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Raspberry ketone in food supplements – High intake, few toxicity data – A cause for safety concern?
Abstract
Raspberry ketone (4-(4-hydroxyphenyl)-2-butanone) is marketed on the Internet as a food supplement. The recommended intake is between 100 to 1 400 mg per day. The substance is naturally occurring in raspberries (up to 4.3 mg/kg) and is used as a flavouring substance. Toxicological studies on raspberry ketone are limited to acute and subchronic studies in rats. When the lowest recommended daily dose of raspberry ketone (100 mg) as a food supplement is consumed, it is 56 times the established threshold of toxicological concern (TTC) of 1 800 μg/day for Class 1 substances. The margin of safety (MOS) based on a NOAEL of 280 mg/kg bw/day for lower weight gain in rats is 165 at 100 mg and 12 at 1 400 mg. The recommended doses are a concern taking into account the TTC and MOS. Investigations of raspberry ketone in quantitative structure-activity relationship (QSAR) models indicated potential cardiotoxic effects and potential effects on reproduction/development. Taking into account the high intake via supplements, the compound's toxic potential should be clarified with further experimental studies. In UK the pure compound is regarded as novel food requiring authorisation prior to marketing but raspberry ketone is not withdrawn from Internet sites from this country.
Copyright © 2015. Published by Elsevier Inc.
... Aromatic alcohol with a rose-like odor, which is widely used in cosmetics and perfumery (Etschmann et al. 2004) Raspberry ketone An aromatic phenolic compound, which is most commonly present in red raspberry, followed by other berry fruits (Bredsdorff et al. 2015) Vanillin Phenolic aldehyde with ether, hydroxyl and aldehyde functional groups, which is naturally derived from the seeds of the vanilla plant (Goodner et al. 2000) Benezonic derivatives ...
... For the phenolic derivatives of phenylpropene, phenylethyl alcohol is an aromatic alcohol with a rose-like odor, which is widely used in cosmetics and perfumery (Etschmann, Sell, and Schrader 2004). Raspberry ketone is an aromatic phenolic compound, which is most commonly present in red raspberry, followed by other berry fruits such as boysenberry, loganberry, sea buckthorn, blackberry, cranberry, and buckwheat honey (Bredsdorff et al. 2015). Vanillin is a phenolic aldehyde with ether, hydroxyl and aldehyde functional groups, which is naturally derived from the seeds of the vanilla plant. ...
... Similar to strawberry, raspberry scent is also widely used as aroma/flavor additive in food industry (Bredsdorff et al. 2015). The key aroma constituent in raspberry is 4-(4hydroxyphenyl)-2-butanone (raspberry ketone), which is found in bound form (Pabst, Barron, Etievant, et al. 1991). ...
Fruit aroma is mainly contributed by free and glycosidically bound aroma compounds, in which glycosidically bound form can be converted into free form during storage and processing, thereby enhancing the overall aroma property. In recent years, the bound aroma precursors have been widely used as flavor additives in the food industry to enhance, balance and recover the flavor of products. This review summarizes the fruit-derived aroma glycosides in different aspects including chemical structures, enzymatic hydrolysis, biosynthesis and occurrence. Aroma glycosides structurally involve an aroma compound (aglycone) and a sugar moiety (glycone). They can be hydrolyzed to release free volatiles by endo- and/or exo-glucosidase, while their biosynthesis refers to glycosylation process using glycosyltransferases (GTs). So far, aroma glycosides have been found and studied in multiple fruits such as grapes, mangoes, lychees and so on. Additionally, their importance in flavor perception, their utilization in food flavor enhancement and other industrial applications are also discussed. Aroma glycosides can enhance flavor perception via hydrolyzation by β-glucosidase in human saliva. Moreover, they are able to impart product flavor by controlling the liberation of active volatiles in industrial applications. This review provides fundamental information for the future investigation on the fruit-derived aroma glycosides.
... In the present investigation, we tried to test the ameliorative effect of raspberry ketone and white tea against acrylamide-induced toxicity in rats. Our observations showed that the total body weights of RK and AA treated groups were significantly declined (p < 0.001) if compared to the control group, and this was in agreement with the previous findings of ( Wang et al. 2012, Bredsdorff et al. 2015, Wang et al. 2016, Mehanna et al. 2018. Who reported that raspberry ketone administration could effectively induce lipolysis and abrogate hyperlipidemia, oxidative stress and improve the insulin sensitivity. ...
... AA administration exhibited disturbance in the hepatic lobules, vacuoles in the hepatocytes, massive lymphocytes infiltration in the portal and peripheral spaces with dilated and this is in agreement with (Singh et al. 2015) and (Ansar et al. 2016). The Supplementation of Raspberry ketone and white tea had a significant improvement in the liver histological architecture as they counteracted the effect of AA toxicity on liver tissue (Wang et al. 2012, Bredsdorff et al. 2015, Gedik et al. 2017. After supplementation, portal and peripheral dilations greatly diminished, vascular congestion, inflammatory cell infiltration, and intracytoplasmic vacuolization in hepatocytes were significantly diminished in liver sections if compared to those treated with AA, while hepatocellular necrosis and hemorrhage were not indicated at all. ...
The current investigation was accomplished to evaluate the hepatoprotective effect of White tea and Raspberry Ketone against toxicity induced by acrylamide in rats. Sixty adult male rats were divided randomly into group (I) control; group (II) rats received RK with dose (6 mg/kg/day); Group III: rats received 5 ml of WT extract/kg/day; Group IV rats received AA (5 mg/kg/day); Group V: rats administrated with both AA (5 mg/kg/day) and RK (6 mg/kg/day) and Group VI: rats administrated AA (5 mg/kg/day) and 5 ml of WT extract/kg/day. The biochemical assays exhibited a significant increase in serum levels of Adiponectin, AST, ALT, ALP of the group treated with acrylamide if compared to the control group and an improvement in their levels of groups V and VI. The histopathological and immunohistochemical findings confirm the biochemical observations. In conclusion, the present investigation proved that the supplementation of WT and RK enhanced the liver histology, immunohistochemistry and biochemistry against the oxidative stress induced by acrylamide.
... Thus, it is utilized by food and beverage industries to flavor beverages and foods, e.g. pudding, yogurt or sweets [1,2]. In addition, its presumed activity as an anti-obesity or skinwhitening agent, drew consumers interest, although a potential toxicity of this compound for humans has not yet been clarified [2][3][4][5][6]. ...
... pudding, yogurt or sweets [1,2]. In addition, its presumed activity as an anti-obesity or skinwhitening agent, drew consumers interest, although a potential toxicity of this compound for humans has not yet been clarified [2][3][4][5][6]. ...
Background:
The phenylbutanoid 4-(4-hydroxyphenyl)butan-2-one, commonly known as raspberry ketone, is responsible for the typical scent and flavor of ripe raspberries. Chemical production of nature-identical raspberry ketone is well established as this compound is frequently used to flavor food, beverages and perfumes. However, high demand for natural raspberry ketone, but low natural abundance in raspberries, render raspberry ketone one of the most expensive natural flavoring components.
Results:
In this study, Corynebacterium glutamicum was engineered for the microbial synthesis of the character impact compound raspberry ketone from supplemented p-coumaric acid. In this context, the NADPH-dependent curcumin/dihydrocurcumin reductase CurA from Escherichia coli was employed to catalyze the final step of raspberry ketone synthesis as it provides a hitherto unknown benzalacetone reductase activity. In combination with a 4-coumarate: CoA ligase from parsley (Petroselinum crispum) and a monofunctional benzalacetone synthase from Chinese rhubarb (Rheum palmatum), CurA constitutes the synthetic pathway for raspberry ketone synthesis in C. glutamicum. The resulting strain accumulated up to 99.8 mg/L (0.61 mM) raspberry ketone. In addition, supplementation of other phenylpropanoids allowed for the synthesis of two other naturally-occurring and flavoring phenylbutanoids, zingerone (70 mg/L, 0.36 mM) and benzylacetone (10.5 mg/L, 0.07 mM).
Conclusion:
The aromatic product portfolio of C. glutamicum was extended towards the synthesis of the flavoring phenylbutanoids raspberry ketone, zingerone and benzylacetone. Key to success was the identification of CurA from E. coli having a benzalacetone reductase activity. We believe, that the constructed C. glutamicum strain represents a versatile platform for the production of natural flavoring phenylbutanoids at larger scale.
... In the present investigation, we tried to test the ameliorative effect of raspberry ketone and white tea against acrylamide-induced toxicity in rats. Our observations showed that the total body weights of RK and AA treated groups were significantly declined (p < 0.001) if compared to the control group, and this was in agreement with the previous findings of ( Wang et al. 2012, Bredsdorff et al. 2015, Wang et al. 2016, Mehanna et al. 2018. Who reported that raspberry ketone administration could effectively induce lipolysis and abrogate hyperlipidemia, oxidative stress and improve the insulin sensitivity. ...
... AA administration exhibited disturbance in the hepatic lobules, vacuoles in the hepatocytes, massive lymphocytes infiltration in the portal and peripheral spaces with dilated and this is in agreement with (Singh et al. 2015) and (Ansar et al. 2016). The Supplementation of Raspberry ketone and white tea had a significant improvement in the liver histological architecture as they counteracted the effect of AA toxicity on liver tissue (Wang et al. 2012, Bredsdorff et al. 2015, Gedik et al. 2017. After supplementation, portal and peripheral dilations greatly diminished, vascular congestion, inflammatory cell infiltration, and intracytoplasmic vacuolization in hepatocytes were significantly diminished in liver sections if compared to those treated with AA, while hepatocellular necrosis and hemorrhage were not indicated at all. ...
The toxic effects of ACR monomer include carcinogenesis, cellular genotoxic, and neurotoxicity. In this study, we examined the effect of acrylamide on biochemical and hematologic parameters in Wistar rats and explored the renal and hepatic function of these animals through a complementary anatomopatho-logic study. For it, thirty female Wistar rats aged 4 weeks and weighing 100 ± 10 g were housed six animals per cage and divided as follows: two groups were exposed for 2 months to drinking water containing 5 mg (Group 2) or 10 mg acrylamide (Group 3); one group of 12 rats received the median lethal dose of acrylamide by gavage (Group 4); and the control group (Group 1) received pure water. The results clearly showed that acrylamide affects various biochemical parameters, such as creatinine, urea, and serum globulin levels and the lipid balance, which are directly related to renal and hepatic dysfunc-tion and disruption of the hematologic system. In addition, the data revealed changes in the complete blood count (CBC); significant increases in the number of leukocytes (9.95 ± 1.44 and 10.44 ± 1.21) and lymphocytes (6.11 ± 0.48 and 6.33 ± 0.76) in Groups 3 and 4, respectively; and decreases in total protein (88.95 ± 6.36), albumin (37.65 ± 1.65) and a-1 globulin levels (24.84 ± 2.10) in Group 3. The anatomopa-thologic study confirmed liver damage in the animals administered an acrylamide containing diet compared with those in the control group. The present study confirmed the effects of acrylamide on different hematologic, biochemical and immunologic parameters, with a specific focus on the liver and kidney, and on the induction of neurotoxic disorders. The results showed that oral exposure to acryl-amide via drinking water or gavage induces kidney damage, hepatocellular insufficiency and chronic liver disease, resulting in primary immunodeficiency and activation of the immune system following the possible expression of certain immunoreaction genes. ARTICLE HISTORY
... Raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] is an aromatic substance used by the food industry for flavoring [50]. In vitro studies using adipocytes have observed an increase in fatty acid oxidation, suppression in lipid accumulation, and increased secretion of adiponectin [51]. ...
... Although raspberry ketone has been considered within alternative weight loss management, no clinical evidence is available, and furthermore, raspberry ketone has the potential adverse effect of cardiotoxicity as well as a teratogenic effect, as identified in silico [50]. ...
Obesity and its associated cardiometabolic alterations currently are considered an epidemic; thus, their treatment is of major importance. The cornerstone for such treatment involves therapeutic lifestyle changes; however, the vast majority of cases fail and/or significant weight loss is maintained only in the short term because of lack of compliance. The popularity of dietary supplements for weight management has increased, and a wide variety of these products are available over the counter. However, the existing scientific evidence is insufficient to recommend their safe use. Hence, the purpose of this article is to review the clinical effects, proposed mechanism of action, and safety profile of some of the new dietary supplements, including white bean extract, Garcinia cambogia, bitter orange, Hoodia gordonii, forskolin, green coffee, glucomannan, β-glucans, chitosan, guar gum, and raspberry ketones.
... Isolation of low concentrations of this natural RK is very expensive. Hence, it can be produced through chemical or biosynthesis reactions (Bredsdorff et al. 2015). RK has been widely used as a flavouring agent in food products and whitening agent in cosmetics (Lin et al. 2011). ...
In this article, we designed one-step economic eco-harmonious microwave-assisted procedure to prepare nitrogen-doped carbon dots. We selected egg white as a cheap glycoprotein-based carbon source without the assistance of any chemicals. The synthetic process requires only 3 min during which carbonization and nitrogen doping are realized at the same time. The fabricated carbon dots were characterized for particle size, structure and photoluminescence behaviour. The nanodots were amorphous carbon-rich naturally nitrogen-doped particles with plentiful attached hydrophilic functional groups. They had average particle size 2.98 ± 1.57 nm, emitted strong blue fluorescence and showed excitation-dependant emission behaviour. What is more, the practical use of this system for raspberry ketone determination in commercially available weight loss dietary supplement product is demonstrated successfully. In ethylene glycol medium, the addition of raspberry ketone enhances the emission intensity of the synthesized carbon dots. The effect of reaction time and solvent was investigated. After optimization, the intensity enhancement was linear to the amount of raspberry ketone added to the assay solution in the concentration range of 100–1000 ng/ml, with detection and quantitation limits of 15.10 and 45.45 ng/ml, respectively. The method was validated in accordance to International Conference on Harmonization (ICH) guidelines and further applied to raspberry ketone capsules showing excellent results.
Graphical abstract
... At least one case of coronary vasospasm has been associated with raspberry ketone intake [5]. Investigations of raspberry ketone in quantitative structure-activity relationship (QSAR) models indicated potential cardiotoxic effects [6]. ...
A 32-year-old female with no cardiac risk factors was admitted for treatment of a perianal abscess. During her hospital stay, she had a pulseless electrical activity arrest with a return of spontaneous circulation after one round of cardiopulmonary resuscitation (CPR). After transfer to the Intensive Care Unit (ICU), the patient had polymorphic ventricular tachycardia (PVT) requiring defibrillation shock. Her PVT was resistant to medical interventions. She was shocked a total of 33 times before her arrhythmia was terminated by passing a temporary transvenous pacemaker with overdrive pacing. After an extensive review of her history and presentation, no clear cause of her resistant arrhythmia was identified, however, she was found to have recently started taking over-the-counter weight loss supplements containing raspberry ketones which is a potentially cardiotoxic ingredient.
... These properties suggest that raspberry ketone supplementation could be an alternative weight-loss measure, but sufficient clinical evidence is lacking and certain teratogenic and cardiotoxic effects of raspberry ketones identified by in-silico research, indicate the need for further detailed study [77]. ...
Obesity and associated complications including diabetes, cardiometabolic dysfunction, disability, malignancy and premature mortality are considered epidemic. Research on obesity is therefore of worldwide importance. The development of obesity is a multifactorial phenomenon with contributions from biological, behavioral, genetic and environmental factors. Obesity and its associated issues require various lifestyle modifications and treatment options such medication, exercise, diet, surgery, pharmacological therapy and dietary supplements. Dietary supplements are considered an attractive alternative to traditional therapy due to their low toxicity profile and their accessibility to the general population. Dietary supplements may include one or more dietary ingredients. In this narrative review, we analyze the effects on obesity and obesity-related issues of various natural components. For example, there are a myriad of supplements that have been used as dietary supplements for weight loss such as minerals, vitamins, amino acids, metabolites, herbs, and plant extracts. This narrative review aims to present the benefits and side-effects of several ingredients of dietary supplements for weight loss and treatment of obesity. In particular, the mechanism of action, results of clinical trials, and possible side effects will be presented for the following ingredients: β-Glucans, bitter orange, calcium, vitamin D, chitosan, chromium, cocoa, coleus forskohlii, conjugate linoleic acid, ephedra sinica, fucoxanthin, garcinia cambogia, glucomannan, green coffee, green tea, guar gum, raspberry, hoodia gordonii, irvingia gabonensis, phenylpropylamine, pyruvate, white kidney bean.
... Citrus fruits Stimulates thermogenesis [48,49] Pyruvate Intermediate of glycolysis Reduces appetite and fatigue, increases energy levels and muscle glycogen stores [24,41] Conjugated Linoleic Acid Meat & dairy products Transports dietary fats to cells for lipolysis [50,51] ...
Lipedema is a chronic disease that mostly manifests in females as the abnormal distribution of subcutaneous adipose connective tissue, usually coupled with bruising, pain, and edema. Lipedema molecular pathophysiology is currently not clear, but several studies suggest that genetics and hormonal imbalance participate in lipedema pathogenesis. Women with lipedema present in some cases with elevated body mass index, and the appearance of obesity in addition to lipedema, where the obesity can cause serious health issues as in lipedema-free individuals with obesity, such as diabetes and cardiovascular disorders. Unlike obesity, lipedema tissue does not respond well to diet or physical exercise alone. Therefore, in this review we discuss the effect of various dietary supplements that, along with diet and physical exercise, cause fat burning and weight loss, and which could potentially be important in the treatment of lipedema. Indeed, an effective fat burner should convert stored fats into energy, mobilize and break down triglycerides in adipocytes, boost metabolism and inhibit lipogenesis. Common ingredients of fat burning supplements are green tea, caffeine, chromium, carnitine, and conjugated linoleic acid. The use of fat burners could act synergistically with a healthy diet and physical exercise for decreasing adipose tissue deposition in patients with lipedema and resolve related health issues. The effects of fat burners in human studies are sometimes contradictory, and further studies should test their effectiveness in treating lipedema.
... BAS shares 70% amino acid sequence identity with CHS. It condenses one p-coumaroyl-CoA with one malonyl-CoA to produce C6-C4 diketide benzalacetone, which can lead to valuable flavoring agent such as raspberry ketone used in cosmetics, food industry, and pharmaceutics (Wang et al., 2012;Bredsdorff et al., 2015;Kim et al., 2016). Till now, BAS have been cloned from Rheum palmatum, Wachendorfia thyrsiflora, Rubus idaeus, and Polygonum cuspidatum (Shimokawa et al., 2012). ...
Plant specialized metabolites occupy unique therapeutic niches in human medicine. A large family of plant specialized metabolites, namely plant polyketides, exhibit diverse and remarkable pharmaceutical properties and thereby great biomanufacturing potential. A growing body of studies has focused on plant polyketide synthesis using plant type III polyketide synthases (PKSs), such as flavonoids, stilbenes, benzalacetones, curcuminoids, chromones, acridones, xanthones, and pyrones. Microbial expression of plant type III PKSs and related biosynthetic pathways in workhorse microorganisms, such as Saccharomyces cerevisiae , Escherichia coli , and Yarrowia lipolytica , have led to the complete biosynthesis of multiple plant polyketides, such as flavonoids and stilbenes, from simple carbohydrates using different metabolic engineering approaches. Additionally, advanced biosynthesis techniques led to the biosynthesis of novel and complex plant polyketides synthesized by diversified type III PKSs. This review will summarize efforts in the past 10 years in type III PKS-catalyzed natural product biosynthesis in microorganisms, especially the complete biosynthesis strategies and achievements.
... The phenolic compounds, benzene acetic acid and phenyl ethanol, that have higher levels in the bark of the susceptible families, have diverse medicinal properties (Bredsdorff et al. 2015;Madan et al. 2016) and may be beneficial to the marsupials. On bark stripping in P. radiata, Smith et al. (2020) for example suggested that non-preferred food sources, such as bark in small quantities, form part of a mixed diet, which may have positive effects on nutrition and digestion, as predicted by the nutrient balance hypothesis (Westoby 1978). ...
Pinus radiata (radiata pine) is native to California but the main plantation softwood in both Australia and New Zealand where it has been subject to breeding to improve productivity and wood quality. However, in many plantations in Australia trees are subject to bark stripping by mammalian (mainly marsupial) herbivores, which can markedly reduce the genetic gain achieved in breeding programmes. This thesis explores the mechanisms and potential for exploiting natural genetic variation in resistance/susceptibility to minimise bark stripping in P. radiata. The study uses field and nursery experiments, integrating results from quantitative genetics, genomics, gene expression, analytical chemistry and rapid phenotyping to understand the genetic basis of variation in bark stripping and associated physical and chemical traits.
To understand the genetic control and the stability of the genetic signal, bark stripping was scored in three Pinus radiata family trials (Chapter 2). Quantitative genetic analysis, using pedigree-based mixed linear models (ABLUP) revealed significant additive genetic variation in bark stripping. Non additive genetic effects were insignificant. While narrow-sense heritability estimates were low, the significant genetic signal was relatively stable across sites. The highest damaged families had approximately two-fold more bark removed than the least browsed families. Selecting the top 20% least susceptible families for planting could potentially reduce bark stripping by up to 22%. In the two older trials, reduced bark stripping was genetically associated with the presence of thick and rough bark while the presence of obstructive branches and needles on the lower stem (stem access) reduced bark stripping in the younger field trial. These important physical traits were also under significant genetic control. A positive additive correlation between prior height and bark stripping in the younger trial suggests that selecting faster growing trees may make P. radiata more vulnerable in the early stages of tree growth. However, when accounting for these physical and growth traits as covariates, significant additive genetic variation in bark stripping was still evident suggesting that genetic-based chemical properties of the bark were also important.
To provide a framework to assess if chemical traits mediated variation in bark-stripping, the plant wide constitutive and induced chemistry was first assessed. In a shade house experiment, induction over a 4-week period was achieved by treating trees with methyl jasmonate (a chemical stressor) and artificial bark stripping (Chapter 3), following which 81 chemical compounds were quantified in the needles, stem and roots. These plant parts had different constitutive chemical profiles, with quantitatively and qualitatively more secondary plant compounds in the bark. After treatment, an overall upregulation of terpenes and phenolics and a down-regulation of sugars and fatty acids was observed. However, the quantitative and qualitative chemical responses differed between plant parts, treatments and time period over the 4 weeks of the experiment. Stronger responses were observed for primary compared to secondary metabolites suggesting their potential roles in plant stress responses, including bark stripping.
To identify the specific constitutive and induced chemical traits that differentiated families with extreme levels of bark stripping, 21 of the most damaged and 21 of the least damaged families were selected from a fenced area within the younger trial used in Chapter 2. This field experiment examined the constitutive and induced chemistry with 83 compounds quantified (Chapter 4). Of the constitutive chemical traits in the bark, specific sugars, phenolics and terpenes were significantly different between the resistant and susceptible families. The bark sugars - fructose and glucose - and the phenolics - phenyl ethanol and benzene acetic acid - increased in the more susceptible families. The bark sesquiterpenoids - bicyclogermacrene and an unknown sesquiterpenoid alcohol - increased in the less susceptible families. The resistant and susceptible families could not be separated based on induced bark chemistry nor constitutive and induced needle chemistry.
An important aim of this thesis was to generate genetic parameters for the chemical traits and identify those that are genetically correlated with bark stripping. To gain sufficient sample size for the genetic study, Chapter 5 explored the potential of near infra-red spectroscopy (NIRS) in qualitative classification and in quantifying the amounts of compounds identified in the samples from the methyl jasmonate treated, artificially bark stripped and non-treated trees used in Chapter 3. NIRS was successful in qualitatively separating samples from different plant parts as well as separating the treated from non-treated samples. NIRS models with high accuracy were developed for individual sugars, terpenes, phenolics and fatty acids. Highest accuracy models were developed for the sugars - glucose and fructose, suggesting practical application of such models, while models for most secondary compounds were able to give proximate amounts. The NIRS modelling was extended to quantify the chemistry for all samples in Chapter 6 for quantitative genetic analysis. Quantitative genetic analysis of the NIRS predicted values of 65 compounds in the bark using pedigree-based mixed models (ABLUP) showed significant additive genetic variation for individual chemical traits with low to moderate narrow-sense heritability estimates (Chapter 6). Results further showed strong positive genetic correlation of the sugar – glucose with bark stripping and a strong negative correlation with the unknown sesquiterpenoid alcohol. The results strengthen the findings based on the wet chemistry of the extreme families in Chapter 4. More positive genetic correlations were detected between bark stripping and fatty acids and an unknown diterpenoid, possibly due to the increased sample size gained from using NIRS prediction. No additive genetic variation in inducibility was detected and non-additive genetic variation in the constitutive chemistry was also not significant. However, most of the heritability estimates were low, implying that response to selection will be slow for these traits. Therefore, the potential improvement in the heritability estimates was tested using genomic models.
To develop the genomic models, SNP genotyping was performed on needles from trees collected in Chapter 6; giving a total of 15,624 SNPs (Chapter 7). Using linear mixed models, the narrow-sense heritability estimates based on genomic models, genomic best linear unbiased prediction (GBLUP) and single-step GBLUP (ssGBLUP) were substantially better for both resistance and chemical traits compared to estimates obtained from the pedigree-based models (ABLUP). For the chemical traits, the average of the univariate GBLUP heritability estimates was1.6- fold higher than the average of the univariate ABLUP heritabilities, suggesting that the SNPs were able to capture additional genetic information. Similarly, the heritability of all the compounds based on the trivariate ssGBLUP was 1.7 – fold higher than the trivariate ABLUP estimates. The predictive ability (PA) of the ssGBLUP was comparable to the trivariate ABLUP model. Similarly, the PA of univariate GBLUP was mostly comparable to the univariate generalised ridge regression (GRR) with a few exceptions. The better performance of the GBLUP over the GRR for most traits suggests that the traits are quantitative in nature, influenced by many genes.
The final chapter examined the expression of genes following methyl jasmonate and bark stripping with the aim of linking the chemical phenotypes in Chapter 3 to the underlying molecular activity, both in the needles and bark samples (Chapter 8). RNA was extracted and sequenced to yield 100bp paired-end sequences and each sample was sequenced to a depth of 20m reads per sample. After aligning the project transcriptome with the available P. radiata transcriptome, gene expression analysis showed up- and downregulation of genes associated with primary and secondary metabolism, with differences in transcript expression in the needles and the bark, between treatments and at different times. Consistent with the chemistry results, the genes that were related to secondary metabolism were also mainly up-regulated. Genes related to primary metabolism were more responsive than those related to secondary metabolism by up-regulation or down-regulation. Methyl jasmonate and bark-stripping showed many non-overlapping responses. Whereas maximum expression of the transcripts was observed 7 days after treatment, on the same population stronger chemical changes were detected 14 and 21 days after treatment, suggesting a time-lag between gene and phenotypic expression.
Overall, the results indicated the potential for selection of less susceptible germplasm for operational plantings as a strategy to reduce the effects of bark stripping in plantation forestry. Selection against bark stripping in P. radiata can also be performed indirectly based on physical or chemical traits. Further tests may be required to establish the stability of the less susceptible families when planted as a monoculture.
... The raspberry phenylbutanoid ketone 4-(4-hydroxyphenyl)butan-2-one (RK) is a natural flavor in plants such as raspberries, grapes, peaches, and rhubarb. The berry flavor of RK with a low odor threshold is used as a food additive to create various aromas such as cherry, strawberry, kiwi and other fruits (Beekwilder et al., 2007;Bredsdorff et al., 2015;Sun et al., 2021). The alleged health benefits of RK include weight reduction (Morimoto et al., 2005;Wang et al., 2012) and skin lightening (Harada et al., 2008) and it is in high demand in the supplements and cosmetics industries (Milke et al., 2020;Vandamme and Soetaert, 2002). ...
The demand for raspberry ketone (RK) as a plant-based natural flavoring agent is high, but natural RK is one of the most expensive flavor compounds due to its limited content in plants. Here, we produced RK de novo from simple carbon sources in Escherichia coli. We genetically engineered E. coli metabolism to overproduce the metabolic precursors tyrosine and p -coumaric acid and increase RK production. The engineered E. coli produced 19.3- and 1.9 g/L of tyrosine and p -coumaric acid from glucose, respectively. The p -coumaric acid CoA ligase from Agrobacterium tumefaciens and amino acid substituted benzalacetone synthase of Rhemu palmatum (Chinese rhubarb) were overexpressed in E. coli overproducing p -coumaric acid . The overexpression of fabF , encoding β-ketoacyl-acyl carrier protein synthetase II increased intracellular malonyl-CoA, the precursor of benzalacetone synthase for RK biosynthesis, and improved RK production. Fed-batch cultures given glucose as a carbon source produced 62 mg/L of RK under optimized conditions. Our production system is inexpensive and does not rely on plant extraction; thus, it should significantly contribute to the flavor and fragrance industries.
... First identified in 1903, the chemical structure of RK was isolated and determined from red raspberries (Rubus idaeus L.) in 1951 (Hugueny et al., 1995). As the key aroma compound of raspberries, RK has been widely used in daily health products and food products as a fragrance and flavoring agent (Bredsdorff et al., 2015). RK is mainly found in red raspberry (0.001-4.2 mg/kg) (Paterson et al., 2013), but is also in a small amount in other plants (0.00081-0.7 mg/kg), such as yew (Taxus baccata L.) (Akiyama et al., 2007(Akiyama et al., , 2008Garcia et al., 2011;Keng-Hong & Nishida, 2005). ...
Novel food and food compounds interventions have attracted a lot of attention nowadays for the prevention and treatment of metabolic diseases. Raspberry ketone (RK) is aromatic compound found within red fruits and berries, has been used as an over-the-counter product for weight loss. However, actually, the effect of RK on weight loss is still controversial, and the mechanism is largely unknown. Besides, in vivo and in vitro studies have demonstrated the beneficial effect of RK on the development of other metabolic diseases. In this review, we comprehensively highlighted the synthesis, bioavailability, and metabolism of RK, and summarized the progress made in our understanding of the potential biological activities of RK, including antiobesity, antidiabetes, cardioprotection, and hepatoprotection, as well as their underlying mechanisms. This paper provides a critical overview about the current findings and proposes the future studies in the area of RK on human health.
Practical applications
Raspberry ketone (RK) has been used for weight control for years, but this effect is controversial considering food intake. Additionally, RK is beneficial for T2DM, liver and heart injury. The underlying mechanisms of the protective effect of RK including accelerating fatty acid oxidation, balancing serum glucose level, anti-inflammation, antioxidant process, and so on. In this context, we provide a comprehensive analysis of the benefits of RK against many metabolic diseases and discuss the underlying molecular mechanisms. We hope our work will be helpful for further researches on RK and improve its public recognition.
... Keywords: frambinone, p-hydroxybenzyl acetone, rasketone, α-glucosidase inhibitor, appetite suppressant, weight supplement INTRODUCTION Raspberry ketone {RK; [4-(4-hydroxyphenyl)-2-butanone]} is a natural phenolic compound derived from red raspberries (Borejsza-Wysocki et al., 1992;Borejsza-Wysocki and Hrazdina, 1994). It is the primary flavor and aroma compound of raspberries and considered safe for food and cosmetic applications in small quantities (Bredsdorff et al., 2015;Administration, 2019). Similar to other naturally derived products with functional hydroxyl groups, such as capsaicin, p-synephrine, and ephedrine, RK has also been investigated for its potential anti-obesity effects (Morimoto et al., 2005). ...
Raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] is a natural aromatic compound found in raspberries and other fruits. Raspberry ketone (RK) is synthetically produced for use as a commercial flavoring agent. In the United States and other markets, it is sold as a dietary supplement for weight control. The potential of RK to reduce or prevent excessive weight gain is unclear and could be a convergence of several different actions. This study sought to determine whether acute RK can immediately delay carbohydrate hyperglycemia and reduce gastrointestinal emptying. In addition, we explored the metabolic signature of chronic RK to prevent or remedy the metabolic effects of diet-induced weight gain. In high-fat diet (HFD; 45% fat)-fed male mice, acute oral gavage of RK (200 mg/kg) reduced hyperglycemia from oral sucrose load (4 g/kg) at 15 min. In HFD-fed female mice, acute oral RK resulted in an increase in blood glucose at 30 min. Chronic daily oral gavage of RK (200 mg/kg) commencing with HFD access (HFD_RK) for 11 weeks resulted in less body weight gain and reduced fat mass compared with vehicle treated (HFD_Veh) and chronic RK starting 4 weeks after HFD access (HFD_RKw4) groups. Compared with a control group fed a low-fat diet (LFD; 10% fat) and dosed with vehicle (LFD_Veh), glucose AUC of an oral glucose tolerance test was increased with HFD_Veh, but not in HFD_RK or HFD_RKw4. Apelin ( Apln) gene expression in epididymal white adipose tissue was increased in HFD_Veh, but reduced to LFD_Veh levels in the HFD_RK group. Peroxisome proliferator activated receptor alpha ( Ppara) gene expression was increased in the hepatic tissue of HFD_RK and HFD_RKw4 groups. Overall, our findings suggest that long term daily use of RK prevents diet-induced weight gain, normalizes high-fat diet-induced adipose Apln , and increases hepatic Ppara expression.
... Żywność bogata w antyutleniacze odgrywa istotną rolę w pro laktyce chorób cywilizacyjnych i dlatego wiedza na ten temat powinna być ciągle aktualizowana. Szczególnie w celu dokładnego poznania składu chemicznego poszczególnych odmian owoców malin, a zwłaszcza zawartości związków polifenolowych, kwasu askorbinowego i ich korzystnego oddziaływania na ludzki organizm [27,28,29]. ...
Malina właściwa (Rubus idaeus L.) jest jedną z najstarszych roślin znanych ludzkości i od wieków wykorzystywana do celów spożywczych oraz leczniczych. O przydatności owoców maliny (Fructus Rubi idaei) i liści (Folium Rubi idaei) decyduje w dużej mierze ich skład chemiczny. Wartość biologiczna owoców maliny właściwej zależy od poziomu antyoksydantów, do których między innymi zalicza się kwas askorbinowy i antocyjany. Natomiast o smaku i aromacie owoców decyduje stopień ich dojrzałości, odmiana, zawartość cukrów prostych, kwasów organicznych oraz substancji lotnych. Owoce maliny są również bogatym źródłem witamin (głównie witaminy C, witamin z grupy B, PP, A, E oraz K), składników mineralnych: potasu (K), wapnia (Ca), magnezu (Mg), żelaza(Fe) oraz w mniejszych ilościach manganu (Mn), miedzi (Cu), cynku (Zn) (dlatego mają działanie odkwaszające, wzmacniają serce i regulują pracę układu nerwowego). Zawierają również spore ilości błonnika i pektyn. Wyniki ostatnich badań naukowych dowiodły,że zawarty w owocach malin kwas elagowy (pestki malin zawierają aż 87,5% kwasu elagowego) hamuje procesy nowotworowe oraz posiada właściwości przeciwwirusowe i przeciwzapalne. Najnowsze badania naukowe potwierdzają również pozytywny wpływketonu malinowego (C10H12O2) na leczenie otyłości.
... The association of phenolics with susceptibility in this study points to the possibility that phenolics may have an attractant rather than a defensive effect, especially in low concentrations. The phenolic compounds, benzeneacetic acid and phenylethanol, that have higher levels in the bark of the susceptible families, have diverse medicinal properties (Bredsdorff et al. 2015;Madan et al. 2016) and may be beneficial to the marsupials. Various studies have demonstrated the beneficial effects of phenolics in both mammals and insects (Johnson and Felton 2001). ...
Bark stripping by mammals is a major problem in managed conifer forests worldwide. In Australia, bark stripping in the exotic plantations of Pinus radiata is mainly caused by native marsupials and results in reduced survival, growth, and in extreme cases death of trees. Herbivory is influenced by a balance between primary metabolites that are sources of nutrition and secondary metabolites that act as defences. Identifying the compounds that influence herbivory may be a useful tool in the management of forest systems. This study aimed to detect and identify both constitutive and induced compounds that are associated with genetic differences in susceptibility of two-year-old P. radiata trees to bark stripping by marsupials. An untargeted profiling of 83 primary and secondary compounds of the needles and bark samples from 21 susceptible and 21 resistant families was undertaken. These were among the most and least damaged families, respectively, screened in a trial of 74 families that were exposed to natural field bark stripping by marsupials. Experimental plants were in the same field trial but protected from bark stripping and a subset were subjected to artificial bark stripping to examine induced and constitutive chemistry differences between resistant and susceptible families. Machine learning (random forest), partial least squares plus discriminant analysis (PLS-DA), and principal components analysis with discriminant analysis (PCA-DA), as well as univariate methods were used to identify the most important totals by compound group and individual compounds differentiating the resistant and susceptible families. In the bark, the constitutive amount of two sesquiterpenoids — bicyclogermacrene and an unknown sesquiterpenoid alcohol —were shown to be of higher levels in the resistant families, whereas the constitutive sugars, fructose, and glucose, as well individual phenolics, were higher in the more susceptible families. The chemistry of the needles was not useful in differentiating the resistant and susceptible families to marsupial bark stripping. After artificial bark stripping, the terpenes, sugars, and phenolics responded in both the resistant and susceptible families by increasing or reducing amounts, which leveled the differences in the amounts of the compounds between the different resistant and susceptible classes observed at the constitutive level. Overall, based on the families with extreme values for less and more susceptibility, differences in the amounts of secondary compounds were subtle and susceptibility due to sugars may outweigh defence as the cause of the genetic variation in bark stripping observed in this non-native tree herbivory system.
... However, at this time there are no in vivo studies to address these possible adverse effects with RK. Considering the very high recommended daily doses between 100 and 1400 mg, it is vital to evaluate the hazards that may occur with daily supplementation of RK [16,75,76]. ...
Raspberry ketone (RK) is an aromatic phenolic compound naturally occurring in red raspberries, kiwifruit, peaches, and apples and reported for its potential therapeutic and nutraceutical properties. Studies in cells and rodents have suggested an important role for RK in hepatic/cardio/gastric protection and as an anti-hyperlipidemic, anti-obesity, depigmentation, and sexual maturation agent. Raspberry ketone-mediated activation of peroxisome proliferator-activated receptor-α (PPAR-α) stands out as one of its main modes of action. Although rodent studies have demonstrated the efficacious effects of RK, its mechanism remains largely unknown. In spite of a lack of reliable human research, RK is marketed as a health supplement, at very high doses. In this review, we provide a compilation of scientific research that has been conducted so far, assessing the therapeutic properties of RK in several disease conditions as well as inspiring future research before RK can be considered safe and efficacious with limited side effects as an alternative to modern medicines in the treatment of major lifestyle-based diseases.
... RK for 13 weeks showed no significant subacute toxicity including weight gain [52]. On the basis of these data, RK is currently being marketed as a dietary supplement for weight loss, with the recommended doses ranging from 100 to 1400 mg/day [97]. Nevertheless, some researchers still warn of the risk of excessive use of RK supplements because the safety and toxicity of RK has not been fully evaluated, especially in high doses. ...
Oxidative stress is closely linked to various diseases, and many studies have been conducted to determine how to reduce this stress. In particular, efforts are being made to find potential antioxidants from natural products. Studies have shown that raspberry ketone (RK; 4-(4-hydroxyphenyl)-2-butanone) has various pharmacological activities. This review summarizes the antioxidant activities of RK and their underlying mechanisms. In several experimental models, it was proven that RK exhibits antioxidant properties through increasing total antioxidant capacity (TAC); upregulating antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT); and improving lipid peroxidation. In conclusion, research about RK’s antioxidant activities is directly or indirectly related to its other various physiological activities. Further studies at the clinical level will be able to verify the value of RK as an effective antioxidant, functional health food, and therapeutic agent.
... Raspberry ketone (RK; 4-(4-hydroxyphenyl)-2-butanone) is a naturally occurring phenolic compound responsible for the aroma and flavor of raspberries (Rubus idaeus) [1,2]. Naturally derived RK is costly to produce, therefore synthetic sources of RK are readily available [3,4]. In the United States, RK is designated as a generally recognized as safe (GRAS) food additive and is listed by the Food and Drug Administration (FDA) as a synthetic flavoring substance [5]. ...
Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is a popular nutraceutical used for weight management and appetite control. We sought to determine the physiological benefits of RK on the meal patterns and cardiovascular changes associated with an obesogenic diet. In addition, we explored whether the physiological benefits of RK promoted anxiety-related behaviors. Male and female C57BL/6J mice were administered a daily oral gavage of RK 200 mg/kg, RK 400 mg/kg, or vehicle for 14 days. Commencing with dosing, mice were placed on a high-fat diet (45% fat) or low-fat diet (10% fat). Our results indicated that RK 200 mg/kg had a differential influence on meal patterns in males and females. In contrast, RK 400 mg/kg reduced body weight gain, open-field total distance travelled, hemodynamic measures (i.e., reduced systolic blood pressure (BP), diastolic BP and mean BP), and increased nocturnal satiety ratios in males and females. In addition, RK 400 mg/kg increased neural activation in the nucleus of the solitary tract, compared with vehicle. RK actions were not influenced by diet, nor resulted in an anxiety-like phenotype. Our findings suggest that RK has dose-differential feeding and cardiovascular actions, which needs consideration as it is used as a nutraceutical for weight control for obesity.
... Le prove a sostegno dell'attività di questa sostanza come agente lipolitico provengono soprattutto da studi preclinici su cavia, che suggeriscono un suo possibile ruolo nella promozione della lipolisi norepinefrino-indotta e nell'ossidazione degli acidi grassi (23,24). I dati sulla sicurezza del "chetone del lampone" sono quasi del tutto assenti, con potenziali effetti avversi (cardiotossicità, alterazioni dello sviluppo e della riproduzione) indicati da modelli predittivi basati sui dati di studi di laboratorio (25). ...
Background. Overweight and obesity are conditions characterized by a growing epidemiological trend.
Objective. The present review aims to collect evidence on the efficacy and safety of remedies derived from medicinal herbs and mushrooms commonly used for weight loss.
Results. Various remedies, grouped on the basis of their mechanism of action, have been analyzed and discussed.
Conclusions. Overall, the most interesting integrative remedies which favor weight loss in overweight or obese subjects seem to be Garcinia cambodia, Camellia sinensis, green coffee, Amorphophallus konjac, chitosan, and Phaseolus vulgaris, acting through different mechanisms on metabolism, nutrient absorption and the sensation of hunger. Further studies are needed to better evaluate the efficacy and safety profile of weight-loss supplements.
CITE AS: Antonelli, M., & Donelli, D. (2019). Medicinal herbs and mushrooms for weight loss: an overview. Pharmanutrition and Functional Foods, 4(4), 12–17.
... It helps the body lose fat by way of raising the body's core temperature through the process of thermogenesis, thereby increasing the metabolic rate speed and burning more calories (Rios-Hoyo et al. 2016;Uckoo et al. 2011). 5. Synephrine is an alkaloid, derived primarily from the immature fruit of Citrus aurantium, and is commonly used in weight loss. It has gained significant popularity as an alternative to ephedrine but it is safer and effective than ephedrine (Bredsdorff et al. 2015). ...
Adipose tissue is a type of connective tissue composed of adipocytes. Recently, this tissue has been recognized as a major endocrine organ. The physiological process of fat loss occurs when fats are liberated from adipocytes into circulation to supply the needed energy. Nutrition supplements that increase fat metabolism, impair fat absorption, increase weight loss, and increase fat oxidation during exercise are known as fat burners. A good fat burner must burn the stored fats, break down the fat cells, and increase the metabolic rate. Eating thermogenic foods helps burn fats. Fat flush diet comes to repair the damage that resulted from ingested and environmental toxins stored in adipocytes. This review will focus on the recent advances in fat burning supplements, fat burning foods, and fat flash diet. The human body can act as a fat-burning machine by depending on low-calorie foods instead of high-calorie foods in addition to doing regular exercise, avoiding toxins and processed food, and applying any fat flush dietary program under the approval of a professional doctor. What’s new in this review is that it may orient our attention to the importance of using natural fat burners in the fat burning process in an attempt to avoid medications that have many side effects by targeting other organs and it also gives an idea of the importance of increasing the brown adipose tissue content because its activation could be linked to a feeling of being full. We need further studies in this context.
... Several reports revealed that the amount of RK sold in US markets in dietary supplements is well above the maximum recommended concentration for food products. 7 8 9 0 1 2 3 4 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 2 Further studies have been recommended to ensure its safety at such concentrations (Bredsdorff et al. 2015;Lee 2016). As the weight reducing products are usually consumed by overweight individuals, it is imperative that a safe dose be determined. ...
Raspberry ketone (RK)—an aromatic compound found mostly in red raspberries (Rubus idaeus) is widely used as an over the counter product for weight loss. The present study was conducted to determine adverse effects associated with RK in obese and health-compromised obese mice. Two sets of experiments were conducted on normal obese and health-compromised obese mice treated with RK for a duration of 10 days. Obese conditions were induced by feeding mice a high fat diet for 10 weeks, while the health compromised obese mouse model was developed by a single intraperitoneal injection of a nontoxic dose of lipopolysaccharide (LPS) (6 mg/kg) to obese mice. Results showed that RK (165, 330, and 500 mg/kg) under obese as well as health-compromised condition retarded the gain in body weights as compared to the control groups. RK at doses 330 and 500 mg/kg resulted in 67.6 and 50% mortality, respectively in normal obese mice and 70% mortality was observed in health-compromised obese mice treated with RK at 500 mg/kg. At higher doses deaths were observed earlier than those given lower doses of RK. Significant elevations in blood alanine transaminase (ALT) were also observed with RK treatment in obese mice. Blood glucose levels were significantly elevated in all groups of mice treated with RK. This study suggests that higher doses of RK may cause adverse effects in health compromised conditions. Under these conditions, prolonged use of RK, especially in high doses, may pose a health hazard.
... Among the large number of volatile compounds identified, 4-(4-hydroxyphenyl)-2-butanone, commonly known as raspberry ketone (RK), is recognized as the primary compound responsible for the characteristic raspberry flavor [1e3]. In addition, RK is an FDA-designated generally recognized as safe (GRAS) additive, which has been widely used in the perfumery, cosmetics and food industry to impart raspberry aroma [4]. Due to its low abundance in nature, fruitderived RK is among the most expensive natural flavor compounds with an estimated market value up to $20,000/kg [5]. ...
Raspberry ketone (RK) is the characteristic aromatic compound in raspberry (Rubus idaeus L.) with wide applications as food additive and anti-obesity agent. However, quantification of RK has presented difficulties in MS detection and reliable LC-MS method for RK analysis in literature is in limit to date. In order to facilitate quality control of raspberry derived products and RK metabolomics study, this study aimed to develop a validated and sensitive UHPLC-MS/MS method. Strong in-source fragmentation was noted and the fragmental ion of 107 m/z produced was selected as the precursor ion for MRM detection, and as such the electrospray ionization performance was optimized by fractional factorial design to accommodate such ion-source dissociation behavior as well as its moderate volatility. A pathway involving the formation of quinone-like structure with strong conjugation was proposed to explain the intense in-source fragmentation. The MRM transition was optimized with product ion of 77 m/z selected as the quantifier ion. The method featured low limit of quantification of ∼2 ng/mL and allowed for rapid detection of RK in fresh raspberries following direct sample preparation. RK contents were found to be higher from locally grown and harvested farm sources compared to commercial products shipped into the state, and higher in those at late-stage compared with early-stage maturity. No correlations in RK content between organic and non-organic labels were noted.
... Moreover, it can help increase the skin's elasticity and promote hair growth by increasing dermal IGF-I production [2][3][4]. It has been reported that raspberry ketone is produced by the Claisen-Schmidt condensation reaction between p-hydroxy benzaldehyde and acetone [5,6]. During the whole manufacturing process, crystallization is one of the most crucial operations that plays an important role in controlling the quality of the product raspberry ketone. ...
The solubility of 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone) in six pure solvents was experimentally determined at temperatures ranging from 283.15 to 313.15 K under the pressure 0.10 MPa by employing a gravimetrical method. The experimental results indicate that the solubility of raspberry ketone in all studied solvents is temperature dependent, a rise in temperature brings about an increase in solubility. The experimental solubility data of raspberry ketone in six pure solvents (acetone, ethanol, ethyl acetate, n-propyl alcohol, n-butyl alcohol, and distilled water) was correlated by using several commonly used thermodynamic models, including the Apelblat, van’t Hoff and λh equations. The results of the error analysis indicate that the van’t Hoff equation was able to give more accurate and reliable predictions of solubility with root-mean-square deviation less than 0.56%. Furthermore, the changes of dissolution enthalpies (ΔdissH°), dissolution entropies (ΔdissS°) and dissolution Gibbs energies (ΔdissG°) of raspberry ketone in the solvents studied were estimated by the van’t Hoff equation. The positive value of ΔdissH°, ΔdissS°, and ΔdissG° indicated that these dissolution processes of raspberry ketone in the solvents studied were all endothermic and enthalpy-driven.
... Therefore, recommended RK daily doses for food supplements are 26-368 times higher than the highest estimated exposure from diet (1.8-3.8 mg/for an adult). This situation is cause of concern and needs to be faced by Food and Health authorities of the EU member states as also reported in a recent toxicological survey (Bredsdorff et al. 2015). ...
In recent years food supplement market increased constantly, including slimming products and against obesity. The case of rasberry ketone (RK) is here reported. HPTLC and HPLC-DAD analyses on a marketed product containing raspberry juice evidenced an abnormal quantity of RK, not in accordance with the juice natural content. The reported data confirm the need of adequate controls on marketed food supplements and the necessity of a complete adherence between labelling and real constitution of the product. Determining the natural origin and assuring the consumers’ safety for raspberry-based food supplements.
... One manufacturer recommended taking 300 mg twice a day (total 600 mg), while the other proposed one 500 mg capsule daily, with neither label describing such dosage in relation to the GRAS advised minimum level of raspberry ketone that achieves raspberry flavor and aroma. As pointed out in European Union by Bredsdorff et al. [46], there is real toxicological concern with the amount of raspberry ketone that (US) dietary supplements advertise will aid weight loss. Additionally, the intake of raspberry ketone at supplement levels also means consumers experience elevated exposure to manufacturing byproducts from the synthesis or extraction of target compounds (residual processing chemicals, etc.), and this has not been studied either. ...
Raspberry ketone supplements have grabbed consumer attention with the possibility they might help burn fat and aid weight loss. While raspberry ketone occurs naturally, and is found in raspberry fruit, most is synthetically produced for use in commercial products as flavorings, fragrances, or dietary supplements. Currently, the amount of raspberry ketone in dietary supplements (currently sold in the US) is well above the maximum concentration recommended for food and fragrance products, so additional toxicology work is needed to ensure such concentrations of raspberry ketone are safe. In addition to safety data, clinical studies are also needed to validate any health benefits. Without research on the effects of consuming high concentrations of raspberry ketone, consumers should be wary of unsubstantiated claims and mindful of potential harm to their health.
Background: Raspberry ketone (RK), derived from red raspberry fruit (Rubus idaeus, family Rosaceae), is a reported potent antiobesity agent. This study aims to investigate method development, validation, and in vitro and in vivo pharmacokinetics in rats. Materials & methods: LC-MS/MS was used to conduct method development, validation, stability, and oral PK samples of RK in plasma analyses. Results: RK was highly soluble in Tris buffer and stable in gastrointestinal fluids as well as plasma. Rat liver microsomal stability of RK in phase I and II studies was 84.96 ± 2.39 and 69.98 ± 8.69%, respectively, after 60 min. Intestinal permeability was 4.39 ± 1.37 × 10-5 cm/s. Maximal concentration was 1591.02 ± 64.76 ng/ml, which was achieved after 1 h (time to maximal concentration), and absolute oral bioavailability was 86.28%. Conclusion: Pharmacokinetic data serve as a keystone for preclinical and clinical adjuvant therapy.
Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is a synthetic flavoring agent and dietary supplement for weight control. This study investigated the metabolic signature of oral doses of RK that prevent weight gain or promote loss of righting reflex (LORR) in C57Bl/6J mice. Daily RK 200 mg/kg prevented high-fat diet (HFD; 45% Kcal fat) fed weight gain (∼8% reduction) over 35 days. RNA-seq of inguinal white adipose tissue (WAT) performed in males revealed 12 differentially expressed genes. Apelin (Apln) and potassium voltage-gated channel subfamily C member (Kcnc3) expression were elevated with HFD and normalized with RK dosing, which was confirmed by qPCR. Acute RK 640 mg/kg produced a LORR with a <5 min onset with a >30 min duration. Acute RK 200 mg/kg increased gene expression of Apln, Kcnc3, and nuclear factor erythroid 2-related factor 2 (Nrf2), but reduced acetyl-COA carboxylase (Acc1) and NAD(P)H quinone dehydrogenase 1 (Nqo1) in inguinal WAT. Acute RK 640 mg/kg elevated interleukin 6 (Il 6) and heme oxygenase 1 (Hmox1) expression, but reduced Nrf2 in inguinal and epididymal WAT. Our findings suggest that RK has a dose-dependent metabolic signature in WAT associated with either weight control or LORR.
Case: 32-year-old obese female with no known medical history who presented with fever and perianal pain for 5 days. She underwent perirectal abscess I&D with drain placement. She was working with physical therapy on the floor when she became unresponsive and had a PEA arrest. Code blue was called with ROSC achieved, and the patient was transferred to ICU. On arrival, patient had polymorphic ventricular tachycardia requiring defibrillation shock. She briefly converted to sinus rhythm but the polymorphic VT recurred-over the course of 2 hours. She received 33 defibrillation shocks per ACLS protocol. Magnesium, calcium chloride, amiodarone, and lidocaine was given. Later, amiodarone was discontinued as per on-call Cardiology recommendation and lidocaine drip was initiated. When Cardiology arrived at bedside, an emergent transvenous pacemaker was placed and set at overdrive pacing, which successfully terminated the arrhythmia. The patient's baseline EKG showed QTc of 339. Electrolytes were within normal limits. The urine drug screen was negative. Post arrest echocardiogram showed LVEF of 20% with global hypokinesis. Family history was not significant for premature coronary artery disease, arrhythmia, or sudden death. The patient's father did suffer a recent stroke for which he was being monitored for A-fib. After extensive discussion with family members, it was revealed that the patient was taking an over-the-counter fat burner which contains raspberry ketones 300 mg and green coffee bean extract 260 mg.
Discussion:
Polymorphic ventricular tachycardia is a type of arrhythmia characterized by multiple foci in the ventricles resulting in QRS complexes which vary significantly in their amplitude, duration, and morphology.
•Differential diagnosis of polymorphic VT includes cardiac ischemia, cardiomyopathies, electrolyte abnormalities, electrophysiologic abnormalities (short or long QT syndromes), and certain medications.
•Considering the lack of any other precipitating factors, it is possible that our patient's run of VT was induced by a combination of the stress of infection and OTC dietary supplements containing high amounts of raspberry ketones and caffeine.
•In the acute setting, management of VT may require immediate cardioversion, defibrillation, or administration of antiarrhythmic drugs.
•Refractory ventricular electrical storm can be terminated with a transvenous pacemaker. Long-term management includes ablation or ICD implantation among whom a completely reversible cause is not identified.
• Resistant polymorphic ventricular tachycardia can potentially be a rare but life-threatening complication of non-FDA regulated OTC weight loss supplements.
• Public awareness, strict regulation policies by the government, along with visible clearly stated disclaimer from the manufacturers should be encouraged
After analyzing multiple pharmaceutical databases like ScienceDirect, PubMed, Google Scholar, and others, it was discovered that RK has yet to be linked to any anti-depressant action. The primary goal of this work was to use in-silico techniques to investigate the anti-depressant capability of RK against three major targets (monoamine oxidases, MAOs; human serotonin transporter, SERT; and serotonin receptors, 5HTs). Moreover, prediction of drug-likeliness, bioavailability, and pharmacokinetics of RK has been done using online computational tools (SwissADME, SwissTargetPrediction, and SwissBioisostere). Thein silico study indicated the emerging role of RK in the management of clinical depression. The pharmacokinetic studies, target prediction studies against 3 species, and biosisosteric-based studies also supported the possibilities of lead development. The study will open new avenues of application of this low-molecular-weight-ligand (LMWL) for the clinicians, chemists, and other scientific professionals in context to emerging depression challenges.
Dietary supplements (DSs) are used by 50% of Americans and 70% of United States military service members (SMs); some have adverse effects (AEs). This cross-sectional investigation examined AEs associated with specific DSs. A stratified random sample of SMs from the Air Force, Army, Marine Corps, and Navy was obtained. Volunteers completed a questionnaire reporting AEs for 96 generic and 62 specific DSs. The highest prevalence (≥1 AE) in specific DS categories was 35% prohormones, 33% weight loss supplements, 26% pre/post workout supplements, 14% herbal products, 12% multivitamin/multiminerals, 11% protein/amino acids, 9% muscle building supplements, 7% other DSs, 6% joint health products, and 5% individual vitamins/minerals. Specific DSs of concern (with proportion reporting AEs) included: Libido Max® (35%), Hydroxycut Hardcore® (33%), OxyElite® (33%), Roxylean® (31%), Growth Factor 9® (30%), Super HD® (29%), Hydroxycut Advanced® (29%), Lipo 6® (28%), The Ripper® (27%), Test Booster® (27%), Xenadrine Xtreme Thermogenic® (27%), C4 Extreme® (26%), and C4 Origional® (25%). Products marketed for weight loss, use before/after workout, and prohormones had the highest AE prevalence. DSs can contain substances with independent/additive AEs and/or interact with other ingredients or prescribed medications. Methods described here could provide a continuous surveillance system detecting dangerous DSs entering the market.
Although Dietary supplements are readily accessible and extensively used worldwide, they are inadequately regulated and consumers are victims of manufacturers' fraud. Thus, quality regulations are required to ensure safety of products available to the public. We propose the first native spectrofluorimetric quality control assay of raspberry ketone, a popular dietary supplement ingredient for weight loss. This work relies on the constant wavelength synchronous scan of the Raspberry Ketone native fluorescence, overcoming the demerits of conventional excitation/ emission spectra. For the best measurement conditions, several parameters were optimized including Δλ value, diluting solvent, medium pH and the effect of surfactants/ macromolecules. In aqueous medium (Δλ = 110 nm), a linear relationship exists between synchronous fluorescence intensity at peak maximum 405.6 nm and solution concentration in the range 300-1500 ng/mL. Method sensitivity was recorded with LOD and LOQ values 60.63 and 183.72 ng/mL; respectively. Validation was done in accordance to International Conference on Harmonization (ICH) guidelines. This simple procedure was successfully applied to the analysis of Raspberry Ketone in commercially available dietary supplement capsules with average recovery 98.67% ± 1.74 and further extended to weight variation testing following the official United States Pharmacopeial (USP) guidelines. Finally, green assessment was done using the ''Analytical Eco-scale'' tool. The total score was 89/100 points revealing excellent greenness of our proposal. Our proposal is simple, eco-friendly and cheap. It can be conveniently adopted for routine quality control practices especially in developing countries.
According to the European Union regulation, some countries have established a pre-market notification system for food supplements while others have not. As this regulation is unfulfilled, a notified and marketed food supplement ingredient in one country may be forbidden in another. Even though food supplements shall not be placed on the market if unsafe, some products may still expose the consumers to risks. The risk is increased by easier access due to worldwide dissemination fostered by the internet and free movement of goods in the European Union. The Rapid Alert System for Food and Feed and the Emerging Risks Exchange Network are described. To date, the European Union legislation does not include a provision to establish a dedicated vigilance system for food supplements (Nutrivigilance). Six European Union countries have nevertheless set up national systems, which are presented. The present lack of European Union data collection harmonization, does not allow easy cooperation between countries. This article advocates for creating a coordinated European Nutrivigilance System to detect and scrutinize adverse effects of food supplements. This, to help in directing science-based risk assessments and reinforce the science-based decision of policy makers to improve public health safety.
Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is used by the food and cosmetic industry as a flavoring agent. RK is also marketed as a dietary supplement for weight maintenance and appetite control. The purpose of the study was to characterize the acute feeding suppression with RK (64-640 mg/kg) by oral gavage in male and female C57BL/6J mice. Cumulative 24 h food intake was reduced at 200 mg/kg (24% feeding suppression) in males and reliably reduced at 640 mg/kg (49-77% feeding suppression). Feeding suppression was not associated with pica behavior over the range of doses or conditioned taste aversion. In a separate experiment, a single oral gavage of RK (640 mg/kg) resulted in approximate 43% mortality rate (6 out 14 male mice) within 2 days. Atrophy of white adipose tissue, splenic abnormalities, and thymus involution were noted after 2 to 4 days after oral gavage RK. Total white blood cell count, lymphocytes, monocytes, eosinophils were significantly lower, while mean red blood cells, hemoglobin, and hematocrit were significantly higher with RK treatment. Our findings indicated a dose-dependent feeding suppression with acute RK, but doses that reliable suppress food intake are associated with pathological changes.
Raspberry ketone (RK) (4-(4-hydroxyphenyl)-2-butanone) is the major compound responsible for the characteristic aroma of red raspberries, and has long been used commercially as a flavoring agent and recently as a weight loss supplement. A targeted UHPLC-QqQ-MS/MS method was developed and validated for analysis of RK and 25 associated metabolites in mouse plasma and brain. Dispersion and projection analysis and central composite design were used for method optimization. Random effect analysis of variance was applied for validation inference and variation partition. Within this framework, repeatability, a broader sense of precision, was calculated as fraction of accuracy variance, reflecting instrumental imprecision, compound degradation and carry-over effects. Multivariate correlation analysis and principle component analysis were conducted, revealing underlying association among the manifold of method traits. R programming was engaged in streamlined statistical analysis and data visualization. Two particular phenomena, the analytes’ background existence in the enzyme solution used for phase II metabolites deconjugation, and the noted liability of analytes in pure solvent at 4 ℃ vs. elevated stability in biomatrices, were found critical to method development and validation. The approach for the method development and validation provided a foundation for experiments that examine RK metabolism and bioavailability.
Objectives:
Raspberry ketone (RK) is the primary aroma compound in red raspberries and a dietary supplement for weight loss. This work aims to 1) Compare RK bioavailability among male vs. female, normal-weight vs. obese mice; and 2) Characterize RK metabolic pathways.
Methods:
Study 1: C57BL/6J male and female mice fed a low-fat-diet (LFD; 10% fat) received a single oral gavage dose of RK (200 mg/kg). Blood, brain and white adipose tissue (WAT) were collected over 12 h. Study 2: Male mice were fed a LFD or high-fat-diet (HFD; 45% fat) for 8 weeks before RK dosing. Samples collected were analyzed by UPLC-QqQ-MS/MS for RK and its metabolites.
Results:
RK was rapidly absorbed (Tmax ∼15 min), deposited in brain and bioconverted into diverse metabolites in mice. Total bioavailability (AUC0-12 h ) was slightly lower in females than males (566 vs. 675 nmol/mL*min). Total bioavailability in obese mice was almost doubled that of control mice (1197 vs. 679 nmol/mL*min), while peaking times and elimination half-lives were delayed. Higher levels of RK and major metabolites were found in WAT of the obese than normal-weight animals.
Conclusions:
RK was highly bioavailable, rapidly metabolized, and exhibited significantly different pharmacokinetic behaviors between obese and control mice. Lipid-rich tissues, especially WAT, could be a direct target of RK. This article is protected by copyright. All rights reserved.
Electrospinning and electrospraying are versatile techniques for the production of nano- to micro-scale fibers and particles. Over the past 2 decades, significant progresses have been made to advance the fundamental understandings of these electrohydrodynamic processes. Researchers have investigated different polymeric and non-polymeric substrates for producing submicron electrospun/electrosprayed materials of unique morphologies and physicochemical properties. This chapter provides an overview on the basic principles of electrospinning and electrospraying, highlighting the effects of key processing and solution parameters. Electrohydrodynamic phenomena of edible substrates, including polysaccharides (xanthan, alginate, starch, cyclodextrin, pullulan, dextran, modified celluloses, and chitosan), proteins (zein, what gluten, whey protein, soy protein, gelatin, etc.), and phospholipids are reviewed. Selected examples are presented on how ultrafine fibers and particles derived from these substrates are being exploited for food and nutraceutical applications. Finally, the challenges and opportunities of the electrostatic methods are discussed.
Over the past 20 years the use of dietary supplements as adjuvant therapy for weight loss gained growing favor among consumers and dietician–nutritionists, with the subsequent astounding increase in health costs. Despite the reassuring label of natural remedy for losing weight, dietary supplements contain a wide variety of ingredients on which available information is rather scanty and scientifically incomplete. Currently, there is little evidence that weight-loss supplements offer effective aids to reduce weight and meet criteria for recommended use. Robust, randomized, placebo-controlled studies to provide clear-cut scientific evidence of their efficacy and potential side effects in clinical practice are still lacking. Understanding the evidence for the efficacy, safety, and quality of these supplements among nutritionists and physicians is critical to counsel patients appropriately, especially considering the risk of serious adverse effects and interference with concomitant therapies. Detailed information on the efficacy and safety of the most commonly used weight-loss dietary supplements has been recently published by the National Institutes of Health (NIH). However, in this report the thorny issue that may result from drug interactions with weight-loss dietary supplements has been not sufficiently addressed. The aim of this review was to provide a synthetic, evidence-based report on efficacy and safety of the most commonly used ingredients in dietary supplements marketed for weight loss, particularly focusing on their possible drug interactions.
Dietary supplements “fat burners” freely available on the market, are intended to promote weight loss and reduce fat accumulation, either via stimulation of lipolysis or by inhibition of lipogenesis. Proponents claim that fat burners can increase fat metabolism, although their usefulness remains controversial. Fat burners are usually claimed to be of natural origin and viewed as being inherently safe. This review focuses on the most common ingredients of natural origin usually found in the fat burners, their molecular mechanisms of action and the toxicological profiles of these compounds in order to gain an insight into their safety.
The solubility and dissolution thermodynamic properties of raspberry ketone in a set of binary solvent mixtures (ethanol + water) with different compositions were experimentally determined by static gravimetrical method in the temperature range of 283.15–313.15 K at 0.10 MPa. The solubility of raspberry ketone in this series of ethanol/water binary solvent mixtures was found to increase with a rise in temperature and the rising mole fraction of ethanol in binary solvent mixtures. The van’t Hoff, modified Apelblat and 3D Jouyban–Acree–van’t Hoff equations were increasingly applied to correlate the solubility in ethanol/water binary solvent mixtures. The former two models could reach better fitting results with the solubility data, while the 3D model can be comprehensively used to estimate the solubility data in all the ratios of ethanol and water in binary solvent mixtures at random temperature. Furthermore, the changes of dissolution thermodynamic properties of raspberry ketone in experimental ethanol/water solvent mixtures were obtained by van’t Hoff equation. For all the above experiments, these dissolution processes of raspberry ketone in experimental ethanol/water binary solvent mixtures were estimated to be endothermic and enthalpy-driven.
During the past decade, a large number of reports described the roles of in silico approaches in the development of new molecules in the field of pharmaceuticals, agrochemicals , food science, materials science, environmental science, etc. In silico techniques like quantitative structure-activity relationships (QSAR), pharmacophore , docking and virtual screenings are playing crucial roles for the design of “better” molecules that may later be synthesized and assayed. This chapter presents the currently available information on diverse groups of molecules with applications in agriculture and food science that have been subjected to in silico studies. A hefty numbers of successful applications of QSARs in the development of agrochemicals , food products and food supplements are thoroughly discussed. The QSAR studies summarized here would help readers to understand the proper mechanism for the activity of miscellaneous agrochemicals and food products as well as the interaction between the free radicals and antioxidant molecules. This chapter justifies the need to develop additional QSAR models in combination with other in silico approaches for the design of better agrochemicals, food and food supplements , especially antioxidants and flavoring agents, in order to explore the largely unexplored field of plant sources in addition to synthetic molecules as well as to reduce time and cost involvement in such exercises. Further, we have enlisted most of the available agrochemical, food and flavor databases for convenience of researchers working in the area along with an extensive list of software tools.
RASPBERRY ketone (4-(4-hydroxyphenyl)-2-butanone) has become popular as a weight loss supplement in humans and is often found in multi-ingredient preparations, particularly with caffeine (usually 30 to 200 mg, but the dosage may not be declared on the label).
Raspberry ketone is structurally similar to other naturally occurring botanical compounds (capsaicin and synephrine) and is thought to have sympathomimetic effects. Experimental studies have shown that it alters lipid metabolism in adipocytes (Park 2015) and enhances noradrenaline-induced lipolysis (Morimoto and others 2005). There is limited information on the safety and toxicity …
The protective effect of raspberry ketone against nonalcoholic steatohepatitis (NASH) was tested by using a high-fat diet-induced NASH model, and its mechanism was explored. Forty Sprague-Dawley rats with a 1:1 male to female ratio were randomly divided into five groups: the normal control (NC) group (n=8) fed normal diet for 8 weeks, the model control (MC) group (n=8) fed high-fat diet (82% standard diet, 8.3% yolk powder, 9.0% lard, 0.5% cholesterol, and 0.2% sodium taurocholate), and the raspberry ketone low-dose (0.5%) (RKL) group (n=8), the raspberry ketone middle-dose (1%) (RKM) group (n=8), and the raspberry ketone high-dose (2%) (RKH) group (n=8) fed high-fat diet for 4 weeks. After 8 weeks of experiment, all the rats were sacrificed, and blood lipid parameters (total cholesterol [TC], triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol [LDL-C]), liver function parameters (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]), leptin (LEP), free fatty acid (FFA), tumor necrosis factor α (TNF-α), blood glucose (GLU), and insulin (INS) with calculated INS resistance index (IRI) and INS-sensitive index (ISI) were measured in rats. Therefore, we determined the peroxisome proliferator-activated receptor (PPAR)-α activity in liver homogenate and the levels of low-density lipoprotein receptor (LDLR), high-sensitivity C-reactive protein (hs-CRP), adiponection (APN), superoxide dismutase, and malondialdehyde (MDA). The liver tissues of rats in each group were imaged by electron microscopy with hematoxylin-eosin as the staining agent. The levels of TG, TC, LDL-C, ALT, AST, ALP, GLU, INS, IRI, FFA, LEP, TNF-α, MDA, and hs-CRP of MC rats were significantly increased (P<.05, P<.01). Therefore, the levels of HDL-C, ISI, PPAR-α, LDLR, and APN were significantly decreased (P<.05, P<.01). Compared with the MC group, each parameter in the RKL, RKM, and RKH groups was significantly improved (P<.05, P<.01). Thus raspberry ketone was an effective intervention for NASH in rats. It was believed that raspberry ketone had a dual effect of liver protection and fat reduction, and the mechanism was probably mediated by alleviation of fatty degeneration of liver cells, decreased liver inflammation, correction of dyslipidemia, reversal of LEP and INS resistance, and improved antioxidant capacity.
This study aimed to compare different methods of assessing dietary exposure to flavourings in the context of a stepwise approach. The dietary exposure to four flavourings--raspberry ketone, glycyrrhizinic acid, coumarin, and caffeine--was determined. When dietary exposure exceeded the safety limits, the need for more detailed assessment using less aggregated data was judged necessary. First, screening methods--maximized survey-derived daily intake (MSDI), single-portion exposure technique (SPET), and modified theoretical added maximum daily intake (mTAMDI)--were applied. Next, individual food consumption data were used for creating models with different levels of detail to identify the foods: a model based on food groups and models based on food items. These were collected from 121 Dutch adults using a standardized 2 x 24-h dietary recall (EPIC-Soft) in the European Food Consumption Validation (EFCOVAL) study. Three food item models were developed: without improvements of the flavouring descriptor built in the software; with improvements; and with use of non-specified flavour descriptors. Based on the results of at least one of the three screening methods, refined assessment was necessary for raspberry ketone, glycyrrhizinic acid, and caffeine. When applying the food group model, the need for refinement was indicated for the four flavourings. When applying the food item models, only glycyrrhizinic acid and caffeine presented dietary exposure above the safety limits. In the raspberry ketone case, dietary exposure increased when improvements in food description were considered. The use of non-specified flavour descriptors hardly changed the results. The collection of detailed food consumption data at the individual level is useful in the dietary exposure assessment of these flavourings.
The main objective of this study was to evaluate the capability of 120 aromatic chemicals to bind to the human alpha estrogen receptor (hER alpha) by the use of quantum similarity methods. The experimental data were segregated into two categories, i.e., those compounds with and without estrogenicity activity (active and inactive). To identify potential ligands, semiquantitative structure-activity relationships were developed for the complete set correlating the presence or lack of binding affinity to the estrogen receptor with structural features of the molecules. The structure-activity relationships were based upon molecular similarity indices, which implicitly contain information related to changes in the electron distributions of the molecules, along with indicator variables, accounting for several structural features. In addition, the whole set was split into several chemical classes for modeling purposes. Models were validated by dividing the complete set into several training and test sets to allow for external predictions to be made.
Raspberry ketone is an important compound for the flavour industry. It is frequently used in products such as soft drinks, sweets, puddings and ice creams. The compound can be produced by organic synthesis. Demand for "natural" raspberry ketone is growing considerably. However, this product is extremely expensive. Consequently, there is a remaining desire to better understand how raspberry ketone is synthesized in vivo, and which genes and enzymes are involved. With this information we will then be in a better position to design alternative production strategies such as microbial fermentation. This article focuses on the identification and application of genes potentially linked to raspberry ketone synthesis. We have isolated candidate genes from both raspberry and other plants, and these have been introduced into bacterial and yeast expression systems. Conditions have been determined that result in significant levels of raspberry ketone, up to 5 mg/L. These results therefore lay a strong foundation for a potentially renewable source of "natural" flavour compounds making use of plant genes.
Natural fragrant chemicals have been screened for their potential uses as alternatives such as antimicrobials and antioxidants. Recently, glycosidically bound volatiles have been studied as fragrant precursors in essential oil plants and have also been the subject of interest in various industries. Raspberry ketone (RK; 4-(p-hydroxyphenyl)-2-butanone) is well known as a typical aroma chemical of red raspberry (Rubus idaeus), and its β-Dglucoside (RaG) has been isolated as its precursor. RK has a similar structure to capsaicin, a compound known to exert an anti-obesity action. We confirmed that RK accelerated lipolysis in vitro more potently than capsaicin and prevented high-fat diet (HFD)-induced elevations in body and liver weights. We found that RaG inhibited melanin synthesis more than hydroquinone β- D-glucoside (arbutin), a compound that is already used as a melanin inhibitor in cosmetics.
Amomum longiligulare or Amomum villosum showed oestrogenic activity. In the present study, oestrogen-active components in fructus amomi, the seeds of A. longiligulare were separated by high-speed countercurrent chromatography (HSCCC) using stepwise elution of eight mobile phases with gradient polarity and advanced separation by high performance liquid chromatography (HPLC). The results yielded 17 compounds with the amount of 8-138mg and a purity of 94.3-99.8% from a 3g ethanolic extract of fructus amomi. The chemical structures of the compounds were identified by ESI-MS and NMR spectra, in which eight diarylheptanoids were demonstrated as the main oestrogen-active compounds in the fructus amomi. Determination of the diarylheptanoids in fructus amomi from various origins showed that fructus amomi contains more than 0.5% total diarylheptanoids. The results showed that fructus amomi is a diarylheptanoids-rich food resource possessing oestrogen-activity. The combination method of HSCCC and HPLC can be applied for the analysis of bioactive compounds by detecting the corresponding bioactivity in the HSCCC fractions and separating the target compounds with HPLC.
The Purpose of this research is to discuss the function mechanism of raspberry ketone on simple obesity and the influence of resistance on obesity relevant insulin. There were 40 SD rats of SPF grade, and the male to female ratio was 1:1. They were randomly divided into 5 groups: NC fed with normal diet. MC fed with high-fat diet. RKL, RKM, and RKH groups fed with high-fat diet and were administered intragastrically with 0.5%, 1%, and 2% of RK for 4 weeks. After 8 weeks, some parameters were tested. The results were processed by statistical analysis. Compared with NC, TG, TC, LDL-C, GLU, INS, IRI, FFA, LEP, TNF- �. of MC were significantly increased. Therefore, HDL-C, ISI and APN were significantly decreased. Compared with MC, each parameter in RKL, RKM, and RKH was significantly improved. The results showed that RK have anti-obesity function through combined effects of improving insulin resistance.
The effect of essential oils, such as raspberry ketone, on androgen (AR) receptor was investigated using a MDA-kb2 human breast cancer cell line for predicting potential AR activity. Among them, eugenol had the highest AR antagonistic activity with its IC(50) value of 19 microM. Raspberry ketone, which has threefold higher anti-obese activity than that of capsaicin, also had AR antagonist activity with its IC(50) value of 252 microM. Based on these findings, a more precise CoMFA model was proposed as follows: pIC(50) [log (1/IC(50))]=3.77+[CoMFA field terms] (n=39, s=0.249, r(2)=0.834, s(cv)=0.507, q(2)=0.311 (three components).
Endocrine disrupters (EDs) form an interesting field of application attracting great attention in the recent years. They represent a number of exogenous substances interfering with the function of the endocrine system, including the interfering with developmental processes. In particular EDs are mentioned as substances requiring a more detailed control and specific authorization within REACH, the new European legislation on chemicals, together with other groups of chemicals of particular concern. QSAR represents a challenging method to approach data gap which is foreseen by REACH. The aim of this study was to provide an insight into the use of QSAR models to address ED effects mediated through the estrogen receptor (ER). New predictive models were derived to assess estrogenicity for a very large and heterogeneous dataset of chemical compounds. QSAR binary classifiers were developed based on different data mining techniques such as classification trees, decision forest, fuzzy logic, neural networks and support vector machines. The focus was given to multiple endpoints to better characterize the effects of EDs evaluating both binding (RBA) and transcriptional activity (RA). A possible combination of the models was also explored. A very good accuracy was reached for both RA and RBA models (higher than 80%).
Safety evaluation is caught in a frustrating circle. It is neither possible nor sensible to try to obtain the information needed to assess every imaginable toxic risk associated with every substance, and pursuit of greater safety therefore demands the setting of priorities as well as sensible limits for investigation. To do this with confidence requires possessing the very information that is lacking and that can be won only slowly on a few substances at a time, with significant uncertainty and at considerable cost. This requires priorities, and completes the circle of frustration. Individual texicologists deal with this problem by using ‘experience’, a personal synthesis of accumulated knowledge of structure-activity relationships, metabolic mechanisms, chemical reactivity, human exposure and other relevant information. Such expert judgement is often very effective in distinguishing potential risks worth pursuing from problems on which effort would be wasted but, because it is usually so inexplicit and subjective, it is seldom able to invoke the public confidence most decisions now require.
The acute LD50s of p-hydroxybenzyl acetone were 1·3 and 1·4 g/kg when given orally and 0·70 and 0·35 g/kg when given intraperitoneally to male and female rats respectively.Rats were fed on diets containing 0·0 (control), 0·1, 0·2, 0·4 or 1·0% p-hydroxybenzyl acetone for 13 wk. No effects on body weight were recorded in animals on diets containing 0·4% or less of the flavouring and food and water consumption was similar in all test and control animals. Transient changes in haemoglobin and leucocyte levels at wk 7 in animals on the highest dosage were considered unlikely to be of toxicological significance. Serum and urine analyses were comparable in all groups, except that a positive reaction for acetone was found in the urine of all treated animals. Further tests showed, however, that this was related to the excretion of p-hydroxybenzyl acetone or its metabolites and not to any pathological change. No other effects were seen at the two lower levels but animals given the two higher dosage levels showed slight increases in liver, kidney and adrenal weight relative to body weight. The types and incidence of histological findings were comparable, however, in the control and highest dosage groups.The no-effect level of 100 mg/kg/day is 200 times greater than the estimated intake in man of 0·42 mg/kg/dayRésuméLa DL50 aiguë orale de la p-hydroxybenzyl-acétone est de 1,3 g/kg pour le rat màle et de 1,4 g/kg pour le rat femelle. Les DL50 aiguës intrapéritonéales sont de 0,70 et 0,35 g/kg, respectivement.Les rats ont consommé de la p-hydroxybenzyl-acétone pendant 13 semaines à raison de 0,0 (témoins), 0,1, 0,2, 0,4 ou 1,0% du régime. Aucun effet sur le poids du corps n'a été observé chez les animaux dont le régime comportait 0,4% ou moins de ce produit aromatisant. Les consommations de nourriture et d'eau de tous les animaux soumis à l'essai sont restées similaires à celles des animaux témoins. Des altérations passagères des taux d'hémoglobine et de leucocytes observées la 7e semaine chez les animaux qui recevaient les plus fortes doses ont été considérées comme probablement dépourvues de signification toxicologique. Les analyses du sérum et de l'urine ont donné des résultats comparables pour tous les groupes, á l'exception d'une réaction positive de l'urine pour l'acétone, constatée chez tous les animaux traités. Des tests complémentaires ont toutefois prouvé que cette réaction était en corrélation avec l'excrétion de la p-hydroxybenzylacétone ou de ses métabolites et non avec une altération pathologique quelconque. Aucun autre effet n'a été observé aux deux doses inférieures, mais on a constaté de légères augmentations du poids du foie, des reins et des glandes surrénales, par rapport au poids du corps, chez les animaux qui recevaient les deux plus fortes doses. Les types et la fréquence des observations histologiques faites sur les animaux témoins et sur les animaux recevant la plus forte dose étaient toutefois comparables.La dose correspondant au seuil d'indifférence, 100 mg/kg/jour, est 200 fois plus élevée que la consommation humaine, estimé à 0,42 mg/kg/jour.ZusammenfassungDie akute LD50 von p-Hydroxybenzylaceton betrug 1,3 und 1,4 g/kg bei oraler und 0,70 und 0,35 g/kg bei intraperitonealer Verabreichung an männliche bzw. weibliche Ratten.Ratten erhielten 13 Wochen lang Futter mit 0 (Kontrolle), 0,1, 0,2, 0,4 und 1,0% p-Hydroxybenzylaceton. Bei Tieren, die Futter mit 0,4% oder weniger des Aromas erhielten, wurde keine Wirkung auf das Körpergewicht bemerkt, und der Futter- und Wasserverbrauch war bei den Versuchs- und Kontrolltieren gleich. Vorübergehende Änderungen der Hämoglobinwerte und Leucocytenzahl in der 7. Woche bei Tieren, welche die höchste Dosierung erhielten, wurden nicht als toxikologisch signifikant angesehen. Die Serum- und Urinanalyse waren in allen Gruppen vergleichbar mit der Ausnahme, dass im Urin aller mit der Substanz behandelten Tiere eine positive Reaktion auf Aceton gefunden wurde. Weitere Prüfungen zeigten jedoch, dass dies mit der Ausscheidung von p-Hydroxybenzylaceton oder dessen Stoffwechselprodukten und nicht mit einer pathologischen Veränderung zusammenhing. Bei den zwei niedrigeren Konzentrationen wurden keine anderen Wirkungen beobachtet, aber Tiere, welche die beiden höheren Dosierungen erhielten, zeigten leichte Vergrösserungen des Gewichts von Leber, Nieren und Nebennieren im Verhältnis zum Körpergewicht. Die Typen und die Häufigkeit der histologischen Ergebnisse waren jedoch in der Kontrollgruppe und der Gruppe mit der höchsten Dosierung vergleichbar.Die wirkungsfreie Konzentration von 100 mg/kg/Tag ist 200mal grösser als die geschätzte Aufnahme durch den Menschen in Höhe von 0,42 mg/kg/Tag.
1. The metabolism of 4-(4-hydroxyphenyl)butan-2-one(raspberry ketone) was studied in rats, guinea-pigs and rabbits. 2. Following intragastric dosage (1 mmol/kg) urinary metabolite excretion was nearly complete within 24 h, amounting to roughly 90% of the dose in all species. 3. The most prominent urinary metabolites were raspberry ketone and its corresponding carbinol, both largely conjugated with glucuronic acid and/or sulphate. The extent of ketone reduction was greatest in rabbits. 4. Oxidative metabolism included ring hydroxylation and side-chain oxidation. The latter pathway led to 1,2- and 2,3-diol derivatives. It is proposed that the latter undergo cleavage to furnish the C6-C3 and C6-C2 derivatives detected.
The relationship between chemical structure and toxicity was explored through the compilation of a large reference database consisting of over 600 chemical substances tested for a variety of endpoints resulting in over 2900 no-observed-effect levels (NOELs). Each substance in the database was classified into one of three structural classes using a decision tree approach. The resulting cumulative distributions of NOELs for each of the structural classes differed significantly from one another, supporting the contention that chemical structure defines toxicity. The database was used to derive a threshold of acceptable human exposure for each of the structural classes that could be applied in the absence of specific toxicity data on a substance within one of the three structural classes. The human exposure thresholds provide guidance on the degree of testing and evaluation required for substances that lack toxicity data.
Structure-activity relationships for oestrogenicity were developed based on 120 aromatic chemicals evaluated in the Saccharomyces cerevisiae-based Lac-Z reporter assay. Relative gene activation was compared to 17 beta-estradiol and varied over eight orders of magnitude. Analysis of the data compared to 17 beta-estradiol identified three structural criteria that were related to xenoestrogen activity and potency: (1) the hydrogen-bonding ability of the phenolic ring mimicking the A-ring, (2) a hydrophobic centre similar in size and shape to the B- and C-rings, and (3) a hydrogen-bond donor mimicking the 17 beta-hydroxyl moiety of the D-ring, especially with an oxygen-to-oxygen distance similar to that between the 3- and 17 beta-hydroxyl groups of 17 beta-estradiol. Binding data were segregated into activity clusters including strong, moderate, weak, and detectable gene expression, and those compounds that were inactive. The hydrogen-bonding ability of hydroxy group in the 3-position on 17 beta-estradiol was observed to be essential for gene activation. Compounds with a 4-hydroxyl substituted benzene ring and a hydrophobic moiety of size and shape equivalent to the B-ring of 17 beta-estradiol were generally observed to be weakly active compounds. Moderately active compounds have a 4-hydroxyl substituted benzene ring with a hydrophobic moiety equivalent in size and shape to the B- and C-ring of 17 beta-estradiol, or have a high hydrogen-bond donor capacity owing to the presence of halogens on a nonphenolic ring. Strongly active compounds, similar to 4,4'-diethylethylene bisphenol (DES), possess the same hydrophobic ring structure as described for moderately active compounds and an additional hydroxyl group with an oxygen-to-oxygen distance close to that exhibited by the 3- and 17-hydroxyl groups of 17 beta-estradiol.
During the past years biocatalytic production of fine chemicals has been expanding rapidly. Flavours and fragrances belong to many different structural classes and therefore represent a challenging target for academic and industrial research. Here, we present a condensed overview of the potential offered by biocatalysis for the synthesis of natural and natural-identical odorants, highlighting relevant biotransformations using microorganisms and isolated enzymes. The industrial processes based on biocatalytic methods are discussed in terms of their advantages over classical chemical synthesis and extraction from natural sources. Recent applications of the biocatalytic approach to the preparation of the most important fine odorants are comprehensively covered.
Raspberry ketone (4-(4-hydroxyphenyl) butan-2-one; RK) is a major aromatic compound of red raspberry (Rubus idaeus). The structure of RK is similar to the structures of capsaicin and synephrine, compounds known to exert anti-obese actions and alter the lipid metabolism. The present study was performed to clarify whether RK helps prevent obesity and activate lipid metabolism in rodents. To test the effect on obesity, our group designed the following in vivo experiments: 1) mice were fed a high-fat diet including 0.5, 1, or 2% of RK for 10 weeks; 2) mice were given a high-fat diet for 6 weeks and subsequently fed the same high-fat diet containing 1% RK for the next 5 weeks. RK prevented the high-fat-diet-induced elevations in body weight and the weights of the liver and visceral adipose tissues (epididymal, retroperitoneal, and mesenteric). RK also decreased these weights and hepatic triacylglycerol content after they had been increased by a high-fat diet. RK significantly increased norepinephrine-induced lipolysis associated with the translocation of hormone-sensitive lipase from the cytosol to lipid droplets in rat epididymal fat cells. In conclusion, RK prevents and improves obesity and fatty liver. These effects appear to stem from the action of RK in altering the lipid metabolism, or more specifically, in increasing norepinephrine-induced lipolysis in white adipocytes.
Chemical carcinogenicity has been the target of numerous attempts to create predictive models alternative to the animal ones, ranging from short-term biological assays (e.g. mutagenicity tests) to theoretical models. Among the theoretical models, the application of the science of structure-activity relationships (SAR) has earned special prominence. The qualitative approach to SAR has lead to the identification of a large number of reactive chemical substructures that are both mutagenic and carcinogenic. More sophisticated developments are the quantitative structure-activity relationship (QSAR) models, that link the physical chemical or structural properties of the molecules to the toxicological endpoints. Both approaches provide strong support to the process of risk assessment of the chemicals, especially in the phase of priority setting. Among the areas potentially able to contribute to further developments of (Q)SAR, the novel chemical relational databases are presented and discussed. The freely downloadable ISSCAN database on chemical carcinogens is presented.