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Food Sci Nutr ; 8(10): 5673-5682, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33133569


Cruciferous vegetables are primary sources of dietary isothiocyanates (ITCs), a group of phytochemicals showing promising cancer-chemopreventive activities in multiple cancer models. However, no study has thoroughly examined how cooking affects the yields of ITCs from cruciferous vegetables. In this study, a high-performance liquid chromatography (HPLC)-based cyclocondensation assay was performed to examine the ITC yields from four major cruciferous vegetables (broccoli, cabbage, cauliflower, and kale) under six cooking conditions (stir-frying, steaming, microwaving, boiling, stewing, and chip-baking for kale only) and measured the level of ITCs under the raw condition for a comprehensive list of cruciferous vegetables and ITC-containing condiments. A wide range of ITC yields was found across vegetables and condiments. Cooking significantly altered the ITC yields, showing an averagely four-fold increase by lightly cooking (stir-frying, steaming, and microwaving) and a 58% decrease by heavily cooking (boiling, stewing, and chip-baking). These findings will provide the evidence-based cooking guidance on cruciferous vegetable consumption and help better estimate dietary ITC exposure in epidemiologic studies.

Mol Cell Endocrinol ; 477: 121-131, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29928927


Steroid hormones play important roles in normal physiological functions and diseases. Sex steroids hormones are important in the biology and treatment of sex hormone-related cancer such as prostate cancer and breast cancer. Cells may take up steroids using multiple mechanisms. The conventionally accepted hypothesis that steroids cross cell membrane through passive diffusion has not been tested rigorously. Experimental data suggested that cells may take up sex steroid using an active uptake mechanism. 3H-testosterone uptake by prostate cancer cells showed typical transporter-mediated uptake kinetic. Cells retained testosterone taken up from the medium. The uptake of testosterone was selective for certain steroid hormones but not others. Data also indicated that the active and selective uptake mechanism resided in cholesterol-rich membrane domains, and may involve ATP and membrane transporters. In summary, the present study provided strong evidence to support the existence of an active and selective molecular mechanism for sex steroid uptake.

Hormônios Esteroides Gonadais/metabolismo , Neoplasias da Próstata/metabolismo , Glândulas Suprarrenais/metabolismo , Linhagem Celular Tumoral , Colesterol/metabolismo , Estrogênios/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Progesterona/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Progesterona/metabolismo , Testosterona/metabolismo , Trítio/metabolismo , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , ATPases Vacuolares Próton-Translocadoras/metabolismo
Elife ; 72018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29400649


Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anticancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin.

Cromatina/metabolismo , Metilação de DNA , Instabilidade Genômica , Interferons/metabolismo , Transcrição Genética , Animais , Antineoplásicos/metabolismo , Células Cultivadas , Inibidores de Histona Desacetilases/metabolismo , Humanos , Camundongos
Diabetologia ; 61(5): 1124-1134, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29445851


AIMS/HYPOTHESIS: Improved biomarkers are acutely needed for the detection of developing type 1 diabetes, prior to critical loss of beta cell mass. We previously demonstrated that elevated beta cell microRNA 21-5p (miR-21-5p) in rodent and human models of type 1 diabetes increased beta cell apoptosis. We hypothesised that the inflammatory milieu of developing diabetes may also increase miR-21-5p in beta cell extracellular vesicle (EV) cargo and that circulating EV miR-21-5p would be increased during type 1 diabetes development. METHODS: MIN6 and EndoC-ßH1 beta cell lines and human islets were treated with IL-1ß, IFN-γ and TNF-α to mimic the inflammatory milieu of early type 1 diabetes. Serum was collected weekly from 8-week-old female NOD mice until diabetes onset. Sera from a cross-section of 19 children at the time of type 1 diabetes diagnosis and 16 healthy children were also analysed. EVs were isolated from cell culture media or serum using sequential ultracentrifugation or ExoQuick precipitation and EV miRNAs were assayed. RESULTS: Cytokine treatment in beta cell lines and human islets resulted in a 1.5- to threefold increase in miR-21-5p. However, corresponding EVs were further enriched for this miRNA, with a three- to sixfold EV miR-21-5p increase in response to cytokine treatment. This difference was only partially reduced by pre-treatment of beta cells with Z-VAD-FMK to inhibit cytokine-induced caspase activity. Nanoparticle tracking analysis showed cytokines to have no effect on the number of EVs, implicating specific changes within EV cargo as being responsible for the increase in beta cell EV miR-21-5p. Sequential ultracentrifugation to separate EVs by size suggested that this effect was mostly due to cytokine-induced increases in exosome miR-21-5p. Longitudinal serum collections from NOD mice showed that EVs displayed progressive increases in miR-21-5p beginning 3 weeks prior to diabetes onset. To validate the relevance to human diabetes, we assayed serum from children with new-onset type 1 diabetes compared with healthy children. While total serum miR-21-5p and total serum EVs were reduced in diabetic participants, serum EV miR-21-5p was increased threefold compared with non-diabetic individuals. By contrast, both serum and EV miR-375-5p were increased in parallel among diabetic participants. CONCLUSIONS/INTERPRETATION: We propose that circulating EV miR-21-5p may be a promising marker of developing type 1 diabetes. Additionally, our findings highlight that, for certain miRNAs, total circulating miRNA levels are distinct from circulating EV miRNA content.

Biomarcadores/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Células Secretoras de Insulina/metabolismo , MicroRNAs/genética , Animais , Apoptose , Vesículas Extracelulares , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos NOD , MicroRNAs/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
Oncotarget ; 8(36): 60080-60093, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947955


Metastasis is the major cause of bladder cancer death. 1,25D3, the active metabolite of vitamin D, has shown anti-metastasis activity in several cancer model systems. However, the role of 1,25D3 in migration and invasion in bladder cancer is unknown. To investigate whether 1,25D3 affects migration and invasion, four human bladder cell lines with different reported invasiveness were selected: low-invasive T24 and 253J cells and highly invasive 253J-BV and TCCSUP cells. All of the four bladder cancer cells express endogenous and inducible vitamin D receptor (VDR) as examined by immunoblot analysis. 1,25D3 had no effect on the proliferation of bladder cancer cells as assessed by MTT assay. In contrast, 1,25D3 suppressed migration and invasion in the more invasive 253J-BV and TCCSUP cells, but not in the low-invasive 253J and T24 cells using "wound" healing, chemotactic migration and Matrigel-based invasion assays. 1,25D3 promoted the expression of miR-101-3p and miR-126-3p in 253J-BV cells as examined by qRT-PCR. miR-101-3p inhibitor partially abrogated and pre-miR-101-3p further suppressed the inhibition of 1,25D3 on migration and invasion in 253J-BV cells. Further, 1,25D3 enhanced VDR recruitment to the promoter region of miR-101-3p using ChIP-qPCR assay. 1,25D3 enhanced the promoter activity of miR-101-3p as evaluated by luciferase reporter assay. Taken together, 1,25D3 suppresses bladder cancer cell migration and invasion in two invasive/migration competent lines but not in two less invasive/motile lines, which is partially through the induction of miR-101-3p expression at the transcriptional level.

J Steroid Biochem Mol Biol ; 148: 166-71, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25263658


Bladder cancer is the fourth most commonly diagnosed cancer in men and eighth leading cause of cancer-related death in the US. Epidemiological and experimental studies strongly suggest a role for 1α,25(OH)2D3 in cancer prevention and treatment. The antitumor activities of 1α,25(OH)2D3 are mediated by the induction of cell cycle arrest, apoptosis, differentiation and the inhibition of angiogenesis and metastasis. miRNAs play important regulatory roles in cancer development and progression. However, the role of 1α,25(OH)2D3 in the regulation of miRNA expression and the potential impact in bladder cancer has not been investigated. Therefore, we studied 1α,25(OH)2D3-regulated miRNA expression profiles in human bladder cancer cell line 253J and the highly tumorigenic and metastatic derivative line 253J-BV by miRNA qPCR panels. 253J and 253J-BV cells express endogenous vitamin D receptor (VDR), which can be further induced by 1α,25(OH)2D3. VDR target gene 24-hydroxylase was induced by 1α,25(OH)2D3 in both cell lines, indicating functional 1α,25(OH)2D3 signaling. The miRNA qPCR panel assay results showed that 253J and 253J-BV cells have distinct miRNA expression profiles. Further, 1α,25(OH)2D3 differentially regulated miRNA expression profiles in 253J and 253J-BV cells in a dynamic manner. Pathway analysis of the miRNA target genes revealed distinct patterns of contribution to the molecular functions and biological processes in the two cell lines. In conclusion, 1α,25(OH)2D3 differentially regulates the expression of miRNAs, which may contribute to distinct biological functions, in human bladder 253J and 253J-BV cells. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.

Calcitriol/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Vitaminas/farmacologia , Humanos , Masculino , Células Tumorais Cultivadas