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1.
Int. braz. j. urol ; 45(3): 541-548, May-June 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1012322

RESUMO

ABSTRACT Objectives: To investigate whether Glasgow Prognostic Score has prognostic significance in patients with upper urinary urothelial carcinoma. Patients and methods: We retrospectively reviewed the clinical records of 74 patients with upper urinary urothelial carcinoma. We set the cut-off value for C-reactive protein as 1.0mg/dL, and 3.5mg/dL for albumin as Glasgow Prognostic Score. Their blood data including albumin and C-reactive protein for Glasgow Prognostic Score and cytokeratin 19 fragment 21-1 as a tumor marker were measured before starting treatment. The patients were stratified into three groups with Glasgow Prognostic Score: The Group-1, albumin ≥3.5g/dL and C-reactive protein < 1.0mg/dL; Group-2, albumin < 3.5g/dL or C-reactive protein ≥1.0mg/dL; Group-3, albumin < 3.5g/dL and C-reactive protein ≥1.0mg/dL. Results: The median follow-up for all patients was 26.9 months (range: 10.9-91.1 months), during which 37 (50%) patients died. There was a significant difference in the estimated survival rate among the 3 groups stratified by Glasgow Prognostic Score. The estimated survival rate in the Group-1 was significantly higher than those in Groups 2 and 3. In the univariate analysis C-reactive protein, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were significant predictors of overall survival. On the multivariate analysis, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were independently associated with shorter overall survival. Conclusion: Our review suggests Glasgow Prognostic Score may play as a prognostic predictor for upper urinary urothelial carcinoma.

2.
Int Braz J Urol ; 45(3): 541-548, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038863

RESUMO

OBJECTIVES: To investigate whether Glasgow Prognostic Score has prognostic significance in patients with upper urinary urothelial carcinoma. PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 74 patients with upper urinary urothelial carcinoma. We set the cut-off value for C-reactive protein as 1.0mg/dL, and 3.5mg/dL for albumin as Glasgow Prognostic Score. Their blood data including albumin and C-reactive protein for Glasgow Prognostic Score and cytokeratin 19 fragment 21-1 as a tumor marker were measured before starting treatment. The patients were stratified into three groups with Glasgow Prognostic Score: The Group-1, albumin ≥3.5g/dL and C-reactive protein < 1.0mg/dL; Group-2, albumin < 3.5g/dL or C-reactive protein ≥1.0mg/dL; Group-3, albumin < 3.5g/dL and C-reactive protein ≥1.0mg/dL. RESULTS: The median follow-up for all patients was 26.9 months (range: 10.9-91.1 months), during which 37 (50%) patients died. There was a signifi cant difference in the estimated survival rate among the 3 groups stratified by Glasgow Prognostic Score. The estimated survival rate in the Group-1 was significantly higher than those in Groups 2 and 3. In the univariate analysis C-reactive protein, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were significant predictors of overall survival. On the multivariate analysis, serum cytokeratin 19 fragment 21-1 and Glasgow Prognostic Score were independently associated with shorter overall survival. CONCLUSION: Our review suggests Glasgow Prognostic Score may play as a prognostic predictor for upper urinary urothelial carcinoma.


Assuntos
Carcinoma/sangue , Neoplasias Urológicas/sangue , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/sangue , Biomarcadores Tumorais/sangue , Proteína C-Reativa/análise , Carcinoma/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Queratina-19/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Albumina Sérica/análise , Estatísticas não Paramétricas , Neoplasias Urológicas/patologia , Urotélio/patologia
3.
Sex Med ; 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30522975

RESUMO

INTRODUCTION: Management of erectile dysfunction (ED) is beset with assumptions around spontaneity of sexual intercourse, requiring candor between the physician and patient if appropriate treatment is to be implemented. AIM: To evaluate the degree to which men who take ED medications plan for and have sex. METHODS: Men from China, Japan, and Taiwan aged 40-70 years who had taken ED medications within the past 3 months were invited to participate anonymously in an online, self-administered survey that enquired about frequency and advance planning of sex, time between taking ED medication and intercourse, and treatment satisfaction. Data were analyzed using descriptive statistics. MAIN OUTCOME MEASURE: Frequency of planning of sexual intercourse, planning and ED medication dosing interval, and frequency of ED medication use. RESULTS: Data from 604 respondents (mean age 50.8 years) from China (n = 254), Japan (n = 250), and Taiwan (n = 100) were collected. Men used ED medications a median of ≤4 times per month in all 3 territories. 76% who used ED medication during the past 3 months planned for sex on specific occasions, with 59% and 52% agreeing that they plan for sex on specific days of the week and times of the day, respectively. Most commonly, men planned for sex up to several hours to a day beforehand, with 94% taking ED medication within 4 hours of sex. Satisfaction with ED medication was generally high and related to erection rigidity, speed of onset, and safety. CONCLUSION: Knowledge of the degree to which individuals with ED plan for sex may have important implications for the appropriate prescription of ED medication. The high degree of planning around sexual activities exhibited by men taking ED medication suggests there is a need for appropriate counseling to ensure that treatment is aligned with patient behavior. Jiann BP, Nakajima K, Dighe S, et al. Degree of planning of sexual intercourse among men from China, Japan, and Taiwan taking medication for erectile dysfunction: Findings of an observational, cross-sectional survey. Sex Med 2018;XX:XXX-XXX.

4.
J Invest Dermatol ; 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30447237

RESUMO

Oculocutaneous albinism (OCA) is an autosomal recessive disease characterized by the reduction or complete lack of melanin pigment in the skin, hair and eyes. No effective treatment for OCA is available at present. OCA type 1 (OCA1) is caused by mutations that disrupt the function of tyrosinase (TYR), the rate-limiting enzyme of melanin synthesis. Recently, it was shown that tyrosinase in some OCA1 mutants is retained within the endoplasmic reticulum (ER) and its catalytic activity is lost, a phenomenon known as ER-retention. However, the intracellular localization of tyrosinase in Japanese OCA1 missense mutants has not been reported. In this study, we firstly investigated the intracellular localization of Japanese OCA1A missense mutant tyrosinases using western blotting and immunohistochemical staining. R77Q, R239W, D383N and P431L mutant tyrosinases were retained within the ER, while H211Y mutant tyrosinase was partially transported to the Golgi apparatus. Secondly, we explored the possibility of chemical chaperone therapy for Japanese OCA1A missense mutants and found that HeLa cells expressing P431L mutant tyrosinase have restored tyrosinase activity following treatment with a low dose tyrosinase inhibitor, as a chemical chaperone, in a dose-dependent manner. These results provide the basis for a possible chemical chaperone therapy recovering tyrosinase activities of OCA1A.

6.
Int J Mol Sci ; 19(9)2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30149646

RESUMO

Interleukin-7 (IL-7) is essential for lymphocyte development. To identify the functional subdomains in the cytoplasmic tail of the IL-7 receptor (IL-7R) α chain, here, we constructed a series of IL-7Rα deletion mutants. We found that IL-7Rα-deficient hematopoietic progenitor cells (HPCs) gave rise to B cells both in vitro and in vivo when a wild-type (WT) IL-7Rα chain was introduced; however, no B cells were observed under the same conditions from IL-7Rα-deficient HPCs with introduction of the exogenous IL-7Rα subunit, which lacked the amino acid region at positions 414⁻441 (d414⁻441 mutant). Signal transducer and activator of transcription 5 (STAT5) was phosphorylated in cells with the d414⁻441 mutant, similar to that in WT cells, in response to IL-7 stimulation. In contrast, more truncated STAT5 (tSTAT5) was generated in cells with the d414⁻441 mutant than in WT cells. Additionally, the introduction of exogenous tSTAT5 blocked B lymphopoiesis but not myeloid cell development from WT HPCs in vivo. These results suggested that amino acids 414⁻441 in the IL-7Rα chain formed a critical subdomain necessary for the supportive roles of IL-7 in B-cell development.

7.
Case Rep Anesthesiol ; 2018: 9593458, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29971168

RESUMO

A patient with congenital insensitivity to pain with anhidrosis (CIPA) underwent revision of total hip arthroplasty under general anesthesia with only propofol. During surgery, neither elevation of stress hormones nor hemodynamic changes associated with pain occurred; however, when blood was rapidly lost, compensatory tachycardia was observed. Although patients with CIPA are complicated with autonomic disturbance due to dysfunction of postganglionic sympathetic fibers, this compensatory response indicated that the adrenal glands in patients with CIPA secrete catecholamine as part of a compensatory response during bleeding under general anesthesia.

8.
Case Rep Urol ; 2018: 8598195, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29862115

RESUMO

We treated a 65-year-old Japanese man with a giant penile lymphedema due to chronic penile strangulation with a rubber band. He was referred to our hospital with progressive penile swelling that had developed over a period of 2 years from chronic use of a rubber band placed around the penile base for prevention of urinary incontinence. Under a diagnosis of giant penile lymphedema, we performed resection of abnormal penile skin weighing 4.8 kg, followed by a penile plasty procedure. To the best of our knowledge, this is only the seventh report of such a case worldwide, with the present giant penile lymphedema the most reported.

9.
Hinyokika Kiyo ; 64(3): 127-130, 2018 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-29684963

RESUMO

A 62-year-old man presented to our hospital with the chief complaint of continuous penile pain and swelling for 4 months. Computed tomography and magnetic resonance imaging showed an invasive bladder tumor with penile, bone, and lymph node metastases. Needle biopsies of the bladder and penile lesions were obtained, and histological evaluation of these specimens revealed urothelial carcinoma, findings which are consistent with invasive bladder cancer with penile metastasis. After several therapeutic options were discussed with the patient, he decided toundergogeneral chemotherapy. However, the patient died about 16 days after admission without treatment because of his poor general condition.

10.
Asian J Endosc Surg ; 11(3): 277-279, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29316322

RESUMO

Obturator hernia (OH) is a rare cause of bowel obstruction. Although several surgical approaches, including the laparoscopic approach, have been reported to date, a standard approach for treating OH has not been established. A 101-year-old woman who presented with constipation and vomiting was admitted to our hospital. CT revealed an incarcerated small bowel within the left obturator foramen, and a diagnosis of left-sided incarcerated OH with small bowel ileus was made. With the patient under general anesthesia, exploratory laparoscopy was performed; we identified an OH with an incarcerated small bowel, which was judged viable after hernia reduction. We repaired the hernia using an anterior preperitoneal approach under laparoscopic assistance and placed a prosthetic mesh over the obturator foramen. The patient recovered with no postoperative complications and was discharged on postoperative day 4. A hybrid laparoscopic and anterior preperitoneal approach is safe and effective for treating an incarcerated OH in an elderly patient.

11.
Immunol Lett ; 194: 21-28, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29248490

RESUMO

T cell functions are regulated by multiple signaling cascades, including the MKK4-JNK (c-Jun NH2 terminal kinase) pathway. However, the mechanism regulating the MKK4-JNK axis in T cells remains unclear. Herein, we demonstrated that protein acetylation modulates JNK activity induced by T cell receptor (TCR) activation. The acetyltransferase, CREB-binding protein (CBP), is transported from the nucleus to the cytoplasm in response to TCR cross-linking. To investigate the role of CBP in TCR signaling, we overexpressed CBP in the cytoplasm of Jurkat cells, a human T lymphocyte line. Enforced expression of cytoplasmic CBP led to MKK4 acetylation and interfered with MKK4-mediated JNK phosphorylation. Insufficient JNK activity decreased the activity of the transcription factor, AP-1. In contrast, other transcription factors, NF-κB and NFAT, stimulated with anti-CD3 and anti-CD28 antibodies were activated normally in the presence of cytoplasmic-CBP. These results provide valuable insights into the role of acetylation in MKK4-JNK signaling in T cells.

12.
Reprod Med Biol ; 16(4): 320-324, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-29259484

RESUMO

Purpose: Oncofertility is a subspecialty that is concerned with helping patients with cancer preserve their ability to have children in the future. For men, sperm banking is an established way to preserve fertility. The aim was to determine the prefreeze semen characteristics and reproductive outcomes according to cancer type for men who chose semen cryopreservation. Methods: The records of 122 men with cancer who requested semen cryopreservation at the authors' hospital from 2006 to 2015 were reviewed. The mean patient age when the semen was cryopreserved was 33.6 years. Results: The 122 men who banked sperm during the study period had the following types of cancer: testicular (44.3%), hematological (31.1%), digestive (8.2%), and other types (16.4%). The mean sperm concentration by cancer type was 30.5 × 106/mL for testicular, 45.0 × 106/mL for hematological, 40.5 × 106/mL for digestive, and 68.4 × 106/mL for the other types. The mean sperm motility by cancer type was 59.6% for testicular, 50.1% for hematological, 43.0% for digestive, and 44.8% for the other types. For 12 (9.8%) men who used the banked semen, there were five (41.7%) clinical pregnancies. Conclusion: Semen cryopreservation is a simple procedure that can be accomplished quickly and can preserve fertility.

13.
J Mol Graph Model ; 76: 551-561, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28688705

RESUMO

Structural and electronic properties of eight isolated azo dyes (ArNNAr', where Ar and Ar' denote the aryl groups containing benzene and naphthalene skeletons, respectively) were investigated by density functional theory (DFT) based on the B3LYP/6-31G(d,p) and TD-B3LYP/6-311G(d,p) methods The effect of methanol solvent on the structural and electronic properties of the azo dyes was elucidated by employing a polarizable continuum model (PCM). Then, the azo dyes adsorbed onto the anatase TiO2 (101) slab surface through a carboxyl group. The geometries and electronic structures of the adsorption complexes were determined using periodic DFT based on the PWC/DNP method. The calculated adsorption energies indicate that the adsorbed dyes preferentially take configuration of the bidentate bridging rather than chelating or monodentate ester-type geometries. Furthermore, the azo compounds having two carboxyl groups are coordinated to the TiO2 surface more preferentially through the carboxyl group connecting to the benzene skeleton than through that connecting to the naphthalene skeleton. The dihedral angles (ΦB-N) between the benzene- and naphthalene-skeleton moieties are smaller than 10° for the adsorbed azo compounds containing one carboxyl group. In contrast, ΦB-N>30° are obtained for the adsorbed azo compounds containing two carboxyl groups. The almost planar conformations of the former appear to strengthen both π-electrons conjugation and electronic coupling between low-lying unoccupied molecular orbitals of the azo dyes and the conduction band of TiO2. On the other hand, such coupling is very weak for the latter, leading to a shift of the Fermi level of TiO2 in the lower-energy direction. The obtained results are useful to the design and synthesize novel azo-dye-based molecules that give rise to higher photovoltaic performances of the dye-sensitized solar cells.


Assuntos
Compostos Azo/química , Elétrons , Modelos Teóricos , Energia Solar , Titânio/química , Adsorção , Modelos Moleculares , Estrutura Molecular , Propriedades de Superfície
14.
Int. braz. j. urol ; 43(3): 496-504, May.-June 2017. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-840849

RESUMO

ABSTRACT Objective To compare the efficacy and safety of amoxapine and vitamin B12 for treating retrograde ejaculation (RE). Materials and Methods Between May 2009 and November 2012, this open-label, randomized, crossover study enrolled 26 men suffering with RE at Department of Reproductive Medicine, Omori Hospital. Patients were randomly allocated into two groups (n=13 each). The amoxapine-B12 group received amoxapine (50 mg daily for 4 weeks, orally) followed (after a 1-week washout period) by vitamin B12 (500 μg three-times daily for 4 weeks). The B12-amoxapine group received the opposite regimen. All patients masturbated to ejaculation at least twice during each treatment period. The primary outcome was antegrade ejaculation of semen, as reported by the patient, on more than one occasion during either treatment period (defined as treatment success). Any adverse events were noted. Success rates were compared between treatments using Fisher’s exact test. Results One patient (B12-amoxapine group) withdrew for personal reasons (breakdown of marital relations); all other patients completed the study. Overall success rate was 88% (22/25). Success rate was higher for amoxapine than for vitamin B12 (80%, 20/25 vs 16%, 4/25; P<0.0001). 18 patients were responsive to amoxapine but not to vitamin B12, 2 patients were responsive to vitamin B12 but not amoxapine, 2 patients were responsive to both drugs, and 3 patients had no response to either drug. One patient (4%) reported sleepiness and 2 (8%) reported constipation while receiving amoxapine. No adverse events were reported during vitamin B12 treatment. Conclusions Amoxapine may be an effective, safe and well-tolerated therapy for RE.

15.
Int Braz J Urol ; 43(3): 496-504, 2017 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28266821

RESUMO

OBJECTIVE: To compare the efficacy and safety of amoxapine and vitamin B12 for treating retrograde ejaculation (RE). MATERIALS AND METHODS: Between May 2009 and November 2012, this open-label, randomized, crossover study enrolled 26 men suffering with RE at Department of Reproductive Medicine, Omori Hospital. Patients were randomly allocated into two groups (n=13 each). The amoxapine-B12 group received amoxapine (50 mg daily for 4 weeks, orally) followed (after a 1-week washout period) by vitamin B12 (500 µg three-times daily for 4 weeks). The B12-amoxapine group received the opposite regimen. All pa-tients masturbated to ejaculation at least twice during each treatment period. The primary outcome was antegrade ejaculation of semen, as reported by the patient, on more than one occasion during either treatment period (defined as treatment success). Any adverse events were noted. Success rates were compared between treatments using Fisher's exact test. RESULTS: One patient (B12-amoxapine group) withdrew for personal reasons (breakdown of marital relations); all other patients completed the study. Overall success rate was 88% (22/25). Success rate was higher for amoxapine than for vitamin B12 (80%, 20/25 vs 16%, 4/25; P<0.0001). 18 patients were responsive to amoxapine but not to vitamin B12, 2 patients were responsive to vitamin B12 but not amoxapine, 2 patients were responsive to both drugs, and 3 patients had no response to either drug. One patient (4%) reported sleepiness and 2 (8%) reported constipation while receiving amoxapine. No adverse events were reported during vitamin B12 treatment. CONCLUSIONS: Amoxapine may be an effective, safe and well-tolerated therapy for RE.


Assuntos
Amoxapina/uso terapêutico , Ejaculação , Inibidores de Captação de Serotonina/uso terapêutico , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Adulto , Amoxapina/efeitos adversos , Estudos Cross-Over , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vitamina B 12/efeitos adversos , Deficiência de Vitamina B 12
16.
Mol Cancer Res ; 15(7): 884-895, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28242813

RESUMO

The proteoglycan versican (VCAN) promotes tumor progression and enhances metastasis in several cancers; however, its role in clear cell renal cell carcinoma (ccRCC) remains unknown. Recent evidence suggests that VCAN is an important target of chromosomal 5q gain, one of the most prevalent genetic abnormalities in ccRCC. Thus, we investigated whether VCAN expression is associated with the pathogenesis of ccRCC. VCAN expression was analyzed using three RCC and normal kidney cell lines as well as a clinical cohort of 84 matched ccRCC and normal renal tissues. Functional analyses on growth and progression properties were performed using VCAN-depleted ccRCC cells. Microarray expression profiling was employed to investigate the target genes and biologic pathways involved in VCAN-mediated ccRCC carcinogenesis. ccRCC had elevated VCAN expression in comparison with normal kidney in both cell lines and clinical specimens. The elevated expression of VCAN was significantly correlated with metastasis (P < 0.001) and worse 5-year overall survival after radical nephrectomy (P = 0.014). In vitro, VCAN knockdown significantly decreased cell proliferation and increased apoptosis in Caki-2 and 786-O cells, and this was associated with alteration of several TNF signaling-related genes such as TNFα, BID, and BAK Furthermore, VCAN depletion markedly decreased cell migration and invasion which correlated with reduction of MMP7 and CXCR4. These results demonstrate that VCAN promotes ccRCC tumorigenesis and metastasis and thus is an attractive target for novel diagnostic, prognostic, and therapeutic strategies.Implications: This study highlights the oncogenic role of VCAN in renal cell carcinogenesis and suggests that this gene has therapeutic and/or biomarker potential for renal cell cancer. Mol Cancer Res; 15(7); 884-95. ©2017 AACR.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Renais/genética , Proteínas de Neoplasias/genética , Versicanas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Análise Serial de Tecidos
18.
Int Immunol ; 29(12): 581-591, 2017 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-29309623

RESUMO

RNA-binding motif 10 (Rbm10) is an RNA-binding protein that regulates alternative splicing, but its role in inflammation is not well defined. Here, we show that Rbm10 controls appropriate splicing of DNA (cytosine-5)-methyltransferase 3b (Dnmt3b), a DNA methyltransferase, to regulate the activity of NF-κB-responsive promoters and consequently inflammation development. Rbm10 deficiency suppressed NF-κB-mediated responses in vivo and in vitro. Mechanistic analysis showed that Rbm10 deficiency decreased promoter recruitment of NF-κB, with increased DNA methylation of the promoter regions in NF-κB-responsive genes. Consistently, Rbm10 deficiency increased the expression level of Dnmt3b2, which has enzyme activity, while it decreased the splicing isoform Dnmt3b3, which does not. These two isoforms associated with NF-κB efficiently, and overexpression of enzymatically active Dnmt3b2 suppressed the expression of NF-κB targets, indicating that Rbm10-mediated Dnmt3b2 regulation is important for the induction of NF-κB-mediated transcription. Therefore, Rbm10-dependent Dnmt3b regulation is a possible therapeutic target for various inflammatory diseases.

19.
Oncotarget ; 7(31): 49107-49121, 2016 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-27203547

RESUMO

Cytochrome P450 (CYP) 1A1 is a phase I enzyme that can activate various compounds into reactive forms and thus, may contribute to carcinogenesis. In this study, we investigated the expression, methylation status, and functional role of CYP1A1 on prostate cancer cells. Increased expression of CYP1A1 was observed in all cancer lines (PC-3, LNCaP, and DU145) compared to BPH-1 (P < 0.05); and was enhanced further by 5-aza-2'-deoxycytidine treatment (P < 0.01). Methylation-specific PCR (MSP) and sequencing of bisulfite-modified DNA of the xenobiotic response element (XRE) enhancer site XRE-1383 indicated promoter methylation as a regulator of CYP1A1 expression. In tissue, microarrays showed higher immunostaining of CYP1A1 in prostate cancer than normal and benign prostatic hyperplasia (BPH; P < 0.001), and methylation analyses in clinical specimens revealed significantly lower methylation levels in cancer compared to BPH at all enhancer sites analyzed (XRE-1383, XRE-983, XRE-895; P < 0.01). Interestingly, smoking affected the XRE-1383 site where the methylation level was much lower in cancer tissues from smokers than non-smokers (P < 0.05). CYP1A1 levels are thus increased in prostate cancer and to determine the functional effect of CYP1A1 on cells, we depleted the gene in LNCaP and DU145 by siRNA. We observe that CYP1A1 knockdown decreased cell proliferation (P < 0.05) and increased apoptosis (P < 0.01) in both cell lines. We analyzed genes affected by CYP1A1 silencing and found that apoptosis-related BCL2 was significantly down-regulated. This study supports an oncogenic role for CYP1A1 in prostate cancer via promoter hypomethylation that is influenced by tobacco smoking, indicating CYP1A1 to be a promising target for prostate cancer treatment.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Metilação de DNA , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Fumar Tabaco/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Apoptose , Azacitidina/análogos & derivados , Azacitidina/química , Linhagem Celular Tumoral , Ilhas de CpG , Citocromo P-450 CYP1A1/genética , Decitabina , Elementos Facilitadores Genéticos , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Sulfitos/química , Análise Serial de Tecidos , Xenobióticos/química
20.
Acta Neuropathol Commun ; 3: 51, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26293809

RESUMO

INTRODUCTION: Synaptic dysfunction and intracellular transport defects are early events in Alzheimer's disease (AD). Extracellular amyloid ß (Aß) oligomers cause spine alterations and impede the transport of proteins and organelles such as brain-derived neurotrophic factor (BDNF) and mitochondria that are required for synaptic function. Meanwhile, intraneuronal accumulation of Aß precedes its extracellular deposition and is also associated with synaptic dysfunction in AD. However, the links between intracellular Aß, spine alteration, and mechanisms that support synaptic maintenance such as organelle trafficking are poorly understood. RESULTS: We compared the effects of wild-type and Osaka (E693Δ)-mutant amyloid precursor proteins: the former secretes Aß into extracellular space and the latter accumulates Aß oligomers within cells. First we investigated the effects of intracellular Aß oligomers on dendritic spines in primary neurons and their tau-dependency using tau knockout neurons. We found that intracellular Aß oligomers caused a reduction in mushroom, or mature spines, independently of tau. We also found that intracellular Aß oligomers significantly impaired the intracellular transport of BDNF, mitochondria, and recycling endosomes: cargoes essential for synaptic maintenance. A reduction in BDNF transport by intracellular Aß oligomers was also observed in tau knockout neurons. CONCLUSIONS: Our findings indicate that intracellular Aß oligomers likely contribute to early synaptic pathology in AD and argue against the consensus that Aß-induced spine loss and transport defects require tau.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Espinhas Dendríticas/patologia , Líquido Intracelular/metabolismo , Neurônios/ultraestrutura , Organelas/metabolismo , Transporte Proteico/fisiologia , Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/citologia , Camundongos , Camundongos Transgênicos , Mutação/genética , Transfecção , Proteínas tau/deficiência , Proteínas tau/genética
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