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1.
Biol Trace Elem Res ; 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792773

RESUMO

This study aimed to investigate the role and molecular mechanism of L-type calcium channel (LTCC) on fluoride exposure-induced kidney injury. Subchronic and chronic fluoride exposures were included in the experiment. Each part contained 140 ICR male mice. They were randomly divided into 7 groups: control group, high-fluoride group (NaF 30 mg/L), low-fluoride group (NaF 5 mg/L), high/low-fluoride + agonist (FPL64176) group, high/low-fluoride + inhibitor (nifedipine) group. One week before the end of fluoride exposure, each mouse in the fluoride exposure group was injected intraperitoneally with LTCC agonist (FPL64176) or inhibitor (nifedipine) (5 mg/kg day). The apoptosis of kidney cell was observed by TUNEL, and the protein expression levels of Cav1.2 and CaM, CaMKII, Bcl-2, and Bax were detected by Western blot. Compared with the control group, the protein expression levels of Cav1.2, CaM, and Bax significantly increased, and those of CaMKII and Bcl-2 significantly decreased, the ratio of Bax/Bcl-2 also significantly increased, and the number of apoptotic kidney cells significantly increased in the high/low-fluoride group and in the high/low-fluoride + agonist group. The above indicators and fluoride exposure concentrations showed in time- and dose-dependent changes. Compared with the high/low-fluoride + agonist group, the protein expression level of the molecular in the kidney cells above mentioned was significantly opposite and the number of apoptotic kidney cells significantly decreased in the high/low-fluoride + inhibitor group. In conclusion, LTCC mediates the kidney injury induced by fluoride exposure in mice. Fluoride exposure induced abnormal expression of the Cav1.2 protein, Ca2+ signal transduction pathway, and apoptosis-regulated proteins, which is one of the molecular mechanisms. Nifedipine may be a new and effective anti-fluoride drug.

2.
Chemosphere ; 220: 169-175, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30583209

RESUMO

The study aimed to investigate the effects of drinking water fluorosis on L-type calcium channels (LTCCs) in mouse hippocampal neurons. A total of 60 newly weaned ICR male mice were randomly divided into control, low fluoride and high fluoride groups. After 3 and 6 months of exposure to fluoride, the patch clamp technique was used to detect the peak and relative values (I/Imax), steady-state activation curve ratio (G/Gmax), decay time constant, and tail current time constant of LTCCs currents in hippocampal CA1 region of mouse brain slices. Fluoride greatly reduced the serum and urinary calcium concentrations in mice, and the chronic fluorosis has a greater impact than subchronic fluorosis. The peak value of LTCCs current in pyramidal neurons of hippocampal CA1 area was significant and increased with the prolonged exposure time. The relative values of current and steady-state coefficients were changed greatly. The decay and tail current time increased significantly. High fluorine concentration indicates great peak value and open time of LTCCs opening. LTCCs are sensitive to fluoride exposure. The activation voltage of calcium channels induced by fluoride exposure is decreased, the opening time of calcium channels is prolonged, and the calcium influx per unit time increased, thereby overloading calcium concentration in neurons and this may be an explanation for intracellular calcium overload caused by fluoride. The imbalance of calcium metabolism caused by fluorosis may be a pathogenesis of brain injury induced by fluoride. Furthermore, the risk of brain damage from low-fluorine exposure cannot be ignored.


Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Água Potável/química , Fluorose Dentária/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Fluoretos/farmacologia , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurônios/química , Técnicas de Patch-Clamp
3.
Biol Trace Elem Res ; 182(2): 295-302, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28730575

RESUMO

This study investigated neurotoxicity of chronic fluorosis in the rat hippocampus. Newly weaning, male, Sprague-Dawley (SD) rats were administered 15, 30, and 60 mg/L sodium fluoride (NaF) solution (fluorine ion concentration 8.25, 16.50, and 33.00 mg/L, respectively), and tap water, for 18 months. The neurotoxicological mechanism was examined with a focus on intracellular calcium overload. Results showed that as the fluoride concentration increased, calcium ion concentration [Ca2+], the expression of calcium/calmodulin-dependent protein kinase II α (CaMKIIα), and the expression of catus proto-oncogene protein c-fos (c-fos) all tend to increase. Compared to the control group, Ca2+, CaMKIIα, and c-fos significantly increased (P < 0.05) in the moderate-fluoride and the high-fluoride groups. These results indicate that Ca2+/CaMKIIα/c-fos channel signal may be the molecular mechanism of central nervous system damage caused by chronic fluoride intoxication. Moreover, elevated Ca2+ concentration in the hippocampus may be the initiating factor of neuronal apoptosis induced by fluoride.


Assuntos
Região CA3 Hipocampal/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Fluorose Dentária/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Região CA3 Hipocampal/efeitos dos fármacos , Cariostáticos/farmacologia , Cariostáticos/toxicidade , Doença Crônica , Relação Dose-Resposta a Droga , Fluorose Dentária/etiologia , Imuno-Histoquímica , Íons/metabolismo , Masculino , Ratos Sprague-Dawley , Fluoreto de Sódio/farmacologia , Fluoreto de Sódio/toxicidade , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo
4.
Chemosphere ; 195: 567-575, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29278848

RESUMO

Bisphenol A (BPA), a common environmental endocrine disruptor, modulates estrogenic, antiestrogenic, and antiandrogenic effects throughout the lifespan. Recent studies found more obvious adverse effect of BPA on some neurobehavior in males than that in females. In this study, BPA at 10-100 nM rapidly increased the densities of the dendrite spine and synapse in cultured hippocampal neurons of rats in vitro within 1 h. Co-treatment of BPA (100 nM) with dihydrotestosterone (DHT, 10 nM) or with 17ß-E2 (10 nM) completely eliminated the promotion of DHT or 17ß-E2 in the densities of the dendritic spine and synapse. Pretreatment of estrogen receptors (ERs) antagonist ICI182,780 but not of androgen receptors (ARs) antagonist flutamide (Flu) for 30min completely blocked BPA-enhanced densities of the dendritic spine and synapse. Pretreatment of flutamide for 30min before BPA and DHT completely rescued BPA-enhanced densities of the dendritic spine and synapse. Furthermore, pretreatment of ERK1/2 inhibitor U0126 or p38 inhibitor SB203580 entirely eliminated BPA-induced increases in the densities of the dendritic spine and synapse. Meanwhile, BPA (100 nM) enhanced long-term potentiation (LTP) induction of dentate gyrus in hippocampal slices of younger male rats, which was not blocked by co-incubation of flutamide but was inhibited by pretreatment of an P38 inhibitor SB203580. Co-application of BPA with DHT inhibited DHT-suppressed LTP. These results are the first demonstrating the antagonism of BPA to the rapid modification of DHT in synaptic plasticity. However, BPA alone rapidly promotes spinogenesis and synaptic activity through ER instead of AR, and both ERKs and p38 signaling pathways are involved in these processes.


Assuntos
Compostos Benzidrílicos/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Di-Hidrotestosterona/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fenóis/farmacologia , Animais , Disruptores Endócrinos/farmacologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Sinapses/efeitos dos fármacos
5.
Environ Toxicol Pharmacol ; 54: 74-79, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28697452

RESUMO

This study investigated the effects of fluoride exposure on the mRNA expression of Cav1.2 calcium signaling pathway and apoptosis regulatory molecules in PC12 cells. The viability of PC12 cell receiving high fluoride (5.0mM) and low fluoride (0.5mM) alone or fluoride combined with L-type calcium channel (LTCC) agonist/inhibitor (5umol/L FPL6417/2umol/L nifedipine) was detected using cell counting kit-8 at different time points (2, 4, 6, 8, 12, 10, and 24h). Changes in the cell configuration were observed after exposing the cells to fluoride for 24h. The expression levels of molecules related to the LTCC were examined, particularly, Cav1.2, c-fos, CAMK II, Bax, and Bcl-2. Fluoride poisoning induced severe cell injuries, such as decreased PC12 cell activity, enhanced cell apoptosis, high c-fos, CAMKII, and Bax mRNA expression levels. Bcl-2 expression level was also reduced. Meanwhile, high fluoride, high fluoride with FPL64176, and low fluoride with FPL64176 enhanced the Cav1.2 expression level. In contrast, low fluoride, high fluoride with nifedipine, and low fluoride with nifedipine reduced the Cav1.2 expression level. Thus, Cav1.2 may be an important molecular target for the fluorosis treatment, and the LTCC inhibitor nifedipine may be an effective drug for fluorosis.


Assuntos
Canais de Cálcio Tipo L/genética , Cálcio/metabolismo , Fluoretos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Agonistas dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Fluoretos/toxicidade , Fluorose Dentária/tratamento farmacológico , Nifedipino/farmacologia , Células PC12 , Pirróis/farmacologia , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
6.
Horm Behav ; 93: 151-158, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28576649

RESUMO

Bisphenol-A (BPA) is a common environmental endocrine disruptor. Our recent studies found that exposure to BPA in both adolescent and adulthood sex-specifically impaired spatial memory in male mice. In this study, 11-week-old gonadectomied (GDX) male mice daily received subcutaneous injections of testosterone propionate (TP, 0.5mg/kg), TP and BPA (0.4 and 4mg/kg), or vehicle for 45days. The results of Morris water maze task showed that exposure to BPA did not affect the spatial memory of GDX mice but impaired that of sham (4mg/kg/day) and TP-treated GDX mice (0.4mg/kg/day). In addition, BPA reduced the level of testosterone (T) in the serum and brain of sham and TP-treated GDX mice. Exposure to BPA decreased the synaptic density and had an adverse effect on the synaptic interface of the hippocampus in sham and TP-treated GDX mice. The results of western blot analysis further showed that BPA (4mg/kg) reduced the levels of synaptic proteins (synapsin I and PSD-95) and NMDA receptor subunit NR2B in sham and TP-treated GDX mice. BPA decreased the phosphorylation of ERK1/2 but increased the phosphorylation of p38 in sham and TP-treated GDX mice. These results suggest that impairment of spatial memory and adverse effects on synaptic remodeling of hippocampal neurons in males after long-term BPA exposure is related to the anti-androgen effect of BPA. These effects of BPA may be associated with downregulated synaptic proteins and NMDA receptor through inhibiting ERKs and promoting the p38 pathways.


Assuntos
Antagonistas de Androgênios/farmacologia , Compostos Benzidrílicos/farmacologia , Disruptores Endócrinos/farmacologia , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsinas/metabolismo , Testosterona/metabolismo
7.
Biol Trace Elem Res ; 176(2): 355-366, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27655243

RESUMO

The purpose of the investigation is to reveal the influence of dietary calcium on fluorosis-induced brain cell apoptosis in rat offspring, as well as the underlying molecular mechanism. Sprague-Dawley (SD) female rats were randomly divided into five groups: control group, fluoride group, low calcium, low calcium fluoride group, and high calcium fluoride group. SD male rats were used for breeding only. After 3 months, male and female rats were mated in a 1:1 ratio. Subsequently, 18-day-old gestation rats and 14- and 28-day-old rats were used as experimental subjects. We determined the blood/urine fluoride, the blood/urine calcium, the apoptosis in the hippocampus, and the expression levels of apoptosis-related genes, namely Bcl-2, caspase 12, and JNK. Blood or blood/urine fluoride levels and apoptotic cells were found significantly increased in fluorosis rat offspring as compared to controls. Furthermore, the Bcl-2 messenger RNA (mRNA) expression levels significantly decreased, and caspase 12 mRNA levels significantly increased in each age group as compared to controls. Compared with the fluoride group, the blood/urine fluoride content and apoptotic cells evidently decreased in the high calcium fluoride group, Bcl-2 mRNA expression significantly increased and caspase 12 mRNA expression significantly decreased in each age group. All results showed no gender difference. Based on these results, the molecular mechanisms of fluorosis-induced brain cell apoptosis in rat offspring may include the decrease in Bcl-2 mRNA expression level and increase in caspase 12 mRNA expression signaling pathways. High calcium intake could reverse these gene expression trends. By contrast, low calcium intake intensified the toxic effects of fluoride on brain cells.


Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Cálcio/administração & dosagem , Cálcio/farmacologia , Intoxicação por Flúor/patologia , Administração Oral , Animais , Encéfalo/embriologia , Caspase 12/genética , Caspase 12/metabolismo , Feminino , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
8.
Environ Toxicol Pharmacol ; 43: 134-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26991847

RESUMO

This study investigated the molecular mechanism of brain impairment induced by drinking fluoridated water and selenium intervention. Results showed that the learning and memory of rats in NaF group significantly decreased. Moreover, the number of apoptotic cells, the expression levels of Cytc mRNA and protein, and the expression levels of Caspase-9 and Caspase-3 mRNA significantly increased; by contrast, Caspase-9 and Caspase-3 protein levels significantly decreased. Compared with the NaF group, the mRNA levels of Cytc and Caspase-9, as well as the protein levels of Cytc in NaF+Se group, significantly decreased. Conversely, the protein levels of Caspase-3 and Caspase-9, as well as the mRNA levels of Caspase-3, significantly increased. Thus, the mitochondrial CytC-Caspase-9-Caspase-3 apoptosis pathway in the hippocampus was one of the mechanisms leading to fluorosis-induced brain damage. Furthermore, the Cytc signaling molecules were possibly the key target molecules in fluorosis-induced apoptosis, and selenium could alleviate fluorosis-induced brain injury.


Assuntos
Encéfalo/fisiologia , Fluoretos/toxicidade , Fluorose Dentária/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Substâncias Protetoras/farmacologia , Selênio/farmacologia , Poluentes Químicos da Água/toxicidade , Animais , Apoptose , Encéfalo/efeitos dos fármacos , Caspase 3/genética , Caspase 9/genética , Água Potável , Fluorose Dentária/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos
9.
Biol Trace Elem Res ; 173(1): 161-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26883836

RESUMO

This study aims to clarify the molecular mechanism of fluorine exposure that leads to nerve injury. PC12 cells were treated with fluorine at different concentrations (0.5, 1.0, 1.5, and 2.0 mM). Cytoactivity was detected at different time points (2, 4, 6, 8, 12, 24, and 48 h). After 2 h, DCF was used to detect and mark the level of reactive oxygen species (ROS) within cells. After 24 h, cellular metamorphosis was observed using an inverted microscope. After 2 h, Hoechst-33342 was used to detect apoptosis. After 24 h, Western blot analysis was performed to detect apoptosis-related poly (ADP-ribose) polymerase (PARP) protein, p-elF, and expression of the endoplasmic reticulum stress-related X-box binding protein 1 (XBP-1). The results showed that Fluorine exposure resulted in a reduction of cell viability, which was negatively correlated with fluorine dose. Within certain fluorine exposure duration, the ROS level within the cell and the apoptotic level are linearly related to fluorine exposure level. XBP-1 and PARP protein are sensitive to variations in fluorine concentration, which indicates that oxidative stress from fluorine exposure can lead to apoptosis. XBP-1 and PARP may be the key proteins during the entire process. These results provide a valid basis for fluorine-induced free radical injury theory.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/biossíntese , Fluoreto de Sódio/farmacologia , Proteína 1 de Ligação a X-Box/biossíntese , Animais , Relação Dose-Resposta a Droga , Células PC12 , Ratos
10.
Environ Toxicol Pharmacol ; 36(3): 913-20, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24008008

RESUMO

Fluorosis is a major public health problem in numerous areas around the world, including China. To alleviate this problem, selenium has been used. In this study, we aimed to investigate the influence of selenium on apoptosis in fluorosis-affected rat livers and determine the optimal selenium concentration in drinking water to fight fluorosis. The protein levels of Fas in NaF and NaF+Se (0.375 and 0.75 mg/L) groups as well as FasL in NaF, Se (0.75 and 1.5 mg/L), and NaF+Se (0.375 mg/L) groups were significantly increased compared with those in the control group. The mRNA levels of Fas in NaF and Se (1.5 mg/L) groups as well as FasL in NaF and NaF+Se (0.375 mg/L) groups were significantly increased. The protein levels of Fas in NaF+Se (1.5 mg/L) group and FasL in three NaF+Se groups were significantly decreased compared with those in the NaF group. The mRNA levels of Fas in the three NaF+Se groups and FasL in NaF+Se (0.75 and 1.5 mg/L) groups were significantly decreased. Compared with the control group, activity of GSH-Px, and SOD in the NaF group decreased obviously and MDA content increased obviously; activity of SOD in 1.5 mg/L Se group decreased obviously. Compared with the NaF group, activity of GSH-Px in NaF+Se (1.5 mg/L) group significantly increased, and MDA content decreased obviously. Thus, fluoride induced apoptosis in the liver, thereby causing liver damage in the rats. Selenium could alleviate fluorosis-induced liver injury. In particular, selenium at 1.5 mg/L is considered the optimum concentration against fluorosis.


Assuntos
Apoptose/efeitos dos fármacos , Proteína Ligante Fas/biossíntese , Fígado/metabolismo , Fluoreto de Sódio/farmacologia , Selenito de Sódio/farmacologia , Receptor fas/biossíntese , Animais , Western Blotting , Água Potável , Fluorose Dentária/prevenção & controle , Glutationa Peroxidase/metabolismo , Marcação In Situ das Extremidades Cortadas , Fígado/efeitos dos fármacos , Fígado/ultraestrutura , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Superóxido Dismutase/metabolismo
11.
Biol Trace Elem Res ; 155(2): 253-60, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23959921

RESUMO

This study was conducted to further explore the effect of selenium on fluoride-induced changes in the synaptic plasticity in rat hippocampus. Animals were randomly divided into control group, F group (sodium fluoride: 50 mg/L), three Se groups (sodium selenite: 0.375, 0.75, and 1.5 mg/L), and three F+Se groups (sodium fluoride: 50 mg/L; sodium selenite:0.375, 0.75, and 1.5 mg/L) and subjected to an exposure time of 6 months. The changes in synaptic plasticity in rat hippocampus were observed by electron microscopy. Compared with the fluoride group, the length of the synaptic active zone and the thickness of the postsynaptic density (PSD) increased significantly, whereas the width of the synaptic cleft decreased with high significance in the F+Se (0.75 mg/L) group. Moreover, the nitric oxide synthase activity and the nitric oxide content in the hippocampus decreased significantly in the F+Se (0.75 and 1.5 mg/L) groups. Furthermore, reverse transcriptase polymerase chain reaction and Western blot analyses showed that postsynaptic density-93 (PSD-93) expression in the hippocampus was increased significantly, whereas postsynaptic density-95 (PSD-95) expression decreased significantly in the fluoride group compared with the control group. The PSD-93 expression was inhibited in the three F+Se groups, whereas the opposite result was observed in PSD-95 expression. Based on the results, the optimal selenium dosage range that can antagonize the neurotoxicity of fluorosis is from 0.75 to 1.5 mg/L. The changes in PSD-93 expression may be the key factor to fluoride-induced central nervous toxicity and the effect of selenium intervention.


Assuntos
Fluoretos/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Selênio/farmacologia , Animais , Western Blotting , Proteína 4 Homóloga a Disks-Large , Fluoretos/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Sprague-Dawley , Selênio/administração & dosagem , Sinapses/efeitos dos fármacos
12.
Biol Trace Elem Res ; 153(1-3): 237-42, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23591959

RESUMO

This study aims to explore the effect of selenium in fluoride-induced renal cell apoptosis in rats and determine the optimal level of selenium in drinking water to prevent fluorosis. Experimental animals were divided into a control group, a sodium fluoride-treated group (NaF, 50 mg/L), three sodium selenite-treated groups (Na2SeO3, 0.375, 0.75, and 1.5 mg/L), and three selenium + NaF-treated groups (Na2SeO3, 0.375, 0.75, and 1.5 mg/L; NaF, 50 mg/L). Ultrastructural changes in the kidney tissues of each group were observed by transmission electron microscopy. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and the expressions of Bcl-2 and Bax proteins were detected by immunohistochemical methods. The expressions of Bcl-2 and Bax mRNA were detected by reverse transcription-polymerase chain reaction. The results showed that Bcl-2, Bax, and Bax/Bcl-2 protein expressions in the fluoride and high selenium groups were highly elevated compared with the control group (P < 0.01). Bax expression in the low selenium group and Bcl-2, Bax, and Bax/Bcl-2 protein expressions in the moderate selenium groups were observably elevated (P < 0.05). Bax and Bax/Bcl-2 expressions in the fluoride group and Bax mRNA expression in the high selenium group were highly elevated (P < 0.01). Bax/Bcl-2 mRNA expression in the high selenium group was also highly elevated (P < 0.05). Compared with the fluoride group, the group treated with low selenium has Bax protein expression that was observably reduced (P < 0.05); the group treated with moderate selenium has Bcl-2 protein expression that was observably elevated (P < 0.05), Bax protein expression that was highly reduced (P < 0.01), and Bax/Bcl-2 protein expression that was observably reduced (P < 0.05); the group treated with high selenium has Bcl-2 protein expression that was highly elevated (P < 0.01), Bax protein expression that was highly elevated (P < 0.01), and Bax/Bcl-2 protein expression that was highly reduced (P < 0.01); the groups treated with moderate selenium and high selenium have Bax mRNA expression that was highly reduced (P < 0.01), and the groups treated with high selenium have Bax/Bcl-2 mRNA expression that was observably reduced (P < 0.05). Selenium may inhibit the apoptosis of renal cells in fluorosis rats by regulating the expressions of Bcl-2 and Bax. The optimal dose of Na2SeO3 to protect against fluoride-induced renal cell apoptosis was determined to be 1.5 mg/L.


Assuntos
Apoptose/efeitos dos fármacos , Fluorose Dentária/patologia , Rim/efeitos dos fármacos , Selênio/farmacologia , Animais , Sequência de Bases , Primers do DNA , Rim/metabolismo , Rim/patologia , Masculino , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
13.
Wei Sheng Yan Jiu ; 41(4): 627-31, 2012 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-23057329

RESUMO

OBJECTIVE: To further explore the intervention of selenium on liver impairment induced by chronic fluorosis in rats. METHODS: Animals were divided into 8 groups and treated by different programs (In the 4 prevention groups, 0, 0.375, 0.75 and 1.5 mg/L sodium selenite solution were given for 6 months and then 50mg/L fluoride solution for another 6 months. In the 4 treatment groups, 50mg/L fluoride solution was given for 6 months and then 0, 0.375, 0.75 and 1. 5mg/L sodium selenite solution for another 6 months). The pathological change of liver was observed. The activities of GSH-Px, SOD, the level of MDA and the expression of NF-kappaB in liver were also determined. RESULTS: In the prevention groups, the activity of GSH-Px in the LSe-F and MSe-F groups was higher than the noSe-F control group (P < 0.05). The activity of SOD in the LSe-F group was higher than the noSe-F control group (P < 0.05). The MDA levels in LSe-F, MSe-F and HSe-F groups were lower than the noSe-F control group (P < 0.05). In the treatment groups, the activity of GSH-Px in the F-LSe and F-HSe groups was higher than the F-noSe control group (P < 0.05). The activity of SOD in the F-MSe group was higher than the F-noSe control group (P < 0.05). The MDA levels in the F-LSe, F-MSe and F-HSe groups were lower than the F-noSe control group (P < 0.05). CONCLUSION: There were a certain effects of selenium intervention on liver impairment induced by chronic fluorosis in rats. The preventive effect of selenium was better than the therapeutic effect, and the level of 0.375 mg/L Na2SeO3 was considered as the optimal concentration for the prevention of liver impairment induced by chronic fluorosis under this experimental condition.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Intoxicação por Flúor/tratamento farmacológico , Selênio/farmacologia , Animais , Fluoretos , NF-kappa B , Fosfatos , Ratos , Ratos Sprague-Dawley , Selênio/uso terapêutico , Compostos de Selênio , Selenito de Sódio
14.
Exp Toxicol Pathol ; 64(6): 565-8, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21146966

RESUMO

This study is to explore the effect of selenium and fluoride on blood antioxidant capacity of rats, and try to find out the optimal level of selenium in drinking water against fluorosis. Animals were divided into control group, sodium fluoride treated group (NaF, 50 mg/L) and selenium+NaF treated group (sodium selenite 0.375, 0.75, 1.5 mg/L) in water were respectively administered to male rats, which were decapitated after 6 months. Their blood was collected for GSH-Px activity, plasma SOD activity, T-AOC assay, uric acid assay, sialic acid (SA) content and MDA content, and the fluidity of erythrocyte membrane by electron spin resonance (ESR) was analyzed. The results showed that, compared with the control group, the blood antioxidant capacity of the rats exposed to fluoride was down-regulated significantly (P<0.05, P<0.01), MDA content increased significantly (P<0.05), the fluidity of erythrocyte membrane decreased (P<0.05, P<0.01). Meanwhile, the treatments of selenium along with NaF compared with fluorosis group, SOD activity, GSH-Px activity and T-AOC assay increased respectively, MDA content decreased significantly (P<0.05) in NaF+Se (Se 0.75, 1.5 mg/L) treated groups, uric acid level was up-regulated, but had no statistical significant difference (P>0.05). The fluidity of erythrocyte membrane showed significant increase (P<0.05), the content of SA was lower. Fluorosis could induce the decline of blood antioxidant capacity and the fluidity of erythrocyte membrane, as evident in this study, and Se at different levels possess some antagonistic effects on blood induced by fluoride. However, high dose of selenium (1.5 mg/L) is the optimum concentration.


Assuntos
Antioxidantes/farmacologia , Cariostáticos/toxicidade , Eritrócitos/efeitos dos fármacos , Fluoretos/toxicidade , Fluidez de Membrana/efeitos dos fármacos , Selênio/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Espectroscopia de Ressonância de Spin Eletrônica , Fluorose Dentária/sangue , Fluorose Dentária/prevenção & controle , Masculino , Ratos , Ratos Sprague-Dawley
15.
Biol Trace Elem Res ; 144(1-3): 1024-31, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21647758

RESUMO

This study was conducted to further explore the effects of selenium on the blood antioxidant capacity in rats exposed to fluoride to find out the optimal dosage level of selenium. Animals were divided into prevention sequence (Selenium → NaF, water → NaF) and treatment sequence (NaF → Selenium, NaF → water) (sodium fluoride 50 mg/L; sodium selenite 0.375, 0.75, 1.5 mg/L). The exposure time was 12 months. Then, the fluidity of erythrocyte membrane by electron spin resonance was analyzed, and the blood was collected for GSH-Px and SOD activity, total antioxidant capacity (T-AOC) and uric acid assay, sialic acid and MDA content. The results showed that, compared with control group, GSH-Px activity and T-AOC level increased significantly (P < 0.05), and SOD activity was raised in varying degrees in prevention and treatment groups, respectively. Uric acid level was up-regulated, but no significant differences were observed (P > 0.05). The fluidity of erythrocyte membrane showed significant increase (P < 0.05). As evident in this study, when the dose of selenium was 0.75 mg/L, all the activities of antioxidant enzymes increased significantly in prevention sequence; but in treatment sequence, the optimum intervention concentration was 1.5 mg/L. On the basis of results, the preventive effect of selenium was superior to treatment effect on the oxidative stress induced by an overdose of fluoride.


Assuntos
Antioxidantes/metabolismo , Antioxidantes/farmacologia , Intoxicação por Flúor/sangue , Intoxicação por Flúor/prevenção & controle , Selênio/farmacologia , Fluoreto de Sódio/envenenamento , Algoritmos , Animais , Nitrogênio da Ureia Sanguínea , Membrana Eritrocítica/efeitos dos fármacos , Radicais Livres/metabolismo , Glutationa Peroxidase/metabolismo , Indicadores e Reagentes , Masculino , Malondialdeído/sangue , Fluidez de Membrana/efeitos dos fármacos , Ácido N-Acetilneuramínico/sangue , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo
16.
Biol Trace Elem Res ; 139(2): 197-203, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20217272

RESUMO

The objective of this study is to investigate the neurotoxicity of drinking water fluorosis on rat hippocampus. Just weaning male Sprague-Dawley rats were randomly divided into four groups and given 15, 30, and 60 mg/L NaF solution and distilled water, respectively, for 9 months. The fluidity of brain synaptic membrane and expression level of postsynaptic density 95 (PSD-95) were tested. Results showed that the fluidity of brain synaptic membrane decreased gradually with increasing of fluoride concentration, and it was significantly decreased (P < 0.05) in moderate-fluoride group compared with control group, and expression level of PSD-95 was significantly decreased (P < 0.01) in moderate-fluoride group when compared with that of control group. These results indicate that decrease of synaptic membrane fluidity and PSD-95 expression level may be the molecular basis of central nervous system damage caused by fluoride intoxication; PSD-95 in CA3 region of hippocampus is probably a target molecule for fluoride.


Assuntos
Fluoretos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Membranas Sinápticas/efeitos dos fármacos , Membranas Sinápticas/metabolismo , Animais , Proteína 4 Homóloga a Disks-Large , Imuno-Histoquímica , Masculino , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
17.
Exp Toxicol Pathol ; 63(5): 407-11, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20304620

RESUMO

The study investigated the neurotoxicity of drinking water fluorosis in rat hippocampus. Just weaning male Sprague-Dawley (SD) rats were given 15, 30, 60 mg/L NaF solution and tap water for 9 months. The calcium ion concentration ([Ca(2+)]) in synaptosomes was measured by double wavelength fluorescence spectrophotometer and the expression level of nuclear transcription factor kappa-B ρ65 (NF-κB ρ65) in hippocampal CA3 region was measured by immunohistochemistry. The results showed that [Ca(2+)] significantly increased (F = 33.218, P < 0.01) in moderate fluoride group compared with the control group, and the expression level of NF-κB ρ65 in CA3 region presented an increasing trend as fluoride concentration increased. These results indicate that increase of synaptosomes [Ca(2+)] and NF-κB ρ65 expression level may be the molecular basis of central nervous system damage caused by chronic fluoride intoxication. NF-κB ρ65 in CA3 region is probably a target molecule for fluorosis.


Assuntos
Região CA3 Hipocampal/metabolismo , Cálcio/metabolismo , Síndromes Neurotóxicas/metabolismo , Fluoreto de Sódio/toxicidade , Fator de Transcrição RelA/metabolismo , Animais , Região CA3 Hipocampal/patologia , Relação Dose-Resposta a Droga , Intoxicação por Flúor/etiologia , Intoxicação por Flúor/metabolismo , Intoxicação por Flúor/patologia , Fluorose Dentária/etiologia , Fluorose Dentária/metabolismo , Fluorose Dentária/patologia , Masculino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Ratos , Ratos Sprague-Dawley , Sinaptossomos/metabolismo , Sinaptossomos/patologia , Desmame
18.
Planta Med ; 73(10): 1047-53, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17628835

RESUMO

There is growing interest in whether phytoestrogens, especially isoflavones, affect cognitive function and have beneficial effects on neurodegenerative diseases. Previous work from our laboratory showed that puerarin (Pur), a major component of the Pueraria lobata isoflavones, displayed protective effects on learning and memory in ovariectomized (Ovx) female mice. In the present study, we investigated the effects of Pur on the synaptic structural modifications of the hippocampus in Ovx female mice. One week after ovariectomy or sham operation, female mice were given a 4-week treatment of Pur (50 or 100 mg/kg, I. G.) or estradiol benzoate (EB, 120 microg/kg, S. C.). The results from synaptic structural measurement and analysis did not show any differences in the hippocampal volumes, the synaptic numeric density, and the curvature of synaptic interface among Sham, Ovx, and Ovx plus EB or Pur replacement female mice. However, Pur replacement effectively normalized some structural changes induced by Ovx, reducing the width of the synaptic cleft, enlarging the thickness of postsynaptic density (PSD), and lengthening the synaptic active zone of the pre-existing synapses in the hippocampus CA1 area (P < 0.05 or P < 0.01). Furthermore, through Western blotting, we found that the immunocontent of the NMDA receptor subunit NR2 was not altered by Pur (108 % and 114 % of Ovx); however, the content of postsynaptic protein PSD-95 (145 % and 176 % of Ovx) and phosphorylation of NMDA receptor subunit NR2B (141 % and 172 % of Ovx) strongly increased in Ovx mice following treatment with Pur (50 or 100 mg/kg) for 4 weeks. These results suggest that Pur possesses phytoestrogen activity with 1,000 -fold lower activity than EB, and the beneficial effects of Pur on improving memory behavior of Ovx female mice are associated with the changes of synaptic structural modifications in the hippocampus.


Assuntos
Hipocampo/efeitos dos fármacos , Fitoestrógenos/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Pueraria , Animais , Relação Dose-Resposta a Droga , Feminino , Hipocampo/patologia , Hipocampo/ultraestrutura , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Ovariectomia , Fitoestrógenos/administração & dosagem , Fitoestrógenos/uso terapêutico , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico
19.
Life Sci ; 79(16): 1553-60, 2006 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-16750837

RESUMO

There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by altering neuronal plasticity, including increased hippocampus CA1 dendritic spine density and enhanced long-term potentiation (LTP). In the present study, we investigated the effects of estrogen on the ultrastructural modifications in cerebral frontal cortex and hippocampus of female ovariectomized mice. One week after ovariectomy (Ovx), ICR female mice received daily injection of estradiol benzoate (EB, 20, 100, 200 microg/kg, s.c.) for 4-5 weeks. Spatial memory was then tested in the water maze, and the overall locomotor activity was monitored in open field. Synaptic morphologic parameters were examined using a graph analyzer. The results from open field did not show any alterations in locomotor activity following Ovx and EB replacement. Both the latency to find the platform and the distance to reach the platform were significantly reduced in Ovx mice by EB at 20 or 100 microg/kg when compared to vehicle treated Ovx mice. The results from synaptic ultrastructural measurement and analysis did not show any differences in hemispheric or hippocampal volumes, the numeric synaptic density, the length of active zones, or the curvature of synaptic interface among Sham, Ovx, and Ovx plus EB replacement mice. However, EB replacement effectively normalized the changes induced by Ovx, reducing the width of the synaptic cleft, enlarging the thickness of postsynaptic density (PSD), and increasing the number of synaptic vesicles in the presynapse in both cerebral cortex Fr1 and hippocampus CA1 areas. These results suggest that the beneficial effects of EB on improving memory behavior of Ovx female mice are associated with the changes of some subtle structural parameters of synapses, including the width of PSD and synaptic cleft rather than some basic and permanent structure in frontal cortex and hippocampus regions.


Assuntos
Estradiol/análogos & derivados , Aprendizagem/efeitos dos fármacos , Memória/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura , Animais , Estradiol/farmacologia , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/ultraestrutura , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Tamanho do Órgão , Ovariectomia , Útero/anatomia & histologia
20.
Wei Sheng Yan Jiu ; 33(2): 158-61, 2004 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-15208994

RESUMO

OBJECTIVE: Investigating the influence of combined iodine and fluoride on phospholipid and fatty acid composition in brain cells of rats. METHODS: Five groups of rats were provided with deionized drinking water containing 0 and 150 mg/L NaF, and containing both 150 mg/L NaF and 0.003, 0.03 or 3 mg/L KI respectively for 5 months. Then phospholipid and fatty acid composition were determined using liquid chromatography. RESULTS: The phospholipid composition had no obvious change. The high concentration fluoride (150 mg/L) and high concentration Iodine (3 mg/L) with high concentration fluoride could cause significant changes of the fatty acid composition in brain cells of rats, the proportion of unsaturated fatty acid (C18:2) was significantly decreased and the saturated fatty acid (C12:0) increased obviously. The antagonistic action of 0.03 mg/L KI drinking water on this kind of influence induced by 150 mg/L NaF was the most evident, whereas that of 3 mg/L KI was action of synergetic toxicity. CONCLUSION: Fluorosis had obvious influence on phospholipid and fatty acid composition in brain cells of rats, and its mechanism might be associated with action of lipid peroxidation, and 0.03 mg/L KI is the optimal concentration for the antagonistic action with this influence from fluorosis.


Assuntos
Química Encefálica/efeitos dos fármacos , Ácidos Graxos/análise , Fosfolipídeos/análise , Iodeto de Potássio/farmacologia , Fluoreto de Sódio/toxicidade , Animais , Encéfalo/patologia , Membrana Celular/química , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Fluoreto de Sódio/antagonistas & inibidores
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