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Introduction/Aim: Clinical and experimental evidence highlights an important role for altered iron metabolism in the pathogenesis and severity of asthma. Elevated iron in airway cells and tissues and increased gene expression of the iron uptake protein, transferrin receptor (TFR)1, correlates with increased Type-2 (T2) cytokine responses, worsened lung function and development of key disease features. Here, we examined the relationship between the T2 cytokine, interleukin (IL)-13 and TFR1 in the pathogenesis of key features of asthma. Methods: Anti-TFR1 (αTFR1) and -IL-13 (αIL-13) was administered intranasally during a murine model of house dust mite (HDM)-induced asthma. The effects of αTFR1 or αIL-13 on inflammatory and TFR1+ cell numbers, collagen deposition and mucus secreting cell (MSC) numbers in the airways, iron metabolism, T2 and pro-inflammatory gene expression or lung function was assessed. The effects of IL-13 on TFR1 and matrix metalloprotease (MMP)9 responses in murine bone marrow derived macrophages (BMDM) was also assessed. Results: TFR1 is increased on macrophages and epithelial cells in HDM-induced asthma. αTFR1 reduces TFR1+ macrophages, but not TFR1+ epithelial cells, in disease. Importantly, αTFR1 reduces inflammation, fibrosis, MSC numbers, airflow obstruction in disease. αTFR1 has no effect on HDM-induced IL-13, but significantly suppresses MMP9, which is implicated in airway remodelling, expression in the lungs. IL-13 increases TFR1 expression in BMDMs and intranasal administration of αIL-13 reduces the numbers of TFR1+ macrophages in HDM-induced asthma. Significantly, the combination of IL-13 and HDM increases MMP9 expression in BMDMs. Conclusion: We show a critical role for IL-13-mediated increases in TFR1 responses in macrophages in driving the pathogenesis of asthma. These findings highlight the potential for the therapeutic manipulation of TFR1 and/or iron metabolism for the treatment of not only asthma but also other respiratory diseases associated with altered iron metabolism such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and cystic fibrosis. Grant Support: University of Newcastle, HMRI.

Aim: In this study, curcumin was encapsulated in niosomes (Nio-Curc) to increase its effectiveness for the treatment of asthma. Materials & methods: The formulation underwent various physicochemical characterization experiments, an in vitro release study, molecular simulations and was evaluated for in vitro anti-inflammatory activity. Results: Results showed that Nio-Curc had a mean particle size of 284.93 ± 14.27 nm, zeta potential of -46.93 and encapsulation efficacy of 99.62%, which demonstrates optimized physicochemical characteristics. Curcumin release in vitro could be sustained for up to 24 h. Additionally, Nio-Curc effectively reduced mRNA transcript expression of pro-inflammatory markers; IL-6, IL-8, IL-1β and TNF-α in immortalized human airway basal cell line (BCi-NS1.1). Conclusion: In this study, we have demonstrated that Nio-Curc mitigated the mRNA expression of pro-inflammatory markers in an in vitro study, which could be applied to treatment of asthma with further studies.

© 2019 Elsevier B.V. The present study aims to formulate quercetin loaded liquid crystalline nanoparticles (LCN) and surface modified liquid crystalline nanoparticles (sm-LCN) as well as investigate their anti-inflammatory activity in human primary bronchial epithelial cell line (BCi-NS1.1) induced with lipopolysaccharide (LPS). Quercetin LCN were prepared using ultrasonication method. The formulated LCNs and sm-LCNs were characterised in terms of particle size, zeta potential as well as the drug encapsulation efficiency. Furthermore, their morphology and in vitro release profile were also studied. In addition, the anti-inflammatory activity of quercetin LCN and sm-LCNs were evaluated by measuring the concentration of pro-inflammatory markers namely interleukin (IL)-1β, IL-6 and IL-8 in BCI-NS1.1 cell lines via cytometric bead array. The molecular mechanism inherent to the inclusion of quercetin into monoolein nanosystem and surface modification of the nanosystem with chitosan was elucidated via molecular mechanics simulations. Quercetin LCN and sm-LCN significantly (p < 0.05) decreased the production of IL-1β, IL-6 and IL-8 compared to LPS only group. Encapsulation of quercetin into LCN and sm-LCN further enhanced its anti-inflammatory activity compared to quercetin in dimethyl sulfoxide (DMSO). In addition to that, quercetin LCN and sm-LCN also exhibited comparable activity to fluticasone in terms of significantly (p < 0.05) reducing the production of IL-1β and IL-6. Quercetin loaded LCN and sm-LCN could be a potential therapeutic intervention for asthma as they are efficacious in suppressing the production of key pro-inflammatory cytokines associated with the development of asthma.

The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.

Background Online dietary assessment tools can reduce administrative costs and facilitate repeated dietary assessment during follow-up in large-scale studies. However, information on bias due to measurement error of such tools is limited. We developed an online 24-h recall (myfood24) and compared its performance with a traditional interviewer-administered multiple-pass 24-h recall, assessing both against biomarkers. Methods Metabolically stable adults were recruited and completed the new online dietary recall, an interviewer-based multiple pass recall and a suite of reference measures. Longer-term dietary intake was estimated from up to 3 × 24-h recalls taken 2 weeks apart. Estimated intakes of protein, potassium and sodium were compared with urinary biomarker concentrations. Estimated total sugar intake was compared with a predictive biomarker and estimated energy intake compared with energy expenditure measured by accelerometry and calorimetry. Nutrient intakes were also compared to those derived from an interviewer-administered multiple-pass 24-h recall. Results Biomarker samples were received from 212 participants on at least one occasion. Both self-reported dietary assessment tools led to attenuation compared to biomarkers. The online tools resulted in attenuation factors of around 0.2–0.3 and partial correlation coefficients, reflecting ranking intakes, of approximately 0.3–0.4. This was broadly similar to the more administratively burdensome interviewer-based tool. Other nutrient estimates derived from myfood24 were around 10–20% lower than those from the interviewer-based tool, with wide limits of agreement. Intraclass correlation coefficients were approximately 0.4–0.5, indicating consistent moderate agreement. Conclusions Our findings show that, whilst results from both measures of self-reported diet are attenuated compared to biomarker measures, the myfood24 online 24-h recall is comparable to the more time-consuming and costly interviewer-based 24-h recall across a range of measures.

Rationale: Aberrant expression of microRNAs (miRNAs) can have a detrimental role in disease pathogenesis. Objectives: To identify dysregulated miRNAs in lung tissue of patients with chronic obstructive pulmonary disease (COPD). Methods: We performed miRNA and mRNA profiling using high throughput stem-loop reverse-transcriptase quantitative polymerase chain reaction and mRNA microarray, respectively, on lung tissue of 30 patients (screening cohort) encompassing 8 never-smokers, 10 smokers without airflow limitation, and 12 smokers with COPD. Differential expression of miRNA-218-5p (miR-218-5p) was validated by reverse-transcriptase quantitative polymerase chain reaction in an independent cohort of 71 patients, an in vivo murine model of COPD, and primary human bronchial epithelial cells. Localization of miR-218-5p was assessed by in situ hybridization. In vitro and in vivo perturbation of miR-218-5p combined with RNA sequencing and gene set enrichment analysis was used to elucidate its functional role in COPD pathogenesis. Measurements and Main Results: Several miRNAs were differentially expressed among the different patient groups. Interestingly, miR-218-5p was significantly down-regulated in smokers without airflow limitation and in patients with COPD compared with never-smokers. Decreased pulmonary expression of miR-218-5p was validated in an independent validation cohort, in cigarette smoke-exposed mice, and in human bronchial epithelial cells. Importantly, expression of miR-218-5p strongly correlated with airway obstruction. Furthermore, cellular localization of miR-218-5p in human and murine lung revealed highest expression of miR-218-5p in the bronchial airway epithelium. Perturbation experiments with a miR-218-5p mimic or inhibitor demonstrated a protective role of miR-218-5p in cigarette smoke-induced inflammation and COPD. Conclusions: We highlight a role for miR-218-5p in the pathogenesis of COPD.

OBJECTIVE: Younger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by adiposity. RESEARCH DESIGN AND METHODS: The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI. RESULTS: Mean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m2 lower adult BMI. Women in the earliest menarche quintile (8-11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio [HR], 1.70; 95% CI, 1.49-1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18-1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes. CONCLUSIONS: Women with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk.

Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake 5 1.03, 95% CI: 0.95–1.11 and 1.02; 95% CI: 0.89– 1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake 5 0.96, 95% CI: 0.91–1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort.

Background: There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. Results: During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n = 430) and non-aggressive (n = 413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend = 0.009) and lignans (HRQ5-Q 10.78, 95% CI: 0.62-0.96; P-trend = 0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. Conclusions: Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

Prevention of hip fractures is of critical public health importance. In a cohort of adults from eight European countries, evidence was found that increased adherence to Mediterranean diet, measured by a 10-unit dietary score, is associated with reduced hip fracture incidence, particularly among men. Evidence on the role of dietary patterns on hip fracture incidence is scarce. We explored the association of adherence to Mediterranean diet (MD) with hip fracture incidence in a cohort from eight European countries. A total of 188,795 eligible participants (48,814 men and 139,981 women) in the European Prospective Investigation into Cancer and nutrition study with mean age 48.6 years (+/- 10.8) were followed for a median of 9 years, and 802 incident hip fractures were recorded. Diet was assessed at baseline through validated dietary instruments. Adherence to MD was evaluated by a MD score (MDs), on a 10-point scale, in which monounsaturated were substituted with unsaturated lipids. Association with hip fracture incidence was assessed through Cox regression with adjustment for potential confounders. Increased adherence to MD was associated with a 7 % decrease in hip fracture incidence [hazard ratio (HR) per 1-unit increase in the MDs 0.93; 95 % confidence interval (95 % CI) = 0.89-0.98]. This association was more evident among men and somewhat stronger among older individuals. Using increments close to one standard deviation of daily intake, in the overall sample, high vegetable (HR = 0.86; 95 % CI = 0.79-0.94) and high fruit (HR = 0.89; 95 % CI = 0.82-0.97) intake was associated with decreased hip fracture incidence, whereas high meat intake (HR = 1.18; 95 % CI = 1.06-1.31) with increased incidence. Excessive ethanol consumption (HR high versus moderate = 1.74; 95 % CI = 1.32-2.31) was also a risk factor. In a prospective study of adults, increased adherence to MD appears to protect against hip fracture occurrence, particularly among men.

BACKGROUND/OBJECTIVES: Phytoestrogens are estradiol-like natural compounds found in plants that have been associated with protective effects against chronic diseases, including some cancers, cardiovascular diseases and osteoporosis. The purpose of this study was to estimate the dietary intake of phytoestrogens, identify their food sources and their association with lifestyle factors in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. SUBJECTS/METHODS: Single 24-hour dietary recalls were collected from 36 037 individuals from 10 European countries, aged 35-74 years using a standardized computerized interview programe (EPIC-Soft). An ad hoc food composition database on phytoestrogens (isoflavones, lignans, coumestans, enterolignans and equol) was compiled using data from available databases, in order to obtain and describe phytoestrogen intakes and their food sources across 27 redefined EPIC centres. RESULTS: Mean total phytoestrogen intake was the highest in the UK health-conscious group (24.9 mg/day in men and 21.1 mg/day in women) whereas lowest in Greece (1.3 mg/day) in men and Spain-Granada (1.0 mg/day) in women. Northern European countries had higher intakes than southern countries. The main phytoestrogen contributors were isoflavones in both UK centres and lignans in the other EPIC cohorts. Age, body mass index, educational level, smoking status and physical activity were related to increased intakes of lignans, enterolignans and equol, but not to total phytoestrogen, isoflavone or coumestan intakes. In the UK cohorts, the major food sources of phytoestrogens were soy products. In the other EPIC cohorts the dietary sources were more distributed, among fruits, vegetables, soy products, cereal products, non-alcoholic and alcoholic beverages. CONCLUSIONS: There was a high variability in the dietary intake of total and phytoestrogen subclasses and their food sources across European regions.