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Molecular mechanisms of lipid- and glucose-lowering activities of bergamot flavonoids

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Abstract

Bergamot (Citrus bergamia Risso et Poiteau) juice has a particularly high content and a unique composition of flavonoids. Neoeriocitrin, neohesperidin, naringin, melitidin and brutieridin represent more than 95% of Bergamot Polyphenol Fraction (BPF), while rhoifolin, diosmin, poncirin and others can be found in the remaining 5%. The brilliant performance of BPF in clinical practice against as a treatment for hyperlipidemia and moderate hyperglycemia in metabolic syndrome, awaits a plausible mechanistic explanation. Considering the overwhelming scientific evidence, it is likely that flavonoid components of BPF are responsible for majority of pharmacological effects. Here, we will review the scientific evidence showing that flavonoids, in particular citrus flavonoids present in bergamot fruits, influence lipid and sugar metabolism at the molecular level. Anti-diabetic and dyslipidemia-correcting effects of bergamot polyphenols may be explained by their ability to activate AMP kinase (AMPK), which is a central regulator of glucose and fatty acids metabolism and inhibit cAMP phosphodiesterases (PDE), involved in regulation of lipolysis in adipocytes and liver. Importantly, certain polyphenols can act as 3-hydroxy-3-methlglutaryl coenzyme A (HMG-CoA) reductase inhibitors, thereby mimicking statins action. In addition, flavonoids bind and act as natural inhibitors of quinone oxidoreductase 2 (QR2/NQO2) and other enzymes with potential roles in metabolic regulation. Finally, pleiotropic and possible synergistic effects may account for enhanced nutraceutical effects of natural flavonoid mixtures, such as BPF as compared to purified flavonoids.

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... Several molecular mechanisms have been proposed to explain the biological functions of flavonoids. According to the oldest, but highly controversial view, flavonoids would exert their effects by free-radical scavenging [16,18,19], which is proportional to the redox potential of these molecules, usually correlating with the number of hydroxyl groups [20][21][22]. However, the last two decades have provided more convincing explanations of antioxidant effects of flavonoids, which suggest that these compounds (i) interact with specific proteins central to signaling cascades and modulate the activity and/or expression of key antioxidant proteins; (ii) influence the epigenetic mechanisms of gene expression; and (iii) modulate the gut microbiota profile and metabolites. ...
... However, the last two decades have provided more convincing explanations of antioxidant effects of flavonoids, which suggest that these compounds (i) interact with specific proteins central to signaling cascades and modulate the activity and/or expression of key antioxidant proteins; (ii) influence the epigenetic mechanisms of gene expression; and (iii) modulate the gut microbiota profile and metabolites. Thus, while the current view is that pleiotropic mechanisms contribute to the final beneficial effect of polyphenols [21,22], the role of specific flavonoid-protein interactions is increasingly recognized [23]. A well-recognized direct target of polyphenols are phosphodiesterases (PDEs). ...
... A likely candidate is AMPK. In addition to its role as a central sensor of cellular bioenergetic status [22], it is also an established inducer of autophagy and several publications have demonstrated a role of AMPK in polyphenol-induced autophagy [8,41,45]. First, we tested if luteolin and apigenin stimulate AMPK activity in HepG2 cells in our culture conditions. ...
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Dietary flavonoids stimulate autophagy and prevent liver dysfunction, but the upstream signaling pathways triggered by these compounds are not well understood. Certain polyphenols bind directly to NRH-quinone oxidoreductase 2 (NQO2) and inhibit its activity. NQO2 is highly expressed in the liver, where it participates in quinone metabolism, but recent evidence indicates that it may also play a role in the regulation of oxidative stress and autophagy. Here, we addressed a potential role of NQO2 in autophagy induction by flavonoids. The pro-autophagic activity of seven flavonoid aglycons correlated perfectly with their ability to inhibit NQO2 activity, and flavones such as apigenin and luteolin showed the strongest activity in all assays. The silencing of NQO2 strongly reduced flavone-induced autophagic flux, although it increased basal LC3-II levels in HepG2 cells. Both flavones induced AMP kinase (AMPK) activation, while its reduction by AMPK beta (PRKAB1) silencing inhibited flavone-induced autophagy. Interestingly, the depletion of NQO2 levels by siRNA increased the basal AMPK phosphorylation but abrogated its further increase by apigenin. Thus, NQO2 contributes to the negative regulation of AMPK activity and autophagy, while its targeting by flavones releases pro-autophagic signals. These findings imply that NQO2 works as a flavone receptor mediating autophagy and may contribute to other hepatic effects of flavonoids.
... Frakcja bergamotowo-polifenolowa dokładnie odzwierciedla profil polifenoli soku bergamotowego (ryc. 2), z tą tylko różnicą, że flawonoidy są w niej ponad 200 razy bardziej skoncentrowane [26]. ...
... Wydaje się więc oczywiste, że polifenole bergamotowe i sama BPF powinny być badane w ustalonych układach modelowych in vitro oraz in vivo, aby uzyskać bardziej szczegółowy wgląd w mechanizmy ich działania. Najważniejsze potencjalne cele molekularne flawonoidów bergamotowych przedstawiono na rycinie 3 [26]. [25]. ...
... Potencjalne cele molekularne flawonoidów bergamotowych (na podstawie[26]); PDE (phosphodiesterase) -fosfodiesteraza; ACC (acetyl-CoA carboxylase) -karboksylaza acetylokoenzymu A; AMPK (adenosine monophosphate-activated protein kinase) -kinaza białkowa aktywowana przez adenozynomonofosforan; QR2 (quinone reductase) -reduktaza chinonowa; HMG-CoA (hydroxymethylglutaryl-CoA) badania, przeprowadzonego przez Mollace i wsp.[25] metodą podwójnie ślepej próby i kontrolowanego placebo, zakwalifikowano 237 chorych z hipercholesterolemią. Pacjentów podzielono na 3 grupy: grupę A -104 osoby z izolowaną hipercholesterolemią (stężenie cholesterolu frakcji LDL [LDL-C, low-density lipoprotein-cholesterol] ≥ 130 mg/dl), grupę B -42 osoby z hiperlipidemią mieszaną, grupę C -59 osób z zespołem metabolicznym (hiperlipidemią mieszaną i glikemią > 110 mg/dl). Każda grupa została podzielona na 3 podgrupy, w których pacjenci otrzymywali BPF w dawce 500 mg/dobę, 1000 mg/dobę lub placebo. ...
... Indeed, dietary polyphenols, a large and heterogeneous group of phytochemicals in herbs and plant-based foods, have been associated with lower risk of NAFLD [16,17]. In particular, Citrus flavonoids have been shown to exert several positive health effects on glucose and lipid metabolism in experimental models [12,16,[18][19][20][21][22] and humans [23][24][25]. ...
... In particular, bergamot is an endemic plant of Calabria region (Italy) belonging to the Rutaceae family [26]. Bergamot has attracted considerable attention due to its peculiar composition and high content of flavonoids, some of which are also found in other Citrus species [18,27]. BPF is a highly concentrated extract of glycosylated flavanones (naringin, neoeriocitrin and hesperidin) and flavones (diosmetin, apigenin and luteolin glycosides) from bergamot fruit juice [19,20,28]. ...
... BPF was prepared by the absorption on polystyrene resin columns and alkaline elution as described in detail in the European patent (No. EP 2 364 158 B1) and characterized for polyphenol content by high-pressure liquid chromatography [12,18,20]. It was kindly provided by Herbal and Antioxidant Derivatives S.r.l. ...
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Wrong alimentary behaviors and so-called "junk food" are a driving force for the rising incidence of non-alcoholic fatty liver disease (NAFLD) among children and adults. The "junk food" toxicity can be studied in "cafeteria" (CAF) diet animal model. Young rats exposed to CAF diet become obese and rapidly develop NAFLD. We have previously showed that bergamot (Citrus bergamia Risso et Poiteau) flavonoids, in the form of bergamot polyphenol fraction (BPF), effectively prevent CAF diet-induced NAFLD in rats. Here, we addressed if BPF can accelerate therapeutic effects of weight loss induced by a normocaloric standard chow (SC) diet. 21 rats fed with CAF diet for 16 weeks to induce NAFLD with inflammatory features (NASH) were divided into three groups. Two groups were switched to SC diet supplemented or not with BPF (CAF/SC±BPF), while one group continued with CAF diet (CAF/CAF) for 10 weeks. BPF had no effect on SC diet-induced weight loss, but it accelerated hepatic lipid droplets clearance and reduced blood triglycerides. Accordingly, BPF improved insulin sensitivity, but had little effect on leptin levels. Interestingly, the inflammatory parameters were still elevated in CAF/SC livers compared to CAF/CAF group after 10 weeks of dietary intervention, despite over 90% hepatic fat reduction. In contrast, BPF supplementation decreased hepatic inflammation by reducing interleukin 6 (Il6) mRNA expression and increasing anti-inflammatory Il10, which correlated with fewer Kupffer cells and lower inflammatory foci score in CAF/SC+BPF livers compared to CAF/SC group. These data indicate that BPF mediates a specific anti-inflammatory activity in livers recovering from NASH, while it boosts lipid-lowering and anti-diabetic effects of the dietary intervention.
... Polyphenols can act as HMG-CoA reductase inhibitors, thus by mimicking statins action, polyphenols could covalently linked to sugar residue so HMG-CoA reductase cannot hydrolase R-linked HMG which competes with the S-linked substrate for catalytic pocket of the enzyme then cannot be mevalonate, which is a precursor of later steps in cholesterol synthesis. 13 Some polyphenols, such as naringenin and hesperidin are identical to S-linked 3-hydroxy-3-methyl-glutaryl residue of HMG-CoA, a substrate of HMG-CoA reductase. AMPK activation is also a molecular target of many natural polyphenols, and AMPK may be responsible for therapeutic effects of polyphenols against various metabolic disorders, including obesity, diabetes, hyperlipidemia and nonalcoholic fatty liver disease. ...
... AMPK activation is also a molecular target of many natural polyphenols, and AMPK may be responsible for therapeutic effects of polyphenols against various metabolic disorders, including obesity, diabetes, hyperlipidemia and nonalcoholic fatty liver disease. 13 Flavonoids could be cyclic nucleotide phosphodiesterases (PDEs), PDEs catalyze hydrolysis of cAMP (cyclic adenosine monophosphate) and The rate of triglyceride (TG) hydrolysis (lipolysis) is positively regulated by increase in intracellular cAMP. cAMP activates, a cAMP dependent protein kinase, PKA which stimulates hormone-sensitive lipase (HSL), one of the key molecules controlling lipolysis, by promoting its phosphorylation. ...
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Background: A native plant from Indonesia, Garcinia daedalanthera has been scientifically proven have antidiabetic effects and antioxidant activity. We hypothesized that Garcinia daedalanthera can modulate the lipid profiles of hyperlipidemic rats. Objective: This study aimed to evaluate the antihyperlipidemic potential of Garcinia daedalanthera extract. Materials and Methods: Garcinia daedalanthera leaves extract (GDE) were orally administrated to high fat diet-induced rats for 15 days. After the end of experimental period (43 days) the lipid profiles were estimated along with histopathological liver examination of animals. Results: The results showed that Garcinia daedalanthera extract significantly reduced the level of serum total cholesterol, total triglycerides and low-density lipoprotein as compared to control group with an increasing level of serum high-density lipoprotein. Furthermore, the extract has a favorable effect on histopathological study. Conclusion: This study proved antilipidemic property by lowering altered levels of lipid profile in male wistar rats and suggest lipid lowering effects of Garcinia daedalanthera extract which serves as a new potential natural product for preventing hyperlipidemia.
... In previous studies, different flavonoids have been demonstrated to activate AMPK in vitro and in vivo to trigger lipophagy. 80 Similar results have been observed in many polyphenols. 43 Compared with lipophagy, different mechanisms are also involved in the lipid metabolism by flavonoids and polyphenols. ...
... For example, the bergamot polyphenol fraction contains two rare flavonoids acting as direct 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with function of downregulating cholesterol synthesis. 80 Flavonoids with the hydroxylated phenolic structure sometimes act as a kind of anti-diabetic drugs due to anti-inflammatory, attenuating insulin resistance, increasing glycogen synthesis, and ameliorating islets dysfunction effects. 81 The structures of these polyphenols are characterized by a different number of phenolic hydroxyl groups, which could neutralize the acid or remove the free radicals. ...
Article
Autophagy has been reported to involve in the pathogenesis of type 2 diabetes mellitus (T2DM), which protects the insulin target tissues and pancreatic β-cells. However, autophagy is inhibited when the cells are lipid overload. That, in turn, increases the accumulation of fat. Lipotoxicity caused by excessive lipid accumulation contributes to pathogenesis of T2DM. Therefore, it is undeniable to break the vicious circles between lipid excess and autophagy deficiency. Lipophagy, a selective form of autophagy, is characterized by selective breakdown of lipid droplets (LDs). The nutritional status of cells contributes to the way of autophagy (selective or non-selective), while selective autophagy helps to accurately remove excess substances. It seems that lipophagy could be an effective means to decrease abnormal lipid accumulation that leads to insulin resistance and β-cell impairment by removing ectopic LDs. Based on this process, many natural compounds have been reported to decrease lipid accumulation in tissues through autophagy-lysosomal pathway, which gradually highlights the significance of lipophagy. In this review, we focus on the mechanisms that lipophagy improves T2DM and natural products that are applied to induce lipophagy. It is also suggested that natural herbs with rich contents of natural products inducing lipophagy would be potential candidates for alleviating T2DM.
... Thus, these parameters of lipid alteration were significantly decreased in the bergamot phytosome group, but not in placebo group. These results are in agreement with previous studies that have shown that bergamot phytosome was effective in modulating lipid profile, (Mollace et al., 2011) Both in vitro and human studies indicate that bergamot extract directly stimulates AMPK activity leading to increase AMPK levels (Janda, Lascala, Martino, Ragusa, & PharmaNutrition, 2016); this can reasonably explain the double hypolipidemic and hypoglycemic activity demonstrated for bergamot phytosome (Mollace et al., 2019). According to literature data, flavanones such as naringin and naringenin seem to be directly involved in up-regulation of the AMPK pathway and, consequently, in lipid and glucose metabolism (Zygmunt, Faubert, MacNeil, & Tsiani, 2010). ...
... A so-called statin-like effect has been also potentially mentioned for bergamot phytosome due to the content of flavanones such as (Janda et al., 2016). ...
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Bergamot has been traditionally used for the relief of diseases related to oxidative stress. Our aim was to investigate the effect of bergamot phytosome on visceral adipose tissue (VAT) and on metabolic profile, in overweight and obese subjects with mild hypercholesterolemia. A total of 64 participants were randomized into two groups for 12 weeks: a supplemented group (33 individuals, BMI 27 ± 3 kg/m² receiving 500 mg of bergamot phytosome, two daily tablets) and placebo group (31 subjects, BMI 28 ± 3 kg/m², two daily tablets). As to the within differences, the parameters of VAT, total and LDL‐cholesterol were significantly decreased in the bergamot phytosome group, but not in the placebo group. As to between‐group differences, a statistically significant interaction between time and group, that is, the change in score over time differs between the two groups was observed 30 days after supplementation for VAT (p‐value = .005), total cholesterol (p‐value <.0002), and LDL (p = .004) in respect to placebo. The other parameters (glucose, insulin, Homeostasis Model Assessment, high‐density lipoprotein cholesterol, triglycerides, fat free mass, fat mass) were not significant. In conclusion, this clinical study gives evidence that bergamot phytosome provides beneficial effects, such as decrease of VAT and modulation of metabolic alterations, after just 30 days of supplementation, resulting a very promising protection of cardiovascular health.
... Citrus fruits and their juices show a high content of flavonoids and their nutraceutical efficacy has been shown in many studies. Bergamot (Citrus bergamia Risso et Poiteau) and bergamot-derived extracts, such as bergamot polyphenol fraction (BPF) have attracted a considerable attention due to its peculiar composition and the highest content of Citrus flavonoids, such as naringin, hesperidin and neoeriocitrin [26,27]. Its lipid-lowering, anti-diabetic, anti-inflammatory, and autophagy-stimulating activity have been confirmed in both animal models and clinical studies [28][29][30][31][32]. ...
... BPF contains 40% of flavonoids. The remaining part of BPF is a mixture of other polyphenols (mainly catechins, salts, fatty acids, carbohydrates and other compounds ( [27] and unpublished observations). Neohesperidose-linked flavanones, such as naringin, neoeriocitrin and neohesperidin, account for over 60% of all flavonoids. ...
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Obesity is a potent risk factor for kidney disease as it increases the possibility of developing diabetes and hypertension, and it has a direct impact on the development of chronic kidney disease and end-stage renal disease. In this study, we tested the effect of bergamot polyphenolic fraction in a cafeteria with diet-fed rats, an excellent experimental model for studying human metabolic syndrome, as it is able to induce severe obesity with insulin resistance and high plasma triglyceride levels more efficiently than a traditional lard-based high-fat diet used in rodent models. We analyzed the plasmatic oxidative balance by photometric tests, and the expression of cytoplasmic antioxidant enzymes (superoxide dismutase 1 and glutatione S-tranferasi P1) and apoptotic markers (Caspase 8 and 9) in kidney tissues by Western blot analysis. Our results clearly showed that the cafeteria diet induces a marked pro-oxidant effect: significant reduction of plasmatic antioxidant capacity; downregulation of cytoplasmic antioxidant enzymes expression; and activation of apoptotic pathways. All these hallmarks of redox disequilibrium were mitigated by treatment with polyphenolic fraction of bergamot, highlighting its antioxidant effect in the metabolic syndrome. Our data show that the link between obesity and renal damage could be represented by oxidative stress.
... Of note, in one of these studies [52], the improvement in flow mediated dilation coincided with the peak of naringenin/hesperetin metabolites in circulation, supporting a causal relationship. Some results have also been published reporting the effects of BJ and its flavanones on the CV system [20,34,42,54]. BJ has been reported to exert anti-inflammatory activities [21], as recently demonstrated in an experimental model of bowel disease via modulation of several pathways [55]. ...
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Myeloid angiogenic cells (MACs) play a key role in endothelial repairing processes and functionality but their activity may be impaired by the lipotoxic effects of some molecules like stearic acid (SA). Among the dietary components potentially able to modulate endothelial function in vivo, (poly)phenolic compounds represent serious candidates. Here, we apply a comprehensive multidisciplinary approach to shed light on the prospects of Bergamot (Citrus bergamia), a citrus fruit rich in flavanones and other phenolic compounds, in the framework of lipotoxicity-induced MACs impairment. The flavanone profile of bergamot juice was characterized and 16 compounds were identified, with a new 3-hydroxy-3-methylglutaryl (HMG) flavanone, isosakuranetin-7-Oneohesperidoside-6”-O-HMG, described for the first time. Then, a pilot bioavailability study was conducted in healthy volunteers to assess the circulating flavanone metabolites in plasma and urine after consumption of bergamot juice. Up to 12 flavanone phase II conjugates (sulfates and glucuronides of hesperetin, naringenin and eriodyctiol) were detected and quantified. Finally, the effect of some of the metabolites identified in vivo, namely hesperetin-7-O-glucuronide, hesperetin-30-O-glucuronide, naringenin-7-O-glucuronide and naringenin-40-O-glucuronide, was tested, at physiological concentrations, on gene expression of inflammatory markers and apoptosis in MACs exposed to SA. Under these conditions, naringenin-40-O-glucuronide and hesperetin-7-O-glucuronide were able to modulate inflammation, while no flavanone glucuronide was effective in curbing stearate-induced lipoapoptosis. These results demonstrate that some flavanone metabolites, derived from the in vivo transformation of bergamot juice phenolics in humans, may mitigate stearate-induced inflammation in MACs.
... The digestive system is another target for anti-obesogenicity via inhibition on two key enzyme inhibitors-Orlistat and Acarbose-widely used as anti-obesity drugs. The inhibitory effect on amylase and lipase enzyme activity of MM extract was manifest, and flavonoid derivatives in the MM extract were assumed to contribute to these activities since they has been reported to possess a wide range of biological activities including regulation of glucose and lipid absorption via inhibition of pancreatic lipase, α-glucosidase and α-amylase enzyme activity [22,23], however, this is in a manner of structure-related potency of action [24,25]. In addition, anti-diabetic activities related to anti-α-glucosidase effect, anti-oxidation, and improving insulin secretion of Antidesma bunius L. fruit and seed extract were evidenced by preceding reports [10,26], yet, reports regarding the effect on lipase enzyme of MM extract have been very limited. ...
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To investigate the anti-obesity potential of Antidesma bunius L. (MM), a Thai local fruit which is named “Mao Luang,” we have focused on the effects on pancreatic α-amylase and lipase enzyme activity and on adipocyte life cycle using the 3T3-L1 cell line as a model. In addition, the phytochemical composition and anti-oxidation potential were also analyzed using HPLC-PDA UV and colorimetric methods. The ethanolic extract of MM fruits prepared by a maceration method was used in the experiments. MM extract, yield 12.08% w/w, is composed primarily of phenolics and anthocyanins as the major phytochemicals, among which, gallic acid, catechin, anthocyanin-3-glucoside, and protocatechuic acid were initially identified. In addition, susceptibly inhibitory effects on oxidation in a DPPH assay; on lipase enzyme activity rather than amylase enzyme; and on adipocyte adipogenesis of MM were demonstrated. Interestingly, a concentration-dependent bi-modular manner of activity on adipocyte adipogenesis was discovered, whereby a significant anti-adipogenic effect was demonstrated at high concentration, whilst low concentrations of MM showed adipogenic induction. Lipolytic induction was manifested. Conclusively, the ethanolic MM extract was discovered to be a potential anti-obesity agent contributed by inhibitory effects on lipase enzyme and anti-differentiation and -adipogenesis in adipocytes which significantly correlated to the total phenolics content, as well as anti-oxidation as the mechanism of action. Nevertheless, to achieve effective application, further investigation in in vivo models should be considered.
... The mechanism of action for polyphenols is yet to be clarified [53]. However, competitive inhibition of HMG-CoA reductase by certain HMG-type fractions (for example 3-hydroxy-3-methylglutaryl flavanone glycosides such as melitidin, brutieridin, and bergamot polyphenols [54]) has been hypothesized [55]. ...
Article
Current evidence shows that cholesterol management either reduces the likelihood of cardiovascular disease (CVD) or slows down its progression. Hence, it is important that all health professionals make appropriate use of all the available intervention strategies to control risk factors: from dietary improvement and positive lifestyle changes to the use of functional foods, food supplements, and drugs. This review examines the effect of the most frequently occurring cholesterol-lowering substances in functional foods or in supplements across Europe, namely plant sterols and stanols, monacolin K found in red yeast rice, berberine and beta-glucans. We conclude that currently available supplements and functional foods can effectively reduce plasma LDL cholesterol levels by about 5 to 25%, either alone or in combination. Suitable candidates for these products are mainly individuals at low absolute cardiovascular risk at a young age or according to classic algorithms. Of note, despite being freely available for purchase, these products should be used following shared agreement between the caring physician and the patient ("concordance").
... Bergamot Polyphenol Fraction (BPF s ) is a natural mixture of Citrus flavonoids extracted from processed bergamot fruits [2,3]. It has been shown to counteract cardiovascular risk factors and to prevent liver steatosis in rats and patients [4][5][6][7][8][9][10]. ...
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Bergamot Polyphenol Fraction (BPF®) is a natural mixture of Citrus flavonoids extracted from processed bergamot fruits. It has been shown to counteract cardiovascular risk factors and to prevent liver steatosis in rats and patients. Hepatic effects of BPF correlate with its ability to stimulate liver autophagy. Six aglyconic flavonoids have been identified in the proautophagic fraction of the hydrolysis product of BPF (A-BPF): naringenin, hesperetin, eridictyol, diosmetin, apigenin and luteolin. We report here the output parameters of high resolution mass spectrometry analysis of these flavonoids and chemical structures of their parent compounds. The second set of data shows the proautophagic activity of BPF flavonoids in a hepatic cell line HepG2 analyzed by a flow cytometry approach. The method is based on the red to green fluorescence intensity ratio analysis of DsRed -LC3- GFP, which is stably expressed in HepG2 cells. Proportional analysis of ATG indexes allowed us to address a relative contribution of individual compounds to the proautophagic activity of the A-BPF mixture and evaluate if the effect was additive. Qualitative analysis of ATG indexes compared the effects of flavonoids at equal concentrations in the presence and absence of palmitic acid and chloroquine. The Excel files reporting the analysis of flow cytometry data are available in the public repository.
... The mechanism might have a correlation to the ability of flavonoids which are the main secondary metabolites of EAFML bound to pectin. Flavonoid cooperation with pectin can work at the level of intestine and liver to stimulate fat excretion and reduce fat absorption, which augments the direct activity on enzymes, involved in the regulation of carbohydrate and lipid metabolism [21]. ...
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Objective: Moringa oleifera is a medicinal plant species that has potential as an antidiabetic. The present study was designed to evaluated molecullar mechanism antidiabetic ethyl acetate fraction of Moringa oleifera leaves (EAFML).Methods: The study was conducted on 30 male wistar rats which were induced with the combination of streptozotocin and nicotinamide by intraperitoneal administration to make a model of type 2 diabetes. After the diabetic induction, all rats were divided into six group and once daily administered orally EAFML in doses standardized quercetine. The treatment was given for ten days, and on the final treatment, all rats were checked their blood glucose level and lipid profile. The skeletal muscles and liver were taken to examine glucose transporter-4 (GLUT4) expression by immunohistochemistry.Results: The result of this study shows that the blood glucose level in diabetic rats with the treatment of EAFML decreased significantly from 355.8±83.7 mg/dL to 177.5±89.3 mg/dL. The cholesterol decreased significantly from 105.2±47.4 mg/dL to 58.6±6.9 mg/dL and low-density lipoprotein (LDL) in diabetic rats with the treatment of EAFML decreased significantly compared to control group from 175.6±41.9 mg/dL to 95.3±8.0 mg/dL. The expression of GLUT4 in skeletal muscles increased from 0.7±1.0 to 3.9±1.1 and in the liver increased significantly from 1.8±1.3 to 2.9±1.9.Conclusion: The EAFML can decrease blood glucose level, cholesterol and low-density lipoprotein in type 2 diabetic rat model. Other than that, this fraction can improve insulin sensitivity by the increase of GLUT4 expressions.
... This has been first suggested for naringin and more recently for melitidin and brutieridin. Structural characteristics of latter compounds allow them to mimic the natural substrates of HMG-CoA reductase and block the rate-limiting step in cholesterol synthesis [105]. Indeed, bergamot juice is rich in melitidin and brutieridin. ...
Article
The good nutritional value and the interesting biological activities of the plant-based nutraceuticals are primarily due to the polyphenols. These latter are among the most important and extensively studied plant secondary metabolites and their interaction with proteins is the subject of considerable researches. This interaction is fundamental to the rational design of functional foods as well as to improve the bioavailability and the biofunctionality of the polyphenols. In this work, we emphasized that the types of proteins and polyphenols influence this interaction and chemical bindings are primarily hydrophobic interactions and hydrogen bonds. We highlighted further the anti- atherosclerosis, anti-inflammatory, anti-diabetic, neuro-protective, antioxidant, anti-proliferative, antimicrobial and the hepatoprotective activities of the polyphenols. We also mentioned that astringency and these health benefits may be caused by the interaction with proteins, and that the proteins targeted by polyphenols are: Kelch-like ECH-associated protein 1, extracellular microbial enzymes, phospholipase A2, monoamine oxidase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, laminin receptor, hepatitis C virus NS3 protease, virus-encoded integrase, retroviral reverse transcriptase, leukotoxin, enterotoxin, cholera toxin, α-glucosidase, α-amylase, pro-oxidant enzymes, nuclear factor kappa B, cytochrome P450, metalloproteinases, β- and γ-secretases. A healthy, balanced diet and rich in polyphenols can prevent and even control the major public health problems worldwide.
... Finally, we have demonstrated that BPF modulates AMP (adenosine monophosphate)-activated protein kinase (AMPK) which plays a key role in the regulation of the metabolic pathways involved in ATP production in mammalian cells [7]. On the other hand, AMPK plays a central role in the integrated modulation of both lipidic and glycidic metabolism in the liver, while dysregulation of AMPK has been associated with fat accumulation and liver dysfunction in subjects with hyperlipemia [8]. ...
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Background Experimental and epidemiological studies show that bergamot polyphenolic fraction (BPF) ameliorates the serum lipemic profile, normalizes blood pressure and improves non alcoholic fatty liver disease in patients suffering from metabolic syndrome. Despite this evidence, the molecular mechanisms responsible for these beneficial effects remain unclear. The aim of our study is to clarify the effects of BPF on the lipoprotein assembly and to identify oxidative stress biomarkers correlating hyperlipidaemia and BPF-induced metabolic changes. Methods Male Wistar rats (180–200 g) were randomly assigned to receive a standard diet, a hypercholesterolemic diet or a hypercholesterolemic diet+BPF (20 mg/Kg/rat daily, gavage), respectively, for 90 days. Total cholesterol (tChol), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and fasting plasma glucose were evaluated at the baseline as well as at the end of the treatment. To assess the effect of BPF on the Lipid Transfer Protein System, detection of ACAT, LCAT, CETP, PON1, Apo A1 and Apo B have also been carried out. Finally, the lipid peroxidation biomarker (TBARS) and oxyLDL were also measured. Results BPF prevented tChol, LDL-C, TG and fasting plasma glucose enhancement and improved HDL-C. Treatment of hyperlipæmic rats with BPF significantly restored altered the serum concentration of lipemic biomarkers and the activity of ACAT, LCAT, CETP and PON1, an effect accompanied by the concomitant normalization of Apo A1 and APO B levels. In addition, TBARS levels were reduced significantly by the treatment with BPF. Conclusions BPF prevents diet-induced alteration of the lipid profile in rats, counteracting oxidative stress and improving the dysregulation of the Lipid Transfer Protein System. These data add new insights into the molecular mechanisms underlying the beneficial role of BPF in the therapy of hyperlipidaemia, thus suggesting a novel approach in the prevention of cardiovascular disease.
... 47 This protection is attributed to the metabolic exchange between glia and neurons: glial lactate can supply neuronal lipogenesis in response to ROS production, and neuronal lipids are transported and stored in glia as lipid droplets. 10 Flavonoids can protect against cognitive deficits, neuronal injury, and oxidative stress induced in a rat model of Alzheimer's disease, whereas genistein administration had the minor effect. 48 Similarly, isoquercetin and quercetin protect neurons from different cellular stresses. ...
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Lipid droplets (LDs), cytosolic fat storage organelles, are emerging as major regulators of lipid metabolism, trafficking, and signaling in various cells and tissues. LDs are altered in cardiovascular and neuronal disorders, inflammation, obesity, and cancer. Flavonoids comprise different classes of molecules, characterized by a well-known antioxidant activity and a beneficial effect in several diseases. However, the cellular mechanism by which different classes of flavonoids improve health is poorly understood, in particular as far as LDs biogenesis is concerned. Here we used Drosophila melanogaster as a model system to investigate the effects of a selected group of flavonoids on larval tissues by examining LDs biogenesis. In our study, fruit flies were grown in xanthohumol-, isoquercetin-, and genistein-enriched food and larval tissues were analyzed using a LD marker. Total mRNA expression of two main enzymes (minotaur and midway) responsible for triacylglycerides synthesis was evaluated after treatments. Among the flavonoids analyzed, xanthohumol and isoquercetin resulted to be potent regulators of LDs biogenesis in a tissue-specific manner, inducing fat storage decrease in fat bodies and accumulation of LDs in nerves. Since LDs have been suggested to play a protective role against intracellular stress in nonadipocyte cells, our data support the hypothesis that some phytochemicals could act as strong modulators of LDs biogenesis in vivo. The knowledge of how different flavonoids act on lipid metabolism in different tissues can help to manage the use of phytochemicals with the aim of selectively ameliorating specific neuronal and metabolic diseases’ manifestations.
... The BPF exercises various actions on glycolipid metabolism, including the ability to reduce the hepatic accumulation of triglycerides, the partial inhibition of their synthesis, and the ability to inhibit the action of acyl-CoA cholesterol acyltransferase (ACAT) (Janda et al. 2016). The result is a lower production of apoB-containing lipoproteins. ...
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Nutritional interventions are effective and – in theory – easy to implement primary and secondary prevention strategies that reduce several risk factors of atherosclerosis and cardiovascular disease (CVD). Yet, because of (a) the severe impact of CVD in terms of mortality, morbidity, quality of life, and economy, (b) the proved role of LDL plasma concentrations as the most critical risk factor, and (c) the obstacles found both in terms of biological effects and compliance of the patient by an exclusively dietary intervention, food supplements or nutraceuticals are now valuable resources for physicians. As regards cholesterol control, several preparations are available in the market, and we will critically review them in this chapter.
... These data, even if collected from a limited cohort of diabetic patients, are totally in accordance with previous data obtained in vitro and in vivo in which supplementation of patients with bergamot-derived antioxidants, and CyC extract led to a significant improvement of both glycemic and lipemic profile [18,24,[31][32][33][34]. In addition, this effect was accompanied with an improved vascular reactivity (explored via EndoPAT methodology) and to a better profile of biomarkers of NAFLD (detected via ultrasound measurement of fatty accumulation in the liver as well as via quantification of serum biomarkers of liver injury). ...
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Background and aim Non-Alcoholic Fatty Liver Disease (NAFLD) represents a risk factor for cardiovascular diseases. NAFLD is worsened by the simultaneous occurrence of type 2 diabetes mellitus (T2DM) causing an enhancement of inflammatory and fibrotic processes. Although insulin resistance appears the link between NAFLD and T2DM, current pharmacological treatments of T2DM failed to produce relevant benefits in preventing T2DM-related liver dysfunction. In this randomized, double blind, placebo-controlled clinical study, we evaluated the effect of Bergacyn, an innovative formulation originating from the combination of Bergamot Polyphenolic Fraction (BPF) and Cynara cardunculus (CyC). Experimental procedure 80 adult patients with a history of at least 12 months of T2DM and NAFLD received orally BPF (300 mg/daily) Cyc (300 mg/daily), separately or formulated in combination 50/50% (Bergacyn; 300 mg/daily), or placebo all containing 300 mg of bergamot albedo fibers micronized and co-grinded as excipients. Results and conclusion Serum measurements and liver ultrasound analyses showed that concomitant administration of BPF and CyC produced significant improvement of NAFLD biomarkers in patients with T2DM. This effect was associated with a substantial reduction of oxidative stress/inflammatory biomarkers, thus contributing to a significant improvement of NO-mediated reactive vasodilation. Furthermore, the effect of Bergacyn showed a synergistic effect of both extracts, thus suggesting that this peculiar formulation represents a novel therapeutic strategy to counteract vascular inflammation and endothelial dysfunction in patients suffering from T2DM and NAFLD. Further studies in larger cohort of diabetic patients are required to better identify the potential of Bergacyn on metabolic disorders accompanying T2DM and NAFLD.
... (Zhao et al., 2016). Recent studies suggested that flavonoids have potential therapeutic effects in the treatment of diabetes (Janda et al., 2016) and its complications including nephropathy (Athira et al., 2016;Vargas et al., 2018;Zhao et al., 2016). In the present study, using HPLC-UV& MS, several bioactive compounds were identified and quantified such as hyperozide extract. ...
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Ethnopharmacological relevance Combretum micranthum G. Don (CM) is extensively used in traditional medicine throughout West Africa and commonly known as "long-life herbal tea" or "plant to heal". Further, traditional healers frequently use the title plant to mitigate of renal disorders. Aim of the study To explore the nephroprotective property of standardised hydroalcoholic extract of Combretum micranthum in nicotinamide-streptozotocin induced diabetic nephropathy in rats. In addition, in-silico computational experiments were performed with bioactive compounds of the title plant against PPARα and PPARγ. Material and methods Male rats were made diabetic by a single intraperitoneal (ip) injection of STZ (50 mg/Kg), 15 min after ip administration of NA (100 mg/Kg) dissolved in normal saline. The diabetic rats received CM extract (200 and 400 mg/kg p.o.) daily, for eight weeks. Body weights and blood glucose (non-fasting and fasting) of rats were measured weekly. Daily food and water consumption were also measured. After 8 weeks of treatment, urine biochemical parameters such as N-Acetyl-β-D-Glucosaminidase (NAG), urea (UR), uric acid (UA), creatinine (CRE), and serum markers of diabetes, kidney damage and liver damage such as insulin, lipid parameters), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (γGT), albumin (Alb), magnesium (Mg²⁺), calcium (Ca²⁺), phosphorus (P), were estimated. Blood glycosylated hemoglobin (HbA1C) were also estimated. kidney and liver were used for biochemical estimation of oxidative stress markers such as lipid peroxidation, superoxide dismutase (SOD) activity and glutathione peroxidase (GPx) activity. The kidney and pancreas were used for histopathological study. Further, HPLC chemoprofiling of CM extract and in-silico molecular simulation experiments were performed. Results At the end of eight weeks, renal damage induced by the consequence of prolong diabetic condition was confirmed by altered levels of serum and urine kidney and liver function markers, oxidative stress markers and histopathological variations in kidney. Treatment with CM extract ameliorated the diabetes mellitus-induced renal biochemical parameters and histopathological changes. Further, HPLC-UV & MS experiments revealed that CM extract contains several bioactive compounds including hyperozide (62.35 μg/mg of extract) and quercitrin (19.07 μg/mg of extract). In-silico experiment exhibited Cianidanol (-17.133), epicatechin (-15.107) exhibited higher docking score against PPARα and luteoforol (-11.038), epigallocatechin (-10.736) against PPARγ. Based on docking and drug likeness score, four bioactive compounds were selected for molecular dynamic experiments. Cianidanol and epigallocatechin out of the 30 compounds are concluded as a potential candidate for the treatment of DN through activating PPARα and PPARγ target protein. Conclusions Taken together, the present study provided the scientific footage for the traditional use of Combretum micranthum.
... Flavonoids, glycosides, alkaloids, terpenoids, and others were present in the leaf latex of Aloe pulcherrima and have shown antidiabetic and antidyslipidemic activity in various plant extracts [9,11,13,24,30,34,50]. Many bioactive compounds isolated from Aloe species have sugar moiety and structurally resemble with glucose which is a key factor for insulin release [51]. ...
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The leaf latex of Aloe pulcherrima has been used as remedy for diabetes mellitus. This was carried out to determine in vitro and in vivo antidiabetic activities of the leaf latex of Aloe pulcherrima. Methods. Sucrase and maltase inhibitory activity of the leaf latex of A. pulcherrima was determined in glucose oxidase assay, and α-amylase inhibitory activity was determined in dinitrosalicylic acid assay. Normoglycemic, glucose-loaded, and streptozotocin-induced diabetic mice were treated orally to determine blood glucose lowering activity of the latex. Effect of the latex on serum lipid level and body weight was measured in streptozotocin-induced diabetic mice. Additionally, DPPH assay was used to determine free radical scavenging capacity of the latex. Results. Antioxidant activity of the latex was concentration dependent; the strongest inhibition was measured at 800 μg/ml (80.57%). The leaf latex of A. pulcherrima inhibited sucrase (IC50 = 2.92 μg/ml), maltase (IC50 = 11.81 μg/ml) and α-amylase (IC50 = 14.92 μg/ml) enzymes. All doses of the leaf latex induced hypoglycemic effect after 4 h in normal mice, and low dose of the latex did not show significant effect after 6 h. Glucose reduction of the leaf latex of A. pulcherrima was significant (p < 0.05) in oral glucose-loaded mice compared to the vehicle control. Blood glucose level of diabetic mice was significantly (p < 0.05) reduced on week one and weak two in a streptozotocin-induced diabetic mouse model. Glucose reduction increased with increasing the doses of the leaf latex of A. pulcherrima on week one (p < 0.05 (200 mg/kg), p < 0.01 (400 mg/kg), and p < 0.001 (600 mg/kg)). Administration of the leaf latex of A. pulcherrima for two weeks significantly (p < 0.05) improved diabetic dyslipidemia and body weight of diabetic mice. Conclusion. The study confirmed that the leaf latex of the plant showed a significant antidiabetic activity justifying the traditional uses of the plant.
... A considerable amount of literature has reported that flavonoids and their derivatives could enhances glucose uptake in insulin resistant HepG2 cells and inhibit lipid accumulation in oleic acid-induced HepG2 cells via different pathway (He et al., 2018;Janda et al., 2016;Jin et al., 2013;Mokashi et al., 2017). Phenylpropanoids have also been reported to show promising insulin resistance and glucose metabolism activity (Saadeldeen et al., 2020). ...
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Hypericum patulum has been used as a folk medicine for its varied therapeutic effects including antifungal, wound-healing, spasmolytic, stimulant, hypotensive activities. The water decoction is drank as tea could treat cold, infantile malnutrition. The present study aims to isolate the constituents of the plant and investigate their effects on the glucose consumption in insulin-resistant HepG2 cells, furthermore, lipid metabolism in oleic acid (OA)-treated HepG2 cells was also studied. The phytochemical investigation of the plant led to the isolation of eleven compounds, and their structures were identified by spectroscopic analysis as n-dotriacontanol (1), shikimic acid (2), 1-O-caffeoylquinic acid methyl ester (3), 5-O-caffeoylquinic acid methyl ester (4), 5-O-coumaroylquinic acid methyl ester (5), 5-O-caffeoylquinic acid butyl ester (6), quercetin-3-O-α-L-rhamnoside (7), quercetin (8), quercetin-3-O-(4״-methoxy)-α-L-rahmnopyranosyl (9), hyperoside (10), and rutin (11). The results revealed that compounds 7, 9, and 10 could enhance glucose consumption significantly in hyperglycemia induced HepG2 cells and insulin-resistant HepG2 cells. In addition, the western blotting analysis result exhibited that compounds 7, 9, and 10 in high concentration (5 μM, H) group could dramatically upregulate the expression of PPARγ protein, and even the effect of them had no significant difference compared with that of rosiglitazone. Furthermore, compounds 9 and 10 in middle concentration (2.5 μM, M) group and H group could dramatically promote triglyceride metabolism and decrease TG content in OA-treated HepG2 cells, and even in H group, reactive oxygen species (ROS) level were significantly decreased compared with model group. Practical applications Hypericum patulum is a well-known plant of the genera Hypericum for its varied preventive and therapeutic potential activities. To study the chemical constituents and their effects on glucose and lipid metabolism in vitro, we detected glucose consumption in insulin-resistant HepG2 cells, triglyceride content and reactive oxygen species level in OA-treated HepG2 cells. In addition, PPARγ protein was also detected by western blotting analysis in the study. Compounds 1, 2, 3, 5, 6, 9, 10, and 11 were isolated from the plant for the first time. Quercetin-3-O-(4"-methoxy)-α-L-rahmnopyranosyl (9) and hyperoside (10) had potential therapeutic benefit against glucose and lipid metabolic disease. Therefore, this study might have certain guiding significance for further research and development of H. patulum.
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Ege bölgelerinde yetiştirilmektedir. Üretilen turunçgil meyvelerinin yaklaşık %60’ı taze olarak, %40’ı ise meyve suyu olarak tüketilmektedir. C vitamininin önemli bir kaynağı olmasının yanı sıra posa, folat ve B vitaminleri ile potasyum, kalsiyum, fosfor, magnezyum, bakır minerallerini içermektedir. Turunçgil meyveleri, polifenolik bileşiklerinden flavonoidlerin de önemli bir kaynağıdır. Flavonoid miktarı, bitkinin türü, konsantrasyonu ve meyvenin bölümlerine göre dağılımı gibi genetik ve çevresel faktörlere bağlı olarak değişmektedir. Son yıllarda turunçgil flavonoidlerinin sağlık üzerindeki potansiyel terapötik etkileri ilgi çekicidir. Kardiyovasküler hastalıklar ve turunçgil flavonoidleri içeren meyve ve meyve suları tüketimi ile ilgili yapılan araştırmalarda bu bileşiklerin lipid düşürücü, insülin duyarlılığını arttırıcı, antihipertansif ve antiinflamatuar etkileri olduğu gözlenmiş ancak etki mekanizmaları net olarak belirlenememiştir. Bu derleme makalede, turunçgil flavonoidlerinin kimyasal özellikleri ve kardiyovasküler sağlık üzerindeki potansiyel etkileri güncel yaklaşımlara göre değerlendirilmiştir.
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Ege bölgelerinde yetiştirilmektedir. Üretilen turunçgil meyvelerinin yaklaşık %60’ı taze olarak, %40’ı ise meyve suyu olarak tüketilmektedir. C vitamininin önemli bir kaynağı olmasının yanı sıra posa, folat ve B vitaminleri ile potasyum, kalsiyum, fosfor, magnezyum, bakır minerallerini içermektedir. Turunçgil meyveleri, polifenolik bileşiklerinden flavonoidlerin de önemli bir kaynağıdır. Flavonoid miktarı, bitkinin türü, konsantrasyonu ve meyvenin bölümlerine göre dağılımı gibi genetik ve çevresel faktörlere bağlı olarak değişmektedir. Son yıllarda turunçgil flavonoidlerinin sağlık üzerindeki potansiyel terapötik etkileri ilgi çekicidir. Kardiyovasküler hastalıklar ve turunçgil flavonoidleri içeren meyve ve meyve suları tüketimi ile ilgili yapılan araştırmalarda bu bileşiklerin lipid düşürücü, insülin duyarlılığını arttırıcı, antihipertansif ve antiinflamatuar etkileri olduğu gözlenmiş ancak etki mekanizmaları net olarak belirlenememiştir. Bu derleme makalede, turunçgil flavonoidlerinin kimyasal özellikleri ve kardiyovasküler sağlık üzerindeki potansiyel etkileri güncel yaklaşımlara göre değerlendirilmiştir.
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Background: Nature has gifted a variety of phytochemicals having a potential effect against diabetes mellitus. Datura stramonium has been used as a remedy for the treatment of diabetes mellitus. The study aimed to determine the in vivo antidiabetic potential of hydromethanolic seed extract of the plant. Methods: Dried seeds of Datura stramonium were macerated in hydromethanol. Three doses (100, 200, and 400 mg/kg) of the seed extract were given orally to normoglycemic, glucose-loaded, and Streptozocin-induced diabetic mice. Diphenyl-1-picrylhydrazine (DPPH) assay was employed to determine antioxidant activity of the seed extract. Results: All doses of hydromethanolic seed extract of D. stramonium were devoid of any significant hypoglycemic effect in normoglycemic mice compared to the negative control group. Acute glucose reduction was significant (P<0.05 at 100, P<0.01 at 200 and 400 mg/kg) with respect to negative control in oral glucose-loaded mice. All doses of seed extract significantly (P<0.0l) reduced blood glucose level on weeks 1 and 2 in STZ-induced daily-treated diabetic mice. The seed extract at the doses of 200 and 400 mg/kg significantly (P<0.05) improved the body weight of diabetic mice on weeks 1 and 2. A low (100 mg/kg) dose of the seed extract delayed and significantly (P<0.05) increased body weight of mice on week 2 compared to negative control. The finding showed that the antioxidant activity of the hydromethanolic seed extract was concentration dependent and comparable with ascorbic acid. IC50 of the seed extract and ascorbic acid was found to be 11.95 and 5.07 mg/mL, respectively. Conclusion: The findings of the study showed that hydromethanolic seed extract of Datura stramonium endowed significant antihyperglycemic and antioxidant activity.
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There have been appreciable numbers of reviews on monophenols, catechols, and hydroquinones. However, the resorcinol class has received less attention. This review deals with resorcinols and flavonoids. Emphasis is on cell signaling in addition to antioxidant (AO) properties and pro-oxidant effects. The apparent dichotomy is rationalized. There is extensive literature dealing with various aspects of cell signaling in addition to receptor involvement. The physiological responses are provided along with integration into the unifying mechanistic theme of electron transfer (ET)-reactive oxygen species (ROS)-oxidative stress (OS). The multifaceted approach involving redox processes and cell signaling is unique in providing novel insight.
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Excessive lipid accumulation within liver has been proposed to cause obesity, hyperlipidemia, diabetes, and fatty liver disease. Rutin, a common dietary flavonoid that is consumed in fruits, vegetables, and plant-derived beverages, has various biological functions, including antioxidant, anti-inflammatory, and anticancer effects. However, a hypolipidemic effect of rutin on fatty liver disease has not been reported. In this study, we examined the effect of rutin on reducing lipid accumulation in hepatic cells. Hepatocytes were treated with oleic acid (OA) containing with or without rutin to observe the lipid accumulation by Nile red stain. The result showed rutin suppressed OA-induced lipid accumulation and increased adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activity in hepatocytes. The expression of critical molecule involved in lipid synthesis, sterol regulatory element binding proteins-1 (SREBP-1), was attenuated in rutin-treated cells. Moreover, long-term incubation of rutin inhibited the transcriptions of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR), glycerol-3-phosphate acyltransferase (GPAT), fatty acid synthase (FAS), and acetyl-coenzyme carboxylase (ACC). Besides, we also found out the antioxidative effect of rutin by increasing the expression of peroxisome proliferator-activated receptor (PPAR)-α and antioxidative enzymes. Taken together, our findings suggest rutin could attenuate lipid accumulation by decreasing lipogenesis and oxidative stress in hepatocyte.
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Metabolic syndrome represents a clustering of risk factors related to an elevated risk of cardiovascular disease and type 2 diabetes. Occurrence of both metabolic syndrome and diabetes and their vascular complications share several pathogenetic features including subclinical, low-grade inflammation, altered oxidative/antioxidant status, and persistent platelet activation. Despite the availability of multiple interventions to counteract these metabolic changes, including appropriate diet, regular exercise, weight control and drugs, epidemiological data are witnessing the growing trend of the problem, reflecting both the multifactorial nature of these diseases as well as the scarce compliance of patients to established strategies. Several nutraceuticals used in clinical practice have been shown to target the pathogenesis of diabetes mellitus, metabolic syndrome and their complications and to favorably modulate a number of biochemical and clinical endpoints. These compounds include antioxidant vitamins, such as vitamins C and E, flavonoids, vitamin D, conjugated linoleic acid, omega-3 fatty acids, minerals such as chromium and magnesium, alpha-lipoic acid, phytoestrogens, and dietary fibers. Several areas of concern exist regarding the use of dietary supplements and nutraceuticals in this setting, including product standardization, definition of optimal dosing regimen, potential side effects, drug interactions, and need for evidence-based indications.
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The high prevalence of obesity, atherosclerosis, and cardiovascular disease (CVD) is largely attributable to the contemporary lifestyle that is often sedentary and includes a diet high in saturated fats and sugars and low ingestion polyunsaturated fatty acids (PUFAs), fruit, vegetables, and fiber. Epidemiological studies have confirmed a strong association between fat intake, especially saturated- and transfatty acids, plasma cholesterol levels, and rate of coronary heart disease (CHD) mortality. In counterpart, beneficial cardiovascular effects have been reported in populations consuming the "healthy" Mediterranean-type diet. Indeed, many nutrients and phytochemicals in fruits, vegetables, and wine, including fiber, vitamins, minerals, antioxidants, have shown to be independently or jointly responsible for the apparent reduction in CVD risk. Therefore, in patients with overt CVD, efforts have focused on combining both drug treatments and nutrition interventions. Undoubtedly, the advances in the knowledge of both the disease processes and healthy dietary components have provided new avenues to develop pharmaceutical and/or dietary strategies to halt the development of vascular disease. In this regard, within the last years, pioneering nutritional strategies, such as nutraceuticals, have been developed aimed at reducing the main atherosclerotic risk factors and promoting cardiovascular health. Furthermore, a growing body of clinical evidence has demonstrated positive cardiovascular effects associated with dietary fibers, cholesterol-lowering natural agents, olive oil, omega-3 PUFAs, antioxidants, and polyphenols intake. Moreover, monounsaturated fatty acids intake has shown to modulate the expression of key atherosclerotic-related genes. Yet, in the case of antioxidants, some large clinical trials have failed to confirm such atheroprotective effects. Furthermore, there might be interactions between these natural food supplements and cardiovascular medications that cannot be overlooked. Hence, there is a need for a better understanding and more scientific evidence of the relative contribution of major nutraceutical constituents to the inhibition of the progression of atherosclerosis and its clinical consequences.
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Naringenin, a flavonoid found in high concentrations in grapefruit, has been reported to have antioxidant, antiatherogenic, and anticancer effects. Effects on lipid and glucose metabolism have also been reported. Naringenin is structurally similar to the polyphenol resveratrol, that has been reported to activate the SIRT1 protein deacetylase and to have antidiabetic properties. In the present study we examined the direct effects of naringenin on skeletal muscle glucose uptake and investigated the mechanism involved. Naringenin stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner. Maximum stimulation was seen with 75 microM naringenin for 2 h (192.8+/-24%, p<0.01), a response comparable to maximum insulin response (190.1+/-13%, p<0.001). Similar to insulin, naringenin did not increase glucose uptake in myoblasts indicating that GLUT4 glucose transporters may be involved in the naringenin-stimulated glucose uptake. In addition, naringenin did not have a significant effect on basal or insulin-stimulated Akt phosphorylation while significantly increased AMPK phosphorylation/activation. Furthermore, silencing of AMPK, using siRNA approach, abolished the naringenin-stimulated glucose uptake. The SIRT1 inhibitors nicotinamide and EX527 did not have an effect on naringenin-stimulated AMPK phosphorylation and glucose uptake. Our data show that naringenin increases glucose uptake by skeletal muscle cells in an AMPK-dependent manner.
Article
Resveratrol has demonstrated cancer chemopreventive activity in animal models and some clinical trials are underway. In addition, resveratrol was shown to promote cell survival, increase lifespan and mimic caloric restriction, thereby improving health and survival of mice on high-calorie diet. All of these effects are potentially mediated by the pleiotropic interactions of resveratrol with different enzyme targets including COX-1 (cyclo-oxygenase-1) and COX-2, NAD+-dependent histone deacetylase SIRT1 (sirtuin 1) and QR2 (quinone reductase 2). Nonetheless, the health benefits elicited by resveratrol as a direct result of these interactions with molecular targets have been questioned, since it is rapidly and extensively metabolized to sulfate and glucuronide conjugates, resulting in low plasma concentrations. To help resolve these issues, we tested the ability of resveratrol and its metabolites to modulate the function of some known targets in vitro. In the present study, we have shown that COX-1, COX-2 and QR2 are potently inhibited by resveratrol, and that COX-1 and COX-2 are also inhibited by the resveratrol 4'-O-sulfate metabolite. We determined the X-ray structure of resveratrol bound to COX-1 and demonstrate that it occupies the COX active site similar to other NSAIDs (non-steroidal anti-inflammatory drugs). Finally, we have observed that resveratrol 3- and 4'-O-sulfate metabolites activate SIRT1 equipotently to resveratrol, but that activation is probably a substrate-dependent phenomenon with little in vivo relevance. Overall, the results of this study suggest that in vivo an interplay between resveratrol and its metabolites with different molecular targets may be responsible for the overall beneficial health effects previously attributed only to resveratrol itself.
Article
The qualitative and quantitative compositions of chinotto juice in two different maturation periods were determined via chromatographic separation of extracted aliquots of juice of Citrus x myrtifolia Raf. by using reverse-phase LC-DAD-ESI-MS-MS. This provides a comprehensive chromatographic evaluation of 11 compounds (furanocoumarins and flavonoids C- and O-glycosides). Five flavonoids and two furanocoumarins were identified for the first time in chinotto juice: two C-glucosides (vicenin-2 and lucenin-2 4'-methyl ether), two O-glycosides (narirutin and rhoifolin), and a 3-hydroxy-3-methylglutaryl flavanone (brutieridin). Bergapten and epoxybergamottin were the primary furanocoumarins found. Overall, the juice from immature chinotto fruits is richer in bioactive compounds than that obtained from ripe fruits. The free radical and superoxide anion scavenging activities of juice from both green and ripe fruits were assessed, and results showed that the former is much more efficient in scavenging radical and superoxide species than the latter.
Article
Naringenin is a citrus flavonoid that potently inhibits the assembly and secretion of apolipoprotein B100-containing lipoproteins in cultured hepatocytes and improves the dyslipidemia and insulin resistance in a mouse model of the metabolic syndrome. In the present study, we used low-density lipoprotein receptor-null mice fed a high-fat diet (Western, TD96125) to test the hypothesis that naringenin prevents atherosclerosis. Three groups (chow, Western, and Western plus naringenin) were fed ad libitum for 6 months. The Western diet increased fasting plasma triglyceride (TG) (5-fold) and cholesterol (8-fold) levels compared with chow, whereas the addition of naringenin significantly decreased both lipids by 50%. The Western-fed mice developed extensive atherosclerosis in the aortic sinus because plaque area was increased by 10-fold compared with chow-fed animals. Quantitation of fat-soluble dye (Sudan IV)-stained aortas, prepared en face, revealed that Western-fed mice also had a 10-fold increase in plaque deposits throughout the arch and in the abdominal sections of the aorta, compared with chow. Atherosclerosis in both areas was significantly decreased by more than 70% in naringenin-treated mice. Consistent with quantitation of aortic lesions, the Western-fed mice had a significant 6-fold increase in cholesterol and a 4-fold increase in TG deposition in the aorta compared with chow-fed mice. Both were reduced more than 50% by naringenin. The Western diet induced extensive hepatic steatosis, with a 10-fold increase in both TG and cholesteryl ester mass compared with chow. The addition of naringenin decreased both liver TG and cholesteryl ester mass by 80%. The hyperinsulinemia and obesity that developed in Western-fed mice was normalized by naringenin to levels observed in chow-fed mice. These in vivo studies demonstrate that the citrus flavonoid naringenin ameliorates the dyslipidemia in Western-fed low-density lipoprotein receptor-null mice, leading to decreased atherosclerosis; and suggests a potential therapeutic strategy for the hyperlipidemia and increased risk of atherosclerosis associated with insulin resistance.
Article
A reduced life span is an outcome associated with many prevalent diseases, including diabetes, obesity, and high blood pressure. In seeking to prevent these diseases, many researchers have looked into potential therapeutic benefits of naturally occurring compounds. AMP-activated protein kinase (AMPK) is a major metabolic-sensing protein implicated in the prevention of metabolic disorders, or in minimizing the effects thereof, via the regulation of both upstream and downstream target molecules. In the field of food and nutrition, the current focus lies in the finding of components that activate AMPK. AMPK is a serine/threonine protein kinase and is activated by several natural compounds, including resveratrol, epigallocatechin gallate, berberine, and quercetin. AMPK activation can induce ATP (adenosine triphosphate) generation through pathways such as glycolysis and beta-oxidation. By contrast, ATP-consuming pathways, including fatty acid and cholesterol syntheses, and gluconeogenesis, are suppressed by AMPK activation. In this review, we will discuss how the activation of AMPK by naturally occurring compounds could help to prevent the development of numerous diseases; the potential mechanism underlying these effects will also be addressed.
Article
The 3-hydroxy-3-methylglutaryl neohesperidosides of hesperetin (brutieridin, 1) and naringenin (melitidin, 2) were isolated and detected from the fruits of bergamot (Citrus bergamia). The structures of these compounds were determined by spectroscopic and chemical methods.
Article
A large body of evidence supports that the dietary intake of polyphenols - particularly of flavonoids and the specific class of flavonoids named flavanols - might be able to exert some beneficial vascular effects and reduce the risk for cardiovascular morbidity and mortality. The review of epidemiological and mechanistic studies supports the role of flavonoids, particularly cocoa and tea flavanols, in protecting the cardiovascular system against cardiovascular disease. Nevertheless, flavonoids are an heterogeneous group of natural molecules differently represented in fruit and vegetables and definitive data on cardiovascular benefits are lacking. The weakness of the available data include few and very small studies, no crossover designed studies and a wide range of dose and type of flavonoids tested. Thus, although flavonoid-rich foods and beverages are likely to protect cardiovascular system, further research is needed to characterize the mechanism of action on flavanol-rich foods. Long-term clinical trials are also needed to definitively clarify the benefits deriving from long-term consumption of flavanol-rich foods, particularly focussing on the lowest effective levels as well as synergism or antagonistic actions between different classes of flavonoids commonly found in foods.
Article
An EtOAc-soluble partition of the MeOH extract of a branch of Tetracera scandens (Dilleniaceae family) was subjected to a glucose-uptake assay, which led to the isolation and identification of five isoflavones of previously known structure namely, genistein (1), its derivatives 3',5'-diprenylgenistein (2), 6,8-diprenylgenistein (3), derrone (4) and alpinumisoflavone (5). Of these, compounds 2--5 exhibited significant glucose-uptake activity in basal and insulin-stimulated L6 myotubes. The findings from adenosine monophosphate-activated kinase (AMPK) activation and glucose transport protein4 (GLUT4) and GLUT1 over-expression revealed certain characteristics of compounds 2--5. These compounds inhibited protein tyrosine phosphatase 1B (PTP1B) activities with IC50 values ranging from 20.63 +/- 0.17 to 37.52 +/- 0.31 microM. No muscle cell toxicity was reported with compounds 3--5, while compounds 1 and 2 reduced muscle cell viability with IC50 values of 34.27 +/- 0.35 and 18.69 +/- 0.19 microM, respectively. It was concluded that T. scandens and its constituents exerted highly desirable activities on type 2 diabetes mellitus treatment since they significantly stimulated the uptake of glucose, AMPK phosphorylation, GLUT4 and GLUT1 mRNA expressions and PTP1B inhibition in L6 myotubes.
Article
To assess the role of the cGMP-inhibitable phosphodiesterase (cGI-PDE) in the action of insulin on glucose transport, adipocytes from young, lean rats were preincubated for 20 min at 37 degrees C with and without OPC 3911, a specific inhibitor of cGI-PDE, and 3-O-methylglucose uptake was measured. Insulin-stimulated glucose transport was impaired by OPC 3911 (approximately 15%) and this impairment became more pronounced in the presence of the degradable cAMP-analogue 8-bromo-cAMP (approximately 45%). This analogue alone did not significantly decrease glucose transport. Furthermore, insulin sensitivity was impaired by the combination of OPC 3911 and 8-bromo-cAMP. Maximal insulin-stimulated glucose transport in adipocytes from aging, obese rats was affected similarly by OPC 3911 and 8-bromo-cAMP, suggesting that cGI-PDE activity is not markedly altered in this insulin-resistant state. In conclusion, cGI-PDE exerts a modulating effect on the stimulatory action of insulin on glucose transport. This effect is particularly pronounced when the cellular cAMP levels are elevated.
Article
An AMP-activated protein kinase has been reported to phosphorylate rodent 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMG-CoA reductase; (S)-mevalonate:-NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88] at Ser-871, thereby lowering its catalytic activity [Clarke, P. R. & Hardie, D. G. (1990) EMBO J. 9, 2439-2446]. To explore the physiologic role of this reaction, we prepared a cDNA encoding a mutant form of hamster HMG-CoA reductase with alanine substituted for serine at residue 871. When overexpressed in transfected cells, the wild-type enzyme, but not the Ser-871 to Ala mutant, was labeled with [32P]phosphate, confirming Ser-871 as the site of phosphorylation. The wild-type enzyme, but not the mutant enzyme, showed reduced activity when the cells were harvested with the phosphatase inhibitor KF, confirming phosphorylation as a mechanism for inactivation within the cell. Despite the lack of phosphorylation, the posttranscriptional feedback regulation of the mutant enzyme was normal, as indicated by reduced activity when cells were incubated with mevalonate, 25-hydroxycholesterol, or low density lipoprotein. Moreover, the mutant enzyme showed a normal acceleration of degradation when the transfected cells were incubated with sterols. Cells expressing the wild-type enzyme showed a decreased incorporation of [14C]pyruvate into sterols when ATP was depleted by incubation with 2-deoxy-D-glucose. No such reduction was seen in cells expressing the Ser-871 to Ala mutant enzyme. We conclude that the AMP-activated protein kinase does not play a role in end-product feedback regulation of HMG-CoA reductase, but rather it comes into play when cellular ATP levels are depleted, thereby lowering the rate of cholesterol synthesis and preserving the energy stores of the cell.
Article
Both insulin and insulin-like growth factor 1 (IGF-1) are known to reduce glucose-dependent insulin secretion from the beta cells of pancreatic islets. In this paper we show that the mechanism by which IGF-1 mediates this effect is in large part through activation of a specific cyclic nucleotide phosphodiesterase, phosphodiesterase 3B (PDE3B). More specifically, in both isolated pancreatic islets and insulin-secreting HIT-T15 cells, IGF-1 inhibits insulin secretion that has been increased by glucose and glucagonlike peptide 1 (GLP-1). Moreover, IGF-1 decreases cAMP levels in parallel to the reduction of insulin secretion. Insulin secretion stimulated by cAMP analogs that activate protein kinase A and also are substrates for PDE3B is also inhibited by IGF-1. However, IGF-1 does not inhibit insulin secretion stimulated by nonhydrolyzable cAMP analogs. In addition, selective inhibitors of PDE3B completely block the ability of IGF-1 to inhibit insulin secretion. Finally, PDE3B activity measured in vitro after immunoprecipitation from cells treated with IGF-1 is higher than the activity from control cells. Taken together with the fact that pancreatic beta cells express little or no insulin receptor but large amounts of IGF-1 receptor, these data strongly suggest a new regulatory feedback loop model for the control of insulin secretion. In this model, increased insulin secretion in vivo will stimulate IGF-1 synthesis by the liver, and the secreted IGF-1 in turn feedback inhibits insulin secretion from the beta cells through an IGF-1 receptor-mediated pathway. This pathway is likely to be particularly important when levels of both glucose and secretagogues such as GLP-1 are elevated.
Article
Flavonoid glycosides were metabolized to phenolic acids via aglycones by human intestinal microflora producing alpha-rhamnosidase, exo-beta-glucosidase, endo-beta-glucosidase and/or beta-glucuronidase. Rutin, hesperidin, naringin and poncirin were transformed to their aglycones by the bacteria producing alpha-rhamnosidase and beta-glucosidase or endo-beta-glucosidase, and baicalin, puerarin and daidzin were transformed to their aglycones by the bacteria producing beta-glucuronidase, C-glycosidase and beta-glycosidase, respectively. Anti-platelet activity and cytotoxicity of the metabolites of flavonoid glycosides by human intestinal bacteria were more effective than those of the parental compounds. 3,4-Dihydroxyphenylacetic acid and 4-hydroxyl-phenylacetic acid were more effective than rutin and quercetin on anti-platelet aggregation activity. 2,4,6-Trihydroxybenzaldehyde, quercetin and ponciretin were more effective than rutin and ponciretin on the cytotoxicity for tumor cell lines. We insist that these flavonoid glycosides should be natural prodrugs.
Article
The cholesterol-lowering effects of tangerine peel extract and a mixture of two citrus flavonoids were tested. Male rats were fed a 1 g/100 g high-cholesterol diet for 42 d with supplements of either tangerine-peel extract or a mixture of naringin and hesperidin (0.5 g/100 g) to study the effects of plasma and hepatic lipids, hepatic enzyme activities, and the excretion of fecal neutral sterols. Both the tangerine-peel extract and mixture of two flavonoids significantly lowered the levels (mean +/- SE) of plasma (2.44 +/- 0. 59 and 2.42 +/- 0.31 mmol/L, vs. 3.80 +/- 0.28 mmol/L, P < 0.05), hepatic cholesterol (0.143 +/- 0.017 and 0.131 +/- 0.010 mmol/g vs. 0.181 +/- 0.003 mmol/g, P < 0.05), and hepatic triglycerides (0.069 +/- 0.007 and 0.075 +/- 0.006 mmol/g vs. 0.095 +/- 0.002 mmol/g, P < 0.05) compared to those of the control. The 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (1565.0 +/- 106. 0 pmol. min-1. mg protein-1 and 1783.0 +/- 282 pmol. min-1. mg protein-1 vs. 2487.0 +/- 210.0 pmol. min-1. mg protein-1, P < 0.05) and acyl CoA: cholesterol O-acyltransferase (ACAT) activities (548.0 +/- 65.0 and 615.0 +/- 80.0 pmol. min-1. mg protein-1 vs. 806.0 +/- 105.0 pmol. min-1. mg protein-1, P < 0.05) were significantly lower in the experimental groups than in the control. These supplements also substantially reduced the excretion of fecal neutral sterols compared to the control (211.1 +/- 26.7 and 208.2 +/- 31.6 mg/d vs. 521.9 +/- 53.9 mg/d). The inhibition of HMG-CoA reductase and ACAT activities resulting from the supplementation of either tangerine-peel extract or a combination of its bioflavonoids could account for the decrease in fecal neutral sterol that appears to compensate for the decreased cholesterol biosynthesis in the liver.
Article
The effects of dietary supplementation of a citrus bioflavonoid, naringenin, on the cholesterol metabolism were studied. For 42 days male rats were fed a 1% (wt/wt) high-cholesterol diet with or without a naringenin supplementation (0.1%, wt/wt) to study its effect on plasma lipid levels, hepatic lipid contents, activities of hepatic acyl coenzyme A:cholesterol O-acyltransferase (ACAT) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and the excretion of fecal neutral sterols. Naringenin did not significantly alter the concentration of plasma triglycerides, but lowered the plasma cholesterol (3.80 vs. 3.12 mmol/l) concentration and the hepatic cholesterol content (70.3 vs. 54.0 mg/g) significantly (p < 0.05) compared to those of the controls. HMG-CoA reductase (1,879.0 vs. 1,715.0 pmol/min/mg) and ACAT activities (806.0 vs. 563.0 pmol/min/mg) were significantly lower in the naringenin-supplemented group than in controls. Naringenin supplementation caused a marked decrease in the excretion of fecal neutral sterols (242.9 mg/day) compared to the controls (521.9 mg/day). These results show that naringenin lowers the plasma and hepatic cholesterol concentrations by suppressing HMG-CoA reductase and ACAT in rats fed a high-cholesterol diet.
Article
A series of isoflavone and tyrphostin compounds were found to inhibit the degradation of cAMP by several cyclic nucleotide phosphodiesterase (PDE) isozymes. Specific hydroxyl groups on the isoflavone structure were critical for PDE isozyme-selective inhibition. Replacement of the C-7 hydroxyl group of the isoflavone with a methoxy group raised the IC(50) for PDE1, PDE3, and PDE4. The absence of the C-5 hydroxyl group raised the IC(50) from 5 to >100 microM for PDE4, but actually lowered the IC(50) for PDE3 and PDE1. Replacement of the C-4' hydroxyl group with a methoxy group raised the IC(50) for PDE3 and PDE1, yet only slightly changed the IC(50) for PDE4. Various tyrphostins were also potent inhibitors of PDE1, PDE3, and PDE4. The four-carbon side chained tyrphostins were much less potent; however, a very interesting pattern was observed in which removal of phenolic hydroxyls on the tyrphostin structure increased the potency for PDE1 and PDE3, but not PDE4. These results may help to explain some of the therapeutic and intracellular signaling effects of isoflavones and tyrphostins. Moreover, the isozyme selectivity demonstrated by the isoflavones and tyrphostins can serve as a pharmacophore for the design of specific PDE inhibitors.
Article
Although many effects of leptin are mediated through the central nervous system, leptin can regulate metabolism through a direct action on peripheral tissues, such as fat and liver. We show here that leptin, at physiological concentrations, acts through an intracellular signaling pathway similar to that activated by insulin in isolated primary rat hepatocytes. This pathway involves stimulation of phosphatidylinositol 3-kinase (PI3K) binding to insulin receptor substrate-1 and insulin receptor substrate-2, activation of PI3K and protein kinase B (AKT), and PI3K-dependent activation of cyclic nucleotide phosphodiesterase 3B, a cAMP-degrading enzyme. One important function of this signaling pathway is to reduce levels of cAMP, because leptin-mediated activation of both protein kinase B and phosphodiesterase 3B is most marked following elevation of cAMP by glucagon, and because leptin suppresses glucagon-induced cAMP elevation in a PI3K-dependent manner. There is little or no expression of the long form leptin receptor in primary rat hepatocytes, and these signaling events are probably mediated through the short forms of the leptin receptor. Thus, leptin, like insulin, induces an intracellular signaling pathway in hepatocytes that culminates in cAMP degradation and an antagonism of the actions of glucagon.
Article
This chapter discusses some general information about cyclic nucleotide phosphodiesterases (PDEs). It also discusses the PDE3 gene family, emphasizing the molecular biology, structure/function relationships, and cellular regulation and functional roles of PDE3s, as well as physiological/pharmacological actions, therapeutic applications, and potential benefits of PDE3 inhibitors. The major cause of concern in the use of PDE3 inhibitors as therapeutic agents is the potential for increased mortality in patients with known heart disease. Although caution is certainly warranted in this context, conclusions should not be indiscriminately applied to all PDE3 inhibitors. The pharmacological profiles of newer PDE3 inhibitors differ from those of the PDE3 inhibitors used in earlier heart failure clinical trials. Although milrinone and cilostazol are similar in potency as inhibitors of PDE3, milrinone had greater effects than cilostazol on increasing both cyclic adenosine monophosphate (cAMP) and contractility in isolated rabbit cardiomyocytes. The ability to target PDE3 inhibitors to specific isoforms in specific intracellular compartments and/or specific cells may be critical for improvement in efficacy and safety. The acute benefits and chronic adverse actions of PDE3 inhibitors in patients, with heart failure, may result from the phosphorylation of different substrates of Protein kinase A (PKA) in different intracellular compartments. Newer PDE3 inhibitors that target a specific isoform in the appropriate compartment could potentially confer beneficial hemodynamic effects without adverse effects on mortality.
Article
Insulin resistance in skeletal muscle is present in humans with type 2 diabetes (noninsulin-dependent diabetes mellitus) and obesity and in rodents with these disorders. Malonyl CoA is a regulator of carnitine palmitoyl transferase I (CPT I), the enzyme that controls the transfer of long chain fatty acyl CoA into mitochondria where it is oxidized. In rat skeletal muscle, the formation of malonyl CoA is regulated acutely (in minutes) by changes in the activity of acetyl CoA carboxylase (ACC), the enzyme that catalyzes malonyl CoA synthesis. ACC activity can be regulated by changes in the concentration of citrate which is both an allosteric activator of ACC and a source of its precursor, cytosolic acetyl CoA. Increases in cytosolic citrate leading to an increase in the concentration of malonyl CoA occur when muscle is presented with insulin and glucose, or when it is made inactive by denervation. In contrast, exercise lowers the concentration of malonyl CoA, by activating an AMP activated protein kinase (AMPK), which phosphorylates and inhibits ACC. Recently we have shown that the activity of malonyl CoA decarboxylase (MCD), an enzyme that degrades malonyl CoA, is also regulated by phosphorylation. The concentration of malonyl CoA in liver and muscle in certain circumstances correlates inversely with changes in MCD activity. This review will describe the current literature on the regulation of malonyl CoA/AMPK mechanism and its physiological function.
Article
The purpose of the current study was to evaluate the lipid lowering and antioxidant capacity of naringin in LDL receptor knockout (LDLR-KO) mice fed a cholesterol (0.1 g/100 g) diet. As such, naringin or lovastatin (0.02 g/100 g) was supplemented in a cholesterol diet for 6 weeks. The naringin and lovastatin supplementation significantly lowered the plasma total cholesterol level compared to the control group. The plasma and hepatic triglyceride level was only lowered by the lovastatin supplement, while the hepatic cholesterol content was lowered by both the naringin and lovastatin supplements compared to the control group. The hepatic HMG-CoA reductase activity was significantly lower in the naringin and lovastatin supplemented groups than in the control group, whereas the ACAT activity was unaffected. The excretion of total sterol was significantly higher in the naringin and lovastatin groups compared to the control group due to significant changes in the acidic and neutral sterol, respectively. When comparing the hepatic antioxidant enzyme activities, the superoxide dismutase, catalase, and glutathione reductase activities were all significantly higher in the naringin-supplemented group than in the control group, while only the lovastatin supplement increased the glutathione reductase activity. Accordingly, the current results confirmed that naringin lowers the plasma cholesterol level via the inhibition of hepatic HMG-CoA reductase activity and increases the excretion of fecal sterol. Naringin was also found to improve the activities of hepatic antioxidant enzymes against oxidative stress in a hypercholesterolemic animal model, i.e. cholesterol-fed LDLR-KO mice.
Article
Resveratrol has been shown to have chemopreventive, cardioprotective, and antiaging properties. Here, we report that resveratrol is a potent inhibitor of quinone reductase 2 (QR2) activity in vitro with a dissociation constant of 35 nM and show that it specifically binds to the deep active-site cleft of QR2 using high-resolution structural analysis. All three resveratrol hydroxyl groups form hydrogen bonds with amino acids from QR2, anchoring a flat resveratrol molecule in parallel with the isoalloxazine ring of FAD. The unique active-site pocket in QR2 could potentially bind other natural polyphenols such as flavonoids, as proven by the high affinity exhibited by quercetin toward QR2. K562 cells with QR2 expression suppressed by RNAi showed similar properties as resveratrol-treated cells in their resistance to quinone toxicity. Furthermore, the QR2 knockdown K562 cells exhibit increased antioxidant and detoxification enzyme expression and reduced proliferation rates. These observations could imply that the chemopreventive and cardioprotective properties of resveratrol are possibly the results of QR2 activity inhibition, which in turn, up-regulates the expression of cellular antioxidant enzymes and cellular resistance to oxidative stress.