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1.
Crit Rev Oncog ; 24(1): 89-98, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679223

RESUMO

The aging of society has led to an increase in the incidence of urological cancers. Surgery, radiotherapy, and chemotherapeutic agents are widely used treatment options, in addition to minimally invasive new therapeutical approaches developed in the past decade. Unfortunately, we are still a long way from preventing mortality due to urological cancers or to achieving long-term progression-free disease control. Extensive research in recent years has established the presence of a relatively small population of cancer stem cells, which may be targeted to reach these goals. Mounting evidence points to the role of CSCs in metastasis, treatment resistance, and recurrence. In this chapter, we review the presence of CSCs in bladder, prostate, and kidney cancers with emphasis on their identification and clinical relevance.

2.
Balkan Med J ; 36(5): 257-262, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31140236

RESUMO

Background: It is known that regular physical activity reduces anxiety. Low anxiety levels affect mood, emotions, and empathy. Oxytocin is a powerful hormone that regulates social interaction, sexual reproduction, maternal­infant bonding, milk release, empathy, and anxiety. Empathy is an important behavior in the living community; and also important for sportsmen during sportive competition and daily living life, because sportsmen are also role model of people. Aims: To investigate the effects of voluntary physical activity on oxytocin, anxiety, and empathy levels as well as the relationship between them. Study Design: Animal experiment. Methods: Male and female mice were made to exercise in running wheel cages for 6 weeks. Their empathy and anxiety levels were evaluated by using Helping Behavior test and elevated plus maze and open field test, respectively. And then the brain and blood oxytocin levels were measured. Results: Empathy-like behavior was improved in both genders of the exercise groups (door-opening time decreased in both genders of exercise groups, p for both=0.0001). As a response to exercise, both the brain and serum oxytocin levels increased in female mice (both of p=0.0001); however, in males, oxytocin levels increased in only the brain (p<0.05). Anxiety levels decreased in all the exercise groups (increased time spent in the middle area of open field test, both genders, p=0.002; increased time spent in the open arms of elevated plus maze test, females p=0.004, males p=0.0001). There was a strong negative correlation between serum oxytocin levels and door opening time of helping behavior equipment, and moderate negative correlation was found between the brain oxytocin levels and door-opening time of helping behavior equipment in females. However, there was no correlation between both the brain and serum oxytocin levels and empathy behavior in males. But there were very strong positive correlations between low anxiety indicators and both the brain and serum oxytocin levels in both the genders. Conclusion: Voluntary physical activity decreases anxiety and increases empathy-like behavior in mice; which is associated with increased oxytocin levels in female mice but not in male mice. Further research is required to investigate the mechanisms of exercise effect on anxiety and empathic brain pathways in males.

3.
PLoS Genet ; 15(4): e1008038, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946743

RESUMO

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Espondilite Anquilosante/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Febre Familiar do Mediterrâneo/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Humanos , Interleucina-1beta/sangue , Interleucina-23/sangue , Irã (Geográfico) , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , Turquia
4.
Biol Trace Elem Res ; 192(2): 244-251, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30761462

RESUMO

Magnesium, one of the basic elements for the human body, is necessary for many physiological functions. Magnesium deficiency is widely observed as a result of the reduced nutrient content of foods, over-cooking, diseases, drugs, alcohol, and caffeine consumption. Taking a dietary supplement is necessary magnesium deficiency. It has been demonstrated that absorption of organic magnesium compounds is better than absorption of inorganic compounds. The aim of this study is to investigate transitions to tissues of different organic magnesium compounds in different doses and whether there is a difference in the organic acid-bounded compounds (magnesium citrate and magnesium malate) and the amino acid-bounded compounds (magnesium acetyl taurate and magnesium glycinate), associated with transition and bioavailability. In addition, the effects of split dosages of high doses in a high volume of solvent on tissue magnesium levels are being investigated, because galenic formulation problems are regarded to prepare convenient dosage that can be taken once a day. All magnesium compounds were administered as three different doses, 45, 135, and 405 mg/70 kg elemental magnesium, were given per orally to Balbc mice. In a second set of experiments, 405 mg/70 kg high dose was divided into two doses of 202.5 mg/70 kg each and administered every 12 h. Brain, muscle tissues, and serum magnesium levels measured in all experimental groups and control 24 h later. Brain magnesium levels were found increased in all magnesium acetyl taurate administered subjects. Magnesium citrate increased muscle and brain magnesium levels in a dose-independent manner. We showed that dividing high doses of daily administered magnesium compounds did not sufficiently increase tissue magnesium levels. Although passive paracellular mechanism by solvent drag is the main mechanism of Mg absorption, other factors (electrochemical gradient effects, transcellular transporter mechanisms, magnesium status) should be effective on our results. It is necessary for further research on long-term administration of different magnesium compounds and their effect on other tissues.

5.
Biol Trace Elem Res ; 187(1): 128-136, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29679349

RESUMO

Magnesium is an element of great importance functioning because of its association with many cellular physiological functions. The magnesium content of foods is gradually decreasing due to food processing, and magnesium supplementation for healthy living has become increasingly popular. However, data is very limited on the bioavailability of various magnesium preparations. The aim of this study is to investigate the bioavailability of five different magnesium compounds (magnesium sulfate, magnesium oxide, magnesium acetyl taurate, magnesium citrate, and magnesium malate) in different tissues. Following a single dose 400 mg/70 kg magnesium administration to Sprague Dawley rats, bioavailability was evaluated by examining time-dependent absorption, tissue penetration, and the effects on the behavior of the animals. Pharmacokinetically, the area under the curve calculation is highest in the magnesium malate. The magnesium acetyl taurate was found to have the second highest area under the curve calculation. Magnesium acetyl taurate was rapidly absorbed, able to pass through to the brain easily, had the highest tissue concentration level in the brain, and was found to be associated with decreased anxiety indicators. Magnesium malate levels remained high for an extended period of time in the serum. The commonly prescribed dietary supplements magnesium oxide and magnesium citrate had the lowest bioavailability when compared to our control group. More research is needed to investigate the bioavailability of magnesium malate and acetyl taurate compounds and their effects in specific tissues and on behavior.


Assuntos
Compostos de Magnésio/metabolismo , Compostos de Magnésio/farmacocinética , Animais , Área Sob a Curva , Disponibilidade Biológica , Suplementos Nutricionais , Compostos de Magnésio/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
6.
Pharmacol Biochem Behav ; 175: 146-151, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30359628

RESUMO

Empathy is the ability to recognize, process and respond to another's emotional state and empathic functions have been linked with a multitude of cognitive and affective processes. Impaired empathy has been linked to aggression and criminal behavior in society. Acetaminophen (paracetamol) is among the most common nonprescription (over the counter) analgesics in the world and has been already linked to reducing empathic behavior in humans. The aim of this study is to investigate the effects of acetaminophen on empathy-like behavior in Sprague Dawley rats, and we further explored the underlying mechanisms by analyzing empathy related neurohormones, e.g. oxytocin and vasopressin, in association with acetaminophen exposure in rats. Empathic behavior was assessed 30 min following acetaminophen administration (100, 200, and 400 mg/kg). The impact of single and repeated acetaminophen administrations on empathy-like behavior and anxiety level were evaluated separately. Empathy-like behavior was reduced with a single high dose of acetaminophen. Subsequent low dose administration of acetaminophen also reduced empathy-like behavior. In this study we also showed that acetaminophen decreased oxytocin and vasopressin levels in the prefrontal cortex and amygdalae. We found a negative correlation between delay in door opening time and measured prefrontal cortex oxytocin levels; we adjudged the latency in door opening time as enhanced empathic behavior which seemingly suggested the existence of a mechanism between empathy-like behavior and the prefrontal oxytocin. We observed that both a single high dose or repeated low dose administrations of acetaminophen reduced empathy-like behavior in correlation with a decrease in oxytocin and vasopressin levels in the prefrontal cortex and amygdala. Further research is needed to investigate the role of acetaminophen on the other empathic brain pathways.


Assuntos
Acetaminofen/farmacologia , Comportamento Animal/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Sprague-Dawley , Comportamento Social
7.
Neurosci Lett ; 676: 92-97, 2018 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-29655944

RESUMO

We have recently shown that regular voluntary aerobic exercised rats have low levels of anxiety. Irisin is an exercise-induced myokine that is produced by many tissues; and the role it plays in anxiolytic behavior is unknown. In this study we aimed to investigate the correlation between anxiety like behavior and irisin levels following regular voluntary aerobic exercise in male mice. We've have shown that anxiety levels decreased in exercised mice, while irisin levels increased in the brain, brown adipose tissue, white adipose tissue, kidney, and pancreas tissues. No significant difference of irisin levels in the liver, muscle and serum were detected in the exercise group, when compared to controls. In addition, there was a strong positive correlation between brain irisin levels and activity in middle area of open field test and in the open arms of elevated plus maze test; both which are indicators of low anxiety levels. Our results suggest that decrease in anxiolytic behavior due to regular voluntary exercise may be associated with locally produced brain irisin. White adipose tissue irisin levels also correlated very strongly with low anxiety. However, no serum irisin increase was detected, ruling out the possibility of increased peripheral irisin levels affecting the brain via the bloodstream. Further research is necessary to explain the mechanisms of which peripheral and central irisin effects anxiety and the brain region affected.


Assuntos
Tecido Adiposo Branco/metabolismo , Ansiedade/metabolismo , Encéfalo/metabolismo , Fibronectinas/metabolismo , Condicionamento Físico Animal , Tecido Adiposo Marrom/metabolismo , Animais , Rim/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Atividade Motora , Pâncreas/metabolismo
8.
Leuk Res ; 69: 24-30, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29625321

RESUMO

Wnt signaling has been a topic of research for many years for its diverse and fundamental functions in physiological (such as embryogenesis, organogenesis, proliferation, tissue repair and cellular differentiation) and pathological (carcinogenesis, congenital/genetic diseases, and tissue degeneration) processes. Wnt signaling pathway aberrations are associated with both solid tumors and hematological malignancies. Unregulated Wnt signaling observed in malignancies may be due to a wide spectrum of abnormalities, from mutations in the genes of key players to epigenetic modifications of Wnt antagonists. Of these, Wnt antagonists are gaining significant attention for their potential of being targets for treatment and inhibition of Wnt signaling. In this review, we discuss and summarize the significance of Wnt signaling antagonists in the pathogenesis and treatment of hematological malignancies.


Assuntos
Antineoplásicos/farmacologia , Leucemia/metabolismo , Proteínas Wnt/antagonistas & inibidores , Via de Sinalização Wnt/efeitos dos fármacos , Neoplasias Hematológicas/metabolismo , Humanos , Proteínas Wnt/metabolismo
9.
FASEB J ; 32(7): 3502-3517, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29452566

RESUMO

A considerable proportion of tumors exhibit aneuploid karyotypes, likely resulting from the progressive loss of chromosomes after whole-genome duplication. Here, by using isogenic diploid and near-tetraploid (4N) single-cell-derived clones from the same parental cell lines, we aimed at exploring how polyploidization affects cellular functions and how tetraploidy generates chromosome instability. Gene expression profiling in 4N clones revealed a significant enrichment of transcripts involved in cell cycle and DNA replication. Increased levels of replication stress in 4N cells resulted in DNA damage, impaired proliferation caused by a cell cycle delay during S phase, and higher sensitivity to S phase checkpoint inhibitors. In fact, increased levels of replication stress were also observed in nontransformed, proliferative posttetraploid RPE1 cells. Additionally, replication stress promoted higher levels of intercellular genomic heterogeneity and ongoing genomic instability, which could be explained by high rates of mitotic defects, and was alleviated by the supplementation of exogenous nucleosides. Finally, our data found that 4N cancer cells displayed increased migratory and invasive capacity, both in vitro and in primary colorectal tumors, indicating that tetraploidy can promote aggressive cancer cell behavior.-Wangsa, D., Quintanilla, I., Torabi, K., Vila-Casadesús, M., Ercilla, A., Klus, G., Yuce, Z., Galofré, C., Cuatrecasas, M., Lozano, J. J., Agell, N., Cimini, D., Castells, A., Ried, T., Camps, J. Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness.


Assuntos
Movimento Celular , Instabilidade Cromossômica , Dano ao DNA , Neoplasias/genética , Tetraploidia , Linhagem Celular Tumoral , Replicação do DNA , Humanos , Fase S
10.
Mol Biol Rep ; 44(5): 391-397, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28840581

RESUMO

Dishevelled (Dvl) proteins are activated by Wnt pathway stimulation and have crucial roles in the regulation of ß-catenin destruction complex. CYLD is a tumor suppressor and a deubiquitination enzyme. CYLD negatively regulates the Wnt/ß-catenin signaling pathway by deubiquitinating Dvl proteins. Loss of function and mutations of CYLD were linked to different types of solid tumors. Loss of function in CYLD is associated with Dvl hyper ubiquitination, resulting in the transmission of Wnt signaling to downstream effectors. ß-catenin upregulation is observed during disease progression in chronic myeloid leukemia (CML). Deregulated Dvl signaling may be a reason for ß-catenin activation in CML; and CYLD may contribute to Dvl deregulation. First, we evaluated mRNA expression in three CML cell lines and mRNA expression of the CYLD gene was found to be present in all (K562, MEG01, KU812). Unlike solid tumors sequencing revealed no mutations in the coding sequences of the CYLD gene. DVL genes were silenced by using a pool of siRNA oligonucleotides and gene expression differences in CYLD was determined by RT-PCR and western blot. CYLD protein expression decreased after Dvl silencing. An opposite approach of overexpressing Dvl proteins resulted in upregulated CYLD expression. While previous reports have described CYLD as a regulator of DVL proteins; our data suggests the presence of a more complicated reciprocal regulatory mechanism in CML cell lines.


Assuntos
Enzima Desubiquitinante CYLD/metabolismo , Proteínas Desgrenhadas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular , Enzima Desubiquitinante CYLD/genética , Enzima Desubiquitinante CYLD/fisiologia , Proteínas Desgrenhadas/genética , Proteínas Desgrenhadas/fisiologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Fosfoproteínas/genética , Processamento de Proteína Pós-Traducional/fisiologia , Transdução de Sinais , Transativadores/genética , Ativação Transcricional , Ubiquitinação , Proteínas Wnt/metabolismo , beta Catenina/metabolismo
11.
Tumour Biol ; 39(5): 1010428317701654, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28468589

RESUMO

Chronic myeloid leukemia is a clonal myeloproliferative disorder that arises from the neoplastic transformation of the hematopoietic stem cell, in which the Wnt/ß-catenin signaling pathway has been demonstrated to play an important role in disease progression. However, the role of Wnt signaling antagonists in therapy resistance and disease progression has not been fully investigated. We aimed to study the effects of Wnt/ß-catenin pathway antagonists-secreted frizzled-related protein 1 and Wnt inhibitory factor 1-on resistance toward tyrosine kinase inhibitors in chronic myeloid leukemia. Response to tyrosine kinase inhibitors was analyzed in secreted frizzled-related protein 1 and Wnt inhibitory factor 1 stably transfected K562 cells. Experiments were repeated using a tetracycline-inducible expression system, confirming previous results. In addition, response to tyrosine kinase inhibitor treatment was also analyzed using the secreted frizzled-related protein 1 expressing, BCR-ABL positive MEG01 cell line, in the presence and absence of a secreted frizzled-related protein 1 inhibitor. Our data suggests that total cellular ß-catenin levels decrease in the presence of secreted frizzled-related protein 1 and Wnt inhibitory factor 1, and a significant increase in cell death after tyrosine kinase inhibitor treatment is observed. On the contrary, when secreted frizzled-related protein 1 is suppressed, total ß-catenin levels increase in the cell and the cells become resistant to tyrosine kinase inhibitors. We suggest that Wnt antagonists carry the potential to be exploited in designing new agents and strategies for the advanced and resistant forms of chronic myeloid leukemia.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas Repressoras/genética , beta Catenina/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Mutadas de Ataxia Telangiectasia/biossíntese , Proteínas Mutadas de Ataxia Telangiectasia/genética , Progressão da Doença , Proteínas de Fusão bcr-abl/genética , Células-Tronco Hematopoéticas/patologia , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Repressoras/biossíntese , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
12.
Farmaco ; 60(9): 763-70, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16019001

RESUMO

This study was carried out to develop a membrane-controlled transdermal formulation (TF) of nicotine by using sustained release dosage design (SRDD). TFs were prepared with polyethylene membrane as a rate-controlling barrier; a carbomer was used as the gel reservoir with or without propylene glycol (PG). The in vitro target flux (0.0535 mg cm(-2) h(-1)) was calculated according to SRDD calculations. Nicotine permeation through the membrane with or without transfer adhesive was also studied using diffusion cells. Nicotine permeated through membrane (without adhesive) with a flux of 0.0555 mg cm(-2) h(-1) and this value was similar to that of the in vitro target flux. The release from the TFs and from a commercial product (Nicotinell, 52.5 mg 30 cm(-2)) was studied using the FDA paddle method. The nicotine amount was increased from 22.7 to 56.5 mg in gel reservoir, and a plateau was reached beyond 45.4 mg of drug; the system attained the maximum thermodynamic activity with 56.5 mg of nicotine. The release rate from TFs (without adhesive layer) containing PG in the reservoir was very similar to the target release rate (1.07 mg h(-1)). The fluxes of nicotine from Nicotinell and TF containing 45.4 mg of nicotine were close to the in vitro target release rate.


Assuntos
Nicotina/administração & dosagem , Administração Cutânea , Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada , Difusão , Estabilidade de Medicamentos , Nicotina/sangue , Nicotina/farmacocinética , Espectrofotometria Ultravioleta
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