A Two-Generation Reproductive Toxicity Study of Cerium Nitrate in Sprague-Dawley Rats.

A two-generation reproductive toxicity study was performed to evaluate the effects of cerium nitrate on the development of the parent, offspring, and third generation of Sprague-Dawley (SD) rats. A total of 240 SD rats (30 rats/sex/group) were randomly divided into four dosage groups according to body weight: 0 mg/kg, 30 mg/kg, 90 mg/kg, and 270 mg/kg. The rats were administered different dosages of cerium nitrate by oral gavage. There were no observed changes related to cerium nitrate in body weight, food consumption, sperm survival rate, motility, mating rate, conception rate, abortion rate, uterine plus fetal weight, uterine weight, corpus luteum number, implantation rate, live fetus number (rate), stillbirth number (rate), absorbed fetus number (rate), appearance, visceral, and skeletal in rats of each generation dosage group. In addition, the pathological findings showed no significant lesions associated with cerium nitrate toxicity in all tissues and organs, including reproductive organs. In conclusion, the present study showed that long-term oral gavage of cerium nitrate at 30 mg/kg, 90 mg/kg, and 270 mg/kg had no significant effect on reproduction and the developmental ability of their offspring in rats. The no-observed-adverse-effect level (NOAEL) of cerium nitrate in SD rats was higher than 270 mg/kg.

Evaluation of silver sulfadiazine 1%-cerium nitrate 2.2% cream efficacy and safety in moderate to severe burn patients: a single-blind randomized clinical trial.

BACKGROUND: Burn injury is a major global health crisis. Topical antimicrobials such as silver sulfadiazine (SSD) are commonly used for superficial burn wounds. SSD has a broad-spectrum antimicrobial activity and also anti-inflammatory property, but also suffers from some limitations. Therefore, some studies suggest to add cerium nitrate (CN) to SSD, as an immunomodulatory and tanning agent with antitoxic properties, but its effect on patients' mortality, length of hospital stay, and bacterial colonization is contraversial. OBJECTIVES: In this research, we evaluated the efficacy and safety of SSD 1%+CN 2.2% cream in patients with moderate to severe burn. MATERIAL AND METHODS: Twenty-two patients who fulfilled the inclusion criteria randomly were assigned to the intervention (n=7) or control (n=15) group and received SSD 1%+CN 2.2% or SSD cream 1% respectively, once daily until the complete re-epithelization or prepration of the burned skin for grafting. Intesity of pain, re-epithelialization time, required interventions, laboratory and clinical findings and final outcome were recorded. RESULTS: There was no significant difference in re-epithelialization time between the treatment and control groups (P>0.05). The same findings were reported about the required interventions and laboratory and clinical parameters. However, the final outcome and the pain score on third day were significantly better in the treatment group (P=0.017). On the other hand, all patients in the treatment group needed graft surgery. CONCLUSION: Use of SSD 1%+CN 2.2% cream did not significantly improve re-epithelization time or infection occurrence and patients' pain, but also increased graft surgery rate in comparison with SDD 1% cream in moderate to severe burns.

Cerium Nitrate Stiffens In Vitro Skin Models and Reduces Pseudomonas aeruginosa Pathogenicity and Penetration Through Skin Models.

Objective: Cerium nitrate (CeN) plus silver sulfadiazine (SSD) cream has been used for 40-plus years to manage burns. CeN produces a hardened eschar believed to resist bacterial colonization/infection. To evaluate this potential mechanism, we treated in vitro skin models or Pseudomonas aeruginosa with CeN and measured mechanical properties of the models and bacterial virulence, respectively. Approach: We treated three-dimensional-collagen matrix and ex-vivo-burned porcine skin with CeN and evaluated stiffness and P. aeruginosa penetration. In addition, we treated P. aeruginosa with CeN and evaluated the bacteria's motility, skin model penetration, susceptibility to be phagocytized by the human monocytic cell line THP-1, and ability to stimulate this cell line to produce cytokines. Results: CeN treatment of skin models stiffened them and made them resistant to P. aeruginosa penetration. Inversely, CeN treatment of P. aeruginosa reduced their motility, penetration through skin models (ex-vivo-burned porcine skin), and ability to stimulate cytokine production (tumor necrosis factor-α [TNF-α] and interleukin 8 [IL-8]) by THP-1 cells. In addition, CeN-treated Pseudomonas was more readily phagocytized by THP-1 cells. Finally, P. aeruginosa inoculated on CeN-treated ex-vivo-burned porcine skin was more susceptible to killing by a silver dressing. Innovation: In vitro skin models offer a platform for screening drugs that interfere with bacterial penetration into wounded tissue. Conclusion: CeN treatment reduced P. aeruginosa virulence, altered the mechanical properties of ex-vivo-burned porcine skin and collagen matrix, retarded penetration of P. aeruginosa through the skin models, and resulted in increased vulnerability of P. aeruginosa to killing by antimicrobial wound dressings. These data support the use of CeN in burn management.

Maternal cerium nitrate exposure induces developmental immunotoxicity in BALB/c mouse offspring.

With the increasing application of cerium and rare-earth elements (REEs), cerium exposure is becoming more widespread. However, there remains a paucity of evidence on developmental immunotoxicity of cerium. This study was designed to examine the developmental immunotoxicity of gestational and postnatal exposure to cerium nitrate (CN) in BALB/C mouse offspring. Dams were given CN by oral gavage at 0, 0.002, 0.02 and 0.2 mg/kg from gestation day 5 (GD5) to postnatal day 21 (PND 21). On PND 21, the highest dose of CN significantly suppressed the NK cell cytotoxicity, and reduced the proportions of NK cells in peripheral blood and spleen of both female and male pups, however, the proportions of monocytes in peripheral blood and macrophages in spleen only increased in female pups. For adaptive immunity, on PND 21, the suppression of T/B lymphocyte proliferation, humoral and cellular immune responses (number of splenic plaque-forming cells, PFC, and delayed-type hypersensitivity, DTH) were observed in both female and male pup mice exposed to 0.2 mg/kg CN. However, the fall of proportions of T/B lymphocytes in peripheral blood (PB), spleen and mesenteric lymph node (MLN) only found in female pups at 0.2 mg/kg on PND 21. Most indications recovered to normal after 3-week cessation of CN exposure, except the reduction of DTH and PFC. From the findings in this study, the lowest-observed-adverse-effect level (LOAEL) of CN for developmental immunotoxicity was estimated to be 0.2 mg/kg bw per day.

Hyaluronic acid-guided assembly of ceria nanozymes as plaque-targeting ROS scavengers for anti-atherosclerotic therapy.

Oxidative stress is a distinguishing feature in atherosclerosis disease. Reactive oxygen species (ROS) can increase the oxidized low density lipoprotein (ox-LDL) and oxidative damage to macrophages in the plaque. Although antioxidant agents such as N-acetylcysteine are used to treat atherosclerosis, but provide a poor clinical benefit to the majority of patients with atherosclerosis. Here we have designed hyaluronic acid-guided assemblies of ceria nanozymes (HA-CeO2 NPs) as novel plaque-targeting ROS scavengers. The introduction of hyaluronic acid not only provide the stability and biocompatibility, but also surprisingly enhance SOD-mimic activities of ceria nanozymes compared to bare CeO2 precipitates, dextran or poly-aspartic acid coated ceria nanozymes. Interestingly, we find HA-CeO2 NPs not only actively target plaque-associated macrophages in atherosclerosis to remove superfluous ROS and protect macrophages from ROS-caused damages, but also effectively inhibit endocytosis of ox-LDL by activated macrophages. We believe HA-CeO2 nanozymes can serve as a simple and promising platform for anti-atherosclerotic therapy.

The Use of Cerium Compounds as Antimicrobials for Biomedical Applications.

Cerium and its derivatives have been used as remedies for wounds since the early 20th century. Cerium nitrate has attracted most attention in the treatment of deep burns, followed later by reports of its antimicrobial properties. Its ability to mimic and replace calcium is presumed to be a major mechanism of its beneficial action. However, despite some encouraging results, the overall data are somewhat confusing with seemingly the same compounds yielding opposing results. Despite this, cerium nitrate is currently used in wound treatment in combination with silver sulfadiazine as Flammacérium. Cerium oxide, especially in nanoparticle form (Nanoceria), has lately captured much interest due to its antibacterial properties mediated via oxidative stress, leading to an increase of published reports. The properties of Nanoceria depend on the synthesis method, their shape and size. Recently, the green synthesis route has gained a lot of interest as an alternative environmentally friendly method, resulting in production of effective antimicrobial and antifungal nanoparticles. Unfortunately, as is the case with antibiotics, emerging bacterial resistance against cerium-derived nanoparticles is a growing concern, especially in the case of bacterial biofilm. However, diverse strategies resulting from better understanding of the biology of cerium are promising. The aim of this paper is to present the progress to date in the use of cerium compounds as antimicrobials in clinical applications (in particular wound healing) and to provide an overview of the mechanisms of action of cerium at both the cellular and molecular level.

In Situ Constructing a Stable Solid Electrolyte Interface by Multifunctional Electrolyte Additive to Stabilize Lithium Metal Anodes for Li-S Batteries.

Lithium (Li) metal is considered to be the most promising anode due to the ultrahigh capacity and extremely low electrochemical potential. The tricky thing is that the growth of dendritic Li brings huge safety hazards to Li metal batteries. Herein, we demonstrate cerium nitrate as a multifunctional electrolyte additive to form a stable solid electrolyte interface on the metallic Li anode surface for durable Li-S batteries. The presence of Ce3+ helps to modulate the electroplating/stripping of Li and inhibits the growth of dendritic Li. An excellent cycle life exceeding 1400 h at the current density of 1 mA cm-2 can be realized in symmetric Li||Li cells. In addition, the in situ formed robust solid-electrolyte interface (SEI) layer containing cerium sulfide on the Li anode surface conduces to weaken the reducibility of Li and regulate the electrochemical dissolution/deposition reaction on the Li anode. Surprisingly, by virtue of cerium nitrate additive with a low concentration of 0.03 M, the Li-S batteries can afford a capacity of 553 mA h g-1 at 5 C and a long cycle life at 1 C with a high capacity retention of 70.4%. Therefore, this study provides a novel idea to realize a uniform and dendrite-free Li anode for practical Li-S batteries.

Cerium(III) Nitrate Containing Electrospun Wound Dressing for Mitigating Burn Severity.

Thermal injuries pose a risk for service members in prolonged field care (PFC) situations or to civilians in levels of lower care. Without access to prompt surgical intervention and treatment, potentially salvageable tissues are compromised, resulting in increases in both wound size and depth. Immediate debridement of necrotic tissue enhances survivability and mitigates the risks of burn shock, multiple organ failure, and infection. However, due to the difficulty of surgical removal of the burn eschar in PFC situations and lower levels of care, it is of utmost importance to develop alternative methods for burn stabilization. Studies have indicated that cerium(III) nitrate may be used to prolong the time before surgical intervention is required. The objective of this study was to incorporate cerium(III) nitrate into an electrospun dressing that could provide burst release. Select dosages of cerium(III) nitrate were dissolved with either pure solvent or polyethylene oxide (PEO) for coaxial or traditional electrospinning set-ups, respectively. The solutions were coaxially electrospun onto a rotating mandrel, resulting in a combined nonwoven mesh, and then compared to traditionally spun solutions. Dressings were evaluated for topography, morphology, and porosity using scanning electron microscopy and helium pycnometry. Additionally, cerium(III) loading efficiency, release rates, and cytocompatibility were evaluated in both static and dynamic environments. Imaging showed randomly aligned polymer nanofibers with fiber diameters of 1161 ± 210 nm and 1090 ± 250 nm for traditionally and coaxially spun PEO/cerium(III) nitrate dressings, respectively. Assay results indicated that the electrospun dressings contained cerium(III) nitrate properties, with the coaxially spun dressings containing 33% more cerium(III) nitrate than their traditionally spun counterparts. Finally, release studies revealed that PEO-based dressings released the entirety of their contents within the first hour with no detrimental cytocompatibility effects for coaxially-spun dressings. The study herein shows the successful incorporation of cerium(III) nitrate into an electrospun dressing.

A multifunctional CeO2@SiO2-PEG nanoparticle carrier for delivery of food derived proanthocyanidin and curcumin as effective antioxidant, neuroprotective and anticancer agent.

The nanoparticle systems could effectively overcome the drug delivery challenges of food bioactive compounds. In this study, a novel and effective multifunctional PEG modified CeO2@SiO2 nanoparticle (CSP-NPs) system was successfully fabricated. Food derived proanthocyanidin (PAC) and curcumin (Cur) were loaded onto CSP-NPs and formed as PAC-NPs and Cur-NPs. Fourier transform Infrared spectra, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and dynamic light scattering were used to characterize the prepared NPs. CSP-NPs, PAC-NPs and Cur-NPs displayed spherical shape with about 35-45 nm size. The bioactivity analysis revealed that CSP-NPs system could effectively deliver PAC and Cur to exhibit strong antioxidant activity, potent neuroprotective effect against Aß1-42-mediated toxicity in PC-12 cells (recovered cell viability from 57.5% to 81.0% at the dose of 25 µg/mL) and effective antiproliferative effects on HepG2 and Hela cells. Besides, all prepared nanoparticles (0-100 µg/ml) used in this study showed no significant toxicity on cell models of antioxidative and neuroprotective activities, excepting for cancer cells, suggesting that these nanoparticles had the potential of being utilized in drug delivery. Therefore, CSP-NPs might be a promising delivery system for hydrophilic molecule proanthocyanidin and hydrophobic molecule curcumin against the oxidative damage, neurodegenerative diseases and cancer, which could facilitate the application of food derived nutrients in functional foods industry.

Cerium nitrate enhances anti-bacterial effects and imparts anti-inflammatory properties to silver dressings in a rat scald burn model.

Current commercially available silver-based wound dressings such as silver-nylon have been used as antimicrobial barriers for burn and trauma care in combat conditions for over 10 years. However, these dressings do not stabilize the eschar or reduce its toxicity. Cerium nitrate (CN) solutions have been established clinically to stabilize the eschar by decreasing release of inflammatory mediators from burned tissue thereby allowing delayed excision and grafting. In this report, we tested the extent to which CN imparts CN benefits to silver dressings for temporizing treatments of burn wounds and enhancing anti-bacterial activity. Using a rat full-thickness scald burn model, we showed that CN enhanced the anti-bacterial effects of the tested silver-based dressings (Acticoat™, Mepilex™, and Silverlon®), while also imparting anti-inflammatory properties to these dressings. Compared to the use of silver dressings alone, CN significantly decreased the levels of IL-1ß and GRO/KC, and exhibited downward trending levels of IL-1α, MIP-1α, and bacterial bioburden within the wound. Based on our findings, we conclude that CN has the ability to expand and enhance the function of several silver dressings. We propose the use of CN in combination with silver dressings to stabilize burn wounds thereby allowing postponement of excision and grafting, most notably in scenarios where the standard of care is not feasible such as in combat situations, resource limited regions, and new emergent health care challenges as seen during the COVID-19 pandemic in which COVID-positive severe burn patients are not able to undergo surgery during an active outbreak.

Subchronic toxicity of cerium nitrate by 90-day oral exposure in wistar rats.

This study evaluated the subchronic toxicity of cerium nitrate and determined the no observed adverse effect level (NOAEL) in Wistar rats. In accordance with the Organization for Economic Co-operation and Development guidelines, cerium nitrate was orally administered to Wistar rats by gavage at 0, 0.2, 75, 150, and 300 mg/kg bw/day for 90 days, followed by 28 days of recovery period in the 300 mg/kg bw/day and the control groups. The following parameters were evaluated: mortality, abnormalities, body weight, food consumption, hematology, serum biochemistry, urinanalysis, gross necropsy and histopathology. At the end of the treatment, several significant changes were observed in the 300 mg/kg bw/day groups: relatively decreased mean body weight of males, increased LYMPH%, RET% and decreased NEUT%, RBC of the females, increased ALT, AST and decreased ALB, T-Bil, CHO, CK, LDH of males. Significantly decreased T-Bil, CHO, CK and LDH were also observed in males of the 150 mg/kg bw/day group. Pathological examination revealed that the incidences of foreign body granulomatous lesions in lungs were higher in the 150 and 300 mg/kg bw/day groups as compared with the control group. These findings were attributed to unexpected gavage exposure because the granuloma exhibited a bronchiole-derived distribution. Taken together, the NOAEL of cerium nitrate in Wistar rats is set to be 75 mg/kg bw/day in the present study.

The Effectiveness of Topical Cerium Nitrate-Silver Sulfadiazine Application on Overall Outcome in Patients with Calciphylaxis.

BACKGROUND: Calciphylaxis (CPX) is a rare and life-threatening disease characterized by vascular calcification and development of painful and necrotizing skin lesions with a challenging management. Mechanisms of CPX are complex and include an imbalance between vascular calcification promoters and inhibitors, and frequently vitamin K deficiency. OBJECTIVES: To describe the various presentations and identify predictive factors of death in patients with CPX. METHODS: In this multicenter retrospective study, we included 71 CPX patients followed in South-West France (n = 26) and in French Polynesia (n = 45), and who all received sodium thiosulfate (25 g thrice weekly for a median of 61 days). RESULTS: Characteristics at presentation significantly differed between metropolitan and Polynesian French patients. Polynesians were less frequently on regular dialysis at the onset of CPX, had a higher incidence of diabetes mellitus and obesity, more disturbances of calcium-phosphorus metabolism, and received vitamin K antagonists less frequently than patients from South-West France. Despite intensive management, the 1-year mortality rate was 66% and median time to death was 200 days (IQR, 40; 514). The number of body areas involved (i.e., three: OR 2.70 [1.09; 6.65], p = 0.031; four: OR 8.79 [1.54; 50.29], p = 0.015) was the only predictive factor for death, whereas application of topical cerium nitrate-silver sulfadiazine was protective (OR 0.44 [0.20; 0.99], p = 0.046). Surgical debridement, hyperbaric oxygenation therapy, and geographical origin were not associated with overall outcomes. CONCLUSIONS: Cerium nitrate may lead to vascular decalcification and chelation of reactive oxygen species, and prevent infection. Cerium nitrate-silver sulfadiazine was associated with better outcomes and should be tested in a prospective comparative trial in CPX patients.

Silver Sulfadiazine and Cerium Nitrate in Ischemic Skin Necrosis of the Leg and Foot: Results of a Prospective Randomized Controlled Study.

Flammacerium is a topical treatment composed of silver sulfadiazine and cerium nitrate initially used in burns. The objective was to assess the effectiveness of silver sulfadiazine and cerium nitrate on ischemic necrosis wounds of the lower limb as an alternative to amputation for a period of 12 weeks. Patients were prospectively randomized to receive silver sulfadiazine and cerium nitrate or standard care. Patients included adults with an ischemic wound of the lower limb, with necrosis covering over at least 50%. Critical ischemia limb was confirmed by an ankle-brachial index <0.7 or >1.3 with radiological confirmation. Patient demographic data, amputations procedures, wound area, Visual Analogue Scale pain rating, clinical infection, and adverse events were recorded. Fifty patients, 34 males and 16 females, were recruited between January 2010 and April 2014, 25 in each group. The mean age was 75.14 years (±11.64). Nine amputations (36%) occurred in each group. Amputation-free survival was superior in the active treatment group versus the standard group (169 393 days, 95% confidence interval = 134.926-203.861, vs 169 393 days, 95% confidence interval = 134.926-203.861). It was not statistically significant (log-rank, P = .958). Wound area reduction between both groups was not statistically different ( P = .651). Less adverse events of the lower limb occurred in the active treatment group ( P = .001). Our study showed that silver sulfadiazine and cerium nitrate is not inferior to standardized care on ischemic necrotic wounds of the lower extremity. Further studies are still needed to confirm its effectiveness.

Partial-thickness scalds in children: A comparison of different treatment strategies.

AIM: The aim of this study was to compare the clinical outcomes of different treatment strategies for children with partial-thickness scalds at two burn centers. At the first burn center, these burns were treated with a hydrofiber dressing (Aquacel®, Convatec, Inc.®, Princeton, NJ, USA) or silver sulfadiazine (SSD, Flammazine®, Sinclair IS Pharma, London, UK Pharmaceuticals), while at the second burn center, cerium nitrate-silver sulfadiazine (CN-SSD, Flammacerium®, Sinclair IS Pharma, London, UK Pharmaceuticals) was used. METHODS: A two-center retrospective study was conducted of children admitted between January 2009 and December 2013 for partial-thickness scalds up to 10% TBSA who were treated primarily with a hydrofiber dressing or silver sulfadiazine (Burn Center Rotterdam) vs. cerium nitrate-silver sulfadiazine (Burn Center Groningen). The Dutch Burn Repository R3 and the electronic medical records of the study population were used for data extraction. The primary outcome was the time to wound healing. The secondary outcomes were the length of hospital stay, wound infection, and surgical treatment. RESULTS: The time to wound healing differed between the groups (HR=1.46, 95%CI 1.17-1.82); the shortest time to wound healing was observed in the patients treated with CN-SSD (median 13 days), compared with 15 days for the patients treated with hydrofiber and 16 days for the patients treated with SSD (p<0.01). The length of stay was significantly shorter for the hydrofiber patients (medians: hydrofiber 3 days, SSD 10 days and CN-SSD 7 days; p<0.01), but their outpatient treatment period was significantly longer (medians: hydrofiber 12 days, SSD 6 and CN-SSD 4 days; p<0.01). The proportion of surgeries and the mean time to surgery was similar between the burn centers. CONCLUSIONS: This study compared different burn centers' treatment strategies for children with partial-thickness scalds and found a shorter time to wound healing in the CN-SSD group. Patients treated with hydrofiber had a shorter clinical period in comparison with the SSD and CN-SSD patients. The results of CN-SSD are promising and warrant further study. A prospective study is needed to gain full insight into the merits and drawbacks of the treatment strategies. This will allow clinicians to make full use of the strengths of particular treatments to benefit specific patients.