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Fraxinus excelsior seed extract FraxiPure™ limits weight gains and hyperglycemia in high-fat diet-induced obese mice

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Abstract

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.

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... indole derivatives and simple phenolics has been commonly used in traditional medicine against various inflammatory diseases, infections, constipation, as a diuretic and as a hepatoprotective agent [1]. Additionally, an extract produced from the seeds/fruits of Fraxinus has been shown to moderate body weight gain, body fat, glucose and insulin levels, fatty liver incidence as well as blood pressure in various animal models of obesity, diabetes and hypertension [2][3][4][5] supporting potential beneficial properties of Fraxinus against metabolic disorders. 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. ...
... These two compounds were shown to activate peroxisome proliferator-activated receptor alpha (PPARα) and to inhibit adipocyte differentiation in cultured adipocytes providing a potential molecular mechanism underlying the metabolic regulatory activity of the Fraxinus extract [9]. These secoiridoids have thus been proposed as the main bioactive constituents of the extract potentially responsible for its beneficial effects [4,6,9] but the biological effects of these compounds within the organism depend largely on their metabolism and uptake from the gastrointestinal tract. ...
... Molecules 2015, 20, page-page 2 diseases, infections, constipation, as a diuretic and as a hepatoprotective agent [1]. Additionally, an extract produced from the seeds/fruits of Fraxinus has been shown to moderate body weight gain, body fat, glucose and insulin levels, fatty liver incidence as well as blood pressure in various animal models of obesity, diabetes and hypertension [2][3][4][5] supporting potential beneficial properties of Fraxinus against metabolic disorders. 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. ...
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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.
... Scientific evaluation of F. excelsior has revealed several biological activities including anti-oxidative (Meyer et al., 1995; Middleton et al., 2005; Schempp et al., 2000 ), anti-inflammatory (Ghazaly et al., 1992; von Kruedener et al., 1996), analgesic (Okpanyi et al., 1989), antipyretic, both individually (Okpanyi et al., 1989) and as part of a combined plant drug (Strehl et al., 1995), hypoglycemic (Eddouks and Maghrani, 2004; Maghrani et al., 2004 ), and hypotensive effects (Eddouks et al., 2005). More recent studies on a patented seed extract of F. excelsior, marketed as FraxiPure™, have confirmed the ability of this seed extract to reduce glycemia both in vivo and in an acute clinical study (Visen et al., 2009; Ibarra et al., 2011 ). Mice fed a highfat diet supplemented with FraxiPure™ displayed significant ...
... e l s e v i e r . c o m / l o c a t e / f o o d c h e m t o x reductions in fasting blood glucose and fasting plasma insulin levels at study end compared to the high-fat diet control (Ibarra et al., 2011). Body weights were significantly decreased in mice fed FraxiPure™ compared to mice fed the high-fat diet from week 9 of the 20-week study. ...
... HPLC-DAD analysis of nuzhenide and GI3 in the FraxiPure™ samples was conducted as described by Ibarra et al. (2011) with the following modification; a Zorbax SB 18 column (25 cm  4.6 mm, 5 lm) was used under identical conditions of flow rate, temperature and solvent gradient. ...
... Visen et al. (2009) suggested that acute consumption of FXE may produce a slight reduction in glucose levels in healthy individuals without significantly altering insulin secretion. A subchronic study in a high-fat diet animal model confirmed it to regulate glycaemia and fasting plasma insulin levels (Ibarra et al., 2011). The beneficial health effects of this extract may be due to the ability of its active components, the secoiridoid glycosides to activate Peroxisome proliferator-activated receptor alpha (PPARa) and inhibit adipocyte differentiation (Bai et al., 2010), thus contributing to the regulation of both lipid and glucose metabolism over time. ...
... HPLC-DAD analysis of nuzhenide and GI3 in the samples was conducted according to Ibarra et al. (2011); a Zorbax SB18 column (25 cm  4.6 mm, 5 mm; Agilent Technologies, Madrid, Spain) was used under identical conditions of flow rate, temperature and solvent gradient. Nuzhenide and GI3, prepared internally, were used as standards. ...
... Both consumer samples, after reading the concept, demonstrated an understanding of the claimed benefits of the FXE enrichment. The product perception supports the reported benefits of FXE such as control of postprandial glycaemia and insulin secretion in healthy human volunteers (Visen et al., 2009) and control of body weight (Ibarra et al., 2011). ...
Article
To be successful, an innovative functional food must be perceived by the consumer to present a clear concept and significant health benefit. The main purpose of this study was to evaluate the perception of diabetic and non-diabetic populations to a newly developed beverage containing a Fraxinus excelsior seed extract with previously demonstrated effects on glucose homeostasis in an apple juice. Both the diabetic and non-diabetic populations accepted the health benefits of the functional beverage and no differences were found between their perceptions. No difference was found between perception of both population and specific product information provides a better functional benefits understanding. The consumers made a strong connection between F excelsior seed extract and diabetes in agreement with provided information. Sensory evaluation of the developed functional beverage compared with the apple juice matrix showed that perceived bitterness affected product acceptance and should be corrected.
... More recent studies on a patented seed extract of F. excelsior, marketed as FraxiPure™, have confirmed the ability of this seed extract to reduce glycemia both in vivo and in an acute clinical study (Visen et al., 2009;Ibarra et al., 2011). Mice fed a highfat diet supplemented with FraxiPure™ displayed significant reductions in fasting blood glucose and fasting plasma insulin levels at study end compared to the high-fat diet control (Ibarra et al., 2011). ...
... More recent studies on a patented seed extract of F. excelsior, marketed as FraxiPure™, have confirmed the ability of this seed extract to reduce glycemia both in vivo and in an acute clinical study (Visen et al., 2009;Ibarra et al., 2011). Mice fed a highfat diet supplemented with FraxiPure™ displayed significant reductions in fasting blood glucose and fasting plasma insulin levels at study end compared to the high-fat diet control (Ibarra et al., 2011). Body weights were significantly decreased in mice fed FraxiPure™ compared to mice fed the high-fat diet from week 9 of the 20-week study. ...
... HPLC-DAD analysis of nuzhenide and GI3 in the FraxiPure™ samples was conducted as described by Ibarra et al. (2011) with the following modification; a Zorbax SB 18 column (25 cm  4.6 mm, 5 lm) was used under identical conditions of flow rate, temperature and solvent gradient. ...
... More recent studies on a patented seed extract of F. excelsior, marketed as FraxiPure™, have confirmed the ability of this seed extract to reduce glycemia both in vivo and in an acute clinical study (Visen et al., 2009;Ibarra et al., 2011). Mice fed a highfat diet supplemented with FraxiPure™ displayed significant reductions in fasting blood glucose and fasting plasma insulin levels at study end compared to the high-fat diet control (Ibarra et al., 2011). ...
... More recent studies on a patented seed extract of F. excelsior, marketed as FraxiPure™, have confirmed the ability of this seed extract to reduce glycemia both in vivo and in an acute clinical study (Visen et al., 2009;Ibarra et al., 2011). Mice fed a highfat diet supplemented with FraxiPure™ displayed significant reductions in fasting blood glucose and fasting plasma insulin levels at study end compared to the high-fat diet control (Ibarra et al., 2011). Body weights were significantly decreased in mice fed FraxiPure™ compared to mice fed the high-fat diet from week 9 of the 20-week study. ...
... HPLC-DAD analysis of nuzhenide and GI3 in the FraxiPure™ samples was conducted as described by Ibarra et al. (2011) with the following modification; a Zorbax SB 18 column (25 cm  4.6 mm, 5 lm) was used under identical conditions of flow rate, temperature and solvent gradient. ...
... Studies in recent years have demonstrated that secoiridoid-enriched extract from F. excelsior seed reduced gains in body weight, omental fat and retroperitoneal fat in obese C57BL/6J mice, and alleviated triglyceridemia, body weight gain and systolic blood pressure in SHR and Zucker rats [22,23]. In the present study, treatment with FM for 8 weeks reduced body weight in obese mice. ...
... Obesity is usually associated with chronic metabolic diseases such as nonalcoholic fatty liver disease [45]. Ibarra et al. have proved that extract from F. excelsior seed lowered liver weight gains and the incidence of fatty livers in obese C57BL/6J mice [22]. ALT and AST levels are clinically considered as credible markers for monitoring liver injury or liver function [46,47]. ...
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Previously we conducted a phytochemical study on the seeds of Fraxinus excelsior and isolated nine secoiridoid compounds with adipocyte differentiation inhibitory activity and peroxisome proliferator activated receptor alpha (PPARα) activation effects. However, the bioactive constituents and functions of Fraxinus mandshurica seeds have not been studied. In the present study, we investigated the secoiridoid compounds in F. mandshurica seed extract (FM) using column chromatography, 1H-NMR, 13C-NMR and HPLC-DAD methods. The pancreatic lipase inhibitory activities of isolated compounds were evaluated in vitro. Additionally, the anti-obesity and gut microbiota modulation effect of FM on high-fat diet-induced obesity in C57BL/6 mice were also studied in vivo. The results showed that 19 secoiridoids were isolated from FM and identified. The total content of secoiridoids in FM reached 181.35 mg/g and the highest content was nuzhenide (88.21 mg/g). All these secoiridoid compounds exhibited good pancreatic lipase inhibitory activity with inhibition rate ranged from 33.77% to 70.25% at the concentration of 100 μM. After obese mice were administrated with FM at 400 mg/kg.bw for 8 weeks, body weight was decreased by 15.81%. Moreover, FM could attenuate the lipid accumulation in serum and liver, relieve the damage in liver and kidney, and extenuate oxidative stress injury and inflammation caused by obesity in mice. FM could also modulate the structural alteration of gut microbiota in obese mice, increasing the proportion of anti-obesity gut microbiota (Bacteroidetes, Bacteroidia, S24-7 and Allobaculum), and reducing the proportion of obesogenic gut microbiota (Firmicutes and Dorea). This study suggests that F. mandshurica seeds or their secoiridoids may have potential for use as a dietary supplement for obesity management.
... Nuzhenide and GI3 were found to activate peroxisome proliferator-activated receptor alpha (PPARa) in vitro and inhibit differentiation of 3T3-L1 mouse embryonic broblasts into adipocytes. 9 Ibarra et al. 10 found that mice fed a high-fat diet and administered FXE (0.5% of the diet) had signicantly lower fasting insulin levels at the end of the 16-week study compared to mice fed a high-fat diet alone, and displayed signicantly reduced fasting blood glucose levels from week 5 and throughout the remainder of the study. ...
... Maghrani et al. 13 reported no effect on insulin levels following single or repeated administration (15 days) of 20 mg per kg body weight of an F. excelsior L. extract in mice. In contrast, Ibarra et al. 10 found that mice fed a high-fat diet and administered FXE (0.5% of the diet) had signicantly lower fasting insulin levels at the end of the 16-week study compared to mice fed a high-fat diet alone. The differing effects on fasting insulin levels reported in these studies could be due to differences in the extract composition, dose, study duration, or background diet. ...
Article
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Nuzhenide and GI3, the principal secoiridoids of an extract obtained from the seeds of Fraxinus excelsior L. (FXE), are believed to be the active compounds responsible for the previously reported hypoglycemic effects of this extract. In this study, the effects of FXE were studied in two animal models which are representative of metabolic disorders: spontaneously hypertensive rats (SHR) and obese Zucker rats. SHR were acutely treated (oral gavage) with different doses of FXE. In addition, SHR and Zucker rats were chronically fed (20 or 5 weeks, respectively) with standard chow supplemented with FXE. Acute treatment with FXE (200 mg per kg body weight) decreased systolic blood pressure as in the case with captopril (50 mg per kg body weight). Chronic treatment with FXE at 100 mg per kg body weight per day, a dose equivalent to that showing hypoglycemic activity in humans, resulted in a significant decrease in glycemia (-16.3%), triglyceridemia (-33.4%) and body weight (-8.1%) in Zucker rats as well as a significant decrease in SBP in SHR (-6.7%), with a concomitant improvement in endothelial function in both strains. The broad-ranging effects of FXE may be due to a unique compositional profile that could be useful to prevent the metabolic syndrome, characterized by obesity, insulin resistance, glucose intolerance, hypertriglyceridemia and elevated blood pressure.
... According to this limited amount of information, 26 can only can be proposed to be an isomer of Gl5. 29,30 Triterpenes. Oleanolic acid, 27, and ursolic acid, 28, were confirmed based on comparison to commercial standards, and for both compounds, there was only one major product ion observed at m/z 407.2. ...
... Optimization of Extraction and Analytical Conditions. To extract the phenylethanoid glycosides and triterpenes efficiently, the variables involved in the procedure such as the extraction solvent (60, 70, 80, 90, and 100% methanol), the volume of extraction solvent (6, 8, 10, 12, and 14 mL), and extraction time (15,30,45, and 60 min) were optimized. The final optimized method for phenylethanoid glycosides was as follows: 0.10 g of the O. f ragrans fruit powder was extracted with 10 mL of 70% methanol in an ultrasonic water bath for 45 min at room temperature. ...
Article
Ripe O. fragrans fruit is composed of purple peels, green pulps and light brown seeds. Since the biological effects such as antioxidative activities and platelet-aggregation inhibition are related to the phenolic compounds and flavonoids in O. fragrans fruits, these components have a great potential as functional food ingredient. In the work, active components in O. fragrans fruits extraction were investigated by HPLC-ESI-MS/MS. A total of twenty-eight compounds were identified and sixteen components were first discovered in O. fragrans fruits, most of which were a series of phenylethanoid glucosides. These compounds are assigned as methyloleoside neonuezhenide and possible fragmentation pathway of mass spectrometry is first elucidated. Additionally, sensitive HPLC-ESI-MS/MS method for five phenylethanoid glycosides of salidroside, acteoside, isoacteoside, neonuezhenide and nuezhenide and two triterpenes of oleanolic acid and ursolic acid has been established for the quality of O. fragrans fruits comprehensively.
... (Okpanyi et al. 1989;Meyer et al. 1995) as well as hypotensive properties (Eddouks et al. 2005). In animals, some findings suggest that this extract has antihyperglycemic and antiobesity effects Ibarra et al. 2011). In humans, the aqueous seed extract of the ash tree is prescribed as a hypoglycemic and antidiabetic agent in Morocco (Jouad et al. 2001). ...
... The authors hypothesized that Fraxinus excelsior L. seed extract may significantly prevent the development of insulin resistance since that total postprandial insulinemia was not statistically different as compared to placebo (Visen et al. 2009). The literature describe that the reduction in glycemia might be partly attributed to the glycoside secoiridoids present in Fraxinus excelsior L. seed extract, likely due to an action of the plant extract on the pancreatic islet cells (Zhang et al. 2006), in addition to antiobesity properties, related to the ability to activate PPAR␣ in vitro (Bai et al. 2010;Ibarra et al. 2011), which may contribute to the reported beneficial hypoglycemic properties. Although cumarins were present in the extract administered, their concentration was too low to attribute them any effect (Prabakaran and Ashokkumar 2013). ...
... Moreover, the differentiation of 3T3-L1 mouse embryonic fibroblasts into adipocytes was shown to be inhibited by isolated secoiridoid glucosides of Glucevia ® . Chronic administration of the extract (0.5% of the diet) to mice fed a high fat diet resulted in significantly lower liver weight by 63.6% and reduction of the incidence of fatty livers by 66.7% compared to mice fed a highfat diet alone, and authors have first suggested that Glucevia ® could prevent against obesity-related hepatic steatosis [7]. ...
... These effect could be due to enhanced glucose uptake in the liver and skeletal muscle as was previously described for another iridoid glycoside extracted from the roots of Rehmannia glutinosa [30]. Ibarra et al. [7] reported that mice fed a high-fat diet and administered Glucevia ® also decreased significantly fasting insulin levels at the end of the 16-week study compared to mice fed a high-fat diet alone. Furthermore, the extract was found to maintain a similar insulin area under the curve, concomitant with a better glucose tolerance after an OGTT in acute clinical trial on healthy subjects [4]. ...
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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
... Their lipophilic nature also favours partitioning into adipose tissue, where they appear to inhibit the formation of pro-inflammatory adipocytokines. 51 Detailed chemical analyses of unprocessed whale and seal oils are scarce. It is known, however, that unprocessed whale oil is typically a very pale brown in colour; and accounts of seal oil preparation involving rendering for five days at about 40 F indicate surprising stability, considering its highly unsaturated fatty acids content. ...
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While the Inuit diet was highly cardio-protective and consuming oily fish within a Western diet is to a lesser degree, the case for purified fish oil supplements is less convincing. Purification of fish oil removes lipophilic polyphenols which likely contribute to the health benefits of oily fish; leaving the ω3 highly unsaturated fatty acids exposed and prone to conferring oxidative and inflammatory stress. The authors believe that due to such issues as dietary shift, it may now be inadvisable to prescribe or sell purified ω3 highly unsaturated fatty acids supplements, unless the appropriate co-factors are included.
... The analytical study of FESE revealed that it was rich in nuzhenide and GI3, two phenolic compounds belonging to the secoiridoid type [11]. FESE lowered the incremental postprandial plasma glucose concentration in nondiabetic volunteers [11] and limited weight gain and hyperglycemia in high-fat induced obese mice [12]. Recently, we have demonstrated the short-term antihypertensive effect of this extract in spontaneously hypertensive rats (SHR), a model for essential hypertension in humans. ...
Article
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The effect of long-term intake of different doses (20, 40, and 60 mg/kg/day) of a Fraxinus excelsior L. seed extract (FESE) on spontaneously hypertensive rats (SHR) was evaluated. Water was used as control and captopril (50 mg/kg/day) was used as positive control. Systolic blood pressure, body weight, and food and liquid intake were registered weekly in SHR. The antioxidant and vascular relaxing properties of FESE were also studied in these animals. The development of hypertension was attenuated in the groups treated with captopril or FESE. The antihypertensive effect was more accentuated in the captopril group than in the FESE groups, and it was paradoxically more accentuated in the groups treated with 20 mg/kg/day or 40 mg/kg/day of FESE than in the group treated with the highest dose of this extract. Body weight gain and food intake increased in the FESE groups. After removing the corresponding antihypertensive treatment, the arterial blood pressure and the body weight of the FESE treated animals returned to control values. In addition, FESE increased plasma antioxidant capacity and decreased plasma and liver malondialdehyde levels. Moreover, acetylcholine relaxation improved in the aorta rings from the FESE treated rats.
... These molecules interact and interconnect the major metabolic organs, i.e. gut, brain, liver, pancreas, adipose tissue, and muscle, in a complex regulatory network [1,3]. The prevalence of metabolic syndrome and obesity is one of the most serious health problems worldwide, and numerous in vitro and animal studies indicate that plant extracts and derived bioactive compounds ameliorate dyslipidemia, body fat accumulation [4,5], and inflammatory status [6]. Thus, they may contribute to reduce or prevent the risk of these disorders. ...
Article
ScopeCarnosic acid (CA) and rosemary extracts (REs) have antiobesity effects but the mechanisms are not understood. We investigated some of the potential mechanisms contributing to the metabolic effects of an RE enriched in CA. Methods and resultsAn RE (∼40% CA) was administered to lean (Le, fa/+) and obese (Ob, fa/fa) female Zucker rats for 64 days. Several adipocytokines, brain-derived neurotrophic factor, phosphorylated AMP-activated protein kinase, and hepatic gene expression changes were investigated. The RE significantly decreased circulating tumor necrosis factor alpha (RE/CT = 0.36, p < 0.0003), IL-1β (0.48, p < 0.032), and leptin (0.48, p < 0.002), and upregulated adiponectin (1.47, p < 0.045) in the Le rats. The RE also induced phase I and phase II gene expression and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Notably, the RE decreased adipose phosphorylated AMP-activated protein kinase and did not affect hepatic peroxisome proliferator-activated receptor gamma coactivator 1-alpha in the Ob rats. Conclusion Our results show that an RE rich in CA exerts anti-inflammatory effects and affects hepatic metabolism in normal Le rats. We report significant differences in the expression and regulation of key metabolic sensors between Le and Ob rats that may contribute to explain the different ability of the two genotypes to respond to the RE.
... The potential therapeutic and preventive benefits of herb-based medications have been the subject of extensive studies, and many natural constituents have been discovered with significant pharmacologic activity including agents with antiglycemic, hypolipidemic and antihypertensive properties (Abeywickrama et al. 2011;Xia et al. 2011;Hellström et al. 2010). In the past decade, there has been a growing recognition that certain phytochemicals may suppress diet-induced obesity and protect against chronic diseases (van Heerden 2008;Ibarraa et al. 2010;Kim et al. 2012). ...
... High fat diet induced mice [85] 50 ...
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Obesity is a complex health issue to address, it is a serious and chronic disease that can have a negative effect on many systems in your body. Overweight and obesity may increase the risk of many health problems, including diabetes, heart disease, osteoarthritis and certain cancers. Obesity is increasing at an alarming rate throughout the world. Today it is estimated that there are more than 300 million obese people world-wide. Obesity is regarded as a disorder of lipid metabolism and the enzymes involved in this process could be targeted selectively for the development of antiobesity drugs. However, most of the anti-obesity drugs that were approved and marketed have now been withdrawn due to serious adverse effects. The naturopathic treatment for obesity has been explored extensively since ancient times and gaining momentum in the present scenario. Traditional medicinal plants and their active phytoconstituents have been used for the treatment of obesity and their associated secondary complications. Some active medicinal plants and their respective bioactive compounds were also tested by clinical trials and are effective in traemnet of obesity. This review focus on natural phytoextracts with their mechanism of action and their preclinical experimental model for further scientific research.
... The analytical study of FESE revealed that it was rich in nuzhenide and GI3, two phenolic compounds belonging to the secoiridoid type [11]. FESE lowered the incremental postprandial plasma glucose concentration in nondiabetic volunteers [11] and limited weight gain and hyperglycemia in high-fat induced obese mice [12]. Recently, we have demonstrated the short-term antihypertensive effect of this extract in spontaneously hypertensive rats (SHR), a model for essential hypertension in humans. ...
Article
Full-text available
The effect of long-term intake of different doses (20, 40, and 60 mg/kg/day) of a Fraxinus excelsior L. seed extract (FESE) on spontaneously hypertensive rats (SHR) was evaluated. Water was used as control and captopril (50 mg/kg/day) was used as positive control. Systolic blood pressure, body weight, and food and liquid intake were registered weekly in SHR. The antioxidant and vascular relaxing properties of FESE were also studied in these animals. The development of hypertension was attenuated in the groups treated with captopril or FESE. The antihypertensive effect was more accentuated in the captopril group than in the FESE groups, and it was paradoxically more accentuated in the groups treated with 20 mg/kg/day or 40 mg/kg/day of FESE than in the group treated with the highest dose of this extract. Body weight gain and food intake increased in the FESE groups. After removing the corresponding antihypertensive treatment, the arterial blood pressure and the body weight of the FESE treated animals returned to control values. In addition, FESE increased plasma antioxidant capacity and decreased plasma and liver malondialdehyde levels. Moreover, acetylcholine relaxation improved in the aorta rings from the FESE treated rats.
... Use of the extract of F. excelsior seeds in diabetic volunteers had significantly reduced the postprandial rise in glycemia while enhanced the insulin secretion [21]. Treatment of obese mice with extracts of F. excelsior seeds limited the gain in weight and hyperglycemia [22]. Further, seed extract of F. excelsior protected the micronuclei in irradiated human lymphocytes and did not induce changes in hematological and biochemical parameters after 90 days of its use in human [23]. ...
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Background Leaves and root bark of Fraxinus xanthoxyloides Wall. (Oleaceae) are used locally for the treatment of jaundice, malaria and pneumonia. Decoction of stem, twigs and bark is used in pain, internal injuries, rheumatism and in bone fracture. In this investigation we have evaluated the methanol extract of leaves for its hepatoprotective potential against CCl4 induced hepatic injuries in rat. Methods Powder of F. xanthoxyloides leaves was extracted with methanol (FXM) and subjected for the determination of polyphenolics through HPLC-DAD analysis. Sprague–Dawley (Rattus novergicus) male rats were divided into eight groups (six rats in each). Group I: non-treated control; Group II: vehicle treated (DMSO plus olive oil) while Group III- VI treated with 1 ml/kg body weight (bw) of CCl4 (30 % in olive oil) for 30 days (15 dosages) to induce the hepatic injuries. Group IV: treated with silymarin (100 mg/kg bw); Group V and VI with FXM (200, 400 mg/kg bw) on alternate days with CCl4 treatment. Group VII and VIII was administered with FXM (200, 400 mg/kg bw) alone (15 dosages). After 30 days the serum was evaluated for liver function enzymes and biochemical markers, liver samples for antioxidant enzymes, biochemical markers, comet assay and for histopathology. Results HPLC-DAD analysis of FXM revealed the existence of rutin and caffeic acid. In CCl4 treated rats the level of alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin was significantly increased while the albumin concentration in serum was decreased as compared to control group. The level of hepatic antioxidant enzymes, catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), glutathione-S-transferase (GST) and glutathione reductase (GSR) was significantly decreased against the control group. Further, significant decrease in GSH while increase in lipid peroxides (TBARS), H2O2, DNA damages and comet length was induced with CCl4 in hepatic tissues of rat. In contrast, co-administration of FXM and silymarin restored the biochemical and histopathological status of the liver. Conclusion Results of present investigation revealed that F. xanthoxyloides leaves possibly protect the liver against CCl4 induced injuries like silymarin by its antioxidant constituents.
... These parts have been widely used in folk medicine against various inflammatory diseases, infections, constipation, as diuretic and hepatoprotective agents (Kostova & Iossifova, 2007). Moreover, F. excelsior seeds, consumed as a food or condiment, are traditionally employed in folk medicine as a potent hypoglycemic agent (Gomez Garcia et al., 2015;Ibarra et al., 2011;Montó et al., 2014;Visen et al., 2009;Zulet et al., 2014) to be used in the treatment of metabolic disorders. ...
Article
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.
... 0.5% extract in the diet for 17 weeks markedly reduced blood glucose (6.6 vs 10 mmol/L) in mice fed a high-fat diet (Ibarra et al., 2011). ...
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 FE species have been used as food and stuffing as well as in traditional medicine due to a number of claimed beneficial biological activities including anti-oxidative, anti-inflammatory, anti-pyretic and anti-rheumatic properties (Eddouks, Maghrani, Zeggwagh, Haloui, & Michel, 2005;Meyer, Schneider, & Elstner, 1995). Some findings suggest that its extract has anti-hyperglycemic, anti-hypoglycemic, anti-diabetic and anti-obesity effects Ibarra et al., 2011;Visen et al., 2009). ...
Article
In this study, common ash (Fraxinus excelsior L.) seed oil compositions were determined for the first time. Effect of the moisture content and microwave pretreatment of the seeds on the oil yield and its composition were also investigated. The optimum level of moisture content to obtain the maximum oil (18.18%) yield was 1% with 3 min pre-treatment. The main triacylglycerol composition of the oil was linoleic–linoleic–oleic, followed by oleic-oleic-linoleic and linoleic–linoleic-linoleic. The main fatty acid of the oil was linoleic acid (C18:2), followed by oleic acid (C18:1) and palmitic acid (C16:0). The main phytosterol of the oil was β-sitosterol, followed by Δ⁵-avenasterol and campesterol. The main tocopherol of the oil was α-tocopherol, followed by β and γ-tocopherols. The main essential oil of the oil was bicyclogermacrene, followed by delta-cadinene. These results suggest that this oil is a good source of valuable nutritional compounds and that microwave pretreatment is a promising and environmentally friendly method to extract it as a new vegetable oil source.
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Obesity is a disease whose incidence has increased over the last few decades. Despite being a multifactorial disease, obesity results essentially from excessive intake of high-calorie foods associated with low physical activity. The demand for a pharmacological therapy using natural compounds as an alternative to synthetic drugs has increased. Natural compounds may have few adverse effects and high economic impact, as most of them can be extracted from underexploited plant species and food by-products. To test the potential anti-obesogenic effects of new natural substances, the use of preclinical animal models of obesity has been an important tool, among which rat and mouse models are the most used. Some animal models are monogenic, such as the db/db mice, ob/ob mice, Zucker fatty rat and Otsuka Long-Evans Tokushima fatty rat. There are also available chemical models using the neurotoxin monosodium glutamate that induces lesions in the ventromedial hypothalamus nucleus, resulting in the development of obesity. However, the most widely used are the obesity models induced by high-fat diets. The aim of this review was to compile detail studies on the anti-obesity effects of natural compounds or their derivatives on rodent models of obesity as well as a critical analysis of the data.
Chapter
The chemistry and pharmacology of iridoids, a special class of cyclopentanoid monoterpenes, are highlighted. Occurrence of some typical members of iridoids, secoiridoids, and their derivatives from different plant sources with their physical constants is listed in Table 97.1. Structural classification, synthesis, biosynthesis, and important pharmacological activities of iridoids and secoiridoids such as antiallergic, antiarthritis, antibacterial, anticancer, anticoagulant, antidiabetic, anti-inflammatory, anti-osteoporosis, immunomodulatory, insecticidal, melanogenesis inhibitory, nerve growth factor-potentiating, neuroprotective, and wound-healing activities are briefly discussed.
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A high-performance liquid chromatography-diode array detector (HPLC-DAD) method was established for quantitative evaluation of nine constituents of Fraxinus rhynchophylla such as four coumarins, esculin (1), fraxin (2), esculetin (3), fraxetin (4), three lignans, syringaresinol 4,4′-O-β-diglucoside (5), pinoresinol 4-O-β-glucoside (6), pinoresinol (9), one secoiridoid, oleuropein (7), and one coumarinolignan, cleomiscosin C (8). The preferred chromatographic condition was obtained on Phenomenex Gemini-NX (3 μm, C18 110A, 150 × 4.60 mm) and the mobile phase was composed of water and acetonitrile using a gradient elution. The wavelength was set at 220 nm. Extraction condition of these constituents in F. rhynchophylla was also optimized through extraction time, extraction solvent and extraction method using established method. From this study, extraction at 70 °C with the mixture of ethanol and water for more than 12 h was suggested to be good extraction condition for these constituents. Quantitation of nine constituents in different F. rhynchophylla samples was also successfully accomplished with the newly established method.
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Objectives Fraxinus excelsior L. (FE) is traditionally used to treat inflammatory and pain disorders. This study aimed to identify the constituents of FE leaves and evaluate the effects of its n-hexane (FEH), ethyl acetate (FEE), methanol (FEM) extracts and constituents on the viability of THP-1 cells and their ability to release pro-inflammatory cytokines. Methods THP-1 cell viability was assessed using an MTT assay. The immunomodulatory activity was evaluated by measuring tumour necrosis factor-alpha (TNF-α) and interleukin 12 (IL-12) released by lipopolysaccharide-stimulated THP-1 cells using enzyme-linked immunosorbent assays. Key findings Triterpenes, tyrosol esters, alkanes, phytyl and steryl esters, pinocembrin and bis(2-ethylhexyl)phthalate were isolated from FE. The tyrosol esters showed no significant effect on THP-1 cell viability. FEH, FEE, FEM, and pinocembrin, ursolic acid, oleanolic acid had IC50 values of 56.9, 39.9, 124.7 µg/ml and 178.6, 61.5 and 199.8 µM, respectively. FE extracts, ursolic acid, oleanolic acid and pinocembrin significantly reduced TNF-α/IL-12 levels. The tyrosol esters did not significantly affect TNF-α/IL-12 production. Conclusions FE was able to reduce pro-inflammatory cytokine production indicating a mechanistic focus in its use for inflammation and pain. Further investigations are warranted to unravel the mode of action of the tested constituents and discover other potentially active compounds in FE extracts.
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At an excavation of the late medieval St Margaretha Convent in Leiden (The Netherlands), archaeobotanical results could be compared with historical data. Both wood and macroremains were analysed to reconstruct the local vegetation and seek evidence of the cultivation of plants. The historical sources available for this estate are a charter prepared in 1572, which listed all trees present just after the abandonment of the convent, and an illustration from 1574 of the convent and its grounds. The charter mentions Salix and Alnus as the most numerous trees present, followed by several other taxa. The archaeological evidence from the wood remains, mostly construction timber with a dominance of Quercus, shows the use of indigenous taxa and some non-indigenous material, which was partly re-used. It is possible that some of the Coniferae were very early home-grown specimens. The trees represented in the macroremains were most probably growing in the immediate vicinity. They specify some of the taxa found as wood or mentioned in the historical text. The identified cultivated plants could all have been grown locally. The vegetation is in general represented by ruderal taxa and plants growing in wet conditions, which form an assemblage typical of an abandoned rural area.
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Pour tester les effets du Svetol®, un extrait de café vert décaféiné possédant un ratio spécifique entre l’acide 5-caféyl-quinique (acide chlorogénique) et les autres isomères d’acides caféylquiniques, sur la perte de poids, 50 volontaires ayant un indice de masse corporelle (IMC) supérieur à 25 ont été sélectionnés. Ils ont été randomisés en deux groupes : l’un (n = 20) recevant le placebo, l’autre (n = 30) recevant le Svetol® en parallèle d’une alimentation légèrement hypocalorique. Chaque volontaire consomme une capsule de Svetol® ou de placebo deux fois par jour pendant 60 jours, au moment des repas principaux. Le poids, l’IMC, le ratio masse maigre/masse grasse (MM/MG) et l’auto-évaluation de l’aspect physique ont été déterminés à Jo et J60. Après 60 jours de traitement, une réduction significative du poids de 4,97 +/- 0,32 kg (5,7 %) a été observée dans le groupe Svetol® comparé au groupe contrôle (p < 0,001). Le ratio MM/MG est augmenté de façon significative dans le groupe Svetol® comparé au groupe contrôle : 4,1 +/- 0,7 %vs 1,6 +/- 0,6 % respectivement (p < 0,01). Ces résultats démontrent que le Svetol® est capable d’augmenter l’effet d’une alimentation légèrement hypocalorique chez des volontaires ayant des problèmes de surpoids. Cet effet pourrait être expliqué par une meilleure utilisation des graisses et par la prévention de leur accumulation.
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The long-chain acyl-coenzyme A synthetase (ACS) gene gives rise to three transcripts containing different first exons preceded by specific regulatory regions A, B, and C. Exon-specific oligonucleotide hybridization indicated that only A-ACS mRNA is expressed in rat liver. Fibrate administration induced liver C-ACS strongly and A-ACS mRNA to a lesser extent. B-ACS mRNA remained undetectable. In primary rat hepatocytes and Fa-32 hepatoma cells C-ACS mRNA increased after treatment with fenofibric acid, alpha-bromopalmitate, tetradecylthioacetic acid, or alpha-linolenic acid. Nuclear run-on experiments indicated that fenofibric acid and alpha-bromopalmitate act at the transcriptional level. Transient transfections showed a 3.4-, 2.3-, and 2.2-fold induction of C-ACS promoter activity after fenofibric acid, alpha-bromopalmitate, and tetradecylthioacetic acid, respectively. Unilateral deletion and site-directed mutagenesis identified a peroxisome proliferator activator receptor (PPAR)-responsive element (PPRE) mediating the responsiveness to fibrates and fatty acids. This ACS PPRE contains three imperfect half sites spaced by 1 and 3 oligonucleotides and binds PPAR.retinoid X receptor heterodimers in gel retardation assays. In conclusion, the regulation of C-ACS mRNA expression by fibrates and fatty acids is mediated by PPAR.retinoid X receptor heterodimers interacting through a PPRE in the C-ACS promoters. PPAR therefore occupies a key position in the transcriptional control of a pivotal enzyme controlling the channeling of fatty acids into various metabolic pathways.
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WY14,643 is a specific peroxisome proliferator-activated receptor alpha (PPARalpha) agonist with strong hypolipidemic effects. Here we have examined the effect of WY14,643 in the A-ZIP/F-1 mouse, a model of severe lipoatrophic diabetes. With 1 week of treatment, all doses of WY14,643 that were tested normalized serum triglyceride and fatty acid levels. Glucose and insulin levels also improved but only with high doses and longer treatment duration. WY14,643 reduced liver and muscle triglyceride content and increased levels of mRNA encoding fatty acid oxidation enzymes. In liver, the elevated lipogenic mRNA profile (including PPARgamma) in A-ZIP/F-1 mice remained unchanged. These results suggest that WY14,643 acts by increasing beta-oxidation rather by than decreasing lipogenesis or lipid uptake. Hyperinsulinemic euglycemic clamp studies indicated that WY14,643 treatment improved liver more than muscle insulin sensitivity and that hepatic mRNA levels of gluconeogenic enzymes were reduced. Combination treatment with both WY14,643 and a PPARgamma ligand, rosiglitazone, did not lower glucose levels more effectively than did treatment with WY14,643 alone. These data support the hypothesis that reducing intracellular triglycerides in non-adipose tissues improves insulin sensitivity and suggest that further investigation of the role of PPARalpha agonists in the treatment of lipoatrophic diabetes is warranted.
Chapter
This chapter discusses the health benefits of fruit and vegetables intake in daily diet. The low consumption of fruit and vegetables is associated with higher risk of cardiovascular disease (CVD), stroke, type 2 diabetes and high blood pressure among others. Moreover, the concentrations of CVD biomarkers, including inflammation and oxidative stress have been shown to be lower with greater amounts of intake of fruit and vegetables. The bioactive compounds found in fruit and vegetables are classified as nitrogen-containing alkaloids, phenolics and polyphenolics, sulfur-containing compounds and terpenoids. Fruits and vegetables are major sources of antioxidants, including vitamin C, carotenoids and selenium. It mentions that intake of 5 or more servings of fruit and vegetables each day is recommended to reduce the risk of chronic diseases, stroke, cancer and obesity. It presents the results of a health survey on the proportion of intake of fruit and vegetables by adults in United States which showed an increase in the percentage of intake.
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The root of Panax ginseng C.A. Meyer, is a well-known important Chinese traditional medicine used as a stomachic, tonic, sedative and as an elixir called Ginseng in China and Japan. The precise mechanism of the biological actions of this plant is not fully understood. In order to elucidate the immunomodulating activities of this plant, we examined the direct effects of four of its components, acidic polysaccharides isolated in previous studies, on cytokine (interleukin-8; IL-8) production by a human monocytic cell line, THP-1, and human blood monocytes in vitro, as IL-8 is a potent inflammatory cytokine involved in neutrophil chemotaxis and activation. We found that one component, ginsenan S-IIA, is a potent inducer of IL-8 production by human monocytes and THP-1 cells, and this induction is accompanied by increased IL-8 mRNA expression.
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
The purposes of the present work were twofold: (1) investigate same mechanisms involved in the development of fat cell hypertrophy in the experimental model of dyslipidemia and whole-body insulin resistance induced in rats chronically fed a sucrose-rich diet (SRD); and (2) analyze the possible beneficial effect of fish oil on these mechanisms. For 6 mo, male Wistar rats received a sucrose-rich diet (62.5% w/w sucrose, 8% corn oil) or a control diet in which sucrose was replaced by starch. After this period, the sucrose-fed animals were divided randomly into two groups: the first one continued with the same diet up to 8 mo and the second one received the same diet, but with corn oil replaced by 7% fish oil+1 % corn oil. Rats were fed with this diet for the next 2 mo. Although an enlarged fat cell lipolysis and an impaired insulin-stimulated glucose uptake were present in the fat cells of SRD-fed rats, an increase of several key enzymes of the novo lipogenesis could be one of the possible mechanisms involved in visceral adiposity. The addition of dietary fish oil restored or improved the above abnormalities. This study shows possible mechanisms conditioning the influence of nutrients on the development and management of dyslipidemia, insulin sensitivity, and fat cell accretion, all abnormalities present in the metabolic syndrome.
Article
In the previous studies, we reported that carnosic acid (CA) and carnosol (CS) originating from rosemary protected cortical neurons by activating the Keap1/Nrf2 pathway, which activation was initiated by S-alkylation of the critical cysteine thiol of the Keap1 protein by the "electrophilic"quinone-type of CA or CS. Here, we found that CA and CS inhibited the in vitro differentiation of mouse preadipocytes, 3T3-L1 cells, into adipocytes. In contrast, other physiologically-active and rosemary-originated compounds were completely negative. These actions seemed to be mediated by activation of the antioxidant-response element (ARE) and induction of phase2 enzymes. This estimation is justified by our present findings that only CA and CS among rosemary-originated compounds significantly activated the ARE and induced the phase2 enzymes. Next, we performed cDNA microarray analysis in order to identify the gene(s) responsible for these biological actions and found that phase2 enzymes (Gsta2, Gclc, Abcc4, and Abcc1), all of which are involved in the metabolism of glutathione (GSH), constituted 4 of the top 5 CA-induced genes. Furthermore, CA and CS, but not the other compounds tested, significantly increased the intracellular level of total GSH. Thus, we propose that the stimulation of GSH metabolism may be a critical step for the inhibition of adipocyte differentiation in 3T3-L1 cells and suggest that pro-electrophilic compounds such as CA and CS may be potential drugs against obesity-related diseases.
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Despite decades of intensive investigation, the basic pathophysiological mechanisms responsible for the metabolic derangements associated with diabetes mellitus have remained elusive. Explored here is the possibility that traditional concepts in this area might have carried the wrong emphasis. It is suggested that the phenomena of insulin resistance and hyperglycemia might be more readily understood if viewed in the context of underlying abnormalities of lipid metabolism.
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Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-alpha form mediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-I and apoA-II. Fibrates lower hepatic apoC-III production and increase lipoprotein lipase--mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the beta-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. In summary, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression.
Article
beta-Oxidation occurs in both mitochondria and peroxisomes. Mitochondria catalyze the beta-oxidation of the bulk of short-, medium-, and long-chain fatty acids derived from diet, and this pathway constitutes the major process by which fatty acids are oxidized to generate energy. Peroxisomes are involved in the beta-oxidation chain shortening of long-chain and very-long-chain fatty acyl-coenzyme (CoAs), long-chain dicarboxylyl-CoAs, the CoA esters of eicosanoids, 2-methyl-branched fatty acyl-CoAs, and the CoA esters of the bile acid intermediates di- and trihydroxycoprostanoic acids, and in the process they generate H2O2. Long-chain and very-long-chain fatty acids (VLCFAs) are also metabolized by the cytochrome P450 CYP4A omega-oxidation system to dicarboxylic acids that serve as substrates for peroxisomal beta-oxidation. The peroxisomal beta-oxidation system consists of (a) a classical peroxisome proliferator-inducible pathway capable of catalyzing straight-chain acyl-CoAs by fatty acyl-CoA oxidase, L-bifunctional protein, and thiolase, and (b) a second noninducible pathway catalyzing the oxidation of 2-methyl-branched fatty acyl-CoAs by branched-chain acyl-CoA oxidase (pristanoyl-CoA oxidase/trihydroxycoprostanoyl-CoA oxidase), D-bifunctional protein, and sterol carrier protein (SCP)x. The genes encoding the classical beta-oxidation pathway in liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Evidence derived from mice deficient in PPAR alpha, peroxisomal fatty acyl-CoA oxidase, and some of the other enzymes of the two peroxisomal beta-oxidation pathways points to the critical importance of PPAR alpha and of the classical peroxisomal fatty acyl-CoA oxidase in energy metabolism, and in the development of hepatic steatosis, steatohepatitis, and liver cancer.
Article
In this study, the medicinal plants used in the treatment of diabetes mellitus, hypertension and cardiac diseases were inventoried based on the ethnopharmacological survey in south-eastern Morocco: Tafilalet region. Seven hundred persons including 320 diabetic patients and 380 patients with hypertension and cardiac disorders and 20 traditional herbal healers were interviewed in different areas of Tafilalet. The results indicated that 80% of patients interviewed used medicinal plants to treat diabetes, hypertension and cardiac diseases because they state that phytotherapy is cheaper (58%), more efficient (40%) and better (65%) than modern medicine. In this ethnobotanic enquiry, about 92 medicinal plants were cited. A lot of them are cited for the first time in Morocco. Many parameters have been evaluated such as knowledge of the toxic plants, doses, parts used, etc. Also, we have reported that 75% of type 2 diabetic patients used medicinal plants in association with modern drugs, while 10% of type 1 diabetic patients regularly used medicinal plants combined with insulin treatment. Some toxic plants have also been reported. In conclusion Tafilalet region disposes of a large phytotherapy knowledge which must be scientifically investigated especially in treating diabetes mellitus, hypertension and cardiac diseases.
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 World Medical Association's Declaration of Helsinki was first adopted in 1964. In its 40-year lifetime the Declaration has been revised five times and has risen to a position of prominence as a guiding statement of ethical principles for doctors involved in medical research. The most recent revision, however, has resulted in considerable controversy, particularly in the area of the ethical requirements surrounding placebo-controlled trials and the question of responsibilities to research participants at the end of a study. This review considers the past versions of the Declaration of Helsinki and asks the question: How exactly has the text of the Declaration changed throughout its lifetime? Regarding the present form of the Declaration of Helsinki we ask: What are the major changes in the most recent revision and what are the controversies surrounding them? Finally, building on the detailed review of the past and present versions of the Declaration of Helsinki, we give consideration to some of the possible future trajectories for the Declaration in the light of its history and standing in the world of the ethics of medical research.
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
Peroxisome proliferator-activated receptor (PPAR)-alpha is a ligand-activated transcriptional factor that belongs to the family of nuclear receptors. PPAR-alpha regulates the expression of genes involved in fatty acid beta-oxidation and is a major regulator of energy homeostasis. Fibrates are PPAR-alpha agonists and have been used to treat dyslipidemia for several decades because of their triglyceride (TG) lowering and high-density lipoprotein cholesterol (HDL-C) elevating effects. More recent research has demonstrated anti-inflammatory and anti-thrombotic actions of PPAR-alpha agonists in the vessel wall as well. Thus, PPAR-alpha agonists decrease the progression of atherosclerosis by modulating metabolic risk factors and by their anti-inflammatory actions on the level of the vascular wall. This is confirmed by several clinical studies, in which fibrates have shown to reduce atherosclerotic plaque formation and the event rate of coronary heart disease (CHD), especially in patients suffering from metabolic syndrome (MS). MS is characterized by a group of metabolic risk factors that include obesity, raised blood pressure, dyslipidemia, insulin resistance or glucose intolerance, and a prothrombotic state, and its incidence in the Western world is rising to epidemic proportions. This review paper will focus on the functions of PPAR-alpha in fatty acid beta-oxidation, lipid metabolism, and vascular inflammation. Furthermore, PPAR-alpha genetics, the clinical use of PPAR-alpha activators and their future perspective will be discussed.
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
The pathological sequence for type 2 diabetes is complex and entails many different elements that act in concert to cause that disease. This review proposes a sequence of events and how they interact by a careful analysis of the human and animal model literature. A genetic predisposition must exist, although to date very little is known about specific genetic defects in this disease. Whether the diabetes phenotype will occur depends on many environmental factors that share an ability to stress the glucose homeostasis system, with the current explosion of obesity and sedentary lifestyle being a major cause of the worldwide diabetes epidemic. We also propose that a lowered beta-cell mass either through genetic and/or beta-cell cytotoxic factors predisposes for glucose intolerance. As the blood glucose level rises even a small amount above normal, then acquired defects in the glucose homeostasis system occur--initially to impair the beta cell's glucose responsiveness to meals by impairing the first phase insulin response--and cause the blood glucose level to rise into the range of impaired glucose tolerance (IGT). This rise in blood glucose, now perhaps in concert with the excess fatty acids that are a typical feature of obesity and insulin resistance, cause additional deterioration in beta-cell function along with further insulin resistance, and the blood glucose levels rise to full-blown diabetes. This sequence also provides insight into how to better prevent or treat type 2 diabetes, by studying the molecular basis for the early defects, and developing targeted therapies against them.
Article
Peroxisome proliferator-activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPARalpha and -gamma are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPARalpha. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPARgamma, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPARgamma agonists are therefore used to treat type 2 diabetes. PPARalpha and -gamma agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPARalpha/gamma agonists (currently in development) look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPARdelta, and its potential as a therapeutic target are currently under investigation.
Article
Phytochemicals such as soy isoflavone genistein have been reported to possess therapeutic effects for obesity, diabetes, and cardiovascular diseases. In the present study, the molecular basis of selective phytochemicals with emphasis on their ability to control intracellular signaling cascades of AMP-activated kinase (AMPK) responsible for the inhibition of adipogenesis was investigated. Recently, the evolutionarily conserved serine/threonine kinase, AMPK, emerges as a possible target molecule of anti-obesity. Hypothalamic AMPK was found to integrate nutritional and hormonal signals modulating feeding behavior and energy expenditure. We have investigated the effects of genistein, EGCG, and capsaicin on adipocyte differentiation in relation to AMPK activation in 3T3-L1 cells. Genistein (20-200muM) significantly inhibited the process of adipocyte differentiation and led to apoptosis of mature adipocytes. Genistein, EGCG, and capsaicin stimulated the intracellular ROS release, which activated AMPK rapidly. We suggest that AMPK is a novel and critical component of both inhibition of adipocyte differentiation and apoptosis of mature adipocytes by genistein or EGCG or capsaicin further implying AMPK as a prime target of obesity control.
Article
Many factors affect the onset of obesity including satiety control, reduced levels of physical exercise as well as hormonal and genetic parameters which influence the metabolic pathways leading to the net accumulation of triacylglycerol (TAG). The predominant fatty acid of human adipose tissue TAGs is oleic acid, reflecting primarily the composition of the diet but also the product of de novo lipogenesis. Consequently, both carbohydrates and lipids are potential sources of these stored fats. Many studies have been carried out using a variety of differing experimental protocols on healthy, obese or diabetic humans and animals in positive or neutral energy balance to establish the underlying molecular basis for obesity particularly in humans. This short review discusses the interdependence and control of the metabolism of lipids and carbohydrates as it relates to lipogenesis and proposes a unified hypothesis for obesity which brings together a number of different approaches focusing on (i) the interaction of dietary fat and carbohydrate, which typically represent approximately 80% of the daily caloric intake, and their role in the synthesis of TAGs, (ii) the biochemical pathways which control the amount of TAG produced by controlling the composition of their fatty acids via the action of stearoyl-CoA desaturase (SCD), (iii) the control of lipogenesis and SCD by dietary polyunsaturated fatty acid (PUFA) and (iv) the interaction of PUFAs with the transcription factors, peroxisome proliferator activated receptors (PPAR) alpha and gamma, which maintain the balance between oxidation and storage of lipids. The hypothesis focuses on the central role of stearoyl-CoA desaturase (SCD) and its inhibition by polyunsaturated fatty acids (PUFAs) acting via transcription factors based upon data obtained from both animal and human studies. From these observations it should be possible to determine the relevance of the hypothesis to humans and to speculate how these aspects of metabolism may impact the risk of developing related diseases such as coronary heart disease, Type 2 diabetes and certain forms of cancer.
Potential cellular and genetic mechanisms for insulin resistance in the common disorders of diabetes and obesity
  • B L Seely
  • J M Olefsky
Seely, B.L., Olefsky, J.M., 1993. Potential cellular and genetic mechanisms for insulin resistance in the common disorders of diabetes and obesity. In: Moller, D. (Ed.), Insulin Resistance and its Clinical Disorders, pp. 187-252.
Sturtevant's Notes on Edible Plants
  • U P Hedrick
  • J T Hwang
  • I J Park
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  • Y K Lee
  • S K Lee
Hedrick, U.P., 1919. Sturtevant's Notes on Edible Plants, 1st ed. State of New York – Department of Agriculture, Albany. Hwang, J.T., Park, I.J., Shin, J.I., Lee, Y.K., Lee, S.K., Baik, H.W., Ha, J., Park, O.J., 2005.
and capsaicin inhibit adipocyte differentiation process via acti-vating AMP-activated protein kinase
  • Genistein
  • Egcg
Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via acti-vating AMP-activated protein kinase. Biochemical and Biophysical Research Communications 338 (2), 694–699.
Moroccan Cafe: Casual Moroccan Cooking at Home. Silverback Books
  • E Vergne
Vergne, E., 2001. Moroccan Cafe: Casual Moroccan Cooking at Home. Silverback Books.
Plantes et remèdes naturels Genève
  • T C Boisver
Boisver, T.C., 2003. Plantes et remèdes naturels Genève.
Sturtevant's Notes on Edible Plants, 1st ed. State of New York -Department of Agriculture
  • U P Hedrick
Hedrick, U.P., 1919. Sturtevant's Notes on Edible Plants, 1st ed. State of New York -Department of Agriculture, Albany.
Technical Guidelines for genetic conservation: common ash (Fraxinus excelsior)
  • A Pliûra
  • M Heuertz
Pliûra, A., Heuertz, M., 2003. Technical Guidelines for genetic conservation: common ash (Fraxinus excelsior). European Forest Genetic Resources Programme 1 (1).
Moroccan Cafe: Casual Moroccan Cooking at Home
  • E Vergne
Vergne, E., 2001. Moroccan Cafe: Casual Moroccan Cooking at Home. Silverback Books.