RESUMO
Aluminum hydroxide nanoparticles have been employed in many industries, which are widely abundant in many aspects of human life. The role of the aluminum hydroxide nanoparticles adjuvant is to enhance the immune response. However, the impact of nanoparticles exposure has not been perfectly investigated yet. Accordingly, some questions have been raised about their potentially harmful effects, based on which the current research aims to answer them. This study aimed to investigate the histological effects of aluminum hydroxide nanoparticles and bulk-aluminum hydroxide (bulk Al[OH]3) on the liver, lung, heart, and kidney tissues. For this reason, an experiment was implemented on the aluminum hydroxide nanoparticles adjuvant in five neonatal mice. Intramuscularly, the mice were injected with 0.125 mL of adjuvanted vaccine, while five neonatal mice were injected with bulk and nanoparticles of Al (OH)3 and then sacrificed after one and two months, respectively. Vaccines were controlled by evaluating the histopathological response in neonatal mice. Subsequently, the pathological effect of both adjuvants was surveyed using the histological study of the lung, liver, heart, and kidney of the animals. The obtained recorded data indicated that both types of vaccine adjuvants caused pathological lesions on the histology sections of the liver, lung, heart, and kidney tissues. Moreover, bulk Al (OH)3 adjuvant vaccine was more effective and had a higher pathological response than aluminum hydroxide nanoparticles adjuvant vaccine. In addition, the total DNA content in both groups was estimated using Fluorometer from Promega. Compared to aluminum hydroxide nanoparticles groups, the tissues indicated a decrease in total DNA content obtained in bulk Al (OH)3 groups. Therefore, it can be concluded that the exposure to aluminum hydroxide nanoparticles would result in less pronounced toxicity, as well as systemic inflammation, compared to the bulk Al (OH)3 aluminum hydroxide.
Assuntos
Nanopartículas , Vacinas , Adjuvantes Imunológicos/toxicidade , Hidróxido de Alumínio/toxicidade , Animais , Animais Recém-Nascidos , DNA , Camundongos , Nanopartículas/toxicidadeRESUMO
Toxoplasma gondii (T. gondii) infection causes severe zoonotic toxoplasmosis, which threatens the safety of almost one-third of the human population globally. However, there is no effective protective vaccine against human toxoplasmosis. This necessitates anti-T. gondii vaccine development, which is a main priority of public health. In this study, we optimized the adjuvant system 04 (AS04), a vaccine adjuvant constituted by 3-O-desacyl-4'-monophosphoryl lipid A (a TLR4 agonist) and aluminum salts, by packing it within natural extracts of ß-glucan particles (GPs) from Saccharomyces cerevisiae to form a GP-AS04 hybrid adjuvant system. Through a simple mixing procedure, we loaded GP-AS04 particles with the total extract (TE) of T. gondii lysate, forming a novel anti-T. gondii vaccine GP-AS04-TE. Results indicated that the hybrid adjuvant can efficiently and stably load antigens, mediate antigen delivery, facilitate the dendritic uptake of antigens, boost dendritic cell maturation and stimulation, and increase the secretion of pro-inflammatory cytokines. In the mouse inoculation model, GP-AS04-TE significantly stimulated the function of dendritic cells, induced a very strong TE-specific humoral and cellular immune response, and finally showed a strong and effective protection against toxoplasma chronic and acute infections. This work proves the potential of GP-AS04 for exploitation as a vaccine against a range of pathogens.
Assuntos
Adjuvantes de Vacinas/uso terapêutico , Hidróxido de Alumínio/uso terapêutico , Lipídeo A/análogos & derivados , Nanocompostos/uso terapêutico , Vacinas Protozoárias/uso terapêutico , Toxoplasma/imunologia , Toxoplasmose/prevenção & controle , Adjuvantes de Vacinas/química , Adjuvantes de Vacinas/toxicidade , Hidróxido de Alumínio/química , Hidróxido de Alumínio/imunologia , Hidróxido de Alumínio/toxicidade , Animais , Células Dendríticas/efeitos dos fármacos , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/uso terapêutico , Polissacarídeos Fúngicos/toxicidade , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Lipídeo A/química , Lipídeo A/imunologia , Lipídeo A/uso terapêutico , Lipídeo A/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Nanocompostos/química , Nanocompostos/toxicidade , Fagócitos/efeitos dos fármacos , Vacinas Protozoárias/química , Vacinas Protozoárias/imunologia , Vacinas Protozoárias/toxicidade , Saccharomyces cerevisiae/química , Extratos de Tecidos/química , Extratos de Tecidos/imunologia , Extratos de Tecidos/uso terapêutico , Extratos de Tecidos/toxicidade , Toxoplasma/química , Toxoplasmose/imunologia , beta-Glucanas/química , beta-Glucanas/uso terapêutico , beta-Glucanas/toxicidadeRESUMO
Asthma is characterized by airway remodeling. Glucocorticoid induced transcript 1 (GLCCI1) was reported to be associated with the development of asthma, while its exact mechanism is still not clear. In our study, ovalbumin (OVA) combined with aluminum hydroxide were used to establish asthmatic mouse model. ELISA assay was fulfilled to ensure the concentration of inflammatory factors in both bronchoalveolar lavage fluid and serum. The pathological changes and collagen deposition in lung tissues were analyzed using H&E staining and Masson staining, respectively. The expression of proteins was measured using western blot, and the expression of GLCCI1 mRNA was ensured by qRT-PCR. Here, we demonstrated that OVA-induced inflammation, lung structural remodeling and collagen deposition in asthmatic mice was notably improved by hydroprednisone treatment or GLCCI1 overexpressing. The expression of GLCCI1 was decreased, while IL-13, periostin and TGF-ß1 were increased in the lung tissue of asthmatic mice. Importantly, upregulation of GLCCI1 suppressed the expression of IL-13, periostin and TGF-ß1, phosphorylation of Smad2 and Smad3, and extracellular matrix (ECM) deposition-related proteins expression. IL-13-induced upregulation of periostin and TGF-ß1 expression, phosphorylation of Smad2 and Smad3, and ECM deposition in airway epithelial cells (AECs) was repressed by GLCCI1 increasing. Furthermore, our results showed that overexpression of GLCCI1 repressed the effect of IL-13 on AECs via inhibiting periostin expression. Overall, our data revealed that GLCCI1 limited the airway remodeling in mice with asthma through inhibiting IL-13/periostin/TGF-ß1 signaling pathway. Our data provided a novel target for asthma treatment.
Assuntos
Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Pulmão/patologia , Receptores de Glucocorticoides/metabolismo , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/toxicidade , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Asma/patologia , Moléculas de Adesão Celular/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-13/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Prednisona/administração & dosagem , Receptores de Glucocorticoides/agonistas , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
The European Union's REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.
Assuntos
Hidróxido de Alumínio/toxicidade , Óxido de Alumínio/toxicidade , Alumínio/toxicidade , Sistema Nervoso/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Testes de Toxicidade , Alumínio/farmacocinética , Hidróxido de Alumínio/farmacocinética , Óxido de Alumínio/farmacocinética , Animais , Europa (Continente) , União Europeia , Humanos , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Sistema Nervoso/fisiopatologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/fisiopatologia , Medição de Risco , ToxicocinéticaRESUMO
Influence of floc breakage and re-growth on the release of natural dissolved organic matter (DOM) and dissolved Al was explored. Results indicated that Al species including monomeric species (Ala), medium polymer species (Alb), and colloidal or solid species (Alc) in polyaluminum chlorides (PACls) played significant role. At lower doses ranged from 5 to 20 mg/L, floc breakage damaged Ala-NOM bonds for AlCl3, causing obvious release of DOM and dissolved Al. After re-growth, dissolved Al mainly connected with broken flocs, rather than released DOM. Thus, after re-growth, DOM release was still remarkable, but additional removal of dissolved Al was observed. At higher doses above 20 mg/L, more Ala transformed to Alb and Alc. Due to the enmeshment effect induced by Alc coagulation, fewer DOM and dissolved Al were released after breakage, and additional removal of DOM and dissolved Al were attained after re-growth. For PAClAl13 which mainly contained Alb, at optimal dose, floc breakage generated the most severe release of DOM and dissolved Al, while the result after re-growth was just reverse. This was ascribed to stronger charge neutralization ability of Alb. Furthermore, the influence of floc breakage and re-growth on DOM and dissolved Al for PAClC was similar to that for AlCl3. The reason was fully analyzed in this research. This study may give further indication regarding reaction mechanisms of floc breakage and re-growth for PACls.
Assuntos
Alumínio/toxicidade , Eliminação de Resíduos Líquidos/métodos , Hidróxido de Alumínio/toxicidade , Cloretos , Floculação , Polímeros/químicaRESUMO
Purpose: Aluminum is the third most abundant metal in the earth's crust and is widely used in industry. Chronic contact with aluminum results in a reduction in the activity of electron transport chain complexes, leading to excessive production of reactive oxygen species (ROS) and oxidative stress. This study aimed to evaluate the effects of short-term exposure of aluminum hydroxide on oxidative stress and pulmonary inflammatory response.Materials and methods: Male BALB/c mice were divided into three groups: control group (CG); phosphate buffered saline group (PBSG) and aluminum hydroxide group (AHG). CG was exposed to ambient air, while PBSG and AHG were exposed to PBS or aluminum hydroxide solutions via nebulization, three times per day for five consecutive days. Twenty-four hours after the last exposure, all animals were euthanized for subsequent analysis.Results: Exposure to aluminum hydroxide in the blood resulted in lower platelet levels, higher neutrophils, and lower monocytes compared to CG and PBSG. Aluminum hydroxide promoted the recruitment of inflammatory cells to the lung. Macrophage, neutrophil and lymphocyte counts were higher in AHG compared to CG and PBSG. Protein oxidation and superoxide dismutase activity were higher, while catalase activity and reduced and oxidizes glutathione ratio in AHG were lower compared to CG and PBSG. Furthermore, there was an increase in the inflammatory markers CCL2 and IFN-γ in AHG compared to CG and PBSG.Conclusion: In conclusion, short-term nebulization with aluminum hydroxide induces the influx of inflammatory cells and oxidative stress in adult BALB/c mice.
Assuntos
Hidróxido de Alumínio/toxicidade , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Animais , Masculino , Camundongos Endogâmicos BALB C , Nanopartículas/efeitos adversos , Distribuição AleatóriaRESUMO
Ox66™ is a novel solid state oxygenating compound. In order to support the use of Ox66™ as a potential oxygenating supplement to injured cells, this study evaluated the safety of Ox66™, its ability to withstand the conditions in the digestive tract, and its potential to increase oxygenation in the mesentery in rats. The toxicity of Ox66™ was evaluated by performing acute (10-day) and chronic (90-day) feeding studies on rats, the stability of the compound in the digestive tract was evaluated via ex vivo simulated digestion and subsequent CFDA viability assay on gut epithelial cells, and its capacity for oxygenation in the mesenteric microcirculation was determined by interstitial fluid pressure (PISF) O2 measurements upon injection into the small intestine of rats. No toxicity was found associated with acute or chronic oral administration of the compound in rats, and the compound was able to withstand the environment of the digestive tract in vitro. Based on the acute animal feeding study, the NOAEL was considered to be 1000â¯mg/kg/day. This proof-of-concept study further demonstrates the potential of Ox66™ to function as an oxygenating supplement that might be useful for treating either pathological hypoxic-related conditions or to improve oxygenation levels during or after exercise under healthy conditions.
Assuntos
Oxigênio/química , Oxigênio/toxicidade , Administração Oral , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/química , Hidróxido de Alumínio/toxicidade , Animais , Células CACO-2 , Portadores de Fármacos , Feminino , Humanos , Masculino , Mesentério/irrigação sanguínea , Microcirculação/efeitos dos fármacos , Oxigênio/administração & dosagem , Ratos Sprague-DawleyRESUMO
The number of products containing nanomaterials is increasing this last ten years. Information and literature about the end-of-life of nanocomposites often remains partial and does not address the overall fate and transformations of nanoparticles that may affect biological responses. This paper underlines that the physico-chemical features of nanoparticles can be modified by the incineration process and the available toxicological data on pristine nanofillers might not be relevant to assess the modified nanoparticles included in soot. Combustion tests have been performed at lab-scale using a cone calorimeter modified to collect fumes (particulate matter and gas phase) and have been characterized using various techniques. Nanocomposites selected were poly(ethylene vinyl acetate) containing Al-based nanoparticles, i.e. boehmites or alumina. Evaluations of in vitro cytotoxicity responses on pristine nanofillers, soot and residual ash, show that safe boehmite nanoparticles, become toxic due to a chemical modification after incineration process.
Assuntos
Hidróxido de Alumínio , Óxido de Alumínio , Nanoestruturas , Polivinil , Alumínio , Hidróxido de Alumínio/química , Hidróxido de Alumínio/toxicidade , Óxido de Alumínio/química , Óxido de Alumínio/toxicidade , Animais , Incineração , Camundongos , Nanoestruturas/química , Nanoestruturas/toxicidade , Polivinil/química , Polivinil/toxicidade , Células RAW 264.7 , Fuligem/análiseRESUMO
This study introduces a new strategy for periodic stacking of positively charged NiAl layered double hydroxides (LDHs) nanosheets with negatively charged monolayers of graphene (G) by systematically optimizing several parameters in a controlled co-feeding fashion and resultant heterostacked NiAl LDH/G LBL nanocomposites have been practically applied in sensitive detection of dopamine released from live cells as early Parkinson's disease (PD) diagnostic tool. PD is the second most chronic neurodegenerative disorder with gradual progressive loss of movement and muscle control causing substantial disability and threatening the life seriously. Unfortunately majority of dopaminergic neurons present in substantia nigra of PD patients are destroyed before it is being clinically diagnosed, so early stages PD diagnosis is essential. Because of direct neighboring of extremely conductive graphene to semiconductive LDHs layers, enhanced intercalation capability of LDHs, and huge surface area with numerous active sites, good synergy effect is harvested in heteroassembled NiAl LDH/G LBL material, which in turn shows admirable electrocatalytic ability in DA detection. The interference induced by UA and AA is effectively eliminated especially after the modifying the electrode with Nafion. The outstanding electrochemical sensing performance of NiAl LDH/G LBL modified electrode has been achieved in terms of broad linear range and lowest real detection limit of 2â¯nMâ¯(S/Nâ¯=â¯3) towards DA oxidation. Benefitting from superior efficiency, biosensor has been successfully used for real-time in-vitro tracking of DA efflux from live human nerve cell after being stimulated. We believe that our biosensing platform of structurally integrated well-ordered LBL heteroassembly by inserting graphene directly to the interlayer galleries of LDHs material will open up new avenue in diseases determination window.
Assuntos
Dopamina/análise , Grafite/química , Nanocompostos/química , Hidróxido de Alumínio/síntese química , Hidróxido de Alumínio/química , Hidróxido de Alumínio/toxicidade , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Linhagem Celular Tumoral , Técnicas Eletroquímicas/métodos , Eletrodos , Grafite/síntese química , Grafite/toxicidade , Humanos , Hidróxidos/síntese química , Hidróxidos/química , Hidróxidos/toxicidade , Limite de Detecção , Nanocompostos/toxicidade , Níquel/química , Níquel/toxicidade , Eletricidade EstáticaAssuntos
Hidróxido de Alumínio/metabolismo , Alumínio/metabolismo , Peptídeos beta-Amiloides/metabolismo , Quelantes/metabolismo , Complexos de Coordenação/metabolismo , Modelos Moleculares , Fragmentos de Peptídeos/metabolismo , Fosfosserina/metabolismo , Alumínio/química , Alumínio/toxicidade , Hidróxido de Alumínio/química , Hidróxido de Alumínio/toxicidade , Motivos de Aminoácidos , Peptídeos beta-Amiloides/química , Sítios de Ligação , Quelantes/química , Biologia Computacional , Simulação por Computador , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Transferência de Energia , Poluentes Ambientais/química , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Humanos , Cinética , Ligantes , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Fragmentos de Peptídeos/química , Fosforilação , Fosfosserina/química , Conformação Proteica/efeitos dos fármacos , Teoria Quântica , Eletricidade Estática , TermodinâmicaRESUMO
The objective of this study was to examine the impact of aluminium on the perennial macroalgae Chara hispida L. and its bioaccumulation capacities. Aluminium (Al) was introduced into the environment in the form of polyaluminium chloride, an agent utilized in the restoration of waterbodies. Research was conducted in an experimental setting using mesocosms (volume 0.8m3) placed in the littoral zone of a lake with C. hispida. Three doses of the coagulant were applied, each with a different volume: low - 6.1g Al m-3, medium - 12.2gm-3 and high - 24.5g Al m-3. A significant acidification of environment was determined, which would imply the presence of toxic Al3+ ions. It has been demonstrated that aluminium penetrates and accumulates in the cells of the charophyte. This caused damage to the thalli, which manifested itself in chloroses, necroses, flaking of the cortex cells and softening of the thallus, whose severity was proportionate to the dose of the coagulant. The first negative signs were observed after 24h. The study shows that C. hispida is a poor accumulator of aluminium (bioconcentration factor < 200), while bioaccumulation capacity was inhibited at the concentration of approx. 2.0mg Al g-1 d.w. Accumulation in the thalli of the charophytes accounted for 58% of variation following removal of aluminium from the environment. The results of the experiment demonstrate a negative impact of aluminium on charophytes at concentrations used in aggressive restoration of lakes.
Assuntos
Hidróxido de Alumínio/toxicidade , Chara/efeitos dos fármacos , Lagos/química , Alga Marinha/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Biodegradação Ambiental , Chara/metabolismo , Alga Marinha/metabolismoRESUMO
Sporotrichosis is an important zoonosis in Brazil and the most frequent subcutaneous mycosis in Latin America, caused by different Sporothrix species. Currently, there is no effective vaccine available to prevent this disease. In this study, the efficacy and toxicity of the adjuvant Montanide™ Pet Gel A (PGA) formulated with S. schenckii cell wall proteins (ssCWP) was evaluated and compared with that of aluminum hydroxide (AH). Balb/c mice received two subcutaneous doses (1st and 14th days) of either the unadjuvanted or adjuvanted vaccine candidates. On the 21st day, anti-ssCWP antibody levels (ELISA), the phagocytic index, as well as the ex vivo release of IFN-γ, IL-4, and IL-17 by splenocytes and IL-12 by peritoneal macrophages were assessed. Cytotoxicity of the vaccine formulations was evaluated in vitro and by histopathological analysis of the inoculation site. Both adjuvanted vaccine formulations increased anti-ssCWP IgG, IgG1, IgG2a, and IgG3 levels, although IgG2a levels were higher in response to PGA+CWP100, probably contributing to the increase in S. schenckii yeast phagocytosis by macrophages in the opsonophagocytosis assay when using serum from PGA+CWP100-immunized mice. Immunization with AH+CWP100 led to a mixed Th1/Th2/Th17 ex vivo cytokine release profile, while PGA+CWP100 stimulated a preferential Th1/Th2 profile. Moreover, PGA+CWP100 was less cytotoxic in vitro, caused less local toxicity and led to a similar reduction in fungal load in the liver and spleen of S. schenckii- or S. brasiliensis-challenged mice as compared with AH+CWP100. These results suggest that PGA may be an effective and safe adjuvant for a future sporotrichosis vaccine.
Assuntos
Adjuvantes Imunológicos , Hidróxido de Alumínio/imunologia , Vacinas Fúngicas/efeitos adversos , Vacinas Fúngicas/imunologia , Sporothrix/imunologia , Esporotricose/prevenção & controle , Adjuvantes Imunológicos/toxicidade , Hidróxido de Alumínio/toxicidade , Animais , Anticorpos Antifúngicos/biossíntese , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Brasil , Vacinas Fúngicas/administração & dosagem , Vacinas Fúngicas/química , Imunidade Celular , Imunogenicidade da Vacina , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose , Esporotricose/imunologia , Equilíbrio Th1-Th2 , VacinaçãoRESUMO
ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) has been previously implicated in asthma pathogenesis, its effect on airway remodeling remains to be elucidated. The present study examined the expression levels of ORMDL3 in a mouse model of asthma. Mice were divided into three groups: Asthmatic model (n=10), budesonidetreated (n=10) and a control group (n=8). Asthma was induced by sensitization with ovalbumin (OVA) and aluminum hydroxide on day 1, 7 and 14. Subsequently mice were exposed to OVA three times per week from day 28. In order to investigate the mechanism of airway remodeling 100 µg/kg aerosol budesonide was administered to 6 animals prior to exposure to OVA. The condition of lung tissues was assessed through histology, and the expression levels of ORMDL3, phosphorylatedextracellularsignal regulated kinase (pERK) and matrix metallopeptidase9 (MMP9) were quantified using immunohistochemistry, reverse transcriptionquantitative polymerase chain reaction and western blotting. A severe inflammatory response and airway remodeling were pretreatment with budesonide. Expression levels of ORMDL3, phosphorylated (p)ERK and MMP9 were significantly greater in the asthmamodel group; however, in the group pretreated with budesonide their expression was reduced. Expression levels of ORMDL3, pERK and MMP9 were significantly positively correlated with bronchial wall thickness. ORMDL3 expression was significantly positively correlated with pERK and MMP9. Therefore, increased ORMDL3 expression may induce the pERK/MMP9 pathway to promote pathological airway remodeling in patients with asthma.
Assuntos
Asma/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Hidróxido de Alumínio/toxicidade , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Budesonida/farmacologia , Budesonida/uso terapêutico , Colágeno/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Imuno-Histoquímica , Pulmão/patologia , Metaloproteinase 9 da Matriz/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Transdução de SinaisRESUMO
Aluminium (Al) oxyhydroxide (Alhydrogel®), the main adjuvant licensed for human and animal vaccines, consists of primary nanoparticles that spontaneously agglomerate. Concerns about its safety emerged following recognition of its unexpectedly long-lasting biopersistence within immune cells in some individuals, and reports of chronic fatigue syndrome, cognitive dysfunction, myalgia, dysautonomia and autoimmune/inflammatory features temporally linked to multiple Al-containing vaccine administrations. Mouse experiments have documented its capture and slow transportation by monocyte-lineage cells from the injected muscle to lymphoid organs and eventually the brain. The present study aimed at evaluating mouse brain function and Al concentration 180days after injection of various doses of Alhydrogel® (200, 400 and 800µg Al/kg of body weight) in the tibialis anterior muscle in adult female CD1 mice. Cognitive and motor performances were assessed by 8 validated tests, microglial activation by Iba-1 immunohistochemistry, and Al level by graphite furnace atomic absorption spectroscopy. An unusual neuro-toxicological pattern limited to a low dose of Alhydrogel® was observed. Neurobehavioural changes, including decreased activity levels and altered anxiety-like behaviour, were observed compared to controls in animals exposed to 200µg Al/kg but not at 400 and 800µg Al/kg. Consistently, microglial number appeared increased in the ventral forebrain of the 200µg Al/kg group. Cerebral Al levels were selectively increased in animals exposed to the lowest dose, while muscle granulomas had almost completely disappeared at 6 months in these animals. We conclude that Alhydrogel® injected at low dose in mouse muscle may selectively induce long-term Al cerebral accumulation and neurotoxic effects. To explain this unexpected result, an avenue that could be explored in the future relates to the adjuvant size since the injected suspensions corresponding to the lowest dose, but not to the highest doses, exclusively contained small agglomerates in the bacteria-size range known to favour capture and, presumably, transportation by monocyte-lineage cells. In any event, the view that Alhydrogel® neurotoxicity obeys "the dose makes the poison" rule of classical chemical toxicity appears overly simplistic.
Assuntos
Hidróxido de Alumínio/metabolismo , Hidróxido de Alumínio/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Adjuvantes Imunológicos , Hidróxido de Alumínio/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Camundongos , Nanopartículas/administração & dosagem , Dinâmica não LinearRESUMO
This is a safety assessment of alumina and aluminum hydroxide as used in cosmetics. Alumina functions as an abrasive, absorbent, anticaking agent, bulking agent, and opacifying agent. Aluminum hydroxide functions as a buffering agent, corrosion inhibitor, and pH adjuster. The Food and Drug Administration (FDA) evaluated the safe use of alumina in several medical devices and aluminum hydroxide in over-the-counter drugs, which included a review of human and animal safety data. The Cosmetic Ingredient Review (CIR) Expert Panel considered the FDA evaluations as part of the basis for determining the safety of these ingredients as used in cosmetics. Alumina used in cosmetics is essentially the same as that used in medical devices. This safety assessment does not include metallic or elemental aluminum as a cosmetic ingredient. The CIR Expert Panel concluded that alumina and aluminum hydroxide are safe in the present practices of use and concentration described in this safety assessment.
Assuntos
Hidróxido de Alumínio/toxicidade , Óxido de Alumínio/toxicidade , Qualidade de Produtos para o Consumidor , Cosméticos/normas , Hidróxido de Alumínio/análise , Hidróxido de Alumínio/farmacocinética , Óxido de Alumínio/análise , Óxido de Alumínio/farmacocinética , Animais , Qualidade de Produtos para o Consumidor/legislação & jurisprudência , Cosméticos/química , Equipamentos e Provisões/normas , Regulamentação Governamental , Humanos , Estrutura Molecular , Testes de Toxicidade/métodos , Toxicocinética , Estados Unidos , United States Food and Drug AdministrationRESUMO
With the rapid development of the nano-industry, concerns about their potential adverse health effects have been raised. Thus, ranking accurately their toxicity and prioritizing for in vivo testing through in vitro toxicity test is needed. In this study, we used three types of synthesized aluminum oxide nanoparticles (AlONPs): γ-aluminum oxide hydroxide nanoparticles (γ-AlOHNPs), γ- and α-AlONPs. All three AlONPs were spherical, and the surface area was the greatest for γ-AlONPs, followed by the α-AlONPs and γ-AlOHNPs. In mice, γ-AlOHNPs accumulated the most 24 h after a single oral dose. Additionally, the decreased number of white blood cells (WBC), the increased ratio of neutrophils and the enhanced secretion of interleukin (IL)-8 were observed in the blood of mice dosed with γ-AlOHNPs (10 mg kg(-1)). We also compared their toxicity using four different in vitro test methods using six cell lines, which were derived from their potential target organs, BEAS-2B (lung), Chang (liver), HACAT (skin), H9C2 (heart), T98G (brain) and HEK-293 (kidney). The results showed γ-AlOHNPs induced the greatest toxicity. Moreover, separation of particles was observed in a transmission electron microscope (TEM) image of cells treated with γ-AlOHNPs, but not γ-AlONPs or α-AlONPs. In conclusion, our results suggest that the accumulation and toxicity of AlONPs are stronger in γ-AlOHNPs compared with γ-AlONPs and α-AlONPs owing their low stability within biological system, and the presence of hydroxyl group may be an important factor in determining the distribution and toxicity of spherical AlONPs.
Assuntos
Hidróxido de Alumínio/toxicidade , Óxido de Alumínio/toxicidade , Nanopartículas Metálicas/toxicidade , Trifosfato de Adenosina/metabolismo , Administração Oral , Hidróxido de Alumínio/metabolismo , Óxido de Alumínio/metabolismo , Animais , Bioensaio , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Interleucina-8/sangue , Rim/efeitos dos fármacos , Rim/ultraestrutura , L-Lactato Desidrogenase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/ultraestrutura , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/ultraestrutura , Masculino , Camundongos Endogâmicos ICR , Microscopia Eletrônica de Transmissão , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Tamanho da Partícula , Ratos , Medição de Risco , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/ultraestrutura , Propriedades de Superfície , Fatores de Tempo , Distribuição TecidualRESUMO
The efficacy of H4R antagonist JNJ7777120 on nasal symptoms, cough, airway resistance (Raw), inflammatory cell count in bronchoalveolar lavage (BAL) and blood in ovalbumin (OVA) induced allergic rhinitis (AR) was studied in guinea pigs. Animals (n=8) were sensitized by i.p. OVA and were repeatedly challenged with nasal OVA to induce rhinitis, seven animals were not sensitized. Animals were pre-treated with JNJ7777120 2.5 and 5mg/kg i.p. 30 min prior OVA. Cough was induced by inhalation of citric acid, Raw was measured in vivo by Pennock's method as baseline, during AR and after JNJ7777120 treatment. Leucocyte count in BAL and blood was analyzed. JNJ7777120 (5mg/kg) significantly suppressed nasal symptoms and the number of coughs. This compound significantly inhibited airway reactivity to histamine, but not methacholine. Pre-treatment with JNJ7777120 5mg/kg did not influence significantly the leucocyte count in BAL and blood except for a significant decrease in monocyte count in blood compared to the control group (p<0.05). We conclude that the antitussive action of JNJ7777120 is peripheral. The primary effect of the compound is anti-inflammatory, and the suppression of cough is a consequence of reduced airway inflammation.
Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Tosse/tratamento farmacológico , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Doenças Nasais/tratamento farmacológico , Piperazinas/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Hidróxido de Alumínio/toxicidade , Animais , Líquido da Lavagem Broncoalveolar , Ácido Cítrico/toxicidade , Tosse/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Inflamação/induzido quimicamente , Injeções Intraperitoneais , Doenças Nasais/induzido quimicamente , Ovalbumina/toxicidade , PletismografiaRESUMO
The human papillomavirus (HPV)-16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer. The vaccine contains recombinant virus-like particles assembled from the L1 major capsid proteins of the cervical cancer-causing viral types HPV-16 and HPV-18, and Adjuvant System 04 (AS04), which contains the immunostimulant MPL and aluminium salt. To evaluate potential local and systemic toxic effects of the HPV-16/18 vaccine or AS04 alone, three repeated-dose studies were performed in rabbits and rats. One rabbit study also included a single-dose evaluation. In rabbits (~2.5 kg), the full human dose (HD) of the vaccine was evaluated (0.5 ml per injection site), and in rats (~250 g), 1/5 HD of vaccine was evaluated, corresponding to ≥ 12 times the dosage in humans relative to body weight. In both animal models, the treatment-related changes included a slight transient increase in the number of circulating neutrophils as well as a local inflammatory reaction at the injection site. These treatment-related changes were less pronounced after four doses of AS04 alone than after four doses of the HPV-16/18 vaccine. Additional treatment-related changes in the rat included lower albumin/globulin ratios and microscopic signs of inflammation in the popliteal lymph nodes. In both animal models, 13 weeks after the fourth dose, recovery was nearly complete, although at the injection site in some animals there were signs of discoloration, muscle-fibre regeneration and focal points of macrophage infiltration. Therefore, in these non-clinical models, the single and repeated dose administrations of the HPV-16/18 vaccine or AS04 alone were safe and well tolerated.
Assuntos
Hidróxido de Alumínio/toxicidade , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Lipídeo A/análogos & derivados , Vacinas contra Papillomavirus/toxicidade , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/imunologia , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Injeções Intramusculares , Lipídeo A/administração & dosagem , Lipídeo A/imunologia , Lipídeo A/toxicidade , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Vacinas contra Papillomavirus/imunologia , Coelhos , Ratos , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/prevenção & controleRESUMO
The primary challenge in finding a treatment for tuberculosis (TB) is patient non-compliance to treatment due to long treatment duration, high dosing frequency, and adverse effects of anti-TB drugs. This study reports on the development of a nanodelivery system that intercalates the anti-TB drug isoniazid into Mg/Al layered double hydroxides (LDHs). Isoniazid was found to be released in a sustained manner from the novel nanodelivery system in humans in simulated phosphate buffer solutions at pH 4.8 and pH 7.4. The nanodelivery formulation was highly biocompatible compared to free isoniazid against human normal lung and 3T3 mouse fibroblast cells. The formulation was active against Mycobacterium tuberculosis and gram-positive bacteria and gram-negative bacteria. Thus results show significant promise for the further study of these nanocomposites for the treatment of TB.