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1.
PeerJ ; 11: e15043, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37013148

RESUMO

Dill (Anethum graveolens L.) is an aromatic herb widely used in the food industry, with several commercial cultivars available with different qualitative characteristics. Commercial cultivars are usually preferred over landraces due to their higher yield and also the lack of improved landraces than can be commercialized. In Greece, however, traditional dill landraces are cultivated by local communities. Many are conserved in the Greek Gene Bank and the aim here was to investigate and compare the morphological, genetic, and chemical biodiversity of twenty-two Greek landraces and nine modern/commercial cultivars. Multivariate analysis of the morphological descriptors, molecular markers, and essential oil and polyphenol composition revealed that the Greek landraces were clearly distinguished compared with modern cultivars at the level of phenological, molecular and chemical traits. Landraces were typically taller, with larger umbels, denser foliage, and larger leaves. Plant height, density of foliage, density of feathering as well as aroma characteristics were desirable traits observed for some landraces, such as T538/06 and GRC-1348/04, which were similar or superior to those of some commercial cultivars. Polymorphic loci for inter-simple sequence repeat (ISSR) and start codon targeted (SCoT) molecular markers were 76.47% and 72.41% for landraces, and 68.24% and 43.10% for the modern cultivars, respectively. Genetic divergence was shown, but not complete isolation, indicating that some gene flow may have occurred between landraces and cultivars. The major constituent in all dill leaf essential oils was α-phellandrene (54.42-70.25%). Landraces had a higher α-phellandrene and dill ether content than cultivars. Two dill landraces were rich in chlorogenic acid, the main polyphenolic compound determined. The study highlighted for the first-time Greek landraces with desirable characteristics regarding quality, yield, and harvest time suitable for breeding programs to develop new dill cultivars with superior features.


Assuntos
Anethum graveolens , Essências Florais , Óleos Voláteis , Anethum graveolens/genética , Genótipo , Melhoramento Vegetal , Óleos Voláteis/química , Análise Multivariada
2.
Foods ; 9(6)2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32545662

RESUMO

In this study, three pearling fractions, namely bran, dehulled grains and pearled grains, derived from fourteen hulled and one hull-less Greek barley cultivars (Hordeum vulgare L.), were analyzed for the protein, ash, ß-glucan, phenolic compounds and tocols contents. High variations appeared in the bioactive contents across the barley cultivars and fractions as well. The protein and ash contents decreased from the outer to the inner layers, whereas ß-glucans presented an inverse trend. The highest protein and ß-glucan contents were in the hull-less cultivar; however, one hulled cultivar (Sirios) exhibited similar ß-glucan content, while another (Constantinos) had even higher protein content. The results also revealed that functional compounds were mainly located in bran fraction. Similar trends were also noted for the antioxidant activity. Ferulic acid was the primary phenolic acid in all fractions, followed by sinapic and p-coumaric acids that were dominant in bound form. However, oligomeric flavonoids, such as prodelphinidin B3, catechin, and procyanidin B2, were more abundant in free form. Overall, this study highlights that different barley cultivars can provide pearling flour fractions of varying composition (nutrients and bioactives), which have the potential to serve as nutritionally valuable ingredients in formulations of cereal-based functional food products.

3.
Oncol Lett ; 13(4): 2495-2501, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28454426

RESUMO

Infection with certain types of human papillomavirus (HPV) has been associated with the development of cervical and anal cancer. Worldwide, the incidence of anal cancer has increased markedly. The present study aimed to evaluate the prevalence of HPV infection of the uterine cervix and anal canal in human immunodeficiency virus (HIV)- and non-HIV-infected risk populations. Cervical and anal HPV swabs and cytology samples were collected from 287 patients at the University Hospital of Munich, Germany between 2011 and 2013. Patients were divided into HIV-negative controls (G1) and two risk groups, including HIV-negative patients with cytological abnormalities of the cervix (G2) and HIV-infected patients (G3). Data, including clinical parameters, were analysed. The risk groups had significantly more positive results for HPV in the anus (71.03 and 83.15% for G2 and G3, respectively), as compared with G1. The predominant HPV genotypes found in the anus were high-risk HPV genotypes, which were significantly correlated with concomittant cervical HPV findings. In the risk groups, a significant association between the cytological findings and HPV detection in the cervix was found, while the results of the anus revealed no significance. The results of the present study suggested that the prevalence of HPV infection in the anal canal of risk populations is high. Furthermore, patients with abnormal cervical cytology results and HIV-infected women, irrespective of their individual cervical findings, may have a risk of concomittant anal high-risk HPV infection. Based on the predominant HPV genotypes found in the study, HPV vaccination could reduce the incidence of anal cancer. Nevertheless, high-risk patients should be intensively screened for anal squamous intraepithelial abnormalities to avoid invasive cancer stages.

4.
Oncol Rep ; 37(1): 617-621, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27878300

RESUMO

As part of the efforts to drug repurposing, some HIV drugs have recently been identified to exert anticancer effects. Selected nucleoside analogues of nucleosidic reverse-transcriptase inhibitors (NRTIs) have been shown to interfere with RNA transcription of HI viruses as well as with the replication of DNA in cancer cells. Non-nucleosidic reverse transcriptase inhibitors (NNRTIs) are believed to have less effects on human DNA replication and, thus, on cancer cell proliferation. Assessment of the effect of the NNRTI efavirenz in human cancer cells, however, revealed a high sensitivity of leukemia cells to this agent at pharmacologically relevant concentrations of less than 10 µg/ml. Cell death induced by efavirenz was caused by apoptosis, as shown by FACScan analysis (Annexin binding) and western blot analysis (cleavage of caspases and PARP). Western blot analyses also revealed a pronounced activation and phosphorylation of the DNA damage marker proteins p53, chk2 and H2AX, indicating DNA replication and genomic integrity as primary targets of efavirenz in leukemia cells.


Assuntos
Apoptose/efeitos dos fármacos , Benzoxazinas/farmacologia , Dano ao DNA/efeitos dos fármacos , Leucemia/patologia , Alcinos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Ciclopropanos , Células HL-60 , Humanos , Células Jurkat , Leucemia/genética , Leucemia/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
5.
Anticancer Res ; 36(5): 2153-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27127117

RESUMO

BACKGROUND/AIM: Activins are dimeric glycoproteins that play a significant role in reproduction and in endocrine-active tumors. The aim of this study was to evaluate the potential correlation between the concentration of activins (activin A, activin B, and activin AB) in patients receiving adjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: The serum concentration of activins in 30 patients receiving chemotherapy within the German SUCCESS A study was analyzed using different enzyme-linked immunosorbent assays at three time points: After primary surgery, but before chemotherapy; 4 weeks after the end of chemotherapy; and 2 years after chemotherapy during recurrence-free follow-up. RESULTS: The activin concentration decreased in all patients after chemotherapy. Premenopausal patients had significantly lower concentrations of activin AB during follow-up than postmenopausal women (p=0.037). Thirteen out of 16 premenopausal patients developed chemotherapy-related amenorrhea (CRA) but did not significantly differ in their activin concentrations compared to the other premenopausal women. A positive human epidermal growth factor receptor 2/neu status was associated with a significant reduction of activin AB concentration (p=0.02), and trastuzumab treatment correlated with significantly decreased activin A concentration (p=0.012). CONCLUSION: Serial measurements of activin A concentration might be used for monitoring trastuzumab treatment. A sudden increase of activin concentration could be an early indicator of disease recurrence.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos
6.
Cancer Metastasis Rev ; 33(4): 943-51, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25319202

RESUMO

The family of metastasis-associated (MTA) genes is a small group of transcriptional co-regulators which are involved in various physiological functions, ranging from lymphopoietic cell differentiation to the development and maintenance of epithelial cell adhesions. By recruiting histone-modifying enzymes to specific promoter sequences, MTA proteins can function both as transcriptional repressors and activators of a number of cancer-relevant proteins, including Snail, E-cadherin, signal transducer and activator of transcriptions (STATs), and the estrogen receptor. Their involvement in the epithelial-mesenchymal transition process and regulatory interactions with estrogen receptor activity has made MTA proteins highly interesting research candidates, especially in the field of hormone-sensitive breast cancer and malignancies of the female reproductive tract. This review focuses on the current knowledge about the function and regulation of MTA1 and MTA3 proteins in gynecological cancer, including ovarian, endometrial, and cervical tumors.


Assuntos
Transição Epitelial-Mesenquimal/genética , Neoplasias dos Genitais Femininos/genética , Histona Desacetilases/genética , Proteínas de Neoplasias/genética , Proteínas Repressoras/genética , Diferenciação Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias dos Genitais Femininos/patologia , Histona Desacetilases/biossíntese , Humanos , Proteínas de Neoplasias/biossíntese , Receptores de Estrogênio/metabolismo , Proteínas Repressoras/biossíntese , Transativadores
7.
Arch Gynecol Obstet ; 290(1): 149-54, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24554348

RESUMO

PURPOSE: Due to very unspecific symptoms ovarian cancer often is diagnosed only at a late stage of the disease. Thus, morbidity and mortality of the patients are high. Even the established tumor marker CA12-5 shows only low specificity, rising the need for alternative biomarkers capable of detecting early stages of ovarian cancer. We analyzed the expression of the tumor suppressor candidate gene LDOC1 (leucine zipper downregulated in cancer 1) as a potential early biomarker in ovarian cancer cell lines. METHODS: A total of seven ovarian cancer cell lines were analyzed by RT-PCR (reverse transcriptase polymerase chain reaction) and real-time PCR for expression of LDOC1. Verification of promoter methylation was performed using methylation-specific primers on bisulfite-modified genomic DNA. RESULTS: Three out of seven ovarian cancer cell lines showed a complete loss of LDOC1 gene expression. LDOC1 silencing was caused neither by gene deletion nor gene rearrangements, but by methylation and subsequent inactivation of the concerned promoter as proofed by methylation specific primers. Similarly, promoter methylation could be inhibited by adding AdC (5-aza-2'-deoxycytidine), an inhibitor of DNA methyltransferases. As a result, a reactivation of the LDOC1 gene was seen. CONCLUSIONS: The tumor suppressor gene LDOC1 in ovarian cancer cell lines is downregulated by promoter methylation and thus may serve as an early biomarker. Further investigation will show if detection of methylated LDOC1 in peripheral blood has both adequate sensitivity and specificity for a timely non-invasive detection of ovarian cancer.


Assuntos
Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/análogos & derivados , Biomarcadores Tumorais/genética , Linhagem Celular , Metilases de Modificação do DNA/antagonistas & inibidores , Metilases de Modificação do DNA/genética , Primers do DNA/genética , Decitabina , Inibidores Enzimáticos , Feminino , Inativação Gênica , Genes Supressores de Tumor/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Arch Gynecol Obstet ; 289(6): 1263-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24474636

RESUMO

INTRODUCTION: Pelvic inflammatory disease (PID) is frequent in adolescents and younger women. Diagnosis is usually based on the clinical findings, and the threshold for empiric antibiotic therapy should be low. However, at least in cases of resistance toward therapy or deterioration of symptoms, laparoscopic evaluation can be helpful. METHODS: We searched the hospital charts for in-house patients who were treated for PID or tubo-ovarian abscess between 2007 and 2010. In cases with both vaginal and intra-abdominal bacterial cultures, results of those were compared. RESULTS: 73 patients with suspected PID or tubo-ovarian abscess were included. Median patients' age was 40 years (18-88), 18 of 73 (24.7 %) patients had an IUD at the time of consultation. 58 patients underwent laparoscopy or laparotomy. In 41 patients (70.7 %) tubo-ovarian abscess could be confirmed, four patients had differential gynecologic diagnoses, and two patients appendicitis. In vaginal swabs, most frequent bacteria were Streptococcus sp. (28.5 %), Escherichia coli (22.2 %), Enterococcus faecalis (15.9 %), and Staphylococcus sp. (9.5 %). In eight patients (11 %) Chlamydia trachomatis could be found, there was no case of Neisseria gonorrhea. In 33 patients both vaginal and abdominal cultures were available. In nine cases (27.3 %), identical bacteria could be found, however, 11 cases (33.3 %) showed different results. CONCLUSION: In severe cases of PID, laparoscopic evaluation and taking an intra-abdominal bacterial culture are helpful for the confirmation of diagnosis, accurate microbiologic testing and specific therapy.


Assuntos
Abdome/microbiologia , Doença Inflamatória Pélvica/diagnóstico , Doença Inflamatória Pélvica/microbiologia , Vagina/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Proteína C-Reativa/análise , Quimioterapia Combinada , Feminino , Humanos , Período Intraoperatório , Dispositivos Intrauterinos/microbiologia , Laparoscopia , Laparotomia , Tempo de Internação/estatística & dados numéricos , Leucocitose/etiologia , Pessoa de Meia-Idade , Doença Inflamatória Pélvica/terapia , Estudos Retrospectivos , Adulto Jovem
9.
J Appl Toxicol ; 34(10): 1109-13, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24155182

RESUMO

Clinically effective anti-cancer drugs have to tread a narrow line between selective cytotoxicity on tumor cells and tolerable adverse effects against healthy tissues. This causes the failure of many potential cancer drugs in advanced clinical trials, hence signifying the importance of a comprehensive initial estimate of the cytotoxicity of prospective anti-cancer drugs in preclinical studies. In this study, the cytotoxicity of borrelidin, a macrolide antibiotic with a high cytotoxic selectivity for proliferating endothelial cells and leukemia cells, was tested on malignant and non-malignant breast cells. Highly metastatic breast cancer cell lines (MDA-MB-231 and MDA-MB-435) showed promising results and exhibited good sensitivity to borrelidin at low nanomolar concentrations, but borrelidin was cytotoxic to a non-malignant breast epithelial cell line (MCF10A) as well. Furthermore, although a high sensitivity of endothelial cells (human umbilical vein endothelial cells; HUVEC) and individual leukemia cell lines (Jurkat and IM9) to borrelidin was confirmed in this study, another leukemia cell line (HL60) and an immortalized endothelial cell line (EA.hy926) displayed a significantly decreased sensitivity. Reduced sensitivity to borrelidin was associated with elevated bcl-2 expression in these cell lines. In conclusion, the results presented show that borrelidin displays high and selective cytotoxicity against subgroups of cancer cells and endothelial cells, but, owing to its non-specific toxicity to non-malignant cells, its clinical application might be restricted because of likely adverse effects and limited efficacy in bcl2-overexpressing cancer cells.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Mama/metabolismo , Células Epiteliais/metabolismo , Genes bcl-2/genética , Leucemia/tratamento farmacológico , Leucemia/genética , Trifosfato de Adenosina/metabolismo , Western Blotting , Mama/efeitos dos fármacos , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Álcoois Graxos/farmacologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Sais de Tetrazólio , Tiazóis
10.
Exp Cell Res ; 320(2): 281-9, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24280420

RESUMO

Tetracyclines have long been used as valuable broad-spectrum antibiotics. The high antibacterial activity of tetracyclines, combined with their good tolerability, has led to their widespread use in treating various infectious diseases. However, similar to other antibiotics, tetracyclines are also known for their adverse effects on different human tissues, including hepatic steatosis. We observed that tetracyclines, including doxycycline and minocycline, caused enhanced expression of the liver chalone inhibin ßE in HepG2 cells, mediated by the cell stress-regulated transcription factor ATF4. ATF4 and its target genes ATF3, CHOP, and inhibin ßE are involved in cell cycle control, cell survival, cell metabolism, and modulation of cytokine expression. Furthermore, we observed that long term tetracycline incubation also caused inhibition of the mTOR complex, a central regulator of cell metabolism, further contributing to the observed cell-cycle arrest and autophagy in doxycycline- and minocycline-treated cell lines. ATF4 activation and mTOR inhibition link two crucial regulators of the cellular stress response and cell metabolism to the effects of tetracyclines on eukaryotic cell metabolism, and may help to understand the antibiotic-independent influence of these drugs on human tissues. Since the observed effects of tetracyclines on human cells were also found to be dependent on the magnesium ion concentrations supplied, the data further indicate the importance of magnesium supplementation to reduce or prevent side effects of long term treatment with tetracyclines.


Assuntos
Fator 4 Ativador da Transcrição/agonistas , Serina-Treonina Quinases TOR/antagonistas & inibidores , Tetraciclinas/farmacologia , Fator 4 Ativador da Transcrição/metabolismo , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Células Hep G2 , Humanos , Subunidades beta de Inibinas/genética , Subunidades beta de Inibinas/metabolismo , Estresse Fisiológico/fisiologia , Ativação Transcricional/efeitos dos fármacos
11.
Oncoscience ; 1(1): 21-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25593981

RESUMO

A valuable strategy to develop new therapeutic options for a variety of diseases has been the identification of new targets and applications for already approved drugs, the so-called drug repositioning. Recurrent ovarian cancer is a nearly incurable malignancy for which new and effective treatments are urgently needed. The alcohol-deterring drug disulfiram has been shown to cause preferential cell death in a variety of cancer cells. In this study, it is shown that disulfiram mediates effective cell death in ovarian cancer cells by promoting a pro-oxidative intracellular environment in a copper-dependent mechanism. Within few hours of application, disulfiram caused irreversible cell damage associated with pronounced induction of the inducible heat shock proteins HSP70, HSP40, and HSP32. The small heat shock protein HSP27 was found to be covalently dimerized via oxidized disulfide bonds and precipitated in para-nuclear protein aggregates. Simultaneous inhibition of the cellular thioredoxin system by auranofin further enhanced the cytotoxic effect of disulfiram. These data indeed indicate that the combination of two approved drugs, the anti-alcoholic disulfiram and the anti-rheumatic auranofin, may be of interest for the treatment of recurrent and genotoxic drug-resistant ovarian cancer by inducing a proteotoxic cell death mechanism.

12.
Cancer Invest ; 31(9): 571-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24125169

RESUMO

Cervical cancer lacks reliable prognostic factors for both progression and chemotherapeutic responsiveness. The expression of the LDOC1 tumor suppressor candidate was therefore investigated. In four of six cervical cancer cell lines tested, expression of LDOC1 was silenced. Downregulation of LDOC1 could also be shown in biopsies of cervical cancer specimens. PCR-based promoter methylation analysis revealed a significant association between promoter methylation and the loss of LDOC1 expression, which could be reverted by DNA methyltransferase inhibitors. This indicates that silencing of LDOC1 is a frequent event in cervical cancer and may be of interest as a molecular marker in cervical cancer.


Assuntos
Metilação de DNA , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Neoplasias do Colo do Útero/genética , Biópsia , Morte Celular , Metilases de Modificação do DNA/antagonistas & inibidores , Metilases de Modificação do DNA/metabolismo , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células HeLa , Humanos , Proteínas Nucleares/metabolismo , Transfecção , Proteínas Supressoras de Tumor/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
13.
Arch Gynecol Obstet ; 288(4): 883-8, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23580013

RESUMO

INTRODUCTION: Inhibins are important regulators of the female reproductive system. Recently, two new inhibin-subunits ßC and ßE have been described, although, their function is still quite unclear. Interestingly, there is an association between interferon and TGF-ß expression. Therefore, the aim of this study was to determine expression changes of inhibin-ßC and -ßE subunits in endometrial Ishikawa carcinoma cell line after stimulation with interferon-ß1a. MATERIALS AND METHODS: The Ishikawa cell line was cultured until confluence was observed (after 2 days). After adding interferon-ß1a (1,000 IE/ml), Ishikawa cells were analyzed for inhibin-ßC and -ßE subunits by RT-PCR. The fibroblast cell line BJ6 served as negative control. Experiments were performed in triplicates. RESULTS: The endometrial adenocarcinoma cell line Ishikawa synthesized the inhibin- ßC and -ßE subunits. The fibroblast cells BJ6 did not demonstrate an inhibin -ßC and -ßE mRNA expression, while inhibin-ßC subunit is down-regulated and inhibin-ßE is up-regulated in Ishikawa carcinoma cell line after stimulation with interferon-ß1a in Ishikawa. DISCUSSION: We demonstrated for the first time a functional relationship between interferon and the novel inhibin-ßC and -ßE subunits. It might be possible that interferon exerts a possible apoptotic function through the ßE-subunit, while, by down-regulating the ßC isoform, cell proliferation is inhibited. However, the precise function of the novel ßC- and ßE-subunits are still not known in human endometrial tissue and a possible association with interferon is still unclear and warrants further research.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias do Endométrio/genética , Regulação Neoplásica da Expressão Gênica , Subunidades beta de Inibinas/genética , Interferon beta/genética , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Subunidades beta de Inibinas/metabolismo , Interferon beta-1a , Interferon beta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima
15.
Gynecol Oncol ; 128(2): 383-90, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23107612

RESUMO

OBJECTIVE: The proteasome inhibitor bortezomib is currently being tested in clinical trials against refractory cervical cancer. However, high doses of bortezomib are associated with adverse effects, which may lead to treatment abrogation or to the use of lower, ineffective doses. We investigated combination drug treatments that could enhance the efficacy of low bortezomib concentrations on cervical cancer cells. METHODS: The cervical cancer cell lines CaSki, HeLa and SW756 were treated with various combinations of bortezomib and eeyarestatin. Treated cells were analyzed for cell viability by clonal assays and the MTT assay, and for expression of pro-apoptotic proteins and cell stress markers by immunofluorescence, immunoblots and RT-PCR analysis. RESULTS: Cotreatment of bortezomib with eeyarestatin markedly enhanced cell death in cervical cancer cells, allowing reduction of the bortezomib concentration necessary for efficient cell death to as low as 5 ng/ml. Combination of bortezomib with eeyarestatin resulted in a massive induction of the endoplasmic reticulum stress reaction, small and large heat shock protein activation, autophagy, and upregulation of pro-apoptotic CHOP. CONCLUSION: Eeyarestatin is a small molecule recently shown to cause endoplasmic reticulum stress by inhibiting the endoplasmic reticulum-associated degradation pathway, which directs misfolded cytotoxic proteins to proteasomal degradation. Concomitant inhibition of both pathways markedly enhances the efficacy of bortezomib against cervical cancer cells and thus may be applied to reduce the bortezomib dosage required for efficient cervical cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fator de Transcrição CHOP/biossíntese , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Ácidos Borônicos/administração & dosagem , Bortezomib , Sinergismo Farmacológico , Feminino , Células HeLa , Humanos , Hidrazonas/administração & dosagem , Hidroxiureia/administração & dosagem , Hidroxiureia/análogos & derivados , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pirazinas/administração & dosagem , Ubiquitina/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
Toxicol Appl Pharmacol ; 264(2): 300-4, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22935518

RESUMO

Inhibins and activins are gonadal peptide hormones of the transforming growth factor-ß super family with important functions in the reproductive system. By contrast, the recently identified inhibin ßE subunit, primarily expressed in liver cells, appears to exert functions unrelated to the reproductive system. Previously shown downregulation of inhibin ßE in hepatoma cells and anti-proliferative effects of ectopic inhibin ßE overexpression indicated growth-regulatory effects of inhibin ßE. We observed a selective re-expression of the inhibin ßE subunit in HepG2 hepatoblastoma cells, MCF7 breast cancer cells, and HeLa cervical cancer cells under endoplasmic reticulum stress conditions induced by tunicamycin, thapsigargin, and nelfinavir. Analysis of XPB1 splicing and ATF4 activation revealed that inhibin ßE re-expression was associated with induction of the endoplasmic reticulum stress reaction by these drugs. Transfection of an ATF4 expression plasmid specifically induced inhibin ßE expression in HeLa cells and indicates inhibin ßE as a hitherto unidentified target gene of ATF4, a key transcription factor of the endoplasmic reticulum stress response. Therefore, the inhibin ßE subunit defines not only a new player but also a possible new marker for drug-induced endoplasmic reticulum stress.


Assuntos
Fator 4 Ativador da Transcrição/genética , Antivirais/farmacologia , Estresse do Retículo Endoplasmático/fisiologia , Subunidades beta de Inibinas/biossíntese , Nelfinavir/farmacologia , Western Blotting , Linhagem Celular Tumoral , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Imunofluorescência , Marcação de Genes , Células HeLa , Humanos , Subunidades beta de Inibinas/genética , Células MCF-7 , Plasmídeos/genética , Reação em Cadeia da Polimerase , Splicing de RNA , Regulação para Cima/efeitos dos fármacos
17.
Arch Gynecol Obstet ; 285(5): 1271-85, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22350326

RESUMO

INTRODUCTION: Urogenital infection by Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the world. C. trachomatis is the etiologic agent of several common genital tract syndromes such as urethritis, cervicitis, and pelvic inflammatory disease in women. MATERIALS AND METHODS: In this review, the pathophysiology of a chlamydial infection as well as diagnosis, therapy and prevention strategies regarding female chlamydial infection are reviewed. RESULTS: A chlamydial infection results in minimal or even no symptoms in approximately two-thirds of women, remaining therefore clinically apparent and undiagnosed. C. trachomatis infections are of great socioeconomic and public health concern due to the potential for severe long-term consequences in women, including an increased risk of ectopic pregnancy, tubal infertility and chronic pelvic pain. Moreover, if the bacterium is transmitted during labor to a newborn, it can cause ophthalmia neonatorum and atypical neonatal pneumonia. Due to the documented increased risk of morbidity, several national guidelines are available, including a routine screening for young women and screening during pregnancy that is recommended in several countries. DISCUSSION: A routine screening for young women and screening during pregnancy is recommended in several countries. However, additional prospective studies of the effectiveness of chlamydia screening are warranted and might be feasible within established screening programs. Moreover, the transition from cervicitis to infertility should be also evaluated in future controlled studies to underline the existing evidence. Additionally, there is an urgent need to educate and inform health-care providers about implementation of screening programs to reduce the spread of chlamydial infection. Moreover, awareness and use of screening programs by the public is needed, which requires informational campaigns for the general public using different media. For improved screening strategies and public awareness, novel approaches have to be developed and evaluated. Finally, guidelines should be actively disseminated to all medical practitioners to increase their use in daily practice. Although the major socioeconomic and public health concerns of C. trachomatis infection are recognized, several considerations and additional measures for addressing this increasingly urgent health problem remain.


Assuntos
Infecções por Chlamydia/fisiopatologia , Chlamydia trachomatis , Infecções por Chlamydia/diagnóstico , Infecções por Chlamydia/epidemiologia , Infecções por Chlamydia/terapia , Feminino , Humanos , Programas de Rastreamento , Gravidez , Fatores de Risco
19.
Invest New Drugs ; 30(4): 1389-95, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21713384

RESUMO

Selected HIV drugs, either of the protease inhibitor type or the nucleoside antagonist type, have been shown to exert tumoricidal effects. Here, we show that the HIV reverse transcriptase inhibitor Truvada, a combination drug of the cytidine analogue emtricitabine and the adenosine analogue tenofovir, induces DNA damage and cell cycle arrest in human cancer cells. Phosphorylation of the DNA repair enzyme H2AX by emtricitabine/tenofovir indicated that it interfered with the integrity of the DNA and replication machinery in human cancer cells. Long term incubation of cancer cells with emtricitabine/tenofovir caused the formation of multi-nuclear giant cells, further indicating DNA replication problems. When tested as single agents, the anti-tumoral activity of emtricitabine/tenofovir was predominantly caused by tenofovir, although the combination with emtricitabine enhanced its effect on cancer cells. Combined with established anti-cancer drugs, emtricitabine/tenofovir was preferentially found to enhance the cytotoxic effect of doxorubicin, a promising drug for the treatment of relapsed, chemoresistant cancer. These results show that especially the adenosine analogue tenofovir could be used to interfere with the proliferation machinery of human cancer cells and to be applied for chemosensitization of cancer cells to already established DNA-interacting drugs.


Assuntos
Adenina/análogos & derivados , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , Organofosfonatos/farmacologia , Neoplasias Ovarianas/patologia , Inibidores da Transcriptase Reversa/farmacologia , Adenina/farmacologia , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Citostáticos/farmacologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Doxorrubicina/farmacologia , Combinação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Emtricitabina , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila , Feminino , Transcriptase Reversa do HIV/metabolismo , Histonas/metabolismo , Humanos , Compostos Organofosforados/farmacologia , Tenofovir , Fatores de Tempo
20.
Arch Gynecol Obstet ; 285(1): 207-14, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21538008

RESUMO

INTRODUCTION: A pelvic lymphadenectomy with or without para-aortic lymphadenectomy is performed during surgery for endometrial cancer at least in high-risk patients for recurrence or progression. The question of whether pelvic and/or para-aortic lymphadenectomy improves survival rates of high-risk patients with uterine non-endometrioid carcinoma is still unclear. Therefore, the aim of this study was to evaluate the outcome of patients with uterine non-endometrioid cancer, with regard to the performance of a lymphadenectomy in a well-characterized cohort population. MATERIALS AND METHODS: The prognostic value of a performed lymphadenectomy was examined in 55 patients with a histological diagnosis of a uterine non-endometrioid carcinoma. A performed lymphadenectomy was analyzed with respect to the surgical and pathological stage and characteristics. RESULTS: Of the 55 patients with an uterine non-endometrioid carcinoma, 38 (69.1%) and 2 (3.6%) patients were diagnosed in FIGO stage I and II, respectively, while 14 (25.5%) patients had FIGO stage III and 1 patient (1.8%) presented with metastatic disease (FIGO IV). 16 patients (29.1%) demonstrated a myometrial invasion of more than 50%, while a cervical and ovarian involvement could be observed in 7 (12.7%) and 9 (16.4%) cases, respectively. Pelvic and/or para-aortic lymph node sampling was performed for 42 patients (76.4%) while 7 patients (12.7%) demonstrated lymph node metastasis. Univariate survival analysis demonstrated no differences in progression-free survival, cause-specific survival or overall survival for a performed lymphadenectomy. Regression analysis led to a model containing only the FIGO surgical stage as an independent term that was predictive of progression-free survival, cause-specific survival and overall survival. DISCUSSION: Although a performed lymphadenectomy did not have any positive benefit in the survival of patients with uterine non-endometrioid carcinomas in this study, it might provide important prognostic information with a subsequent adjuvant treatment. However, these results remain to be confirmed in further larger and prospective studies.


Assuntos
Carcinoma/mortalidade , Carcinoma/patologia , Excisão de Linfonodo , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologia , Idoso , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/secundário , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/patologia
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