RESUMO
Zearalenone (ZEA) is a mycotoxin that is highly contaminated in feed and can cause severe toxic effects on the kidneys and other organs of animals. Quercetin (QUE) is a plant-derived flavonoid with a variety of detoxification properties, but the mechanism by which QUE detoxifies the toxic effects induced by ZEA has not yet been fully elucidated. We treated porcine kidney cells (PK15) with 80 µM ZEA and/or 30 µM QUE. The results showed that ROS and MDA levels were increased, antioxidant system levels were down-regulated, anti-apoptotic factor expression levels were decreased, and apoptotic and necroptosis-related factors were up-regulated after ZAE exposure. In addition, the results of Ca2+ staining, mitochondrial membrane potential, and mitochondrial dynamics-related indicators showed that ZEA induced Ca2+ overload in PK15 cells and increased mitochondrial Ca2+ uptake (MCU expression increased). The accumulated ROS and free Ca2+ further aggravate mitochondrial damage and eventually lead to mitochondrial pathway apoptosis and necroptosis. Nevertheless, QUE targets CaSR to inhibit the CaSR/CaMKII pathway and regulate calcium homeostasis, thereby alleviating apoptosis and necroptosis mediated by mitochondrial dynamic disorder and dysfunction. The present study demonstrated the mechanism by which ZEA induces apoptosis and necroptosis in PK15 and the protective role of QUE in this process.
Assuntos
Quercetina , Zearalenona , Animais , Suínos , Quercetina/farmacologia , Zearalenona/toxicidade , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Necroptose , Apoptose , Células Epiteliais , Transdução de SinaisRESUMO
Mercuric chloride (HgCl2) is an environmental pollutant with serious nephrotoxic effects, but the underlying mechanism of HgCl2 nephrotoxicity is not well understood. Ferroptosis and necroptosis are two programmed cell death (PCD) modalities that have been reported singly in heavy metal-induced kidney injury. However, the interaction between ferroptosis and necroptosis in HgCl2-induced kidney injury is unclear. Here, we established a model of HgCl2-exposed chicken embryo kidney (CEK) cells to dissect the progresses and mechanisms of these two PCDs. We found that ferroptosis was initially activated in CEK cells after HgCl2 exposure for 12 h, and necroptosis was activated subsequently at 24 h. Importantly, further study indicated that the shift from ferroptosis to necroptosis was driven by ROS, which was produced by iron-dependent Fenton reaction, and the iron chelation by DFO prevented the sequential activation of both ferroptosis and necroptosis. To investigate the source of intracellular iron, the regulation of iron homeostasis was first explored and demonstrated a tendency for intracellular iron overload in CEK cells. Interestingly, the cellular ferritin, a free iron depository, decreased in a time-dependent manner. Further studies revealed that the degradation of ferritin was attributed to the activation of selective cargo receptor nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy, and the inhibition of ferritinophagy by CQ prevented the HgCl2-induced cell death. In conclusion, our study demonstrated that HgCl2 released excess free iron via ferritinophagy, led to a sustained accumulation of ROS and ultimately activated ferroptosis and necroptosis sequentially. These findings provide a new understanding for the nephrotoxic mechanism of HgCl2.
Assuntos
Ferroptose , Sobrecarga de Ferro , Animais , Autofagia , Embrião de Galinha , Galinhas/metabolismo , Ferritinas/metabolismo , Ferro/metabolismo , Rim/metabolismo , Cloreto de Mercúrio/metabolismo , Cloreto de Mercúrio/toxicidade , Necroptose , Espécies Reativas de Oxigênio/metabolismoRESUMO
Mercuric chloride (HgCl2) is a well-known toxic heavy metal contaminant, which causes male reproductive function defects. Selenium (Se) has been recognized as an effective antioxidant against heavy metals-induced male reproductive toxicity. The aim of present study was to explore the potentially protective mechanism of Se on HgCl2-induced testis injury in chicken. Firstly, the results showed that Se mitigated HgCl2-induced testicular injury through increasing the blood-testis barrier (BTB) cell-junction proteins expression of occludin, zonula occludens-1 (ZO-1), connexin 43 (Cx43), and N-cadherin. Secondly, Se alleviated HgCl2-induced oxidative stress through decreasing the malondialdehyde (MDA) content and increasing the superoxidase dismutase (SOD), glutathione peroxidase (GSH-Px) activities as well as the total antioxidant capacity (T-AOC) level. Thirdly, Se inhibited the activation of p38 MAPK signaling through decreasing the proteins expression of phosphorylated-p38 (p-p38) and phosphorylated-ATF2 (p-ATF2), and alleviated inflammation response through decreasing the proteins expression of inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB), tissue necrosis factor-alpha (TNF-α), and cyclooxygenase 2 (COX2). Collectively, these results demonstrated that Se effectively alleviated HgCl2-induced testes injury via improving antioxidant capacity to reduce inflammation mediated by p38 MAPK/ATF2/iNOS signaling pathway in chicken. Our data shed a new light on potential mechanisms of Se antagonized HgCl2-induced male reproductive toxicity.
Assuntos
Cloreto de Mercúrio , Selênio , Animais , Antioxidantes/farmacologia , Galinhas/fisiologia , Inflamação/metabolismo , Inflamação/veterinária , Masculino , Cloreto de Mercúrio/metabolismo , Cloreto de Mercúrio/toxicidade , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Selênio/farmacologia , Transdução de Sinais , Testículo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Mercury (Hg) is a persistent environmental and industrial pollutant that accumulated in the body and induces oxidative stress and inflammation damage. Selenium (Se) has been reported to antagonize immune organs damage caused by heavy metals. Here, we aimed to investigate the prevent effect of Se on mercuric chloride (HgCl2 )-induced thymus and bursa of Fabricius (BF) damage in chickens. The results showed that HgCl2 caused immunosuppression by reducing the relative weight, cortical area of the thymus and BF, and the number of peripheral blood lymphocytes. Meanwhile, HgCl2 induced oxidative stress and imbalance in cytokines expression in the thymus and BF. Further, we found that thioredoxin-interacting protein (TXNIP) and the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome mediated HgCl2 -induced oxidative stress and inflammation. Mechanically, the targeting and inhibitory effect of microRNA (miR)-135b/183 on forkhead box O1 (FOXO1) were an upstream event for HgCl2 -activated TXNIP/NLRP3 inflammasome pathway. Most importantly, Se effectively attenuated the aforementioned damage in the thymus and BF caused by HgCl2 and inhibited the TXNIP/NLRP3 inflammasome pathway by reversing the expression of FOXO1 through inhibiting miR-135b/183. In conclusion, the miR-135b/183-FOXO1/TXNIP/NLRP3 inflammasome axis might be a novel mechanism for Se to antagonize HgCl2 -induced oxidative stress and inflammation in the central immune organs of chickens.
Assuntos
MicroRNAs , Selênio , Animais , Galinhas/metabolismo , Inflamassomos/metabolismo , Cloreto de Mercúrio/toxicidade , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Selênio/farmacologiaRESUMO
Mercuric chloride (HgCl2), a heavy metal compound, causes neurotoxicity of animals and humans. Selenium (Se) antagonizes heavy metal-induced organ damage with the properties of anti-oxidation and anti-inflammation. Nevertheless, the molecular mechanism underlying the protective effects of sodium selenite (Na2SeO3) against HgCl2-induced neurotoxicity remains obscure. Therefore, the present study aimed to explore the protective mechanism of Na2SeO3 on HgCl2-induced brain damage in chickens. Morphological observations showed that Na2SeO3 alleviated HgCl2-induced brain tissues damage. The results also showed that Na2SeO3 decreased the protein expression of S100 calcium binding protein B (S100B), and increased the levels of nerve growth factors (NGF), doublecortin domain containing 2 (DCDC2), as well as neurotransmitter to reverse HgCl2-induced brain dysfunction. Further, Na2SeO3 attenuated HgCl2-induced oxidative stress by decreasing the level of malondialdehyde (MDA) and increasing the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). Mechanistically, Na2SeO3 activated the brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor type B (TrKB)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and suppressed the nuclear factor kappa B (NF-κB) signaling pathway to inhibit apoptosis and inflammation caused by HgCl2 exposure. In summary, Na2SeO3 ameliorated HgCl2-induced brain injury via inhibiting apoptosis and inflammation through activating BDNF/TrKB/PI3K/AKT and suppressing NF-κB pathways.
Assuntos
Encefalopatias/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Intoxicação do Sistema Nervoso por Mercúrio/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Selenito de Sódio/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Encefalopatias/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Galinhas , Inflamação/tratamento farmacológico , Masculino , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor trkB/metabolismoRESUMO
Mercury (Hg) is a heavy metal widely distributed in ecological environment, poisoning the immune system of humans and animals. Selenium (Se) is an essential microelement and selenoproteins involved in the procedure of Se antagonizing organ toxicity induced by heavy metals. The aim of this research was to investigate the changes of gene expression profile of selenoproteins induced by mercuric chloride (HgCl2) in chicken spleen lymphocytes. We established cytotoxicity model of chicken spleen lymphocytes by HgCl2 exposure, the messenger RNA (mRNA) expression levels of 25 selenoproteins in spleen lymphocytes were analyzed by real-time quantitative PCR (qPCR), and the gene expression pattern of selenoproteins was revealed by principal component analysis (PCA). The results showed that the mRNA expression levels of 13 selenoproteins (GPX3, GPX4, TXNRD2, TXNRD3, DIO2, SELENOS, SELENON, SELENOT, SELENOO, SELENOP, SELENOP2, MSRB1, and SEPHS2) were decreased in HgCl2 treatment group, and there was strong positive correlation between these selenoproteins and component 1 as well as component 2 of the PCA. At the same time, the protein expression levels of GPX4, TXNRD1, TXNRD2, SELENOM, SELENOS, and SELENON were detected by Western blotting, which were consistent with the changes of gene expression. The results showed that the expression levels of selenoproteins were aberrant in response to HgCl2 toxicity. The information presented in this study provided clues for further research on the interaction between HgCl2 and selenoproteins, and the possible mechanism of immune organ toxicity induced by HgCl2.
Assuntos
Cloreto de Mercúrio , Selênio , Animais , Galinhas/metabolismo , Linfócitos/metabolismo , Cloreto de Mercúrio/toxicidade , RNA Mensageiro/genética , Selênio/metabolismo , Selênio/farmacologia , Selenoproteínas/genética , Selenoproteínas/metabolismo , Baço/metabolismo , TranscriptomaRESUMO
Mercury (Hg) is a persistent heavy metal contaminant with definite hepatotoxicity. Selenium (Se) has been shown to alleviate liver damage induced by heavy metals. Therefore, the present study aimed to explore the mechanism of the antagonistic effect of Se on mercury chloride (HgCl2)-induced hepatotoxicity in chickens. Firstly, we confirmed that Se alleviated HgCl2-induced liver injury through histopathological observation and liver function analyzation. The results also showed that Se prevented HgCl2-induced liver lipid accumulation and dyslipidemia by regulating the gene expression related to lipid as well as glucose metabolism. Moreover, Se blocked the nuclear factor kappa B (NF-κB)/NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathway, which was the key to alleviate the inflammation caused by HgCl2. Mechanically, Se inhibited immoderate mitochondrial division, fusion, and biogenesis caused by HgCl2, and also improved mitochondrial respiration, which were essential for preventing energy metabolism disorder and inflammation. In conclusion, our results suggested that Se inhibited energy metabolism disorder and inflammation by regulating mitochondrial dynamics, thereby alleviating HgCl2-induced liver injury in chickens. These results are expected to provide potential intervention and therapeutic targets for diseases caused by inorganic mercury poisoning.
RESUMO
Kidney is a primary target organ for mercuric chloride (HgCl2) toxicity. Selenium (Se) can exert antagonistic effect on heavy metals-induced organ toxicity by regulating the expression of selenoproteins. The objective of this study was to investigate the effect of HgCl2 on the gene expression of selenoproteins in chicken kidney. Sixty male Hyline brown chickens were randomly and evenly divided into two groups. After acclimatization for one week, chickens were provided with the standard diet as well as non-treated water (CON group), and standard diet as well as HgCl2-treated water (250â¯ppm, HgCl2 group). After seven weeks, kidney tissues were collected to examine the mRNA expression levels of 25 selenoproteins genes and protein expression levels of 4 selenoproteins. Moreover, correlation analysis and principal component analysis (PCA) were used to analyze the expression patterns of 25 selenoproteins. The results showed that HgCl2 exposure significantly decreased the mRNA expression of Glutathione peroxidase 1 (GPX1), GPX4, Thioredoxin reductase 2 (TXNRD2), Iodothyronine deiodinase 1 (DIO1), Methionine-Rsulfoxide reductase 1 (SELR), 15-kDa selenoprotein (SEP15), selenoprotein I (SELI), SELK, SELM, SELN, SELP, SELS, SELT, SELW, and SEPHS2. Meanwhile, HgCl2 exposure significantly increased the mRNA expression of GPX3, TXNRD1, and SELU. Western blot analysis showed that the expression levels of GPX3, TXNRD1, SELK, and SELN were concordant with these mRNA expression levels. Analysis results of selenoproteins expression patterns showed that HgCl2-induced the main disorder expression of selenoproteins with antioxidant activity and endoplasmic reticulum resident selenoproteins. In conclusion, selenoproteins respond to HgCl2 exposure in a characteristic manner in chicken kidney.
Assuntos
Galinhas , Rim/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Selenoproteínas/metabolismo , Animais , Western Blotting/veterinária , Galinhas/genética , Galinhas/metabolismo , Rim/metabolismo , Masculino , Análise em Microsséries/veterinária , Análise de Componente Principal , RNA Mensageiro/genética , Distribuição Aleatória , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Selênio/farmacologia , Selenoproteínas/genética , TranscriptomaRESUMO
In this work, air-stable palladium(II) catalysts bearing bidentate phosphine ligands were designed and prepared, which could initiate fast and living polymerizations of various diazoacetate monomers under mild conditions. The polymerization afforded the desired polymers in high yields with controlled molecular weights ( Mns) and narrow molecular weight distributions ( Mw/ Mns). The Mns of the isolated polymers were linearly correlated to the initial feed ratios of monomer to catalyst, confirming the living/controlled manner of the polymerizations. The Mn also increased linearly with the monomer conversion, and all of the isolated polymers showed narrow Mw/ Mns. The polymerization was relatively fast and could be accomplished within several minutes. Such fast living polymerization method can be applied to a wide range of diazoacetate monomers in various organic solvents at room temperature in air. Taking advantage of the living nature, we facilely prepared a series of block copolymers through chain extension reactions. The amphiphilic block copolymers synthesized by this method exhibited interesting self-assembly properties. Moreover, polymerization of achiral bulky diazoacetate by Pd(II) catalysts bearing a chiral bidentate phosphine ligand leads to the formation of polymers with high optical activity due to the formation of the predominantly one-handed helix of the main chain. The helix sense of the polymers was determined by the chirality of the Pd(II) catalysts.
RESUMO
In this paper, the facile synthesis of hybrid Fe3 O4 magnetic nanoparticles carrying helical poly(phenyl isocyanide) (PPI) arms via both "grafting from" and "grafting onto" strategies is reported. First, alkyne-Pd(II) catalysts are anchored onto the surface of the Fe3 O4 magnetic nanoparticle, which promote the polymerization of enantiopure phenyl isocyanide, affording the expected hybrid magnetic nanoparticle with Fe3 O4 in core and helical PPI as arms. The nanoparticle also exhibits highly optical activity due to the excess of one-handed helicity of the PPI arms. Moreover, the hybrid magnetic nanoparticle can be alternatively synthesized via "grafting onto" strategy. A triethoxysilanyl-terminated single handed helical PPI bearing l-alanine ester pendants is prepared and grafted onto the surface of Fe3 O4 nanoparticle. The generated hybrid magnetic nanoparticles show both magnetic character and optical activity. Taking advantage of these properties, they can be used in enantioselective crystallization of racemic threonine. The enantiomeric excess (ee) of the induced crystals is up to 93%. Moreover, the nanoparticles can be facilely recovered and recycle used for at least four times in enantioselective crystallization without significantly loss of its enantioselectivity.
Assuntos
Isocianatos/química , Magnetismo , Nanopartículas de Magnetita/química , Polímeros/química , Cristalização , Microscopia de Força Atômica , Modelos Químicos , Estrutura Molecular , Polimerização , Espectrofotometria/métodos , Estereoisomerismo , TemperaturaRESUMO
A left-handed helical poly(phenyl isocyanide) bearing a norbornene unit and a Pd(II) complex on each terminus was prepared. The norbornene terminus was core cross-linked with a bisnorbornene linker via ring-opening metathesis polymerization (ROMP), yielding a star polymer carrying left-handed helical arms decorated with Pd(II) units at the exterior. The optical activities of the helical arms were maintained after the cross-linking reaction. The Pd(II) units on the surface of the star polymer were chain extended with a new phenyl isocyanide bearing three hydrophilic triethylene glycol monomethyl chains, which afforded an amphiphilic star block copolymer carrying helical arms. Such a star block copolymer showed excellent thermoresponsiveness with the lower critical solution temperature (LCST) around 55 °C. This optically active and thermoresponsive star polymer can enantioselectively capture the S-enantiomer of racemic methyl benzyl alcohol solution at a temperature lower than the LCST and precipitated when the temperature was higher than the LCST, leaving the R-enantiomer in the solution. The enantiomeric excess (ee) of the isolated enantiomer is up to 75%.