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1.
Anticancer Res ; 41(11): 5477-5480, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732417

RESUMO

BACKGROUND/AIM: Itraconazole shows anticancer activity in various types of cancer but its underlying mechanism is unclear. We investigated the effect of itraconazole on membrane-associated lipids. MATERIALS AND METHODS: To investigate the influences of itraconazole on cholesterol trafficking, cervical cancer CaSki cells were cultured with itraconazole and analyzed by Filipin staining followed by confocal microscopy. Effect on the glycerophospholipid profiles was analyzed by liquid chromatography/mass spectrometry (LC/MS). RESULTS: After itraconazole treatment, Filipin staining revealed cholesterol accumulation in the intracellular compartments, which was similar to the distribution after treatment of U18666A (cholesterol transport inhibitor). LC/MS analysis showed a significant decrease in phosphatidylserine levels and an increase in lysophosphatidylcholine levels in CaSki cells. CONCLUSION: Itraconazole inhibited cholesterol trafficking and altered the phospholipid composition. Alterations in the cell membrane can potentiate the anticancer activity of itraconazole.


Assuntos
Antineoplásicos/farmacologia , Colesterol/metabolismo , Itraconazol/farmacologia , Fosfatidilserinas/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Transporte Biológico , Linhagem Celular Tumoral , Feminino , Humanos , Lisofosfatidilcolinas/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
2.
Anticancer Res ; 41(9): 4271-4276, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475046

RESUMO

BACKGROUND/AIM: The anticancer mechanism of itraconazole remains unsolved; therefore, we studied itraconazole-induced alterations in specialized pro-resolving mediators (SPMs) in cancer cells. MATERIALS AND METHODS: The human cervical squamous carcinoma cell line CaSki was cultured with or without 1 µM itraconazole. Liquid chromatography/mass spectrometry analysis was conducted to identify SPMs that were influenced by itraconazole. Cell growth experiments were conducted using itraconazole and inhibitors targeting the metabolic pathways of candidate SPMs. RESULTS: Resolvin E3, resolvin E2, prostaglandin J2 (PGJ2), delta-12-PGJ2, and maresin 2 were identified as candidate SPMs. The 12/15-lipoxygenase inhibitor, which is involved in the conversion of 18-hydroxy-eicosapentaenoic acid to resolvin E3, attenuated the inhibitory effect of itraconazole. Inhibition of the PGJ2 metabolic pathway did not interfere with itraconazole treatment. CONCLUSION: The metabolic pathway of SPMs, including resolving E3, could be proposed as an anticancer target of itraconazole.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Ácidos Graxos Insaturados/metabolismo , Itraconazol/farmacologia , Inibidores de Lipoxigenase/farmacologia , Neoplasias do Colo do Útero/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Espectrometria de Massas , Redes e Vias Metabólicas/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico
3.
Neurochem Int ; 148: 105104, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34153352

RESUMO

Although the exact etiology of Alzheimer's disease (AD) is poorly understood, experimental and clinical evidences suggest the contribution of neuroinflammation in the pathogenesis of AD. Pathologically, AD brain is characterized by an imbalance in redox status, elevated endoplasmic reticulum (ER) stress, synaptic dysfunction, inflammation, and progressive neurodegeneration. It has been noted that continuous accumulation of amyloid-beta (Aß) and intracellular neurofibrillary tangles (NFTs) in AD brain trigger ER stress, which contributes to neurodegeneration. Similarly, experimental evidences supports the hypothesis that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox regulator thioredoxin (TRX), is activated by ER stress and contributes to activation of NLRP3 (NOD-like receptor protein 3) inflammatory cascade in hippocampus of the AD brain. Hippocampus of postmortem human AD and aged matched non-AD controls were analyzed for the expression ER stress markers and TXNIP-NLRP3 inflammasome at cellular and molecular levels. We found higher expression of TXNIP at protein and transcript levels in close association with pathological markers of AD such as Aß and NFTs in AD hippocampus. In addition, our results demonstrated that TXNIP was co-localized in neurons and microglia. Moreover, expression of binding immunoglobulin protein (BiP), activated eukaryotic initiation factor-2α (eIf2α) and C/EBP homology protein (CHOP), proteins involved the development of ER stress, were elevated in AD hippocampus. Further, elevated expression of effector molecules of NLRP3 inflammasome activation such as apoptosis associated speck-like protein (ASC), cleaved caspase-1 and cleaved interleukin-1ß were observed in the AD hippocampus. The study suggests that TXNIP could be a link that connect ER stress with neuroinflammation. Thus, TXNIP can be a possible therapeutic target to mitigate the progression of neuroinflammation in the pathogenesis of AD.

4.
J Neurochem ; 154(1): 41-55, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32222968

RESUMO

Deficiency of activity-induced expression of brain-derived neurotrophic factor (BDNF) disturbs neurotransmitter gene expression. Enriched environment treatment (EET) ameliorates the defects. However, how BDNF deficiency and EET affect the neurotransmitter gene expression differently across ages remains unclear. We addressed this question by determining the neurotransmitter gene expression across three life stages in wild-type and activity-dependent BDNF-deficient (KIV) mice. Mice received 2-months of standard control treatment (SCT) or EET at early-life development (ED: 0-2 months), young adulthood (2-4 months), and old adulthood (12-14 months) (N = 16/group). Half of these mice received additional 1-month SCT to examine persisting EET effects. High-throughput quantitative reverse transcription polymerase chain reaction measured expression of 81 genes for dopamine, adrenaline, serotonin, gamma aminobutyric acid, glutamate, acetylcholine, and BDNF systems in the frontal cortex (FC) and hippocampus. Results revealed that BDNF deficiency mostly reduced neurotransmitter gene expression, greatest at ED in the FC. EET increased expression of a larger number of genes at ED than adulthood, particularly in the KIV FC. Many genes down-regulated in KIV mice were up-regulated by EET, which persisted when EET was provided at ED (e.g., 5-hydroxytryptamine (serotonin) transporter [5HTT], ADRA1D, GRIA3, GABRA5, GABBR2). In both the regions, BDNF deficiency decreased the density of gene co-expression network specifically at ED, while EET increased the density and hub genes (e.g., GAT1, GABRG3, GRIN1, CHRNA7). These results suggest that BDNF deficiency, which occurs under chronic stress, causes neurotransmitter dysregulations prominently at ED, particularly in the FC. EET at ED may be most effective to normalize the dysregulations, providing persisting effects later in life. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. More information about the Open Science badges can be found at https://cos.io/our-services/open-science-badges/.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/deficiência , Encéfalo/metabolismo , Expressão Gênica/fisiologia , Neurogênese/fisiologia , Neurotransmissores/metabolismo , Animais , Animais Recém-Nascidos , Abrigo para Animais , Camundongos , Camundongos Endogâmicos C57BL
5.
J Alzheimers Dis ; 68(1): 255-265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30741672

RESUMO

Alzheimer's disease (AD) is the most common form of age-associated dementia characterized by amyloid-ß plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1ß (IL-1ß) were co-localized near Aß plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1ß, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Proteínas de Transporte/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Encéfalo/patologia , Caspase 1/metabolismo , Feminino , Humanos , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Proteínas tau/metabolismo
6.
BMC Cancer ; 18(1): 630, 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866134

RESUMO

BACKGROUND: Primary malignant melanoma of the vagina is extremely rare, with a poorer prognosis than cutaneous malignant melanoma. Previous studies have explored the repurposing of itraconazole, a common oral anti-fungal agent, for the treatment of various cancers. Here, we describe a patient with metastatic, unresectable vaginal malignant melanoma treated with 200 mg oral itraconazole twice a day in a clinical window-of-opportunity trial. CASE PRESENTATION: A 64-year-old Japanese woman with vaginal and inguinal tumours was referred to our institution. On the basis of an initial diagnosis of vaginal cancer metastatic to the inguinal lymph nodes, we treated her with itraconazole in a clinical trial until the biopsy and imaging study results were obtained. During this period, biopsies were performed three times, and 18F-fluoro-deoxyglucose positron emission tomography (FDG/PET)-computed tomography (CT) was performed twice. Biopsy results confirmed the diagnosis of primary malignant melanoma of the vagina. Imaging studies revealed metastases to multiple sites, including the brain, for which she underwent gamma-knife radiosurgery. During the window period before nivolumab initiation, the patient received itraconazole for 30 days. Within a week of itraconazole initiation, pain in the inguinal nodes was ameliorated. PET-CT on days 6 and 30 showed a reduction in tumour size and FDG uptake, respectively. The biopsied specimens obtained on days 1, 13, and 30 were subjected to cDNA microarray analysis, which revealed a 100-fold downregulation in the transcription of four genes: STATH, EEF1A2, TTR, and CDH2. After 12 weeks of nivolumab administration, she developed progressive disease and grade 3 immune-related hepatitis. Discontinuation of nivolumab resulted in the occurrence of left pelvic and inguinal pain. Following re-challenge with itraconazole, the patient has not reported any pain for 4 months. CONCLUSION: The findings of this case suggest that itraconazole is a potential effective treatment option for primary malignant melanoma of the vagina. Moreover, we identified potential itraconazole target genes, which could help elucidate the mechanism underlying this disease and potentially aid in the development of new therapeutic agents.


Assuntos
Antineoplásicos/uso terapêutico , Itraconazol/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Vaginais/tratamento farmacológico , DNA Complementar/análise , Feminino , Humanos , Melanoma/diagnóstico por imagem , Melanoma/genética , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/genética , Análise Serial de Tecidos , Neoplasias Vaginais/diagnóstico por imagem , Neoplasias Vaginais/genética
7.
Oncol Lett ; 14(2): 1240-1246, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28789339

RESUMO

Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including reversing chemoresistance mediated by P-glycoprotein, modulating the signal transduction pathways of Hedgehog, mechanistic target of rapamycin and Wnt/ß-catenin in cancer cells, inhibiting angiogenesis and lymphangiogenesis, and possibly interfering with cancer-stromal cell interactions. Clinical trials have suggested the clinical benefits of itraconazole monotherapy for prostate cancer and basal cell carcinoma, as well as the survival advantage of combination chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic and biliary tract cancer. As drug repurposing is cost-effective and timesaving, a review was conducted of preclinical and clinical data focusing on the anticancer activity of itraconazole, and discusses the future directions for repurposing itraconazole as an anticancer agent.

8.
Anticancer Res ; 37(7): 3521-3526, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28668841

RESUMO

BACKGROUND/AIM: Repurposing itraconazole as an anticancer agent has been evaluated in several studies. The present study investigated whether itraconazole exerts an anticancer effect on cervical cancer cells. MATERIALS AND METHODS: CaSki and HeLa cells were cultured in itraconazole and vehicle after which colony-forming and cell viability assays were performed. Transcription and protein expression were assessed by cDNA microarray analysis and immunoblotting, respectively. RESULTS: Itraconazole suppressed proliferation of CaSki and HeLa cells in a dose- and time-dependent manner. Furthermore, CaSki cells were more significantly affected by itraconazole than HeLa cells. The microarray analysis showed an 8-fold down-regulation in the expression of GLI1, WNT4 and WNT10A among itraconazole-treated CaSki cells. Moreover, the transcription of sterol carrier protein-2 and ATP-binding cassette transporter-1 was unaffected by itraconazole. Immunoblots showed suppression in ß-catenin expression and Akt phosphorylation. CONCLUSION: Itraconazole is a multi-targeting anticancer agent and a promising therapeutic agent for cervical cancer.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Itraconazol/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/metabolismo , Proteína Wnt4/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo
9.
J Neurochem ; 143(1): 49-64, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28722769

RESUMO

Brain-derived neurotrophic factor (BDNF) promotes maturation of cholinergic neurons. However, how activity-dependent BDNF expression affects specific cholinergic gene expression remains unclear. This study addressed this question by determining mRNA levels of 22 acetylcholine receptor subunits, the choline transporter (CHT), and the choline acetyltransferase (ChAT) in mice deficient in activity-dependent BDNF via promoter IV (KIV) and control wild-type mice. Quantitative RT-PCR revealed significant reductions in nicotinic acetylcholine receptor alpha 5 (CHRNA5) in the frontal cortex and hippocampus and M5 muscarinic acetylcholine receptor (CHRM5) in the hippocampus, but significant increases in M2 muscarinic acetylcholine receptor (CHRM2) in the frontal cortex of KIV mice compared to wild-type mice. Three-week treatments with fluoxetine, phenelzine, duloxetine, imipramine, or an enriched environment treatment (EET) did not affect the altered expression of these genes except that EET increased CHRNA5 levels only in KIV frontal cortex. EET also increased levels of CHRNA7, CHT, and ChAT, again only in the KIV frontal cortex. The imipramine treatment was most prominent among the four antidepressants; it up-regulated hippocampal CHRM2 and frontal cortex CHRM5 in both genotypes, and frontal cortex CHRNA7 only in KIV mice. To the best of our knowledge, this is the first evidence that BDNF deficiency disturbs expression of CHRNA5, CHRM2, and CHRM5. Our results suggest that promoter IV-BDNF deficiency - which occurs under chronic stress - causes cholinergic dysfunctions via these receptors. EET is effective on CHRNA5, while its compensatory induction of other cholinergic genes or drugs targeting CHRNA5, CHRM2, and CHRM5 may become an alternative strategy to reverse these BDNF-linked cholinergic dysfunctions.


Assuntos
Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/deficiência , Meio Ambiente , Receptor Muscarínico M2/biossíntese , Receptor Muscarínico M5/biossíntese , Receptores Nicotínicos/biossíntese , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/fisiologia , Receptor Muscarínico M2/genética , Receptor Muscarínico M5/genética , Receptores Nicotínicos/genética
10.
PLoS Genet ; 13(7): e1006849, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28678786

RESUMO

The unfolded protein response (UPR) in the endoplasmic reticulum (ER) and the cytoplasmic heat stress response are two major stress response systems necessary for maintaining proteostasis for cellular health. Failure of either of these systems, such as in sustained UPR activation or in insufficient heat shock response activation, can lead to the development of neurodegeneration. Alleviation of ER stress and enhancement of heat shock response through heat shock factor 1 (HSF1) activation have previously been considered as attractive potential therapeutic targets for Alzheimer's disease (AD)-a prevalent and devastating tauopathy. Understanding the interplay of the two aforementioned systems and their cooperative role in AD remain elusive. Here we report studies in human brain and tau pathogenic mouse models (rTg4510, PS19, and rTg21221), identifying HSF1 degradation and UPR activation as precursors of aberrant tau pathogenesis. We demonstrate that chemical ER stress inducers caused autophagy-lysosomal HSF1 degradation, resulting in tau hyperphosphorylation in rat primary neurons. In addition, permanent HSF1 loss reversely causes chronic UPR activation, leading to aberrant tau phosphorylation and aggregation in the hippocampus of aged HSF1 heterozygous knock-out mice. The deleterious interplay of UPR activation and HSF1 loss is exacerbated in N2a cells stably overexpressing a pro-aggregation mutant TauRD ΔK280 (N2a-TauRD ΔK280). We provide evidence of how these two stress response systems are intrinsically interweaved by showing that the gene encoding C/EBP-homologous protein (CHOP) activation in the UPR apoptotic pathway facilitates HSF1 degradation, which likely further contributes to prolonged UPR via ER chaperone HSP70 a5 (BiP/GRP78) suppression. Upregulating HSF1 relieves the tau toxicity in N2a-TauRD ΔK280 by reducing CHOP and increasing HSP70 a5 (BiP/GRP78). Our work reveals how the bidirectional crosstalk between the two stress response systems promotes early tau pathology and identifies HSF1 being one likely key player in both systems.


Assuntos
Doença de Alzheimer/genética , Proteínas de Ligação a DNA/genética , Proteínas de Choque Térmico/genética , Fator de Transcrição CHOP/genética , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/genética , Proteínas tau/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Autofagia/genética , Proteínas de Ligação a DNA/biossíntese , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica , Fatores de Transcrição de Choque Térmico , Resposta ao Choque Térmico/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Agregação Patológica de Proteínas/genética , Proteólise , Ratos , Tauopatias/genética , Tauopatias/metabolismo , Tauopatias/patologia , Fator de Transcrição CHOP/biossíntese , Fatores de Transcrição/biossíntese , Proteínas tau/metabolismo
11.
Anticancer Res ; 37(2): 515-519, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179296

RESUMO

BACKGROUND: Itraconazole is a common antifungal agent that has demonstrated anticancer activity in preclinical and clinical studies. This study investigated whether itraconazole exerts this effect in endometrial cancer (EC) cells. MATERIALS AND METHODS: Cell viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and gene and protein expression were assessed by microarray analysis and immunoblotting, respectively, in five EC cell lines. RESULTS: Itraconazole-suppressed proliferation of AN3-CA, HEC-1A and Ishikawa cells (p<0.05) but not of HEC-50B or SNG-II cells. Itraconazole did not suppress GLI1 or GLI2 transcription but did inhibit the expression of mammalian target of rapamycin (mTOR) signaling components in AN3-CA and HEC-1A cells, while inducing that of microtubule-associated protein 1A/1B-light chain 3-II, a marker of autophagy. ATP-binding cassette transporter A1 gene was down-regulated in Ishikawa, HEC-50B and SNG-II cells. CONCLUSION: Itraconazole treatment suppresses the growth of EC cells by inhibiting AKT/mTOR signalling.


Assuntos
Neoplasias do Endométrio/tratamento farmacológico , Itraconazol/farmacologia , Proteína Oncogênica v-akt/antagonistas & inibidores , Serina-Treonina Quinases TOR/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Oncogênica v-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
12.
J Assist Reprod Genet ; 33(3): 367-371, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26749386

RESUMO

PURPOSE: The aim of this study was to establish a simple tool to predict good-quality embryos in in vitro fertilization (IVF) by using cumulus cells (CCs) or peripheral blood cells (PBCs). METHODS: Mitochondrial DNA was extracted from CCs and PBCs in patients undergoing IVF. Using real-time polymerase chain reaction, mtDNA copy number in a single cell was calculated. Embryo quality was assessed when it was transferred or frozen. RESULTS: CCs were obtained from 60 oocyte cumulus-cell complexes (OCCCs) in 30 women, and PBCs were collected from 18 women. For the 30 women in the study, the median age was 37 years old (range, 24-43), and the mean body mass index was 21.4 (standard error, 2.0). mtDNA content of CCs and PBCs was highly correlated (Pearson's r = 0.900, p < 0.0001). The median mtDNA content of CCs for good- and poor-quality embryos was 140 and 57, respectively (p < 0.0001). The median mtDNA content of PBCs for good- and poor-quality embryos was 36 and 13, respectively (p = 0.604). The logistic regression model indicated that mtDNA content in CCs was the only parameter that predicted good-quality embryos (p = 0.020). The receiver operating characteristic curve for obtaining good-quality embryos by mtDNA copy number in CCs had an area under the curve of 0.823, and using a threshold of 86, positive and negative predictive values were 84.4 and 82.1 %, respectively. CONCLUSIONS: The determination of mtDNA content in CCs can be used to predict good-quality embryos.


Assuntos
Blastômeros/fisiologia , Células do Cúmulo/fisiologia , DNA Mitocondrial , Adulto , Estradiol/metabolismo , Fertilização In Vitro , Dosagem de Genes , Humanos , Leucócitos Mononucleares/fisiologia , Modelos Logísticos , Estudos Prospectivos , Curva ROC
13.
Anticancer Res ; 36(1): 149-53, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26722038

RESUMO

BACKGROUND: There exist limited therapeutic opportunities for the treatment of endometrial cancer (EC). Itraconazole, a common anti-fungal agent and a potent inhibitor of the Hedgehog pathway, has been shown to be clinically effective for various types of cancers, but its clinical efficacy for EC is unknown. Herein, we evaluated the efficacy of itraconazole in treating EC. MATERIALS AND METHODS: We performed immunohistochemistry on EC tumour samples including serous endometrial intraepithelial carcinoma (SEIC). We further evaluated the in vitro efficacy of itraconazole for inhibiting proliferation and migration of EC cell lines. RESULTS: Sonic Hedgehog and glioma-associated oncogene homolog 1 (GLI1) were expressed in SEIC and endometrioid adenocarcinoma. We found that itraconazole significantly inhibited tumour cell growth in both dose-dependent and time-dependent manners and inhibited migration of HEC-1A cells. CONCLUSION: Hedgehog signaling plays a role in carcinogenesis and malignant progression in EC. Itraconazole at a physiological dose may suppress progression of EC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Endometrioide/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Endométrio/tratamento farmacológico , Itraconazol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Imuno-Histoquímica , Fatores de Tempo , Proteína GLI1 em Dedos de Zinco
14.
Anticancer Res ; 36(1): 199-203, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26722044

RESUMO

BACKGROUND: There exist limited therapeutic opportunities regarding the treatment of endometrial cancer (EC), and novel therapies based on the molecular profiling of EC cells are required. MATERIALS AND METHODS: We used microarray analysis of EC tumour samples in order to identify tumour-specific changes regarding gene expression. RESULTS: It was found that gremlin 2, an inhibitor of bone morphogenetic protein (BMP) signaling, was repressed in EC samples, and that gremlin 2 inhibited tumour cell growth. CONCLUSION: Down-regulation of gremlin 2 may lead to carcinogenesis and progression of EC. We suggest that re-activation of gremlin 2-associated pathways could suppress EC progression and should thus be explored as a potential novel therapeutic approach.


Assuntos
Neoplasias do Endométrio/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Movimento Celular , Proliferação de Células , Neoplasias do Endométrio/patologia , Feminino , Humanos , Técnicas In Vitro , Transdução de Sinais
15.
Anticancer Res ; 34(10): 5331-6, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25275026

RESUMO

BACKGROUND/AIM: The identification of novel molecules associated with endometrial cancer (EC) development might offer less invasive surgery, better fertility preservation, and avoidance of unnecessary adjuvant therapy. MATERIALS AND METHODS: Microarray analysis was conducted using fresh surgically-obtained specimens from five EC patients and five cases with benign tumours. Additionally, immunohistochemical studies of the most highly expressed molecules were performed on paraffin-embedded tissues from these patients and others with stage IA, grade 1-2 EC (n=3) with or without (n=7) recurrent disease. RESULTS: The most highly expressed gene in EC was chemokine ligand 18 (CCL18), with a 35.6-fold change compared to benign tumors. CCL18 expression was observed in tumor cells at the myometrial invasive front in 9 out of 11 tested samples. CONCLUSION: CCL18 expression was positively correlated with malignancy in EC. Further investigation with a larger number of samples or examination of serum CCL18 levels is warranted.


Assuntos
Quimiocinas CC/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocinas CC/metabolismo , Neoplasias do Endométrio/metabolismo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias
16.
J Neurosci ; 34(7): 2464-70, 2014 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-24523537

RESUMO

The excessive accumulation of soluble amyloid peptides (Aß) plays a crucial role in the pathogenesis of Alzheimer's disease (AD), particularly in synaptic dysfunction. The role of the two major chaperone proteins, Hsp70 and Hsp90, in clearing misfolded protein aggregates has been established. Despite their abundant presence in synapses, the role of these chaperones in synapses remains elusive. Here, we report that Hsp90 inhibition by 17-AAG elicited not only a heat shock-like response but also upregulated presynaptic and postsynaptic proteins, such as synapsin I, synaptophysin, and PSD95 in neurons. 17-AAG treatment enhanced high-frequency stimulation-evoked LTP and protected neurons from synaptic damage induced by soluble Aß. In AD transgenic mice, the daily administration of 17-AAG over 7 d resulted in a marked increase in PSD95 expression in hippocampi. 17-AAG treatments in wild-type C57BL/6 mice challenged by soluble Aß significantly improved contextual fear memory. Further, we demonstrate that 17-AAG activated synaptic protein expression via transcriptional mechanisms through the heat shock transcription factor HSF1. Together, our findings identify a novel function of Hsp90 inhibition in regulating synaptic plasticity, in addition to the known neuroprotective effects of the chaperones against Aß and tau toxicity, thus further supporting the potential of Hsp90 inhibitors in treating neurodegenerative diseases.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Lactamas Macrocíclicas/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Sinapses/metabolismo , Doença de Alzheimer/patologia , Animais , Western Blotting , Modelos Animais de Doenças , Imuno-Histoquímica , Potenciação de Longa Duração/fisiologia , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos , Sinapses/efeitos dos fármacos , Sinapses/patologia
17.
Gynecol Oncol Case Rep ; 5: 16-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24371685

RESUMO

•A seminoma developed in a patient with androgen insensitivity syndrome.•The patient had a de novo androgen receptor mutation.•Proper management of AIS, including appropriate genetic counseling, is necessary.

18.
Proc Natl Acad Sci U S A ; 110(37): 15103-8, 2013 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-23980178

RESUMO

Activity-dependent gene transcription, including that of the brain-derived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal-PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders.


Assuntos
Comportamento Animal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Região CA1 Hipocampal/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/deficiência , Cognição/fisiologia , Condicionamento Psicológico/fisiologia , Expressão Gênica , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Knockout , Camundongos Mutantes
19.
Eur J Neurosci ; 37(11): 1863-74, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23406189

RESUMO

Brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depression; mice lacking BDNF expression through promoter IV (BDNF-KIV) exhibit a depression-like phenotype. We tested our hypothesis that deficits caused by promoter IV deficiency (depression-like behavior, decreased levels of BDNF, and neurogenesis in the hippocampus) could be rescued by a 3-week treatment with different types of antidepressants: fluoxetine, phenelzine, duloxetine, or imipramine. Each antidepressant reduced immobility time in the tail suspension test without affecting locomotor activity in the open field test in both BDNF-KIV and control wild type mice, except that phenelzine increased locomotor activity in wild type mice and anxiety-like behavior in BDNF-KIV mice. The antidepressant treatments were insufficient to reverse decreased BDNF levels caused by promoter IV deficiency. No antidepressant treatment increased the hippocampal progenitors of either genotype, whereas phenelzine decreased the surviving progenitors in both genotypes. The antidepressant treatments differently affected the dendritic extension of hippocampal immature neurons: fluoxetine and imipramine increased extension in both genotypes, duloxetine increased it only in BDNF-KIV mice, and phenelzine decreased it only in wild type mice. Interestingly, a saline-only injection increased neurogenesis and dendrite extensions in both genotypes. Our results indicate that the behavioral effects in the tail suspension test by antidepressants do not require promoter IV-driven BDNF expression and occur without a detectable increase in hippocampal BDNF levels and neurogenesis but may involve increased dendritic reorganisation of immature neurons. In conclusion, the antidepressant treatment demonstrated limited efficacy; it partially reversed the defective phenotypes caused by promoter IV deficiency but not hippocampal BDNF levels.


Assuntos
Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno Depressivo/tratamento farmacológico , Regiões Promotoras Genéticas , Transcrição Genética , Animais , Antidepressivos/farmacologia , Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dendritos/efeitos dos fármacos , Transtorno Depressivo/genética , Genótipo , Hipocampo/metabolismo , Hipocampo/patologia , Locomoção/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos
20.
Proc Natl Acad Sci U S A ; 108(29): 12131-6, 2011 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-21730187

RESUMO

Mechanisms underlying experience-dependent refinement of cortical connections, especially GABAergic inhibitory circuits, are unknown. By using a line of mutant mice that lack activity-dependent BDNF expression (bdnf-KIV), we show that experience regulation of cortical GABAergic network is mediated by activity-driven BDNF expression. Levels of endogenous BDNF protein in the barrel cortex are strongly regulated by sensory inputs from whiskers. There is a severe alteration of excitation and inhibition balance in the barrel cortex of bdnf-KIV mice as a result of reduced inhibitory but not excitatory conductance. Within the inhibitory circuits, the mutant barrel cortex exhibits significantly reduced levels of GABA release only from the parvalbumin-expressing fast-spiking (FS) interneurons, but not other interneuron subtypes. Postnatal deprivation of sensory inputs markedly decreased perisomatic inhibition selectively from FS cells in wild-type but not bdnf-KIV mice. These results suggest that postnatal experience, through activity-driven BDNF expression, controls cortical development by regulating FS cell-mediated perisomatic inhibition in vivo.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Interneurônios/metabolismo , Mecanotransdução Celular/fisiologia , Neocórtex/fisiologia , Córtex Somatossensorial/fisiologia , Ácido gama-Aminobutírico/metabolismo , Análise de Variância , Animais , Western Blotting , Fator Neurotrófico Derivado do Encéfalo/deficiência , Fator Neurotrófico Derivado do Encéfalo/genética , Cruzamentos Genéticos , Técnicas de Introdução de Genes , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Modelos Neurológicos , Inibição Neural/fisiologia , Vibrissas/inervação
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