RESUMO
Metastasis is the primary stumbling block to the treatment of bladder cancer (BC). In order to spread, tumor cells must acquire increased migratory and invasive capacity, which is tightly linked with pseudopodia formation. Here, we unravel the effects of sulforaphane (SFN), an isothiocyanate in cruciferous vegetables, on the assembly of pseudopodia and BC metastasis, and its molecular mechanism in the process. Our database analysis revealed that in bladder tumor, pseudopodia-associated genes, CTTN, WASL and ACTR2/ARP2 are upregulated. SFN caused lamellipodia to collapse in BC cells by blocking the CTTN-ARP2 axis. SFN inhibited invadopodia formation and cell invasion by reducing WASL in different invasive BC cell lines. The production of ATP, essential for the assembly of pseudopodia, was significantly increased in bladder tumors and strongly inhibited by SFN. Overexpressing AKT1 reversed the downregulation of ATP in SFN-treated bladder cancer cells and restored filopodia and lamellipodia morphology and function. Bioluminescent imaging showed that SFN suppressed BC metastases to the lung of nude mice while downregulating Cttn and Arp2 expression. Our study thus reveals mechanisms of SFN action in inhibiting pseudopodia formation and highlights potential targeting options for the therapy of metastatic bladder cancer.
RESUMO
BACKGROUND AND PURPOSE: Diet might be a modifiable factor in preventing cancer by modulating inflammation. This study aims to explore the association between the dietary inflammatory index (DII) score and the risk of bladder cancer (BC). METHODS: A total of 112 BC patients and 292 control subjects were enrolled in a case-control trial. Additionally, we tracked a total of 109 BC patients and 319 controls, whose propensity scores were obtained from the Nutrition Examination Survey (NHANES) database spanning from 1999 to 2020. The baseline index and dietary intake data were assessed using a food frequency questionnaire (FFQ). DII scores were calculated based on the dietary intake of 20 nutrients obtained from participants and categorized into four groups. The association between the inflammatory potential of the diet and BC risk was investigated using multivariate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: High DII scores were associated with a pro-inflammatory diet and a higher risk of BC, with higher DII scores positively associated with a higher risk of BC (quartiles 4 vs. 1, ORs 4.89, 95% CIs 2.09-11.25 p < 0.001). Specifically, this might promote BC development by inducing oxidative stress and affecting DNA repair mechanisms. This result was consistent with the NHANES findings (quartiles 4 vs. 1, ORs 2.69, 95% CIs 1.25-5.77, p = 0.006) and further supported the association of pro-inflammatory diet and lifestyle factors with the risk of BC. CONCLUSIONS: Diets with the highest pro-inflammatory potential were associated with an increased risk of BC. By adjusting lifestyle factors, individuals might effectively lower their DII, thereby reducing the risk of developing BC. The results are consistent with the NHANES cohort.
Assuntos
Consumo de Bebidas Alcoólicas , Dieta , Inflamação , Inquéritos Nutricionais , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/prevenção & controle , Neoplasias da Bexiga Urinária/etiologia , Masculino , Estudos de Casos e Controles , Feminino , Pessoa de Meia-Idade , Dieta/efeitos adversos , Dieta/estatística & dados numéricos , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Idoso , Razão de Chances , AdultoRESUMO
Human studies have shown the anticancer effects of dietary isothiocyanates (ITCs), but there are some inconsistencies, and more evidence supports that such anticancer effect is from higher doses of ITCs. The inconsistencies found in epidemiological studies may be due to many factors, including the biphasic dose-response (so called hormetic effect) of ITCs, which was found to be more profound under hypoxia conditions. In this comprehensive review, we aim to shed light on the intriguing synergistic interactions between dietary ITCs, focusing on sulforaphane (SFN) and various anticancer drugs. Our exploration is motivated by the potential of these combinations to enhance cancer management strategies. While the anticancer properties of ITCs have been recognized, our review delves deeper into understanding the mechanisms and emphasizing the significance of the hormetic effect of ITCs, characterized by lower doses stimulating both normal cells and cancer cells, whereas higher doses are toxic to cancer cells and inhibit their growth. We have examined a spectrum of studies unraveling the multifaceted interaction and combinational effects of ITCs with anticancer agents. Our analysis reveals the potential of these synergies to augment therapeutic efficacy, mitigate chemoresistance, and minimize toxic effects, thereby opening avenues for therapeutic innovation. The review will provide insights into the underlying mechanisms of action, for example, by spotlighting the pivotal role of Nrf2 and antioxidant enzymes in prevention. Finally, we glimpse ongoing research endeavors and contemplate future directions in this dynamic field. We believe that our work contributes valuable perspectives on nutrition and cancer and holds promise for developing novel and optimized therapeutic strategies.
RESUMO
BACKGROUND: Metastasis and recurrence are the main causes of death in post-operative bladder cancer (BC), emphasizing the importance of exploring early-stage diagnostic markers. Serum biomarkers constitute a promising diagnostic approach for asymptomatic stage cancer as they are non-invasive, have high accuracy and low cost. AIMS: To correlate concentrations of plasma amino acids with BC progression to assess their utility as an early-stage diagnostic. METHODS: Newly diagnosed BC patients (n = 95) and normal controls (n = 96) were recruited during the period from 1 December 2018 to 30 December 2020. General and food frequency questionnaires established their basic information and dietary intake data. Venous blood samples were collected from fasting subjects and used to detect levels of plasma amino acids by liquid chromatography-mass spectrometry. Verification was performed on the GSE13507 transcriptome gene expression matrix of BC from Gene Expression Omnibus (GEO) database. RESULTS: Eleven amino acids have been identified as altered in the plasma of newly diagnosed BC patients compared to controls (P < 0.05). Adjusted by gender, education, smoking and other factors, plasma ornithine level (OR = 0.256, 95% CI: 0.104-0.630) is a protective factor for BC, plasma levels of methionine (OR = 3.460, 95% CI: 1.384-8.651), arginine (OR = 3.851, 95% CI: 1.542-9.616), and glutamate (OR = 3.813, 95% CI: 1.543-9.419) are all risk factors for BC. ROC analysis demonstrated that the combination of plasma ornithine, methionine, arginine and glutamate could accurately diagnose BC (AUC = 0.84, 95% CI: 0.747-0.833). In addition, the mRNA level of arginase 1 was decreased (P < 0.05), while the inducible nitric oxide synthase was increased significantly, which may be linked with the disturbance of arginine metabolism in BC patients. Further analysis of GEO database confirmed the role of arginine metabolism. CONCLUSION: A biomarker panel containing four amino acids may provide a feasible strategy for the early diagnosis of BC. However, further validation is required through prospective studies.
Assuntos
Aminoácidos , Biomarcadores Tumorais , Neoplasias da Bexiga Urinária , Humanos , Masculino , Feminino , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/diagnóstico , Aminoácidos/sangue , Biomarcadores Tumorais/sangue , Pessoa de Meia-Idade , Idoso , Estudos de Casos e Controles , Arginina/sangueRESUMO
The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.
Assuntos
Multiômica , Neoplasias da Glândula Tireoide , Humanos , Glicina Hidroximetiltransferase/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Redes e Vias Metabólicas/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismoRESUMO
The relationship between saturated fatty acids (SFA) and bladder cancer (BC) risk has been conflicting. Our aim was to investigate the relationship between erythrocyte membrane SFA and BC risk. A total of 404 participants were enrolled in the study (including 112 cases and 292 controls). A validated food frequency questionnaire was used to assess the food intake. The constitutive composition of fatty acids in the erythrocyte membrane was measured by gas chromatography. After adjustment for BC risk factors, SFA had no significant association with BC risk. However, C18:0 was positively linked with BC risk with an odds ratio (OR; 95% CI) of 2.99 (1.37-6.53). In contrast, very-long-chain saturated fatty acids (VLCSFA), especially C24:0, were negatively related to BC risk with an OR (95% CI) of 0.28 (0.12-0.65) for VLCSFA and 0.33 (0.15-0.75) for C24:0. Higher total odd-chain SFA (C15:0 and C17:0) were associated with a lower risk of BC with OR (95% CI) of 0.18 (0.076-0.44), 0.18 (0.068-0.47), 0.34 (0.14-0.81), respectively. After subgroup analysis, the protective effects C15:0 and C17:0 were still remained. Receiver operating characteristic analysis displayed that the combination of C15:0 and C17:0 indexes increased the accurate predictive rate of BC risk. Further mediation effect analysis showed that C15:0 and C17:0 could be used as partial mediation effectors for milk and dairy products and bladder carcinogenesis. Overall, the combination of odd-chain SFA (C15:0 and C17:0) in the erythrocyte membrane could serve as a reliable mediator and predictor, indicating a relationship between a high intake of milk and dairy products and a lower risk of BC.
RESUMO
OBJECTIVES: Recent studies have found that dietary fiber improves prognosis in cancer patients. However, few subgroup analyses exist. Subgroups can differ greatly in terms of different factors such as dietary intake, lifestyle, and sex. It is unclear whether fiber benefits all of the subgroups equally. In this study, we examined differences in dietary fiber consumption and cancer mortality between subgroups, including sex. METHODS: This trial was conducted using eight consecutive National Health and Nutrition Examination Surveys (NHANESs) cycles data between 1999 and 2014. Subgroup analyses were used to investigate the results and heterogeneity within subgroups. Survival analysis was performed using the Cox proportional hazard model and Kaplan-Meier curves. Multivariable Cox regression models and restricted cubic spline analysis were applied to examine the association between dietary fiber intake and mortality. RESULTS: In total, 3504 cases were included in this study. Among the participants, the mean age (SD) was 65.5 (15.7) y and 1657 (47.3%) of the participants were men. Subgroup analysis found that men differed significantly from women (P for interaction < 0.001). We found no significant differences in the other subgroups (all P for interaction > 0.05). During an average follow-up of 6.8 y, 342 cancer deaths were recorded. The Cox regression models found that fiber consumption was associated with a lower cancer mortality rate in men (model I: hazard ratio [HR] = 0.60; 95% CI, 0.50-0.72; model II: HR = 0.60; 95% CI, 0.47-0.75; and model III: HR = 0.61; 95% CI, 0.48-0.77). However, there was no relationship between fiber consumption and cancer mortality in women (model I: HR = 1.06; 95% CI, 0.88-1.28; model II: HR = 1.03; 95% CI, 0.84-1.26; and model III: HR = 1.04; 95% CI, 0.87-1.50). The Kaplan-Meier curve illustrates that male patients who consumed higher levels of dietary fiber survived significantly longer than those who consumed lower levels of fiber (P < 0.001). However, there were no significant differences between the two groups in terms of female patients (P = 0.84). A dose-response analysis found an L-shaped relationship between fiber intake and mortality among men. CONCLUSIONS: This study found that higher dietary fiber intake was only associated with better survival in male cancer patients, not in female cancer patients. Sex differences between dietary fiber intake and cancer mortality were observed.
Assuntos
Doenças Cardiovasculares , Neoplasias , Feminino , Humanos , Masculino , Fibras na Dieta , Ingestão de Alimentos , Inquéritos Nutricionais , Fatores de Risco , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
Diet plays an important role in health. A high intake of plant chemicals such as glucosinolates/isothiocyanates can promote optimal health and decrease the risk of cancer. Recent research has discovered more novel mechanisms of action for the effects of isothiocyanates including the modulation of tumor microenvironment, the inhibition of the self-renewal of stem cells, the rearrangement of multiple pathways of energy metabolism, the modulation of microbiota, and protection against Helicobacter pylori. However, the hormetic/biphasic effects of isothiocyanates may make the recommendations complicated. Isothiocyanates possess potent anti-cancer activities based on up-to-date evidence from in vitro and in vivo studies. The nature of hormesis suggests that the benefits or risks of isothiocyanates largely depend on the dose and endpoint of interest. Isothiocyanates are a promising class of cancer-preventative phytochemicals, but researchers should be aware of the potential adverse (and hormetic) effects. In the authors' opinion, dietary isothiocyanates are better used as adjunctive treatments in combination with known anti-cancer drugs. The application of nano-formulations and the delivery of isothiocyanates are also discussed in this review.
Assuntos
Antineoplásicos , Helicobacter pylori , Neoplasias , Humanos , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Dieta , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Antineoplásicos/farmacologia , Sulfóxidos/farmacologia , Microambiente TumoralRESUMO
OBJECTIVE: The aim of this study was to explore the association between dietary fatty foods and the risk for bladder cancer. METHODS: Patients newly diagnosed with bladder cancer (n = 113) and 292 controls were recruited. A food frequency questionnaire (FFQ) was used to investigate the food intake within 1 y. Multivariate logistic regression model was used to estimated odds ratio (OR) between different types of fatty food consumption and bladder cancer. RESULTS: The consumption of soybean oil, the largest proportion of cooking oil, in both groups were much higher than the Chinese recommended dietary intake, especially in the control group. Higher intake of red meat was also observed in bladder cancer cases, although lower intakes of marine fish, egg, milk, and dairy products and nuts were observed in controls. After adjusting for potential confounders, the intakes of marine fish and milk and dairy products were negatively correlated with bladder cancer, with the adjusted OR of 0.28 (95% confidence interval [CI], 0.15-0.55) and 0.36 (95% CI, 0.19-0.69). Total nuts were related to a 76% reduction in bladder cancer risk (OR, 0.24; 95% CI, 0.12-0.48). There was clear and positive association between soybean oil and bladder cancer risk with OR of 3.47 (95 % CI, 1.69-7.14). In stratified analyses by sex and smoking status, the relationship was similar for most results, except for milk and dairy products. The negative correlation between milk and dairy products and bladder cancer risk was only found in men; and milk and dairy products and bladder cancer risk were irrelevant by smoking status. No significant association was found between the intakes of other foods and bladder cancer risk. CONCLUSIONS: Intake of nuts and marine fish may be beneficial for the prevention of bladder cancer. The protective effect of milk and dairy products was only found in men with bladder cancer. High soybean oil intake was a risk factor for bladder cancer.
Assuntos
Óleo de Soja , Neoplasias da Bexiga Urinária , Animais , Estudos de Casos e Controles , Dieta/efeitos adversos , Fatores de Risco , Laticínios , Leite , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/prevenção & controleRESUMO
OBJECTIVE: To evaluate the predictive value of pyroptosis-related genes for the prognosis and immune escape of bladder cancer (BC). METHODS: Transcriptomic and single nucleotide polymorphisms (SNPs) data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) portal. Least absolute shrinkage and selection operator (LASSO) analysis was carried out to construct a prognostic risk model for BC patients. RESULTS: Based on the expression of 50 pyroptosis-related genes, BC patients from TCGA database were divided into two clusters, which showed significant differences in overall survival and disease specific survival. Furthermore, we intersected the differentially expressed genes between these two clusters with those identified from the GSE13507 dataset and finally identified eight survival related genes, which was used to construct a prognostic risk model by LASSO Cox regression. According to the model, the high-risk (HR) group was closely associated with poor survival or the advanced pathological stage of BC. In addition, the HR group was mainly enriched in cell cycle and immune-related pathways and had a higher TP53 mutation rate than the low-risk (LR) group. Furthermore, these two risk groups were significantly related to immune cell composition, immune cell infiltration, and immune response. Importantly, a higher expression of PD-1, PD-L1, and CTLA4 as well as higher immune exclusion scores were found in the HR group, suggesting a higher possibility of immune escape. CONCLUSION: Our studies revealed the key role of pyroptosis in predicting the prognosis, TP53 mutation, and immune escape of patients with BC.
RESUMO
Abnormal oncogenic signatures provide important clues regarding cancer prognosis and treatment. We analysed the variations in 189 oncogenic signature gene sets between normal and tumourous tissues from The Cancer Genome Atlas (TCGA) and found that the "CSR_LATE_UP" signature was the most upregulated oncogenic signature gene set in bladder cancer. Next, we developed a common serum response (CSR) risk score (CRS) model based on fibroblast CSR genes and systematically analysed the correlations of these genes or the CRSs with survival, previously reported molecular subtypes, clinicopathological features, cancer signalling pathways, chemotherapeutic responses, and the tumour microenvironment using TCGA and validation cohorts. The CRS could predict the malignant phenotype, chemotherapeutic efficacy, immune invasion, and disease prognosis. Inflammatory signalling pathways (e.g., inflammatory response, TNFA signalling via NFÆB, IFNα response, and IL2-STAT5 signalling) were markedly upregulated in patients with high CRS. Notably, the CSR-related gene ANLN was positively correlated with CD8+ immune cell infiltration, PD-L1 expression, and sensitivity to PD-L1 inhibitors and could thus provide guidance for clinical immunotherapy. This study highlights the crucial role of the CSR signature in bladder cancer and provides a CRS model for accurate predictions of the disease prognosis and chemotherapy and immunotherapy responses.
Assuntos
Microambiente Tumoral , Neoplasias da Bexiga Urinária , Humanos , Fibroblastos , Fenótipo , Microambiente Tumoral/genética , Neoplasias da Bexiga Urinária/genética , PrognósticoRESUMO
SCOPE: Metabolic disorder is a pivotal hallmark of cancer cells. Sulforaphane (SFN) is reported to improve lipid metabolism. However, the effect of SFN on glucose metabolism in bladder cancer remains unclear. Hence, the effect and underling mechanism is investigated. METHODS AND RESULTS: Biological samples from bladder cancer patients are collected, and also investigated using N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder cancer mice and bladder cancer cell lines. A novel glucose transport aberrant-independent aerobic glycolysis is found in bladder cancer patients, and the lower malignancy tissues have the more obvious abnormality. SFN strongly downregulates ATP production by inhibiting glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). Both in vitro cell culture and in bladder tumor mice, SFN weaken the glycolytic flux by suppressing multiple metabolic enzymes, including hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH). Moreover, SFN decreases the level of AKT1 and p-AKT ser473 , especially in low-invasive UMUC3 cells. The downregulation of ATP and HK2 by SFN is both reversed by AKT1 overexpression. CONCLUSIONS: SFN downregulates the unique glucose transport aberrant-independent aerobic glycolysis existed in bladder cancer via blocking the AKT1/HK2 axis and PDH expression.
Assuntos
Hexoquinase , Neoplasias da Bexiga Urinária , Animais , Linhagem Celular Tumoral , Proliferação de Células , Glucose/metabolismo , Hexoquinase/metabolismo , Hexoquinase/uso terapêutico , Humanos , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfóxidos , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, presents a potential role in improving Alzheimer's disease (AD)-specific symptoms. However, the regulation mechanism of SFN in AD is poorly understood. Here, we established AD models both in vitro and in vivo. Animal behaviors were tested by the Morris water maze test. The pathology of the hippocampus and the content of Aß were detected. SFN (40 mg kg-1) decreased the escape latency (24.96 ± 7.43 s) and increased the target-zone frequency (3.19 ± 1.19) in rats. SFN improved the pathological morphology and the number of neurons in the hippocampus. Additionally, SFN significantly upregulated the contents of thioredoxin and glutathione as well as the activities of antioxidant enzymes, along with the expression of the Nrf2 protein. Conversely, SFN lowered the Aß content and ROS level in N2a/APP cells. After silencing the Nrf2 by SiRNA, the inhibitory effects of SFN on ROS and Aß production were partially weakened. In conclusion, the improvement of AD by SFN was closely related with Nrf2 activation.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sulfóxidos/farmacologia , Animais , Linhagem Celular Tumoral , Masculino , Camundongos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Sulforaphane (SFN), an isothiocyanate (ITCs) derived from glucosinolate that is found in cruciferous vegetables, has been reported to exert a promising anticancer effect in a substantial amount of scientific research. However, epidemical studies showed inconsistencies between cruciferous vegetable intake and bladder cancer risk. In this study, human bladder cancer T24 cells were used as in vitro model for revealing the inhibitory effect and its potential mechanism of SFN on cell growth. Here, a low dose of SFN (2.5 µM) was shown to promote cell proliferation (5.18-11.84%) and migration in T24 cells, whilst high doses of SFN (>10 µM) inhibited cell growth significantly. The induction effect of SFN on nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression at both low (2.5 µM) and high dose (10 µM) was characterized by a bell-shaped curve. Nrf2 and glutathione (GSH) might be the underlying mechanism in the effect of SFN on T24 cell growth since Nrf2 siRNA and GSH-depleting agent L-Buthionine-sulfoximine abolished the effect of SFN on cell proliferation. In summary, the inhibitory effect of SFN on bladder cancer cell growth and migration is highly dependent on Nrf2-mediated GSH depletion and following production. These findings suggested that a higher dose of SFN is required for the prevention and treatment of bladder cancer.
Assuntos
Glutationa/metabolismo , Isotiocianatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Sulfóxidos/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Glucuronosiltransferase/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Humanos , Modelos Biológicos , Transporte Proteico/efeitos dos fármacos , Neoplasias da Bexiga Urinária/enzimologiaRESUMO
BACKGROUND AND OBJECTIVES: This study aimed to explore the changes of gut bacteria in bladder cancer patients. METHODS AND STUDY DESIGN: Newly diagnosed bladder cancer patients were recruited. All participants completed a questionnaire about personal behavior and diet. Pyrosequencing of the total genomic DNA extracted from human feces was carried out by Illumina HiSeq 2000. The copy number of target DNA for bacteria was determined by real-time quantitative PCR assay. Fecal short chain fatty acids contents were measured by gas chromatography (GC) analysis. The concentrations of lipopolysaccharide and D-lactic acid in serum were determined by enzyme-linked immunosorbent assay kits. RESULTS: Fruit intake was significantly lower than in healthy controls. The numbers of Clostridium cluster XI and Prevotella in bladder cancer patients decreased. The numbers of domain bacteria and Prevotella were significantly and positively associated with fruit intake (r=0.002, p<0.05 for domain bacteria; r=0.004, p<0.05 for Prevotella). The concentration of butyric acid decreased significantly in bladder cancer patients, and the quantities of fecal butyric acid were significantly and positively associated with fruit intake (r=0.610, p<0.01). The concentrations of lipopolysaccharide and D-lactic acid, two sensitive markers of gut permeability, were greater in bladder cancer patients. CONCLUSIONS: Dysbiosis of gut microbiota, decreased butyric acid concentrations and impaired intestinal structural integrity were found in bladder cancer patients, which might be associated with inadequate fruit intake.
Assuntos
Dieta , Microbioma Gastrointestinal , Neoplasias da Bexiga Urinária/etiologia , Estudos de Casos e Controles , China , Ensaio de Imunoadsorção Enzimática , Fezes/microbiologia , Feminino , Frutas , Humanos , Ácido Láctico/sangue , Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Inquéritos e QuestionáriosRESUMO
SCOPE: Gut microbiota imbalance, inflammation, and gut barrier deficiency play an important role in carcinogenesis. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, has been proven to be highly effective in inhibiting cancer. The objective of this study is to investigate the potential roles of the gut microbiota in the inhibition of BBN-induced bladder cancer by SFN. METHODS AND RESULTS: N-butyl-N-(4-hydroxybutyl)-nitrosamine is used to induce bladder cancer in male C57BL/6 mice, with or without SFN for 23 weeks. SFN ameliorates the histological changes characteristic of bladder cancer, resulting in fewer submucosal capillaries. SFN normalizes gut microbiota dysbiosis in mice with BBN-induced bladder cancer with a significant increase in Bacteroides fragilis and Clostridium cluster I. SFN also increases butyric acid levels in the mouse colon, and repairs the injury to the mucosal epithelium of the colon and cecum through the upregulation of the expression of tight junction proteins and GLP2. SFN greatly decreases the release of cytokines (IL-6) and secretory immunoglobulin A in the mice with bladder cancer. CONCLUSION: These results suggest that SFN protects against chemical-induced bladder cancer through normalizing the composition of gut microbiota and repairing the physiological destruction of the gut barrier, as well as decreasing inflammation and the immune response.
Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Isotiocianatos/farmacologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Anticarcinógenos/farmacologia , Butilidroxibutilnitrosamina/toxicidade , Ácido Butírico/metabolismo , Células CACO-2 , Microbioma Gastrointestinal/genética , Humanos , Imunoglobulina A Secretora/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Sulfóxidos , Proteínas de Junções Íntimas/metabolismo , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/microbiologiaRESUMO
Sulforaphane (SFN) is a dietary component with multiple bioactivities; however, its role in obesity-related metabolic derangement remains unclear. Here, the effect of SFN on the glucose intolerance of obese mice and the underlying mechanism were determined. C57B/6J male mice were randomly divided into two groups, having free access to water and a normal-fat diet (ND, n = 6) or a high-fat diet (HFD, n = 33) for 8 weeks; thereafter twelve mice having the greatest weight gain among the HFD-fed mice were considered as obese mice. These obese mice were randomly divided into two groups and treated orally for 6 weeks with or without SFN (100 µmol per kg bw, 3 times per week). During this period the animals were continuously maintained on a ND or a HFD. Blood glucose and serum insulin were examined; then glucose tolerance and insulin resistance were evaluated. In addition, the expression of insulin signaling pathway-related genes in the muscle was determined. Our data showed that the obese mice presented a marked insulin resistance and glucose intolerance as compared to the control group, while SFN treatment exerted a prominently protective effect. In addition, the SFN-treated obese mice had a significantly increased insulin receptor substrate 1 (IRS-1) protein level (P < 0.05), markedly elevated Akt activation, as well as dramatically enhanced phosphorylation of PDK-1 (P < 0.05) when compared with the SFN-untreated obese mice. Moreover, the SFN-treated obese mice exhibited a significantly enhanced translocation of GLUT4 (P < 0.05) to the plasma membrane in the muscle compared to the obese mice without SFN treatment. In conclusion, our results support the notion that SFN acts as a promising agent to improve glucose tolerance through the up-regulation of insulin signaling mainly involving the IRS-1/Akt/GLUT4 pathway in the muscle.
Assuntos
Intolerância à Glucose/tratamento farmacológico , Insulina/metabolismo , Isotiocianatos/administração & dosagem , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/genética , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos , Regulação para Cima/efeitos dos fármacosRESUMO
The potential efficacy of sulforaphane in protecting alcohol-induced hepatic injury in vivo and its underlying mechanism were investigated. Male C57BL/6 mice were orally administrated with broccoli sprout extract (BSE) containing sulforaphane [7.6, 25.2, and 50.4 mg/kg of body weight (bw)] once a day for 14 days. At the 13th day, mice were challenged with alcohol (5 g/kg of bw) every 12 h for 3 times, which increased malondialdehyde (MDA) levels (4.44 ± 1.24 nmol/mg of protein, p < 0.01) in the liver. Our results showed that low-, medium-, and high-dose BSE markedly reversed the decrease of antioxidant capacity through enhancing glutathione (GSH) (2.07 ± 0.31 mg/g of protein, p < 0.05; 2.31 ± 0.32 mg/g of protein, p < 0.01; and 2.46 ± 0.21 mg/g of protein, p < 0.01), superoxide dismutase (SOD) (483.20 ± 62.76 units/mg of protein; 500.81 ± 49.82 units/mg of protein, p < 0.05; and 605.00 ± < 64.32 units/mg of protein, p < 0.01), glutathione peroxidase (GSH-Px) (318 ± 60.74 units/mg of protein; 400.67 ± 72.47 units/mg of protein, p < 0.01; and 394.72 ± 62.97 units/mg of protein, p < 0.01), and glutathione S-transferase (GST) (31.84 ± 6.34 units/mg of protein, p < 0.05; 30.34 ± 6.40 units/mg of protein, p < 0.05; and 38.08 ± 7.05 units/mg of protein, p < 0.01) in the liver. The protective actions are also associated activation of phase 2 enzymes via nuclear erythoriod-2-related factor 2 (Nrf2). The endoplasmic reticulum (ER)-stress-specific proteins, such as glucose-regulated protein 78 (GRP78), activating transcription factor 6, and protein kinase RNA (PKR)-like ER kinase (PERK), were also significantly attenuated by BSE. These results indicate that BSE protects the liver against alcohol challenge via upregulating antioxidant capacity and downregulating ER stress.
Assuntos
Brassica/química , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Etanol/toxicidade , Extratos Vegetais/administração & dosagem , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Chaperona BiP do Retículo Endoplasmático , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/administração & dosagem , Superóxido Dismutase/metabolismoRESUMO
Isothiocyanates (ITCs), such as sulforaphane (SFN), exhibit powerful biological functions in fighting cancers, and cardiovascular and neurodegenerative diseases. They normally exist as glucosinolates (GLSs) in cruciferous vegetables, which are not themselves bioactive until they are degraded by myrosinase to form ITCs. Myrosinase coexists in the same plants but is normally kept apart from GLSs in different apparatus. A key point is that myrosinase is temperature sensitive and can be inactivated upon exposure to temperatures over 60 °, as typically occurs during cooking. However, studies using animal models and population trials have suggested that human gut bacteria might act like an 'organ' in that they can secrete their own myrosinase. In this review, the hydrolysis of GLS by myrosinase is discussed, with an important focus on the gut microflora and their myrosinase-producing roles. © 2017 Society of Chemical Industry.
Assuntos
Bactérias/enzimologia , Brassicaceae/química , Microbioma Gastrointestinal/fisiologia , Glucosinolatos/metabolismo , Glicosídeo Hidrolases/metabolismo , Isotiocianatos/metabolismo , Animais , Bactérias/metabolismo , Brassicaceae/enzimologia , Culinária , Estabilidade Enzimática , Glicosídeo Hidrolases/química , Temperatura Alta , Humanos , Intestinos/enzimologia , Estrutura MolecularRESUMO
The aim of the present study was to investigate whether sulforaphane (SFN) and myricetin (Myr) synergistically induce apoptosis in adipocytes. The viability of mature 3T3L1 adipocytes treated with 40 µM SFN and/or 100 µM Myr was assessed using an MTT assay. Apoptosis was assessed by Hoechst 33258 nuclear staining, and by detection of singlestranded DNA using an enzymelinked immunosorbent assay. Compared with the effects of each compound alone, the combination of SFN and Myr synergistically reduced cell viability, induced apoptosis, increased proapoptotic Bcl2 associated X protein expression, decreased antiapoptotic Bcell lymphoma2 expression, enhanced Bcl2associated death promoter (Bad) translocation from the cytoplasm to the mitochondria, and reduced Bad phosphorylation at Ser112. These effects were accompanied by increased cleavage of caspase 3 and polyADPribosepolymerase. In addition, combined SFN and Myr treatment significantly decreased the protein expression levels of phosphorylated AKT serine/threonine kinase 1 (Akt) at Ser473, as well as the phosphorylation of the downstream protein ribosomal protein, S6 kinase ß1. Therefore, SFN plus Myr was a more potent inducer of apoptosis in 3T3L1 adipocytes than either compound alone. The results of the present study suggest that the mechanism of SNF/Myrinduced apoptosis involved activation of the Aktmediated mitochondrial apoptotic pathway. This may aid treatment of animal models of obesity and preclinical testing.