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1.
Cell Mol Neurobiol ; 34(7): 1037-45, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25005833

RESUMO

The brain in Alzheimer's disease is under increased oxidative stress, and this may have a role in the pathogenesis and neural death in this disorder. It has been verified that numerous signaling pathways involved in neurodegenerative disorders are activated in response to reactive oxygen species (ROS). EUK134, a synthetic salen-manganese antioxidant complex, has been found to possess many interesting pharmacological activities awaiting exploration. The present study is to characterize the role of Notch signaling in apoptotic cell death of SK-N-MC cells. The cells were treated with hydrogen peroxide (H2O2) or menadione to induce oxidative stress. The free-radical scavenging capabilities of EUK134 were studied through the MTT assay, glutathione peroxidase (GPx) enzyme activity assay, and glutathione (GSH) Levels. The extents of lipid peroxidation, protein carbonyl formation, and intracellular ROS levels, as markers of oxidative stress, were also studied. Our results showed that H2O2/menadione reduced GSH levels and GPx activity. However, EUK134 protected cells against ROS-induced cell death by down-regulation of lipid peroxidation and protein carbonyl formation as well as restoration of antioxidant enzymes activity. ROS induced apoptosis and increased NICD and HES1 expression. Inhibition of NICD production proved that Notch signaling is involved in apoptosis through p53 activation. Moreover, H2O2/menadione led to Numb protein down-regulation which upon EUK134 pretreatment, its level increased and subsequently prevented Notch pathway activation. We indicated that EUK134 can be a promising candidate in designing natural-based drugs for ROS-induced neurodegenerative diseases. Collectively, ROS activated Notch signaling in SK-N-MC cells leading to cell apoptosis.


Assuntos
Peróxido de Hidrogênio/toxicidade , Compostos Organometálicos/farmacologia , Receptores Notch/metabolismo , Salicilatos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Vitamina K 3/toxicidade , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Caspase 9/metabolismo , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Espaço Intracelular/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Carbonilação Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição HES-1 , Proteína Supressora de Tumor p53/metabolismo , Proteína X Associada a bcl-2/metabolismo
2.
Neuropeptides ; 92: 102228, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35101843

RESUMO

Damage to the spinal cord triggers a local complex inflammatory reaction that results in irreversible impairments or complete loss of motor function. The evidence suggested that inhibiting the pro-inflammatory macrophage/microglia (M1 subsets) and stimulating the anti-inflammatory macrophage/microglia (M2 subsets) are potential strategies for the treatment of neuroinflammation-related diseases. We evaluated the potentially protective effect of Ac-SDKP as an endogenous tetrapeptide on rat spinal cord injury (SCI). Wistar rats were subjected to a weight-drop contusion model and were treated with Ac-SDKP (0.8 mg/kg) given subcutaneously once a day for 7 days starting at two clinically relevant times, at 2 h or 6 h post-injury. The effect of Ac-SDKP was assessed by motor functional analysis, real-time PCR (CD86 and CD206 mRNA), western blot (caspase-3), ELISA (TNF-a, IL-10), and histological analysis (toluidine blue staining). Ac-SDKP improved locomotor recovery and rescue motor neuron loss after SCI. Moreover, a decreased in TNF-a level as well as caspase 3 protein levels occurred in the lesion epicenter of the spinal cord following treatment. In addition, CD206 mRNA expression level increased significantly in Ac-SDKP treated rats compared with SCI. Together these data suggest that Ac-SDKP might be a novel immunomodulatory drug. It may be beneficial for the treatment of SCI with regards to increasing CD206 gene expression and suppress inflammatory cytokine to improve motor function and reducing histopathological lesion.


Assuntos
Traumatismos da Medula Espinal , Animais , Oligopeptídeos/farmacologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo
3.
Brain Res Bull ; 154: 21-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31589901

RESUMO

Despite the attention given to the treatment of multiple sclerosis (MS), still no certain cure is available. The main purpose of MS drugs is acting against neuroinflammation which underlies the pathology of MS. Neuroinflammation is associated with endoplasmic reticulum (ER) stress that mediates neural apoptosis. In the present study, we hypothesized that the tetrapeptide N-acetyl-ser-asp-lys-pro (Ac-SDKP) with the previously described anti-fibrotic effects might have anti-inflammatory, anti-oxidative and anti-ER stress roles in the hippocampus. We used myelin oligodendrocyte glycoprotein (MOG) to induce experimental autoimmune encephalomyelitis (EAE), a widely-accepted animal model of MS, in C57BL/6 mice. The protein levels of ER stress-related molecules including caspase-12, C/EBP homologous protein (CHOP), and protein disulfide isomerase (PDI) in the hippocampus were examined by immunoblotting. Hence, reactive oxygen species (ROS) production, lipid peroxidation and antioxidant capacity of the hippocampus were studied. Moreover, hippocampal morphology changes, leukocytes infiltration, and the levels of IL-6 and IL-1ß pro-inflammatory cytokines were evaluated. Our results displayed that Ac-SDKP down regulates caspase-12 and CHOP expression in the hippocampus-resident oligodendrocytes of EAE mice. Further, treatment with Ac-SDKP decreased oxidative stress markers and caspase-3 activation in the hippocampus of EAE mice. According to our findings, Ac-SDKP showed beneficial effects against ER stress and oxidative stress in addition to inflammation in the hippocampus of EAE mice. The present study provides the basis for further research on the therapeutic applications of Ac-SDKP to reduce ER stress and oxidative stress-induced apoptosis in neurodegenerative disorders.


Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Oligopeptídeos/farmacologia , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Caspase 12/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/fisiopatologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/fisiologia , Feminino , Hipocampo/metabolismo , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Glicoproteína Mielina-Oligodendrócito/farmacologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Oligopeptídeos/metabolismo , Oxirredução , Estresse Oxidativo/fisiologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Fator de Transcrição CHOP/metabolismo
4.
Int Immunopharmacol ; 82: 106286, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32172212

RESUMO

Endoplasmic reticulum (ER) stress is strictly linked to neuroinflammation and involves in the development of neurodegenerative disorders. Protein disulfide isomerase (PDI) is an enzyme that catalyzes formation and isomerization of disulfide bonds and also acts as a chaperone that survives the cells against cell death by removal of misfolded proteins. Our previous work revealed that PDI is explicitly upregulated in response to myelin oligodendrocyte glycoprotein (MOG)-induced ER stress in the brain of experimental autoimmune encephalomyelitis (EAE) mice. The significance of overexpression of PDI in the apoptosis of neural cells prompted us to study the effect of CCF642, efficient inhibitor of PDI, in the recovery of EAE clinical symptoms. Using this in vivo model, we characterized the ability of CCF642 to decrease the expression of ER stress markers and neuroinflammation in the hippocampus of EAE mice. Our observations suggested that CCF642 administration attenuates EAE clinical symptomsand the expression of ER stress-related proteins. Further, it suppressed the inflammatory infiltration of CD4 + T cells and the activation of hippocampus-resident microglia and Th17 cells. We reported here that the inhibition of PDI protected EAE mice against neuronal apoptosis induced by prolonged ER stress and resulted in neuroprotection.

5.
Brain Res Bull ; 147: 174-182, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30738137

RESUMO

The role of endoplasmic reticulum (ER) stress has been proposed in several neurodegenerative and autoimmune diseases and may contribute to neural apoptosis. The complex role of ER stress-mediated apoptosis introduces a novel angle on multiple sclerosis (MS) research. Nevertheless, the mechanisms through which ER stress intermediates apoptosis are not entirely understood. To this aim, we examined the expression of C/EBP homologous protein (CHOP), caspase-12, and protein disulfide isomerase (PDI) in mice with experimental autoimmune encephalomyelitis (EAE). We found the upregulated expression of CHOP, caspase-12, and PDI in the brain of EAE mice in comparison to healthy mice. Furthermore, immunofluorescent dual-label staining verified elevated levels of caspase-12/CHOP in astrocytes, oligodendrocytes, and microglia in the hippocampus section of EAE mice. This study highlighted the presence of ER stress and increased activation of caspase-12 in the hippocampus of mice in response to EAE induction. Higher levels of caspase-12/CHOP in hippocampal oligodendrocytes as compared with microglia and astrocytes denote that oligodendrocytes are particularly sensitive to ER-mediated apoptosis. In conclusion, the regulation of ER stress pathway would be beneficial for the survival of oligodendrocyte.


Assuntos
Caspase 12/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Fator de Transcrição CHOP/metabolismo , Animais , Apoptose/genética , Astrócitos/metabolismo , Encéfalo/metabolismo , Caspase 12/genética , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Oligodendroglia/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Fator de Transcrição CHOP/genética
6.
Ther Clin Risk Manag ; 14: 2029-2049, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464484

RESUMO

Osteoporosis is a bone disorder with remarkable changes in bone biologic material and consequent bone structural distraction, affecting millions of people around the world from different ethnic groups. Bone fragility is the worse outcome of the disease, which needs long term therapy and medical management, especially in the elderly. Many involved genes including environmental factors have been introduced as the disease risk factors so far, of which genes should be considered as effective early diagnosis biomarkers, especially for the individuals from high-risk families. In this review, a number of important criteria involved in osteoporosis are addressed and discussed.

7.
Inflammation ; 38(1): 205-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25342284

RESUMO

Oral pemphigus vulgaris (PV) is a rare blistering disorder of the skin and mucous membranes in the mouth. Inflammasome serves as a molecular platform that mediates the autoactivation of caspase-1, which cleaves the pro-forms of IL-1ß and IL-18 to active forms. Therefore, the main aim of this study was to evaluate the messenger RNA (mRNA) levels of NOD-like receptor-related protein (NLRP)1, NLRP3, and IPAF in the PBMCs of PV patients to determine their effect in PV pathogenesis. This study was designed as a cross-sectional study. We studied mRNA levels of three types of inflammasomes including NLRP1, NLRP3, and IPAF in 43 oral PV patients and 40 healthy controls by real-time PCR technique. Results were analyzed by SPSS software package version 18. Here, we showed that the mRNA levels of NLRP1 and IPAF in patients with active PV remarkably increased compared to those in healthy controls. However, the mRNA level of NLRP3 in PBMC of PV patients was similar to that of the control group. We showed important and emerging relationship of NLRP1 and IPAF mRNAs with PV disease progression. We hypothesize that NLRP1 and IPAF with cytokine activity of IL-1ß are involved in the inflammation in PV patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Adaptadoras de Sinalização CARD/biossíntese , Proteínas de Ligação ao Cálcio/biossíntese , Pênfigo/sangue , Proteínas Adaptadoras de Transdução de Sinal/sangue , Proteínas Reguladoras de Apoptose/sangue , Biomarcadores/sangue , Proteínas Adaptadoras de Sinalização CARD/sangue , Proteínas de Ligação ao Cálcio/sangue , Estudos Transversais , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/sangue , Proteínas NLR , Pênfigo/diagnóstico
8.
Asian Pac J Cancer Prev ; 15(24): 10603-5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25605146

RESUMO

BACKGROUND: The Prostate cancer is the 2nd most common cancer worldwide for males, and the 5th most common cancer overall, with an estimated 900,000 new cases diagnosed in 2008 (14% of the total in males and 7% of the total overall) aim of this study was to assess some of the most proposed environmental factors influencing the incidence of prostate cancer among Iranian men. Smoking, opioids, occupation and living location were considered as studied risk factors of the prostate cancer in this research. MATERIAL AND METHODS: Two groups of affected men with prostate cancer and controls aged 50-75 years referred to medical clinics were subjects in this case-control study. Living and working place, smoking and drug consuming habits were assessed for any associations with prostate cancer. RESULTS: The largest number, of patients, in order, belonged to Tehran, provincial capitals, major industrial cities, small towns and villages, respectively. The disease showed links with smoking and drugs with a significant difference between controls and patients (P value <0.0001). CONCLUSIONS: Our recent evidence duplicates previously done researches confirming the serious adverse effects of smoking and drugs on the prostate cancer occurrence in Iranian men. Living place bearings some hazardous behaviors which increases the rate of diseases as well as advanced chance for associated cancers like prostate.


Assuntos
Exposição Ambiental/efeitos adversos , Neoplasias da Próstata/etiologia , Fumar/efeitos adversos , Idoso , Estudos de Casos e Controles , Seguimentos , Humanos , Incidência , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ocupações , Prognóstico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Fatores de Risco
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