evaluated on days 5, 10, 15, and 20. Tissue TNF-α, IL-1ß and IL-10 levels were determined by quantitative ELISA. Oxidative stress activity was detected by Fe-induced chemiluminescence. Ki-67 expression and CD34 cell positivity were assessed using immunohistochemistry. FGFR3 gene expression was detected by real-time PCR. LHT-8-17 anti-microbial potency was assessed in wound tissues contaminated by MRSA. RESULTS: LHT-8-17 4 mg twice daily accelerated linear and planar wound healing in animals with type 1 and type 2 diabetes. The formulated topical application depressed tissue TNF-α, IL-1ß, and oxidative reaction activity along with sustaining both the IL-10 concentration and antioxidant capacity. LHT-8-17 induced Ki-67 positivity of fibroblasts and pro-keratinocytes, upregulated FGFR3 gene expression, and increased tissue vascularization. The formulation possessed anti-microbial properties. CONCLUSIONS: The obtained results allow us to consider the formulation as a promising pharmacological agent for diabetic wound topical treatment.
Asunto(s)
Aminocaproatos/administración & dosificación , Cerio/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacos , Administración Tópica , Aminocaproatos/metabolismo , Animales , Cerio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Cicatrización de Heridas/fisiologíaRESUMEN
The interactions between pharmaceuticals and nanomaterials and its potentially resulting toxicological effects in living systems are only insufficiently investigated. In this study, two model compounds, acetaminophen, a pharmaceutical, and cerium dioxide, a manufactured nanomaterial, were investigated in combination and individually. Upon inhalation, cerium dioxide nanomaterials were shown to systemically translocate into other organs, such as the liver. Therefore we picked the human liver cell line HuH-7 cells as an in vitro system to investigate liver toxicity. Possible synergistic or antagonistic metabolic changes after co-exposure scenarios were investigated. Toxicological data of the water soluble tetrazolium (WST-1) assay for cell proliferation and genotoxicity assessment using the Comet assay were combined with an untargeted as well as a targeted lipidomics approach. We found an attenuated cytotoxicity and an altered metabolic profile in co-exposure experiments with cerium dioxide, indicating an interaction of both compounds at these endpoints. Single exposure against cerium dioxide showed a genotoxic effect in the Comet assay. Conversely, acetaminophen exhibited no genotoxic effect. Comet assay data do not indicate an enhancement of genotoxicity after co-exposure. The results obtained in this study highlight the advantage of investigating co-exposure scenarios, especially for bioactive substances.
Asunto(s)
Acetaminofén/efectos adversos , Cerio/efectos adversos , Hígado/efectos de los fármacos , Hígado/metabolismo , Nanopartículas , Acetaminofén/administración & dosificación , Transporte Biológico , Línea Celular Tumoral , Cerio/administración & dosificación , Daño del ADN/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Metaboloma , Metabolómica/métodos , Nanopartículas/química , Tamaño de la Partícula , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
Diabetic foot wound healing is a major clinical problem due to impaired angiogenesis and bacterial infection. Therefore, an effective regenerative dressing is desiderated with the function of promoting revascularization and anti-bacteria. Herein, a multifunctional injectable composite hydrogel was prepared by incorporation of the cerium-containing bioactive glass (Ce-BG) into Gelatin methacryloyl (GelMA) hydrogel. The Ce-BG was synthesized by combining sol-gel method with template method, which maintained spherical shape, chemical structure and phase constitution of bioactive glass (BG). The Ce-BG/GelMA hydrogels had good cytocompatibility, promoted endothelial cells migration and tube formation by releasing Si ion. In vitro antibacterial tests showed that 5 mol % CeO2-containing bioactive glass/GelMA (5/G) composite hydrogel exhibited excellent antibacterial properties. In vivo study demonstrated that the 5/G hydrogel could significantly improve wound healing in diabetic rats by accelerating the formation of granulation tissue, collagen deposition and angiogenesis. All in all, these results indicate that the 5/G hydrogel could enhance diabetic wound healing. Therefore, the development of multifunctional materials with antibacterial and angiogenic functions is of great significance to promote the repair of diabetic wound healing.
Asunto(s)
Antibacterianos/administración & dosificación , Cerio/administración & dosificación , Diabetes Mellitus Experimental/complicaciones , Cicatrización de Heridas/efectos de los fármacos , Animales , Antibacterianos/química , Antibacterianos/farmacología , Línea Celular , Movimiento Celular/efectos de los fármacos , Cerio/química , Cerio/farmacología , Colágeno/metabolismo , Diabetes Mellitus Experimental/metabolismo , Gelatina/química , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hidrogeles , Nanopartículas del Metal , Metacrilatos/química , Ratones , Ratas , Estreptozocina/efectos adversosRESUMEN
Large human biomonitoring studies are starting to assess exposure to rare earth elements (REEs). Yet, there is a paucity of data on the toxicokinetics of these substances to help interpret biomonitoring data. The objective of the study was to document the effect of the administered dose on the toxicokinetics of REEs. Male Sprague-Dawley rats were injected intravenously with 0.3, 1 or 10 mg/kg body weight (bw) of praseodynium chloride (PrCl3), cerium chloride (CeCl3), neodymium chloride (NdCl3) and yttrium chloride (YCl3) administered together as a mixture. Serial blood samples were withdrawn up to 72 h following injection, and urine and feces were collected at predefined time intervals up to 7 days post-dosing. The REEs were measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). For a given REE dose, the time courses in blood, urine and feces were similar for all four REEs. However, the REE dose administered significantly impacted their kinetics, as lower cumulative excretion in urine and feces was associated with higher REE doses. The fraction of REE remaining in rat tissues at the terminal necropsy on post-dosing day 7 also increased with the dose administered, most notably in the lungs and spleen at the 10 mg/kg bw dose. The toxicokinetic parameters calculated from the blood concentration-time profiles further showed significant increases in the mean residence time (MRTIV) for all four REEs at the 10 mg/kg bw dose. The shift in the REE kinetics at high dose may be explained by a higher retention in lysosomes, the main organelle responsible for accumulation of these REEs in different tissues.
Asunto(s)
Metales de Tierras Raras/farmacocinética , Metales de Tierras Raras/toxicidad , Animales , Cerio/administración & dosificación , Cerio/farmacocinética , Cerio/toxicidad , Inyecciones Intravenosas , Eliminación Intestinal , Lisosomas/metabolismo , Masculino , Metales de Tierras Raras/administración & dosificación , Neodimio/administración & dosificación , Neodimio/farmacocinética , Neodimio/toxicidad , Praseodimio/administración & dosificación , Praseodimio/farmacocinética , Praseodimio/toxicidad , Ratas Sprague-Dawley , Eliminación Renal , Distribución Tisular , Toxicocinética , Itrio/administración & dosificación , Itrio/farmacocinética , Itrio/toxicidadRESUMEN
BACKGROUND: Intracerebral hemorrhage (ICH) can induce excessive accumulation of reactive oxygen species (ROS) that may subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS also drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration. METHODS: ICH was induced in vivo by collagenase VII injection. Mice were administered with PLX3397 for depleting microglia. Primary microglia and astrocytes were used for in vitro experiments. Transmission electron microscopy analysis and immunostaining were performed to verify the positive effects of CeNP in remyelination and OPC differentiation. Flow cytometry, real-time polymerase chain reaction, immunofluorescence and western blotting were used to detect microglia polarization, astrocyte alteration, and the underlying molecular mechanisms. RESULTS: CeNP treatment strongly inhibited ROS-induced NF-κB p65 translocation in both microglia and astrocytes, and significantly decreased the expression of M1 microglia and A1 astrocyte. Furthermore, we found that CeNP treatment promoted remyelination and OPC differentiation after ICH, and such effects were alleviated after microglial depletion. Interestingly, we also found that the number of mature oligodendrocytes was moderately increased in ICH + CeNP + PLX3397-treated mice compared to the ICH + vehicle + PLX3397 group. Therefore, astrocytes might participate in the pathophysiological process. The subsequent phagocytosis assay indicated that A1 astrocyte highly expressed C3, which could bind with microglia C3aR and hinder microglial engulfment of myelin debris. This result further replenished the feedback mechanism from astrocytes to microglia. CONCLUSION: The present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through ROS-induced NF-κB p65 translocation that hinders OPC maturation. Subsequently, A1 astrocytes inhibit microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis. Polyethylene glycol-CeNP treatment inhibits this pathological process and ultimately promotes remyelination. Such findings enlighten us that astrocytes and microglia should be regarded as a functional unit in future works.
Asunto(s)
Astrocitos/efectos de los fármacos , Hemorragia Cerebral/tratamiento farmacológico , Microglía/efectos de los fármacos , Nanopartículas/administración & dosificación , Remielinización/efectos de los fármacos , Sustancia Blanca/efectos de los fármacos , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Astrocitos/patología , Células Cultivadas , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Cerio/administración & dosificación , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/patología , Remielinización/fisiología , Sustancia Blanca/metabolismo , Sustancia Blanca/patologíaRESUMEN
Traumatic brain injury (TBI) is a sudden injury to the brain, accompanied by the production of large amounts of reactive oxygen and nitrogen species (RONS) and acute neuroinflammation responses. Although traditional pharmacotherapy can effectively decrease the immune response of neuron cells via scavenging free radicals, it always involves in short reaction time as well as rigorous clinical trial. Therefore, a noninvasive topical treatment method that effectively eliminates free radicals still needs further investigation. Methods: In this study, a type of catalytic patch based on nanozymes with the excellent multienzyme-like activity is designed for noninvasive treatment of TBI. The enzyme-like activity, free radical scavenging ability and therapeutic efficacy of the designed catalytic patch were assessed in vitro and in vivo. The structural composition was characterized by the X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy technology. Results: Herein, the prepared Cr-doped CeO2 (Cr/CeO2) nanozyme increases the reduced Ce3+ states, resulting in its enzyme-like activity 3-5 times higher than undoped CeO2. Furthermore, Cr/CeO2 nanozyme can improve the survival rate of LPS induced neuron cells via decreasing excessive RONS. The in vivo experiments show the Cr/CeO2 nanozyme can promote wound healing and reduce neuroinflammation of mice following brain trauma. The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases. Conclusions: The catalytic patch based on nanozyme provides a noninvasive topical treatment route for TBI as well as other traumas diseases.
Asunto(s)
Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Catálisis/efectos de los fármacos , Cerio/administración & dosificación , Compuestos de Cromo/administración & dosificación , Oxidación-Reducción/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Línea Celular , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Tasa de Supervivencia , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Diabetes mellitus is a metabolic disorder associated with properties and an increased risk of chronic wounds due to sustained pro-inflammatory response. We have previously of radical scavenging cerium oxide nanoparticles (CNP) conjugated to the anti-inflammatory microRNA (miR)-146a, termed CNP-miR146a, improves diabetic wound healing by synergistically lowering oxidative stress and inflammation, and we sought to evaluate this treatment in a topical application. Silk fibroin is a biocompatible polymer that can be fabricated into nanostructures, termed nanosilk. Nanosilk is characterized by a high strength-to-density ratio and an ability to exhibit strain hardening. We therefore hypothesized that nanosilk would strengthen the biomechanical properties of diabetic skin and that nanosilk solution could effectively deliver CNP-miR146a to improve diabetic wound healing. The ability of nanosilk to deliver CNP-miR146a to murine diabetic wounds and improve healing was assessed by the rate of wound closure and inflammatory gene expression, as well as histologic analysis. The effect of nanosilk on the properties of human diabetic skin was evaluated by testing the biomechanical properties following topical application of a 7% nanosilk solution. Diabetic murine wounds treated with topical nanosilk and CNP-miR146a healed by day 14.5 compared to day 16.8 in controls (p = 0.0321). Wounds treated with CNP-miR146a had higher collagen levels than controls (p = 0.0126) with higher pro-fibrotic gene expression of TGFß-1 (p = 0.0092), Col3α1 (p = 0.0369), and Col1α2 (p = 0.0454). Treatment with CNP-miR146a lowered pro-inflammatory gene expression of IL-6 (p = 0.0488) and IL-8 (p = 0.0009). Treatment of human diabetic skin with 7% nanosilk solution resulted in significant improvement in maximum load and modulus (p < 0.05). Nanosilk solution is able to strengthen the biomechanical properties of diabetic skin and can successfully deliver CNP-miR146a to improve diabetic wound healing through inhibition of pro-inflammatory gene signaling and promotion of pro-fibrotic processes.
Asunto(s)
Cerio/administración & dosificación , Diabetes Mellitus Experimental/tratamiento farmacológico , MicroARNs/administración & dosificación , Nanopartículas/administración & dosificación , Seda/administración & dosificación , Fenómenos Fisiológicos de la Piel/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Animales , Fenómenos Biomecánicos , Cerio/química , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Ratones , MicroARNs/química , Nanopartículas/química , Seda/química , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patologíaRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disease that affects 1-2% of the human population worldwide, and effective therapies with targeted delivery for local immune suppression have not been described. We address this problem by developing a novel theranostic nanoparticle for RA and assessed its therapeutic and targeting effects under image-guidance. Methods: Albumin-cerium oxide nanoparticles were synthesized by the biomineralization process and further conjugated with near-infrared, indocyanine green (ICG) dye. Enzymatic-like properties and reactive oxygen species (ROS) scavenging activities, as well as the ability to reprogram macrophages, were determined on a monocyte cell line in culture. The therapeutic effect and systemic targeting potential were evaluated in collagen-induced arthritis (CIA) mouse model using optical/optoacoustic tomographic imaging. Results: Small nanotheranostics with narrow size distribution and high colloidal stability were fabricated and displayed high ROS scavenging and enzymatic-like activity, as well as advanced efficacy in a converting pro-inflammatory macrophage phenotype into anti-inflammatory phenotype. When administrated into affected animals, these nanoparticles accumulated in inflamed joints and revealed a therapeutic effect similar to the gold-standard therapy for RA, methotrexate. Conclusions: The inflammation-targeting, inherent contrast and therapeutic activity of this new albumin-cerium oxide nanoparticle may make it a relevant agent for assessing severity in RA, and other inflammatory diseases, and controlling inflammation with image-guidance. The design of these nanotheranostics will enable potential clinical translation as systemic therapy for RA.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Cerio/administración & dosificación , Nanopartículas/administración & dosificación , Animales , Antirreumáticos/química , Antirreumáticos/farmacocinética , Artritis Experimental/diagnóstico , Artritis Experimental/inmunología , Artritis Experimental/patología , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Cerio/química , Cerio/farmacocinética , Colágeno/administración & dosificación , Colágeno/inmunología , Colorantes/administración & dosificación , Colorantes/química , Composición de Medicamentos/métodos , Monitoreo de Drogas/métodos , Adyuvante de Freund/administración & dosificación , Adyuvante de Freund/inmunología , Semivida , Humanos , Verde de Indocianina/administración & dosificación , Verde de Indocianina/química , Inyecciones Intraarticulares , Articulaciones/diagnóstico por imagen , Articulaciones/efectos de los fármacos , Articulaciones/inmunología , Articulaciones/patología , Ratones , Nanopartículas/química , Técnicas Fotoacústicas/métodos , Células RAW 264.7 , Albúmina Sérica Bovina/química , Índice de Severidad de la Enfermedad , Células THP-1 , Nanomedicina Teranóstica/métodos , Tomografía/métodosRESUMEN
BACKGROUND: Excessive use of diazinon, as an organophosphate pesticide (OP), contributes to cytotoxic and pathologic cellular damage and, in particular, oxidative stress. However, metal-oxide nanoparticles (NPs), such as cerium oxide (CeO2) and yttrium oxide (Y2O3), with the property of free radical scavenging demonstrated beneficial effects in the alleviation of oxidative stress biomarkers. OBJECTIVE: The aims of this study include evaluating beneficial effects of CeO2 NPs, Y2O3 NPs, and their combination against diazinon-induced oxidative stress in different tissues of brain, heart, lung, kidney, liver, and spleen. METHODS: Eight randomized groups of 6 adult male Wistar rats were formed. Each group of rats administered a different combination of diazinon, CeO2 and Y2O3 NPs daily and levels of oxidative stress markers, such as reactive oxygen species (ROS), lipid peroxidation (LPO), total thiol molecules (TTM) and total anti-oxidant power (TAP) and catalase enzyme, were measured after 2 weeks of the treatment. RESULTS: Measurements of the mentioned markers in the brain, heart, lung, kidney, liver, and spleen showed that the administration of NPs could significantly alleviate the oxidative stress induced by diazinon. However, the findings of this study illustrated that the combination of both CeO2 and Y2O3 NPs led to a better reduction in oxidative stress markers. CONCLUSION: Sub-acute exposure of diazinon in rats led to increased levels of oxidative stress markers in pivotal tissues such as the brain, heart, lung, kidney, liver, and spleen. CeO2 and Y2O3 NPs neutralize the oxidative stress to compensate diazinon-induced tissue damages. Lay Summary: Organophosphate pesticides (OPs), which are mainly used for pest control, are responsible for the entry of pesticides into the human food cycle. Organophosphate such as diazinon increases the molecular biomarkers of oxidative stress inside the cells of vital tissues such as the heart, liver, lungs, etc. Metal oxide nanoparticles (NPs) such as cerium oxide (CeO2) and yitrium oxide (Y2O3) can have free radical scavenging potential under oxidative stress and through various mechanisms. Although these nanoparticles reduce oxidative stress, it should be borne in the design of the study that additional doses of these substances reverse the beneficial effects.
Asunto(s)
Cerio/administración & dosificación , Diazinón/toxicidad , Insecticidas/toxicidad , Nanopartículas del Metal/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Itrio/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/fisiología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Resultado del TratamientoRESUMEN
Fipronil (FIP) is an insecticide commonly used in many fields, such as agriculture, veterinary medicine, and public health, and recently it has been proposed as a potential endocrine disrupter. The purpose of this study was to inspect the reproductive impacts of FIP and the possible protective effects of cerium nanoparticles (CeNPs) on male albino rats. Rats received FIP (5 mg/kg bwt; 1/20 LD50), CeNPs (35 mg/kg bwt) and FIP+CeNPs per os daily for 28 days. Serum testosterone levels, testicular oxidative damage, histopathological and immunohistochemical changes were evaluated. FIP provoked testicular oxidative damage as indicated by decreased serum testosterone (≈60%) and superoxide dismutase (≈50%), glutathione peroxidase activity (≈46.67%) and increased malondialdehyde (≈116.67%) and nitric oxide (≈87.5%) levels in testicular tissues. Furthermore, FIP induced edematous changes and degeneration within the seminiferous tubules, hyperplasia, vacuolations, and apoptosis in the epididymides. In addition, FIP exposure upregulated interleukin-1ß (IL-1ß), nitric oxide synthase 2 (NOS), caspase-3 (Casp3) and downregulated the Burkitt-cell lymphomas (BCL-2), inhibin B proteins (IBP), and androgen receptor (Ar) mRNA expressions Casp3, nitric oxide synthase (iNOS), ionized calcium-binding adapter molecule 1(IBA1), and IL-1ß immunoreactions were increased. Also, reduction of proliferating cell nuclear antigen (PCNA), mouse vasa homologue (MVH), and SOX9 protein reactions were reported. Interestingly, CeNPs diminished the harmful impacts of FIP on testicular tissue by decreasing lipid peroxidation, apoptosis and inflammation and increasing the antioxidant activities. The findings reported herein showed that the CeNPs might serve as a supposedly new and efficient protective agent toward reproductive toxicity caused by the FIP insecticide in white male rats.
Asunto(s)
Antioxidantes/administración & dosificación , Apoptosis/efectos de los fármacos , Cerio/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/tratamiento farmacológico , Insecticidas/efectos adversos , Nanopartículas del Metal/química , Estrés Oxidativo/efectos de los fármacos , Pirazoles/efectos adversos , Animales , Expresión Génica/efectos de los fármacos , Inmunohistoquímica , Infertilidad Masculina/sangre , Infertilidad Masculina/patología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Testículo/metabolismo , Testículo/patología , Testosterona/sangreRESUMEN
Increasing evidence from toxicological and epidemiological studies indicates that the brain is an important target for ambient (ultrafine) particles. Disturbance of redox-homeostasis and inflammation in the brain are proposed as possible mechanisms that can contribute to neurotoxic and neurodegenerative effects. Whether and how engineered nanoparticles (NPs) may cause neurotoxicity and promote neurodegenerative diseases such as Alzheimer's disease (AD) is largely unstudied. We have assessed the neurological effects of subacute inhalation exposures (4 mg/m3 for 3 h/day, 5 days/week for 4 weeks) to cerium dioxide (CeO2) NPs doped with different amounts of zirconium (Zr, 0%, 27% and 78%), to address the influence of particle redox-activity in the 5xFAD transgenic mouse model of AD. Four weeks post-exposure, effects on behaviour were evaluated and brain tissues were analysed for amyloid-ß plaque formation and reactive microglia (Iba-1 staining). Behaviour was also evaluated in concurrently exposed non-transgenic C57BL/6J littermates, as well as in Western diet-fed apolipoprotein E-deficient (ApoE-/-) mice as a model of vascular disease. Markers of inflammation and oxidative stress were evaluated in brain cortex. The brains of the NP-exposed 5xFAD mice revealed no accelerated amyloid-ß plaque formation. No significant treatment-related behaviour impairments were observed in the healthy C57BL/6J mice. In the 5xFAD and ApoE-/- models, the NP inhalation exposures did not affect the alternation score in the X-maze indicating absence of spatial working memory deficits. However, following inhalation exposure to the 78% Zr-doped CeO2 NPs changes in forced motor performance (string suspension) and exploratory motor activity (X-maze) were observed in ApoE-/- and 5xFAD mice, respectively. Exposure to the 78% doped NPs also caused increased cortical expression of glial fibrillary acidic protein (GFAP) in the C57BL/6J mice. No significant treatment-related changes neuroinflammation and oxidative stress were observed in the 5xFAD and ApoE-/- mice. Our study findings reveal that subacute inhalation exposure to CeO2 NPs does not accelerate the AD-like phenotype of the 5xFAD model. Further investigation is warranted to unravel whether the redox-activity dependent effects on motor activity as observed in the mouse models of AD and vascular disease result from specific neurotoxic effects of these NPs.
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Enfermedad de Alzheimer/patología , Cerio/administración & dosificación , Exposición por Inhalación , Actividad Motora/efectos de los fármacos , Nanopartículas/administración & dosificación , Enfermedades Vasculares/patología , Circonio/administración & dosificación , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/psicología , Animales , Cerio/efectos adversos , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/fisiología , Nanopartículas/efectos adversos , Enfermedades Vasculares/inducido químicamente , Enfermedades Vasculares/psicología , Circonio/efectos adversosRESUMEN
Cerium oxide nanoparticles (CeO2-NPs; or nanoceria) have been largely studied for biomedical applications due to their peculiar auto-regenerative antioxidant activity. This review focuses on ophthalmic applications of nanoceria. Many in vivo data indicate that nanoceria protect the retina from neurodegeneration. In particular, they have been tested in animal models of age-related macular degeneration and retinitis pigmentosa and their neuroprotective properties have been shown to persist for a long time, without any collateral effects. In vitro cytotoxicity studies have shown that CeO2-NPs could be safe for lens cells and could represent a new therapy for cataract treatment, but further studies are needed. To date, different pharmaceutical formulations based on nanoceria have been created looking at future clinical ophthalmic applications, such as water-soluble nanoceria, glycol chitosan-coated ceria nanoparticles (GCCNPs), and alginate-gelatin hydrogel loaded GCCNPs. GCCNPs were also effective in preventing choroidal neovascularization in vivo. Based on the nanosize of nanoceria, corneal permeation could be achieved to allow topical treatment of nanoceria. PEGylation and encapsulation in liposomes represent the main strategies to support corneal permeation, without altering nanoceria chemical-physical properties. Based on their great antioxidant properties, safety, and nanosize, nanoceria represent a new potential therapeutic for the treatment of several eye disorders.
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Antioxidantes/farmacología , Cerio/administración & dosificación , Nanopartículas/administración & dosificación , Fármacos Neuroprotectores/farmacología , Retina/efectos de los fármacos , Administración Oftálmica , Alginatos/metabolismo , Animales , Cerio/química , Quitosano/metabolismo , Neovascularización Coroidal/prevención & control , Córnea/fisiología , Composición de Medicamentos/métodos , Gelatina/metabolismo , Hidrogeles/metabolismo , Liposomas/metabolismo , Degeneración Macular/prevención & control , Ratones , Modelos Animales , Nanopartículas/química , Fármacos Neuroprotectores/administración & dosificación , Permeabilidad/efectos de los fármacos , Ratas , Retina/patología , Retinitis Pigmentosa/prevención & control , SeguridadRESUMEN
Mild traumatic brain injury results in aberrant free radical generation, which is associated with oxidative stress, secondary injury signaling cascades, mitochondrial dysfunction, and poor functional outcome. Pharmacological targeting of free radicals with antioxidants has been examined as an approach to treatment, but has met with limited success in clinical trials. Conventional antioxidants that are currently available scavenge a single free radical before they are destroyed in the process. Here, we report for the first time that a novel regenerative cerium oxide nanoparticle antioxidant reduces neuronal death and calcium dysregulation after in vitro trauma. Further, using an in vivo model of mild lateral fluid percussion brain injury in the rat, we report that cerium oxide nanoparticles also preserve endogenous antioxidant systems, decrease macromolecular free radical damage, and improve cognitive function. Taken together, our results demonstrate that cerium oxide nanoparticles are a novel nanopharmaceutical with potential for mitigating neuropathological effects of mild traumatic brain injury and modifying the course of recovery.
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Conmoción Encefálica/tratamiento farmacológico , Conmoción Encefálica/patología , Cerio/administración & dosificación , Nanopartículas/administración & dosificación , Animales , Animales Recién Nacidos , Conmoción Encefálica/metabolismo , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Células Cultivadas , Técnicas In Vitro , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
Cerium oxide (CeO2), one of many engineered nanomaterials (ENMs), is composed primarily of metal oxides, such as cerium oxide (CeO2). CeO2-containing materials are widely used as a polishing agent for glass mirrors, plate glass, television tubes, ophthalmic lenses, and precision optics. The widespread use of this nanomaterial (NM) resulted in increased environmental contamination levels and consequent human exposure. However, the influence of Ce on humans remains to be determined. The aim of this study was to expose female ICR mice to varying nanoparticle sizes of 35 nm, 300 nm as well as a mixture of 1-5 µM CeO2 particles through intranasal (i.n.) instillation at 40 mg/kg dose on day 1, 3 and 5, and the experiment terminated on day 7. Histopathology findings demonstrated that hydropic degeneration was prominently associated with hemorrhage in renal cortex and medulla in all CeO2-administered groups. In liver of CeO2-exposed mice, hydropic degeneration was also prominent. Serum chemistries also indicated signs of renal and hepatic lesion as evidenced by significantly decreased serum levels of total bilirubin (TBIL) and total phosphate (TP) and activity of alkaline phosphatase (ALP). ICP-MS analysis group demonstrated that Ce levels were not significantly higher in liver and kidneys of mice exposed to 35 nm CeO2. An increase in Ce content was observed in hepatic and renal tissues of mice exposed to 300 nm or 1-5 µM CeO2. The levels of Ce were similar in these two groups suggesting a threshold level of Ce was attained regardless of NP size. Data thus demonstrated that i.n. instillation of different-sized CeO2 particles translocated to liver and kidney and that size difference of CeO2 particles did not exert significant in the observed histopathology responses.
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Cerio/administración & dosificación , Riñón/metabolismo , Hígado/metabolismo , Nanopartículas del Metal/administración & dosificación , Administración Intranasal , Animales , Femenino , Ratones , Ratones Endogámicos ICR , Tamaño de la PartículaRESUMEN
Dry eye (DE) disease is an uprising health epidemic that directly affects the surface of the eye. We developed a water soluble cerium oxide loaded glycol chitosan nanoparticle as a new type of eye drop, namely GCCNP (glycol chitosan cerium oxide nanoparticles). GCCNP is capable of scavenging cellular reactive oxygen species (ROS) for the treatment of DE disease. The antioxidative effects of GCCNP were assessed in mice primary corneal and conjunctival cells in vitro and in a DE murine model in vivo. GCCNP's effect on the DE models was assessed via histological evaluations, migration assays, cell viability assays, cellular uptake analyses, intracellular ROS scavenging assays, wound healing assays, mitochondrial membrane potential readings, corneal fluorescein staining, tear volume concentrations, tear film break up time analyses, and lastly, analytical/spectroscopic analyses of GCCNP eye drop formulations. Spectroscopic analysis showed that cerium oxide was entrapped into the glycol chitosan (GC). The solubility of cerium in GC (GCCNP) increased to 709.854±24.3µg/ml compared to its original solubility in cerium oxide, which was measured as 0.020±0.002µg/ml. GCCNP had no cytotoxic effect and showed improvements on dry eye disease models by stabilizing the tear film, scavenging ROS, up-regulating SOD, promoting and maintaining corneal and conjunctival cell growth and integrity. We provided convincing evidence that GCCNP is an effective treatment for DE and may represent a potential new class of drug for DE disease.