RESUMO
Mechanistic implications of antimicrobial and in vitro antioxidant potentials of a set of newly generated nonbridged mononuclear N,O-orthometallated and carboxylate bridged binuclear nonorthometallated dibutyltin(IV) formulations have been investigated. Some of these formulations were screened for their antibacterial and antifungal activities against Escherichia coli and Candida albicans, respectively whereas in vitro antioxidant potential was examined by Ferric reducing antioxidant power (FRAP) assay. Nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations were generated by the reactions of Bu2 SnCl2 with sodium salts of 2-aminophenol/substituted 2-aminophenol and flexible N-protected amino acids in 1:1:1 molar ratio in refluxing dry THF. Plausible structures of these nonbridged mononuclear N,O-orthometallated dibutyltin(IV) formulations containing flexible N-protected amino acids have been suggested on the basis of spectroscopic and mass studies of some representative formulations. Plausible structures suggested on the basis of spectroscopic studies are corroborated by density functional theory (DFT/B3LYP method) (SPARTAN-20) investigation of a representative dibutyltin(IV) complex and the ligands involved in it. The presence of two different classes of organic ligands in this complex provides an opportunity to study optimized topologies, bonding, distortions, optimized energy, and stability of the complex.
Assuntos
Anti-Infecciosos , Antioxidantes , Antioxidantes/química , Aminofenóis , Antibacterianos/química , Testes de Sensibilidade MicrobianaRESUMO
Environmental contaminant exposures occur due to the widespread use of synthetic chemicals. Tributyltin (TBT), dibutyltin (DBT), and pentachlorophenol (PCP) are each used in a variety of applications, including antifouling paints and stabilizers in certain plastics. Each of these compounds has been found in human blood, as well as other tissues, and they have been shown to stimulate pro-inflammatory cytokine production in human immune cells, Inflammatory cytokines mediate response to injury or infection. However, if their levels are increased in the absence of an appropriate stimulus, chronic inflammation can occur. Chronic inflammation is associated with a number of pathologies including cancer. Stimulation of pro-inflammatory cytokine production by these toxicants is dependent on activation of ERK 1/2 and/or p38 MAPK pathways. MAPK pathways have the capacity to regulate translation by increasing phosphorylation of key translation regulatory proteins. There have been no previous studies examining the effects of TBT, DBT, or PCP on translation. The current study shows that ribosomal protein S6 (S6), eukaryotic initiation factor 4B (eIF4B), and eIF4E are phosphorylated (activated) and/or their total levels are elevated in response to each of these compounds at concentrations found in human blood. Activation/increased levels of translational proteins occurred at concentrations of the compounds that have been shown to elevate pro-inflammatory cytokine production, but where there is no increase in mRNA for those proteins was seen. Compound-stimulated increases in translation appear to be part of the mechanism by which they elevate protein production in immune cells.
Assuntos
Compostos Orgânicos de Estanho , Pentaclorofenol , Humanos , Compostos Orgânicos de Estanho/toxicidade , Fatores de Transcrição , Citocinas , Substâncias Perigosas , InflamaçãoRESUMO
BACKGROUND: Despite advanced research and great progress in understanding the chronic pancreatitis (CP) pathogenesis, no current causal treatment for the condition is available. For preclinical studies, the existence of a well-characterized CP animal model is essential. The aim of the study was to assess the impact of chronic pancreatitis on the antioxidant enzymes activity in rat blood serum and on the level of glutathione (intracellular antioxidant) in rat pancreas. METHODS: The experiments were carried out on the Wistar Kyoto rats in two groups: control and study group (CP), in which chemical induction of pancreatitis with dibutyl dichloride was performed. Serum enzyme activities of amylase, lipase, catalase and superoxide dismutase were analyzed. The levels of the following biochemical parameters were also investigated: total protein, albumin, calcium, magnesium, and triglycerides. Levels of low-molecular-weight thiols: reduced (GSH) and oxidized (GSSG) glutathione, were determined in pancreatic homogenates. RESULTS: Histopathological imaging of rat pancreatic parenchyma with induced inflammation confirmed focal lymphocytic interstitial chronic pancreatitis with fibrosis features and mild parenchymal atrophy, as well as pancreatic islets degeneration. In the CP group, we observed a statistically significant decrease in serum amylase and lipase activities and in total protein/albumin levels. Also, the elevated catalase activity was registered. In CP rats' tissues, we observed a 15-fold reduction in GSH levels. The other examined parameters remained unchanged. Clinically relevant are hypoalbuminemia and a moderate decrease in lipase activity. The described changes are most probably indicative of the impaired exocrine pancreas function, however without organ failure features.
Assuntos
Antioxidantes , Pancreatite Crônica , Ratos , Animais , Catalase/metabolismo , Ratos Wistar , Amilases/metabolismo , Lipase/metabolismo , Glutationa/metabolismo , Albuminas , Modelos TeóricosRESUMO
Organotin (IV) compounds are a focus of research for potential use in cancer chemotherapy. Here, we established anticancer profile of dibutyltin (IV) carboxylate derivatives in prostate cancer (PCa) model. We determined cytotoxicity of a library of dibutyltin (IV) carboxylate derivatives and observed that dibutylstannanediyl (2Z,2'Z)-bis(4-(benzylamino)-4-oxobut-2-enoate (Ch-620; 10 µM) was minimally toxic to normal fibroblasts. Ch-620 (1-1.25 µM) inhibited proliferation of PCa and melanoma cells on short- and long-term exposures with induction of cell cycle arrest. Ch-620 treatment increased population of apoptotic cells, as assessed by flow cytometry, and activated caspase 3. Proteomics showed activation of PPARα, with repression of SMAD4 and integrin ß5 (ITGB5) in Ch-620-treated PCa cells. Further analysis demonstrated that Ch-620 resulted in phosphorylation of p38 MAPK, upregulation of PPARα and decreased expression of SMAD4 and ITGB5 with reduced migration of PCa cells. In vivo studies in PC3M grafted athymic nude mice showed that Ch-620 (5 µg/week; 7 weeks) treatment reduced tumor growth as opposed to untreated controls. Immunoblot analysis of tumors demonstrated upregulated p-p38 MAPK and PPARα, followed by a decline in SMAD4 and ITGB5. Immunohistochemistry reinforced these results with increased caspase 3 and p-p38 MAPK and diminished Ki67 staining in Ch-620 treated animals. Taken together, our data indicate that Ch-620 inhibited proliferation of PCa through modulation of MAPK/PPARα/SMAD4 signaling. Organotin (IV) carboxylate compounds; specifically Ch-620 can be a potential anticancer agent for the treatment of PCa subject to detailed pre-clinical and clinical investigations. This unlocks prospects for the development of new tin-based drugs in cancer therapeutics.
Assuntos
Compostos Orgânicos de Estanho , Neoplasias da Próstata , Proteínas Quinases p38 Ativadas por Mitógeno , Animais , Apoptose , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Nus , Compostos Orgânicos de Estanho/farmacologia , PPAR alfa/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Proteína Smad4/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Previously, dibutyltin dichloride (DBTC) was the putative toxophore for dibutyltin bis-alkyl and bis-thio esters. Recent chemical and toxicological data on dioctyltin bis(2-ethylhexyl thioglycolate) suggest the thioglycolate esters of alkyltins do not generate the dichloride toxophore. Our results, using 119 Sn-nuclear magnetic resonance (NMR) spectroscopy, demonstrated that dibutyltin bis(2-ethylhexyl thioglycolate) (DBTE) is hydrolyzed to dibutyltin chloro-(2-ethylhexyl thioglycolate) (DBTEC) under simulated gastric conditions. No DBTC was detected. DBTE was administered orally to presumed-pregnant Sprague-Dawley rats in a corn oil vehicle at 2.5, 8.5, and 25.0 mg/kg/day (Gestation Day 5 [GD5] through GD19). There were no maternal deaths, no treatment-related statistically significant reductions in feed consumption, maternal body weight or weight gain, or adverse gestational outcomes. Maternal thymus weight was significantly reduced in rats at 25 mg/kg. There were no effects on fetal growth, no dose-dependent pattern of external, visceral, or skeletal malformations, and no increase in anatomical variations. Based on the obtained experimental data, it is concluded here that DBTE forms DBTEC, not DBTC, in the stomach, and DBTE was not teratogenic nor fetotoxic in rats, a species sensitive to DBTC. The maternal no-observed-adverse-effect level (NOAEL) was 8.5 mg/kg/day, and the developmental NOAEL was 25 mg/kg/day, the high dose. The maternal LOAEL was 25 mg/kg/day based on reduced maternal thymus weight.
Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Compostos Orgânicos de Estanho/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Hidrólise , Masculino , Nível de Efeito Adverso não Observado , Ratos/crescimento & desenvolvimento , Ratos Sprague-Dawley , Estômago/fisiologiaRESUMO
Dibutyltin (DBT) is used to stabilize plastics and as a deworming agent in some poultry. It is found in human blood (levels as high as 0.3 µM). Interleukin (IL) 1ß (IL-1ß) and IL-6 are pro-inflammatory cytokines produced by lymphocytes, monocytes, and other cells. Elevated levels of IL-1ß and IL-6 have been associated with pathologies including rheumatoid arthritis and cancers. DBT was shown to decrease IL-1ß and IL-6 secretion from immune cells at higher concentrations while causing increases at lower concentrations. However, it was not clear if these changes were due to DBT's alteration of the secretory process or due its ability to change cellular synthesis/production of these proteins. This study addresses this question, as well as mechanisms for any observed changes in synthesis/production. Monocyte-depleted peripheral blood mononuclear cells (MD-PBMCs) were exposed to DBT at concentrations of 5, 2.5, 1, 0.5, 0.25, 0.1, and 0.05 µM for 1, 6, and 24 h and the production (combination of secreted and intracellular levels from the same cells) of both IL-1ß and IL-6 were measured. Effects of selected DBT exposures on cytokine production were also examined in PBMCs and DBT's effects were similar when monocytes were present. The 24-h exposures to DBT decreased production of both IL-1ß and IL-6 at the two highest concentrations but increased production at lower concentrations. Both decreases and increases in cytokine production appear to be explained by DBT-induced changes in mRNA levels. DBT-induced increases in cellular production of the cytokines appear to require p38 and ERK1/2 MAPK pathways.
Assuntos
Proliferação de Células/efeitos dos fármacos , Interleucina-18/metabolismo , Interleucina-6/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/efeitos dos fármacos , Compostos Orgânicos de Estanho/toxicidade , Células Cultivadas/efeitos dos fármacos , Citocinas/metabolismo , Exposição Ambiental/efeitos adversos , Humanos , RNA Mensageiro/metabolismoRESUMO
Exposure to tin in the general US population is near ubiquitous, as determined using urinary tin levels measured by inductively coupled plasma mass spectrometry (ICP-MS). Urinary tin levels are associated with chronic health outcomes, such as diabetes; however, it is unclear if these associations are due to the presence of inorganic and organic forms of tin in urine. To address this knowledge gap, levels of total tin and several organotin compounds (OTCs) were measured in convenience urine samples from pregnant women and adults from Iowa, United States. Total tin and OTC levels in urine samples were quantified using ICP-MS and gas chromatography with pulsed flame photometric detection (GC-PFPD), respectively. ICP-MS detected tin in almost all urine samples from both study populations. Low levels of dibutyltin were detected in two out of fifty human urine samples. Importantly, storage of urine samples in plastic containers, but not HNO3-pretreated glass vials drastically reduced the recoveries of OTCs, in particular, tributyltin. Although their detection frequency is low, exposures to OTC should be considered when studying associations between human exposures to tin compounds and adverse health outcomes; however, urinary OTC levels measured in banked urine samples may not be suitable as biomarkers of OTC exposure.
Assuntos
Compostos Orgânicos de Estanho/urina , Estanho/urina , Adulto , Feminino , Humanos , Iowa , Masculino , Gravidez , Manejo de Espécimes , Estados UnidosRESUMO
OBJECTIVES: Heat shock protein (HSP) 70 performs a chaperoning function and protects cells against injury. Although the effect of HSPs against acute inflammatory change has been proven, the relationship between HSP70 and chronic pancreatitis remains unclear. This study aimed to investigate the protective effect of increased HSP70 expression induced by thermal stress against pancreatic fibrosis in experimental chronic pancreatitis. MATERIALS AND METHODS: Two experiments to evaluate pancreatic HSP70 expression induced by thermal stress and determine the effect of increased HSP70 expression against pancreatic fibrosis were performed. To investigate HSP70 expression, rats were immersed in a warm bath and sequentially killed, and pancreatic HSP70 expression was measured. To study the effect of increased HSP70 expression, pancreatic fibrosis was induced by intravenous injection of dibutyltin dichloride (DBTC) and analyzed under repeated thermal stress. The severity of pancreatic fibrosis was measured. RESULTS: Thermal stress significantly increased HSP70 expression in the pancreas. HSP70 expression peaked at 6-12 h after warm bathing, and the increased HSP70 expression was associated with the attenuation of pancreatic fibrosis. Although pancreatic fibrosis was induced by DBTC injection, HSP70 expression induced by repeated thermal stress diminished the severity of atrophy and fibrosis. On western blot analysis, collagen type 1 expression was diminished in the increased HSP70 expression group, but not α-smooth muscle actin expression. CONCLUSIONS: Thermal stress could increase pancreatic HSP70 expression, and induced HSP70 expression showed a protective effect against pancreatic fibrosis. Modulation of HSP70 expression could be a potential therapeutic target in the treatment of chronic pancreatitis.
Assuntos
Colágeno Tipo I/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Pâncreas/patologia , Pancreatite Crônica/patologia , Animais , Western Blotting , Fibrose/prevenção & controle , Hipertermia Induzida , Masculino , Compostos Orgânicos de Estanho/administração & dosagem , Pancreatite Crônica/induzido quimicamente , Ratos , Ratos Sprague-DawleyRESUMO
Butenolide is an environmentally friendly antifouling natural product, but its efficiency and mechanism in preventing biofilm formation have not been examined. Furthermore, controlling the release of butenolide from paints into seawater is technically challenging. A coating was developed by mixing butenolide with a biodegradable polymer, poly (ε-caprolactone)-based polyurethane, and a one-month in situ anti-biofilm test was conducted in a subtidal area. The constant release of butenolide from the surface suggested that its release was well controlled. Direct observation and confocal microscope investigation indicated that the coating was effective against both biofilm formation and attachment of large fouling organisms. Metatranscriptomic analysis of biofilm samples implied that the coating selectively inhibited the adhesion of microbes from a variety of phyla and targeted particular functional pathways including energy metabolism, drug transport and toxin release. These integrated analyses demonstrated the potential application of this butenolide/polymer coating as an anti-biofilm material.
Assuntos
4-Butirolactona/análogos & derivados , Biofilmes/efeitos dos fármacos , Incrustação Biológica/prevenção & controle , Consórcios Microbianos/genética , Poliésteres/farmacologia , Poliuretanos/farmacologia , 4-Butirolactona/farmacologia , Adesão Celular , Metagenômica , Água do Mar , Propriedades de Superfície , TranscriptomaRESUMO
Butyltins (BTs), tributyltin (TBT) and dibutyltin (DBT) are organotin compounds that have been used in a variety of industrial applications; as a result, these compounds have been found in human blood. Interleukin (IL)-6 is a proinflammatory mediator that is produced by T lymphocytes and monocytes. It is responsible for immune response regulation as well as tissue repair and cellular growth. Both BTs decrease the ability of human natural killer cells to destroy tumor cells and alter the secretion of proinflammatory cytokines tumor necrosis factor alpha, interferon gamma and IL-1 beta (ß) from human lymphocytes ex vivo. Here, we show that BTs alter the secretion of IL-6 from increasingly reconstituted preparations of human immune cells. IL-6 secretion was examined after 24 hour, 48 hour or 6 day exposures to TBT and DBT in highly enriched human natural killer cells, monocyte-depleted peripheral blood mononuclear cells (PBMCs), PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes (PBMCs + granulocytes). The results indicated that both BTs altered IL-6 secretion from all cell preparations. Significant decreases of IL-6 secretion were seen at the highest concentration of TBT (200 nm) and DBT (5-2.5 µm) while the lower concentrations of DBT (0.05 and 0.1 µm) caused elevation of IL-6 secretion. The data indicate that BT-induced alterations of IL-6 secretion from immune cells may be a significant consequence of BT exposures that may potentially affect immune competence.
Assuntos
Granulócitos/efeitos dos fármacos , Interleucina-6/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Compostos Orgânicos de Estanho/toxicidade , Compostos de Trialquitina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Granulócitos/imunologia , Granulócitos/metabolismo , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismoRESUMO
Dibutyltin (DBT) is the degradation products of TBT, which is generally considered higher toxicity than TBT in the immune system. In order to learn more about the mechanisms of immune-toxic of DBT, we exposed zebrafish (Danio rerio) to 0, 1, 10 and 100 ng/L DBT for 8 weeks. At the end of the experiment, we determined the immune parameters and immune-related genes. The results showed that with an increase in TBT dose, lysozyme activities and IgM, C3, C4 content in intestine, skin and spleen were all significantly inhibited by the DBT exposure. Fish exposed to 10 ng/L and 100 ng/L showed significantly lower lysozyme activities and IgM, C3, C4 content than those of the control group. Zebrafish exposed to 10 ng/L and 100 ng/L DBT, the mRNA transcript levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), interferon γ2 (INFγ2), nuclear factor-κB p65 (NF-kB p65), inhibitor protein-κBα (IκBα), IκB kinases ß (IKKß), Janus family of protein tyrosine kinases (JAKs) and the signal transducers and activators of transcription proteins (STATs) all increased with the DBT levels in the intestine and spleen. Those parameters showed significantly higher values in 10 ng/L and 100 ng/L than those of fish in the control group. However, no significant difference was found in IκB kinases α (IKKα) and IκB kinase γ (IKKγ) mRNA levels in the intestine and spleen. These data imply that DBT might be via suppression on IKKß/IkBa/NF-kBp65 and JAK/STAT signaling pathways to regulate the immunity of zebrafish.
Assuntos
Compostos Orgânicos de Estanho/toxicidade , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/metabolismo , Animais , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Peixe-Zebra/imunologiaRESUMO
Dibutyltin dilaurate (DBTD) has multiple applications in daily life. However, DBTD is easily deposited in the liver and affects liver functions. This study was designed to explore the effects of DBTD on triglyceride metabolism in human normal hepatocyte HL7702 cells. Our results showed that the intracellular fat contents were dose-dependently decreased by DBTD. The expression of lipolysis genes and proteins were elevated while the lipogenesis genes and proteins were diminished by DBTD. The phosphorylation levels of ribosomal S6 kinase 1 were reduced by both rapamycin and DBTD, indicating that the mTOR pathway was suppressed possibly. The decreased sterol regulatory element-binding protein 1C (SREBP1C) transcription levels, as well as the increased peroxisome proliferator-activated receptor alpha (PPARα) transcription levels, caused by rapamycin and DBTD corresponded to the inactive mTOR pathway. In conclusion, it was possible that DBTD reduced the intracellular triglyceride through depressing the mTOR pathway and affecting its downstream transcription factors.
Assuntos
Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Compostos Orgânicos de Estanho/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Triglicerídeos/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , PPAR alfa/genética , Fosforilação/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genéticaRESUMO
Dibutyltin (DBT) is used to stabilize polyvinyl chloride plastics (including pipes that distribute drinking water) and as a de-worming agent in poultry. DBT is found in human blood, and DBT exposures alter the secretion of tumor necrosis factor alpha and interferon gamma from lymphocytes. Interleukin (IL)-1ß is a proinflammatory cytokine that regulates cellular growth, tissue restoration and immune response regulation. IL-1ß plays a role in increasing invasiveness of certain tumors. This study reveals that exposures to DBT (24 h, 48 h and 6 days) modify the secretion of IL-1ß from increasingly reconstituted preparations of human immune cells (highly enriched human natural killer cells, monocyte-depleted [MD] peripheral blood mononuclear cells [PBMCs], PBMCs, granulocytes and a preparation combining both PBMCs and granulocytes). DBT altered IL-1ß secretion from all cell preparations. Higher concentrations of DBT (5 and 2.5 µm) decreased the secretion of IL-1ß, while lower concentrations of DBT (0.1 and 0.05 µm) increased the secretion of IL-1ß. Selected signaling pathways were examined in MD-PBMCs to determine if they play a role in DBT-induced elevations of IL-1ß secretion. Pathways examined were IL-1ß converting enzyme (caspase 1), mitogen-activated protein kinases and nuclear factor kappa B. Caspase 1 and mitogen-activated protein kinase pathways appear to be utilized by DBT in increasing IL-1ß secretion. These results indicate that DBT alters IL-1ß secretion from human immune cells in an ex. vivo system utilizing several IL-1ß regulating signaling pathways. Thus, DBT may have the potential to alter IL-1ß secretion in an in vivo system. Copyright © 2016 John Wiley & Sons, Ltd.
Assuntos
Poluentes Ambientais/toxicidade , Granulócitos/efeitos dos fármacos , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Compostos Orgânicos de Estanho/toxicidade , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Granulócitos/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologiaRESUMO
Tributyltin (TBT) and dibutyltin (DBT) are widespread environmental contaminants found in food, beverages, and human blood samples. Both of these butyltins (BTs) interfere with the ability of human natural killer (NK) cells to lyse target cells and alter secretion of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) from human immune cells in vitro. The capacity of BTs to interfere with secretion of other pro-inflammatory cytokines has not been examined. Interferon gamma (IFNγ) is a modulator of adaptive and innate immune responses, playing an important role in overall immune competence. This study shows that both TBT and DBT alter secretion of IFNγ from human immune cells. Peripheral blood cell preparations that were increasingly reconstituted were used to determine if exposures to either TBT or DBT affected IFNγ secretion and how the makeup of the cell preparation influenced that effect. IFNγ secretion was examined after 24 h, 48 h, and 6 day exposures to TBT (200 - 2.5 nM) and DBT (5 - 0.05 µM) in highly enriched human NK cells, a monocyte-depleted preparation of PBMCs, and monocyte-containing PBMCs. Both BTs altered IFNγ secretion from immune cells at most of the conditions tested (either increasing or decreasing secretion). However, there was significant variability among donors as to the concentrations and time points that showed changes as well as the baseline secretion of IFNγ. The majority of donors showed an increase in IFNγ secretion in response to at least one concentration of TBT or DBT at a minimum of one length of exposure.
Assuntos
Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Compostos Orgânicos de Estanho/toxicidade , Compostos de Trialquitina/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacosRESUMO
The trans-sialidase of Trypanosoma cruzi (TcTS) is a surface enzyme that modifies the parasite glycocalyx covering it with sialic acid. This process is essential to adhesion and invasion mechanisms in life cycle of the protozoan in the human host, making TcTS a very attractive molecular target for drug design. Using the TcTS substrate 3'-sialyllactose as prototype, D-galactose-derived potential inhibitors of TcTS were designed using strategies of molecular modification. Ten new aryl galactosides modified at carbon-3 were synthesized employing classical carbohydrate chemistry and dibutyltin oxide method for regioselective 3-O-alkylations and evaluated against TcTS by spectrofluorimetry. The 4-methoxycarbonyl-2-nitrophenyl 3-O-carboxymethyl-ß-D-galactopyranoside was the most active compound inhibiting 21% of TcTS enzymatic activity at 1 mM.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Galactose/farmacologia , Glicoproteínas/antagonistas & inibidores , Neuraminidase/antagonistas & inibidores , Trypanosoma cruzi/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Galactose/síntese química , Galactose/química , Glicoproteínas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Relação Estrutura-AtividadeRESUMO
Organotin compounds, especially tributyltin chloride (TBT), have been widely used in antifouling paints for marine vessels, but exhibit various toxicities in mammals. The endoplasmic reticulum (ER) is a multifunctional organelle that controls post-translational modification and intracellular Ca(2+) signaling. When the capacity of the quality control system of ER is exceeded under stress including ER Ca(2+) homeostasis disruption, ER functions are impaired and unfolded proteins are accumulated in ER lumen, which is called ER stress. Here, we examined whether TBT causes ER stress in human neuroblastoma SH-SY5Y cells. We found that 700nM TBT induced ER stress markers such as CHOP, GRP78, spliced XBP1 mRNA and phosphorylated eIF2α. TBT also decreased the cell viability both concentration- and time-dependently. Dibutyltin and monobutyltin did not induce ER stress markers. We hypothesized that TBT induces ER stress via Ca(2+) depletion, and to test this idea, we examined the effect of TBT on intracellular Ca(2+) concentration using fura-2 AM, a Ca(2+) fluorescent probe. TBT increased intracellular Ca(2+) concentration in a TBT-concentration-dependent manner, and Ca(2+) increase in 700nM TBT was mainly blocked by 50µM dantrolene, a ryanodine receptor antagonist (about 70% inhibition). Dantrolene also partially but significantly inhibited TBT-induced GRP78 expression and cell death. These results suggest that TBT increases intracellular Ca(2+) concentration by releasing Ca(2+) from ER, thereby causing ER stress.
Assuntos
Cálcio/fisiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Compostos de Trialquitina/toxicidade , Western Blotting , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Dantroleno/farmacologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Análise em Microsséries , Relaxantes Musculares Centrais/farmacologia , Reação em Cadeia da Polimerase , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição/metabolismo , Proteína 1 de Ligação a X-BoxRESUMO
In this study, pH-responsive LC@O-CMCS/PU nanoparticles were prepared by encapsulating λ-cyhalothrin (LC) with O-carboxymethyl chitosan (O-CMCS) to form LC/O-CMCS and then covering it with polyurethane (PU). Characterization and performance test results demonstrate that LC@O-CMCS/PU had good alkaline release properties and pesticide loading performance. Compared to commercial formulations containing large amounts of emulsifiers (e.g., emulsifiable concentrate, EC), LC@O-CMCS/PU showed better leaf-surface adhesion. On the dried pesticide-applied surfaces, the acute contact toxicity of LC@O-CMCS/PU to Harmonia axyridis (H. axyridis) was nearly 20 times lower than that of LC EC. Due to the slow-releasing property of LC@O-CMCS/PU, only 16.38 % of LC was released at 48 h in dew and effectively reduced the toxicity of dew. On the pesticide-applied leaves with dew, exposure to the LC (EC) caused 86.66 % mortality of H. axyridis larvae significantly higher than the LC@O-CMCS/PU, which was only 16.66 % lethality. Additionally, quantitative analysis demonstrated 11.33 mg/kg of λ-cyhalothrin in the dew on LC@O-CMCS/PU lower than LC (EC) with 4.54 mg/kg. In summary, LC@O-CMCS/PU effectively improves the safety of λ-cyhalothrin to H. axyridis and has great potential to be used in pest control combining natural enemies and chemical pesticides.
Assuntos
Besouros , Praguicidas , Piretrinas , Animais , Piretrinas/toxicidade , Praguicidas/toxicidade , Controle de Pragas , Concentração de Íons de HidrogênioRESUMO
Dibutyltin dichloride (DBTCl) is a widespread environmental pollutant that is frequently employed as a light and heat sustainer for polyvinyl chloride (PVC) plastics and is a teratogen in vivo. Nevertheless, its destructiveness in mammalian oocytes remains unclear. This study highlighted the consequences of DBTCl vulnerability on mouse oocyte. Our results revealed that exposure to 5.0 mg/kg/day of DBTCl for ten days reduced the number of mature follicles and oocytes in the ovaries and inhibited the meiotic maturation of oocytes. Single-cell transcriptomic analysis indicated that DBTCl exposure interfered with the expression of more than 400 genes in oocytes, including those involved in multiple biological pathways. Specifically, DBTCl exposure impaired spindle assembly and chromosome alignment. In addition, DBTCl exposure caused mitochondrial dysfunction, which led to the accumulation of reactive oxygen species (ROS) and induced apoptosis. In summary, our study illustrates that mitochondrial dysfunction and redox perturbation are the major causes of the reduced quality of oocytes exposed to DBTCl.
Assuntos
Oócitos , Compostos Orgânicos de Estanho , Animais , Camundongos , Mitocôndrias , Oócitos/metabolismo , Compostos Orgânicos de Estanho/metabolismo , Compostos Orgânicos de Estanho/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Fuso Acromático/metabolismoRESUMO
Dibutyltin (DBT) is an organotine widely applied in stabilizing plastics and de-worm poultry agents. But the effects of DBT on immature Leydig cells remain elusive. Thus, the present study aims to investigate whether in vitro exposure to DBT affects immature Leydig cell function of androgen production and delineate the underlying mechanisms. 35 days old rat immature Leydig cells were isolated and exposed to DBT at different concentrations (0, 0.1, 0.5, and 1 µM). It was found that 0.5 and 1 µM DBT lowered androgen production from immature Leydig cells under basal conditions. DBT at 1 µM lowered androgen production from immature Leydig cells under the stimulations from luteinizing hormone or 8-Br-cAMP. DBT at 1 µM lowered 22R-hydroxycholesterol and pregnenolone-mediated androgen production from immature Leydig cells. DBT at 0.1, 0.5, and 1 µM down-regulated the mRNA expression levels of Lhcgr, Star, Cyp11a1, Hsd3b1, and Nr5a1. Further investigation found that DBT at 1 µM directly inhibited CYP11A1 and 3ß-HSD1 enzyme activities. In conclusion, this study told us that in vitro exposure to DBT inhibited androgen biosynthesis in immature Leydig cells by selectively interfering with the expressions and enzyme activities of CYP11A1 and 3ß-HSD1.
Assuntos
Antagonistas de Androgênios/toxicidade , Androgênios/biossíntese , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/metabolismo , Compostos Orgânicos de Estanho/toxicidade , Fatores Etários , Animais , Células Cultivadas , Enzima de Clivagem da Cadeia Lateral do Colesterol/antagonistas & inibidores , Enzima de Clivagem da Cadeia Lateral do Colesterol/biossíntese , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
The molecular structures of five diorganotin(IV) carboxylates, (I)-(V), can be categorized into two main well-known structural types for such Sn complexes. One is the mononuclear dialkytin(IV) carboxylates with an [R2Sn(LH)2]-type skew-trapezoidal bipyramid, where the alkyl ligands are in pseudo-axial positions and the O atoms from two asymmetrically coordinated bidentate carboxylate ligands are in the equatorial plane. This structure type is adopted by dibutylbis{(E)-2-hydroxy-5-[(3-methylphenyl)diazenyl]benzoato}tin(IV) cyclohexane hemisolvate, [Sn(C4H9)2(C14H11N2O3)2]·0.5C6H12, (I), dibenzylbis{(E)-5-[(4-bromophenyl)diazenyl]-2-hydroxybenzoato}tin(IV), [Sn(C7H7)2(C13H8BrN2O3)2], (II), and aquadibenzylbis(4-{(E)-[(Z)-4-hydroxypent-3-en-2-ylidene]amino}benzoato)tin(IV) benzene disolvate, [Sn(C7H7)2(C12H12NO3)2(H2O)]·2C6H6, (III), although the latter has an additional water ligand to give a distorted pentagonal bipyramidal coordination geometry in which the carboxylate groups are more symmetrically coordinated to the Sn atom than in (I) and (II). The other structure motif is that of the tetranuclear bis(dicarboxylatotetraorganodistannoxanes), {[R2Sn(LH)]2O}2, which contain an Sn4O2 core decorated with four bridging carboxylate ligands, plus two alkyl ligands at each SnIV centre. The complexes octabutyltetrakis{µ-(E)-4-[(4-hydroxy-3,5-dimethylphenyl)diazenyl]benzoato}di-µ3-oxido-tetratin(IV) ethanol disolvate, [Sn4(C4H9)8(C15H13N2O3)4O2]·2C2H6O, (IV), and octabutyltetrakis{(E)-3-[(2-hydroxybenzylidene)amino]propanoato}di-µ3-oxido-tetratin(IV), [Sn4(C4H9)8(C10H10NO3)4O2], (V), display this motif. The structures obtained correlate with the 1:1 and 1:2 stoichiometric ratios of the dialkyltin(IV) and carboxylic acid starting materials in the syntheses. The supramolecular structures arising from consideration of secondary Sn...O interactions and/or classic hydrogen bonds include discrete molecules for (V), centrosymmetric dimers for (I), extended chains for (II) and (III), and sheets for (IV).