RESUMO
Chungshinchongyitang (CSCYT) is an herbal drug formula containing Chrysanthemum indicum and 13 other herbs used for treating auditory diseases. Irreversible hearing loss is a characteristic effect of a number of heavy metals. Cadmium (Cd(2+)) is an environmental contaminant that causes a variety of adverse effects. In the present study, we investigate the protective effects of CSCYT against Cd(2+) induced ototoxicity in vitro and ex vivo. The findings of this study show that CSCYT prevents the destruction of hair cell arrays induced by Cd(2+) in the rat organ of Corti primary explants. CSCYT inhibited cell death, release of cytochrome c and generation of reactive oxygen species induced by Cd(2+) in HEI-OC1 auditory cell line. In addition, we also demonstrated that CSCYT exerted its effect by modulating of apoptosis via the caspase-3 activation and extracellular signal-regulated kinase activation. These results are expected to improve the understanding of the pharmacological mechanism of CSCYT and aid in the development of potential therapeutic strategies against ototoxicity.
Assuntos
Cádmio/toxicidade , Chrysanthemum , Órgão Espiral/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Citocromos c/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Órgão Espiral/citologia , Órgão Espiral/metabolismo , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
Curcuma longa (CL) has been reported to possess a variety of pharmacological activities. However, the effects of CL on acute pancreatitis (AP) have not yet been determined. To this end, we examined the effects of CL on cerulein-induced AP. Cell viability and cytokine productions were measured in pancreatic acini. Mice were divided into 3 groups: i) Normal group, ii) normal saline-treated group, iii) group treated with CL at a dose of 0.05, 0.1, 0.5 and 1 g/kg. CL was administered orally to mice for 7 days. The mice were intraperitoneally injected with the stable cholecystokinin analogue, cerulein (50 µg/kg), every hour for a total of 6 h. The mice were sacrificed 6 h after the completion of the cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphological examination, measurement of tissue myeloperoxidase activity, as well as the level of cytokines and heme oxygenase-1 (HO-1). The CL treatment reduced cerulein-induced cell death and cytokine production in pancreatic acini. The administration of CL significantly ameliorated the severity of pancreatitis and pancreatitis-associated lung injury, as was shown by the reduction in pancreatic edema, neutrophil infiltration, vacuolization, necrosis, serum amylase, lipase and cytokine levels, and mRNA expression of multiple inflammatory mediators such as interleukin (IL)-1ß and -6 and tumor necrosis factor (TNF)-α. In order to identify the regulatory mechanism of CL on cerulein-induced pancreatitis, we examined the level of HO-1 in the pancreas. We found that the administration of CL induced HO-1. Our results suggest that CL plays a protective role in the development of AP and pancreatitis-associated lung injury.
Assuntos
Ceruletídeo/farmacologia , Curcuma/química , Lesão Pulmonar/tratamento farmacológico , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Doença Aguda , Animais , Citocinas/genética , Citocinas/metabolismo , Feminino , Heme Oxigenase-1/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/citologia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite/complicações , Peroxidase/metabolismoRESUMO
OBJECTIVES: Nardostachys jatamansi belonging to the family Valerianaceae has been used as a remedy for stomach and skin ailments in Korea. The effect of N. jatamansi on acute pancreatitis (AP) has not been defined. Therefore, we investigated the effect of N. jatamansi on cerulein-induced AP. METHODS: In the pretreatment group, N. jatamansi was administered orally to mice at 10 and 20 mg/kg for 5 days, and the mice were intraperitoneally injected with the stable cholecystokinin analogue cerulein hourly for 6 hours. In the posttreatment group, cerulein was injected hourly for 6 hours, and N. jatamansi was administered at the indicated time (1, 3, and 5 hours after the first cerulein injection) and dose (10 and 20 mg/kg) during the cerulein injection. Blood samples were taken 6 hours later to determine the serum amylase, the lipase, and the cytokine levels. The pancreas and the lung were rapidly removed for morphologic examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. RESULTS: Nardostachys jatamansi treatment attenuated the AP, as shown by the histological examination results of the pancreas and the lung, reductions in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and messenger RNA expressions of inflammatory mediators. CONCLUSIONS: These results suggest that N. jatamansi attenuates the severity of AP and pancreatitis-associated lung injury.
Assuntos
Nardostachys/química , Pâncreas/efeitos dos fármacos , Pancreatite/prevenção & controle , Extratos Vegetais/farmacologia , Doença Aguda , Amilases/sangue , Animais , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ceruletídeo , Citocinas/sangue , Citocinas/genética , Ativação Enzimática/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Lipase/sangue , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pancreatite/sangue , Pancreatite/induzido quimicamente , Peroxidase/metabolismo , Fitoterapia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The fruits of Cornus officinalis have been used in traditional oriental medicine for treatment of inner ear diseases, such as tinnitus and hearing loss. In the present study, we investigated the protective effect of C. officinalis on hydrogen peroxide-induced cytotoxicity in HEI-OC1 auditory cells. The results from bioassay-guided fractionation of methanol extract of C. officinalis fruits showed that ursolic acid is a major active component. Ursolic acid (0.05-2 microg/ml) had protective effect against the HEI-OC1 cell damage and reduced lipid peroxidation in a dose-dependent manner. In addition, pre-treatment with ursolic acid significantly attenuated the decrease of activities of catalase (CAT) and glutathione peroxidase (GPX), but superoxide dismutase (SOD) activity was not significantly affected by ursolic acid. These results indicate that ursolic acid protects hydrogen peroxide-induced HEI-OC1 cell damage through inhibition of lipid peroxidation and induction of antioxidant enzymes, CAT and GPX, and may be one of the active components responsible for these effects of C. officinalis fruits.
Assuntos
Cornus/química , Células Ciliadas Auditivas/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Substâncias Protetoras/farmacologia , Triterpenos/farmacologia , Animais , Catalase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Fracionamento Químico , Relação Dose-Resposta a Droga , Frutas/química , Glutationa Peroxidase/metabolismo , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Metanol/química , Camundongos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Superóxido Dismutase/metabolismo , Triterpenos/química , Ácido UrsólicoRESUMO
Hwanggunchungyitang (HGCYT) is a newly designed herbal drug formula for the purpose of treating auditory diseases. A number of heavy metals have been associated with toxic effects to the peripheral or central auditory system. Cadmium (Cd(2+)) is a heavy metal and a potent carcinogen implicated in tumor development through occupational and environmental exposure. However, the auditory effect of Cd(2+) is not poorly understood. The purpose of the present study was to investigate whether HGCYT prevent the ototoxic effects induced by Cd(2+) in auditory cell line, HEI-OC1. HGCYT inhibited the cell death, reactive oxygen species generation (ROS), activation of caspase-9, and extracellular signal-related kinase (ERK) induced by Cd(2+). In addition, we observed that cochlear hair cells in middle turn were damaged by Cd(2+). However, HGCYT prevented the destruction of hair cell arrays of the rat primary organ of Corti explants in the presence of Cd(2+). These results support the notion that ROS are involved in Cd(2+) ototoxicity and suggest HGCYT therapeutic usefulness, against Cd(2+)-induced activation of caspase-9 and ERK.
Assuntos
Cádmio/antagonistas & inibidores , Cádmio/toxicidade , Caspase 9/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Transtornos da Audição/induzido quimicamente , Transtornos da Audição/prevenção & controle , Animais , Western Blotting , Cádmio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Ciliadas Auditivas/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patologia , Humanos , Indicadores e Reagentes , Camundongos , Técnicas de Cultura de Órgãos , Órgão Espiral/efeitos dos fármacos , Órgão Espiral/metabolismo , Órgão Espiral/patologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Sais de Tetrazólio , TiazóisRESUMO
AIM: To investigate the effect of Gardenia jasminoides (GJ) on cerulein-induced acute pancreatitis (AP) in mice. METHODS: C57BL/6 mice weighing 18-20 g were divided into three groups. (1) Normal saline-treated group, (2) treatment with GJ at a dose of 0.1 g/kg, (3) treatment with GJ at a dose of 1 g/kg. GJ was administered orally (n = 6 per group) for 1 wk. Three hours later, the mice were given an intraperitoneal injection of cerulein (50 microg/kg), a stable cholecystokinin (CCK) analogue, every hour for a total of 6 h as described previously. The mice were sacrificed at 6 h after completion of cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphologic examination and scoring. A portion of pancreas was stored at -70 degree and prepared for the measurement of tissue myeloperoxidase (MPO) activity, an indicator of neutrophil sequestration, and for reverse-transcriptase PCR (RT-PCR) and real-time PCR measurements. RESULTS: Treatment with GJ decreased significantly the severity of pancreatitis and pancreatitis-associated lung injury. Treatment with GJ attenuated the severity of AP compared with saline-treated mice, as shown by reduction in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and mRNA expression of multiple inflammatory mediators. CONCLUSION: These results suggest that GJ attenuated the severity of AP as well as pancreatitis-associated lung injury.
Assuntos
Anti-Inflamatórios/farmacologia , Gardenia , Lesão Pulmonar/prevenção & controle , Pulmão/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pancreatite/prevenção & controle , Doença Aguda , Administração Oral , Amilases/sangue , Animais , Anti-Inflamatórios/administração & dosagem , Peso Corporal , Ceruletídeo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Mediadores da Inflamação/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Lipase/sangue , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Tamanho do Órgão , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Peroxidase/metabolismo , Extratos Vegetais/farmacologia , RNA Mensageiro/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND & OBJECTIVES: Psoralea corylifolia (PC) is an herb widely used in medicine for the treatment of a variety of ailment. PC is also known to have immunomodulatory activity. However, its mechanism of action is not known. In the present study we investigated effect of PC on nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha) production in mouse peritoneal macrophages and also examined the mechanism by which PC regulates NO production. METHODS: MTT assay performed for cell viability test and nitrite concentration was measured by using Griess reagent. The amount of TNF-alpha secreted by the cells was measured by a modified enzyme-linked immunosorbent assay (ELISA). Expression of iNOS was investigated by western blot analysis. RESULTS: PC in combination with recombinant interferon-gamma (rIFN-gamma) showed a marked co-operative induction of NO production, with no effect on NO production by itself. The increased production of NO from rIFN-gamma plus PC-stimulated cells was almost completely inhibited by pre-treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappa B (NF-kappaB). Furthermore, treatment of peritoneal macrophages with rIFN-gamma plus PC caused a significant increase in tumour necrosis factor-alpha (TNF-alpha) production. PDTC also decreased the effect of PC on TNF-alpha production significantly. INTERPRETATION & CONCLUSION: As NO and TNF-alpha play an important role in immune function and host defense, PC treatment could modulate several aspects of host defense mechanisms due to stimulation of the inducible nitric oxide synthase.
Assuntos
Macrófagos Peritoneais/efeitos dos fármacos , Óxido Nítrico/biossíntese , Extratos Vegetais/farmacologia , Psoralea , Fator de Necrose Tumoral alfa/biossíntese , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interferon gama/farmacologia , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Fructus Ligustrum lucidi (FLL) is a widely used herbal medicine for the treatment of a variety of pathologies. We have investigated the anti-inflammatory mechanism of FLL in mouse peritoneal macrophages. FLL exerted an anti-inflammatory action through inhibition of lipopolysaccharide (LPS)-induced tumour necrosis factor (TNF)-alpha production in mouse peritoneal macrophages. The maximal inhibition rate of TNF-alpha production by FLL (0.5 mg mL(-1)) was 60.88 +/- 0.30%. In the inflammatory process, nitric oxide (NO) and prostaglandin E(2) (PGE(2)) increased in peritoneal macrophages. FLL decreased the protein level of NO and PGE(2) in LPS-stimulated mouse peritoneal macrophages. In addition, FLL inhibited nuclear factor-kappaB activation and IkappaB-alpha degradation by the decrease in IkappaB-alpha phosphorylation. Our study suggested that FLL reduced inflammation via an important molecular mechanism, which might explain its beneficial effect in the regulation of inflammatory reactions.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Ligustrum/química , NF-kappa B/metabolismo , Animais , Western Blotting , Dinoprostona/metabolismo , Frutas , Proteínas I-kappa B/efeitos dos fármacos , Proteínas I-kappa B/metabolismo , Lipopolissacarídeos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidor de NF-kappaB alfa , NF-kappa B/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fosforilação , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
To explore effects of Forsythia koreana methanol extract (FKME) on mast cell-mediated allergic and inflammatory properties, the effect of FKME was evaluated on compound 48/80-induced systemic anaphylaxis, ear swelling, and anti-dinitrophenyl (DNP) immunoglobulin E (IgE)-induced passive cutaneous anaphylaxis (PCA). In addition, the effect of FKME was investigated on the histamine release from rat peritoneal mast cells (RPMCs) stimulated by compound 48/80, which promotes histamine release. The human mast cell line HMC-1 was stimulated by phorbol 12-myristate 13-acetate plus calcium ionophore A23187. Activated HMC-1 can produce several proinflammatory and chemotactic cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8. Cytokine levels in the culture supernatant were measured by an enzyme-linked immunosorbent assay. Cytotoxicity by FKME was determined by a 3-(4,5-dimethylthiazol-2-yl)-diphenyl-tetrazolium bromide (MTT) assay. FKME inhibited compound 48/80-induced systemic anaphylactic shock and ear swelling in mice. When 1 g/kg FKME was pretreated or posttreated with mice, compound 48/80-induced mice morality was 50 and 66.7%, respectively. One gram per kilogram of FKME pretreatment inhibited ear-swelling responses derived from compound 48/80 by 29.75%. A PCA reaction was inhibited by 17.9%. In an in vitro model, FKME (1 mg/ml) inhibited histamine release from the RPMCs by 13.8% and TNF-alpha, IL-6, and IL-8 production from HMC-1 cells by 71.16% (P < 0.001), 86.72% (P < 0.001), and 44.6%, respectively. However, FKME had no cytotoxic effects on cell viability. In conclusion, FKME inhibited not only systemic anaphylaxis and ear swelling induced by compound 48/80 but also inhibited a PCA reaction induced by anti-DNP IgE in vivo. Treatment with FKME showed significant inhibitory effects on histamine, TNF-alpha, IL-6, and IL-8 release from mast cells.
Assuntos
Forsythia , Mastócitos/imunologia , Metanol/química , Extratos Vegetais/imunologia , Anafilaxia/induzido quimicamente , Anafilaxia/imunologia , Animais , Linhagem Celular , Forsythia/química , Forsythia/imunologia , Liberação de Histamina , Humanos , Imunoglobulina E/imunologia , Masculino , Mastócitos/citologia , Camundongos , Anafilaxia Cutânea Passiva/imunologia , Extratos Vegetais/química , Ratos , Ratos Wistar , p-Metoxi-N-metilfenetilamina/imunologiaRESUMO
Gamijeonssibaekchulsan (GJBS) is a typical Oriental medicine prescription which has been used in Korea for the treatment of allergic diseases and the development of physical strength. However, as yet there is no clear explanation of how GJBS affects the anaphylactic reaction and the immune function. In the present study murine models and MOLT-4 cells, a T cell line, were used to investigate these effects. Compound 48/80-induced systemic anaphylactic shock and ear swelling response were firstly analyzed. We also assayed histamine release and passive cutaneous anaphylaxis (PCA) in mice and cytokine productions in MOLT-4 cells. GJBS significantly inhibits compound 48/80-induced systemic anaphylactic shock and ear swelling response. GJBS also inhibits histamine release from rat peritoneal mast cells induced by compound 48/80. PCA activated by anti-dinitrophenyl immunoglobulin E is attenuated by GJBS. However, GJBS dose not affect the production of interferon-gamma, interleukin (IL)-2, and IL-4 in MOLT-4 cells. These results indicate that GJBS has a potential regulatory effect on allergic reactions that are mediated by mast cells.
Assuntos
Anafilaxia/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Anafilaxia/imunologia , Anafilaxia/fisiopatologia , Animais , Linhagem Celular , Liberação de Histamina/efeitos dos fármacos , Humanos , Interferon gama/biossíntese , Interleucina-2/biossíntese , Interleucina-4/biossíntese , Masculino , Mastócitos/imunologia , Camundongos , Camundongos Endogâmicos AKR , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Ratos , Ratos Wistar , p-Metoxi-N-metilfenetilamina/toxicidadeRESUMO
Steamed roots of Rehmannia glutinosa (R. glutinosa) have been traditionally used in Oriental medicine for the treatment of auditory diseases such as tinnitus and hearing loss. To investigate whether the ethanol extract of steamed roots of R. glutinosa (SRG) increases activity of antioxidant enzymes and the level of glutathione (GSH), we measured activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR) and GSH level in HEI-OC1 cells after treatment with 5-50 microg/ml of SRG. The SOD and CAT activities were significantly increased in the presence of SRG compared to the control group. Maximal activities of SOD and CAT were observed in these cells exposed to 10 microg/ml of SRG. The GPX activity also increased dramatically in response to the treatment with SRG in a dose-dependent manner. The GR activity was only increased in the presence of 50 microg/ml of SRG compared to the control group. The level of GSH gradually increased in the presence of 5-50 microg/ml of SRG. In the cytotoxicity test, 5-50 microg/ml of SRG did not show any significant cytotoxicity. These results suggest that the traditional use of R. glutinosa for the treatment of auditory diseases may be explained, in part, by activation of intracellular antioxidant enzyme systems. Further studies are necessary to clarify the active constituents of SRG responsible for such biomolecular activities.
Assuntos
Células Ciliadas Auditivas/metabolismo , Oxirredutases/biossíntese , Rehmannia , Animais , Linhagem Celular , Células Ciliadas Auditivas/citologia , Camundongos , Raízes de PlantasRESUMO
The steamed root of Rehmannia glutinosa has been used in traditional Oriental Medicine for treatment of inner ear diseases, such as tinnitus and hearing loss. In the present study, we showed that the ethanol extract of steamed roots of Rehmannia glutinosa (SRG) protected HEI-OC1 auditory cells from cisplatin cytotoxicity in a dose-dependent fashion. In addition, to investigate the protection mechanism of SRG on cisplatin cytotoxicity towards HEI-OC1, we measured the effects of SRG on lipid peroxidation of cisplatin treated cells as well as scavenging activities against superoxide radical, hydroxyl radical, hydrogen peroxide, and DPPH radical. SRG (5-100 microg/ml) had protective effect against the cisplatin-induced HEI-OC1 cell damage and reduced lipid peroxidation in a dose-dependent manner. Furthermore, SRG showed strong scavenging activity against superoxide radical, hydroxyl radical, hydrogen peroxide, and DPPH radical. These results indicate that SRG protects cisplatin-induced HEI-OC1 cell damage through inhibition of lipid peroxidation and scavenging activities of free radials.
Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Cóclea/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Rehmannia , Animais , Compostos de Bifenilo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cóclea/citologia , Cóclea/metabolismo , Relação Dose-Resposta a Droga , Sequestradores de Radicais Livres/química , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Peroxidação de Lipídeos/efeitos dos fármacos , Picratos/química , Extratos Vegetais/farmacologia , Raízes de Plantas , Superóxidos/químicaRESUMO
In the present study, we investigated the signal transduction pathways of expression of IL-6 in the desferrioxamine (DFX)-stimulated cochlear auditory cell line, HEI-OC1 cells. DFX increased the expression of HIF-1alpha and NF-kappaB in HEI-OC1 cells. DFX significantly increased the production of IL-6 (P<0.05) and expression of IL-6 mRNA but did not affect TNF-alpha production. DFX also induced the activation of mitogen-activated protein kinase (MAPK) including p38, ERK, and JNK on HEI-OC1. Increased IL-6 by DFX was significantly inhibited by p38 inhibitor, SB203580 (about 72% inhibition, P=0.027) but not ERK inhibitor, PD98059 or JNK inhibitor, SP600125. SB203580 inhibited the expression of IL-6 mRNA. Increased IL-6 production was partially inhibited by treatment of iron (HIF-1 inhibitor) or pyrriolidine-dithiocarbamate (PDTC, NF-kappaB inhibitor). DFX also induced IL-6 production and HIF-1alpha expression in the inner ear. We demonstrated the regulatory effects of MAPK, HIF-1alpha, and NF-kappaB on DFX-induced IL-6 production in a HEI-OC1 for the first time. In conclusion, these data indicate that regulation of inflammatory cytokine IL-6 by DFX, through mimicking hypoxic conditions, might explain its beneficial effect in the treatment of hypoxia-induced inner ear diseases.