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Las migraciones transnacionales, la integración del pluralismo cultural en los Es-tados de acogida de inmigrantes, el reconocimiento de sus derechos civiles, económicos y políticos y las condiciones de acceso a la ciudadanía son fenómenos de interés público que nos obligan a repensar las fronteras de la democracia y la someten a una renovación continua. La presencia del extranjero irregular y la llegada masiva de refugiados a las puertas de Europa han tambaleado las bases de nuestra ciudadanía, poniendo en tela de juicio los valores comu-nitarios y desafiando la tradición cosmopolita desde el afuera de la Administración de la UE. Estas contradicciones prácticas llevan a los teóricos de la justicia y la filosofía política, como S. Benhabib, a explorar los límites de la pertenencia, la responsabilidad y la ética en las de-mocracias contemporáneas. El objetivo de conciliar los derechos de autogobierno y libre auto-determinación territorial con la afirmación de los derechos humanos universales pasa, nece-sariamente, por argumentar la vigencia del Estado-nación moderno y problematizar las lógicas divisorias de la soberanía territorial, tan reforzada hoy en día.

Broccoli (Brassica oleracea var. italica) and its bioactive compounds are associated with beneficial health effects, which might be enabled, at least in part, through miRNA regulation, despite recent controversial studies suggesting that exogenous dietary miRNAs may reach host circulation and target cells to regulate gene expression. Here, a computational analysis was performed to explore the processes and pathways associated with genes targeted either by (1) host-expressed miRNAs (endogenous) modulated by the bioactive compounds in broccoli or (2) miRNAs derived from broccoli (exogenous). In addition, the stability of exogenous miRNAs from broccoli was assessed after broccoli was subjected to the usual processing methods and in vitro digestion-simulating gastrointestinal (GI) conditions. Overall, bioinformatic results show that the anticarcinogenic and cancer-preventive properties attributed to cruciferous vegetables might be mediated, at least in part, through miRNA-related mechanisms. Moreover, results show that broccoli-derived miRNAs can survive common food-processing conditions and GI digestion.

The Mediterranean diet (MD) is one of the healthiest ones and is associated with a lower incidence of cardiovascular and cerebrovascular diseases as well as cancer. Extra virgin olive oil (EVOO) is probably the most idiosyncratic component of this diet. EVOO has been attributed with many healthful effects, which may be due to its phenolic components, e.g. including hydroxytyrosol (HT). Recent studies suggest that EVOO and HT have molecular targets in human tissues and modulate epigenetic mechanisms. DNA methylation is one of the most studied epigenetic mechanisms and consists of the addition of a methyl group to the cytosines of the DNA chain. Given the purported health effects of EVOO (poly)phenols, we analyzed the changes induced by HT in DNA methylation, in a colorectal cancer cell line. Caco-2 cells were treated with HT for one week or with the demethylating agent 5'-azacytidine for 48 h. Global DNA methylation was assessed by ELISA. DNA bisulfitation was performed and Infinium Methylation EPIC BeadChips were used to analyze the specific methylation of CpG sites. We show an increase in global DNA methylation in Caco-2 cells after HT treatment, with a total of 32,141 differentially methylated (CpGs DMCpGs). Interestingly, our analyses revealed the endothelin receptor type A gene (EDNRA) as a possible molecular target of HT. In summary, we demonstrate that cellular supplementation with HT results in a specific methylome map and propose a potential gene target for HT.

BACKGROUND: Primary care is often the first point of contact for people living with mental disorders. Community pharmacists, pharmacy staff and students are increasingly being trained to deliver mental health care. However, there is still a gap in the literature exploring the characteristics of all available mental health training programs and their components and their influence on pharmacists, pharmacy staff and students' outcomes. OBJECTIVES: To summarize the evidence evaluating mental health training programs completed by community pharmacists, pharmacy staff and students. More specifically, to explore the components of mental health training programs and identify those that facilitate significant improvements in outcomes. METHODS: A systematic review was conducted following the Cochrane handbook and reported according to PRISMA guidelines. A search for published literature was conducted in three databases (PubMed, Scopus, and Web of Science) in July 2021. Eligible studies were included if they described and evaluated the impact of mental health training programs delivered to community pharmacists, pharmacy staff and pharmacy students regardless of design or comparator. The methodological quality of included studies was appraised using both the NIH quality assessment, to evaluate studies with an uncontrolled pre-post design, and the Cochrane EPOC risk of bias assessment, to evaluate studies with a controlled (randomized and non-randomized) study design. RESULTS: Thirty-three studies were included. Most of the identified mental health training programs contained knowledge-based components and active learning activities. Changes in participants' attitudes, stigma, knowledge, confidence and skills were frequently assessed. An extensive range of self-assessment and observational instruments used to evaluate the impact of the training programs were identified. Positive improvements in participants' attitudes, knowledge and stigma were frequently identified following participation in training programs. CONCLUSIONS: This systematic review highlights the importance of mental health training programs in increasing pharmacists', pharmacy staff and pharmacy students' skills and confidence to deliver mental health care in community pharmacy. Future research should build upon this basis and further focus on finding the most efficient measures to evaluate these training programs and assess their long-term effectiveness, allowing comparison between programs.

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Exosomes are extracellular vesicles secreted by cells, which can transport different molecules, including nucleic acids. Dietary habits may induce gene regulation through the modulation of exosomal RNAs. We aimed at characterizing exosomal lncRNAs, mRNA and miRNAs modulation after a 1-year adherence to a low-fat diet (LFD) or to Mediterranean-based diets enriched in extra-virgin olive oil (MedDiet + EVOO) or in a mixture of nuts (MedDiet + Nuts). Plasma samples were collected, at baseline and after 1 year of dietary interventions, from 150 participants included in the PREDIMED study (Reus Center). LncRNAs, mRNAs and miRNAs were isolated from plasma exosomes and screened. RT-qPCR validation was performed for miRNAs. Compared with LFD, 413 lncRNAs and 188 mRNAs, and 476 lncRNAs and 235 mRNAs were differentially modulated in response to the MedDiet + EVOO and MedDiet + Nuts interventions, respectively. In addition, after 1 year of dietary interventions, 26 circulating miRNAs were identified as differentially expressed between groups. After 1 year of intervention, 11 miRNAs significantly changed in LFD group, while 8 and 21 were modulated in response to the MedDiet enriched with EVOO or nuts, respectively. Bioinformatic analyses of differentially expressed miRNAs and their validated target genes suggest certain metabolic pathways are modulated by LFD (PI3K-Akt and AMPK), MedDiet + EVOO (PI3K-Akt, NF-kappa B, HIF-1, and insulin resistance), and MedDiet-Nuts (FoxO, PI3K-Akt, AMPK, p53 and HIF-1) interventions. Results show that 1-year MedDiet + Nuts and MedDiet + EVOO dietary interventions modulate exosomal RNA content, with the former affecting a higher number of miRNAs. The modulation of exosomal RNAs could help explain how the adherence to a Mediterranean diet may lead to beneficial effects and deserves further investigation.

The role of miRNAs in intestinal lipid metabolism is poorly described. The small intestine is constantly exposed to high amounts of dietary lipids, and it is under conditions of stress that the functions of miRNAs become especially pronounced. Approaches consisting in either a chronic exposure to cholesterol and triglyceride rich diets (for several days or weeks) or an acute lipid challenge were employed in the search for intestinal miRNAs with a potential role in lipid metabolism regulation. According to our results, changes in miRNA expression in response to fat ingestion are dependent on factors such as time upon exposure, gender and small intestine section. Classic and recent intestinal in vitro models (i.e. differentiated Caco-2 cells and murine organoids) partially mirror miRNA modulation in response to lipid challenges in vivo. Moreover, intestinal miRNAs might play a role in triglyceride absorption and produce changes in lipid accumulation in intestinal tissues as seen in a generated intestinal Dicer1-deletion murine model. Overall, despite some variability between the different experimental cohorts and in vitro models, results show that some miRNAs analysed here are modulated in response to dietary lipids, hence likely to participate in the regulation of lipid metabolism, and call for further research.

ObjectivePharmacists have been increasing patient-focused care through the implementation and provision of professional services. However, there is a lack of evidence on how to achieve long-term sustainability of the service once it is implemented. A framework identifying the factors affecting the sustainability of professional pharmacy services was developed. The objectives of this study were to explore the experiences of community pharmacists providing professional services to contextualize and assess the applicability in practice of the sustainability framework.MethodsA qualitative study was undertaken across Australia. Community pharmacists were identified using snowball sampling. Data were collected through semistructured interviews. Eighteen interviews were conducted and analyzed using framework methodology in NVivo 12 (QSR International).ResultsA range of major sustainability factors was identified and organized in social, economic, and environmental domains. In the social domain, most of the interviewees stated the importance of motivating staff to increase service promotion and patients' demand. Most of the participants emphasized that having an adequate number of trained staff is required to enhance and maintain services over time. The perceived reluctance of some patients to spend more time than usual at the community pharmacy was another factor highlighted as affecting service sustainability. In the economic domain, the concern about lack of remuneration for service provision was highlighted by most of the interviewees. Having economic support was seen as essential for achieving sustainable services. In the environmental domain, the necessity of government recognition of the pharmacists' role and value to the health care system was identified as a new key sustainability driver.ConclusionThe applicability of the framework for the sustainability of professional services was evaluated in practice. The identified factors will guide pharmacists to maintain implemented services and achieve their sustainability. Future research should focus on designing a tool to measure the sustainability of pharmacy services.

Objective To determine the body composition profile of forest firefighters. Data were collected from 701 forest firefighters. Methods We have carried out this analysis using a bioimpedance scale BC-601 of the brand Tanita ISO 9001 Certified. Results Obtained values of body mass index 24.85 in women and 27.83 in men. The visceral fat index was 5 in women and 9 in men. In both cases, taking as reference the values proposed by the WHO, women are within a low-moderate risk of cardiovascular or metabolic diseases. Men are at a moderate-high risk. Conclusions The values obtained in the analysis show that forest firefighters have a moderate risk of cardiovascular and metabolic diseases in the future. It is effective to propose future works that elaborate specific physical activity plans to improve their health profile.

The systemic response to exercise is dose-dependent and involves a complex gene expression regulation and cross-talk between tissues. This context ARISES the need for analyzing the influence of exercise dose on the profile of circulating microRNAs (c-miRNAs), as emerging posttranscriptional regulators and intercellular communicators. Thus, we hypothesized that different exercise doses will determine specific c-miRNA signatures that will highlight its potential as exercise dose biomarker. Nine active middle-aged males completed a 10-km race (10K), a half-marathon (HM), and a marathon (M). Blood samples were collected immediately before and after races. Plasma RNA was extracted, and a global screening of 752 microRNAs was analyzed using RT-qPCR. Three different c-miRNA profiles were defined according to the three doses. In 10K, 14 c-miRNAs were found to be differentially expressed between pre- and post-exercise, 13 upregulated and 1 downregulated. Regarding HM, 13 c-miRNAs were found to be differentially modulated, in all the cases upregulated. A total of 28 c-miRNAs were found to be differentially expressed in M, 21 overexpressed and 7 repressed after this race. We had also found 3 common c-miRNAs between 10K and M and 2 common c-miRNAs between 10K and HM. In silico analysis supported a close association between exercise dose c-miRNA profiles and cellular pathways linked to energy metabolism and cell cycle. In conclusion, we have observed that different exercise doses induced specific c-miRNA profiles. So, our results point to c-miRNAs as emerging exercise dose biomarkers and as one of regulatory mechanisms modulating the response to endurance exercise.

The aim of this study was to determine variations in the urinary steroid profile of triathletes following an Ironman event. A total of 10 male participants (age = 36.0 ± 1.27 years; body height = 179.29 ± 10.77 cm; body mass = 74.50 ± 1.04 kg) completed an Ironman Championship. Urine samples were collected before, immediately after, and 24 hours following the race. Gas chromatography-mass spectrometry (GC/MS) was used to detect and quantify catabolic and anabolic hormones: Androsterone, Dehydroepiandrosteone (DHEA), Androstenedione and Testosterone (T), Betaestradiol, Estrone, Progesterone, Cortisol (C), Cortisone, Tetrahydrocortisol (THE) and Tetrahydrocortisone (THF). These were measured in their glucuroconjugated and free forms. Androsterone (3297.80 ± 756.83 vs. 2154.26 ± 1375.38), DHEA (47.80 ± 19.21 vs. 32.62 ± 15.96) and Beta-estradiol (59.36 ± 11.7 vs. 41.67 ± 10.59) levels decreased after the event. The significant decrease of DHEA (47.80 ± 19.21 vs. 32.11 ± 14.03) remained at 24 hours. Cortisol (200.38 ± 56.60 vs. 257.10 ± 74.00) and THE (238.65 ± 81.55 vs. 289.62 ± 77.13) increased after exercise and remained elevated 24 hours later (200.38 ± 56.60 vs. 252.48 ± 62.09; 238.65 ± 81.55 vs. 284.20 ± 66.66). The following anabolic/catabolic ratios fell after exercise: T/C (0.85 ± 0.54 vs. 0.54 ± 0.29), T/THE (0.66 ± 0.29 vs. 0.40 ± 0.08), T/THE+THF (0.38 ± 0.17 vs. 0.24 ± 0.06), DHEA/THE (0.22 ± 0.05 vs. 0.12 ± 0.05), DHEA/THF (0.34 ± 0.02 vs. 0.21 ± 0.01) and DHEA/THE+THF (0.12 ± 0.02 vs. 0.08 ± 0.03). The steroid profile showed that athletes were fatigued after finishing the competition and a catabolic state remained 24 hours later.

Given increasing popularity of triathlon, the objective of this study was to evaluate the acute effects upon the health of triathletes. To do so, with a sample of 23 male athletes (34.4 ± 7.9 years old), an assessment was carried out both before and after an Olympic distance triathlon, of the bodily composition, the jumping ability and the BORG and VAS scales, as well as a blood analysis of the following: Lactate (mmol/L), Hematrocrit (%), Glucose (mg/dL), Total proteins (mg/dL), Triglycerides (mg/dL), Bilirubin (mg/dL), GOT (IU/L), GPT (IU/L), LDH (IU/L), CPK (IU/L). The results showed an increase (p 0.001) in the different markers of metabolic stress and muscular damage following the triathlon, but always within a normal range considered to be healthy, with the exception of CPK (IU/L) (PRE 149.33 ± 108.16 vs POST 290.10 ± 102.48). Therefore, it would seem that competing in an Olympic-distance triathlon does not pose health risks for trained subjects.

Background Many substances poured out from industries can be toxic to humans and can impair physical performance. Besides, physical training may modify the body concentrations of these substances as a result of physiological adaptations. Objectives The aim of the study was to determine if different modalities of exercise might affect serum concentrations of toxic trace elements in sportsmen. Methods 80 Spanish national sportsmen were recruited before the start of their training period. All the athletes had been training regularly for the previous two years with a rigorous training target at high-level competition. 31 sedentary participants from the same geographic area formed the control group. Serum arsenic, beryllium, cadmium, cesium and lead samples were analyzed with an ICP-MS. Results Serum concentrations were higher among the sportsmen group than among the control group, being highly significant in cases of Be from 0.043 ± 0.019 to 0.074 ± 0.029 μg/L, Cs from 0.693 ± 0.305 to 1.358 ± 0.569 μg/L and Pb from 0.162 ± 0.171 to 2.375 ± 1.699 μg/L; and significant in the case of Cd from 0.046 ± 0.027 to 0.067 ± 0.059 μg/L. However, if they were separated according to different sport modalities, it was found that, although they had higher concentrations than controls, there were elements that changed their concentrations in relation to the metabolic type of activity performed. Conclusions In some cases physical exercise induces favorable adaptations to avoid environmental pollution damage. Endurance training (65–75% VO2max) can be considered the most effective exercise to prevent toxicity effects. However, integral-matrixes analysis are required in further research to overcome some controversial behaviors of some elements.

Recent epidemiological evidence demonstrated that diabetes is a risk factor for AD onset and development. Indeed, meta-analyses of longitudinal epidemiologic studies show that diabetes increases AD risk by 50-100%, being insulin resistance (IR) the main binding link between diabetes and AD. Astrocytes are the foremost cerebral macroglial cells and are responsible for converting glucose into lactate and transfer it to neurons that use it as fuel, but Aβ(1-42) impairs insulin signaling and glycogen storage. Recent prospective studies showed that the Mediterranean diet is associated with lower incidence of AD. We hypothesized that hydroxytyrosol (HT, the preeminent polyphenol of olives and olive oil) could exert beneficial effects on IR associated with AD and investigated it mechanisms of action in an astrocytic model of AD. The astrocytic cell line C6 was exposed to Aβ(25-35) and co-incubated with HT for different periods. After treatment with Aβ(25-35), astrocytes' viability was significantly decreased as compared with controls; however, both pre- and post-treatment with HT prevented this effect. Mechanistically, we found that the preventive role of HT on Aβ(25-35)- induced cytotoxicity in astrocytes is moderated by an increased HT-induced activation of Akt, which is mediated by the insulin signaling pathway. In addition, we report that HT prevented the pronounced activation of mTOR, thereby restoring proper insulin signaling. In conclusion, we demonstrate that HT protects Aβ(25-35)-treated astrocytes by improving insulin sensitivity and restoring proper insulin-signaling. These data provide some mechanistic insight on the observed inverse association between olive oil consumption and prevalence of cognitive impairment. © 2017 BioFactors, 43(4):540-548, 2017.

Cognitive decline is one of the hallmarks of aging and can vary from mild cognitive impairment to dementia to Alzheimer's disease. In addition to some lifestyle interventions, there is room for the use of nutraceuticals/functional foods as pharma-nutritional tools to lessen the burden of cognitive decline before it worsens. We previously reported the promising molecular actions of milk fat globule membranes and krill oil concentrates in a rat model of aging. In this study, we concentrated on the activities on cognition, using an array of validated tests. We also performed lipidomic analyses of plasma, erythrocytes, and different brain areas. We report lower emotional memory (contextual fear conditioning) in aged rats supplemented with concentrates of polar lipids from buttermilk or krill oil at doses that approximate human consumption. No other behavioral parameter was significantly influenced by the supplements, calling for further research to confirm or not the purported salubrious activities of polar lipids, namely those rich in ω3 long-chain polyunsaturated fatty acids, on cognitive decline., This study was supported in part by grants from the Spanish Ministry of Science, Innovation and Universities (AGL2014-56464-R1; AGL2014-54565-R2; AGL2017- 87884) and by POR 3S4H. FEDER Funds.

Consumption of highly processed foods, such as those high in trans fats and free sugars, coupled with sedentarism and chronic stress increases the risk of obesity and cardiometabolic disorders, while adherence to a Mediterranean diet is inversely associated with the prevalence of such diseases. Olive oil is the main source of fat in the Mediterranean diet. Data accumulated thus far show consumption of extra virgin, (poly)phenol-rich olive oil to be associated with specific health benefits. Of note, recommendations for consumption based on health claims refer to the phenolic content of extra virgin olive oil as beneficial. However, even though foods rich in monounsaturated fatty acids, such as olive oil, are healthier than foods rich in saturated and trans fats, their inordinate use can lead to adverse effects on health. The aim of this review was to summarize the data on olive oil consumption worldwide and to critically examine the literature on the potential adverse effects of olive oil and its main components, particularly any effects on lipid metabolism. As demonstrated by substantial evidence, extra virgin olive oil is healthful and should be preferentially used within the context of a balanced diet, but excessive consumption may lead to adverse consequences.

The Ironman triathlon consists of a 3.8 km swim, 180 km bike, and 42.195 km run. Thermoregulation responses play an important role in performance optimization and injury prevention. Factors such as environmental conditions including heat and humidity, athlete training level, and race duration can affect thermoregulation. Hyperthermia occurs when the core temperature rises above 38.5 degrees C. The present study aims to describe core temperature (Tcore) in top-level and well-trained age group triathletes during the marathon of Ironman World Championship 2014 in Kona-Hawaii under thermal stress conditions. Tcore of 15 triathletes (age: 36.11 +/- 7.36 years, body mass: 71.14 +/- 7.12 kg, height: 179 +/- 0.04 cm, and fat %: 8.48 +/- 0.85) who classified for the Ironman World Championship was measured by an ingestible pill telemetry system prior to competition, during the marathon and 60 min after finishing the race. Mean wet bulb globe temperature (WBGT) during the marathon was 24.66 degrees C (range 22.44-28.50 degrees C). Body mass index (BMI) and perceived exertion (Borg Scale and Visual Analog Scale-Pain) were collected before the race and 60 min after the event. Time variables were extracted from their official race time and split times. Finish time was 10: 06:56 +/- 0:48:30. Tcore was initially 36.62 +/- 0.17 degrees C, increased at the end of the event (38.55 +/- 0.64; p < 0.01) and remained elevated 60 min after the event (38.65 +/- 0.41 degrees C; p < 0.002). BMI significantly decreased after the event (22.85 +/- 1.11 vs. 21.73 +/- 1.36; p < 0.05), whereas both exercise perceived exertion [Borg Scale (10.2 +/- 1.64 vs. 18.60 +/- 1.67; p < 0.003)] and perceived muscle pain [VAS Pain (2.75 +/- 1.59 vs. 9.08 +/- 1.13; p < 0.001)] increased significantly after the event. Tcore during competition correlated negatively with position in age group (r - 0.949, p = 0.051), but not with race time (r = -0.817; p = 0.183). High-level age group triathletes competing under thermal stress conditions in the Kona Ironman reached a state of hyperthermia during the marathon. After 60 min of recovery the hyperthermia persisted. Strategies to aid post-event cooling and recovery should be considered to avoid the potentially dangerous adverse health effects of hyperthermia. This study has been supported by the Consejeria de Educacion y Empleo, Junta de Extremadura with funding from the European Regional Development Fund under grant (Ref: GR18003). The authors thank support of the Government of Extremadura, Basque Government Center and 226ERS.

Hydroxytyrosol (HT) is involved in healthful activities and is beneficial to lipid metabolism. Many investigations focused on finding tissue-specific targets of HT through the use of different omics approaches such as transcriptomics and proteomics. However, it is not clear which (if any) of the potential molecular targets of HT reported in different studies are concurrently affected in various tissues. Following the bioinformatic analyses of publicly available data from a selection of in vivo studies involving HT-supplementation, we selected differentially expressed lipid metabolism-related genes and proteins common to more than one study, for validation in rodent liver samples from the entire selection. Four miRNAs (miR-802-5p, miR-423-3p, miR-30a-5p, and miR-146b-5p) responded to HT supplementation. Of note, miR-802-5p was commonly regulated in the liver and intestine. Our premise was that, in an organ crucial for lipid metabolism such as the liver, consistent modulation should be found for a specific target of HT even if different doses and duration of HT supplementation were used in vivo. Even though our results show inconsistency regarding differentially expressed lipid metabolism-related genes and proteins across studies, we found Fgf21 and Rora as potential novel targets of HT. Omics approaches should be fine-tuned to better exploit the available databases., This research was funded by grants from the Spanish “Agencia Estatal de Investigación” and the European FEDER Funds to AD and RMH (AGL2016-78922-R); the Ministerio de Economía y Competitividad–Fondo Europeo de Desarrollo Regional (SAF2016-75441-R) and the Fondo Social Europeo–Gobierno de Aragón (B16_17R) to MAN and JO; the Fundación Ramón Areces (CIVP18A3888) to AD, JG-Z, JTC, MCC, FV and RMH; the CIBER de Fisiopatología de la Obesidad y Nutrición (CIBERObn) to JAM, MPP, JO and MAN; and POR FESR 3S4H to FV. CIBERObn. is an initiative of the ISCIII, Spain. MCLH, LdP and MB R-R were recipients of contracts from the Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid, Fondo Social Europeo, and the Iniciativa de Empleo Juvenil YEI (PEJD-2016/BIO-2781, PEJD-2017-PRE/BIO-5100, and PEJD-2018-POST/BIO 8933), respectively.

In addition to providing sensory stimuli, usually taste, smell and sight, olive oil contains a range of minor components, mostly phenolic in nature. These components are endowed with pharmacological or pharma-nutritional properties that are the subject of active research worldwide. Based on our more than 25 years of experience in this field, we critically focus on what we believe are the most pharmacologically prominent actions of the constituents of olive oil. Most of the effects are due to the phenolic compounds in extra virgin olive oil, such as hydroxytyrosol and oleocanthal (which are often mis-categorized as in vivo antioxidants) and concern the cardiovascular system. Other potentially beneficial activities are still to be investigated in depth. We conclude that-in the context of a proper diet that includes high-quality products-the use of high-quality olive oil contributes to achieving and sustaining overall health. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.