Article

The consumption of a Jerte Valley cherry product in humans enhances mood, and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine

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Abstract

Jerte Valley cherries contain high levels of tryptophan, serotonin, and melatonin. These molecules have been shown to be involved in mood regulation. It has been suggested that a complex inter-relationship between brain serotonin, circulating levels of cortisol (the major stress hormone), and the hypothalamus-pituitary-adrenal axis exists in the regulation of stress responses, where cortisol and serotonin act as markers of mood disturbances. Moreover there is growing evidence that altered HPA activity is associated with various age-related pathologies. The present study evaluated the effect of the ingestion of a Jerte Valley cherry-based product, compared to a placebo product, on urine cortisol and 5-hydroxyindoleacetic acid (5-HIAA) levels, and on mood in young, middle-aged, and elderly participants. Cortisol and 5-HIAA acid levels were measured by commercial enzyme-linked immunosorbent assay kits. The mood state profile was analysed using a visual analogue scale and the state-trait anxiety inventory. Our findings showed that the ingestion of the Jerte Valley cherry product decreased urinary cortisol and increased urinary 5-HIAA levels in all the experimental groups. Moreover, the cherry product was able to lessen anxiety status in the middle-aged and elderly participants, and enhanced subjective mood parameters, particularly family relationships in young participants, and frame of mind and fitness in both middle-aged and elderly subjects. The consumption of the Jerte Valley cherry product may protect against stress and act as a mood enhancer by increasing serotonin availability to the organism, particularly with advancing age.

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... Moreover, extracts of sweet and tart cherries also show ability to provide neuroprotection against oxidative stress caused by ROS and against amyloid β protein (related to Alzheimer's cases), in rats' neuronal PC 12 cells. Both sweet and tart cherries also can reduce anxiety and have positive effects in family relationships, social relations, frame of mind, fitness and sleeppromoting actions [176]. These data were supported by 30 volunteers: young (20-30 years old, n = 10; 5 men and 5 women), middle-aged (35-55 years old, n = 10; 5 men and 5 women) and elderly (65-85 years old, n = 10; 5 men and 5 women), who ate 27.85 g of tart cherries twice a day, as lunch and dinner desserts, during 10 d. ...
... These data were supported by 30 volunteers: young (20-30 years old, n = 10; 5 men and 5 women), middle-aged (35-55 years old, n = 10; 5 men and 5 women) and elderly (65-85 years old, n = 10; 5 men and 5 women), who ate 27.85 g of tart cherries twice a day, as lunch and dinner desserts, during 10 d. After this time, it was observed a decrease in cortisol levels, and an increase of serotonin, given by concentration of 5-hydroxyindoleacetic acid present in urine [176]. Again, the neurological effects shown by sweet cherries are mainly due to phenolic compounds. ...
... Moreover, it is important to tacking in account that the presence of tryptophan, serotonin and melatonin in sweet cherries also raises positive neurological effects [45]. They interact with cherry phenolics, improving antioxidant defenses, mood [176], antidepressant actions and regulating sleep cycles [78]. They also have an inter-relationship between the hypothalamus-pituitary-adrenal axis, enhancing brain serotonin, and diminishing cortisol levels (biological marker of stress, anxiety, and depression) [183]. ...
... Cherries also show antioxidant effects in vivo, since an increased activity of the antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as a decrease of lipid peroxidation were reported in mice fed with sour cherry juice (Saric et al. 2009). Garrido et al. (2012) also measured total anthocyanins in the Jerte Valley cherry product. Anthocyanins show one of the strongest antioxidant activities among phenolic compounds. ...
... The results obtained showed that the Jerte Valley cherry product contained 2478.65 ± 113.68 mg Trolox per 100 g of freezedried product, equivalent to 690.30 ± 38.06 mg per single dose. Interestingly, Garrido et al. (2012) showed that a 28 g serving of the Jerte Valley cherry product is 10-fold higher than that found in Bing sweet cherries which present 160-70 mg of total polyphenols in a 100g serving. ...
... Also, it has been reported that both a Jerte Valley cherryenriched diet ) and the ingestion of a Jerte Valley cherry-based product (Garrido et al. 2009) exhibit sleep-promoting actions, and increase both urinary 6sulfatoxymelatonin (aMT6-s) and the antioxidant status in humans. Garrido et al. (2012) observed that the intake of a Jerte Valley cherry product had beneficial effects on the mood of healthy participants. Compared with the placebo, which did not have any effect on the parameters evaluated, the cherry product reduced anxiety (as measured in terms of both state and trait anxieties) and had a positive effect on subjective mood (as measured in terms of family relationships, social relations, frame of mind, and fitness). ...
... Moreover, extracts of sweet and tart cherries also show ability to provide neuroprotection against oxidative stress caused by ROS and against amyloid β protein (related to Alzheimer's cases), in rats' neuronal PC 12 cells. Both sweet and tart cherries also can reduce anxiety and have positive effects in family relationships, social relations, frame of mind, fitness and sleeppromoting actions [176]. These data were supported by 30 volunteers: young (20-30 years old, n = 10; 5 men and 5 women), middle-aged (35-55 years old, n = 10; 5 men and 5 women) and elderly (65-85 years old, n = 10; 5 men and 5 women), who ate 27.85 g of tart cherries twice a day, as lunch and dinner desserts, during 10 d. ...
... These data were supported by 30 volunteers: young (20-30 years old, n = 10; 5 men and 5 women), middle-aged (35-55 years old, n = 10; 5 men and 5 women) and elderly (65-85 years old, n = 10; 5 men and 5 women), who ate 27.85 g of tart cherries twice a day, as lunch and dinner desserts, during 10 d. After this time, it was observed a decrease in cortisol levels, and an increase of serotonin, given by concentration of 5-hydroxyindoleacetic acid present in urine [176]. Again, the neurological effects shown by sweet cherries are mainly due to phenolic compounds. ...
... Moreover, it is important to tacking in account that the presence of tryptophan, serotonin and melatonin in sweet cherries also raises positive neurological effects [45]. They interact with cherry phenolics, improving antioxidant defenses, mood [176], antidepressant actions and regulating sleep cycles [78]. They also have an inter-relationship between the hypothalamus-pituitary-adrenal axis, enhancing brain serotonin, and diminishing cortisol levels (biological marker of stress, anxiety, and depression) [183]. ...
Article
Abstract: Background: Sweet cherries are one of the most appreciated fruits worldwide as well as one of the great sources of several active substances, as phytochemical compounds (carotenoids, serotonin, melatonin and phenolic compounds) as well as in nutritive compounds (sugars and organic acids). Accumulating research demonstrate that their supplementation in our daily diet can contradict oxidative stress, mitigating or even attenuating chronic diseases, as cancerous processes, antiinflammatory-related disorders, diabetes, and neurological and cardiovascular pathologies. Therefore, the aims of this review are to present an overview on the effects of sweet cherries as health promotors, giving emphasis to the health benefits of their bioactive compounds, particularly their antimicrobial, antioxidant, antidiabetic, anticancer, anti-neurodegeneration, anti-inflammatory and cardiovascular effects. Methods: Research and online content about sweet cherry fruits is reviewed. The information available has been read several times to avoid inconsistencies. In addition, according what we read, original figures were done and added to facilitate understanding and to enrich the paper. Results: In this review, a total of 202 original reports were used. In respect to health benefits, it is possible to confirm by several studies that, in fact, the consumption of sweet cherries has positive impacts in human health, owing to their wealthy and vast constitution, particularly in phenolic compounds, vitamins and carotenoids whose health properties were already documented. Conclusion: The findings of this review support the evidence that sweet cherries can be applied in pharmaceutical and food formulations, since they are able to diminish free radical species and proinflammatory markers, preventing and/ or ameliorating oxidative-stress disorders.
... Since serotonin and melatonin have opposite circadian rhythms, for example, serotonin levels peak during the day while those of melatonin peak at night (Figure 3), the cherries and the cherry-based product were consumed twice a day, once at lunch and once as supper desserts. The lunchtime consumption of cherries or the cherry-based product was designed both to directly increase the diurnal circulating serotonin concentration and to indirectly increase the nocturnal circulating melatonin concentration by enhancing the amount of serotonin available to be converted into melatonin at night [31,90]. Hence, together with the ingestion of cherries (or the cherry-based product) at supper time, this boosts the total nighttime circulating melatonin levels [31,91]. ...
... The likelihood that this was indeed due to increases in the melatonin and serotonin concentrations was confirmed indirectly by determining the urine 6-sulfatoxymelatonin (aMT6-s) and 5-hydroxyindoleacetic acid (5-HIAA) levels. Most importantly, both of these nutritional interventions showed sleep-promoting and mood-enhancing actions in the young, middle-aged, and elderly subjects, which correlated with the increments in melatonin and serotonin levels, respectively [31,90,91]. ...
Article
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Free radicals and oxidative stress have been recognized as important factors in the biology of aging and in many age-associated degenerative diseases. Antioxidant systems deteriorate during aging. It is, thus, considered that one way to reduce the rate of aging and the risk of chronic disease is to avoid the formation of free radicals and reduce oxidative stress by strengthening antioxidant defences. Phytochemicals present in fruits, vegetables, grains, and other foodstuffs have been linked to reducing the risk of major oxidative stress-induced diseases. Some dietary components of foods possess biological activities which influence circadian rhythms in humans. Chrononutrition studies have shown that not only the content of food, but also the time of ingestion contributes to the natural functioning of the circadian system. Dietary interventions with antioxidant-enriched foods taking into account the principles of chrononutrition are of particular interest for the elderly since they may help amplify the already powerful benefits of phytochemicals as natural instruments with which to prevent or delay the onset of common age-related diseases.
... Despite of not fully understood protection mechanisms and the plethora of beneficial ingredients existed in fruits, there are consistent evidences on broad-spectrum antioxidant and anti-inflammatory properties of the phytonutrients (Garrido et al., 2012). Garcia-Parrilla et al.(2009) pointed out that melatonin is more powerful than other antioxidants, namely carotenoids, vitamin E, ascorbic acid (AsA) and glutathione (GSH), probably due to its small size and amphipathic nature that makes it easily permeate all tissues and subcellular compartments, thus providing antioxidant defenses where they are needed, whereas other antioxidants are capable of only selective migration. ...
... However, there are limited reports concerning the effect of dietetic tryptophan on melatonin release in humans. Garrido et al.(2012) showed that consumption of a Jert Valley cherry product enhances mood state by improving serotonin availability in the participants, since tryptophan produced an increase of circulating serotonin levels. Johns et al.(2013) suggested that the high tryptophan content as found in banana may enhance or up-regulate melatonin synthesis, leading to increased melatonin in the body. ...
Article
Recently melatonin has been reported in different fruits and its exact amount is influenced by many factors, including fruit type, variety and ripening stage, growth location and condition, and analytical method employed. Validated analytical methods with adequate sample treatment are required to obtain accurate measurement of melatonin in fruits. Importantly, diet high in melatonin from fruits could enhance human health. Also, melatonin could be used to improve the phytoremediation efficiency of plants against different pollutants such as heavy metals. This review discussed the contributing factors on the production and amount of melatonin in fruits, current analytical approaches, its functional roles, as well as the future research needs to clarify the mechanisms of fruit melatonin for improving human health and environment contaminations.
... High levels of melatonin in foods are not only beneficial for consumers, but also may prolong their shelf life [22]. The consumption of a Jerte Valley cherry product in humans enhances mood, and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine [38]. After consumption of pineapple, orange or banana, serum melatonin levels and antioxidant capacities were increased in healthy male volunteers [39]. ...
Article
Melatonin is a well-known molecule which possesses many beneficial effects on human health. Many agriculture products provide natural melatonin in the diet. Cherry is one such fruit as they are rich in melatonin. In order to understand the biological roles of melatonin in cherry fruit, melatonin synthesis and its changes over 24 hr period were systematically monitored both during their development and in the ripe cherries in two cultivars, 'Hongdeng' (Prunus avium L. cv. Hongdeng) and 'Rainier' (Prunus avium L. cv. Rainier). It was found that both darkness and oxidative stress induced melatonin synthesis, which led to dual melatonin synthetic peaks during a 24 hr period. The high levels of malondialdehyde induced by high temperature and high intensity light exposure were directly related to up-regulated melatonin production. A primary function of melatonin in cherry fruits is speculated to be as an antioxidant to protect the cherry from the oxidative stress. Importantly, plant tryptophan decaboxylase gene (PaTDC) was identified in cherry fruits. Our data shows that PaTDC expression is positively related to the melatonin production in the cherry. This provides additional information to suggest that tryptophan decaboxylase is a rate-limiting enzyme of melatonin synthesis in plants.
... MLT consumed in plant products is absorbed, enters the circulation and has physiological effects via receptor-or nonreceptor-mediated processes. A number of reports are available describing the positive health effects of MLT intake form cherry derivatives (Garrido et al., 2009(Garrido et al., , 2012(Garrido et al., , 2013Zhao et al., 2013). ...
... Garrido et al. carried out a study to investigate the effects of cherries on the state of feelings of humans. They prepared a 125 ml cherry drink using approximately 141 g cherries (dried, ground and diluted cherry + maltodextrin + citric acid) and it was consumed for a period of five days, including lunch and dinner (Garrido et al. 2012). Its effects on family relationships, social relationships, mood and well-being were compared between young, middle-aged and elderly individuals and it was observed that it had positive effects on mood and well-being with a decrease in anxiety at middle and advanced ages, and family relationships improved in youth. ...
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Behaviors are outward reflection of personality and is shaped by genetic and environmental factors. Nutrients, one of the environmental factors and consumed with foods, are indispensible elements for both prenatal and postnatal life to lead a healthy life at every stage of life and to demonstrate healthy behaviors. In this survey, the role of food as one of the environmental factors and the additives in them on behavior will be reviewed by taking into account severeal stages of life.
... The melatonin content in edible fruit has been associated with health-benefits, since high levels of this compound in foods are beneficial for consumers. Thus, the consumption of a Jerte Valley cherry product enhances mood and increases 5-hydroxyindoleacetic acid but reduces cortisol levels in urine, which may protect against stress and act as a mood enhancer by increasing serotonin availability in the organism, particularly with advancing age [3]. ...
Article
Full-text available
With the aim to study the effect of melatonin treatment of pomegranate trees on crop yield and fruit quality at harvest and during storage, two experiments were carried out in two consecutive years: 2017 and 2018. In the first year, trees were treated with melatonin (at 0.1 and 1 mM) along the developmental growth cycle and fruit quality parameters were evaluated at harvest and during storage at 10 °C for 90 days. Treatments with melatonin led to an increase of crop yield (number of fruits per tree and kg per tree), as well as higher fruit quality attributes, such as fruit size (diameter and weight), color, total soluble solids (TSS), and total acidity (TA), especially with the 0.1 mM dose. Then, in the second year, melatonin at 0.1 mM was selected for repeating the pre-harvest treatments with similar results in terms of crop yield and fruit quality parameters. During storage, pomegranate fruit treated with 0.1 mM melatonin maintained higher quality attributes than controls, such as TSS, TA, and firmness and lower weight losses were observed in fruit from treated trees, in both trials. In addition, the content of the major sugars (glucose and fructose) and organic acids (malic, succinic and ascorbic acid) were higher in melatonin-treated than in non-treated fruit. These results suggest that pre-harvest melatonin treatment could be a useful tool to increase pomegranate crop yield as well as fruit quality parameters at harvest and their maintenance during storage due to an effect of melatonin on reducing the postharvest ripening process.
... Valley cherry products also improved mood and sleep parameters in healthy participants. 39 Finally, we recently reported that administration of red wine (125 mL) did not decrease the salivary antiradical capacity in humans, thus suggesting that the pro-oxidant effects of ethanol may be counteracted by melatonin present at 0.23 ng mL −1 and polyphenols. 40 ...
Article
Health-promoting properties of Mediterranean diet have been attributed, at least in part, to the chemical diversity of plant foods. Among phytochemicals, polyphenols represent the paradigm of the relationship between healthy foods and reduced risk of chronic-degenerative diseases, even if, in the past few years, a new element enriched this scenario. Melatonin, and possibly other indoleamines recently discovered in some relevant Mediterranean foods, may represent a new factor contributing to the elucidation of the protective effects of diets rich in plant products. Therefore, in synergy with polyphenols and other bioactive phytochemicals (e.g., carotenoids, glucosinolates), melatonin may contribute to maximizing the benefits of healthy dietary styles. This brief survey deals with the occurrence of melatonin in the Mediterranean diet, with an emphasis on grape products, and focuses on the biological significance of dietary melatonin, an emerging and exciting topic in the field of nutritional sciences.
... The intake of 200 mL of grape juice from the Tempranillo cultivar twice a day for 5 days significantly increased urinary 6-sulfatoxymelatonin and total antioxidant capacity in young, middle-aged, and elderly healthy individuals [28]. Similar results were obtained after ingesting Jerte Valley sweet cherry products, Japanese plums, and tropical fruits (including oranges) [29][30][31][32] Jerte Valley cherry products also improved mood and sleep parameters in healthy participants [33]. Finally, we recently reported that administration of red wine (125 mL) did not decrease the salivary antiradical capacity in humans, thus suggesting that the pro-oxidant effects of ethanol may be counteracted by melatonin present at 0.23 ng mL À1 and polyphenols [34]. ...
Chapter
Health-promoting properties of Mediterranean diet have been attributed, at least in part, to the chemical diversity of plant foods. Among phytochemicals, polyphenols represent the paradigm of the relationship between healthy foods and reduced risk of chronic-degenerative diseases, even if, in the past few years, a new element enriched this scenario. Melatonin—and possibly other indoleamines recently discovered in some relevant Mediterranean foods—may represent a new factor contributing to the elucidation of the protective effects of diets rich in plant products. Therefore, in synergy with polyphenols and other bioactive phytochemicals (e.g., carotenoids, glucosinolates), melatonin may contribute to maximizing the benefits of healthy dietary styles. This brief survey deals with the occurrence of melatonin in the Mediterranean diet, with an emphasis on grape products, and focuses on the biological significance of dietary melatonin, an emerging and exciting topic in the field of nutritional sciences.
... The effects of cherry juice on cortisol concentrations were examined in 3 randomised, controlled trials in healthy adults and physically-fit adults comprising a total sample size of 77 participants, with treatment periods ranging from 5 days to 10 days. In a study on healthy adults, 250 mls daily of a Jerte Valley cherry liquid for 5 days was associated with decreases in morning and evening urinary cortisol concentrations compared to the placebo [65]. In a study on marathon runners, the 7-day administration of 472 ml of a pressed blend of Montmorency cherry juice for 7 days had no effect on salivary cortisol concentrations either before or after a marathon race [66]. ...
Article
Introduction: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the stress response. Plants, herbs, spices, and plant-based nutrients may influence HPA-axis activity. Objective: To evaluate randomised controlled, human trials assessing the effects of single plants or phytonutrients on HPA-axis related hormones. Methods: A systematic review of PubMed, Cochrane library, and the Cumulative Index to Nursing and Allied Health Literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria comprised of human, randomised controlled studies with a control intervention examining the effects of a single herb, spice, plant, or extract on pre- and post-changes in blood, saliva, urine, or hair concentrations of cortisol, cortisone, corticotrophin-releasing hormone, or adrenocorticotropic hormone. Databases were searched from inception until October 2020. Results: Fifty-two studies were identified examining the effects of ashwagandha, Korean ginseng, St John's Wort, cannabidiol, Rhodiola rosea, curcumin, cherry juice, asparagus, Jiaogulan, Black cohosh, Siberian ginseng, Bacopa monnieri, blueberries, green tea, Caralluma fimbriata, cashew apple juice, melon, American ginseng, Ginkgo biloba, grape juice, grapefruit juice, rosella, hops, mangosteen, holy basil, and pomegranate juice. Due to significant variability in study designs, the effect of phytonutrients on HPA-axis activity in humans was unclear. The most consistent finding was a morning, cortisol-lowering effect from ashwagandha supplementation. Conclusion: For most phytonutrients, the effects of supplementation on HPA-axis activity in humans is unclear. Before more definitive conclusions about the effects of phytonutrients on the HPA-axis can be made, further research is required.
... The presence of melatonin in plants and fruits has been studied earlier, since it has been proven that these exogenous indoleamines increases their serum contents, and therefore their biological activity is as well increased after ingestion (Garrido et al., 2012;Garrido et al., 2013a;Garrido et al., 2013b;González Flores et al., 2011). ...
Article
Full-text available
The healthy properties due to the regular consumption of fruit and vegetables have been extensively reported before. Different studies have established a direct correlation between the healthy properties and the presence of bioactive compounds in the vegetable products. Bioactive compounds or phytochemicals are secondary metabolites of plants that are synthetized to accomplish a diverse number of functions in plants, among them; they play an important role in plant defense, to attract pollinators or to promote the adaptability between the plant and the environment in which it is growing. For this reason, different authors have established that these bioactive compounds are a shield between the plant and environment. Although they have a great variability, in terms of structure and chemical properties, bioactive compounds are characterized for being potent antioxidants. Thus, these compounds are able to neutralize free radicals reducing the oxidative damages that they cause to cell material, being that the main health property associated with the consumption of fruit and vegetables. Sweet cherries are characterized for having an important amount of bioactive compounds, mostly polyphenols (hydroxycinnamates, flavonols, procyanidins and anthocyanins) together with indolamines such as melatonin and serotonin. Based on that, this communication pretends to review the presence of bioactive compounds in sweet cherries, and how their concentrations are altered according to the pre- and postharvest conditions. Finally, different assays to evaluate the healthy properties of the bioactive compounds in sweet cherries are as well reviewed.
... Effect on sleep could be detected within 3 days of consuming sweet cherries (141 g or 25 cherries/day) and within 5 d of consuming tart cherries (240 mL of tart cherry juice; approximately 100 cherries/day). The studies using sweet cherries also reported a decrease in urinary cortisol and anxiety, and improved mood [38,94]. Those functions were not tested in the studies using tart cherries [65,93]. ...
Article
Full-text available
Increased oxidative stress contributes to development and progression of several human chronic inflammatory diseases. Cherries are a rich source of polyphenols and vitamin C which have anti-oxidant and anti-inflammatory properties. Our aim is to summarize results from human studies regarding health benefits of both sweet and tart cherries, including products made from them (juice, powder, concentrate, capsules); all referred to as cherries here. We found 29 (tart 20, sweet 7, unspecified 2) published human studies which examined health benefits of consuming cherries. Most of these studies were less than 2 weeks of duration (range 5 h to 3 months) and served the equivalent of 45 to 270 cherries/day (anthocyanins 55–720 mg/day) in single or split doses. Two-thirds of these studies were randomized and placebo controlled. Consumption of cherries decreased markers for oxidative stress in 8/10 studies; inflammation in 11/16; exercise-induced muscle soreness and loss of strength in 8/9; blood pressure in 5/7; arthritis in 5/5, and improved sleep in 4/4. Cherries also decreased hemoglobin A1C (HbA1C), Very-low-density lipoprotein (VLDL) and triglycerides/high-density lipoprotein (TG/HDL) in diabetic women, and VLDL and TG/HDL in obese participants. These results suggest that consumption of sweet or tart cherries can promote health by preventing or decreasing oxidative stress and inflammation.
... However, cherry consumption cannot be considered as a major determinant of the 6-sulfatoxymelatonin plasma level, as it can originate from both an endogenous synthesis and other richer dietary sources of melatonin [86,87]. The same conclusion applies for the urinary excretion of 5-hydroxyindoleacetic acid (5HIAA), which increased in 30 volunteers after consumption of cherries for 5 days [88]. 5HIAA is the main metabolite of serotonin. ...
Article
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Abstract Fruit is a key component of a healthy diet. However, it is still not clear whether some classes of fruit may be more beneficial than others and whether all individuals whatever their age, gender, health status, genotype, or gut microbiota composition respond in the same way to fruit consumption. Such questions require further observational and intervention studies in which the intake of a specific fruit can be precisely assessed at the population and individual levels. Within the Food Biomarker Alliance Project (FoodBAll Project) under the Joint Programming Initiative “A Healthy Diet for a Healthy Life”, an ambitious action was undertaken aiming at reviewing existent literature in a systematic way to identify validated and promising biomarkers of intake for all major food groups, including fruits. This paper belongs to a series of reviews following the same BFIRev protocol and is focusing on biomarkers of pome and stone fruit intake. Selected candidate biomarkers extracted from the literature search went through a validation process specifically developed for food intake biomarkers.
... For example, the ingestion of serotonin through a typical dose of 30 g walnuts is approximately the same than the one obtained by the consumption of an average-sized banana of 120 g. Furthermore, 5-HIAA has also been reported after the consumption of a Jerte Valley cherry product [122]. The concentration of serotonin in other common nuts like almonds is low (≤ 0.6 μ/g) [24]. ...
Article
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Nuts and vegetable oils are important sources of fat and of a wide variety of micronutrients and phytochemicals. Following their intake, several of their constituents, as well as their derived metabolites, are found in blood circulation and in urine. As a consequence, these could be used to assess the compliance to a dietary intervention or to determine habitual intake of nuts and vegetable oils. However, before these metabolites can be widely used as biomarkers of food intake (BFIs), several characteristics have to be considered, including specificity, dose response, time response, stability, and analytical performance. We have, therefore, conducted an extensive literature search to evaluate current knowledge about potential BFIs of nuts and vegetable oils. Once identified, the strengths and weaknesses of the most promising candidate BFIs have been summarized. Results from selected studies have provided a variety of compounds mainly derived from the fatty fraction of these foods, but also other components and derived metabolites related to their nutritional composition. In particular, α-linolenic acid, urolithins, and 5-hydroxyindole-3-acetic acid seem to be the most plausible candidate BFIs for walnuts, whereas for almonds they could be α-tocopherol and some catechin-derived metabolites. Similarly, several studies have reported a strong association between selenium levels and consumption of Brazil nuts. Intake of vegetable oils has been mainly assessed through the measurement of specific fatty acids in different blood fractions, such as oleic acid for olive oil, α-linolenic acid for flaxseed (linseed) and rapeseed (canola) oils, and linoleic acid for sunflower oil. Additionally, hydroxytyrosol and its metabolites were the most promising distinctive BFIs for (extra) virgin olive oil. However, most of these components lack sufficient specificity to serve as BFIs. Therefore, additional studies are necessary to discover new candidate BFIs, as well as to further evaluate the specificity, sensitivity, dose-response relationships, and reproducibility of these candidate biomarkers and to eventually validate them in other populations. For the discovery of new candidate BFIs, an untargeted metabolomics approach may be the most effective strategy, whereas for increasing the specificity of the evaluation of food consumption, this could be a combination of different metabolites. Electronic supplementary material The online version of this article (10.1186/s12263-019-0628-8) contains supplementary material, which is available to authorized users.
... Effect on sleep could be detected within 3 days of consuming sweet cherries (141 g or 25 cherries/day). The studies using sweet cherries also reported a decrease in urinary cortisol and anxiety, and improved mood (M Garrido et al. 2013;María Garrido et al. 2012). ...
Chapter
Sweet cherries (Prunus avium L.) are amongst the most consumed and appreciated fruits worldwide, and are an excellent source of phytochemicals (melatonin, serotonin, carotenoids and phenolic compounds, including flavonoids and anthocyanins) and nutritive substances (organic acids and sugars). The concentrations of these compounds can vary between different sweet cherry cultivars and in different plant parts thereof. Recently, this fruit has gained more popularity, as there are many scientific studies that evaluate the effects of sweet cherries as health promoters, emphasizing the health benefits of their bioactive compounds, particularly in what concerns their antioxidant, antimicrobial, antidiabetic, anticancer, anti-inflammatory, anti-neurodegenerative and cardiovascular effects, among others. This chapter will focus on the description of the composition of these fruits, the main factors that influence their profile of bioactive compounds, the different analytical tools to determine the composition, health benefits associated to their consumption, as well as on the recent findings about their potential therapeutic properties. Keywords: Prunus avium L., nutrients, bioactive compounds, analytical methods, bioactivity, health benefits
... Unpredictable chronic exposure to stress-induced high levels of serum corticosterone in mice; however, oral administration of exogenous melatonin for 5 weeks (1 and 10 mg/kg) decreased the higher serum corticosterone levels [18]. These studies provided the direct evidences supporting the hypothesis that the melatonin acts as an antidepressant, and melatonin might have regulatory roles in the activity of hypothalamus-pituitary-adrenal (HPA) axis [19][20][21][22]. ...
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Background. The present work aims at formulating the melatonin-loaded nanoparticles (MTNPs) exhibiting the controlled-release and pH-sensitivity to repurpose the use of melatonin in the treatment of depressive-like behaviors and hypothalamus-pituitary-adrenal (HPA) axis dysregulation. Methods. MTNPs were characterized for the size, drug incorporation, and in vitro release in the different pH environments. Its merits were in vivo tested on the pinealectomized rats presenting the depressive-like behaviors and the abnormal HPA axis activity by calculating the improvement on saccharin preference, swimming immobility time, and the negative feedback of HPA axis. Results. Results revealed that MTNPs showed nanometer size, 15.77% of drug loading, 33.82% of encapsulation efficiency, the different controlled-release profiles in different pH environments (pH 1.2, pH 6.8, and pH 7.4), more sensitivity release in simulated intestinal fluid (pH 7.4) and blood (pH 6.8), and less sensitivity release in simulated gastric fluid (pH 1.2). Furthermore, MTNPs displayed better antidepressant actions in reducing the immobility time of forced swimming test, increasing the preference for saccharin, and sensitizing the blunt negative feedback of HPA axis, when compared to the free melatonin. Conclusions. The controlled-release nanoparticles is shown to be an effective improvement on the dosage form for melatonin, which is worthy of futuristic and complete evaluation.
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Nowadays, halal meat is attracting consumers as a healthier product. However, little is known about the nutritional content and possible health effects. A comparative analysis of the protein and amino acid contents between halal and non-halal meats (beef and lamb) was carried out. Additionally, a pilot study was performed analyzing the impact of its consumption on sleep/wake cycle and mood state profile in general population. Participants (N = 25) were asked to exclusively consume the halal meat (1,000 g of gross weight / week) for 30 days. Objective and subjective sleep qualities, mood state profile and levels of the urinary metabolites of serotonin and melatonin were assessed at baseline and postintervention. Significantly higher contents of proteins and some amino acids were observed in halal-lamb and halal-beef respectively. The consumption of halal meat for one month caused a slight improvement in men´s wake activity and mood state profile, as well as in women´s subjective sleep quality. Significantly higher urine levels of serotonin metabolite were also reported, particularly in men. Halal meat consumption seems to have a positive impact on sleep/wake cycle and mood state profile, likely due to the higher protein and amino acid contents. Additional scientific research is needed to support consumer trends in the coming years.
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The mechanism of action of polyphenolic compounds is attributed to their antioxidant, anti-inflammatory, and anti-proliferative properties and their effects on subcellular signal transduction, cell cycle impairment and apoptosis. A raspberry (Rubus idaeus L.) fruit extract contains various antioxidant active compounds, particularly ellagic acid (EA); however the exact intracellular mechanism of their action is not fully understood. The aim of the study was to evaluate the antioxidant effect of raspberry extracts, and that of ellagic acid by assessment of the production of the reactive oxygen species (ROS) by murine macrophage J774 cells. Raspberry extracts and their active compound EA did not affect or had very minor effects on cell viability. No significant difference in the ROS generation in arachidonic acid stimulated macrophages was determined for raspberry extracts and EA whereas in the phorbol-12 myristate-13 acetate model ROS generation was significantly (p < 0.05) reduced. Our observation that raspberry pomace extracts in vitro reduce ROS production in a J774 macrophage culture suggests that raspberry extract and ellagic acid mediated antioxidant effects may be due to the regulation of NADPH oxidase activity.
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Abstract Cornelian cherry (Cornus mas L.), apple (Malus domestica Borkh.) cultivars 'Jonagold' and 'Red Boskoop', pear (Pyrus communis) cv. 'Conference', and plum (Prunus domestica L.) cv. 'Common Plum' juices were assayed for their quality, organic acids, polyphenol content, and antioxidant activity (determined as a ferric-reducing antioxidant power (FRAP)). Cornelian cherry juice revealed the highest titratable acidity-2.58 g malic acid 100 g(-1). The highest polyphenol content was also noted for Cornelian cherry-45.6 mg gallic acid (GA) g(-1). The medium level of polyphenols was proved for 'Jonagold' (22.8 mg GA g(-1)). The lowest level was recorded for 'Common Plum' (9.60 mg GA g(-1)), followed by 'Conference' pear and 'Red Boskoop' apple (12.3 and 21.3 mg GA g(-1), respectively). The FRAP values ranged from 1.97 mmol Fe L(-1) for 'Common Plum' juices, 2.37 mmol Fe L(-1) for 'Conference' pear to 3.92 mmol Fe L(-1) for 'Red Boskoop' and 'Jonagold' apple. However, the obtained data indicated outstanding antioxidant properties for Cornelian cherry juices. In this case, FRAP reached 23.5 mmol Fe L(-1). The calculated correlation coefficient FRAP versus polyphenols indicates that the antioxidant status for Cornelian cherry is not only correlated with polyphenols but also with other biological compounds. The obtained results indicated that Cornelian cherry is a valuable source of substances with a high antioxidant activity.
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Lactic fermentation is a low-cost and sustainable bio-preservation method that aims to retain the sensory and nutritional characteristics of raw matrices. In this study two lactic fermentation processes were set up to elaborate two fermented cherry beverages as well as to determine their nutritional and functional characteristics. Differences between both processes were based on the pasteurization conditions and ascorbic acid addition time. The results were compared with those obtained in cherry fresh fruit and two pasteurized cherry purées. The purée and beverage obtained through protocol 2 (where ascorbic acid addition was carried out before the pasteurization process, which was applied during 5 minutes) were the most effective in preserving the reddish color of fruits compared to those obtained in protocol 1 (where ascorbic acid addition was carried out after the pasteurization process, which was applied during 10 minutes) . Similarly, protocol 2 was more efficient in preventing the loss of phenolic compounds and anthocyanins. The levels of serotonin did not change after the fermentation processes, whereas the amino acid concentration was higher in cherry-fermented beverages. Better results were obtained in cherry-fermented beverages. The lactic fermentation could be a useful and feasible technique to obtain natural drinks with functional / nutritional qualities.
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Over the past 50 years, relationships between stress and the neurobiological changes seen in psychiatric disorders have been well-documented. A major focus of investigations in this area has been the role of the hypothalamic-pituitary-adrenal (HPA) axis, both as a marker of stress response and as a mediator of additional downstream pathophysiologic changes. This review examines the emerging literature concerning the relationship between stress. HPA axis function, and depression, as well as the role of early life stress as an important risk factor for HPA axis dysregulation. The more recent studies reviewed suggest that the prominence of HPA axis hyperactivity in adults with depressive and anxiety disorders may constitute a link between the occurrence of adversity in childhood and the development of adult psychopathology.
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The involvement of the serotonergic system in the pathophysiology and treatment of affective disorders has been strongly implicated. The tryptophan depletion paradigm is widely used to study the effect of lowering serotonin levels. However, the effects observed in such studies are inconsistent and sometimes contradictory. The present review summarizes and discusses these discrepancies, emphasizing the importance of methodological details such as acute versus chronic tryptophan depletion, patients diagnosis and disease state: euthymic versus acute phase and previous drug treatment. Acute tryptophan depletion as a predictive test for personalized antidepressant treatment is suggested.
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Long distance running causes acute muscle damage resulting in inflammation and decreased force production. Endurance athletes use NSAIDs during competition to prevent or reduce pain, which carries the risk of adverse effects. Tart cherries, rich in antioxidant and anti-inflammatory properties, may have a protective effect to reduce muscle damage and pain during strenuous exercise. This study aimed to assess the effects of tart cherry juice as compared to a placebo cherry drink on pain among runners in a long distance relay race. The design was a randomized, double blind, placebo controlled trial. Fifty-four healthy runners (36 male, 18 female; 35.8 +/- 9.6 yrs) ran an average of 26.3 +/- 2.5 km over a 24 hour period. Participants ingested 355 mL bottles of tart cherry juice or placebo cherry drink twice daily for 7 days prior to the event and on the day of the race. Participants assessed level of pain on a standard 100 mm Visual Analog Scale (VAS) at baseline, before the race, and after the race. While both groups reported increased pain after the race, the cherry juice group reported a significantly smaller increase in pain (12 +/- 18 mm) compared to the placebo group (37 +/- 20 mm) (p < .001). Participants in the cherry juice group were more willing to use the drink in the future (p < 0.001) and reported higher satisfaction with the pain reduction they attributed to the drink (p < 0.001). Ingesting tart cherry juice for 7 days prior to and during a strenuous running event can minimize post-run muscle pain.
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Modulating central serotonergic function by acute tryptophan depletion (ATD) has provided the fundamental insights into which cognitive functions are influenced by serotonin. It may be expected that serotonergic stimulation by tryptophan (Trp) loading could evoke beneficial behavioural changes that mirror those of ATD. The current review examines the evidence for such effects, notably those on cognition, mood and sleep. Reports vary considerably across different cognitive domains, study designs, and populations. It is hypothesised that the effects of Trp loading on performance may be dependent on the initial state of the serotonergic system of the subject. Memory improvements following Trp loading have generally been shown in clinical and sub-clinical populations where initial serotonergic disturbances are known. Similarly, Trp loading appears to be most effective for improving mood in vulnerable subjects, and improves sleep in adults with some sleep disturbances. Research has consistently shown Trp loading impairs psychomotor and reaction time performance, however, this is likely to be attributed to its mild sedative effects.
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Compared with young adults, older adults have significantly impaired capacities to resist oxidative damage when faced with acute stress such as ischemia/reperfusion. This impairment likely contributes to increased morbidity and mortality in older adults in response to acute trauma, infections, and the susceptibility to diseases such as atherosclerosis, cancer, diabetes, and Alzheimer's disease. Consumption of foods high in polyphenols, particularly anthocyanins, have been associated with improved health, but the mechanisms contributing to these salutary effects remain to be fully established. This study tested the hypothesis that consumption of tart cherry juice containing high levels of anthocyanins improves the capacity of older adults to resist oxidative damage during acute oxidative stress. In a double-blind, placebo-controlled, crossover design, 12 volunteers [6 men and 6 women; age 69 +/- 4 y (61-75 y)] consumed in random order either tart cherry juice or placebo (240 mL twice daily for 14 d) separated by a 4-wk washout period. The capacity to resist oxidative damage was measured as the changes in plasma F(2)-isoprostane levels in response to forearm ischemia-reperfusion (I/R) before and after each treatment. The tart cherry juice intervention reduced the I/R-induced F(2)-isoprostane response (P < 0.05), whereas placebo had no significant effect. The tart cherry juice intervention also reduced basal urinary excretion of oxidized nucleic acids (8-hydroxy-2'-deoxyguanosine, 8-hydroxyguanosine) (P < 0.05) but not urinary excretion of isoprostanes. These data suggest that consumption of tart cherry juice improves antioxidant defenses in vivo in older adults as shown by an increased capacity to constrain an oxidative challenge and reduced oxidative damage to nucleic acids.
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Aging is known to alter the circadian rhythms of melatonin, serotonin, thermoregulatory responses, cytokine production, and sleep/wakefulness which affect sleep quality. We tested the possible palliative effects of a 3-day administration of melatonin (0.25 or 2.5 mg/kg of body weight [b.w.] to young and old ringdoves, respectively) or tryptophan (300 mg/kg of b.w. to old ringdoves) on these rhythms. Doves are a monophasic, diurnal species; these characteristics are similar in humans. Old animals presented lower melatonin and serotonin levels; higher interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha values; and reductions in the Midline-Estimating Statistic of Rhythm and amplitude of activity-rest rhythm and in the amplitude of the core temperature rhythm. Melatonin raised serum melatonin levels; tryptophan increased both melatonin and serotonin levels. Melatonin and tryptophan lowered nocturnal activity, core temperature, and cytokine levels and increased peripheral temperature in both groups. Melatonin or tryptophan may limit or reverse some of the changes that occur in sleep-wake rhythms and temperature due to age.
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Serotonin, one of the most important neurotransmitters in the central nervous system, is synthesized by the amino acid, tryptophan. Given that this essential amino acid is consumed in the diet, the aim of this study was to evaluate the effect of orally administered L-tryptophan (125 mg/kg) on circadian variations in the levels of serotonin in brain and plasma. We used male Wistar rats of 14 +/- 2 weeks of age (n = 240), maintained under conditions of a 12-hr light:dark cycle, and food and water ad libitum. Tryptophan administration was by gavage in a daily single dose at 7 p.m. for 7 days. The serotonin levels were measured by ELISA every hour at night (8 p.m. to 8 a.m.) and every 4 hr during daytime (8 a.m. to 8 p.m.). The results show that in both the tryptophan-treated and untreated groups the highest values appeared during the beginning of the darkness with a peak at 9, 10 and 11 p.m. in controls, and at 9 p.m. in the tryptophan-treated group. After tryptophan administration, the levels of serotonin were significantly higher in the plasma and all the brain regions analysed than in the control group. This increase of serotonin levels was greater in the pineal gland than in other brain regions, and the least in plasma. In conclusion, oral administration of tryptophan during 7 days enhances serotonin levels over a 24-hr period, and produces an advance in the peak of serotonin in both plasma and different brain regions.
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To determine the efficacy of cortisol and its metabolite, cortisone, measured simultaneously by high performance liquid chromatography (HPLC) in the diagnosis of Cushing's syndrome, we retrospectively reviewed the histories of 29 surgically proven Cushing's syndrome patients (20 Cushing's disease, 5 ectopic ACTH syndrome, and 4 adrenal Cushing's syndrome) and 6 patients with exogenous Cushing's syndrome. These 35 patients had urinary free cortisol determined by both HPLC and competitive binding methods. The efficacy of the HPLC assay using cortisol alone was equivalent to that of the competitive binding assay; 22 of 29 (76%) patients had increased cortisol. Cortisone also aided in the diagnosis; 25 of 29 (86%) had increased cortisone. Twenty-seven of the 29 (93%) patients had either both cortisone and cortisol (n = 19) or at least 1 of the 2 (n = 8) increased. All 6 patients with exogenous Cushing's syndrome had suppressed urinary free cortisol, cortisone, and the presence of prednisone and prednisolone. In the competitive binding assay, all exogenous Cushing's patients had falsely increased cortisol results. In conclusion, urinary free cortisol plus cortisone determined simultaneously by HPLC added a new dimension to the diagnosis of Cushing's syndrome. It should be considered when exogenous Cushing's syndrome is suspected or when only one urinary cortisol test is allowed to be ordered.
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The transport of neutral amino acids through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo, is an important control point for the overall regulation of cerebral metabolism, including protein synthesis and neurotransmitter production. The Michaelis-Menten kinetics of BBB amino acid transport have been investigated in vivo with the brain uptake index (BUI) technique, and in vitro with the isolated human brain capillary preparation. The only amino acid that is albumin-bound is tryptophan, and the majority of albumin-bound tryptophan in the plasma is available for transport through the BBB via an enhanced dissociation mechanism that operates at the surface of the brain capillary endothelium. The availability in brain of amino acids is predicted from the BBB Km values to be sharply influenced by supra-physiological concentrations of phenyalanine in the 200-500 microM range. Moreover, the measurement of cerebral protein synthesis with an internal carotid artery perfusion technique and HPLC-based measurements of aminoacyl-transfer RNA specific activities shows an inverse relationship between cerebral protein synthesis and plasma phenyalanine concentrations in the 200-500 microM range. These findings indicate the neurotoxicity of hyperphenylalninemia is not restricted to the phenylketonuria range of approximately 2000 microM, but is exerted in the supra-physiological range of 200-500 microM.
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Unlabelled: The advent of managed care, reduction of costs, and advances in medical technology place increasing demands on anesthesiologists. Preoperative anxiety may go unnoticed in an environment that stresses increased productivity. The present study compares different methods for measuring preoperative anxiety, identifies certain patient characteristics that predispose to high anxiety, and describes the quantity and quality of anxiety that patients experience preoperatively. Seven hundred thirty-four patients participated in the study. We assessed aspects of anxiety by means of visual analog scales (VAS) and the State Anxiety Score of the Spielberger State-Trait Anxiety Inventory (STAI). The mean STAI anxiety score was 39 +/- 1 (n = 486) and the mean VAS for fear of anesthesia was 29 +/- 1 (n = 539). Patients feared surgery significantly more than anesthesia (P < 0.001). The VAS measuring fear of anesthesia correlated well with the STAI score (r = 0.55; P < 0.01). Young patients, female patients, and patients with no previous anesthetic experience or a previous negative anesthetic experience had higher anxiety scores. Patients worried most about the waiting period preceding surgery and were least concerned about possible awareness intraoperatively. Factor analysis of various anxiety items showed three distinct dimensions of fear: 1) the fear of the unknown 2) the fear of feeling ill, and 3) the fear for one's life. Among these dimensions, fear of the unknown correlated highest with the anxiety measuring techniques STAI and VAS. The simple VAS proved to be a useful and valid measure of preoperative anxiety. Implications: The study of qualitative aspects of anxiety reveals three distinct dimensions of preoperative fear: fear of the unknown, fear of feeling ill, and fear for one's life. Groups of patients with a higher degree of preoperative anxiety and their specific anesthetic concerns can be identified using the visual analog scale.
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Increased brain serotonin may improve the ability to cope with stress, whereas a decline in serotonin activity is involved in depressive mood. The uptake of the serotonin precursor, tryptophan, into the brain is dependent on nutrients that influence the cerebral availability of tryptophan via a change in the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). Therefore, a diet-induced increase in tryptophan availability may increase brain serotonin synthesis and improve coping and mood, particularly in stress-vulnerable subjects. We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, may increase the plasma Trp-LNAA ratio and reduce depressive mood and cortisol concentrations in stress-vulnerable subjects under acute stress. Twenty-nine highly stress-vulnerable subjects and 29 relatively stress-invulnerable subjects participated in a double-blind, placebo-controlled study. Subjects were exposed to experimental stress after the intake of a diet enriched with either alpha-lactalbumin or sodium-caseinate. Diet-induced changes in the plasma Trp-LNAA ratio and prolactin were measured. Changes in mood, pulse rate, skin conductance, and cortisol concentrations were assessed before and after the stressor. The plasma Trp-LNAA ratio was 48% higher after the alpha-lactalbumin diet than after the casein diet (P = 0.0001). In stress-vulnerable subjects this was accompanied by higher prolactin concentrations (P = 0.001), a decrease in cortisol (P = 0.036), and reduced depressive feelings (P = 0.007) under stress. Consumption of a dietary protein enriched in tryptophan increased the plasma Trp-LNAA ratio and, in stress-vulnerable subjects, improved coping ability, probably through alterations in brain serotonin.
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There is evidence for inhibitory effects of adrenocorticosteroids on serotonergic (5-HT) activity. However, in depression the relationship between altered cortisol levels and brain 5-HT function remains to be clarified. The aim of this study was to investigate whether hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is associated with 5-HT dysfunction in depressed patients, especially in those with suicidal behaviour. Cortisol levels following the dexamethasone suppression test (DST, 1 mg PO) and prolactin, corticotropin and cortisol responses to the d-fenfluramine test (d-FEN, 45 mg PO) - a specific 5-HT releaser/uptake inhibitor - were measured in 71 drug-free DSM-IV major depressed inpatients (40 with a history of suicide attempt, 31 without) and 34 hospitalized healthy control subjects. Depressed patients showed higher post-DST cortisol levels but similar responses to d-FEN compared with control subjects. Hormonal responses to d-FEN were not correlated with cortisol levels (basal or post-DST). Among the depressed patients, DST suppressors and DST nonsuppressors exhibited no significant difference in endocrine responses to d-FEN. However, patients with a history of suicide attempt, when compared with patients without such a history, showed lower hormonal responses to d-FEN but comparable basal and post-DST cortisol levels. Taken together these results suggest that, in depression, HPA axis hyperactivity is not responsible for the reduced 5-HT activity found in patients with a history of suicidal behavior.
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Stress and depression are characterized by elevation of circulating cortisol, as well as by changes in physiological functions. In this study, we addressed the possibility that elevated cortisol is also associated with the origin and development of depression. We report here that cortisol at the nM-microM concentration range induces a substantial increase in serotonin uptake both in vitro, by human peripheral blood lymphocytes (PBLs) and cortical neuronal cells, and in vivo, by rabbit PBLs, owing to promotion of synthesis of the serotonin transporter. These findings offer a novel molecular mechanism for depression associated with stress. Accordingly, the elevated cortisol induced by stress increases serotonin uptake, under both rest and nerve stimulation, which is overtly expressed in symptoms of depression.
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It has been suggested that corticosteroid-serotonin interactions are central to the pathophysiology of depression. These interactions have been investigated in healthy and depressed humans, primarily using neuroendocrine techniques. To review the evidence regarding the nature of these interactions in healthy and depressed humans. Electronic searches were performed for relevant papers, employing MEDLINE and Web of Science. To focus the review, we selected only those articles involving (i) assessment of serotonergic function following experimental manipulation of the HPA axis in healthy volunteers; and (ii) assessment of both serotonergic and HPA axis function in clinically depressed subjects. Pre-treatment with hydrocortisone, both acutely and sub-acutely attenuates the GH response to GHRH in healthy subjects. This complicates the interpretation of 5-HT neuroendocrine studies employing GH output as a measure. In depression there is evidence that reduced availability of l-tryptophan impairs HPA axis feedback. There is also evidence that depressed and healthy subjects may adapt differently both to low tryptophan and hypercortisolaemic challenges. There is no consistent evidence of a simple relationship between HPA axis function and 5-HT function in depression. The putative reduction in central 5-HT function has not been shown to be a direct consequence of hypercortisolaemia. Rather, the 5-HT system and HPA axis have complex inter-relationships. Challenges to either system, such as stress or reduced dietary tryptophan, may perturb the other and subjects vulnerable to depression may fail to adapt to such challenges.
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Juvenile rainbow trout were isolated in individual compartments and allowed to acclimate for 1 week, during which they were fed commercial trout pellets. The feed was then replaced by pelleted feed supplemented with L-tryptophan (TRP) at two, four or eight times the concentration in the commercial feed. Fish were fed these supplemented feeds daily to satiety for 1 week, after which half of the fish were stressed, by lowering the water level for 2 h, while the remaining fish were left undisturbed. In undisturbed fish, supplementary dietary TRP resulted in slightly elevated plasma cortisol levels. In response to the stress, fish that had been fed control feed showed elevated plasma cortisol levels, but fish fed the TRP-supplemented feed displayed a significant reduction in this stress-induced elevation of plasma cortisol levels. Plasma and brain TRP levels were elevated in fish fed TRP-supplemented feed. TRP is the precursor of the monoamine neurotransmitter serotonin. Brain serotonergic activity was elevated by stress and also tended to be increased by elevated dietary TRP intake. The central serotonergic system is involved in the control of the hypothalamic-pituitary-interrenal axis, the action of serotonin being to stimulate or inhibit this neuroendocrine axis through different projections.
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To describe the 12-month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries. A representative random sample of non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older (n = 21425) were interviewed between January 2001 and August 2003. DSM-IV disorders were assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview (WMH-CIDI). Fourteen per cent reported a lifetime history of any mood disorder, 13.6% any anxiety disorder and 5.2% a lifetime history of any alcohol disorder. More than 6% reported any anxiety disorder, 4.2% any mood disorder, and 1.0% any alcohol disorder in the last year. Major depression and specific phobia were the most common single mental disorders. Women were twice as likely to suffer 12-month mood and anxiety disorders as men, while men were more likely to suffer alcohol abuse disorders. ESEMeD is the first study to highlight the magnitude of mental disorders in the six European countries studied. Mental disorders were frequent, more common in female, unemployed, disabled persons, or persons who were never married or previously married. Younger persons were also more likely to have mental disorders, indicating an early age of onset for mood, anxiety and alcohol disorders.
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Individual anthocyanin pigments and phenolic compounds were isolated, identified and quantified in six different sweet-cherry cultivars (Prunus avium L.) grown in Valle del Jerte area (Spain). An extractive-chromatographic method has been optimized for one-step extraction and simultaneous determination of all the studied components by HPLC/DAD-MS. The highest levels of phytochemicals were found in the autochthonous sweet-cherry cultivars that belong to the Protected Designation of Origin (POD) Cereza del Jerte. Van cultivar showed the lowest level of anthocyanin pigments and phenolic compounds. The most abundant anthocyanin pigment in all the studied cultivars was cyanidin-3-rutinoside (105 mg/100 g fresh weight (fwt) in Pico Negro sweet-cherry cultivar). The most abundant phenolic compound was the flavanol p-coumaroylquinic acid (130 mg/100 g fwt in Pico Negro sweet-cherry cultivar). In addition, chemical attributes (antioxidant activity, soluble solid content and pH) were also evaluated.
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Introduction The influence of repetitive transcranial magnetic stimulation (rTMS) on mood in healthy people is uncertain, as former studies show divergent results. Previous studies in healthy volunteers focused exclusively on the immediate effect of a single session of rTMS on mood. Aims The aim of this study was to analyse the influence on mood of a series of 9 High Frequency (HF) rTMS stimulations of the left dorsolateral prefrontal cortex (DLPFC). Methods 44 young healthy male volunteers were randomly assigned to receive 9 sessions of active HF-rTMS (n = 22) or sham rTMS (n = 22) over the left DLPFC. Each session in the active group consisted of 15 trains of 25 Hz starting with 100% of motor threshold. Sham stimulation was performed following the same protocol, but using a sham coil. The variables of interest were the Beck Depression Inventory (BDI) and Visual Analogue Scales (VAS) which quantified “mood”, “enjoyment” and “energy”. Results We found a significant reduction of the BDI score in the active group (GLM, p < 0.001) whereas no significant changes of the BDI score were caused by sham stimulation (GLM, p = 0.109). We did not find significant differences caused by active or sham stimulation in VAS scales except for the VAS labelled lively/gloomy immediately after stimulation. The active group was found to be more “gloomy” (p = 0.001). Conclusions Our data support the hypothesis that a 9-day long series of HF-rTMS of the left DLPFC improves mood, analysed by BDI in healthy young men.
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Background & aims: The relationship between diet and health has led to intense research into bioactive compounds in foods. The present study evaluated the effect of the consumption twice a day of a nutraceutical product made with Jerte Valley cherries (Cáceres, Extremadura, Spain) on nocturnal rest, urinary 6-sulfatoxymelatonin (aMT6-s), and urinary antioxidant capacity in young (20-30 yr-old), middle-aged (45-55 yr-old), and elderly (65-75 yr-old) subjects. Methods: In volunteers (n = 6 per age group), the temporal patterns of the individuals' activity and rest were recorded by actigraphic monitoring. For the quantification of aMT6-s, a commercial ELISA kit was used, and total antioxidant capacity was evaluated by means of a colorimetric assay kit. Results: The intake of the product increased significantly the Actual Sleep Time and Immobility, and decreased significantly the Total Nocturnal Activity in all subjects. Moreover, it increased significantly the urinary aMT6-s and antioxidant capacity in all subjects with respect to their basal values. Conclusions: The consumption of a nutraceutical product made with Jerte Valley cherries improves nocturnal rest and has an antioxidant effect in humans.
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There is now firm evidence that major depression is accompanied by increased baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of 24-h urinary cortisol (UC) excretion. Recently, there were some reports that fibromyalgia and post-traumatic stress disorder (PTSD), two disorders which show a significant amplitude of depressive symptoms, are associated with changes in the baseline activity of the HPA axis, such as low 24-h UC excretion. The aim of the present study was to examine 24-h UC excretion in fibromyalgia and PTSD patients compared to normal controls and patients with major depression. In the three patient groups, severity of depressive symptoms was measured by means of the Hamilton Depression Rating Scale (HDRS) score. Severity of fibromyalgia was measured using a dolorimetrically obtained myalgic score, and severity of PTSD was assessed by means of factor analytical scores computed on the items of the Composite International Diagnostic Interview (CIDI), PTSD Module. Patients with PTSD and major depression had significantly higher 24-h UC excretion than normal controls and fibromyalgia patients. At a threshold value of ≥240 μg/24 h, 80% of PTSD patients and 80% of depressed patients had increased 24-h UC excretion with a specificity of 100%. There were no significant differences in 24-h UC excretion either between fibromyalgia patients and normal controls, or between patients with major depression and PTSD patients. In the three patient groups, no significant correlations were found between 24-h UC excretion and The HDRS score. In fibromyalgia, no significant correlations were found between 24-h UC excretion and the myalgic score. In PTSD, no significant correlations were found between 24-h UC excretion and severity of either depression-avoidance or anxiety-arousal symptoms. In conclusion, this study found increased 24-h UC excretion in patients with PTSD comparable to that in patients with major depression, whereas in fibromyalgia no significant changes in 24-h UC were found.
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Seven varieties of cherry from the “Valle del Jerte” in the Spanish Region of Extremadura were analyzed quantitatively and qualitatively for their content of the amino acid tryptophan. Tryptophan is an essential amino acid in humans, being the precursor of the indolamines serotonin and melatonin which are biogenic amines with great importance in human sleep function. It is also of great importance in the synthesis of indole alkaloids in fruit. The objective of the present work was to determine the levels of tryptophan in “Valle del Jerte” (Extremadura, Spain) cherry varieties by high-performance liquid chromatography with fluorescence detection. Tryptophan was found in all seven varieties tested, the mean concentration being 54.48 ± 17.14g/ml. There were major differences between the varieties. The highest levels corresponded to the variety Navalinda and the lowest to Pico colorado. The tryptophan content of all the cherry varieties tested, in particular Navalinda, will have importance as the precursor for the biosynthesis of the biogenic amines. KeywordsTryptophan– Prunus avium –HPLC-FL–Cherry
Article
Melatonin functions as a free radical scavenger and controls the regulation of the sleep–wake cycle in mammals, while serotonin is the main intermediate in melatonin biosynthesis. In this paper, melatonin and serotonin have been detected and quantified for the first time in eight different sweet cherry cultivars using high performance liquid chromatography with mass spectrometry detection. The limits of detection of the proposed analytical method were 4.3ng/mL for melatonin and 3.0ng/mL for serotonin. An inverse relation between the contents of melatonin and serotonin was observed in the studied sweet cherry cultivars. The highest melatonin amounts were found in ‘Burlat’ sweet cherries (22.4±1.3ng/100g of fresh fruit), while the highest serotonin contents were found in the cultivar ‘Ambrunés’ (37.6±1.4ng/100g of fresh fruit). The results presented in this research allow us to know the amount of melatonin and serotonin bring to the diet.
Article
Middle age is associated with changes in circadian rhythms (e.g., alterations in the timing of the circadian wheel running rhythm) which resemble changes induced by selective destruction of the serotonergic input to the suprachiasmatic nucleus (SCN), the principal mammalian circadian pacemaker. We hypothesized that serotonergic neurotransmission in the SCN is decreased in middle-aged hamsters, as compared to young adults. This hypothesis was tested indirectly by investigating the effect of aging on two markers of serotonin neurotransmission, 5-HT1B receptors and serotonin reuptake sites, which are regulated by serotonin. Previous studies have shown that experimentally induced decreases in serotonergic neurotransmission increase 5-HT1B receptors but decrease serotonin reuptake sites. Quantitative autoradiography was conducted using []iodocyanopindolol ([]ICYP) and []paroxetine, selective radioligands for the 5-HT1B receptors and the serotonin reuptake sites, respectively. Consistent with the hypothesis, specific ([]ICYP binding was significantly elevated in the SCN of middle-aged hamsters, as compared to young hamsters. The results also showed that serotonin reuptake sites in the SCN were significantly increased in both middle-aged and old hamsters, as compared to young controls. This result could not have been caused by decreased serotonin release. Alternatively, increased serotonin reuptake, which would reduce serotonin levels in the synaptic cleft, may cause or contribute to the increase in 5-HT1B receptor binding in the SCN in middle aged animals. These results show that the SCN exhibits changes in serotonergic function during middle age, which has been characterized by changes in the expression of circadian rhythms. Because these changes occur during middle age, they probably reflect the aging process, rather than senescence or disease.
Article
The serotonin and circadian systems are principal regulatory networks of the brain. Each consists of a unique set of neurons that make widespread neural connections and a defined gene network of transcriptional regulators and signaling genes that subserve serotonergic and circadian function at the genetic level. These master regulatory networks of the brain are extensively intertwined, with reciprocal circuit connections, expression of key genetic elements for serotonin signaling in clock neurons and expression of key clock genes in serotonergic neurons. The reciprocal connections of the serotonin and circadian systems likely have importance for neurobehavioral disorders, as suggested by their convergent contribution to a similar range of mood disorders including seasonal affective disorder (SAD), bipolar disorder, and major depression, and as suggested by their overlapping relationship with the developmental disorder, autism spectrum disorder. Here we review the neuroanatomical and genetic basis for serotonin-circadian interactions in the brain, their potential relationship with neurobehavioral disorders, and recent work examining the effects on the circadian system of genetic perturbation of the serotonergic system as well as the molecular and behavioral effects of developmental imprinting of the circadian system with perinatal seasonal light cycles.
Article
The influence of repetitive transcranial magnetic stimulation (rTMS) on mood in healthy people is uncertain, as former studies show divergent results. Previous studies in healthy volunteers focused exclusively on the immediate effect of a single session of rTMS. In contrast the aim of this randomised sham-controlled study was to analyse the influence on mood of a series of 9 High Frequency (HF) rTMS stimulations of the left dorsolateral prefrontal cortex (DLPFC). 44 young healthy male volunteers were randomly assigned to receive 9 sessions of active HF-rTMS (n = 22) or sham rTMS (n = 22) over the left DLPFC. Each session in the active group consisted of 15 trains of 25 Hz starting with 100% of motor threshold. Sham stimulation was performed following the same protocol, but using a sham coil. The variables of interest were the Beck Depression Inventory (BDI) and six Visual Analogue Scales (VAS) which quantified "mood", "enjoyment" and "energy". We found a significant reduction of the BDI sum score in the active group (GLM, p < 0.001) whereas no significant changes of the BDI sum score were caused by sham stimulation (GLM, p = 0.109). The BDI single item analyses revealed within and between group differences supporting the modifying effect of rTMS on BDI. According to the employed VAS we did not find significant differences caused by active or sham stimulation in five of six VAS. In the VAS labelled lively/gloomy the active group was found to be more "gloomy" (p = 0.0111) immediately after stimulation. Our data show that a 9-day long series of HF-rTMS of the left DLPFC improves mood, analysed by BDI in healthy young men, whereas no significant long-term changes were found in VAS.
Article
Cherries, and in particular sweet cherries, are a nutritionally dense food rich in anthocyanins, quercetin, hydroxycinnamates, potassium, fiber, vitamin C, carotenoids, and melatonin. UV concentration, degree of ripeness, postharvest storage conditions, and processing, each can significantly alter the amounts of nutrients and bioactive components. These constituent nutrients and bioactive food components support the potential preventive health benefits of cherry intake in relation to cancer, cardiovascular disease, diabetes, inflammatory diseases, and Alzheimer's disease. Mechanistically, cherries exhibit relatively high antioxidant activity, low glycemic response, COX 1 and 2 enzyme inhibition, and other anti-carcinogenic effects in vitro and in animal experiments. Well-designed cherry feeding studies are needed to further substantiate any health benefits in humans.
Article
Appropriate signaling in the brain by the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) is critical in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, emotional arousal and cognitive performance. To date, few data exist on MR (and GR) expression in the brain of patients suffering from major depressive disorder (MDD). With the help of quantitative PCR we assessed MR and GR mRNA expression, including the splice variants MRα and MRβ, in tissue samples from the hippocampus, amygdala, inferior frontal gyrus, cingulate gyrus and nucleus accumbens. Expression levels were compared between tissue samples from six MDD patients and six non-depressed subjects. Relative to total GR, total MR mRNA expression was higher in hippocampus and lower in the amygdala, inferior frontal gyrus and nucleus accumbens. Both MRα and MRβ could be detected in all brain regions that were analyzed, although MRβ expression was low. Significantly lower expression levels (30-50%) were detected for MR or GR in hippocampal, inferior frontal gyrus and cingulate gyrus tissue from MDD patients (p < .05), while no differences were found in the amygdala or nucleus accumbens. The data show that both MRα and MRβ mRNA are expressed throughout the human limbic brain with highest expressions in the hippocampus. A decreased expression of corticosteroid receptors in specific brain regions of MDD patients could underlie HPA hyperactivity, mood and cognitive disturbances often observed in patients suffering from stress-related psychopathologies.
Article
The major neuroendocrine response mediating stress adaptation is activation of the hypothalamic pituitary adrenal axis, with stimulation of corticotropin releasing hormone (CRH) and vasopressin (VP) from parvocellular neurons of the hypothalamic paraventricular nucleus, leading to stimulation of pituitary ACTH secretion and increases in glucocorticoid secretion from the adrenal cortex. Basal production and transient increases during stress of glucocorticoids and its hypothalamic regulators are essential for neuronal plasticity and normal brain function. While activation of the HPA axis is essential for survival during stress, chronic exposure to stress hormones can predispose to psychological, metabolic and immune alterations. Thus, prompt termination of the stress response is essential to prevent negative effects of inappropriate levels of CRH and glucocorticoids. This review addresses the regulation of HPA axis activity with emphasis on the mechanisms of termination of CRH transcription, which is a critical step in this process. In addition, the actions by which glucocorticoids, CRH and VP can affect the aging process will be discussed.
Article
Melatonin, N-acetyl-5-methoxytryptamine, the major hormone produced by the pineal gland under the influence of the dark/light cycle, has been shown to have a large number of therapeutic possibilities. It has been utilized in several countries for circadian rhythm disorders, sleep disturbances, jet lag, and sleep-wake cycle disturbances in blind people, and shift workers. In our mechanism of act, the G(i) protein-coupled metabotropic melatonin receptors MT1 and MT2 are the primary mediators of the physiological actions of melatonin. This hormone plays an important role in the regulation of physiological and neuroendocrine functions, such as synchronization of seasonal reproductive rhythms and entrainment of circadian cycles. In addition to its chronobiological role, several pharmacological effects of melatonin have been reported in mammals including sedative, antioxidant, anxiolytic, antidepressant, anticonvulsant, and analgesic activities. There is some evidence from clinical trials that melatonin can be helpful in that event. Current trends of pharmacological functions of melatonin pointed out its use in the treatment of neurodegenerative and neoplastic diseases. These effects and uses of melatonin are mentioned but further confirmatory studies are needed in most of them.
Article
Tryptophan, serotonin, and melatonin, present in Jerte Valley cherries, participate in sleep regulation and exhibit antioxidant properties. The effect of the intake of seven different Jerte Valley cherry cultivars on the sleep-wake cycle, 6-sulfatoxymelatonin levels, and urinary total antioxidant capacity in middle-aged and elderly participants was evaluated. Volunteers were subjected to actigraphic monitoring to record and display the temporal patterns of their nocturnal activity and rest. 6-sulfatoxymelatonin and total antioxidant capacity were quantified by enzyme-linked immunosorbent assay and colorimetric assay kits, respectively. The intake of each of the cherry cultivars produced beneficial effects on actual sleep time, total nocturnal activity, assumed sleep, and immobility. Also, there were significant increases in 6-sulfatoxymelatonin levels and total antioxidant capacity in urine after the intake of each cultivar. These findings suggested that the intake of Jerte Valley cherries exerted positive effect on sleep and may be seen as a potential nutraceutical tool to counteract oxidation.
Article
Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS) disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role in control of behavior, cognition, mood, and early life programming of stress reactivity. Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, severe in 5-10% of cases. Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor patients, especially children and/or when administering high doses SGC.
Article
There is a central belief that depression is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in higher cortisol levels. However, results are inconsistent. To examine whether there is an association between depression and various cortisol indicators in a large cohort study. Design, Setting, and Data are from 1588 participants of the Netherlands Study of Depression and Anxiety who were recruited from the community, general practice care, and specialized mental health care. Three groups were compared: 308 control subjects without psychiatric disorders, 579 persons with remitted (no current) major depressive disorder (MDD), and 701 persons with a current MDD diagnosis, as assessed using the DSM-IV Composite International Diagnostic Interview. Cortisol levels were measured in 7 saliva samples to determine the 1-hour cortisol awakening response, evening cortisol levels, and cortisol suppression after a 0.5-mg dexamethasone suppression test. Both the remitted and current MDD groups showed a significantly higher cortisol awakening response compared with control subjects (effect size [Cohen d] range, 0.15-0.25). Evening cortisol levels were higher among the current MDD group at 10 pm but not at 11 pm. The postdexamethasone cortisol level did not differ between the MDD groups. Most depression characteristics (severity, chronicity, symptom profile, prior childhood trauma) were not associated with hypothalamic-pituitary-adrenal axis activity except for comorbid anxiety, which tended to be associated with a higher cortisol awakening response. The use of psychoactive medication was generally associated with lower cortisol levels and less cortisol suppression after dexamethasone ingestion. This large cohort study shows significant, although modest, associations between MDD and specific hypothalamic-pituitary-adrenal axis indicators. Because a higher cortisol awakening response was observed among both subjects with current MDD and subjects with remitted MDD, this may be indicative of an increased biological vulnerability for depression.
Article
It is suggested that stress particularly in subjects with high cognitive reactivity (CR), a psychological vulnerability marker of depression, may increase or even induce serotonergic vulnerability, which in turn may lead to reduced serotonin (5-HT) function, decreased stress coping and an increased risk to develop depressive symptoms. The aim of the present study was to investigate the beneficial effects of 5-HT augmentation through a tryptophan-rich hydrolyzed protein (HP) on mood and stress coping in subjects with high and low CR. We hypothesized that subjects with high CR are more responsive to the beneficial effects of HP than subjects with low CR particularly after acute stress exposure. In a double-blind, crossover study, participants' mood and cortisol was assessed before and after acute stress exposure either following intake of HP or a standard casein protein (CP) as control condition. HP significantly increased positive mood in all subjects and dampened the cortisol response to acute stress. No differences were found between high and low CR subjects. To conclude, because dietary treatment with HP has beneficial effects on mood and physiological stress coping in both high and low CR subjects, HP may be a good dietary method for augmenting brain TRP and 5-HT and thus 5-HT linked stress resilience.
Article
The notion that chewing gum may relieve stress was investigated in a controlled setting. A multi-tasking framework which reliably evokes stress and also includes performance measures was used to induce acute stress in the laboratory. Using a randomised crossover design forty participants (mean age 21.98 years) performed on the multi-tasking framework at two intensities (on separate days) both while chewing and not chewing. Order of workload intensity and chewing conditions were counterbalanced. Before and after undergoing the platform participants completed the state portion of the State-Trait Anxiety Inventory, Bond-Lader visual analogue mood scales, a single Stress Visual Analogue Scale and provided saliva samples for cortisol measurement. Baseline measures showed that both levels of the multi-tasking framework were effective in significantly reducing self-rated alertness, calmness and contentment while increasing self-rated stress and state anxiety. Cortisol levels fell during both levels of the stressor during the morning, reflecting the predominance of a.m. diurnal changes, but this effect was reversed in the afternoon which may reflect a measurable stress response. Pre-post stressor changes (Delta) for each measure at baseline were subtracted from Delta scores under chewing and no chewing conditions. During both levels of stress the chewing gum condition was associated with significantly better alertness and reduced state anxiety, stress and salivary cortisol. Overall performance on the framework was also significantly better in the chewing condition. The mechanisms underlying these effects are unknown but may involve improved cerebral blood flow and/or effects secondary to performance improvement during gum chewing.
Article
Discovered and crystallized over sixty years ago, serotonin's important functions in the brain and body were identified over the ensuing years by neurochemical, physiological and pharmacological investigations. This 2008 M. Rapport Memorial Serotonin Review focuses on some of the most recent discoveries involving serotonin that are based on genetic methodologies. These include examples of the consequences that result from direct serotonergic gene manipulation (gene deletion or overexpression) in mice and other species; an evaluation of some phenotypes related to functional human serotonergic gene variants, particularly in SLC6A4, the serotonin transporter gene; and finally, a consideration of the pharmacogenomics of serotonergic drugs with respect to both their therapeutic actions and side effects. The serotonin transporter (SERT) has been the most comprehensively studied of the serotonin system molecular components, and will be the primary focus of this review. We provide in-depth examples of gene-based discoveries primarily related to SLC6A4 that have clarified serotonin's many important homeostatic functions in humans, non-human primates, mice and other species.
Article
Studies over the last 40 years have demonstrated that hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent biological findings in major depression psychiatry, but the mechanisms underlying this abnormality are still unclear.
Article
The pineal and pituitary-adrenocortical secretions play an important role in adaptive responses of the organism acting as coordinating signals for both several biological rhythms and multiple neuroendocrine and metabolic functions. The more relevant neuroendocrine changes occurring with ageing affect the secretion of melatonin and of corticosteroids. These changes may be clearly appreciated by the study of their circadian rhythmicity. The circadian profile of plasma melatonin was clearly flattened in elderly subjects and even more in old individuals with dementia. Indeed, the impairment of melatonin signal occurring in aging was related either to age itself or to the cognitive performances of subjects. The biosynthetic dissociation between glucocorticoids and androgen secretion is responsible for the selective impairment of androgens, such as DHEA and DHEA-S, by comparison to cortisol. Due to the opposite effects of the two kinds of corticosteroids either in the periphery and in the CNS, the imbalance between glucocorticoids and androgens, well demonstrated by the evaluation of the cortisol/DHEA-S molar ratio, may be responsible for the occurrence in the CNS of a more neurotoxic steroidal milieu, already present in clinically healthy elderly subjects and especially in patients with dementia. The effects of that steroidal milieu are more prominent at the level of the hippocampal-limbic structure, involved both in the modulation of endocrine structures, such as the HPA axis, and in the control of cognitive, behavioral and affective functions.
Article
Open field behavior and age-related changes in anterior pituitary corticotropin-releasing hormone (CRH) receptors, as well as plasma ACTH levels, were measured in two inbred rat strains. The strains utilized were Wistar Kyoto (WKY) and Brown-Norway (BN), the former characterized by shorter life-span and hyper-reactivity to stressors as compared to the latter. Behaviorally, WKY rats showed hyper-responsivity to a novel environment as indicated by their delay in entering the open field, increased grooming, reduced rearing, and reduced locomotion. These strain-dependent behavioral differences were not affected by aging. The binding capacity of CRH receptors was similar in both strains and Bmax values were decreased (25-27%) with aging, with no changes in Kd values. In contrast, plasma ACTH levels were 67% higher in WKY than in BN rats but did not change with aging. Thus, despite pituitary CRH receptor down regulation, plasma ACTH levels following decapitation were sustained during aging. This suggests the presence of some compensatory factors in the hypothalamic-pituitary axis regulation which sustain ACTH response during aging. Furthermore, the findings indicate that higher plasma ACTH levels and hyper-reactivity to a novel environment are inversely correlated with longevity in the rat.
Article
Synopsis Visual Analogue Scales (VAS) provide a simple technique for measuring subjective experience. They have been established as valid and reliable in a range of clinical and research applications, although there is also evidence of increased error and decreased sensitivity when used some subject groups. Decisions concerned with the choice of scoring interval, experimental design, and statistical analysis for VAS have in some instances been based on convention, assumption and convenience, highlighting the need for more comprehensive assessment of individual scales if this versatile and sensitive measurement technique is to be used to full advantage.
Article
There is now firm evidence that major depression is accompanied by increased baseline activity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of 24-h urinary cortisol (UC) excretion. Recently, there were some reports that fibromyalgia and post-traumatic stress disorder (PTSD), two disorders which show a significant amplitude of depressive symptoms, are associated with changes in the baseline activity of the HPA axis, such as low 24-h UC excretion. The aim of the present study was to examine 24-h UC excretion in fibromyalgia and PTSD patients compared to normal controls and patients with major depression. In the three patient groups, severity of depressive symptoms was measured by means of the Hamilton Depression Rating Scale (HDRS) score. Severity of fibromyalgia was measured using a dolorimetrically obtained myalgic score, and severity of PTSD was assessed by means of factor analytical scores computed on the items of the Composite International Diagnostic Interview (CIDI), PTSD Module. Patients with PTSD and major depression had significantly higher 24-h UC excretion than normal controls and fibromyalgia patients. At a threshold value of > or = 240 micrograms/24 h, 80% of PTSD patients and 80% of depressed patients had increased 24 h UC excretion with a specificity of 100%. There were no significant differences in 24-h UC excretion either between fibromyalgia patients and normal controls, or between patients with major depression and PTSD patients. In the three patient groups, no significant correlations were found between 24-h UC excretion and the HDRS score. In fibromyalgia, no significant correlations were found between 24-h UC excretion and the myalgic score. In PTSD, no significant correlations were found between 24-h UC excretion and severity of either depression-avoidance or anxiety-arousal symptoms. In conclusion, this study found increased 24-h UC excretion in patients with PTSD comparable to that in patients with major depression, whereas in fibromyalgia no significant changes in 24-h UC were found.
Article
Middle age is associated with changes in circadian rhythms (e.g., alterations in the timing of the circadian wheel running rhythm) which resemble changes induced by selective destruction of the serotonergic input to the suprachiasmatic nucleus (SCN), the principal mammalian circadian pacemaker. We hypothesized that serotonergic neurotransmission in the SCN is decreased in middle-aged hamsters, as compared to young adults. This hypothesis was tested indirectly by investigating the effect of aging on two markers of serotonin neurotransmission, 5-HT(1B) receptors and serotonin reuptake sites, which are regulated by serotonin. Previous studies have shown that experimentally induced decreases in serotonergic neurotransmission increase 5-HT(1B) receptors but decrease serotonin reuptake sites. Quantitative autoradiography was conducted using [125I]iodocyanopindolol ([125I]ICYP) and [3H]paroxetine, selective radioligands for the 5-HT(1B) receptors and the serotonin reuptake sites, respectively. Consistent with the hypothesis, specific ([125I]ICYP binding was significantly elevated in the SCN of middle-aged hamsters, as compared to young hamsters. The results also showed that serotonin reuptake sites in the SCN were significantly increased in both middle-aged and old hamsters, as compared to young controls. This result could not have been caused by decreased serotonin release. Alternatively, increased serotonin reuptake, which would reduce serotonin levels in the synaptic cleft, may cause or contribute to the increase in 5-HT(1B) receptor binding in the SCN in middle aged animals. These results show that the SCN exhibits changes in serotonergic function during middle age, which has been characterized by changes in the expression of circadian rhythms. Because these changes occur during middle age, they probably reflect the aging process, rather than senescence or disease.
Article
The method for measuring serotonin synthesis in human brain uses [11C]alpha-methyl-L-tryptophan as a tracer and positron emission tomography. The alpha-methyl-L-tryptophan is converted to alpha-methylserotonin, which is not a substrate for monoamine oxidase and therefore accumulates in the brain. In a pilot study published recently, rates of serotonin synthesis were found to be higher in men than in women. This was due to the lower plasma free tryptophan in the women under the experimental conditions used, and does not necessarily reflect the situation in all circumstances. Acute tryptophan depletion lowered brain serotonin synthesis by 90% or more. Patients with borderline personality disorder, who exhibit emotional lability and impulsivity, may have lower brain serotonin synthesis rates than healthy controls.
Article
This study investigated the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left prefrontal cortex (LPFC) on mood in a sham-controlled crossover design. Twenty-five healthy male subjects received HF-rTMS of the LPFC in real and sham conditions. Forty trains (frequency 20 Hz, stimulation intensity 100% of individual motor threshold, train duration 2 s, intertrain interval 28 s) were applied in each session. Mood change from baseline was measured with five visual analog scales (VAS) for sadness, anxiety, happiness, tiredness and pain/discomfort. We were unable to demonstrate significant mood changes from baseline on visual analog scales after either sham or real stimulation of LPFC. There is insufficient evidence to support the general conclusion that HF-rTMS of LPFC has mood effects in healthy volunteers. Future studies should be sham-controlled, have larger sample sizes, and strictly stimulate one single region per session in order to exclude interaction effects with the previous stimulation.
Article
Key proteins regulating serotonergic activity, specifically the serotonin transporter and 5-HT(1A) receptor, were examined in the midbrain raphe nuclei of young (3-4 months) and old (17-19 months) hamsters (N=7-10/group). An age-related decrease in the maximal density of serotonin transporter sites labelled with [(3)H]paroxetine (fmol/mg protein, Old: 396+/-13; Young: 487+/-27) was observed in the dorsal raphe nucleus (DRN) but not the median raphe nucleus (MRN), without affecting the affinity of [(3)H]paroxetine. In the DRN and MRN, the stimulation of [(35)S]GTP gamma S binding by the 5-HT(1A) receptor agonist 8-OH-DPAT, or the number of 5-HT(1A) receptor sites labeled with [(3)H] MPPF, was not different in old versus young animals. Thus in the DRN, aging decreased serotonin transporter sites without changing 5-HT(1A) receptor activation of G proteins or 5-HT(1A) receptor density. In the CA(1) region of hippocampus, 8-OH-DPAT-stimulated [(35)S]GTP gamma S binding was increased in the older animals (% above basal, Old: 141+/-21; Young: 81+/-17) without changing specific [(3)H] MPPF binding sites, suggesting that the capacity of 5-HT(1A) receptors to activate G proteins is enhanced. Aging also appears to enhance this capacity in the dentate gyrus, because this region exhibited a constant level of 8-OH-DPAT-stimulated [(35)S]GTP gamma S binding in spite of an age-related decrease in the number of [(3)H] MPPF binding sites (fmol/mg protein, Old: 203+/-21; Young: 429+/-51).
Article
The aim of the study was to compare the activity of gonadal hormones and serotonergic system in premenopausal women with or without depression in relation to clinical and hormonal indices of menopause. The sample included 60 women with single or recurrent major depressive episode with disease onset after 38 year of age (mean age 43 years) and 30 healthy control women (mean age 41 years). Psychometric assessment was done by means of 17-item Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI). The presence of menopausal symptoms was assessed by Kupperman Menopause Index (KMI). Activity of gonadal axis was measured by estimating estradiol and follicle-stimulating hormone (FSH) levels. For the assessment of central serotonergic activity, the D-fenfluramine test was used. Depressed women had higher intensity of menopausal symptoms, significantly lower concentration of estradiol, and higher of FSH than control women. Severity of depression correlated with both the intensity of menopausal symptoms and the concentration of FSH. Baseline levels of prolactin were not different in both groups. Following D-fenfluramine administration, there was a significant increase in prolactin concentration in healthy women and a transient decrease in depressed ones. Baseline cortisol level was significantly higher in depressed women and correlated with the severity of depression. D-Fenfluramine challenge caused a significant increase of cortisol secretion in healthy women and a significant decrease in depressed ones. A relationship was observed between baseline estradiol, FSH, and cortisol level and the magnitude of prolactin and cortisol response to D-fenfluramine. In premenopausal women, a high degree of interconnections was demonstrated between symptoms of depression and symptoms of menopause on both clinical and hormonal level. The results confirm the association between depressive and menopausal symptoms as well as an involvement of gonadal hormones, cortisol, and serotonin deficiency in this process.
Article
In order to assess the effects of the onset and chronicity of maternal depression on neonatal physiology, eighty pregnant women were assessed for depression during mid-pregnancy (M gestational age = 25.9 weeks) and shortly after delivery. The women were classified as reporting depressive symptoms 1) only during the prepartum assessment; 2) only during the postpartum assessment; 3) during both the prepartum and postpartum assessments; or 4) reporting no depressive symptoms at either the prepartum or the postpartum assessment. Maternal mood and biochemistry were assessed during pregnancy, and the EEG and biochemical characteristics of their 1-week-old infants were assessed shortly after birth. As predicted, the newborns of the mothers with prepartum and postpartum depressive symptoms had elevated cortisol and norepinephrine levels, lower dopamine levels, and greater relative right frontal EEG asymmetry. The infants in the prepartum group also showed greater relative right frontal EEG asymmetry and higher norepinephrine levels. These data suggest that effects on newborn physiology depend more on prepartum than postpartum maternal depression but may also depend on the duration of the depressive symptoms.
Article
The intake of 400-600 g/d of fruits and vegetables is associated with reduced incidence of many common forms of cancer, and diets rich in plant foods are also associated with a reduced risk of heart disease and many chronic diseases of ageing. These foods contain phytochemicals that have anti-cancer and anti-inflammatory properties which confer many health benefits. Many phytochemicals are colourful, and recommending a wide array of colourful fruits and vegetables is an easy way to communicate increased diversity of intake to the consumer. For example, red foods contain lycopene, the pigment in tomatoes, which is localized in the prostate gland and may be involved in maintaining prostate health, and which has also been linked with a decreased risk of cardiovascular disease. Green foods, including broccoli, Brussels sprouts and kale, contain glucosinolates which have also been associated with a decreased risk of cancer. Garlic and other white-green foods in the onion family contain allyl sulphides which may inhibit cancer cell growth. Other bioactive substances in green tea and soybeans have health benefits as well. Consumers are advised to ingest one serving of each of the seven colour groups daily, putting this recommendation within the United States National Cancer Institute and American Institute for Cancer Research guidelines of five to nine servings per day. Grouping plant foods by colour provides simplification, but it is also important as a method to help consumers make wise food choices and promote health.
Article
Aging involves neuronal and synaptic loss, and maintenance of function depends on adaptations in cellular responsiveness. We studied olfactory bulbectomy (OBX), a model that recapitulates monoaminergic dysfunction in depression, in 10-week vs 19-month-old rats, and evaluated 5HT (5-hydroxytryptamine, serotonin) mechanisms. OBX elicited little change in 5HT1A receptors in the cerebral cortex or striatum of either age group. In contrast, 5HT2 receptors showed disparate effects, with a decrease in the cerebral cortex of young OBX but not aging OBX rats, whereas the latter group showed a selective decrease in striatal 5HT2 receptors. Greater differences were apparent for 5HT-mediated cell signaling, assessed for the adenylyl cyclase (AC) cascade. In young animals, 5HT had a stimulatory effect on AC that was unaltered by OBX. However, in aging animals, the pattern of 5HT responses showed marked alterations in response to OBX: under basal conditions, stimulatory effects were enhanced but when AC was activated with forskolin, 5HT became markedly inhibitory in the striatum of aged OBX animals. Assessment of the relative AC responses to two direct stimulants that act on different epitopes of the enzyme, forskolin and Mn2+, pointed to a shift in the AC isoform and/or its ability to associate with G-proteins as the mechanism underlying the age-related differences for OBX effects. These data indicate that there are biological distinctions in the response of 5HT systems to OBX in young adult vs aging animals, which, if present in geriatric depression, could provide a mechanistic basis for differences in responses to antidepressants that act on 5HT.