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1.
Fish Shellfish Immunol ; 94: 258-263, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513913

RESUMO

Grass carp septicemia is a systemic inflammatory response that develops following a bacterial infection. The hyperinflammatory state develops could lead to septic shock and lethality. There is increasing evidence that microRNAs are involved in the regulation of the inflammatory response. In the present study, miR-21 was confirmed to be involved in the inflammatory response following infection with Aeromonas hydrophila and LPS stimulation. Both jnk and ccr7 were identified as target gene of miR-21 by overexpression, inhibition, and dual luciferase reporter assays experiments. Meanwhile, miR-21 targets the jnk and ccr7 to modulate downstream pro-inflammatory factors tnf-α, il-1ß, il-6, and il-12. Our results provide a theoretical basis for exploring the molecular mechanism of grass carp miR-21 regulating inflammation.


Assuntos
Carpas/genética , Carpas/imunologia , Doenças dos Peixes/microbiologia , Inflamação/veterinária , Proteínas Quinases JNK Ativadas por Mitógeno/genética , MicroRNAs/genética , Receptores CCR7/genética , Aeromonas hydrophila/fisiologia , Animais , Sequência de Bases , Doenças dos Peixes/genética , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Infecções por Bactérias Gram-Negativas/genética , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/veterinária , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Lipopolissacarídeos/farmacologia , MicroRNAs/imunologia , Receptores CCR7/imunologia
2.
J Agric Food Chem ; 67(32): 9009-9021, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31319030

RESUMO

Soybean allergy is a serious health risk to humans and animals; ß-conglycinin is the primary antigenic protein in soybean. Intestinal porcine epithelial (IPEC-J2) cells were used as an in vitro physiological model of the intestinal epithelium to study the effects of different concentrations of soybean antigen protein ß-conglycinin to identify the involved signaling pathways. The cells were divided into eight groups and either untreated or treated with different concentrations of ß-conglycinin, pyrrolidine dithiocarbamate (PDTC), Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME), SP600125, and SB202190 either alone or in combination. The cells were incubated with 1, 5, and 10 mg·mL-1 ß-conglycinin or 5 mg·mL-1 ß-conglycinin and 1 µmol·L-1 nuclear factor κB (NF-κB) inhibitor (PDTC), inducible nitric oxide synthase inhibitor (l-NAME), c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and p38 inhibitor (SB202190) for 24 h, separately; controls were left untreated. The mRNA, protein, and phosphorylation levels of NF-κB, p38, and JNK were higher in the treated groups than in the control group. ß-Conglycinin decreased tight junction distribution, destroyed the cytoskeleton of IPEC-J2 cells, and caused cell death. After the addition of the inhibitors, ß-conglycinin-induced IPEC-J2 cell damage was significantly reduced. ß-Conglycinin caused damage to IPEC-J2 cells via the mitogen-activated protein kinase/NF-κB signaling pathway. The results of this study are crucial for exploring the mechanisms underlying allergic reactions caused by soybean antigen proteins.


Assuntos
Antígenos de Plantas/imunologia , Células Epiteliais/imunologia , Hipersensibilidade Alimentar/imunologia , Globulinas/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Proteínas de Armazenamento de Sementes/imunologia , Proteínas de Soja/imunologia , Soja/imunologia , Animais , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Fosforilação , Transdução de Sinais , Suínos , Junções Íntimas/genética , Junções Íntimas/imunologia
3.
BMC Complement Altern Med ; 19(1): 139, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221142

RESUMO

BACKGROUND: Several studies have found that caffeic acid (CA), a well-known phytochemical, displays important antioxidant and anti-cancer activities. However, no evidence exists on the protective effect and its mechanisms that CA treatment alone has against oxidative stress induced by tert-butyl hydroperoxide (t-BHP) in HepG2 cells. METHODS: Hepatoprotective activities such as cell viability, mRNA expression, and report gene assay were measured using HepG2 cell. Three types of genes and proteins related with detoxification in liver were used for measuring the hepatoprotective effects. Statistical analysis was performed using one-way ANOVA test and differences among groups were evaluated by Tukey's studentized range tests. RESULTS: The present study indicate that treatment with CA up-regulates heme oxygenase-1 (HO-1) and glutamate-cysteine ligase (GCL) mRNA and protein expressions in a CA-dose-dependent manner. In addition, translocation of nuclear factor-E2 p45-related factor (Nrf2) from the cytoplasm to the nucleus and phosphorylation of extracellular signal-regulated kinase, ERK and c-Jun N-terminal kinase, JNK which have been shown to be involved in mitogen-activated protein kinases, MAPKs are significantly enhanced by CA treatment. Furthermore, in cell nuclei, CA enhances the 5'-flanking regulatory region of human antioxidant response element (ARE) and activates the ARE binding site. CONCLUSION: Therefore, CA proved to be a stimulant of the expression of detoxification enzymes such as HO-1, GCLC, and GCLM through the ERK/Nrf2 pathway, and it may be an effective chemoprotective agent for protecting liver damage against oxidative damage.


Assuntos
Ácidos Cafeicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , terc-Butil Hidroperóxido/toxicidade , Elementos de Resposta Antioxidante/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/genética , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/genética , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Lipids Health Dis ; 18(1): 135, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174532

RESUMO

BACKGROUND: Heat induced by infrared (IR) radiation from sun exposure increases skin temperature and can lead to thermal and photo-aging. However, little is known about the relationship between heat induced by IR radiation and lipid biosynthesis in human sebocytes. This study investigated the expression of factors involved in lipid biosynthesis in human sebocytes exposed to heat. The effect of Cassia tora extract and chrysophanol, which is widely used as anti-inflammatory agent, on the heat shock effect in sebocytes was then examined. METHODS: For the treatment, cells were maintained in culture medium without FBS (i.e., serum starved) for 6 h and then moved for 30 min to incubators at 37 °C (control), 41 °C, or 44 °C (heat shock). Culture media were replaced with fresh media without FBS. To investigate expression of gene and signaling pathway, we performed western blotting. Lipid levels were assessed by Nile red staining. The cytokine levels were measured by cytokine array and ELISA kit. RESULTS: We found that peroxisome proliferator-activated receptor (PPAR)γ and fatty acid synthase (FAS) were upregulated and the c-Jun N-terminal kinase (JNK)/p38 signaling pathways were activated in human sebocytes following heat exposure. Treatment with Cassia tora seed extract and chrysophanol suppressed this up-regulation of PPARγ and FAS and also suppressed the increase in IL-1ß levels. CONCLUSION: These findings provide evidence that IR radiation can stimulate sebum production; Cassia tora seed extract and chrysophanol can reverse lipid stimulated inflammatory mediation, and may therefore be useful for treating skin disorders such as acne vulgaris.


Assuntos
Antraquinonas/farmacologia , Cassia/química , Lipogênese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Antraquinonas/química , Células Epiteliais/química , Ácido Graxo Sintases/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Temperatura Alta/efeitos adversos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Lipogênese/genética , Lipogênese/efeitos da radiação , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , PPAR gama/genética , Extratos Vegetais/química , Radiação , Transdução de Sinais/efeitos dos fármacos , Temperatura Cutânea/efeitos da radiação , Proteínas Quinases p38 Ativadas por Mitógeno/genética
5.
Genes (Basel) ; 10(5)2019 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-31109086

RESUMO

The GADD45 proteins are induced in response to stress and have been implicated in the regulation of several cellular functions, including DNA repair, cell cycle control, senescence, and apoptosis. In this study, we investigate the role of D-GADD45 during Drosophila development and regeneration of the wing imaginal discs. We find that higher expression of D-GADD45 results in JNK-dependent apoptosis, while its temporary expression does not have harmful effects. Moreover, D-GADD45 is required for proper regeneration of wing imaginal discs. Our findings demonstrate that a tight regulation of D-GADD45 levels is required for its correct function both, in development and during the stress response after cell death.


Assuntos
Proteínas de Drosophila/fisiologia , Drosophila melanogaster/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Animais , Apoptose/genética , Reparo do DNA , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Discos Imaginais/crescimento & desenvolvimento , Discos Imaginais/metabolismo , Discos Imaginais/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Regeneração/genética , Regeneração/fisiologia , Asas de Animais/crescimento & desenvolvimento
6.
Free Radic Res ; 53(5): 562-573, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31039619

RESUMO

The main flavonoid components of Radix Tetrastigma (RTF) were extracted and identified by UPLC-TOF/MS. In vitro, RTF prevented inflammation in RAW 264.7 cells by suppressing morphological (both cell and nucleus) changes, and decreasing nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) contents. Exposure to LPS also leads to oxidant damage, and RTF alleviated damage to mitochondria, decreased O2- accumulation, and restored the glutathione level. RTF intervention decreased the expression of c-Jun N-terminal kinase (JNK) and p38 phosphorylation, accompanied by downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and forkhead box protein O1 (FoxO1). In vivo, aging of Caenorhabditis elegans (C. elegans) by paraquat (PQ) was observed through lifespan, lipofuscin, and enzyme analysis. RTF protected against damage in N2 worms but not in daf-16 mutants. Gene expression was further assessed, and p38/PMK-1 and Nrf2/SKN-1 expression in worms was suppressed by PQ, which was reversed by RTF treatment. Together, these results suggested that RTF could help ameliorate inflammation-induced damage through JNK, p38 and Nrf2 pathways.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Flavonoides/farmacologia , Longevidade/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/genética , Fatores de Transcrição/genética , Vitaceae/química , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Proteínas de Ligação a DNA/metabolismo , Flavonoides/química , Flavonoides/isolamento & purificação , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica , Glutationa/metabolismo , Inflamação , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Longevidade/genética , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Paraquat/antagonistas & inibidores , Paraquat/farmacologia , Extratos Vegetais/química , Células RAW 264.7 , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
7.
Mar Biotechnol (NY) ; 21(4): 565-576, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31079239

RESUMO

In this study, the carotenoid astaxanthin was obtained by supercritical fluid extraction (SFE) from shrimp by-products (SBP). Its bioactive properties were evaluated in vitro in human normal and cancerous cells lines. The antioxidant activity of the extracted astaxanthin of the SFE fraction (ASTA) was tested in fibroblast cells (HS-68), by inducing oxidative stress and by evaluating the protective effect of the pre-treatment with different levels of ASTA against toxicity. The anti-proliferative activity was evaluated in hepatoma cells (HEP-G2), treated with increased concentrations of ASTA and measuring the effects on vitality and on some biomolecular markers related to oxidative stress, cell cycle, and apoptosis. It was found that pre-treating normal fibroblast cells with ASTA resulted in a marked increase in cell viability in a dose-dependent manner (P < 0.05) attesting its antioxidant power; in cancer cell line, increased concentrations of ASTA caused a time-dose-dependent decrease in the vitality, attesting its anti-proliferative activity (P < 0.05). The increased levels of the protein p-53 and the reduced levels of the proteins c-Jun and c-Fos at higher concentrations of ASTA, as well as, suggest the pro-apoptotic and anti-cancerous effects that this extract has on hepatocellular carcinomas, confirmed also by caspase-3 activation. These findings suggest biotechnological utilisation of marine by-products for nutraceutical and pharmaceutical applications avoiding the employment of organic solvents for extraction.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cromatografia com Fluido Supercrítico/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pigmentos Biológicos/farmacologia , Animais , Antineoplásicos/isolamento & purificação , Antioxidantes/isolamento & purificação , Apoptose/genética , Dióxido de Carbono/química , Caspase 3/genética , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Penaeidae/química , Pigmentos Biológicos/isolamento & purificação , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Solventes/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Xantofilas/isolamento & purificação , Xantofilas/farmacologia
8.
Pancreas ; 48(5): 629-635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091208

RESUMO

OBJECTIVE: The aim of this study was to investigate the role of LONP1 in the progression of pancreatic cancer. METHODS: Lentivirus was used to silence LONP1 in PANC-1 cells. Colony formation assay, cell counting kit (CCK8) assay, cell scratch-wound assay, and transwell assay were used to assess the effects of our strategy on inhibiting cancer growth, migration, and invasion. Protein expression was detected by Western blot analysis. RESULTS: The expression of LONP1 in pancreatic carcinoma tissues was higher than that in adjacent normal pancreatic tissues. Downregulation of LONP1 suppressed the proliferation, migration, and invasion of PANC-1 cells. Knockdown of LONP1 in PANC-1 cells inhibited epithelial-mesenchymal transition and matrix metalloprotein (MMP) 2/9 by downregulation of vimentin, snail, slug, MMP2, and MMP9 and upregulation of claudin-1. The c-Jun N-terminal kinase pathway was inactivated in LONP1 knockdown PANC-1 cells. Activation of the c-Jun N-terminal kinase pathway by anisomycin treatment significantly reversed the changes in epithelial-mesenchymal transition markers and MMP2/9 induced by ablation of LONP1 in PANC-1 cells. CONCLUSIONS: LONP1 plays a vital role in the proliferation and metastasis of pancreatic cancer, which provides a potential therapeutic target for the treatment of pancreatic cancer.


Assuntos
Proteases Dependentes de ATP/metabolismo , Transição Epitelial-Mesenquimal , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Mitocondriais/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteases Dependentes de ATP/genética , Anisomicina/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Mitocondriais/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Vimentina/metabolismo
9.
Int J Cancer ; 145(9): 2496-2508, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30963560

RESUMO

JNK activity has been implicated in the malignant proliferation, invasion and drug-resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c-Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel-like factor-5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated-SP1 and acetylated-KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant-negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c-Jun activities was involved in the tumor-growth inhibitory effects induced by LMK235 in U87-xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c-Jun signaling-mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c-Jun signaling in GCs.


Assuntos
Glioma/genética , Histona Desacetilases/genética , Fatores de Transcrição Kruppel-Like/genética , MAP Quinase Quinase 7/genética , Proteínas Repressoras/genética , Fator de Transcrição Sp1/genética , Animais , Linhagem Celular Tumoral , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas/genética , Transcrição Genética/genética , Ativação Transcricional/genética , Regulação para Cima/genética
10.
Diabetes Res Clin Pract ; 150: 81-89, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30825563

RESUMO

AIMS: Negative pressure wound therapy displayed significant clinical benefits in the healing of diabetic foot wounds. In the present study, we investigated the mechanism of regulation of MAPK-JNK (Mitogen-activated protein kinase- c-Jun N-terminal kinase) signaling pathway by negative pressure wound therapy on these wounds. METHODS: Twenty-six type 2 diabetes patients with foot ulceration were randomly assigned to the two groups, thirteen treated with negative pressure wound therapy and the others treated with traditional debridement therapy. Skin samples were harvested and histologically and immunohistochemical analyzed in both groups. Immunofluorescence stain, Enzyme-linked immunosorbent assay and Western blotting were performed for inducible nitric oxide synthase, inter leukin-6, tumor necrosis factor-α, P-c-Jun N-terminal kinase and c-Jun N-terminal kinase. Real time-polymerase chain reaction was performed to evaluate expression of c-Jun N-terminal kinase, extracellular signal regulated kinase1/2 and p38. RESULTS: Negative pressure wound therapy could effectively alleviate inflammatory reaction and reduce inter leukin-6 and inducible nitric oxide synthase production after 7 days treatment. The level of tumor necrosis factor-α, inter leukin-6 and P-c-Jun N-terminal kinase were significantly decreased. However, there was no statistical difference in messenger ribonucleic acid expression of p38, extracellular signal regulated kinase1 and 2. CONCLUSIONS: Negative pressure wound therapy possibly suppress the wound inflammation by inhibiting inter leukin-6, tumor necrosis factor-α and inducible nitric oxide synthase in diabetic foot patients. This effect is maybe mediated at least in part by suppression of Mitogen-activated protein kinase- c-Jun N-terminal kinase signaling pathway.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Pé Diabético/terapia , Inflamação/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Tratamento de Ferimentos com Pressão Negativa/métodos , Cicatrização , Pé Diabético/etiologia , Pé Diabético/patologia , Regulação para Baixo , Feminino , Humanos , Inflamação/etiologia , Inflamação/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais
11.
Artigo em Inglês | MEDLINE | ID: mdl-30822534

RESUMO

The well-known and effective anthelmintic oxibendazole was recently shown to have a broad spectrum of biological abilities, such as anti-cancer and anti-inflammation activities. In contrast, the mechanism of oxibendazole's anti-proliferative effect via cell signaling pathways and its role in pre-implantation has not been studied. Therefore, in this study we demonstrated the effects of oxibendazole on the proliferation of porcine trophectoderm (pTr) cells and porcine luminal epithelial (pLE) cells, a well-known in vitro model system of the fetal-maternal interface. Cell proliferation decreased in both pTr and pLE cells in response to oxibendazole, and we determined that this was modulated through intracellular cell signal transduction. Phosphorylation of ERK1/2, P90RSK, and S6 were downregulated by exposure to a 200 nM dose of oxibendazole in both types of cells, while the expression of phosphorylated JNK, AKT, and P70S6K was upregulated. Pre-treatment with a PI3K/AKT inhibitor (Wortmannin), ERK1/2 inhibitor (U0126), and JNK inhibitor (SP600125) induced the signaling interactions of these molecules, and oxibendazole co-treatment with each inhibitor resulted in even greater decreases in cell proliferation. Furthermore, intracellular and mitochondrial calcium ion accumulation was observed, which would mean that calcium ion homeostasis was disrupted, causing damage to the mitochondrial membrane potential. These deteriorated conditions ultimately led to apoptotic cell death. Taken together, the results of the present study identified that the apoptotic effect of oxibendazole on pTr and pLE cells is regulated by cell signaling pathways, and thus oxibendazole could influence the connection between the conceptus and the maternal uterus.


Assuntos
Apoptose/efeitos dos fármacos , Benzimidazóis/toxicidade , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Útero/citologia , Animais , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos
12.
Molecules ; 24(5)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823626

RESUMO

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ) has previously been found to have effective anti-oxidant and anti-lipid-peroxidative activity. We aimed to elucidate whether HTHQ can prevent dopaminergic neuronal cell death by investigating the effect on l-DOPA-induced cytotoxicity in PC12 cells. HTHQ protected from both l-DOPA-induced cell death and superoxide dismutase activity reduction. When assessing the effect of HTHQ on oxidative stress-related signaling pathways, HTHQ inhibited l-DOPA-induced phosphorylation of sustained extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1/2). HTHQ also normalized l-DOPA-reduced Bcl-2-associated death protein (Bad) phosphorylation and Bcl-2-associated X protein (Bax) expression, promoting cell survival. Taken together, HTHQ exhibits protective effects against l-DOPA-induced cell death through modulation of the ERK1/2-p38MAPK-JNK1/2-Bad-Bax signaling pathway in PC12 cells. These results suggest that HTHQ may show ameliorative effects against oxidative stress-induced dopaminergic neuronal cell death, although further studies in animal models of Parkinson's disease are required to confirm this.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Hidroquinonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Levodopa/efeitos adversos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células PC12 , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ratos , Proteína X Associada a bcl-2/genética , Proteína de Morte Celular Associada a bcl/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
13.
Molecules ; 24(5)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30832267

RESUMO

Chronic exposure to cisplatin, a potent anticancer drug, causes irreversible kidney damage. In this study, we investigated the protective effect and mechanism of nine lupane- and ceanothane-type triterpenoids isolated from jujube (Ziziphus jujuba Mill., Rhamnaceae) on cisplatin-induced damage to kidney epithelial LLC-PK1 cells via mitogen-activated protein kinase (MAPK) and apoptosis pathways. Cisplatin-induced LLC-PK1 cell death was most significantly reduced following treatment with 3-dehydroxyceanothetric acid 2-methyl ester (3DC2ME). Additionally, apoptotic cell death was significantly reduced. Expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 was markedly suppressed by 3DC2ME, indicating inhibition of the MAPK pathway. Treatment with 3DC2ME also significantly reduced expression of active caspase-8 and -3, Bcl-2-associated X protein (Bax), and B cell lymphoma 2 (Bcl-2), indicating the inhibition of apoptosis pathways in the kidneys. We also applied the network pharmacological analysis and identified multiple targets of 3DC2ME related to MAPK signaling pathway and apoptosis.


Assuntos
Nefropatias/tratamento farmacológico , Neoplasias/tratamento farmacológico , Substâncias Protetoras/farmacologia , Triterpenos/farmacologia , Animais , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 8/genética , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/efeitos adversos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Rim/efeitos dos fármacos , Rim/lesões , Nefropatias/induzido quimicamente , Nefropatias/patologia , Células LLC-PK1 , Neoplasias/complicações , Neoplasias/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Transdução de Sinais/efeitos dos fármacos , Suínos , Triterpenos/química , Proteína X Associada a bcl-2/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
14.
Biomed Res Int ; 2019: 5408289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729126

RESUMO

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis in vivo. Isoproterenol (ISO) was used to induce cardiac fibrosis in rats. PCr administration ameliorated fibrosis by reducing collagen accumulation and fibrosis-related signals, including transforming growth factor beta 1 (TGF-ß1), alpha smooth muscle actin (α-SMA), collagen type I, and collagen type III. Mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signaling pathways, including p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p65, were highly activated by ISO and blocked by PCr. Moreover, PCr decreased ISO-induced matrix metalloproteinase-9 (MMP-9) and increased the tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. Furthermore, PCr suppressed cardiomyocyte apoptosis induced by ISO, as shown by downregulated expression of the proapoptotic caspase-3, Bax, and upregulated expression of the antiapoptotic Bcl-2. Taken together, PCr can be an effective agent for preventing cardiac fibrosis and cardiomyocyte apoptosis.


Assuntos
Fibrose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Fosfocreatina/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose/induzido quimicamente , Fibrose/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Cardiopatias/induzido quimicamente , Cardiopatias/patologia , Humanos , Isoproterenol/toxicidade , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Metaloproteinase 9 da Matriz/genética , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NF-kappa B/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/genética , Fator de Crescimento Transformador beta1/genética
15.
Int J Biochem Cell Biol ; 110: 9-20, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30794859

RESUMO

A cross-talk between androgen/androgen receptor signaling and the AP-1 transcription factor has been proposed. In this study, we asked whether activation of AP-1 modifies androgen-responsive gene transcription, and whether androgens effect AP-1-regulated gene transcription. We show that activation of AP-1 via expression of a constitutively active mutant of mitogen-activated/extracellular signal responsive kinase kinase (MEK) kinase-1 did not increase the activity of the androgen-responsive probasin promoter. Likewise, expression of a constitutively active mutant of the transcription factor c-Jun, which is a major constitutent of AP-1, did not increase the activity of the probasin promoter. In contrast, 5α-dihydrotestosterone (DHT) activated both the probasin promoter and the AP-1-regulated collagenase promoter in LNCaP prostate cancer cells. The AP-1 binding site within the collagenase promoter was identified as DHT-responsive element. In line with this, DHT increased the activities of the c-Jun promoter and the tumor necrosis factor alpha promoter, which both contain AP-1 binding sites. The signal transduction pathway coupling DHT stimulation with AP-1 activation required c-Jun, MAP kinases and androgen receptors, but was independent of transient receptor potential melastatin-8 (TRPM8) channels, proposed to function as ionotropic testosterone receptors. Expression of the GTPase activating protein RGS2 attenuated DHT-induced activation of AP-1, indicating that the DHT-induced signaling cascade involves G proteins.


Assuntos
Di-Hidrotestosterona/farmacologia , Neoplasias da Próstata/patologia , Fator de Transcrição AP-1/metabolismo , Proteína de Ligação a Androgênios/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Regiões Promotoras Genéticas/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPM/metabolismo , Transcrição Genética/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética
16.
Chem Biol Interact ; 302: 36-45, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30707979

RESUMO

Aldose reductase (AR), a member of aldo-keto reductase family, is the rate-limiting enzyme in the polyol pathway, and is known to play a key role in the pathogenesis of diabetic complications. AR also catalyzes the reduction of reactive aldehydes, thereby detoxifying endogenous as well as xenobiotic aldehydes in various tissues. The transcription of the AR gene was previously shown to be augmented by various stimuli including osmotic and oxidative stresses. A highly conserved region composed of an antioxidant response element (ARE), AP-1 site, and tonicity responsive enhancer (TonE) has been identified within the 5'-flanking region of the AR genes of humans, rats, and mice, which we designated as the multiple stress response region (MSRR). We previously showed that the transcription factor Nrf2 activated AR transcription via ARE within MSRR. In the present study, we examined the interactions among Nrf2, c-Jun, and the TonE-binding protein (TonEBP) in the regulation of AR gene transcription. In gene reporter assays using luciferase reporter constructs containing the MSRR of the mouse AR (AKR1B3) gene with HepG2 cells, the forced expression of Nrf2 or TonEBP significantly increased promoter activity. The synergistic augmentation of promoter activity was observed when Nrf2 and TonEBP were co-introduced. On the other hand, the co-expression of c-Jun repressed promoter activation by Nrf2 and TonEBP. The mutation of the AP-1 site within MSRR did not affect the repressive effects of c-Jun, while the introduction of truncated c-Jun proteins lacking the leucine zipper domain no longer suppressed Nrf2-or TonEBP-mediated transactivation, suggesting that c-Jun repressed promoter activity independently of the AP-1 site and that interactions with protein factors via the leucine zipper domain were necessary for its negative effects on Nrf2 and TonEBP. These results indicate that AR promoter activity is cooperatively regulated by multiple transcription factors via MSRR.


Assuntos
Aldeído Redutase/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fatores de Transcrição NFATC/metabolismo , Aldeído Redutase/genética , Animais , Genes Reporter , Células Hep G2 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Camundongos , Mutagênese Sítio-Dirigida , Fator 2 Relacionado a NF-E2/genética , Fatores de Transcrição NFATC/genética , Fosforilação , Plasmídeos/genética , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Transcrição Genética
17.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1332-1340, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30763641

RESUMO

Diabetic nephropathy (DN) is one of the major long-term complications of diabetes. Lysophosphatidic acid (LPA) signaling has been implicated in renal fibrosis. In our previous study, we found that the LPA receptor 1/3 (LPAR1/3) antagonist, ki16425, protected against DN in diabetic db/db mice. Here, we investigated the effects of a specific pharmacological inhibitor of LPA receptor 1 (LPA1), AM095, on DN in streptozotocin (STZ)-induced diabetic mice to exclude a possible contribution of LPAR3 inhibition. AM095 treatment significantly reduced albuminuria and the albumin to creatinine ratio and significantly decreased the glomerular volume and tuft area in the treated group compared with the STZ-vehicle group. In the kidney of STZ-induced diabetic mice, the expression of LPAR1 mRNA and protein was positively correlated with oxidative stress. AM095 treatment inhibited LPA-induced reactive oxygen species production and NADPH oxidase expression as well as LPA-induced toll like receptor 4 (TLR4) expression in mesangial cells and in the kidney of STZ-induced diabetic mice. In addition, AM095 treatment suppressed LPA-induced pro-inflammatory cytokines and fibrotic factors expression through downregulation of phosphorylated NFκBp65 and c-Jun N-terminal kinases (JNK) in vitro and in the kidney of STZ-induced diabetic mice. Pharmacological or siRNA inhibition of TLR4 and NADPH oxidase mimicked the effects of AM095 in vitro. In conclusion, AM095 is effective in preventing the pathogenesis of DN by inhibiting TLR4/NF-κB and the NADPH oxidase system, consequently inhibiting the inflammatory signaling cascade in renal tissue of diabetic mice, suggesting that LPAR1 antagonism might provide a potential therapeutic target for DN.


Assuntos
Antioxidantes/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fenilacetatos/farmacologia , Receptores de Ácidos Lisofosfatídicos/genética , Receptor 4 Toll-Like/genética , Fator de Transcrição RelA/genética , Albuminúria/induzido quimicamente , Albuminúria/tratamento farmacológico , Albuminúria/genética , Albuminúria/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Regulação da Expressão Gênica , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Lisofosfolipídeos/antagonistas & inibidores , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transdução de Sinais , Estreptozocina , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/metabolismo
18.
Reprod Toxicol ; 84: 98-107, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30633982

RESUMO

We previously investigated excessive fluoride exposure elicited intracellular endoplasmic reticulum (ER) stress and led to Sertoli cells dysfunction in vitro. However, the mechanisms underlying fluoride-mediated male reproductive damage in vivo remain largely unknown. Considerable evidence has now revealed ER stress is closely linked with testicular oxidative damage. Hence, we aimed to explore whether ER stress signaling was involved in the testicular protective effects of antioxidant N-acetylcysteine (NAC) against testicular apoptosis induced by fluoride. Male SD rats were oral gavaged with sodium fluoride (NaF) for 7 weeks to induce fluorosis. The animals were pretreatment with or without NAC (150 mg/Bw•d). Our results demonstrated that sub-chronic NaF exposure triggered testicular apoptosis and sex hormonal disturbance in pituitary-testicular (PT) axis, promoted oxidative stress and the expression of ER stress mediators. Antioxidant NAC, however, prevented NaF-induced testicular apoptosis accompanied by activating Nrf2-mediated antioxidant potential. Simultaneously, NAC pretreatment downregulated XBP1 splicing, reduced JNK phosphorylation and further blocked cleavage of caspase-3, all these might contribute to the inhibition of testicular cell apoptosis. Collectively, the present results suggested that prolonged administration of NAC preserved testicular function and normalized sex hormonal disruption induced by NaF via the inhibition of Nrf2-associated oxidative damage and Ire1α-JNK-mediated apoptosis in rat testis.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Fluoretos/toxicidade , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Endorribonucleases/genética , Endorribonucleases/metabolismo , Hormônios Esteroides Gonadais/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Testículo/metabolismo
19.
Molecules ; 24(1)2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30621054

RESUMO

We investigated whether 14 phenolic compounds isolated from Artemisia argyi could prevent the apoptotic damage caused by iodixanol, an iodinated contrast agent, on LLC-PK1 cells. Iodixanol was used to induce cytotoxicity in LLC-PK1 cells. Apoptotic cell death was observed as the fluorescence intensity emitted by annexin V and Hoechst 33342 stains. Western blotting was used to detect specific proteins. Seven phenolic compounds protected against iodixanol-induced LLC-PK1 cell death in a concentration-dependent manner. Among them, methyl caffeate exerted the strongest protective effect, and co-treatment with 50 and 100 µM methyl caffeate decreased intracellular reactive oxygen species elevated by 25 mg/mL iodixanol. In addition, the treatment of LLC-PK1 cells with iodixanol resulted in an increase in apoptotic cell death, which decreased by co-treatment with methyl caffeate. Iodixanol caused a cytotoxicity-related increase in the phosphorylation of extracellular-signal-regulated kinase, c-Jun N-terminal kinase, and P38; and a similar increase in the expression levels of kidney injury molecule-1 and cleaved caspase-3. However, the up-regulation of these proteins was reversed by co-treatment with methyl caffeate. These findings suggest that phenolic compounds isolated from A. argyi play an important role in protecting kidney epithelium cells against apoptotic damage caused by iodixanol.


Assuntos
Apoptose/efeitos dos fármacos , Meios de Contraste/efeitos adversos , Rim/efeitos dos fármacos , Fenóis/farmacologia , Animais , Artemisia , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Receptor Celular 1 do Vírus da Hepatite A/genética , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Rim/lesões , Rim/patologia , Células LLC-PK1 , Espécies Reativas de Oxigênio/metabolismo , Suínos , Ácidos Tri-Iodobenzoicos/efeitos adversos , Proteínas Quinases p38 Ativadas por Mitógeno/genética
20.
Hum Exp Toxicol ; 38(1): 95-105, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29896988

RESUMO

Thyroid hormone deficiency can impair testicular function. However, knowledge of the effects of mitogen-activated protein kinase (MAPK) pathways on testicular mitochondrial oxidative damage induced by hypothyroidism is still rudimentary. This study aims to explore the possible mechanisms of testicular mitochondrial oxidative damage in hypothyroidism rats. Wistar male rats were randomly divided into control (C), low- (L), and high-hypothyroidism (H) groups (1 ml/100 g body weights (BWs)/day 0, 0.001% and 0.1% propylthiouracil, respectively) by intragastric gavage for 60 days. Blood samples were collected to measure the levels of serum triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH). Testicular mitochondrial homogenates were used to measure the activities of superoxide dismutase (SOD), catalase (CAT), and Ca2+-ATPase as well as protein and mRNA expression of androgen receptor (AR), p38 MAPK, and c-Jun NH2-terminal kinase (JNK). Results showed that the BWs, testes weights, and levels of T3 and T4 were all significantly decreased and the testes coefficient and level of TSH were significantly increased in the H group. There were significant decreases in SOD activity in the H group as well as decreases in CAT and Ca2+-ATPase activities in the L and H groups. Additionally, protein expression of AR decreased significantly and protein expression of phosphorylated p38MAPK and JNK increased significantly in the H group. Therefore, the study suggests that hypothyroidism could affect male reproductive function by disturbing expression of AR, changing the activity of Ca2+-ATPase, inducing oxidative stress and then leading to activation of p38MAPK and JNK signaling in the testicular mitochondria.


Assuntos
Hipotireoidismo/metabolismo , Mitocôndrias/metabolismo , Testículo/metabolismo , Animais , Peso Corporal , ATPases Transportadoras de Cálcio/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Tamanho do Órgão , Estresse Oxidativo , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais , Testículo/patologia , Hormônios Tireóideos/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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