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1.
Cell Mol Biol (Noisy-le-grand) ; 69(3): 28-32, 2023 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-37300691

RESUMO

Alzheimer's disease (AD) is one of the acute degenerative diseases of the brain that occurs in the central nervous system. This disease is caused by the abnormal deposition of insoluble plaques and peptide amyloid beta (Aß), the formation of nodules, and synaptic disorder. The formation of these nodes disrupts the functioning of neural circuits and changes in behavioral response due to the activation of neurotransmitter receptors. Research in recent years has shown that microRNAs play an effective role in Alzheimer's disease and neurotransmitter factors. Recently, miR-107 is effective in the pathology of Alzheimer's disease (AD) through the regulation of NF-κB signaling pathway. Experiments conducted using the dual luciferase method and western blot analysis also showed that miR-107 in primary neurons affects neurotransmitter factors in Alzheimer's disease through the regulation of the NF-κB signaling pathway. The results showed that the reduction of miR-107 expression through the regulation of the NF-κB signaling pathway leads to the suppression of cell apoptosis in Alzheimer's patients. On the other hand, increasing the expression of miR-107 leads to increasing the breaking process of Amyloid precursor protein (APP). This factor increases the production of amyloid beta (Aß) peptide plaques and increases the expression of the BACE1 gene, which ultimately leads to the induction of apoptosis and induction of Alzheimer's disease.


Assuntos
Doença de Alzheimer , MicroRNAs , Humanos , Doença de Alzheimer/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Peptídeos beta-Amiloides/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Apoptose/genética
2.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(12): 1646-1654, 2022 Dec 28.
Artigo em Inglês, Zh | MEDLINE | ID: mdl-36748374

RESUMO

OBJECTIVES: Glioma is the most common primary intracranial tumor and there is still no ideal treatment at present. Gene therapy, as one of the new methods for treating glioma, has attracted attention in recent years. But its application in treating glioma is very limited due to lack of effective delivery vectors. This study aims to investigate the feasibility of biomimetic nanomaterials made from glioma cells-derived extracellular vesicles (EV) for targeted delivery of signal transducers and activators of transcription 3 (STAT3)-small interfering RNA (siRNA) in treating glioma. METHODS: First, U251 glioma cells-derived extracellular vessel (EVU251) was extracted by ultra-centrifugal method. Nanoparticle tracking analysis was used to characterize the particle size distribution, the transmission electron microscope was used to analyze the morphology, and Western blotting was used to verify the expression of srface characteristic protein. The homing ability was verified by cell uptake assay after labeling EVU251 with membrane dye kit PKH67; the EVU251 contents were removed by a low permeability method and then EVMU251 was prepared through a microporous membrane. Finally, the biomimetic nanomaterials EVMU251@STAT3-siRNA were prepared by loading STAT3-SiRNA with electro-dyeing method. The real-time quantitative PCR was used to quantify the successful encapsulation of siRNA, and the encapsulation and drug loading rate was calculated; then Cy5-labeled siRNA was used to evaluate the ability of biomimetic nanomaterials (EVMU251@CY5-siRNA) to target U251 cells. Lysosomal escape ability of the biomimetic nanomaterial was evaluated by lysosomal dye lyso-tracker green. At last, the ability of EVMU251@STAT3-siRNA to knock down STAT3 gene and selective killing of U251 cells was detected by cell experiments in vitro. RESULTS: The size of EVU251 ranged from 50 nm to 200 nm with a natural disc shape. The expression of extracellular vesicle marker proteins could be detected on the membrane of EVU251. The cell uptake assay demonstrated that it had homing ability to target U251 cells. After EVU251 was prepared as EVMU251@STAT3-siRNA, the particle size was (177.9±5.0) nm, the siRNA loading rate was (33.5±2.2)% and the drug loading rate was (3.24±0.21)%. The biomimetic nanomaterial EVMU251@STAT3-siRNA still had the ability to target U251 cells and successfully deliver siRNA to the cytoplasm without lysosomal degradation. The EVMU251@STAT3-siRNA can effectively knock down the expression of STAT3 gene and produce selective killing ability in U251 cells. CONCLUSIONS: The biomimetic nanomaterials EVMU251@STAT3-siRNA made from glioma U251 cells-derived extracellular vesicles can knock down STAT3 gene of U251 cells and produce selective killing effect, which can provide a new idea for the treatment of glioma.


Assuntos
Glioma , Nanoestruturas , Humanos , RNA Interferente Pequeno/genética , Biomimética , Linhagem Celular Tumoral , Glioma/genética , Glioma/terapia , Proliferação de Células , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
3.
Pharmazie ; 68(8): 649-52, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24020118

RESUMO

Neurodegenerative tauopathy characterized by hyperphosphorylation tau has been implicated in the pathophysiology of diabetic central nervous system (CNS) complication. Emerging evidence has suggested that hyperphosphorylation tau is caused by an imbalance of protein kinase and phosphatase activity. This review focuses on the contributions of impaired insulin signaling to diabetes-related tauopathy through disrupting the balance of tau-related protein kinases and phosphatases. In addition, we describe tau pathology as a potential target for central neuronal degeneration in diabetes mellitus.


Assuntos
Neuropatias Diabéticas/patologia , Tauopatias/etiologia , Tauopatias/patologia , Proteínas tau/fisiologia , Animais , Neuropatias Diabéticas/diagnóstico , Humanos , Insulina/fisiologia , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais/fisiologia , Tauopatias/diagnóstico
4.
Biomed Pharmacother ; 157: 113993, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36379120

RESUMO

Abnormal energy metabolism, as one of the important hallmarks of cancer, was induced by multiple carcinogenic factors and tumor-specific microenvironments. It comprises aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis. Considering that metabolic reprogramming provides various nutrients for tumor survival and development, it has been considered a potential target for cancer therapy. Cannabinoids have been shown to exhibit a variety of anticancer activities by unclear mechanisms. This paper first reviews the recent progress of related signaling pathways (reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), hypoxia-inducible factor-1alpha (HIF-1α), and p53) mediating the reprogramming of cancer metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism). Then we comprehensively explore the latest discoveries and possible mechanisms of the anticancer effects of cannabinoids through the regulation of the above-mentioned related signaling pathways, to provide new targets and insights for cancer prevention and treatment.


Assuntos
Canabinoides , Neoplasias , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Neoplasias/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Glicólise , Microambiente Tumoral
5.
Cancer Gene Ther ; 30(8): 1156-1166, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37231059

RESUMO

Extracellular vesicles (EVs) play a crucial role in regulating cell behavior by delivering their cargo to target cells. However, the mechanisms underlying EV-cell interactions are not well understood. Previous studies have shown that heparan sulfate (HS) on target cell surfaces can act as receptors for exosomes uptake, but the ligand for HS on EVs has not been identified. In this study, we isolated EVs from glioma cell lines and glioma patients and identified Annexin A2 (AnxA2) on EVs as a key HS-binding ligand and mediator of EV-cell interactions. Our findings suggest that HS plays a dual role in EV-cell interactions, where HS on EVs captures AnxA2, and on target cells, it acts as a receptor for AnxA2. Removal of HS from the EV surface inhibits EV-target cell interaction by releasing AnxA2. Furthermore, we found that AnxA2-mediated binding of EVs to vascular endothelial cells promotes angiogenesis, and that antibody against AnxA2 inhibited the ability of glioma-derived EVs to stimulate angiogenesis by reducing the uptake of EVs. Our study also suggests that the AnxA2-HS interaction may accelerate the glioma-derived EVs-mediated angiogenesis and that combining AnxA2 on glioma cells with HS on endothelial cells may effectively improve the prognosis evaluation of glioma patients.


Assuntos
Anexina A2 , Vesículas Extracelulares , Glioma , Humanos , Células Endoteliais/metabolismo , Anexina A2/metabolismo , Ligantes , Vesículas Extracelulares/metabolismo , Glioma/metabolismo , Heparitina Sulfato/metabolismo
6.
J Neurosci Res ; 90(6): 1209-17, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22488726

RESUMO

There are significant morphological and biochemical alterations during nerve growth factor (NGF)-promoted neuronal differentiation, and the process is regulated by molecules, including nitric oxide (NO). Dimethylarginine dimethylaminohydrolase (DDAH) is thought to play a critical role in regulating NO production via hydrolyzing the endogenous NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). Thus, we tested the role of DDAH in NGF-promoted differentiation of PC12 (pheochromocytoma) cells. The present results show that both mRNA and protein levels of DDAH1 were increased, whereas those of DDAH2 were decreased, during NGF-promoted cell differentiation. Both the DDAH activity and the ADMA level in cultured medium were unchanged in this process. NGF promoted neurite formation and induced the expression of microtubule-associated protein 2 (MAP2), a neuronal marker, which were both significantly repressed by DDAH1 silence with small interfering RNA but not by DDAH2 silence. The expressions of three isoforms of NOS were markedly upregulated after NGF stimulation with a time course similar to that of DDAH1, which were attenuated by DDAH1 silence. Conversely, overexpression of DDAH1 accelerated neurite formation in PC12 cells, concomitantly with upregulating the expression of three NOS isoforms. In summary, our data reveal the critical regulatory effect of DDAH1 on NGF-promoted differentiation of PC12 cells in an NOS/NO-dependent but ADMA-independent manner.


Assuntos
Amidoidrolases/metabolismo , Diferenciação Celular/efeitos dos fármacos , Fator de Crescimento Neural/farmacologia , Neuritos/efeitos dos fármacos , Neurônios/citologia , Óxido Nítrico/metabolismo , Amidoidrolases/genética , Análise de Variância , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Arginina/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Células PC12 , RNA Mensageiro/metabolismo , Ratos , Transfecção
7.
Pharmazie ; 67(1): 74-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22393835

RESUMO

The aim of the present study was to evaluate the impact of the UCP2-866 G/A polymorphism on the efficacy of repaglinide in treating patients with diabetes mellitus type 2 (T2DM). 370 patients with T2DM and 166 healthy volunteers were enrolled to identify UCP2-866 G/A genotypes. 16 patients with GG genotype, 14 with GA genotype and 11 with AA genotype of UCP2-866 G/A underwent an 8-week repaglinide treatment regimen. There were no differences in allele frequency of UCP2-866 G/A between T2DM patients and control subjects. The patient with AA genotype of UCP2-866 G/A had higher levels of fasting plasma glucose (FPG), 30-min and 2-h postload plasma glucose, glycated haemoglobin (HbA1c), and lower concentrations of 30-min and 2-h postload plasma insulin, homeostasis model assessment of beta cell function (HOMA-beta), deltaI30/deltaG30 compared with GG genotype. After repaglinide treatment for 8 consecutive weeks, we found that A allele carriers of UCP2 in the T2DM patients had smaller decrease in FPG (P < 0.05) and HbA1c (P < 0.05), and smaller increase in 30-min postload plasma insulin (P < 0.01) compared with GG genotypes. We demonstrated that UCP2-866 G/A polymorphism is associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.


Assuntos
Carbamatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/farmacologia , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Piperidinas/farmacologia , Adulto , Idoso , Alelos , Povo Asiático/genética , Glicemia/metabolismo , Primers do DNA , Feminino , Genótipo , Humanos , Insulina/sangue , Células Secretoras de Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Testes de Função Pancreática , Reação em Cadeia da Polimerase , Proteína Desacopladora 2
8.
J Int Med Res ; 49(9): 3000605211040762, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34590923

RESUMO

OBJECTIVE: Previous investigations indicated the anticancer activity of puerarin. The current study aimed to evaluate the effect and molecular mechanisms of puerarin in chemotherapy-resistant ovarian cancer cells. METHODS: We examined the effects of puerarin in platinum-resistant epithelial ovarian cancer cells in vitro and in vivo. We also analyzed the molecular mechanism underlying Wnt/ß-catenin inhibition and sirtuin 1 (SIRT1) regulation following puerarin treatment. RESULTS: Our study demonstrated that puerarin effectively inhibited cell growth in vitro and in vivo by increasing apoptosis in ovarian cancer cells. More importantly, puerarin sensitized cisplatin-resistant ovarian cancer cells to chemotherapy. Puerarin treatment decreased SIRT1 expression, which attenuated the nuclear accumulation of ß-catenin to inhibit Wnt/ß-catenin signaling. In addition, SIRT1 overexpression diminished the effects of puerarin treatment on cisplatin-resistant ovarian cancer cells. Further analysis supported SIRT1/ß-catenin expression as a candidate biomarker for the disease progression of epithelial ovarian cancer. CONCLUSIONS: Puerarin increased the apoptosis of platinum-resistant ovarian cancer cells. The mechanism is partly related to the downregulation of SIRT1 and subsequent inhibition of Wnt/ß-catenin signaling.


Assuntos
Neoplasias Ovarianas , Sirtuína 1 , Apoptose , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Isoflavonas , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Sirtuína 1/genética , beta Catenina/genética
9.
Cell Death Dis ; 12(3): 261, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712571

RESUMO

In order to set up a reliable prediction system for the tumor grade and prognosis in glioma patients, we clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients. We found that ANXA2-induced glioma cell proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level, forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both mRNA and protein levels of ANXA2 were upregulated in glioma tissues and coincided with the overexpression of GPC1. Besides, we utilized tissue microarrays (TMAs) and immunohistochemistry to demonstrate that glioma patients with both high expression of ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). In conclusion, the overexpression of ANXA2 promotes proliferation of glioma cells by forming a GPC1/c-Myc positive feedback loop, and ANXA2 together with its downstream target GPC1 could be a potential "combination biomarker" for predicting prognosis of glioma patients.


Assuntos
Anexina A2/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Anexina A2/genética , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Linhagem Celular Tumoral , Proliferação de Células , Retroalimentação Fisiológica , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/patologia , Glioma/cirurgia , Glipicanas/genética , Glipicanas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais , Regulação para Cima
10.
Kaohsiung J Med Sci ; 36(6): 429-440, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32125086

RESUMO

Intrahepatic cholangiocarcinoma is a malignant tumor originating from intrahepatic bile ducts. Surgical therapy, radiotherapy, and chemotherapy are taken to treat this disease, but it is prone to recurrence and metastasis, with poor prognosis. Therefore, it is of great significance to explore new targets and molecular mechanisms for the development of cholangiocarcinoma cells. Clinical cholangiocarcinoma tissues from patients and four human cholangiocarcinoma cell lines were analyzed for microRNA-373 (miR-373) expression. For investigating whether miR-373 directly modulated unc-51 like autophagy activating kinase 1 (ULK1), dual-luciferase reporter assay was performed. In addition, CCK-8 assay, flow cytometry, western blot, and immunofluorescence were applied to evaluate the proliferation, apoptosis, and autophagy of cholangiocytic hepatocellular carcinoma cells. miR-373 downregulation was observed in clinical tissues and cell lines of cholangiocarcinoma. Overexpression of miR-373 reduced proliferation, enhanced apoptosis, and raised expression levels of pro-apoptosis proteins including BCL2 associated X (Bax), Caspase-3, and Caspase-9. Moreover, overexpression of miR-373 downregulated expression levels of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II, Beclin-1, and promoted P62 expression on mRNA and protein levels. After miR-373 knockdown, all indexes of apoptosis and autophagy mentioned above were reversed. Luciferase activity was decreased after cotransfection of miR-373 mimic and wild-type ULK1 vector. Also, miR-373 overexpression inhibited ULK1 expression. Importantly, overexpression of miR-373 weakened expressions of ULK1, LC3, Beclin-1, and Bcl-2, and enhanced expressions of P62, Bax, Caspase-3, and Caspase-9. miR-373 mimic treatment and subsequent ULK1 overexpression, induced reverse regulation in expressions of these proteins, compared with overexpression of miR-373 only. miR-373 targeted ULK1 to initiate inhibition of autophagy and subsequent promotion of apoptosis in cholangiocarcinoma cells.


Assuntos
Apoptose/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Autofagia/genética , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Adulto , Idoso , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Pareamento de Bases , Sequência de Bases , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Luciferases/genética , Luciferases/metabolismo , Masculino , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mimetismo Molecular , Estadiamento de Neoplasias , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Transdução de Sinais , Análise de Sobrevida
11.
J Neurosci Res ; 87(8): 1938-46, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19156866

RESUMO

Previous studies have shown that the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its specific hydrolase dimethylarginine dimethylaminohydrolase (DDAH) are involved in the regulation of apoptosis in different cell types. In the present study, we investigated the role of the DDAH/ADMA pathway in cobalt chloride (CoCl(2))-induced apoptosis and the antiapoptotic effect of all-trans retinoic acid (atRA) in undifferentiated pheochromocytoma (PC12) cells. Treatment of CoCl(2) (125 microM) for 48 hr significantly induced the apoptosis of PC12 cells, concomitantly with increased intracellular reactive oxygen species (ROS) production and caspase-3 activity. CoCl(2) treatment also decreased the activity of DDAH and the expression of DDAH2 (mRNA and protein), resulting in an increased level of ADMA. All these alterations induced by CoCl(2) were attenuated by atRA (0.1, 1, or 10 microM). Interestingly, the antiapoptotic effects of atRA were inhibited by DDAH2 small RNA interference. In contrast, DDAH2 overexpression inhibited the proapoptotic effects of CoCl(2). We also found that treatment of exogenous ADMA (3, 10, or 30 microM) induced the apoptosis of PC12 cells in a concentration- and time-dependent manner, which was inhibited by the antioxidant or the caspase-3 inhibitor. These findings suggest that the modulation of the DDAH/ADMA/ROS pathway plays an important role in CoCl(2)-induced apoptosis and the antiapoptotic effects of atRA in undifferentiated PC12 cells.


Assuntos
Amidoidrolases/metabolismo , Apoptose/efeitos dos fármacos , Arginina/análogos & derivados , Cobalto/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Tretinoína/farmacologia , Amidoidrolases/genética , Animais , Apoptose/fisiologia , Arginina/metabolismo , Arginina/farmacologia , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Cobalto/toxicidade , Relação Dose-Resposta a Droga , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
12.
Exp Ther Med ; 17(4): 2931-2936, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30936962

RESUMO

The present study describes the successful application of next-generation sequencing (NGS) in the clinical diagnosis, pathogenic gene identification, treatment and pre-natal diagnosis in a pedigree with chronic granulomatosis disease (CGD). A 36-day-old infant, born to non-consanguineous Chinese parents, was admitted to hospital due to a neck lump for 10 days. A blood sample was collected for NGS to identify the molecular etiology. Sanger sequencing was performed for the patient and his relatives, including the parents. Amniotic fluid exfoliative cells from the mother were collected for pre-natal diagnosis at week 16 of a subsequent pregnancy. A novel c.1520_1521del, p.Lys508Aspfs*10 (NM_000397) variant in the cytochrome b-245 ß chain (CYBB) gene was identified in the proband, while the mother and the proband's 1-year-old sister were heterozygotes at this site. Karyotype analysis indicated that the fetus of the subsequent pregnancy was male. Sanger sequencing of amniotic cell DNA revealed that the fetus did not have the CYBB abnormality at the site. The results of the present study suggest that the variant in the CYBB gene was the cause of CGD in this pedigree and that pre-natal diagnosis using NGS is an effective method for providing genetic counseling to pedigrees with CGD.

13.
Cell Death Dis ; 9(7): 771, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29991726

RESUMO

The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation.


Assuntos
Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Autofagia/fisiologia , Caveolina 1/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Ácido Palmítico/farmacologia , Animais , Apoptose/genética , Apoptose/fisiologia , Autofagia/genética , Western Blotting , Caveolina 1/genética , Células Cultivadas , Imunofluorescência , Marcação In Situ das Extremidades Cortadas , Inflamação/imunologia , Masculino , Microscopia Eletrônica de Transmissão , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
14.
Oncol Lett ; 15(6): 8681-8686, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29805605

RESUMO

Periostin (POSTN) secreted by intrahepatic cholangiocarcinoma stem cells (ICSCs) serves important roles in promoting tumor progression. The present study aimed to investigate POSTN-recruited tumor-associated macrophages (TAMs) in intrahepatic cholangiocarcinoma (ICC). A total of 50 cases were used to investigate the distribution of ICSCs and TAMs in ICC. HCCC-9810 cells were sorted by cluster of differentiation (CD)44, the expression of POSTN of CD44+ (cancer stem cells) and CD44- cells (non-cancer stem cells), and medium were evaluated by western blot analysis. HCCC-9810 cells and THP-1 macrophages were used to detect the effects of POSTN on recruiting TAMs in vitro. The present study revealed that CD44+ cells in ICC tissues and the HCCC-9810 cell line were associated with high POSTN secretion levels. Furthermore, POSTN was associated with TAM density in primary ICC tissues. Additionally, POSTN increased the migration of TAMs derived from THP-1 cells. These findings suggested that POSTN secreted by ICSCs may serve important functions in TAM recruitment, and it may be a potential curative strategy to target the tumor microenvironment in ICC.

15.
Neurobiol Aging ; 67: 171-180, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29674181

RESUMO

High glucose (HG)-induced mammalian target of rapamycin (mTOR) overactivation acts as a signaling hub for the formation of tau hyperphosphorylation, which contributes to the development of diabetes-associated cognitive deficit. How HG induces the sustained activation of mTOR in neurons is not clearly understood. ErbB4, a member of the receptor tyrosine kinase family, plays critical roles in development and function of neural circuitry, relevant to behavioral deficits. Here, we showed HG-induced ErbB4 overexpression in differentiated SH-SY5Y cells and primary hippocampal neurons and hippocampal pyramidal neurons of streptozotocin-induced diabetic rats. Inhibition of ErbB4 signaling prevented the HG-induced activation of mTOR/S6K signaling to suppress tau hyperphosphorylation. In contrast, ErbB4 overexpression increased the activation of mTOR/S6K signaling, resulting in tau hyperphosphorylation similar to HG treatment. We also demonstrated that HG upregulated the expression of ErbB4 at a mTOR-dependent posttranscriptional level. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of mTOR involving overexpressed ErbB4, leading to the formation of tau hyperphosphorylation under HG condition. Therefore, ErbB4 is a potential therapeutic target for diabetes-associated neurodegeneration.


Assuntos
Retroalimentação Fisiológica/fisiologia , Glucose/metabolismo , Hiperglicemia/metabolismo , Neurônios/metabolismo , Receptor ErbB-4/metabolismo , Transdução de Sinais , Proteínas tau/metabolismo , Animais , Células Cultivadas , Disfunção Cognitiva/etiologia , Diabetes Mellitus/etiologia , Expressão Gênica , Hiperglicemia/complicações , Hiperglicemia/genética , Masculino , Fosforilação/genética , Ratos Sprague-Dawley , Receptor ErbB-4/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
16.
Eur J Pharmacol ; 571(1): 44-50, 2007 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-17585900

RESUMO

In the present study, we tested whether the decreased release of calcitonin gene-related peptide (CGRP) observed in nitroglycerin tolerance is associated with the decrease in aldehyde dehydrogenase (ALDH-2) activity. We further investigated the possible involvement of reactive oxygen species in the decrease in ALDH-2 activity. Tolerance was induced by exposure of isolated rat thoracic aortas and human umbical vein endothelial cells (HUVEC) to nitroglycerin in vitro or by pretreatment with nitroglycerin for 8 days in vivo. Pretreatment with ALDH-2 inhibitors and nitroglycerin significantly attenuated vasodilator responses to nitroglycerin concomitantly with a decrease in the release of CGRP from the isolated thoracic aorta. Nitroglycerin produced a depressor effect concomitantly with an increase in plasma concentrations of CGRP, and the effect of nitroglycerin was attenuated after pretreatment with an inhibitor of ALDH-2 or nitroglycerin for 8 days. Exposure of HUVEC to nitroglycerin for 16 h increased reactive oxygen species production and decreased ALDH-2 activity as well as cGMP production in a time-and concentration-dependent manner. Pretreatment with an ALDH-2 inhibitor also significantly decreased the cGMP production. However, tolerance to nitroglycerin in HUVEC was restored in the presence of N-acetylcysteine or captopril. The present results suggest that nitrate tolerance is, at least partially, associated with a decrease in endogenous CGRP release via a decrease in ALDH-2 activity as a result of stimulation of reactive oxygen species production.


Assuntos
Aldeído Desidrogenase/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Tolerância a Medicamentos , Nitroglicerina/farmacologia , Acetilcisteína/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Linhagem Celular , Hidrato de Cloral/farmacologia , Cianamida/farmacologia , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Técnicas In Vitro , Masculino , Doadores de Óxido Nítrico/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/efeitos dos fármacos
17.
Oncotarget ; 8(25): 40843-40856, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28489581

RESUMO

The abnormally hyperphosphorylated tau is thought to be implicated in diabetes-associated cognitive deficits. The role of mammalian target of rapamycin (mTOR) / S6 kinase (S6K) signalling in the formation of tau hyperphosphorylation has been previously studied. Caveolin-1 (Cav-1), the essential structure protein of caveolae, promotes neuronal survival and growth, and inhibits glucose metabolism. In this study, we aimed to investigate the role of Cav-1 in the formation of tau hyperphosphorylation under chronic hyperglycemic condition (HGC). Diabetic rats were induced by streptozotocin (STZ). Primary hippocampal neurons with or without molecular intervention such as the transient over-expression or knock-down were subjected to HGC. The obtained experimental samples were analyzed by real time quantitative RT-PCR, Western blot, immunofluorescence or immunohistochemisty. We found: 1) that a chronic HGC directly decreases Cav-1 expression, increases tau phosphorylation and activates mTOR/S6K signalling in the brain neurons of diabetic rats, 2) that overexpression of Cav-1 attenuates tau hyperphosphorylation induced by chronic HGC in primary hippocampal neurons, whereas down-regulation of Cav-1 using Cav-1 siRNA dramatically worsens tau hyperphosphorylation via mTOR/S6K signalling pathway, and 3) that the down-regulation of Cav-1 induced by HGC is independent of mTOR signalling. Our results suggest that tau hyperphosphorylation and the sustained over-activated mTOR signalling under hyperglycemia may be due to the suppression of Cav-1. Therefore, Cav-1 is a potential therapeutic target for diabetes-induced cognitive dysfunction.


Assuntos
Caveolina 1/metabolismo , Disfunção Cognitiva/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas tau/metabolismo , Animais , Glucose/administração & dosagem , Glucose/metabolismo , Hiperglicemia/metabolismo , Hiperglicemia/psicologia , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Transfecção
18.
J Alzheimers Dis ; 37(3): 495-505, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23948902

RESUMO

Recent evidence implicated aberrant mammalian target of rapamycin (mTOR)-dependent signaling in both Alzheimer's disease (AD) and brain tumors. This review focuses on the potential mechanisms shared by both neurodegeneration and carcinogenesis. In particular, attention was paid to the possible roles of mTOR-dependent signaling in these two fundamental pathophysiological processes. We hypothesize that common stresses could lead either to progressive degeneration or uncontrolled carcinogenesis via cell type specific upregulation of mTOR-dependent signaling in the central nervous system while mTOR-mediated carcinogenesis might permit glial cells to escape from degeneration.


Assuntos
Doença de Alzheimer/metabolismo , Neoplasias Encefálicas/metabolismo , Carcinogênese/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Carcinogênese/patologia , Humanos , Mutação/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Serina-Treonina Quinases TOR/genética
19.
Asian Pac J Trop Med ; 5(2): 165-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22221764

RESUMO

Liver failure is the end stage of hepatopathy with unfavorable prognosis. In two patients with liver failure, viable primary human hepatocytes, obtained from resected liver tissue of patients with hepatolithiasis, were transplanted into the spleen by interventional therapy through femoral arterial cannula. After transplantation, the patients' clinical symptoms and liver function were significantly improved. However, their bilirubin increased within six days following transplantation. One suffered from hepatic coma and give up treatment and the other patient died fourteen days after transplantation. It is technically safe to treat liver failure by intrasplenic transplantation of adult hepatocytes and the clinical efficacy has been confirmed. How to make transplanted hepatic cells proliferate and functionally survive is the key point to maintain continuous improvement of the recipient's hepatic function.


Assuntos
Bilirrubina/metabolismo , Encefalopatia Hepática/patologia , Hepatócitos/transplante , Falência Hepática/cirurgia , Baço/patologia , Adulto , Evolução Fatal , Humanos , Falência Hepática/metabolismo , Falência Hepática/patologia , Testes de Função Hepática , Masculino , Falha de Tratamento
20.
Int J Cardiol ; 125(3): 436-8, 2008 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-17804099

RESUMO

Previous studies have shown that the development of tolerance to nitroglycerin is related to reduction of endogenous calcitonin gene-related peptide (CGRP) release. In the present study, Nitroglycerin caused a concentration-dependent relaxation concomitantly with a significant increase in the release of CGRP in the isolated rat thoracic aorta, an effect that was reduced by preincubation with capsaicin. Pretreatment with nitroglycerin significantly decreased its vasodilation and depressor effect and the release of CGRP, which was restored in the presence of vinpocetine, an inhibitor of phosphodiesterase. The present results suggest that reversal of tolerance to nitroglycerin with vinpocetine is related to the increased release of CGRP in the rat.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Nitroglicerina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Vasodilatadores/farmacologia , Alcaloides de Vinca/farmacologia , Animais , Aorta Torácica/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/efeitos dos fármacos , Tolerância a Medicamentos , Ratos
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