RESUMO
Advances in microelectronics and nanofabrication have led to the development of various implantable biomaterials. However, biofilm-associated infection on medical devices still remains a major hurdle that substantially undermines the clinical applicability and advancement of biomaterial systems. Given their attractive piezoelectric behavior, barium titanate (BTO)-based materials have also been used in biological applications. Despite its versatility, the feasibility of BTO-embedded biomaterials as anti-infectious implantable medical devices in the human body has not been explored yet. Here, the first demonstration of clinically viable BTO-nanocomposites is presented. It demonstrates potent antibiofilm properties against Streptococcus mutans without bactericidal effect while retaining their piezoelectric and mechanical behaviors. This antiadhesive effect led to â¼10-fold reduction in colony-forming units in vitro. To elucidate the underlying mechanism for this effect, data depicting unfavorable interaction energy profiles between BTO-nanocomposites and S. mutans using the classical and extended Derjaguin, Landau, Verwey, and Overbeek theories is presented. Direct cell-to-surface binding force data using atomic force microscopy also corroborate reduced adhesion between BTO-nanocomposites and S. mutans. Interestingly, the poling process on BTO-nanocomposites resulted in asymmetrical surface charge density on each side, which may help tackle two major issues in prosthetics-bacterial contamination and tissue integration. Finally, BTO-nanocomposites exhibit superior biocompatibility toward human gingival fibroblasts and keratinocytes. Overall, BTO-embedded composites exhibit broad-scale potential to be used in biological settings as energy-harvestable antibiofilm surfaces.
Assuntos
Antibacterianos/farmacologia , Compostos de Bário/farmacologia , Materiais Biocompatíveis/farmacologia , Biofilmes/efeitos dos fármacos , Nanocompostos/química , Titânio/farmacologia , Antibacterianos/química , Antibacterianos/toxicidade , Aderência Bacteriana/efeitos dos fármacos , Compostos de Bário/química , Compostos de Bário/toxicidade , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Fibroblastos/efeitos dos fármacos , Humanos , Queratinócitos/efeitos dos fármacos , Nanocompostos/toxicidade , Streptococcus mutans/efeitos dos fármacos , Streptococcus mutans/fisiologia , Propriedades de Superfície , Titânio/química , Titânio/toxicidadeRESUMO
Barium ferrite nanoparticles (BaFeNPs) are a permanent magnetic nanomaterial widely used in electrical energy storage, recording media or in the improvement of the magnetic properties of other nanoparticles (NPs). However, the information about the toxicity of BaFeNPs is almost non-existent. Thus, in the present work, the antimicrobial effect of BaFeNPs was evaluated for the first time in gram-negative and gram-positive bacteria and yeast showing neither antibacterial nor antifungal activity at moderate concentrations. On the other hand, in order to assess the in vivo toxicity of BaFeNPs the model organism Caenorhabditis elegans was used and ingestion, survival, reproduction and ROS production were evaluated in worms treated with different concentrations of BaFeNPs. Our results show that worms ingest these NPs through the digestive system affecting survival, reproduction and ROS production.
Assuntos
Compostos de Bário/toxicidade , Compostos Férricos/toxicidade , Nanopartículas Metálicas/toxicidade , Animais , Bactérias , Caenorhabditis elegans , Reprodução , Saccharomyces cerevisiae , Testes de ToxicidadeRESUMO
Activation, proliferation, and differentiation of satellite cells can be influenced by extracellular factors, such as adiponectin. This adipokine has been proposed as a regulator of in vitro myogenesis, but its action on in vivo regeneration is not still elucidated. We used C57BL/6 (wild-type [WT]) and adiponectin knockout (AdKO) mice injured with barium chloride at periods of 3, 7, and 14 days after injury. The AdKO presented a higher number of centralized nuclei after 7 days, and a reduction in myogenic genes was observed after 3 days. Moreover, these mice presented an increase in anti-inflammatory cytokines after 3 and 7 days, and an increase in the M2 gene marker and proinflammatory cytokines after 7 days. The WT demonstrated an increase in adiponectin messenger RNA after 7 days. These results demonstrate that adiponectin is important in tissue remodeling during regeneration and that its deficiency does not compromise the maturation of muscle fibers, due to an increase in anti-inflammatory response; however, there is a possible impairment in proinflammatory response and an increase in centralized myonuclei.
Assuntos
Adiponectina/genética , Desenvolvimento Muscular/genética , Músculo Esquelético/crescimento & desenvolvimento , Miosite/genética , Regeneração/genética , Animais , Compostos de Bário/toxicidade , Diferenciação Celular/genética , Cloretos/toxicidade , Citocinas/genética , Humanos , Camundongos , Camundongos Knockout , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Mioblastos/patologia , Miosite/induzido quimicamente , Miosite/patologia , Miosite/terapia , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Local injection of BaCl2 is an established model of acute injury to study the regeneration of skeletal muscle. However, the mechanism by which BaCl2 causes muscle injury is unresolved. Because Ba2+ inhibits K+ channels, we hypothesized that BaCl2 induces myofiber depolarization leading to Ca2+ overload, proteolysis, and membrane disruption. While BaCl2 spares resident satellite cells, its effect on other tissue components integral to contractile function has not been defined. We therefore asked whether motor nerves and microvessels, which control and supply myofibers, are injured by BaCl2 treatment. METHODS: The intact extensor digitorum longus (EDL) muscle was isolated from male mice (aged 3-4 months) and irrigated with physiological salt solution (PSS) at 37 °C. Myofiber membrane potential (Vm) was recorded using sharp microelectrodes while intracellular calcium concentration ([Ca2+]i) was evaluated with Fura 2 dye. Isometric force production of EDL was measured in situ, proteolytic activity was quantified by calpain degradation of αII-spectrin, and membrane disruption was marked by nuclear staining with propidium iodide (PI). To test for effects on motor nerves and microvessels, tibialis anterior or gluteus maximus muscles were injected with 1.2% BaCl2 (50-75 µL) in vivo followed by immunostaining to evaluate the integrity of respective tissue elements post injury. Data were analyzed using Students t test and analysis of variance with P ≤ 0.05 considered statistically significant. RESULTS: Addition of 1.2% BaCl2 to PSS depolarized myofibers from - 79 ± 3 mV to - 17 ± 7 mV with a corresponding rise in [Ca2+]i; isometric force transiently increased from 7.4 ± 0.1 g to 11.1 ± 0.4 g. Following 1 h of BaCl2 exposure, 92 ± 3% of myonuclei stained with PI (vs. 8 ± 3% in controls) with enhanced cleavage of αII-spectrin. Eliminating Ca2+ from PSS prevented the rise in [Ca2+]i and ameliorated myonuclear staining with PI during BaCl2 exposure. Motor axons and capillary networks appeared fragmented within 24 h following injection of 1.2% BaCl2 and morphological integrity deteriorated through 72 h. CONCLUSIONS: BaCl2 injures myofibers through depolarization of the sarcolemma, causing Ca2+ overload with transient contraction, leading to proteolysis and membrane rupture. Motor innervation and capillarity appear disrupted concomitant with myofiber damage, further compromising muscle integrity.
Assuntos
Compostos de Bário/toxicidade , Cálcio/metabolismo , Cloretos/toxicidade , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/lesões , Proteólise/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvasos/efeitos dos fármacos , Microvasos/patologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/patologia , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Proteínas Musculares/metabolismo , Força Muscular/efeitos dos fármacos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/inervaçãoRESUMO
Barium (Ba) is one of the environmental pollutant metals that incite deleterious effects on human health. The present study investigated the effects of exposure to different doses of barium chloride (BaCl2 ) on heart and lung of Wistar rats. Rats were exposed to BaCl2 at 150, 300, and 600 mg/L for seven consecutive days. Results indicated that exposure to Ba caused heart and lung damage evidenced by significant increase in plasma lactate dehydrogenase and creatine kinase activities, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels, while high-density lipoprotein-cholesterol level decreased when compared with control. Moreover, BaCl2 significantly decreased superoxide dismutase, catalase, and acetylcholinesterase activities as well as glutathione level in heart and lung of the treated rats. Furthermore, the dose-dependent increase in cardiac and lung lipid peroxidation, advanced oxidative protein product and nitric oxide levels were accompanied by marked increase in metallothionein in the BaCl2 -treated rats. Administration of BaCl2 altered hematological parameters and significantly increased concentrations of interleukin-6 in the treated rats. Histology analysis showed significant alteration in the heart and lung tissues of Ba-treated rats. In conclusion, BaCl2 -induced heart and lung damages via disruption of antioxidant defense systems, and activation of inflammatory mediators and alteration in hematological parameters in rats.
Assuntos
Compostos de Bário/toxicidade , Cloretos/toxicidade , Poluentes Ambientais/toxicidade , Coração/efeitos dos fármacos , Lesão Pulmonar/patologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Creatina Quinase/sangue , Proteínas Ligadas por GPI/metabolismo , Glutationa/metabolismo , Interleucina-6/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lesão Pulmonar/induzido quimicamente , Masculino , Metalotioneína/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Pompe disease is a metabolic myopathy that is caused by glycogen accumulation as a result of deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Previously, we showed that adult muscle stem cells termed satellite cells are present at normal levels in muscle from patients with Pompe disease, but that these are insufficiently activated to repair the severe muscle pathology. Here we characterized the muscle regenerative response during disease progression in a mouse model of Pompe disease and investigated the intrinsic capacity of Gaa-/- satellite cells to regenerate muscle damage. Gaa-/- mice showed progressive muscle pathology from 15 weeks of age as reflected by increased lysosomal size, decreased fiber diameter and reduced muscle wet weight. Only during the first 15 weeks of life but not thereafter, we detected a gradual increase in centrally nucleated fibers and proliferating satellite cells in Gaa-/- muscle, indicating a mild regenerative response. The levels of Pax7-positive satellite cells were increased in Gaa-/- mice at all ages, most likely as result of enhanced satellite cell activation in young Gaa-/- animals. Surprisingly, both young and old Gaa-/- mice regenerated experimentally-induced muscle injury efficiently as judged by rapid satellite cell activation and complete restoration of muscle histology. In response to serial injury, Gaa-/- mice also regenerated muscle efficiently and maintained the satellite cell pool. These findings suggest that, similar to human patients, Gaa-/- mice have insufficient satellite cell activation and muscle regeneration during disease progression. The initial endogenous satellite cell response in Gaa-/- mice may contribute to the delayed onset of muscle wasting compared to human patients. The rapid and efficient regeneration after experimental muscle injury suggest that Gaa-/- satellite cells are functional stem cells, opening avenues for developing muscle regenerative therapies for Pompe disease.
Assuntos
Doença de Depósito de Glicogênio Tipo II/patologia , Músculo Esquelético/fisiopatologia , Regeneração/genética , Células Satélites de Músculo Esquelético/fisiologia , Fatores Etários , Animais , Compostos de Bário/toxicidade , Cardiotoxinas/toxicidade , Cloretos/toxicidade , Modelos Animais de Doenças , Feminino , Glicogênio/metabolismo , Doença de Depósito de Glicogênio Tipo II/genética , Antígeno Ki-67/metabolismo , Laminina/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Fator de Transcrição PAX7/metabolismo , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismoRESUMO
The present study was designed to investigate the hematotoxicity, sero-biochemical and histological changes due to the accumulation of BaCl2 and BaCO3, the most important barium salts in our daily lives, in different soft tissues including the liver, kidney, heart, and spleen of adult rats after an oral exposure for 30 consecutive days, and to explain the different mechanisms by which this metal can exert these impacts. For this purpose, adult male rats were divided into three main groups of 15 animals each: group I, serving as controls, group II, receiving BaCl2 orally in a dose of 179 mg barium/kg b.wt, and group III, receiving BaCO3 orally in a dose of 418 mg barium/kg b.wt. for 30 consecutive days. Obviously, normocytic normochromic anemia was evident in both barium groups. Serum biochemical analysis revealed significant declines in glutathione peroxidase, catalase, superoxide dismutase, and urea with significant elevations in malondialdehyde, lactate dehydrogenase, and creatine kinase levels. Hyperphosphatemia, hypokalemia, hypocalcemia, and hypochloremia were also evident in both barium groups. Besides, residual analysis of both barium salts in different body organs revealed significantly abundant barium residues in the liver, spleen, heart, and kidney, respectively in both barium salts groups. Moreover, splenic tissue showed hemosiderosis, peritubular congestion, and necrotic glomeruli with intratubular hemorrhage. Sever subepicardial congestion with intramuscular edema was evident in the heart. In conclusion, BaCl2 and BaCO3 were able to deliver mortalities, antioxidant enzymes exhaustion, and a sort of normocytic normochromic anemia, as well as marked disturbances in cardiac, hepatic, and renal functions due to the accumulation of these two salts in the soft tissues. Therefore, these results demonstrate the unrecognized toxicity of those two barium salts due to their accumulation in various soft tissues of the body and so, this needs to reconsider about barium exposure.
Assuntos
Anemia/induzido quimicamente , Compostos de Bário/toxicidade , Bário/toxicidade , Carbonatos/toxicidade , Cloretos/toxicidade , Rim/metabolismo , Fígado/metabolismo , Miocárdio/metabolismo , Anemia/sangue , Anemia/enzimologia , Animais , Antioxidantes/metabolismo , Bário/farmacocinética , Compostos de Bário/farmacocinética , Carbonatos/farmacocinética , Cloretos/farmacocinética , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Nowadays, liver diseases constitute a major health problem in the world. The objective of the present study was to elucidate the hepatotoxicity induced by barium chloride (BaCl2) administered at graded doses in order to evaluate redox state and membrane-bound ATPases in the liver of adult rats. Our results showed, after 21 days of treatment with barium at doses 67 150 and 300 ppm, an increase in hepatic biomarkers such as AST, ALT and GGT activities and in bilirubin and albumin levels. A significant increase in MDA, LOOHs, H2O2, AOPP and PCO levels in liver of treated rats with graded doses of BaCl2 was also observed suggesting the implication of oxidative stress with a significant relation between dose and response. Moreover, LDH activity increased in plasma and decreased in liver of all treated groups. Antioxidant activities of glutathione peroxidase and catalase decreased, especially with the highest dose of barium, indicating a failure of antioxidant system defense. Additionally, the activities of Na+K+-ATPase and Mg2+-ATPase significantly decreased in all treated groups. Our biochemical findings were supported by histological observations. These results highlight the subchronic hepatotoxicity of barium.
Assuntos
Adenosina Trifosfatases/metabolismo , Compostos de Bário/toxicidade , Cloretos/toxicidade , Fígado/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Animais , Compostos de Bário/administração & dosagem , Cloretos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Peróxido de Hidrogênio/metabolismo , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Metalotioneína/metabolismo , Oxirredução , Ratos , Ratos WistarRESUMO
Several metals including barium (Ba) known as environmental pollutants provoke deleterious effects on human health. The present work pertains to the potential ability of selenium (Se) and/or vitamin C, used as nutritional supplements, to alleviate the toxic effects induced by barium chloride (BaCl2) in the heart of adult rats. Animals were randomly divided into seven groups of six each: group 1, serving as negative controls, received distilled water; group 2 received in their drinking water BaCl2 (67 ppm); group 3 received both Ba and Se (sodium selenite 0.5 mg kg-1 of diet); group 4 received both Ba and vitamin C (200 mg kg-1 bodyweight) via force feeding; group 5 received Ba, Se, and vitamin C; and groups 6 and 7, serving as positive controls, received either Se or vitamin C for 21 days. The exposure of rats to BaCl2 caused cardiotoxicity as monitored by an increase in malondialdehyde, hydrogen peroxide, and advanced oxidation protein product levels, a decrease in Na+-K+ adenosine triphosphatase (ATPase), Mg2+ ATPase, and acetylcholinesterase activities and in antioxidant defense system (catalase, glutathione peroxidase, superoxide dismutase, glutathione, and nonprotein thiols). Plasma lactate dehydrogenase and creatine kinase activities, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol levels increased, while high-density lipoprotein-cholesterol level decreased. Coadministration of Se and/or vitamin C restored the parameters indicated above to near control values. The histopathological findings confirmed the biochemical results. Se and vitamin C may be a promising therapeutic strategy for Ba-induced heart injury.
Assuntos
Ácido Ascórbico/farmacologia , Compostos de Bário/toxicidade , Cloretos/toxicidade , Cardiopatias/induzido quimicamente , Selênio/farmacologia , Acetilcolinesterase/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Ácido Ascórbico/administração & dosagem , Dieta , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Cardiopatias/tratamento farmacológico , Peróxido de Hidrogênio , Peroxidação de Lipídeos , Miocárdio/enzimologia , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Selênio/administração & dosagem , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.
Assuntos
Alcaloides/farmacologia , Antiarrítmicos/farmacologia , Aporfinas/farmacologia , Fibrilação Ventricular/tratamento farmacológico , Alcaloides/efeitos adversos , Alcaloides/síntese química , Animais , Antiarrítmicos/efeitos adversos , Antiarrítmicos/síntese química , Aporfinas/efeitos adversos , Aporfinas/síntese química , Compostos de Bário/toxicidade , Tetracloreto de Carbono/toxicidade , Cloretos/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/efeitos adversos , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacologia , Fibrilação Ventricular/induzido quimicamenteRESUMO
Satellite cells are stem cells with an essential role in skeletal muscle repair. Precise regulation of gene expression is critical for proper satellite cell quiescence, proliferation, differentiation and self-renewal. Nuclear proteins required for gene expression are dependent on the nucleocytoplasmic transport machinery to access to nucleus, however little is known about regulation of nuclear transport in satellite cells. The best characterized nuclear import pathway is classical nuclear import which depends on a classical nuclear localization signal (cNLS) in a cargo protein and the heterodimeric import receptors, karyopherin alpha (KPNA) and beta (KPNB). Multiple KPNA1 paralogs exist and can differ in importing specific cNLS proteins required for cell differentiation and function. We show that transcripts for six Kpna paralogs underwent distinct changes in mouse satellite cells during muscle regeneration accompanied by changes in cNLS proteins in nuclei. Depletion of KPNA1, the most dramatically altered KPNA, caused satellite cells in uninjured muscle to prematurely activate, proliferate and undergo apoptosis leading to satellite cell exhaustion with age. Increased proliferation of satellite cells led to enhanced muscle regeneration at early stages of regeneration. In addition, we observed impaired nuclear localization of two key KPNA1 cargo proteins: p27, a cyclin-dependent kinase inhibitor associated with cell cycle control and lymphoid enhancer factor 1, a critical cotranscription factor for ß-catenin. These results indicate that regulated nuclear import of proteins by KPNA1 is critical for satellite cell proliferation and survival and establish classical nuclear import as a novel regulatory mechanism for controlling satellite cell fate. Stem Cells 2016;34:2784-2797.
Assuntos
Núcleo Celular/metabolismo , Músculo Esquelético/metabolismo , Sinais de Localização Nuclear/genética , Regeneração/genética , Células Satélites de Músculo Esquelético/metabolismo , alfa Carioferinas/genética , Transporte Ativo do Núcleo Celular/genética , Animais , Compostos de Bário/toxicidade , Proliferação de Células , Sobrevivência Celular , Cloretos/toxicidade , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Citoplasma/metabolismo , Feminino , Regulação da Expressão Gênica , Fator 1 de Ligação ao Facilitador Linfoide/genética , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Sinais de Localização Nuclear/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Satélites de Músculo Esquelético/citologia , Transdução de Sinais , alfa Carioferinas/deficiência , beta Catenina/genética , beta Catenina/metabolismoRESUMO
CONTEXT: Pomegranate peel (PP) has health benefits including antibacterial, antioxidant, anti-inflammatory, and antimutagenic properties. OBJECTIVE: This study investigated the biochemical composition and protective effects of PP against hematotoxicity and genotoxicity induced by barium chloride (BaCl2) in adult rats. MATERIALS AND METHODS: Adult Wistar rats were divided into four groups of six each: control, barium (67 ppm via drinking water), PP (5% via diet), and their combination during 21 d. Oxidative stress was determined by MDA, AOPP, and antioxidant status: CAT, GPx, GSH, Vit C. Osmotic fragility (OF), chromosomal aberrations (CAs), and micronucleus (MN) assays were also studied. RESULTS: PP showed a rich composition of antioxidant compounds. DPPH test found IC50 value= 5.3 µg/mL and a high polysaccharides content (315 ± 5 mg/g of extract). In vivo study showed a decrease in red blood cells (70%) and platelet counts (46%), hemoglobin content (8%), hematocrit percent (7%), and an 80% increase of white blood cells in Ba-treated rats. A reduction in antioxidant status: catalase, glutathione peroxidase activities, glutathione, and vitamin C levels by 31, 21, 28, and 29%, respectively, and an increase in MDA (46%) and AOPP levels (72%) were also observed compared with controls. BaCl2-treatment showed a significant increase in the frequencies of total chromosomal aberrations with abnormal metaphases and micronucleus in bone-marrow cells. Oxidative stress induced by BaCl2 might be the major cause for chromosomal abnormalities leading to DNA damage. DISCUSSION AND CONCLUSION: A decrease in hematotoxic and genotoxic effects induced by PP is due to its powerful antioxidant capacity.
Assuntos
Antioxidantes/farmacologia , Compostos de Bário/toxicidade , Células Sanguíneas/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Cloretos/toxicidade , Aberrações Cromossômicas/efeitos dos fármacos , Lythraceae/química , Animais , Antioxidantes/isolamento & purificação , Compostos de Bifenilo/química , Células Sanguíneas/metabolismo , Células Sanguíneas/patologia , Proteínas Sanguíneas/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Aberrações Cromossômicas/induzido quimicamente , Feminino , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Fragilidade Osmótica/efeitos dos fármacos , Picratos/química , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Ratos WistarRESUMO
CCAAT/enhancer binding protein beta (C/EBPß), a transcription factor expressed in muscle satellite cells (SCs), inhibits the myogenic program and is downregulated early in differentiation. In a conditional null model in which C/EBPß expression is knocked down in paired box protein 7+ (Pax7+) SCs, cardiotoxin (CTX) injury is poorly repaired, although muscle regeneration is efficient in control littermates. While myoblasts lacking C/EBPß can differentiate efficiently in culture, after CTX injury poor regeneration was attributed to a smaller than normal Pax7+ population, which was not due to a failure of SCs to proliferate. Rather, the percentage of apoptotic SCs was increased in muscle lacking C/EBPß. Given that an injury induced by BaCl2 is repaired with greater efficiency than controls in the absence of C/EBPß, we investigated the inflammatory response following BaCl2 and CTX injury and found that the levels of interleukin-1ß (IL-1ß), a proinflammatory cytokine, were robustly elevated following CTX injury and could induce C/EBPß expression in myoblasts. High levels of C/EBPß expression in myoblasts correlated with resistance to apoptotic stimuli, while its loss increased sensitivity to thapsigargin-induced cell death. Using cancer cachexia as a model for chronic inflammation, we found that C/EBPß expression was increased in SCs and myoblasts of tumor-bearing cachectic animals. Further, in cachectic conditional knockout animals lacking C/EBPß in Pax7+ cells, the SC compartment was reduced because of increased apoptosis, and regeneration was impaired. Our findings indicate that the stimulation of C/EBPß expression by IL-1ß following muscle injury and in cancer cachexia acts to promote SC survival, and is therefore a protective mechanism for SCs and myoblasts in the face of inflammation.
Assuntos
Apoptose , Proteína beta Intensificadora de Ligação a CCAAT/genética , Animais , Apoptose/efeitos dos fármacos , Compostos de Bário/toxicidade , Proteína beta Intensificadora de Ligação a CCAAT/deficiência , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Cardiotoxinas/toxicidade , Linhagem Celular , Cloretos/toxicidade , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Mioblastos/citologia , Mioblastos/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , RNA Mensageiro/metabolismo , Tapsigargina/toxicidade , Regulação para Cima/efeitos dos fármacosRESUMO
CONTEXT: Pomegranate (Punica granatum L., Punicaceae) is known to possess enormous antioxidant activity. OBJECTIVE: This study investigates the protective effects of pomegranate peel against barium-mediated renal damage. MATERIALS AND METHODS: Rats were exposed during 21 days either to barium (67 ppm), barium + pomegranate peel (5% of diet) or to only pomegranate peel (5% of diet). RESULTS: Exposure rats to barium provoked a significant increase in kidney malondialdehyde (MDA), advanced oxidation protein products (AOPP) and hydrogen peroxide (H2O2) levels. Creatinine, urea and uric acid levels in plasma and urine were also modified. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, non protein thiol (NPSH) and reduced glutathione (GSH) levels were decreased. Metallothionein (MT) production was increased and their genes expressions were up-regulated. All these changes were improved by dietary pomegranate peel. Moreover, the distorted histoarchitecture in kidney of barium group was alleviated by pomegranate peel. CONCLUSION: Our data showed, for the first time, the protective effects of pomegranate peel against barium-induced renal oxidative damage.
Assuntos
Compostos de Bário/toxicidade , Cloretos/toxicidade , Nefropatias/prevenção & controle , Lythraceae/química , Extratos Vegetais/farmacologia , Animais , Antioxidantes/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/patologia , Masculino , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Adult zebrafish pairs were exposed to sub-lethal concentrations of BaCl2 for 21 days, and the effects on reproduction, sex steroid hormones, and transcription of the genes belonging to the hypothalamic-pituitary-gonad (HPG) axis were investigated. The adverse effects on performances of F1 generation were further examined with or without subsequent exposure to BaCl2. Egg production was significantly decreased, and parental exposure to BaCl2 resulted in lesser rates of hatching. In males, exposure to BaCl2 resulted in greater concentrations of E2 along with greater mRNA expression of cyp19a. The results demonstrated that BaCl2 could modulate gene transcriptions and hormone production of the HPG axis in a sex-dependent way, which could cause adverse effects on reproduction and the development of offspring.
Assuntos
Compostos de Bário/toxicidade , Cloretos/toxicidade , Disruptores Endócrinos/toxicidade , Hormônios Esteroides Gonadais/metabolismo , Gônadas/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Peixe-Zebra , Animais , Aromatase/genética , Relação Dose-Resposta a Droga , Feminino , Gônadas/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Fatores Sexuais , Transcrição Gênica/efeitos dos fármacos , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genéticaRESUMO
BACKGROUND: Abnormal branched myofibers within skeletal muscles are commonly found in diverse animal models of muscular dystrophy as well as in patients. Branched myofibers from dystrophic mice are more susceptible to break than unbranched myofibers suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Previous studies showed ubiquitous over-expression of mouse olfactory receptor 23 (mOR23), a G protein-coupled receptor, in wild type mice decreased myofiber branching. Whether mOR23 over-expression specifically in skeletal muscle cells is sufficient to mitigate myofiber branching in dystrophic muscle is unknown. METHODS: We created a novel transgenic mouse over-expressing mOR23 specifically in muscle cells and then bred with dystrophic (mdx) mice. Myofiber branching was analyzed in these two transgenic mice and membrane integrity was assessed by Evans blue dye fluorescence. RESULTS: mOR23 over-expression in muscle led to a decrease of myofiber branching after muscle regeneration in non-dystrophic mouse muscles and reduced the severity of myofiber branching in mdx mouse muscles. Muscles from mdx mouse over-expressing mOR23 significantly exhibited less damage to eccentric contractions than control mdx muscles. CONCLUSIONS: The decrease of myofiber branching in mdx mouse muscles over-expressing mOR23 reduced the amount of membrane damage induced by mechanical stress. These results suggest that modifying myofiber branching in dystrophic patients, while not preventing degeneration, could be beneficial for mitigating some of the effects of the disease process.
Assuntos
Contração Muscular , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Miofibrilas/metabolismo , Receptores Odorantes/metabolismo , Fatores Etários , Animais , Compostos de Bário/toxicidade , Membrana Celular/metabolismo , Membrana Celular/patologia , Cloretos/toxicidade , Modelos Animais de Doenças , Feminino , Hibridização Genética , Masculino , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Miofibrilas/efeitos dos fármacos , Miofibrilas/patologia , Receptores Odorantes/genética , Regeneração , Estresse Mecânico , Regulação para CimaRESUMO
BACKGROUND: A longstanding goal in regenerative medicine is to reconstitute functional tissues or organs after injury or disease. Attention has focused on the identification and relative contribution of tissue specific stem cells to the regeneration process. Relatively little is known about how the physiological process is regulated by other tissue constituents. Numerous injury models are used to investigate tissue regeneration, however, these models are often poorly understood. Specifically, for skeletal muscle regeneration several models are reported in the literature, yet the relative impact on muscle physiology and the distinct cells types have not been extensively characterised. METHODS: We have used transgenic Tg:Pax7nGFP and Flk1GFP/+ mouse models to respectively count the number of muscle stem (satellite) cells (SC) and number/shape of vessels by confocal microscopy. We performed histological and immunostainings to assess the differences in the key regeneration steps. Infiltration of immune cells, chemokines and cytokines production was assessed in vivo by Luminex®. RESULTS: We compared the 4 most commonly used injury models i.e. freeze injury (FI), barium chloride (BaCl2), notexin (NTX) and cardiotoxin (CTX). The FI was the most damaging. In this model, up to 96% of the SCs are destroyed with their surrounding environment (basal lamina and vasculature) leaving a "dead zone" devoid of viable cells. The regeneration process itself is fulfilled in all 4 models with virtually no fibrosis 28 days post-injury, except in the FI model. Inflammatory cells return to basal levels in the CTX, BaCl2 but still significantly high 1-month post-injury in the FI and NTX models. Interestingly the number of SC returned to normal only in the FI, 1-month post-injury, with SCs that are still cycling up to 3-months after the induction of the injury in the other models. CONCLUSIONS: Our studies show that the nature of the injury model should be chosen carefully depending on the experimental design and desired outcome. Although in all models the muscle regenerates completely, the trajectories of the regenerative process vary considerably. Furthermore, we show that histological parameters are not wholly sufficient to declare that regeneration is complete as molecular alterations (e.g. cycling SCs, cytokines) could have a major persistent impact.
Assuntos
Modelos Animais , Músculo Esquelético/fisiologia , Regeneração , Animais , Compostos de Bário/toxicidade , Cloretos/toxicidade , Proteínas Cardiotóxicas de Elapídeos/toxicidade , Lesão por Frio/patologia , Lesão por Frio/fisiopatologia , Citocinas/fisiologia , Venenos Elapídicos/toxicidade , Fibrose , Congelamento/efeitos adversos , Proteínas de Fluorescência Verde/análise , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Desenvolvimento Muscular , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/lesões , Músculo Esquelético/patologia , Mioblastos/fisiologia , Necrose , Neovascularização Fisiológica , Regeneração/imunologia , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/fisiologia , Células-Tronco/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análiseRESUMO
The present study was performed to establish the therapeutic efficacy of pomegranate peel against barium chloride induced liver injury. Adult rats were divided into four groups of six animals each: group I, serving as controls, received distilled water; group II received by their drinking water 67 ppm of BaCl2; group III received both 67 ppm of BaCl2 by the same way than group II and 5 % of pomegranate peel (PP) via diet; group IV received 5 % of PP. Analysis by HPLC/MS of PP showed its rich composition in flavonoids such as gallic acid, castalin, hyperin, quercitrin, syringic acid, and quercetin. The protective effects of pomegranate peel against hepatotoxicity induced by barium chloride were assessed using biochemical parameters and histological studies. Exposure of rats to barium caused oxidative stress in the liver as evidenced by an increase in malondialdehyde (MDA), lipid hydroperoxides (LOOHs), H2O2 and advanced oxidation protein product (AOPP) levels, and lactate dehydrogenase (LDH), gamma glutamyl transpeptidase (GGT), alanine aminotransferase (AST) and aspartate aminotransferase (ALT) activities, a decrease in catalase (CAT) and glutathione peroxidase (GPx) activities, glutathion (GSH), non-protein thiol (NPSH), vitamin C levels, and Mn-SOD gene expression. Liver total MT levels, MT-1, and MT-2 and pro-inflammatory cytokine genes expression like TNF-α, IL-1ß and IL-6 were increased. Pomegranate peel, supplemented in the diet of barium-treated rats, showed an improvement of all the parameters indicated above.The present work provided ethnopharmacological relevance of pomegranate peel against the toxic effects of barium, suggesting its beneficial role as a potential antioxidant.
Assuntos
Compostos de Bário/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cloretos/toxicidade , Citocinas/genética , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Lythraceae/química , Extratos Vegetais/uso terapêutico , Animais , Antioxidantes/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Suplementos Nutricionais , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Masculino , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos , Ratos Wistar , Regulação para Cima/efeitos dos fármacosRESUMO
Identify and prevent possible adverse effects of nanostructures under conditions of industrial production is the primary hygienic problem is not resolved at this time. In order to approach to solve a series of physiological, hygienic and toxicological studies. Study of harmful production factors in different technologies of metal nanoparticles, analyzed the health of workers employed in manufacturing them. Also established specific mechanisms of toxicity of nanosilver nanometals for example, the technique of hygienic control over the content in the air of the working area metal nanoparticles, the data on the existing approaches to the hygienic standardization of nanoscale objects in the breathing zone of workers.
Assuntos
Compostos de Bário/toxicidade , Expressão Gênica/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Nanotecnologia , Segurança , Prata/toxicidade , Titânio/toxicidade , Aerossóis , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Humanos , Rim/efeitos dos fármacos , Rim/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Masculino , Pessoa de Meia-Idade , Miocárdio/enzimologia , Saúde Ocupacional , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Wistar , Testículo/efeitos dos fármacos , Testículo/enzimologia , UcrâniaRESUMO
Studies have been demonstrating that smaller particles can lead to unexpected and diverse ecotoxicological effects when compared to those caused by the bulk material. In this study, the chemical composition, size and shape, state of dispersion, and surface's charge, area and physicochemistry of micro (BT MP) and nano barium titanate (BT NP) were determined. Green algae Chlorella vulgaris grown in Bold's Basal (BB) medium or Seine River water (SRW) was used as biological indicator to assess their aquatic toxicology. Responses such as growth inhibition, cell viability, superoxide dismutase (SOD) activity, adenosine-5-triphosphate (ATP) content and photosynthetic activity were evaluated. Tetragonal BT (~170 nm, 3.24 m(2) g(-1) surface area) and cubic BT (~60 nm, 16.60 m(2) g(-1)) particles were negative, poorly dispersed, and readily aggregated. BT has a statistically significant effect on C. vulgaris growth since the lower concentration tested (1 ppm), what seems to be mediated by induced oxidative stress caused by the particles (increased SOD activity and decreased photosynthetic efficiency and intracellular ATP content). The toxic effects were more pronounced when the algae was grown in SRW. Size does not seem to be an issue influencing the toxicity in BT particles toxicity since micro- and nano-particles produced significant effects on algae growth.