Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Death Dis ; 10(10): 774, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601780

RESUMO

Neonatal jaundice is prevalent among newborns and can lead to severe neurological deficits, particularly sensorimotor dysfunction. Previous studies have shown that bilirubin (BIL) enhances the intrinsic excitability of central neurons and this can potentially contribute to their overexcitation, Ca2+ overload, and neurotoxicity. However, the cellular mechanisms underlying elevated neuronal excitability remain unknown. By performing patch-clamp recordings from neonatal neurons in the rat medial vestibular nucleus (MVN), a crucial relay station for locomotor and balance control, we found that BIL (3 µM) drastically increases the spontaneous firing rates by upregulating the current-mediated voltage-gated sodium channels (VGSCs), while shifting their voltage-dependent activation toward more hyperpolarized potentials. Immunofluorescence labeling and western immunoblotting with an anti-NaV1.1 antibody, revealed that BIL elevates the expression of VGSCs by promoting their recruitment to the membrane. Furthermore, we found that this VGSC-trafficking process is Ca2+ dependent because preloading MVN neurons with the Ca2+ buffer BAPTA-AM, or exocytosis inhibitor TAT-NSF700, prevents the effects of BIL, indicating the upregulated activity and density of functional VGSCs as the core mechanism accountable for the BIL-induced overexcitation of neonatal neurons. Most importantly, rectification of such overexcitation with a low dose of VGSC blocker lidocaine significantly attenuates BIL-induced cell death. We suggest that this enhancement of VGSC currents directly contributes to the vulnerability of neonatal brain to hyperbilirubinemia, implicating the activity and trafficking of NaV1.1 channels as a potential target for neuroprotection in cases of severe jaundice.

2.
Int Forum Allergy Rhinol ; 8(11): 1334-1341, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30216703

RESUMO

BACKGROUND: The pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) has not been fully elucidated. This study sought to explore the role and mechanism of transient receptor potential canonical channel 6 (TRPC6) in the pathogenesis of CRSwNP. METHODS: Immunohistochemistry (IHC) was employed to evaluate TRPC6 immunolabeling. Real-time polymerase chain reaction (PCR) was conducted to assay TRPC6, stromal interaction molecule 1 (STIM1), and calcium release-activated calcium channel protein 1 (Orai1) messenger RNA (mRNA) levels in 70 patients with CRSwNP, including eosinophilic CRSwNP (ECRSwNP) or non-eosinophilic CRSwNP (nECRSwNP), and 28 control subjects. The concentrations of inflammatory mediators, including interleukin (IL)-1ß, IL-5, and IL-25, were assayed by enzyme-linked immunosorbent assay (ELISA). In experiments on human nasal epithelial cell (HNEC) culture and stimulation, the mean fluorescence intensity (MFI) of intracellular Ca2+ was assayed by flow cytometry. Western blotting, real-time PCR, and ELISA were also conducted to assess the effects and mechanisms of TRPC6 activator 1-oleoyl-2-acetyl-glycerol (OAG) and TRPC6 inhibitor 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) on HNECs. RESULTS: Upregulation of TRPC6, STIM1, and Orai1 levels was found in CRSwNP patients, particularly in those with ECRSwNP. TRPC6-positive cells correlated positively with the numbers of eosinophils and neutrophils, respectively. Moreover, TRPC6 mRNA was positively correlated with STIM1 and Orai1 mRNA levels. The concentrations of inflammatory mediators, including IL-1ß, IL-5, and IL-25, were elevated in CRSwNP, especially in ECRSwNP. In cultured HNECs, TRPC6, STIM1, Orai1, Ca2+ MFI levels, and inflammatory mediators were upregulated by lipopolysaccharide (LPS) and OAG but were inhibited by SKF-96365. CONCLUSION: TRPC6 plays a pro-inflammatory role in the pathogenesis of CRSwNP via regulating Ca2+ flow.


Assuntos
Eosinofilia/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Canal de Cátion TRPC6/imunologia , Adulto , Cálcio/metabolismo , Células Cultivadas , Doença Crônica , Citocinas/imunologia , Eosinofilia/genética , Células Epiteliais/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Nariz/imunologia , Proteína ORAI1/genética , Proteína ORAI1/imunologia , Rinite/genética , Sinusite/genética , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/imunologia , Canal de Cátion TRPC6/genética , Regulação para Cima
3.
Biomed Environ Sci ; 30(12): 922-926, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29335063

RESUMO

Kidney stones are a common urinary system condition that can progress to kidney disease. Previous studies on the association between tea consumption and kidney stones are inconsistent. A cross-sectional study to investigate the association between tea consumption and kidney stones was conducted from 2013 to 2014 and recruited 9,078 northern Chinese adults. A total of 8,807 participants were included in the final analysis. Participants' prevalence of kidney stones was 1.07%, 1.73%, and 2.25% based on their tea consumption frequency of never, occasionally, and often groups, respectively. Compared with the 'never' group, the odds ratios (95% confidence intervals) for the occurrence of kidney stones were 1.57 (1.00-2.46) and 1.65 (1.06-2.57) in the 'occasionally' and 'often' groups, respectively. After adjusting for sex, age, and other potential confounding factors, tea consumption still significantly increased the risk of kidney stones. Tea consumption is independently associated with an increased risk of kidney stones in the investigated population, suggesting that a decrease in the consumption of tea may be a preventive strategy for kidney stones.


Assuntos
Cálculos Renais/epidemiologia , Adulto , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Chá
4.
Sci Rep ; 6: 32872, 2016 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-27611599

RESUMO

Olfactory dysfunction is a common clinical phenomenon observed in various liver diseases. Previous studies have shown a correlation between smell disorders and bilirubin levels in patients with hepatic diseases. Bilirubin is a well-known neurotoxin; however, its effect on neurons in the main olfactory bulb (MOB), the first relay in the olfactory system, has not been examined. We investigated the effect of bilirubin (>3 µM) on mitral cells (MCs), the principal output neurons of the MOB. Bilirubin increased the frequency of spontaneous firing and the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). TTX completely blocked sEPSCs in almost all of the cells tested. Bilirubin activity was partially blocked by N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepro pionic acid (AMPA) receptor antagonists. Furthermore, we found that bilirubin increased the frequency of intrinsic firing independent of synaptic transmission in MCs. Our findings suggest that bilirubin enhances glutamatergic transmission and strengthens intrinsic firing independent of synaptic transmission, all of which cause hyperexcitability in MCs. Our findings provide the basis for further investigation into the mechanisms underlying olfactory dysfunction that are often observed in patients with severe liver disease.


Assuntos
Bilirrubina/farmacologia , Neurônios/efeitos dos fármacos , Bulbo Olfatório/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Hepatopatias/complicações , N-Metilaspartato , Neurônios/metabolismo , Transtornos do Olfato/induzido quimicamente , Transtornos do Olfato/etiologia , Bulbo Olfatório/metabolismo , Ratos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico
5.
Can J Neurol Sci ; 40(5): 628-34, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23968934

RESUMO

Taurine appears to exert potent protections against glutamate (Glu)-induced injury to neurons, but the underlying molecular mechanisms are not fully understood. The possibly protected targets consist of the plasma membrane and the mitochondrial as well as endoplasmic reticulum (ER) membranes. Protection may be provided through a variety of effects, including the prevention of membrane depolarization, neuronal excitotoxicity and mitochondrial energy failure, increases in intracellular free calcium ([Ca2+]i), activation of calpain, and reduction of Bcl-2 levels. These activities are likely to be linked spatially and temporally in the neuroprotective functions of taurine. In addition, events that occur downstream of Glu stimulation, including altered enzymatic activities, apoptotic pathways, and necrosis triggered by the increased [Ca2+]i, can be inhibited by taurine. This review discusses the possible molecular mechanisms of taurine against Glu-induced neuronal injury, providing a better understanding of the protective processes, which might be helpful in the development of novel interventional strategies.


Assuntos
Ácido Glutâmico/toxicidade , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Taurina/uso terapêutico , Animais , Retículo Endoplasmático/efeitos dos fármacos , Humanos , Mitocôndrias/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/patologia , Taurina/metabolismo , Taurina/farmacologia
6.
Int J Pediatr Otorhinolaryngol ; 77(5): 647-54, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23273639

RESUMO

OBJECTIVES: Previous work showed that taurine protects neurons against unconjugated bilirubin (UCB)-induced neurotoxicity by maintaining intracellular calcium homeostasis, membrane integrity, and mitochondrial function, thereby preventing apoptosis from occurring, in primary neuron cultures. In this study, we investigated whether taurine could protect the auditory system against the neurotoxicity associated with hyperbilirubinemia in an in vivo model. METHODS: Hyperbilirubinemia was established in neonatal guinea pigs by intraperitoneal injection of UCB. Hearing function was observed in electrocochleograms (ECochGs) and auditory brainstem responses (ABRs) recorded before and 1, 8, 24, and 72 h after UCB injection. For morphological evaluations, animals were sacrificed at 8h post-injection, and the afferent terminals beneath the inner hair cells (IHCs), spiral ganglion neurons (SGNs), and their fibers were examined. RESULTS: It was found that UCB injection significantly increased latencies and inter-wave intervals, and thresholds of ABR and compound action potentials, and caused marked damage to type I SGNs, their axons, and terminals to cochlear IHCs. When baby guinea pigs were pretreated with taurine for 5 consecutive days and then injected with bilirubin, electrophysiological abnormalities and morphological damage were attenuated significantly in both the peripheral and central auditory system. CONCLUSIONS: From these observations, it was concluded that taurine limited bilirubin-induced neural damage in the auditory system. These findings may contribute to the development of taurine as a broad-spectrum agent for preventing and/or treating hearing loss in neonatal jaundice.


Assuntos
Células Ciliadas Auditivas Internas/efeitos dos fármacos , Hiperbilirrubinemia/complicações , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/tratamento farmacológico , Taurina/administração & dosagem , Animais , Audiometria de Resposta Evocada , Bilirrubina/farmacologia , Potenciais Evocados Auditivos do Tronco Encefálico , Cobaias , Humanos , Hiperbilirrubinemia/tratamento farmacológico , Recém-Nascido
7.
J Neurosci Res ; 90(11): 2201-13, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22847875

RESUMO

Bilirubin can cause temporary or permanent sensorineural deafness in newborn babies with hyperbilirubinemia. However, the underlying targets and physiological effects of bilirubin-induced damage in the peripheral auditory system are unclear. Using cochlear functional assays and electron microscopy imaging of the inner ear in neonatal guinea pigs, we show here that bilirubin exposure resulted in threshold elevation in both compound action potential (CAP) and auditory brainstem response (ABR), which was apparent at 1 hr and peaked 8 hr after drug administration. The threshold elevation was associated with delayed wave latencies and elongated interwave intervals in ABR and CAP. At 72 hr postinjection, these measures returned to control levels, except for the CAP amplitude. Cochlear microphonics remained unchanged during the experiment. Morphological abnormalities were consistent with the electrophysiological dysfunction, revealing fewer auditory nerve fibers (ANFs) in the basal turn, myelin sheath lesions of spiral ganglion neurons (SGNs) and ANFs, and loss of type 1 afferent endings beneath inner hair cells (IHCs) without loss of hair cells at 8 hr posttreatment. Similar to the electrophysiological findings, morphological changes were mostly reversed 10 days after treatment, except for the ANF reduction in the basal turn. These results suggest that hyperbilirubinemia in neonatal guinea pigs impaired auditory peripheral neuromechanisms that targeted mainly the IHC synapses and the myelin sheath of SGNs and their fibers. Our observations indicate a potential connection between hyperbilirubinemia and auditory neuropathy.


Assuntos
Nervo Coclear/ultraestrutura , Perda Auditiva Central/etiologia , Perda Auditiva Central/patologia , Hiperbilirrubinemia/complicações , Gânglio Espiral da Cóclea/ultraestrutura , Potenciais de Ação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Bilirrubina/toxicidade , Nervo Coclear/efeitos dos fármacos , Modelos Animais de Doenças , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Feminino , Cobaias , Masculino , Microscopia Eletrônica de Transmissão , Gânglio Espiral da Cóclea/efeitos dos fármacos
8.
Exp Neurol ; 237(1): 96-102, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22677143

RESUMO

Excitotoxicity has been suggested to play an important role in many central nervous system diseases, particularly in bilirubin encephalopathy. Minocycline treatment has been proposed to be one of the most promising potential therapies for excitotoxicity-induced neurological disorders. However, some key questions, such as the electrophysiological effect of minocycline on neuronal excitability and hyperexcitation in pathological conditions, require clarification. In this study, using patch-clamp techniques, we showed that bilirubin increased the frequency of both spontaneous excitatory postsynaptic currents (sEPSCs) and neuronal firing in isolated ventral cochlear nucleus (VCN) neurons at postnatal days 11-14 (P11-14) in rats but it did not affect the amplitude of sEPSCs or glutamate-activated (I(Glu)) currents. However, minocycline had no effect on sEPSC frequency or I(Glu) amplitude. Furthermore, minocycline pretreatment did not abolish bilirubin-induced sEPSC potentiation or neuron firing. These data suggest that minocycline does not affect excitatory synaptic transmission or hyperexcitation induced by bilirubin in VCN neurons. From these results, we propose that the neuroprotective efficacy of minocycline, if it can protect neurons against neurotoxicity induced by substances like bilirubin, is mediated by either an alternative mechanism or downstream events post neuronal hyperexcitation. Certainly, additional investigation of the neuroprotective effects of minocycline is required before embarking on further clinical trials.


Assuntos
Bilirrubina/toxicidade , Aminoácidos Excitatórios/metabolismo , Ácido Glutâmico/toxicidade , Minociclina/uso terapêutico , Neurônios/patologia , Núcleos Ventrais do Tálamo/patologia , Animais , Apoptose/fisiologia , Bilirrubina/sangue , Necrose , Neurônios/metabolismo , Neurônios/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Técnicas de Patch-Clamp/métodos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/fisiologia , Núcleos Ventrais do Tálamo/citologia , Núcleos Ventrais do Tálamo/fisiologia
9.
Eur J Pharmacol ; 660(2-3): 310-7, 2011 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-21453694

RESUMO

Excitotoxicity contributes to bilirubin-induced central nervous system injury; however, the mechanisms involved remain controversial. Previous studies from our lab have demonstrated that in juvenile rats bilirubin facilitates γ-aminobutyric acid (GABA)/glycinergic synaptic transmission through activation of presynaptic protein kinase A (PKA) in isolated neurons of the ventral cochlear nucleus (VCN). However, the descending mechanism and physiological effects of bilirubin-induced potentiation remain unclear. Here, whole-cell recordings show that 3×10(-6) M bilirubin increased the frequency of both spontaneous (sPSCs) and miniature (mPSCs) GABA/glycinergic postsynaptic currents in VCN neurons of postnatal day 12-14 (P12-14) rats. This action was dependent on the concentration and duration of exposure to bilirubin and was only partially suppressed by 10(-5) M bicuculline. The potentiation effect on mPSCs persisted in a Ca2+-free solution, but was fully occluded by pretreatment with 1,2 bis-(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM), an intracellular Ca2+ chelator. Following pretreatment of the neurons with BAPTA-AM, forskolin, a PKA activator, had no effect on the frequency or amplitude of mPSCs. This suggests that Ca2+ release from presynaptic stores is part of the descending pathway of PKA activation and is responsible for biliurbin-induced potentiation of cell activity. Using gramicidin-perforated patch recordings, the reversal potential of GABA-evoked currents (EGABA) was also investigated. The GABA response resulted in depolarization of 12 of 20 recorded VCN neurons from P12-14 rats. Therefore, potentiation of depolarizing GABA/glycinergic transmission by bilirubin may underlie bilirubin excitotoxicity, which may play a role in the hearing impairment observed among hyperbilirubinemic neonates.


Assuntos
Bilirrubina/farmacologia , Núcleo Coclear/citologia , Núcleo Coclear/efeitos dos fármacos , Glicina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo , Animais , Cálcio/metabolismo , Núcleo Coclear/enzimologia , Núcleo Coclear/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Feminino , Audição/fisiologia , Técnicas In Vitro , Masculino , Potenciais Pós-Sinápticos em Miniatura/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
10.
Brain Res ; 1348: 30-41, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20561511

RESUMO

Previous studies have suggested that bilirubin can potentiate GABA/glycinergic synaptic transmission in lateral superior olivary nucleus neurons, but the cellular mechanism has not been defined. The present study evaluated the possible roles of protein kinase A (PKA) and C (PKC) in bilirubin potentiation of GABA/glycinergic synaptic transmission in rat ventral cochlear nucleus (VCN) neurons. VCN neurons were acutely isolated from postnatal 10-12-day-old (P10-12) rats and were voltage-clamped in whole-cell mode. Miniature inhibitory postsynaptic currents (mIPSC) frequencies, but not amplitude, were increased by bilirubin. Forskolin (PKA activator) and H-89 (PKA inhibitor) also individually increased mIPSCs frequency, with an additional increase induced by co-incubation with bilirubin and H-89. Pretreatment with forskolin blocked bilirubin potentiation. mIPSC frequency was not altered by phorbol 12,13-diacetate (PKC activator), but mIPSC frequency was increased following co-application of bilirubin. The mIPSC frequency was increased by chelerythrine (PKC inhibitor), and then further increased after the addition of bilirubin. Neither H-89, forskolin, nor PDA, nor their co-application with bilirubin affected mIPSC amplitudes of GABA-activated (I(GABA))/glycine-activated (I(gly)) currents, suggesting a presynaptic locus of activity. Chelerythrine decreased the mIPSC amplitudes and I(GABA)/I(gly), suggesting a postsynaptic locus of activity. These data suggest that both PKA and PKC can modulate GABA and glycine release in rat VCN neurons. Bilirubin facilitates transmitter release via presynaptic PKA activation, which might provide insight into the cellular mechanism underlying bilirubin-induced hearing dysfunction.


Assuntos
Bilirrubina/farmacologia , Núcleo Coclear/citologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Neurônios/efeitos dos fármacos , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antioxidantes/farmacologia , Benzofenantridinas/farmacologia , Colforsina/farmacologia , Ativação Enzimática/efeitos dos fármacos , Glicina/metabolismo , Técnicas In Vitro , Isoquinolinas/farmacologia , Inibição Neural/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Ésteres de Forbol/farmacologia , Ratos , Sulfonamidas/farmacologia , Ácido gama-Aminobutírico/metabolismo
11.
J Zhejiang Univ Sci ; 4(4): 474-9, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12861626

RESUMO

Lead concentrations in roots, stems and leaves of accumulating and non accumulating ecotypes of Sedum alfredii (Hance) were studied through a hydroponic experiment with different Pb concentrations supplied as Pb(NO(3))(2). Lead concentrations in leaves and stems of the accumulating ecotype were 4 - 9 times and 3 - 5 times those of the non-accumulating ecotype, and Pb accumulated amounts in stems and leaves of the accumulating ecotype were 4 - 9 times and 8 - 11 times higher than those of the non-accumulating ecotype, respectively. The results indicated that the accumulating ecotype had better ability to transport Pb from roots to shoots. The subcellular distributions of Pb in the root, stem and leaf tissues were studied using sucrose differential centrifugation. Approximately 50% of Pb contents was found to be associated with the cell wall fraction in stems of the accumulating ecotype and the percentage increased to 80% both in roots and leaves, no matter when plants were grown with different levels of Pb. The results indicated that the distribution of Pb on cell walls of the accumulating ecotype could mainly account for the high tolerance to Pb.


Assuntos
Resíduos Industriais/prevenção & controle , Chumbo/farmacocinética , Sedum/metabolismo , Poluentes do Solo/farmacocinética , Adaptação Fisiológica , Biodegradação Ambiental , Genótipo , Folhas de Planta/genética , Folhas de Planta/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/metabolismo , Caules de Planta/genética , Caules de Planta/metabolismo , Sedum/classificação , Sedum/genética , Especificidade da Espécie , Frações Subcelulares/metabolismo , Distribuição Tecidual , Gerenciamento de Resíduos/métodos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA