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A Fraxinus excelsior L. seeds/fruits extract benefits glucose homeostasis and adiposity related markers in elderly overweight/obese subjects: A longitudinal, randomized, crossover, double-blind, placebo-controlled nutritional intervention study

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... Indeed, the effects of a single dose of Glucevia ® have been evaluated on postprandial glycaemia and insulin secretion in nondiabetic healthy individuals and exhibited a significant reduction in the mean area under the plasma time-concentration curve (AUC) for glucose levels without significantly altering insulin secretion [4]. This natural insulin sensitizer property has been checked in a randomized, crossover, double-blind and placebo-controlled 7-week nutritional intervention in non-diabetic overweight/obese healthy subjects [5]. Three weeks Glucevia ® administration resulted in a 2-h blood glucose values reduction following an oral glucose tolerance test (OGTT), while no significant changes were found in the control period. ...
... The standard chow (PanLab, Barcelona) had the following composition: 14.3% protein, 4.0% fat, 48.0% carbohydrate, 4.1% crude fiber, 18.0% neutral detergent fiber and 4.7% ash; energy density, 2.9 kcal/g). The dose correspond to an initial 170 mg of extract per kg body weight per day, approximately 13,7 mg per kg body weight HED, similar to the dose used during the clinical trials conducted [4,5]. Dietary intervention lasted for 28 weeks. ...
... difference between the control and Glucevia® groups control group. In non-diabetic overweight/obese healthy subjects, the administration of Glucevia ® for 3 weeks resulted in fat mass decrease and an improvement of adiposity related markers as adiponectin:leptin ratio, but no change was observed for plasmatic triglycerides between groups [5]. Extract supplementation over a long period should be required to lead to an improvement of plasma triglycerides level. ...
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Background: Non-alcoholic fatty liver is recognized as one of harmful consequences of the metabolic syndrome and hepatocytes steatosis is well connected with loss of insulin sensitivity, impaired glucose tolerance and can lead to impaired fasting glucose and type2 diabetes mellitus. Fraxinus excelsior L. seed extract has been used as traditional folk medicine by Mediterranean population and Glucevia®, a natural extract of Fraxinus excelsior L. derived from seeds/fruits of the plant and standardized to 10% Nuzhenide and GI3, has been previously reported to regulate glucose homeostasis in healthy overweight people. Methods: The effect of seven-month administration of Glucevia® on liver parameters was investigated in a diabetic mouse strain (BKS ++Lepr db (db/db)). The severity of fatty change and grading of hepatic steatosis were determined by estimating the fat hepatocytes contain in animals fed with a control diet or with a control diet supplemented with 0.07 % (w/w) of the extract. Results: Glucevia® was shown to significantly reduce fatty liver in diabetics mice (-54%; p<0.05). A concomitant improvement in alkaline phosphatase (ALP) levels and in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio were observed between groups (p<0.05). A significant decrease in insulin plasma level (-22%; p<0.05) was measured in Glucevia® group leading to an improvement of HOMA-IR between groups (p<0.001) while no significant change of fasting blood glucose was observed between group. Conclusion: The results observed supports the potential hepatoprotective function of Glucevia®, which seems to prevent fatty liver formation in type 2 diabetes mice model
... These beneficial effects were observed with doses ranging between 100 and 200 mg per kg of body weight per day, corresponding to a Human Equivalent Dose (HED = animal dose in mg/kgˆ(animal weight in kg/human weight in kg) 0.33 ) of~1.0 g/day for a 60 kg person. Notably, the acute administration of 1 g of the Fraxinus extract first evidenced the reduction of glycemia in healthy humans [6] and the daily administration of 1 g of the Fraxinus extract for three weeks in elderly overweight/obese subjects resulted in a significantly lower incremental glucose area under the curve, lower 2 h blood glucose levels and modified levels of fructosamine and adiponectin:leptin ratio [7]. This Fraxinus extract, prepared using a patented extraction protocol [8], was reported to contain a standardized amount (~10%) of the secoiridoid glycoside nuzhenide (CAS registry number 60037-39-0) plus the dimeric secoiridoid glycoside GL3 (glycosylated esters of tyrosol and elenolic acid; CAS registry number 39011-92-2) ( Figure 1). ...
... These beneficial effects were observed with doses ranging between 100 and 200 mg per kg of body weight per day, corresponding to a Human Equivalent Dose (HED = animal dose in mg/kg × (animal weight in kg/human weight in kg) 0.33 ) of ~1.0 g/day for a 60 kg person. Notably, the acute administration of 1 g of the Fraxinus extract first evidenced the reduction of glycemia in healthy humans [6] and the daily administration of 1 g of the Fraxinus extract for three weeks in elderly overweight/obese subjects resulted in a significantly lower incremental glucose area under the curve, lower 2 h blood glucose levels and modified levels of fructosamine and adiponectin:leptin ratio [7]. This Fraxinus extract, prepared using a patented extraction protocol [8], was reported to contain a standardized amount (~10%) of the secoiridoid glycoside nuzhenide (CAS registry number 60037-39-0) plus the dimeric secoiridoid glycoside GL3 (glycosylated esters of tyrosol and elenolic acid; CAS registry number 39011-92-2) ( Figure 1). ...
... Generally, the translation of beneficial metabolic effects of dietary polyphenols from pre-clinical animal models to human intervention studies has shown inconsistent evidences possibly and partly due to the variability in the metabolism and uptake of these compounds [28]. In the case of the Fraxinus extract which has been shown to moderate fasting blood glucose (FBG) and insulin levels in rodent models of obesity, intervention in obese and overweight subjects resulted in 2 h-blood glucose improvement following an oral glucose tolerance test but not significant differences for FBG and insulin levels were observed [7]. Small sample size and variability in the capacity of each volunteer to absorb and metabolize the secoiridoids from the Fraxinus extract may contribute to explain the lack of current significant mean effects in humans for those two metabolic biomarkers. ...
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The bark, seeds, fruits and leaves of the genus Fraxinus (Oleaceae) which contain a wide range of phytochemicals, mostly secoiridoid glucosides, have been widely used in folk medicine against a number of ailments, yet little is known about the metabolism and uptake of the major Fraxinus components. The aim of this work was to advance in the knowledge on the bioavailability of the secoiridoids present in a Fraxinus angustifolia Vahl seed/fruit extract using both targeted and untargeted metabolomic analyses. Plasma and urine samples from nine healthy volunteers were taken at specific time intervals following the intake of the extract and analyzed by UPLC-ESI-QTOF. Predicted metabolites such as tyrosol and ligstroside-aglycone glucuronides and sulfates were detected at low intensity. These compounds reached peak plasma levels 2 h after the intake and exhibited high variability among the participants. The ligstroside-aglycone conjugates may be considered as potential biomarkers of the Fraxinus secoiridoids intake. Using the untargeted approach we additionally detected phenolic conjugates identified as ferulic acid and caffeic acid sulfates, as well as hydroxybenzyl and hydroxyphenylacetaldehyde sulfate derivatives which support further metabolism of the secoiridoids by phase I and (or) microbial enzymes. Overall, the results of this study suggest low uptake of intact secoiridoids from a Fraxinus angustifolia Vahl extract in healthy human volunteers and metabolic conversion by esterases, glycosidases, and phase II sulfo- and glucuronosyl transferases to form smaller conjugated derivatives.
... Other rich-phenols medicinal plants such as rosemary (Rosmarinus officinalis L) extract (Labban et al. 2014), licorice flavonoid oil (Tominaga et al. 2009), Fraxinus excelsior L. (Zulet et al. 2014) and cinnamon extract (Sartorius et al. 2014) showed positive effect in lipid and body fat profile. Concretely, a diet supplementation with 10 g of rosemary leaf extract reduced LDL-C and increased HDL-C in 48 participants and after 8 weeks of intervention (Labban et al. 2014). ...
... In this case, hydrophobic flavonoids from Glycyrrhiza glabra could increase energy expenditure by enhancing beta-oxidation and inhibits lipogenesis resulting in reduction in body fat and body weight (Tominaga et al. 2009). The intake of 1000 mg of a commercial extract of F. excelsior L. (Glucevia Ò ) which provided 4 mg/day of coumarins, allowed a significant reduction of the body fat mass and the and the waist:hip ratio in 22 non-diabetic overweight/obese healthy subjects (50-80 years) (Zulet et al. 2014). Despite several phenolic compounds families have been described in this matrix i.e. secoiridoid glucosides, coumarins, flavonoids, phenylethanoids, benzoquinones, indole derivatives, and simple phenolic compounds (Sanz et al. 2012), the lack of enough clinical trials, make difficult attributing it bioactivity to phenolic compounds. ...
Article
Prevalence of obesity worldwide has reached pandemic proportions. Despite the increasing evidence in the implication of phenolic compounds in obesity management, the real effect is not completely understood. The available in vitro and in vivo studies have demonstrated the implication of phenolic compounds in: lowering food intake, decreasing lipogenesis, increasing lipolysis, stimulating fatty acids β-oxidation, inhibiting adipocyte differentiation and growth, attenuating inflammatory responses and suppress oxidative stress. This review encompasses the most recent evidence in the anti-obesity effect of phenolic compounds from plants to different nutraceuticals and functional foods based on the in vitro, in vivo and clinical studies. For that, this review has been focused on popular plant-based products highly consumed today such as cocoa, cinnamon, and olive oil, beverages such as red wine, tea (green, white and black tea) and Hibiscus sabdariffa L. tea, among others.
... Nevertheless, some MH has been reported not to influence IR. This is the case for Marjoram tea [146], the hydroalcoholic extract of Juglans regia leaves [147], the extract from Fraxinus excelsior L. seeds and fruits [148], garlic extract [149], and Bee propolis [150]. Lastly, clinically significant antihyperglycemic effects have been ascribed to over 400 MH [118,[151][152][153]. Robust evidence supports the effects of several parameters such as fasting blood glucose (FBG), postprandial glucose (PPG), and glycated haemoglobin (HbA1c) [154]. ...
... This preparation includes 10 different MH, notably, Astragali radix, Coptidis rhizoma, Panax ginseng, Lycium barbarum, Galla chinensis and Corni fructus. Other concoctions, such as Tangyiping granules [145], Jinlida [170], Qingre Yangyin recipe [138], cinnamon [171], Yiqi Huaju recipe [133], Sancai powder [134] and Fraxinus excelsior [148,172] have also been reported to be beneficial for PPG. Nonetheless, according to the Diabetes Canada Clinical Practice Guidelines Expert Committee [173], only a few MH have been described to reduce HbA1c even by 0.5% in RCT with a duration of at least 3 months. ...
Article
At present, the pathologic spectrum of obesity-insulin resistance (IR)-diabetes mellitus (DM) represents not only a pressing matter in public health but also a paramount object of study in biomedical research, as they constitute major risk factors for cardiovascular disease (CVD), and other chronic non-communicable diseases (NCD). Phytotherapy, the use of medicinal herbs (MH) with treatment purposes, offers a wide array of opportunities for innovation in the management of these disorders; mainly as pharmacological research on small molecules accumulates. Several MH have displayed varied mechanisms of action relevant to the pathogenesis of obesity, IR and DM, including immunological and endocrine modulation, reduction of inflammation and oxidative stress (OS), regulation of appetite, thermogenesis and energy homeostasis, sensitisation to insulin function and potentiation of insulin release, among many others. However, the clinical correlates of these molecular phenomena remain relatively uncertain, with only a handful of MH boasting convincing clinical evidence in this regard. This review comprises an exploration of currently available preclinical and clinical research on the role of MH in the management of obesity, IR, and DM.
... In obese mice, myricetin has shown to reduce hyperleptinemia and to induce insulin action, by promoting insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI 3-kinase) activation, and translocation of glucose transporter subtype 4 (GLUT4) to the plasma membrane [63] . In humans, curcumin and fraxin, an o-methylated coumarin glucoside, have been demonstrated to reduce hyperleptinemia in both overweight and obese humans [64] . These clinical trials showed that leptin and RBP4 levels were decreased with the addition of both bioactive food components. ...
Article
In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.
... After a 12-week consumption of Yerba Mat e (Ilex paraguariensis) capsules, 30 obese participants had a decrease in body fat mass, body fat percentage, and waist-hip ratio . In another trial, 22 obese patients were randomized to take Fraxinus excelsior L. seed/fruit extract capsules or placebo capsules for 3 weeks with one-week washout period, and the results displayed a significant increase in the ratio of adiponectin to leptin and a decrease in the fat mass (Zulet et al. 2014). Moreover, 56 overweight adults were given fruit and vegetable juices or placebo capsules daily for 8 weeks, with decreased obesity-related systemic inflammation, total cholesterol, low-density lipoprotein cholesterol, and TNF-a in the plasma (Williams et al. 2017). ...
Article
In recent years, obesity has become a global public health issue. It is closely associated with the occurrence of several chronic diseases, such as diabetes and cardiovascular diseases. Some edible and medicinal plants show anti-obesity activity, such as fruits, vegetables, spices, legumes, edible flowers, mushrooms, and medicinal plants. Numerous studies have indicated that these plants are potential candidates for the prevention and management of obesity. The major anti-obesity mechanisms of plants include suppressing appetite, reducing the absorption of lipids and carbohydrates, inhibiting adipogenesis and lipogenesis, regulating lipid metabolism, increasing energy expenditure, regulating gut microbiota, and improving obesity-related inflammation. In this review, the anti-obesity activity of edible and medicinal plants was summarized based on epidemiological, experimental, and clinical studies, with related mechanisms discussed, which provided the basis for the research and development of slimming products. Further studies should focus on the exploration of safer plants with anti-obesity activity and the identification of specific anti-obesity mechanisms.
... Similarly, a combined exercise and diet intervention (soy protein supplement) over 12 wk, but not exercise alone, led to significant reductions in fructosamine and FG versus baseline (no between-treatment statistical comparisons reported) (37). Serum fructosamine was significantly lower after 3 wk of a Fraxinus excelsior (common ash) extract supplement, relative to a 3 g/d maltodextrin control (38). Relative to the control, the supplement exposure also significantly reduced 2-h PPG responses in a glucose challenge test, though not FG. ...
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There is considerable interest in dietary and other approaches to maintaining blood glucose concentrations within the normal range and minimizing exposure to postprandial hyperglycemic excursions. The accepted marker to evaluate the sustained maintenance of normal blood glucose concentrations is glycated hemoglobin A1c (HbA1c). However, although this is used in clinical practice to monitor glycemic control in patients with diabetes, it has a number of drawbacks as a marker of efficacy of dietary interventions that might beneficially affect glycemic control in people without diabetes. Other markers that reflect shorter-term glycemic exposures have been studied and proposed, but consensus on the use and relevance of these markers is lacking. We have carried out a systematic search for studies that have tested the responsiveness of 6 possible alternatives to HbA1c as markers of sustained variation in glycemic exposures and thus their potential applicability for use in dietary intervention trials in subjects without diabetes: 1,5-anhydroglucitol (1,5-AG), dicarbonyl stress, fructosamine, glycated albumin (GA), advanced glycated end products (AGEs), and metabolomic profiles. The results suggest that GA may be the most promising for this purpose, but values may be confounded by effects of fat mass. 1,5-AG and fructosamine are probably not sensitive enough to the range of variation in glycemic exposures observed in healthy individuals. Use of measures based on dicarbonyls, AGEs, or metabolomic profiles would require further research into possible specific molecular species of interest. At present, none of the markers considered here is sufficiently validated and sensitive for routine use in substantiating the effects of sustained variation in dietary glycemic exposures in people without diabetes.
... As one of the most prominent hydroxy coumarins, 7-hydroxy-6,8-dimethoxy coumarin [isofraxidin, IF] along with other related lead compounds (Figure 1), such as 8-hydroxy-6,7-dimethoxycoumarin [fraxidin], 7, 8-dihydroxy-6-methoxycoumarin [fraxetin], 5, 6-dihydroxy-7-methoxycoumarin [isofraxetin], 6-hydroxy-5, 7-dimethoxycoumarin [fraxinol], and 7-hydroxy-6-methoxycoumarin 8-glucoside [fraxin] are natural-based multi-targets, isolated from several phytomedicines especially in Acantopanax, Achillea, Artemisia, and Fraxinus genera. IF and related compounds attenuate multiple destructive signaling mediators and therapeutic targets in some diseases [19][20][21][22][23][24]. In this regard, IF has shown several biological and pharmacological activities including antioxidant [25], cardioprotective [26], weight loss [27], anti-osteoarthritis [28], antimalarial [29], and neuroprotective [30] effects, with promising anticancer and anti-inflammatory effects. ...
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Article
Isofraxidin (7-hydroxy-6, 8-dimethoxy coumarin) (IF) is a hydroxy coumarin with several biological and pharmacological activities. The plant kingdom is of the most prominent sources of IF, which, among them, Eleutherococcus and Fraxinus are the well-known genera in which IF could be isolated/extracted from their species. Considering the complex pathophysiological mechanisms behind some diseases (e.g., cancer, neurodegenerative diseases, and heart diseases), introducing IF as a potent multi-target agent, which possesses several herbal sources and the multiple methods for isolation/purification/synthesis, along with the unique pharmacokinetic profile and low levels of side effects, could be of great importance. Accordingly, a comprehensive review was done without time limitations until February 2020. IF extraction methods include microwave, mechanochemical, and ultrasound, along with other conventional methods in the presence of semi-polar solvents such as ethyl acetate (EtOAc). In addition to the isolation methods, related synthesis protocols of IF is also of great importance. From the synthesis point of view, benzaldehyde derivatives are widely used as precursors for IF synthesis. Along with the methods of isolation and biosynthesis, IF pharmacokinetic studies showed hopeful in vivo results of its rapid absorption after oral uses, leading to different pharmacological effects. In this regard, IF targets varieties of inflammatory mediators including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs). thereby indicating anticancer, cardioprotective, and neuroprotective effects. This is the first review on the synthesis, biosynthesis, isolation, and pharmacokinetic and pharmacological properties of IF in combating different diseases.
... Fraxinus excelsior seeds/fruits -Commercial extract (Glucevia) 1000 mg daily for three weeks in people aged 50-80 years, who were overweight or obese and with a BMI < 40.0 kg/m 2 (Zulet et al., 2014) No effect on fasting glucose but a significant reduction in AUC for blood glucose during OGTT. ...
Article
Ethnopharmacological relevance: The global problem of diabetes, together with the limited access of large numbers of patients to conventional antidiabetic medicines, continues to drive the search for new agents. Ancient Asian systems such as traditional Chinese medicine, Japanese Kampo medicine, and Indian Ayurvedic medicine, as well as African traditional medicine and many others have identified numerous plants reported anecdotally to treat diabetes; there are probably more than 800 such plants for which there is scientific evidence for their activity, mostly from studies using various models of diabetes in experimental animals. Aim of the review: Rather than a comprehensive coverage of the literature, this article aims to identify discrepancies between findings in animal and human studies, and to highlight some of the problems in developing plant extract-based medicines that lower blood glucose in patients with diabetes, as well as to suggest potential ways forward. Methods: In addition to searching the 2018 PubMed literature using the terms 'extract AND blood glucose, a search of the whole literature was conducted using the terms 'plant extracts' AND 'blood glucose' AND 'diabetes' AND 'double blind' with 'clinical trials' as a filter. A third search using PubMed and Medline was undertaken for systematic reviews and meta-analyses investigating the effects of plant extracts on blood glucose/glycosylated haemoglobin in patients with relevant metabolic pathologies. Findings: Despite numerous animal studies demonstrating the effects of plant extracts on blood glucose, few randomised, double-blind, placebo-controlled trials have been conducted to confirm efficacy in treating humans with diabetes; there have been only a small number of systematic reviews with meta-analyses of clinical studies. Qualitative and quantitative discrepancies between animal and human clinical studies in some cases were marked; the factors contributing to this included variations in the products among different studies, the doses used, differences between animal models and the human disease, and the impact of concomitant therapy in patients, as well as differences in the duration of treatment, and the fact that treatment in animals may begin before or very soon after the induction of diabetes. Conclusion: The potential afforded by natural products has not yet been realised in the context of treating diabetes mellitus. A systematic, coordinated, international effort is required to achieve the goal of providing anti-diabetic treatments derived from medicinal plants.
... The scientific evidence can be classified in categories depending on the strength of the studies supporting it. In this context, a first discrimination can be done on the nature of previous experiments, in vitro (cell cultures), ex vivo or in vivo studies, being these last ones on laboratory animals or human intervention studies (Ibero-Baraibar et al., 2014; Zulet et al., 2014). Usually, animal studies will be good models to try and establish lineal or final effects (Boque et al., 2013; de la Garza et al., 2011, 2013; Etxeberria et al., 2012), although the results obtained must always be considered with caution, due to a lack of generalizability or extrapolation to the expected effects in humans. ...
Article
The growing worldwide interest on functional food research has been accompanied by increasing regulatory guidelines in this area, with the aim of ensuring that any claimed effect in foods, beyond their nutritional role, is based on scientific unequivocal evidence. In order to assess the cause-effect relationship between the regular consumption of a food or a food component and the beneficial outcome for the consumer, an appropriate study design is required. Previous knowledge and research on the specific claimed food or product may be an adequate basis for defining a hypothesis and accurate objectives. Other key factors to take into account are based on the outcomes studied, the length of the trial, sample size and type, as well as the transparency on reporting the results obtained. Based on the Consolidated Standards on Reporting Trials statement (CONSORT), together with the specific guidelines published by the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies, the present article aims at summarizing key questions conducting to the most appropriate study design for solid health claim substantiation.
... Furthermore, fruit contains phytochemicals that, while not essential for life, can exert long-term beneficial effects. Among them, polyphenols are an important group of compounds present in fruits 10 , and some studies have recently demonstrated that specific polyphenols increase leptin sensitivity in obese animals [11][12][13] . ...
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Leptin has a central role in the maintenance of energy homeostasis, and its sensitivity is influenced by both the photoperiod and dietary polyphenols. The aim of this study was to investigate the effect of seasonal consumption of polyphenol-rich fruits on the hypothalamic leptin signaling system in non-obese and obese animals placed under different photoperiods. Non-obese and diet-induced obese male Fischer 344 rats were placed under either a short-day (SD) or long-day (LD) photoperiod and were supplemented with either 100 mg/kg of lyophilized red grapes or cherries. In non-obese animals, both fruits reduced energy balance independent of the photoperiod to which they were placed. However, the hypothalamic gene expression of Pomc was significantly up-regulated only in the SD photoperiod. In contrast, in obese animals only cherry significantly decreased the energy balance, although both fruits were able to counteract the diet-induced increase in hypothalamic AgRP mRNA levels when consumed during the SD photoperiod. In conclusion, the consumption of rich-polyphenol fruits may increase leptin sensitivity through the modulation of the hypothalamic leptin signal pathway mainly when consumed in the SD photoperiod. Therefore, fruit seasonality should be considered, as it can influence energy homeostasis and obesity.
... Among all of these studies carried out with phenolic compounds, it is worthwhile to highlight that some of them have been conducted in humans. For example, fraxin, a glucoside of an o-methylated coumarin, and curcumin have been confirmed to reduce hyperleptinemia in overweight and obese humans [59], thus emphasizing their suitability for use in the formulation of functional foods directed toward weight reduction. Taking into consideration all of these studies, it seems clear that phenolic compounds are a very interesting family of molecules for finding new molecules from natural sources that could be used to improve hyperleptinemia and leptin resistance. ...
Article
Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (POMC) and/or repressing orexigenic peptides (NPY/AgRP), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound. This article is protected by copyright. All rights reserved.
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This account presents information on all aspects of the biology of Fraxinus excelsior L. (Ash) that are relevant to understanding its ecological characteristics and behaviour. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history, and conservation. Fraxinus excelsior is a large forest tree, native throughout the main islands of Britain and much of mainland Europe. Seedlings are shade tolerant, but adults are not so it tends to be an intermediate successional species, invading gaps in mixed stands rather than forming extensive pure stands. Ash grows on a wide range of soils but is commonest on nutrient-rich soils with a high base status and pH > 4.2, and is at its best on dry calcareous screes and fertile alluvial soils. Fraxinus excelsior is trioecious or subdioecious with male, hermaphrodite and female flowers and trees. Seed production is prolific with periodic higher producing mast years. Seeds are primarily wind-dispersed, but they can float and be moved considerable distances along waterways. Germination is delayed by dormancy until usually the second spring after being shed. Ash is tolerant of drought, but intolerant of spring frosts and so is predicted to fare well under current climate change scenarios, and indeed has recently been expanding in range in Europe. However, ash health and survival is currently seriously compromised by ash dieback caused by the fungus Hymenoscyphus fraxineus (Chalara fraxinea) that has the potential to kill all but a very few resistant trees. Moreover, the emerald ash borer beetle Agrilus planipennis, a serious pest of ash species in N. America, has reached Europe (though not yet the British Isles) and poses an equally if not more serious long-term threat to ash.
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Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an "opening" of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease.
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Osteoarthritis (arthritis) is biomechanical, biochemical and cellular phenomenon, and is not known as a degenerative disease. Arthritis is one of the common chronic diseases and the most important reason of physical disability in the world. According to its side effect such as peptic ulcers, gastrointestinal bleeding, liver toxicity and renal complications dueofprescribing current treatment contain corticosteroid and non-steroidal, we decided to evaluate possible effect of anti-inflammatory Esential oil of Fraxinus excelsior (EOFE) on biomarkers involved in disease. EOFE were prepared of genetic resources center. Bovine articular cartilage derived from the metacarpophalangeal joints of 14–18-month-old animals (without any sign of inflammation and bleeding) sent to laboratory in sterile bags at 4ºC. Cells were cultured in appropriate condition and counted by hemocytometer, viability assessed by trypan blue. After LPS treatment, cytokine levels were assayed. Cells cultures again and were kept in 37C, 90% humidity in CO2 incubator and after RNA extraction, RT-PCR and PCR done. Also by Real-time PCR, gene expression was evaluated. E.E.F.E level cause down regulation of COX-2, IL-1β, TNF-α in LPS-stimulated cells.
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Obesity disrupts the immune system of adipose tissue, and the activation of its macrophages constantly infiltrating adipose tissue is a crucial cause of insulin resistance induced by obesity. We previously reported for the first time in vitro that the antidiabetic effect of CK may be through the inhibition of macrophage activation and we further explored the specific mechanism in vivo. In order to clarify it, the C57BL/6J mice were fed with a high fat diet and then administered with CK orally. The related biochemical indices were detected, the inflammatory factors in serum and tissues were measured, and the related protein expression levels in insulin pathways and inflammatory signaling pathways were observed. The results showed that CK could dose-dependently reduce macrophage M1-type inflammatory factor expression in serum and adipose tissue, improve insulin resistance and glucose tolerance effectively, upregulate PPARγ expression and block TLR4/TRAF6/TAK1/NF-κB activation in obese mice. In addition, CK promoted the expression of IRS1/PI3K/AKT. Furthermore, our study showed that ginsenoside CK could improve insulin resistance by reducing inflammation through the PPARγ/NF-κB signaling pathway, which implies that ginsenoside CK may be an effective agent against obesity or early diabetes.
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Fraxinus angustifolia subsp. angustifolia is a plant with an age-old use for the production of manna. However, it is also a valuable source of fixed oil rich-seeds. In the present study we examined the chemical and biological properties of this oil in order to support a possible application in foodstuffs, nutraceuticals and cosmetics. Fatty acid composition, volatile and phenolic substances were evaluated. Oleic and linoleic acid represented 45.5% and 50.0%, respectively, of the total fatty acid composition. Among polar phenolic substances identified (secoiridoids, phenylethanoid glycosides, phenolic acids and alcohols, flavonoids, coumarins) isoverbascoside is for the first time reported in this species. Volatiles were mainly characterized by sesquiterpenes. The oil showed good antioxidant activity, in terms of ABTS radical scavenging activity, with an IC 50 value of 28.2 μg/mL. The antiproliferative activity was also investigated: amelanotic melanoma (C32) and lung carcinoma (A549) cells were the most sensitive with IC 50 values comparable to that of the positive control vinblastine. These findings shed light on the potential use of F. angustifolia subsp. angustifolia fixed oil in nutraceutics and cosmetics.
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Insulin resistance is a condition in which insulin sensitivity is reduced and the insulin signaling pathway is impaired. Although often expressed as an increase in insulin concentration, the disease is characterized by a decrease in insulin action. This increased workload of the pancreas and the consequent decompensation are not only the main mechanisms for the development of type 2 diabetes (T2D), but also exacerbate the damage of metabolic diseases, including obesity, nonalcoholic fatty liver disease, polycystic ovary syndrome, metabolic syndrome, and others. Many clinical trials have suggested the potential role of herbs in the treatment of insulin resistance, although most of the clinical trials included in this review have certain flaws and bias risks in their methodological design, including the generation of randomization, the concealment of allocation, blinding, and inadequate reporting of sample size estimates. These studies involve not only the single-flavored herbs, but also herbal formulas, extracts, and active ingredients. Numerous of in vitro and in vivo studies have pointed out that the role of herbal medicine in improving insulin resistance is related to interventions in various aspects of the insulin signaling pathway. The targets involved in these studies include insulin receptor substrate, phosphatidylinositol 3-kinase, glucose transporter, AMP-activated protein kinase, glycogen synthase kinase 3, mitogen-activated protein kinases, c-Jun-N-terminal kinase, nuclear factor-kappaB, protein tyrosine phosphatase 1B, nuclear factor-E2-related factor 2, and peroxisome proliferator-activated receptors. Improved insulin sensitivity upon treatment with herbal medicine provides considerable prospects for treating insulin resistance. This article reviews studies of the target mechanisms of herbal treatments for insulin resistance.
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Thesis
Obesity is an increasing health problem and a major risk factor for a number of chronic diseases. Up to now, strategies to reduce and prevent obesity were unsuccessful. Therefore, novel approaches to treat obesity need to be developed. In this sense, several animal and human studies demonstrate that polyphenols protect against metabolic disorders including diabetes and cardiovascular disease. Thus, polyphenols emerge as bioactive compounds useful to reduce obesity and its associated metabolic diseases. Energy balance is regulated by leptin in the central nervous system, particularly in the hypothalamus where it activates POMC and inhibits AgRP neurons to produce satiety and promote energy expenditure. However, leptin action appears to be suppressed in obesity which is reflected by increased appetite and reduced energy expenditure. The aim of this thesis was to identify polyphenols that improve leptin sensitivity under obesogenic environments, which could ultimately result in a loss of body weight. We show that a chronic intake of a grape seed proanthocyanidin extract improves leptin signaling by increasing POMC gene expression and reduces food intake without decreasing body weight in obese animals. Furthermore, we investigated other polyphenols that could complement the effects of proanthocyanidins by enhancing body weight loss. Our results show that high doses of resveratrol effectively reduce body weight, fat mass and correct hyperleptinemia in obese animals acting as a leptin sensitizer compound. Additionally, we demonstrate the potential of seasonal fruits rich in polyphenols to modulate hypothalamic leptin signaling and downstream effectors in normal conditions and during obesity. Finally, the role of a novel target to modulate AgRP neurons activity is explained. The outcome of this research provides insights into the design of functional foods that combine bioactive compounds which could potentially be used as anti-obesity therapy.
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Background. High adiponectin/leptin ratio may be protective from metabolic risks imparted by high triglyceride, low HDL, and insulin resistance. Methods. This cross-sectional study examines plasma adipokine levels in 428 adult men who were subgrouped according to low (<6.5 μg/mL)and high (≥6.5 μg/mL)adiponectin levels or a low or high ratio of adiponectin/leptin. Results. Men with high adiponectin/leptin ratio had lower plasma triglyceride and higher HDL cholesterol than those with low ratio. Similarly, those with high adiponectin/leptin ratio had lower TG/HDL cholesterol ratio and HOMA2-IR than those with low ratio. In contrast, levels of adiponectin or the ratio of adiponectin/leptin did not associate with systolic blood pressure. But the ratio of adiponectin/leptin decreased progressively with the increase in the number of risk factors for metabolic syndrome. Conclusion. Adipokine levels may reflect adipose tissue triglyceride storage capacity and insulin sensitivity. Leptin is an index of fat mass, and adiponectin is a biomarker of triglyceride metabolism and insulin sensitivity. Men with high adiponectin/leptin ratios have better triglyceride profile and insulin sensitivity than men with a low ratio regardless of waist girth.
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Adiponectin and leptin play critical roles in the development of Metabolic Syndrome (MetS). This study was designed to assess the feasibility of using circulating levels of adiponectin and leptin for the early diagnosis of MetS. A cross-sectional study was performed using data from 367 participants randomly selected from a well-characterized cohort of Mexican-Americans living at the US-Mexico border. Significant differences in circulating levels of adiponectin and leptin were observed between males and females. Adiponectin/leptin correlated significantly with MetS in this population. A receiver-operator characteristic (ROC) analysis demonstrated that adiponectin/leptin showed a high sensitivity (70.9% for males, 78.9% for females) and specificity (90.2% for males and 69.8% for females) for the diagnosis of MetS, independent of BMI measurements. These data support the central role of adiponectin and leptin in MetS, and demonstrated that adiponectin/leptin can be used as a highly sensitive and specific biomarker for MetS.
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Personalized nutritional strategies to treat obesity may specifically influence inflammatory markers, in addition to reduce body weight. In the present study, we evaluated the effect of a hypocaloric diet based on a Mediterranean dietary pattern (MDP) on nutritional status as well as on plasma concentrations of retinol binding protein-4 (RBP4) and other proinflammatory markers. Fourty-one subjects (24F/17M; age: 37 ± 7 years; BMI: 32.2 ± 3.9 kg/m²) were assigned to follow a MDP within a caloric-restricted diet over an 8-week period. Anthropometrical, clinical, and biochemical variables were measured at baseline and endpoint after the nutritional program. Dietary intervention resulted in a mean weight loss of -4.4 ± 2.5 kg (P < 0.001) and marked reductions (P < 0.05) in plasma concentrations of RBP4, leptin, C-reactive protein, complement C3, and tumor necrosis factor-alpha (TNFα). Individuals with a higher adherence to the MDP during the nutritional intervention presented differentially higher reductions (P < 0.05) in plasma RBP4, IL6, and TNFα. In addition, the increase in the Mediterranean diet score from baseline was a significant and independent predictor factor for the decrease in plasma RBP4 concentration (P < 0.05). In conclusion, our findings suggest that following a hypocaloric diet accompanying a high adherence to a MDP resulted in specific reductions on proinflammatory markers, in addition to a significant improvement in some metabolic syndrome features induced by weight loss, which could be a good combined strategy to treat obesity as well as related metabolic and inflammatory disorders.
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In order to make an inventory of herbal remedies commonly used in the treatment of diabetes, hypertension and renal diseases in the North centre region of Morocco, 1527 patients (1095 diabetic patients, 274 with renal disorders and 158 with cardiac disorders) and 25 traditional herbal healers were interviewed in four different areas of Fez-Boulemane region. More than 1153 of the total patients interviewed (76%) used regularly medicinal plants to treat diabetes, cardiac and renal diseases. These data showed that phytotherapy has always be practiced in this region. All the persons interviewed have indicated that the reasons of using phytotherapy is that the plant medicines are cheapest (54%) and more efficient (38%) than modern medicine. They also reported that the result of phytotherapy is better (72%). Our survey started at May 1997. About 90 plants were cited (54 plants for diabetes, 11 for cardiac diseases, 19 for hypertension and 33 for renal diseases). The plants reported have been identified and are presented in a table with the vernacular name, useful parts, ecological distribution and medicinal uses. Only 12% of the total patients have a relative knowledge of the toxic plants. The result indicated that nine plants are extremely toxic at high doses and chronic treatment. Fifty nine percent of the interviewers have indicated that they used medicinal plants from the experience of the other.
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Traditional Medicines derived from medicinal plants are used by about 60% of the world's population. This review focuses on Indian Herbal drugs and plants used in the treatment of diabetes, especially in India. Diabetes is an important human ailment afflicting many from various walks of life in different countries. In India it is proving to be a major health problem, especially in the urban areas. Though there are various approaches to reduce the ill effects of diabetes and its secondary complications, herbal formulations are preferred due to lesser side effects and low cost. A list of medicinal plants with proven antidiabetic and related beneficial effects and of herbal drugs used in treatment of diabetes is compiled. These include, Allium sativum, Eugenia jambolana, Momordica charantia Ocimum sanctum, Phyllanthus amarus, Pterocarpus marsupium, Tinospora cordifolia, Trigonella foenum graecum and Withania somnifera. One of the etiologic factors implicated in the development of diabetes and its complications is the damage induced by free radicals and hence an antidiabetic compound with antioxidant properties would be more beneficial. Therefore information on antioxidant effects of these medicinal plants is also included.
Article
The construct validity and the test-retest reliability of a self-administered questionnaire about habitual physical activity were investigated in young males (n = 139) and females (n = 167) in three age groups (20 to 22, 25 to 27, and 30 to 32 yr) in a Dutch population. By principal components analysis three conceptually meaningful factors were distinguished. They were interpreted as: 1) physical activity at work; 2) sport during leisure time; and 3) physical activity during leisure time excluding sport. Test-retest showed that the reliability of the three indices constructed from these factors was adequate. Further, it was found that level of education was inversely related to the work index, and positively related to the leisure-time index in both sexes. The subjective experience of work load was not related to the work index, but was inversely related to the sport index, and the leisure-time index in both sexes. The lean body mass was positively related to the work index, and the sport index in males, but was not related to the leisure-time index in either sex. These differences in the relationships support the subdivision of habitual physical activity into the three components mentioned above.
Article
The objetive of this article is to review biomarkers that have been suggested in recent years as the link between inflammation, obesity and associated co-morbidities, as well as some questions that yet remain unclear. Increasing evidence indicates the important role of inflammation in the etiology of major public health problems. In the last years, several studies have proposed that obesity might be a inflammatory disorder. In addition, oxidative stress has been suggested as a potential inductor of inflammatory status and susceptibility to obesity and related disorders. Several biomarkers are being suggested as the link between obesity, insulin resistance, cardiovascular disease and metabolic syndrome, such as tumor necrosis factor alfa, interleukin-6 and -18, angiotensinogen, transforming grow factor beta, plasminogen activator inhibitor-1, leptin, resistin, C-reactive protein, serum amyloid A, sialic acid, fibrinogen, markers of endothelial dysfunction (von Willebrand factor, ICAMs, VCAMs), complement factor 3, haptoglobin, Zinc-alpha2-glycoprotein, eotaxin, visfatin, apelin, alpha1-antitrypsin, vaspin, omentin, retinol binding protein 4, ceruloplasmin, adiponectin and desnutrin. Some of this biomarkers are good predictors of cardiovascular risk (plasminogen activator inhibitor-1, sialic acid, fribrinogen, complement factor 3, C-reactive protein), adiposity (leptin, visfatin, resistin, haptoglobin) and/or insulin resistance (sialic acid, C-reactive protein, plasminogen activator inhibitor-1, von Willebrand factor). However, it is currently unclear the role of many of them concerning inflammatory processes in humans, as well as the factors involved in their regulation.
Article
Diabetes mellitus is the most common serious metabolic disorder and it is considered to be one of the five leading causes of death in the world. Hyperglycemia-mediated oxidative stress plays a crucial role in diabetic complications. Hence, this study was undertaken to evaluate the protective effect of esculetin on the plasma glucose, insulin levels, tissue antioxidant defense system and lipid peroxidative status in streptozotocin-induced diabetic rats. Diabetic rats exhibited increased blood glucose with significant decrease in plasma insulin levels. Extent of oxidative stress was assessed by the elevation in the levels of lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (HP) and conjugated dienes (CD); reduction in the enzymic antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST); nonenzymic antioxidants Vitamin C, E and reduced glutathione (GSH) were observed in the liver and kidney tissues of diabetic control rats as compared to control rats. Oral supplementation of esculetin to diabetic rats for 45 days significantly brought back lipid peroxidation markers, enzymic and nonenzymic antioxidants to near normalcy. Moreover, the histological observations evidenced that esculetin effectively rescues the hepatocytes and kidney from hyperglycemia mediated oxidative damage without affecting its cellular function and structural integrity. These findings suggest that esculetin (40 mg/kg BW) treatment exerts a protective effect in diabetes by attenuating hyperglycemia-mediated oxidative stress and antioxidant competence in hepatic and renal tissues. Further, detailed studies are in progress to elucidate the molecular mechanism by which esculetin elicits its modulatory effects in insulin signaling pathway.
Article
An anti-diabetic TCM formula consisting of Schizandra chinensis Baill. (SC), Coptis chinensis (CC), Psidium guajava L. leaves (PG) and Morus alba L. leaves (MA) was developed based on its α-glucosidase, DPP-4 and AGE inhibitory activities in vitro using response surface methodology (RSM). Then, the in vivo study was carried out to confirm the anti-diabetic function of the formula. RSM results showed that the optimum anti-diabetic TCM formula is the combination SC (3000 μg mL(-1)), CC (80 μg mL(-1)), PG (374.56 μg mL(-1)) and MA (480 μg mL(-1)). For the in vivo study, insulin resistant mice were induced by high-fat/high-sucrose (HF/HS) feeding for 6 weeks. Administration of the developed formula significantly decreased non-fasting blood glucose in the HF/HS diet mice. Moreover, the formula decreased blood glucose levels in the insulin tolerance test. These results indicated that the anti-diabetic mechanism of the formula might be due to decreased insulin resistance. The serum fructosamine level in the high dose group was significantly lower than the HF/HS and normal control groups, indicating that the formula could improve middle term glucose levels and reduce the risk of complications. The contents of berberine and 1-deoxynojirimycin in the formula were 4.7 ± 0.4 and 77.1 ± 1.1 μg mL(-1), respectively. These two compounds can be used as indicators for quality control during production.
Article
The goal of the study was to determine the association between diabetes and inflammation in clinically diagnosed diabetes patients. We hypothesized that low-grade inflammation in diabetes is associated with the level of glucose control. Using a cross-sectional design we compared pro- and anti-inflammatory cytokines in a community-recruited cohort of 367 Mexican Americans with type 2-diabetes having a wide range of blood glucose levels. Cytokines (IL-6, TNF-α, IL-1β, IL-8) and adipokines (adiponectin, resistin and leptin) were measured using multiplex ELISA. Our data indicated that diabetes as whole was strongly associated with elevated levels of IL-6, leptin, CRP and TNF-α, whereas worsening of glucose control was positively and linearly associated with high levels of IL-6, and leptin. The associations remained statistically significant even after controlling for BMI and age (p=0.01). The association between TNF-α, however, was attenuated when comparisons were performed based on glucose control. Strong interaction effects between age and diabetes and BMI and diabetes were observed for IL-8, resistin and CRP. The cytokine/adipokine profiles of Mexican Americans with diabetes suggest an association between low-grade inflammation and quality of glucose control. Unique to in our population is that the chronic inflammation is accompanied by lower levels of leptin.
Article
This short review outlines the physiology of glucagon in vivo, with an emphasis on its neural control, the author's area of interest. Glucagon is secreted from alpha cells, which are a minority of the pancreatic islet. Anatomically, they are down stream from the majority islet beta cells. Beta-cell secretory products restrain glucagon secretion. Activation of the autonomic nerves, which innervate the islet, increases glucagon secretion. Glucagon is secreted into the portal vein and thus has its major physiologic action at the liver to break down glycogen. Glucagon thereby maintains hepatic glucose production during fasting and increases hepatic glucose production during stress, including the clinically important stress of hypoglycemia. Three different mechanisms proposed to stimulate glucagon secreted during hypoglycemia are discussed: (1) a stimulatory effect of low glucose directly on the alpha cell, (2) withdrawal of an inhibitory effect of adjacent beta cells, and (3) a stimulatory effect of autonomic activation. In type 1 diabetes (T1DM), increased glucagon secretion contributes to the elevated ketones and acidosis present in diabetic ketoacidosis (DKA). It also contributes to the hyperglycemia seen with or without DKA. The glucagon response to insulin-induced hypoglycemia is impaired soon after the development of T1DM. The mediators of this impairment include loss of beta cells and loss of sympathetic nerves from the autoimmune diabetic islet.
Article
The aim of this study was to determine whether a Fraxinus excelsior L. seed extract, FraxiPure™ (0.5% in the diet), limits weight gain and hyperglycemia in mice. In a previous report, we identified several secoiridoids in FraxiPure™, some of which activated peroxisome proliferator-activated receptor alpha (PPARα) in vitro and inhibited the differentiation of 3T3-L1 preadipocyte cells. In a separate study, FraxiPure™ reduced glycemia in healthy volunteers, following an oral glucose tolerance test. These findings suggest that FraxiPure™ has antiobesity and antihyperglycemia effects. FraxiPure™ was tested in mice that were fed a high-fat diet over 16 weeks and compared with low-fat and high-fat diet controls. Weight gain, omental and retroperitoneal fat, fasting blood glucose, and fasting blood insulin were measured. FraxiPure™ reduced gains in body weight by 32.30% (p < 0.05), omental fat by 17.92%, and retroperitoneal fat by 17.78%. FraxiPure™ also lowered fasting blood glucose levels by 76.52% (p < 0.001) and plasma insulin levels by 53.43% (p < 0.05) after 16 weeks. Moreover, FraxiPure™ lowered liver weight gains by 63.62% (p < 0.05) and the incidence of fatty livers by 66.67%. Our novel results demonstrate the antiobesity effects of chronic administration of an F. excelsior seed extract and confirm its ability to regulate glycemia and insulinemia. In addition, this extract, which is rich in secoiridoid glucosides, protects against obesity-related liver steatosis.
Article
Two new secoiridoid glucosides, excelsides A (1) and B (2), were isolated from the seeds of Fraxinus excelsior. Their structures were elucidated as (2S,4S,3E)-methyl 3-ethylidene-4-(2-methoxy-2-oxoethyl)-2-[(6-O-beta-D-glucopyranosyl-beta-d-glucopyranosyl)oxy]-3,4-dihydro-2H-pyran-5-carboxylate and (2S,4S,3E)-methyl 3-ethylidene-4-{2-[2-(4-hydroxyphenyl)ethyl]oxy-2-oxoethyl}-2-[(6-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]-3,4-dihydro-2H-pyran-5-carboxylate, respectively, on the basis of NMR and MS data. Eight known compounds were identified as nuzhenide (3), GI3 (4), GI5 (5), ligstroside (6), oleoside 11-methyl ester (7), oleoside dimethyl ester (8), 1'''-O-beta-D-glucosylformoside (9), and salidroside (10). Compounds 1-9 inhibited adipocyte differentiation in 3T3-L1 cells. Dilutions of the aqueous extract of F. excelsior (1:10,000) as well as compounds 2, 3, 4, 5, and 8 activated the peroxisome proliferator-mediated receptor-alpha (PPARalpha) reporter cell system in the range of 10(-4) M, compared to 10(-7)-10(-8) M for the synthetic PPARalpha activator, WY14,643. Both biological activity profiles support the hypothesis that inhibition of adipocyte differentiation and PPARalpha-mediated mechanisms might be relevant pathways for the antidiabetic activity of F. excelsior extract.
Article
Fraxinus excelsior L. (Family: Oleaceae) seeds are consumed as a food, condiment, and folk medicine. The seeds are traditionally used as a potent hypoglycemic agent, but no clinical evidence exists in as to this regard. We assessed the clinical efficacy and safety of the seed extract (FraxiPure, Naturex), containing 6.8% of nuzhenide and 5.8% of GI3 (w/w), on plasma glucose and insulin levels against glucose (50 g) induced postprandial glycemia. Preselected dose (1.0 g) was used in a double blind, randomized, crossover, placebo (wheat bran) controlled study on 16 healthy volunteers. Each treatment was given immediately after a fasting blood glucose sample (0 min). Postprandial plasma glucose levels were estimated at 0, 15, 30, 45, 60, 90 and 120 min; and postprandial plasma insulin at 0, 30, 60, 90 and 120 min. The extract lowered the incremental postprandial plasma glucose concentration as compared to placebo at 45 min (P = 0.06) and 120 min (P = 0.07). It statistically (P = 0.02) reduced the glycemic area under the blood glucose curve. The seed, also, induced a significant (P = 0.002) secretion of insulin at 90 min after glucose administration. However, the insulinemic area under the blood insulin curve was not different than the placebo. No adverse events were reported. Our findings confirm the hypoglycemic action of Fraxinus excelsior L. seed extract. These promising results, thus, encourage conducting long-term clinical studies to further evaluate the efficacy and safety of Fraxinus excelsior L. seed extract in healthy and diabetic volunteers and also to explore the possible mechanism(s) of action.
Article
Osthole is an agent isolated from Cnidium monnieri (L.) Cusson and Angelica pubescens and has been used to treat several diseases, including metabolic syndromes. To investigate the hypoglycemic effects of osthole in diabetic db/db mice and the underlying mechanisms of these effects by in vitro assay, diabetic db/db mice and cell experiments were utilized to understand its possible effects. Osthole significantly activated both PPARalpha and PPARgamma in a dose-dependent manner based on the results of the transition transfection assay. The activation of PPARalpha and PPARgamma by osthole also resulted in an increase in the expression of PPAR target genes such as PPAR itself, adipose fatty acid-binding protein 2, acyl-CoA synthetases, and carnitine palmitoyltransferase-1A. In vitro results suggested that osthole might be a dual PPARalpha/gamma activator, but its chemical structure differed from that of the thiazolidinedione class of antidiabetic drugs. In addition, osthole markedly activated the AMP-activated protein kinase and its downstream acetyl CoA carboxylase molecules by increasing their phosphorylation levels. Finally, obese diabetic db/db mice were treated with osthole by different administered routes, and osthole was found to markedly reduce blood glucose level. Interestingly, osthole did not reduce the blood insulin or lipid levels, two phenomena that did occur in animals treated with insulin sensitizers like PPAR agonists. These results suggest that osthole can alleviate hyperglycemia and could be potentially developed into a novel drug for treatment of diabetes mellitus.
Article
Antiinflammatory, Analgesic and Antipyretic Effects of Various Plant Extracts and a Combination Thereof in Animal Models. The three main components comprising the efficacy of non-steroidal antiinflammatory drugs could be demonstrated for STW 1 in different animal models. The phytotherapeutic preparation, containing three individual plant extracts (Populus tremula, Solidago virgaurea, Fraxinus excelsior) produced dose-dependent antiinflammatory, analgesic and antipyretic effects which were similar to those of the reference substances salicyl alcohol and indometacin. As each of the individual extracts displayed considerable efficacy, it may be assumed that each of them contributes to the overall effects of the combination STW 1.
Article
The construct validity and the test-retest reliability of a self-administered questionnaire about habitual physical activity were investigated in young males (n = 139) and females (n = 167) in three age groups (20 to 22, 25 to 27, and 30 to 32 yr) in a Dutch population. By principal components analysis three conceptually meaningful factors were distinguished. They were interpreted as: 1) physical activity at work; 2) sport during leisure time; and 3) physical activity during leisure time excluding sport. Test-retest showed that the reliability of the three indices constructed from these factors was adequate. Further, it was found that level of education was inversely related to the work index, and positively related to the leisure-time index in both sexes. The subjective experience of work load was not related to the work index, but was inversely related to the sport index, and the leisure-time index in both sexes. The lean body mass was positively related the the work index, and the sport index in males, but was not related to the leisure-time index in either sex. These differences in the relationships support the subdivision of habitual physical activity into the three components mentioned above.
Article
Aqueous-ethanolic extracts from Fraxinus excelsior, Populus tremula and Solidago virgaurea inhibit biochemical model reactions representing inflammatory situations to various extents. These model reactions include xanthine oxidase, diaphorase in the presence of the autoxidizable quinone juglone, lipoxygenase and photodynamic reactions driven by riboflavin or rose bengal. The tested extracts are the components of the phytomedicine Phytodolor N (abbreviated as PD) which possesses antipyretic, analgesic, antiinflammatory and antirheumatic activity. Since several reactive oxygen species produced by the mentioned model systems are also involved in inflammatory processes, the beneficial activities of the complete drug may at least in part be due to the reported antioxidative functions of the individual components.
Article
Previous studies demonstrated that both ginseng root and ginseng berry possess anti-diabetic activity. However, a direct comparison between the root and the berry under the same experimental conditions has not been conducted. In the present study, we compared anti-hyperglycemic effect between Panax ginseng root and Panax ginseng berry in ob/ob mice, which exhibit profound obesity and hyperglycemia that phenotypically resemble human type-2 diabetes. We observed that ob/ob mice had high baseline glucose levels (195 mg/dl). Ginseng root extract (150 mg/kg body wt.) and ginseng berry extract (150 mg/kg body wt.) significantly decreased fasting blood glucose to 143 +/- 9.3 mg/dl and 150 +/- 9.5 mg/dl on day 5, respectively (both P < 0.01 compared with the vehicle). On day 12, although fasting blood glucose level did not continue to decrease in the root group (155 +/- 12.7 mg/dl), the berry group became normoglycemic (129 +/- 7.3 mg/dl; P < 0.01). We further evaluated glucose tolerance using the intraperitoneal glucose tolerance test. On day 0, basal hyperglycemia was exacerbated by intraperitoneal glucose load, and failed to return to baseline after 120 min. After 12 days of treatment with ginseng root extract (150 mg/kg body wt.), the area under the curve (AUC) showed some decrease (9.6%). However, after 12 days of treatment with ginseng berry extract (150 mg/kg body wt.), overall glucose exposure improved significantly, and the AUC decreased 31.0% (P < 0.01). In addition, we observed that body weight did not change significantly after ginseng root extract (150 mg/kg body wt.) treatment, but the same concentration of ginseng berry extract significantly decreased body weight (P < 0.01). These data suggest that, compared to ginseng root, ginseng berry exhibits more potent anti-hyperglycemic activity, and only ginseng berry shows marked anti-obesity effects in ob/ob mice.
Article
The hypoglycaemic effect of the aqueous extracts of Fraxinus excelsior (FE) seed and Silybum marianum (SM) aerial part was investigated in normal and streptozotocin (STZ) diabetic rats. After a single dose or 15 daily doses, oral administration of the aqueous extracts (20 mg/kg) produced a significant decrease of blood glucose levels in both normal and STZ diabetic rats (P < 0.001). From the first week, the body weight was increased in normal rats (P < 0.05) and decreased in STZ rats (P < 0.01) after FE administration. In addition, no changes were observed in basal plasma insulin concentrations after both FE and SM treatments in either normal and STZ diabetic rats indicating that these plants exert their pharmacological activity without affecting insulin secretion. We conclude that the aqueous extracts of FE and SM exhibit potent hypoglycaemic and anti-hyperglycaemic activities in normal and STZ rats, respectively, without affecting basal plasma insulin concentrations.
Article
The purpose of this study was to determine the underlying mechanism of the hypoglycaemic activity of the aqueous extract perfusion of Fraxinus excelsior L. (FE) in normal and streptozotocin-induced diabetic rats. The aqueous extract was administered intravenously and the blood glucose changes were determined within four hours after starting the treatment. Plasma insulin concentrations and glycosuria were determined. The aqueous extract at a dose of 10 mg/kg/h produced a significant decrease in blood glucose levels in normal rats (P < 0.001) and even more in diabetic rats (P < 0.001). This hypoglycaemic effect might be due to an extra-pancreatic action of the aqueous extract of FE, since the basal plasma insulin concentrations were unchanged after FE treatment. A potent increase of glycosuria was observed both in normal and diabetic rats (P < 0.001). We conclude that aqueous extract perfusion of FE caused a potent inhibition of renal glucose reabsorption. This renal effect might be at least one mechanism explaining the observed hypoglycaemic activity of this plant in normal and diabetic rats.
Article
The hypotensive effect of an aqueous extract of Fraxinus excelsior L. was investigated in both normotensive (WKY) and spontaneously hypertensive rats (SHR). Daily oral administration of Fraxinus excelsior (20 mg/kg) aqueous extract for 3 weeks produced a significant decrease in systolic blood pressure (SBP) with variation coefficient (Delta%) of 13.5% in SHR (p<0.01) and 9% in WKY rats (p<0.05). The aqueous extract of Fraxinus excelsior significantly enhanced the urination in both SHR (p<0.05 compared to control) and WKY (p<0.05 compared to control). Irbesartan (Avapro), an angiotensin II antagonist, was used as reference drug. Furthermore, oral administration of aqueous Fraxinus excelsior extract at a dose of 20 mg/kg produced a significant increase in urinary excretion of sodium (p<0.01 compared to control), potassium (p<0.001 compared to control) and chlorides (p<0.01) in SHR rats. In normal rats, the aqueous Fraxinus excelsior extract administration induced a significant increase of the urinary elimination of sodium (p<0.05 compared to control), chlorides (p<0.01 compared to control) and potassium (p<0.01 versus control). While there were no significant changes in heart rate (HR) after Fraxinus excelsior treatment in both SHR and WKY rats, glomerular filtration rate (GFR) showed a significant increase in SH rats (p<0.001) after Fraxinus excelsior treatment. These results suggest that oral administration of aqueous extract of Fraxinus excelsior exhibited hypotensive and diuretic actions.
Article
Uncoupling protein 2 (UCP2) negatively regulates insulin secretion. UCP2 deficiency (by means of gene knockout) improves obesity- and high glucose-induced beta cell dysfunction and consequently improves type 2 diabetes in mice. In the present study, we have discovered that the small molecule, genipin, rapidly inhibits UCP2-mediated proton leak. In isolated mitochondria, genipin inhibits UCP2-mediated proton leak. In pancreatic islet cells, genipin increases mitochondrial membrane potential, increases ATP levels, closes K(ATP) channels, and stimulates insulin secretion. These actions of genipin occur in a UCP2-dependent manner. Importantly, acute addition of genipin to isolated islets reverses high glucose- and obesity-induced beta cell dysfunction. Thus, genipin and/or chemically modified variants of genipin are useful research tools for studying biological processes thought to be controlled by UCP2. In addition, these agents represent lead compounds that comprise a starting point for the development of therapies aimed at treating beta cell dysfunction.
Article
The objective: [corrected] of this article is to review biomarkers that have been suggested in recent years as the link between inflammation, obesity and associated co-morbidities, as well as some questions that yet remain unclear. Increasing evidence indicates the important role of inflammation in the etiology of major public health problems. In the last years, several studies have proposed that obesity might be a inflammatory disorder. In addition, oxidative stress has been suggested as a potential inductor of inflammatory status and susceptibility to obesity and related disorders. Several biomarkers are being suggested as the link between obesity, insulin resistance, cardiovascular disease and metabolic syndrome, such as tumor necrosis factor alfa, interleukin-6 and -18, angiotensinogen, transforming grow factor beta, plasminogen activator inhibitor-1, leptin, resistin, C-reactive protein, serum amyloid A, sialic acid, fibrinogen, markers of endothelial dysfunction (von Willebrand factor, ICAMs, VCAMs), complement factor 3, haptoglobin, Zinc-alpha2-glycoprotein, eotaxin, visfatin, apelin, alpha1-antitrypsin, vaspin, omentin, retinol binding protein 4, ceruloplasmin, adiponectin and desnutrin. Some of this biomarkers are good predictors of cardiovascular risk (plasminogen activator inhibitor-1, sialic acid, fribrinogen, complement factor 3, C-reactive protein), adiposity (leptin, visfatin, resistin, haptoglobin) and/or insulin resistance (sialic acid, C-reactive protein, plasminogen activator inhibitor-1, von Willebrand factor). However, it is currently unclear the role of many of them concerning inflammatory processes in humans, as well as the factors involved in their regulation.
Guidance on the scientific requirements for health claims related to appetite ratings, weight management, and blood glucose concentrations
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), 2012. Guidance on the scientific requirements for health claims related to appetite ratings, weight management, and blood glucose concentrations. EFSA J. 10, 2604-2615.