Article

Flavonoids from Artichoke (Cynara scolymus L.) Up-Regulate Endothelial-Type Nitric-Oxide Synthase Gene Expression in Human Endothelial Cells

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Abstract

Nitric oxide (NO) produced by endothelial nitric-oxide synthase (eNOS) represents an antithrombotic and anti-atherosclerotic principle in the vasculature. Hence, an enhanced expression of eNOS in response to pharmacological interventions could provide protection against cardiovascular diseases. In EA.hy 926 cells, a cell line derived from human umbilical vein endothelial cells (HUVECs), an artichoke leaf extract (ALE) increased the activity of the human eNOS promoter (determined by luciferase reporter gene assay). An organic subfraction from ALE was more potent in this respect than the crude extract, whereas an aqueous subfraction of ALE was without effect. ALE and the organic subfraction thereof also increased eNOS mRNA expression (measured by an RNase protection assay) and eNOS protein expression (determined by Western blot) both in EA.hy 926 cells and in native HUVECs. NO production (measured by NO-ozone chemiluminescence) was increased by both extracts. In organ chamber experiments, ex vivo incubation (18 h) of rat aortic rings with the organic subfraction of ALE enhanced the NO-mediated vasodilator response to acetylcholine, indicating that the up-regulated eNOS remained functional. Caffeoylquinic acids and flavonoids are two major groups of constituents of ALE. Interestingly, the flavonoids luteolin and cynaroside increased eNOS promoter activity and eNOS mRNA expression, whereas the caffeoylquinic acids cynarin and chlorogenic acid were without effect. Thus, in addition to the lipid-lowering and antioxidant properties of artichoke, an increase in eNOS gene transcription may also contribute to its beneficial cardiovascular profile. Artichoke flavonoids are likely to represent the active ingredients mediating eNOS up-regulation.

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... The flower buds, prior to blooming, of Cynara scolymus (artichoke), are relevant for culinary purposes, while the leaves are processed for phytotherapeutic applications. Extracts from artichoke leaves are used in the prevention of arteriosclerosis due to cholesterol-lowering [39,40] and antihypertensive effects [41]. The antihypertensive effect results from an upregulation of endothelial-type nitric oxide synthase genes [41]. ...
... Extracts from artichoke leaves are used in the prevention of arteriosclerosis due to cholesterol-lowering [39,40] and antihypertensive effects [41]. The antihypertensive effect results from an upregulation of endothelial-type nitric oxide synthase genes [41]. Furthermore, artichokes have antioxidant properties as they are rich in phenolic compounds, such as chlorogenic acids and flavones [42,43]. ...
... Hence, ALE showed a fairly strong inhibitory effect on PDE, possibly through dicaffeoylquinic acids and/or flavones that were not identified in the extract yet. The antihypertensive effect of Cynara scolymus [41] may result from PDE inhibition, but further investigations are necessary to confirm this role. As the content of phenolic compounds is higher in artichoke leaves than in the edible flower buds [47], the effect of consuming artichokes or drinking teas from artichoke leaves on PDE activity should be of relevance. ...
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Background: Phosphodiesterases (PDEs) play a major role in the regulation of cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-mediated pathways. Their inhibitors exhibit anti-inflammatory, vasodilatory and antithrombotic effects. Therefore, consumption of foods with PDE-inhibiting potential may possess beneficial influence on the risk of cardiovascular diseases. Methods: Four plant extracts (Arbutus unedo, Camellia sinensis, Cynara scolymus, Zingiber officinale) with promising ingredient profiles and physiological effects were tested for their ability to inhibit cAMP-specific PDE in vitro in a radioactive assay. Results: Strawberry tree fruit (Arbutus unedo) and tea (Camellia sinensis) extracts did not inhibit PDE markedly. Alternatively, artichoke (Cynara scolymus) extract had a significant inhibitory influence on PDE activity (IC50 = 0.9 ± 0.1 mg/mL) as well as its flavone luteolin (IC50 = 41 ± 10 μM) and 3,4-dicaffeoylquinic acid (IC50 > 1.0 mM). Additionally, the ginger (Zingiber officinale) extract and one of its constituents, [6]-gingerol, significantly inhibited PDE (IC50 = 1.7 ± 0.2 mg/mL and IC50 > 1.7 mM, respectively). Crude fractionation of ginger extract showed that substances responsible for PDE inhibition were in the lipoid fraction (IC50 = 455 ± 19 μg/mL). Conclusions: A PDE-inhibitory effect was shown for artichoke and ginger extract. Whether PDE inhibition in vivo can be achieved through ingestion of artichoke or ginger extracts leading to physiological effects concerning cardiovascular health should be addressed in future research.
... Their chemical structures are depicted in A. Zayed, et al. Journal of Functional Foods 69 (2020) 103937 action and showed up-regulation of the eNOS promotor and eNOS mRNA expression, which led to nitric oxide (NO) production and consequent anti-thrombotic and anti-atherosclerotic activities (Li, Xia, Brausch, Yao, & Forstermann, 2004). These activities contributed to the beneficial and health-promoting effects of C. cardunculus L. in cardiovascular diseases treatment. ...
... Since eNOS and iNOS have different functions in the vascular system with eNOS being beneficial and iNOS mostly harmful, artichoke flavonoids, especially cynarin, activated specifically the NO endothelial type (eNOS) expression with a vasoprotective activity, whereas artichoke anthocyanins downregulated the iNOS expression suggestive for a synergistic effect of artichoke flavonoids. Opposed effects of artichoke on both NOS isoforms could contribute to the valuable effects of artichoke as a cardioprotective agent (Li et al., 2004;Xia et al., 2014) and urging for the development of functional foods from artichoke specialized for the treatment of cardiovascular disorders. ...
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Cynara cardunculus L. with its three botanical varieties are presented as potential food and drug resources. Its young flower heads are commonly consumed as a principal part of different Mediterranean dishes, especially the globe artichoke, whereas its different plant parts are considered potential sources of valuable phytoconstituents, mainly polysaccharides, and polyphenols. These chemicals contribute to its nutrition, industry, and bioactivities, including hepatic-and cardiovascular protection and inflammation disorders. A holistic comparative study of artichoke phytochemicals make-up as determinants of its quality, nutritive value and health benefits is presented for its different varieties. Such reviewed evidence is an essential prerequisite for a future better selection of certain variety, and or utilization in therapeutic, food and pharmaceutical applications. The review presented few endeavors for the development of potential novel functional foods fortified with artichoke extracts and/or its bioactive which are of value and need to be more recognized commercially.
... Bulb and stem vegetables have been less extensively studied than leafy vegetables and constitute a rather heterogenous group including in particular celery, artichoke and asparagus. Celery (Apium graveolens L.) has been proposed to possess anti-oxidative and anti-inflammatory potency [10,11], whereas artichoke (Cynara scolymus) received attention through its potential beneficial impact on LDLcholesterol, endothelial NOS expression, and hepatodigestive function [12]. Asparagus (Asparagus officinialis with Asparagales as the botanical family) on its turn is a rich source of asparagine, potassium, vitamin C, and antioxidative glycolipids [13]. ...
... Artichoke (Cynara scolymus), from the family of Asteraceae, has been used for centuries as food and herbal medicine, already by the ancient Egyptians, Greeks, and Romans who considered it as a digestive aid and a treatment for hepato-digestive diseases [77]. It has more recently received substantial attention for its potential beneficial effects on dyslipidemia, e.g., lowering blood LDL-cholesterol and triglycerides [78], stimulation of bile secretion, prebiotic effects, upregulation of endothelial NOS expression [12], and for its hepato-protective effects [79]. These health benefits have been attributed to the synergy between inulin, a soluble fiber of the fructans family and polyphenols such as cynarin (1,3-Odicaffeoylquinic acid; HMDB0029279), chlorogenic acid, and luteolin glycosides [77,79]. ...
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Background: Numerous studies acknowledged the importance of an adequate vegetable consumption for human health. However, current methods to estimate vegetable intake are often prone to measurement errors due to self-reporting and/or insufficient detail. More objective intake biomarkers for vegetables, using biological specimens, are preferred. The only concentration biomarkers currently available are blood carotenoids and vitamin C, covering total fruit and vegetable intake. Identification of biomarkers for specific vegetables is needed for a better understanding of their relative importance for human health. Within the FoodBAll Project under the Joint Programming Initiative "A Healthy Diet for a Healthy Life", an ambitious action was undertaken to identify candidate intake biomarkers for all major food groups consumed in Europe by systematically reviewing the existent literature. This study describes the review on candidate biomarkers of food intake (BFIs) for leafy, bulb, and stem vegetables, which was conducted within PubMed, Scopus and Web of Science for studies published through March 2019. Results: In total, 65 full-text articles were assessed for eligibility for leafy vegetables, and 6 full-text articles were screened for bulb and stem vegetables. Putative BFIs were identified for spinach, lettuce, endive, asparagus, artichoke, and celery, but not for rocket salad. However, after critical evaluation through a validation scheme developed by the FoodBAll consortium, none of the putative biomarkers appeared to be a promising BFI. The food chemistry data indicate that some candidate BFIs may be revealed by further studies. Conclusion: Future randomized controlled feeding studies combined with observational studies, applying a non-targeted metabolomics approach, are needed in order to identify valuable BFIs for the intake of leafy, bulb, and stem vegetables.
... The restoration of ethylene glycol-induced renal micro-architecture alterations was accredited to multiple bioactive antioxidant vizcynarin, luteolin, and chlorogenic acids in the artichoke leaf extract [100]. Caffeoylquinic acids and flavonoids in artichoke leaf extract yielded efficient antioxidant activity [101]. Morsy and Kamel [102] also found reduced oxidative damage by artichoke leaf extract, evidenced by declined MDA level and SOD activity in tissue. ...
... Artichoke extract Chocolate flavored beverage in rats [61][62][63] C. scolymus extract A double-blind placebo-controlled clinical trial [65] Artichoke extract High fat-induced obesity in rats [49] Antidiabetic effects Artichoke extract Patients with metabolic syndrome [66] Artichoke extract Wistar rats and obese Zucker rats [67] Artichoke leaf extract Streptozotocin-induced diabetic rats [51] Ethanolic extract Alloxan-diabetic rats [30] Aqueous extract Streptozotocin-induced hyperglycemic rats [70] Hepatoprotective effects Stem extract of artichoke H4IIE Hepatocytes culture [68] Artichoke leaf extract High fat-induced hepatotoxicity in rats [75] Artichoke leaf extract Diazinon-induced liver injury in rats [76] Artichoke leaf extract Carbon tetrachloride-induced hepatotoxicity in rats [77][78]82] Methanolic extract Steatohepatitis induced in rat [85] Artichoke leaf extract Chronic hepatitis C-a pilot study [86] Aqueous artichoke extract Alpha-amanitine induced hepatotoxicity in rats [87] Artichoke extract Carbon tetrachloride-induced hepatotoxicity [31] Artichoke floral extract Cisplatin-induced hepatotoxicity in rats [90] Artichoke leaf extract Paracetamol induced hepatotoxicity [102] Artichoke leaf extract Hypercholesterolemic rats [57] Nephroprotective effects Ethanolic leaf extract High-fat diet rats [49] Ethanolic leaf extract Rats [98] Artichoke leaf extract Ethylene induced nephrolith rats [99][100][101][102][103] Chlorogenic acid Cisplatin-induced renal damage in mice [104] C.cardunculus extract Hypercholesterolemic rats [105] Artichoke leaf extract Gentamicin induced nephrotoxicity in rats [106] Artichoke extract 5-fluorouracil induced nephrotoxicity in rats [107] Artichoke floral extract Cisplatin-induced nephrotoxicity in rats [108] Artichoke leaf extract Diclofenac induced nephrotoxicity [109] Gastrointestinal effects ...
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Background: Medicinal herbs remain vital source of new chemical entities, instead of the attempt of pharmaceutical companies using combinatorial and synthetic chemistry techniques for developing new drugs. Material and methods: Cynara scolymus commonly known as Artichoke is a rich source of polyphenolic compounds, mainly caffeoylquinic acids and flavonoids, isolated in the polar extracts of the plant, together with the polysaccharide inulin. The worldwide accepted scientific databases were comprehensive reviewed and summarized in systemic manner. Results: The beneficial effects of artichoke in experimental studies include antidiabetic, anti-obesity, anti-inflammatory, anti-hypercholesterolemic, hepatoprotective, nephroprotective, gastrointestinal protectant, reproductive, and anticancer effect. Studies with artichoke conducted in experimental animals have not reported mortality or significant toxicity. Increasing attention is being paid for the development of herbal medicines as newly emerging treatment for the welfare of the patients in the last few decades. Conclusion: The present review detailed the versatile therapeutic efficiency and diverse application of C. scolymus. It is concluded that this medicinal herb has been used in traditional medicine rightly since long, and is helpful in cure of various ailments.
... Long term incubation of HUVECs with the crude extract or organic subfraction of artichoke leafs, rich in flavonoids, increased eNOS expression and NO production. Additionally ex vivo incubation of aortic rings with the organic subfraction of artichoke leafs enhanced the NO mediated vasodilator response to Ach (Li et al., 2004). Anthocyanin-rich berry extracts showed considerable inhibitory effects on NO production from macrophages, and their inhibitory effects were significantly correlated with the content of total phenolics, tartaric ester, flavonols, and anthocyanins (Wang and Mazza, 2002). ...
... Similarly, incubation of SD rat aortic rings with the flavonoid-rich artichoke leaf organic subtraction was shown to enhance the NO mediated vasodilator response to Ach (Li et al., 2004). ...
Article
The effect of wild blueberries on major endothelium-dependent vasodilation pathways and arterial blood pressure (BP) was examined in the young adult Spontaneously Hypertensive rat (SHR), used as a model of endothelial dysfunction, and the Wistar Kyoto (WK) rat, with functional endothelium, used as the control. Male SHR and WK rats were fed a control (SHR-C and WK-C), or a wild blueberry-enriched (SHR-B and WK-B) diet for nine weeks. By the age of 21 weeks, thoracic aortae were excised and 3mm arterial rings were prepared and immersed in Radnoti tissue baths. Rings were precontractred with phenylephrine (Phe) (10"6M), followed by cumulative acetylcholine (Ach) doses (10"9M to 3x10" 6M) to generate dose-response curves in the absence or in the presence of either a nitric oxide synthase (NOS) inhibitor (L-NMMA at 10"4M), a cyclooxygenase (COX) inhibitor (MFA at 10"5M) or both inhibitors added simultaneously. The maximum Ach-induced vasodilation force (Fmax) and vessel sensitivity (pD2) were determined for each treatment group. A two-way analysis of variance (ANOVA) demonstrated no significant difference in the Fmax between the WK-B and WK-C groups. However, wild blueberries were found to reduce the pD2 in response to Ach in the young adult WK rat (WKB: 7.41 ± 0.02 vs. WK-C 7.49 ± 0.02, p
... It was previously described that this flavone has beneficial effects on oxidative stress and inflammation associated with cardiovascular diseases [10][11][12][13]. In addition, luteolin hampers cholesterol biosynthesis [14], decreases insulin resistance and hepatic steatosis [15][16][17], and enhances endothelial NO synthase (eNOS) gene expression [18]. ...
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We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT-) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. Results: Endothelial function was impaired in diabetic GK rats (47% (GK - PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK - PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products' levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. Conclusions: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes.
... Interestingly, this specific phyto-ingredient has been shown, when employed at higher dosages, to exert a cholesterol-lowering effect even in healthy athletes under high-intensity exercise [37]. This property together with its flavonoids-related endothelial function protection by iNOS upregulation [38] shared most recently by corosolic acidcontaining banaba extracts [39] may widen its potential application. Moreover, although fasting glycaemia didn't show any significant change during treatment, group I showed a trend improvement of HbA1c. ...
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About one fourth of all American adults and a bit less than one sixth of Europeans are reported to be affected by metabolic syndrome. Aging seem associated to a consistent increase of this phenomenon which is now clear to be associated with a low-grade pro-inflammatory cascade. Dyslipidemia is a characteristic factor involved in this multifaceted metabolic setting and this provides new avenues to non-chemical biopharmaceutical interventions. Eighty-two patients (66 males and 16 females, 38-69 as age range) with metabolic syndrome were selected randomly. Patients meeting inclusion criteria were advised to adhere to a standard balanced diet but no specific dietary calorie-restriction or life-style modifications. Two matched patients groups were assigned either to 1 tab/ dinner of drug A and another group received 1 tab/dinner of drug B, both for 3 months. Physicians and patients were blinded as for the content of the tablets except being aware that one being P3/GB-2016 while the other a looking alike placebo. A third group of 25 healthy, normal-weight subjects without any biochemical abnormalities served as control. The mean HbA1c level showed a trend decrease in group I at 3-month observation but this group showed a significant decrease of total and LDL cholesterol, non-HDL aliquot and triglycerides throughout the study period (p<0.05). Serum concentration of either MIP1α or MIF were significantly higher in dysmetabolic patients as compared to healthy control (p<0.01). Treatment with P3/GB-2016 proved to significantly decrease both parameters at 3-month observation (p<0.01). Whereas circulating levels of MCP-1 appeared showed a wide dispersion of data and appearing to be higher in those subjects with highest (n.s.). Overall, P3/GB-2016 seems to be an effective oral agent in controlling dyslipidemia and key regulatory modulator within the management of metabolic syndrome.
... Recent data suggested also that this flavonoid reduces hepatic steatosis and insulin resistance (El-Bassossy et al., 2013;Xu et al., 2014;Kwon et al., 2015), inhibits cholesterol biosynthesis (Gebhardt, 2002) and increases endothelial NO synthase (eNOS) gene expression (Li et al., 2004). However, the effects of luteolin on obesity-related endothelial dysfunction have not been clarified yet. ...
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Purpose: Luteolin exerts beneficial effects against obesity-associated comorbidities, although its influence on vascular dysfunction remains undetermined. We examined the effects of luteolin on endothelial dysfunction in a mouse model of diet-induced obesity. Methods: Standard diet (SD) or high-fat diet (HFD)-fed mice were treated daily with luteolin intragastrically. After 8 weeks, body and epididymal fat weight, as well as blood cholesterol, glucose, and triglycerides were evaluated. Endothelium-dependent relaxations of resistance mesenteric vessels was assessed by a concentration-response curve to acetylcholine, repeated upon Nw-nitro-L-arginine methylester (L-NAME) or ascorbic acid infusion to investigate the influence of nitric oxide (NO) availability and reactive oxygen species (ROS) on endothelial function, respectively. Intravascular ROS production and TNF levels were measured by dihydroethidium dye and ELISA, respectively. Endothelial NO synthase (eNOS) and superoxide dismutase 1 (SOD1), as well as microRNA-214-3p expression were examined by Western blot and RT-PCR assays, respectively. Results: HFD animals displayed elevated body weight, epididymal fat weight and metabolic indexes. Endothelium-dependent relaxation was resistant to L-NAME and enhanced by ascorbic acid, which restored also the inhibitory effect of L-NAME, suggesting a ROS-dependent reduction of NO availability in HFD vessels. Moreover, media-lumen ratio, intravascular superoxide anion and TNF levels were increased, while vascular eNOS, SOD1, and microRNA-214-3p expression were decreased. In HFD mice, luteolin counteracted the increase in body and epididymal fat weight, and metabolic alterations. Luteolin restored vascular endothelial NO availability, normalized the media-lumen ratio, decreased ROS and TNF levels, and normalized eNOS, SOD1 and microRNA-214-3p expression. Conclusion: Luteolin prevents systemic metabolic alterations and vascular dysfunction associated with obesity, likely through antioxidant and anti-inflammatory mechanisms.
... Leur mécanisme d'action antioxydante implique le transfert sur l'entité réactive d'un électron ou d'un atome d'hydrogène pour le stabiliser (Riee-Evans et Miller, 1996). Ils possèdent de nombreuses propriétés in vivo : antiallergiques, anti-inflammato ires, antioxydantes, antimutagènes, anti-carcinogènes (Kandaswami et al., 1992;Galati et al., 2000;Yang et al., 2001) et sont impliquées dans la régulation de nombreuses activités enzymatiques (Li et al., 2004). Figure 9 : Structures de base des quatre familles des flavonoïdes (d'après Ren et al., 2003 (Parker, 1996). ...
Thesis
Les méthionine sulfoxyde réductases (Msr) permettent de restaurer la fonction des protéines oxydées sur leur résidus Methionine. Dans un premier temps, le mécanisme catalytique de la MsrA et de la MsrB de la protéine PilB de la bactérie pathogène Neisseria meningitidis a été étudié. Les deux classes de Msr, qui sont structuralement différentes, partagent un même mécanisme catalytique en trois étapes avec formation d'un intermédiaire acide sulfénique suivie de la formation d'un pont disulfure intra moléculaire qui est réduit par la thiorédoxine (Trx). Elles présentent en revanche une stéréospécificité de substrat inverse vis-à-vis de la fonction sulfoxyde. Dans un deuxième temps, les trois étapes du mécanisme catalytique de la MsrB ont été caractérisées au niveau cinétique. L'étude du rôle des acides aminés du site actif dans la catalyse, la caractérisation biochimique de l'interaction MsrB-Trx et, enfin, l'étude du rôle du métal coordiné ont également été abordées.
... Вазопротекторный и кардиопротекторный эффекты ЭА ассоциируются в литературе с высоким содержанием полифенольных антиоксидантов, что существенно увеличивает антиоксидантные ресурсы плазмы крови [17]. ЭА более эффективно, чем аскорбиновая кислота, защищает эндотелий от оксидативного стресса [18] и обладает способностью повышать секрецию NO, что обусловливает ангиопротекторное действие [5,19]. Исследования свойств экстракта на клетках гладкомышечных клеток коронарной артерии in vitro обнаружили, что действующие вещества, с одной стороны, не только стимулируют выделение эндотелиальной NOS (которая является вазопротектором), но и тормозят, а с другой стороны -экспрессию митохондриальной индукции iNOS, которая играет провоспалительную роль в сосудах. ...
Article
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Herbal preparations in the world today become more and more popular due to their inherent advantages over drugs of chemical origin. Long historical experience of application, high safety profile, complex action and the possibility of long-term use without significant side effects cause an increase in their consumption throughout the world. At the same time, the practice of using herbal preparations is significantly constrained by the lack of scientific information about their mechanisms of action, potential adverse reactions, contraindications and interactions with other drugs and food. The publication deals with the scientific data on the possibilities of application in clinical medicine of preparations based on extract of leaves of artichoke seed. The existing information based on preclinical and clinical research has been analyzed. Particular attention is paid to the results of controlled clinical trials. Attention is drawn to the very good tolerability and safety of plant preparations from artichoke, which, in particular, allows their use in children, gerontological patients, during pregnancy. It is concluded that these drugs have significant prospects for widespread use, and existing scientific data allow their wide clinical use separately and in combination with a variety of diseases and pathological conditions.
... Вазопротекторний та кардіопротективний ефекти ЕА асоціюються в науковій літературі з високим вмістом поліфенольних антиоксидантів, що суттєво збільшує антиоксидантні ресурси плазми [33]. ЕА більш ефективно, ніж аскорбінова кислота захищає ендотелій від оксидативного стресу [34] і має здатність підвищувати секрецію вазодилататора NO, що обумовлює ангіопротекторну дію [7,35]. Дослідження властивостей екстракту на клітинах гладком'язових клітин коронарної артерії in vitro виявили, що діючі речовини, з одного боку, стимулюють виділення ендотеліальної NOS, що є вазопротектором, та гальмують, з іншого боку, експресію мітохондріальної індукції iNOS, що відіграє прозапальну роль у судинах. ...
Article
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Today herbal medicines become more and more popular in the world due to their inherent advantages over drugs of the chemical origin. A long historical experience of application, the high safety profile, its complex action, as well as the possibility of the long-term use without significant side effects cause an increase in their consumption around the world. At the same time, the practice of using herbal medicines is significantly hindered by the lack of scientific information about their mechanisms of action, potential adverse reactions, contraindications and interactions with other drugs and food. The publication considers scientometric data on the possible use of medicines based on leaves of artichoke and garlic in the clinical medicine. The existing information based on the preclinical and clinical studies has been analyzed. Particular attention is paid to the results of controlled clinical trials. The attention is drawn to very good tolerability and safety of herbal medicines from artichoke and garlic, which, in particular, allows their use in children, geriatric patients, pregnancy, etc. The conclusion has been made that these medicines have significant prospects for widespread use, and the existing scientific data allow their wide clinical use separately and in combination with a variety of diseases and pathological conditions.
... The leaves of artichoke contain more flavonoids than the other parts of this plant and their quantity is different in particular cultivars [Romani et al. 2006]. Some therapeutic effects of artichoke are attributed to the presence of flavonoids whose level depends, among others, on extraction method [Li et al. 2004, Vamanu et al. 2011]. The average flavonoid content in artichoke leaves studied was 0.19% (tab. ...
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Artichoke is valued as a vegetable and medicinal plant. The aim of the study was to determine the effect of irrigation and leaf harvest date of artichoke grown in southeastern Poland on total yield and marketable fresh leaf yield, its structure and the content of biologically active substances: total phenolic acids, flavonoids and tannins. Irrigation contributed to an increase in fresh leaf yield, percentage of marketable yield in total yield, as well as the increase in tannin content, decrease in total phenolic acid content, and no effect on the change in total flavonoid content. The plant material harvested in September was characterized by a higher content of phenolic acids and a lower content of flavonoids compared to the raw material obtained in October.
... There have been a number of scientific research efforts investigating the effect of natural products on ED [15,54,55] . Quercetin, resveratrol and other phenolic compounds have been reported to provide an advantage with ED and cardiovascular diseases due to their effect on eNOS upregulation and activation [56][57][58][59][60][61][62][63] . ...
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Objective: To investigate the biological effects of the Mucuna pruriens (M. pruriens) seed extracts that lacked l-DOPA, which was formerly reported as the active ingredient, on erectile dysfunction (ED) both in vitro and in vivo. Methods: Seed of M. pruriens plant that cultivated in Mae Taeng District, Chiang Mai Province, Thailand, was collected. Component of its seeds were extracted and isolated into 2 fractions using methanol, polar and nonpolar. Each fraction was investigated for phytochemicals using gas chromatography and mass spectroscopy and was screened for biological activity in vitro using three different cell lines. The most biological active fraction was used to treat both streptozotocin (STZ)-induced diabetes mellitus-erectile dysfunction (DM-ED) male Wistar rats and normal rats (n = 6 per groups) to compare the effect on sexual behavior parameters, including number of intromission, mounting and ejaculation, with that of rats given Sildenafil by individually pairing with their female counterparts. Penile tissues and serums were collected to determine histological structure, related gene expression and biomolecules. Results: The phytochemicals of the polar fraction were possibly catechol and its derivatives plus polyphenols, whereas the nonpolar fraction consisted of lipid derivatives. l-DOPA was not detected in either of the extracts. The polar fraction was able to up-regulate the expression of ED-related genes including eNOS and nNOS in vitro which subsequently promotes nitric oxide production and maintains intracellular cyclic guanosine monophosphate levels. When administrated to DM-ED rats, the polar extract significantly improved all sexual behavior parameters in DM-ED rats compared to untreated group (18.3 ± 1.8 to 10.8 ± 2.9 for intromission, 9.8 ± 2.2 to 5.7 ± 1.3 for mounting, and 1.8 ± 0.6 to 0.2 ± 0.4 for ejaculation). That effect might due to the ability of the extract to stimulate the expression of eNOS and nNOS which results in nitric oxide production and subsequently maintains cyclic guanosine monophosphate levels in penile tissue. Moreover, this extract may also prevent penile tissue deterioration due to diabetes. Conclusions: The polar extract of M. pruriens seed can be used for ED therapy, especially in patients with metabolic diseases including diabetes. The action of the extract might be due to catechol and its derivatives and polyphenols.
... Antioxidant activity of artichoke extracts is associated with the high content of caffeic acid and its derivatives with chlorogenic acid as the most important of these derivatives. Also, other phenolic compounds such as the flavonoids (apigenin and luteolin) as well as different cyanidin caffeoylglucoside derivatives have been identified [30][31][32]. Moreover, it is well proved that bioactive substances e.g. ...
Article
The study was focused on the phytochemicals-mediated biosynthesis of silver nanoparticles using leaf extracts and infusions from Cynara scolymus. To identify the antioxidant activity and total phenolic content, the 1,1-diphenyl-1-picrylhydrazyl and Folin-Ciocalteau methods were applied, respectively. The formation and stability of the reduced silver ions were monitored by UV-vis spectrophotometer. The particle sizes of the silver nanoparticles were characterised using the dynamic light scattering technique and scanning electron microscope. The phase composition of the obtained silver nanoparticles was characterised by X-ray diffraction. The silver nanoparticles suspension, artichoke infusion, and silver ions were separately tested towards potential cytotoxicity and pro-inflammatory effect using mouse fibroblasts and human monocytes cell line, respectively. The total phenolic content and antioxidant activity of ethanol extract and infusion were found significantly higher as compared to aqueous extract and infusion. The UV-visible spectrophotometric analysis revealed the presence of the characteristic absorption band of the Ag nanoparticles. Moreover, it was found that with the increasing volume of plant extract, the average size of particles was increased. Biocompatibility results evidently showed that silver nanoparticles do not induce monocyte activation, however in order to avoid their cytotoxicity suspension at a concentration <2 ppm should be applied.
... Flavonoids may modulate the activation status of neuronal receptors, signaling proteins and gene expression that are central to synaptic function during learning and memory recall. It has been shown that the administration of an artichoke leaf extract increased in the human diet increase the activity of the eNOS promoter that is an antithrombotic and anti-atherosclerotic principle in the vasculature (Li et al., 2004). ...
... An artichoke globe presents no fat, 170 mg of potassium and is rich in vitamin C, cynarin, orthophenole derivates, magnesium, folate and dietary fiber [101]. Recent studies indicated that artichoke flavonoids upregulated nitric-oxide synthase expression in endothelial cells [102]. NO synthesis can be adjusted through the activity of endothelial nitric-oxide synthase (eNOS); the eNOS can generate both nitric oxide (NO), causing blood vessels to dilate, and superoxide, making blood vessels shrink. ...
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In this paper, the biosynthesis process of phenolic compounds in plants is summarized, which includes the shikimate, pentose phosphate and phenylpropanoid pathways. Plant phenolic compounds can act as antioxidants, structural polymers (lignin), attractants (flavonoids and carotenoids), UV screens (flavonoids), signal compounds (salicylic acid and flavonoids) and defense response chemicals (tannins and phytoalexins). From a human physiological standpoint, phenolic compounds are vital in defense responses, such as anti-aging, anti-inflammatory, antioxidant and anti-proliferative activities. Therefore, it is beneficial to eat such plant foods that have a high antioxidant compound content, which will cut down the incidence of certain chronic diseases, for instance diabetes, cancers and cardiovascular diseases, through the management of oxidative stress. Furthermore, berries and other fruits with low-amylase and high-glucosidase inhibitory activities could be regarded as candidate food items in the control of the early stages of hyperglycemia associated with type 2 diabetes.
... eNOS mRNA was analyzed at 6 or 24 h after DRB. eNOS mRNA showed a half-life of approximately 24 h, which is consistent with previous findings (Li et al., 2004). Neither AVE9488 nor AVE3085 had an effect on eNOS mRNA stability ( Fig. 2A). ...
... Total NOS content was significantly increased in AS195-treated HUVEC. Flavonoids extracted from Artichoke have been shown to increase eNOS protein expression in HUVEC (Li et al. 2004), and the recent data suggest a positive role of red-vine-leaf flavonols on the expression of eNOS. Total RBC-NOS was not affected by the intervention because RBCs are incapable of protein neoformation. ...
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The red-vine-leaf extract AS195 improves cutaneous oxygen supply and the microcirculation in patients suffering from chronic venous insufficiency. Regulation of blood flow was associated to nitric oxide synthase (NOS)-dependent NO (nitric oxide) production, and endothelial and red blood cells (RBC) have been shown to possess respective NOS isoforms. It was hypothesized that AS195 positively affects NOS activation in human umbilical vein endothelial cells (HUVECs) and RBC. Because patients with microvascular disorders show increased oxidative stress which limits NO bioavailability, it was further hypothesized that AS195 increases NO bioavailability by decreasing the content of reactive oxygen species (ROS) and increasing antioxidant capacity. Cultured HUVECs and RBCs from healthy volunteers were incubated with AS195 (100 μmol/L), tert-butylhydroperoxide (TBHP, 1 mmol/L) to induce oxidative stress and with both AS195 and TBHP. Endothelial and red blood cell–nitric oxide synthase (RBC-NOS) activation significantly increased after AS195 incubation. Nitrite concentration, a marker for NO production, increased in HUVEC but decreased in RBC after AS195 application possibly due to nitrite scavenging potential of flavonoids. S-nitrosylation of RBC cytoskeletal spectrins and RBC deformability were increased after AS195 incubation. TBHP-induced ROS were decreased by AS195, and antioxidative capacity was significantly increased in AS195-treated cells. TBHP also reduced RBC deformability, but reduction was attenuated by parallel incubation with AS195. Adhesion of HUVEC was also reduced after AS195 treatment. Red-vine-leaf extract AS195 increases NOS activation and decreases oxidative stress. Both mechanisms increase NO bioavailability, improve cell function, and may thus account for enhanced microcirculation in both health and disease.
... Since many years it was reported that artichoke (Cynara scolimus) induces regeneration of rat liver (Maros et al., 1966), mainly due to cynarin, a phenolic derivative which stimulates liver cell excretion (Li et al., 2004a;Wang et al., 2003). Luteolin, a flavone which inhibit the de novo cholesterol synthesis as well sesquiterpene lactones has coleretic and cholagogue effects (Saenz Rodriguez et al., 2002). ...
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The present study was aimed to compare the polyphenolic composition of six medicinal herbs, from wild flora of Romania. The plants investigated, Cynara scolimus (artichoke), Taraxacum officinalis (dandelion), Chelidonium majus (celandine), Hypericum perforatum (St. John's wort), Silybum marianum (Mary thistle) and Lycopodium clavatum (Wolf's claw) are known, to have hepatoprotective action. Using in parallel glycerol-water, ethanol-water and methanol, the solvent-dependence of the extract fingerprint and composition in bioactive molecules was studied by UV-Vis and Infrared (FT-MIR) spectrometry. The extraction yields, calculated as an extraction factor (EF) were superior in acidic methanol comparative to glycerin and ethanol, favorising the increase in phenolic acids against flavonoid derivatives. Based on the differences of polarity between the three solvents used, higher EF values were obtained for dandelion, artichoke, celandine and St. John wort, more rich in phenolic acids than flavonoids. Mary thistle and Wolf's claw had lower concentrations of phenolics, but higher content of lignans and terpenoids. Based on the FT-MIR peaks from 8 regions, for each plant extract, has been determined the fingerprint region between 900 and 1500 cm-1and identified the specific functional groups. A good, significant correlation was found between the concentration of total phenolics calculated by UV-Vis spectrometry and FTIR methods, after calibration with gallic acid. The value of the MIR signal at 1743 cm-1 may be considered a good indicator of phenolics concentration in such extracts. Combined UV-Vis and FTIR spectroscopy are recommended as rapid and reliable tools to investigate the fingerprint and to predict the composition of medicinal plants or to evaluate the quality and authenticity of different standardized formulas.
... This antioxidant and anti-inflammatory effects of artichoke extracts are attributed to phenolic compounds [44,45]. Different studies about artichoke extracts have demonstrated their health-protective potential, especially their hepatoprotective [46,47] and health promoting properties in preventing cardiovascular disease (CVD) by its hypo lipidemic action [48] or by upregulation of endothelial nitric-oxide synthase (eNOS)gene expression and eNOS protein expression [49]. Also, artichoke extracts have anticancer effects by increasing apoptosis either in hepatocellular carcinoma in rats [50] or human hepatoma cells [51]. ...
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Objective: The present study aimed to evaluate the cardioprotective effects of ethyl acetate and methanolartichoke extracts(Cynara scolymus L.) against 5-Flurouracil (5-FU) induced cardiotoxicity in rats. Methods: Thirty-six albino rats were divided randomly and equallyin to six groups (each group with 6 rats): I, negative control, received (2 ml/kg/d)of dimethyl sulfoxide (DMSO) orally for 30 successive d; II, positive control, received (2 ml/kg/d) of (DMSO) orally for 30 successive d, and subsequently administered a single dose of 5-FU (150 mg/kg) by intraperitoneal injection on 27thd in assossiation with DSMO; III and V, received (200 mg/kg/d) of oral methanol and ethyl acetate artichoke extracts respectivelyfor 30 successive d; V and VI, received(200 mg/kg/d) of oral methanol and ethyl acetate artichoke extracts respectively for 30 successive d,with a subsequently received single dose of 5-FU (150 mg/kg) by intraperitoneal injection on 27thd of the experiment. Results: Prophylactic treatment of ethyl acetate and methanol artichoke extracts significantly attenuates the increased level of serum cardiac troponin T (CTn-T) and tumor necrosis factor-α(TNF-α)caused by 5-FU-induced cardiotoxicity in experimental albino rats while it increases the serum level of total antioxidant capacity (T-AOC). Conclusion: Results of the present study suggest that methanol and ethyl acetate artichoke extracts may be an effective modulator in mitigating 5-FU induced cardiotoxicity. © 2015, International Journal of Pharmacy and Pharmaceutical Science. All rights reserved.
... Many edible and culinary herbs and condiments were also included in these two tables as they were used in certain instances as medicinal herbs to treat diseases. These included fruits and seeds of Balanites aegyptiaca, leaves of Boscia senegalensis, leaves of Entada africana and seeds of Parkia biglobosa, from Niger [11], also leaves, seeds, and stem-bark of Mangifera indica from Benin and Burkina Faso [12,13], leaves of Cynara scolymus from Ethiopia [14,15], leaves of Aspalathus linearis from South Africa [16][17][18][19][20][21], leaves of Cinnamomum zeylanicum from Madagascar and Ethiopia [22][23][24], essential oils from the bark and leaves of Ravensara aromatica from Madagascar [23,25], buds of Syzygium aromaticum from Madagascar [23], seeds of Trigonella foenumgraecum from Ethiopia and Morocco [26][27][28], and oils in seeds of Nigella sativa from African countries of the Mediterranean region [29][30][31]. ...
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The use of traditional herbal remedies as alternative medicine plays an important role in Africa since it forms part of primary health care for treatment of various medical conditions, including wounds. Although physiological levels of free radicals are essential to the healing process, they are known to partly contribute to wound chronicity when in excess. Consequently, antioxidant therapy has been shown to facilitate healing of such wounds. Also, a growing body of evidence suggests that, at least, part of the therapeutic value of herbals may be explained by their antioxidant activity. This paper reviews African herbal remedies with antioxidant activity with the aim of indicating potential resources for wound treatment. Firstly, herbals with identified antioxidant compounds and, secondly, herbals with proven antioxidant activity, but where the compound(s) responsible for the activity has not yet been identified, are listed. In the latter case it has been attempted to ascribe the activity to a compound known to be present in the plant family and/or species, where related activity has previously been documented for another genus of the species. Also, the tests employed to assess antioxidant activity and the potential caveats thereof during assessment are briefly commented on.
... Many studies have demonstrated its antioxidant and anti-inflammatory capacities [144,145]. It inhibits oxidization of LDL and expression of VCAM-1, while it decreases plasma lipids and benefits vascular dilatation through enhanced expression of eNOS gene [146,147]. These results were demonstrated both in in vivo and in vitro studies with humans or rodents. ...
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The role of nutrition in the pathogenesis of cardiovascular disease has long been debated. The established notion of the deleterious effects of fat is recently under question, with numerous studies demonstrating the benefits of low-carbohydrate, high-fat diets in terms of obesity, diabetes, dyslipidemia, and metabolic derangement. Monounsaturated and polyunsaturated fatty acids, especially n-3 PUFAs (polyunsaturated fatty acids), are the types of fat that favor metabolic markers and are key components of the Mediterranean Diet, which is considered an ideal dietary pattern with great cardioprotective effects. Except for macronutrients, however, micronutrients like polyphenols, carotenoids, and vitamins act on molecular pathways that affect oxidative stress, endothelial function, and lipid and glucose homeostasis. In relation to these metabolic markers, the human gut microbiome is constantly revealed, with its composition being altered by even small dietary changes and different microbial populations being associated with adverse cardiovascular outcomes, thus becoming the target for potential new treatment interventions. This review aims to present the most recent data concerning different dietary patterns at both the macro- and micronutrient level and their association with atherosclerosis, obesity, and other risk factors for cardiovascular disease.
... Nevertheless, the difference in DBP was nearly significant at the p = 0.05 level. Any effect of artichoke leaf extract on BP may well be due to its content of flavonoids, such as luteolin and cynaroside, which upregulate endothelial-type nitric-oxide synthase gene expression in human endothelial cells, potentially promoting vasodilation and thus contributing to the control of BP [22]. Furthermore, flavonoids such as luteolin and apigenin can inhibit angiotensin-converting enzyme activity in vitro [23]. ...
Article
Background: Recent studies have suggested that artichoke (Cynara scolymus L.) may reduce certain biochemical blood factors but the efficacy of this plant on blood pressure (BP) has not yet been investigated. In this study, we determined the clinical efficacy of C. scolymuson BP and body mass index (BMI) in hypertensive patients as an adjunctive to captopril for the first time. Methods: The total phenolic content and gas chromatography-mass spectrometry metabolite profiling in leaves of C. scolymus have been evaluated. A clinical trial was subsequently carried out on 40 patients to determine the effect of C. scolymus on BP and BMI in hypertensive patients. The treatment group received capsules containing C. scolymus(500 mg twice daily) and the placebo group received starch powder for 8 weeks. Systolic blood pressure (SBP), diastolic blood pressure, and BMI were determined before and after the study. Results: A significant improvement of the BMI was seen in the C. scolymus group compared with the placebo group (p = 0.04). Conclusions: Our findings demonstrated that the consumption of C. scolymus powder as a rich source of phenolic and antioxidant compounds could potentially improve BMI and SBP in hypertensive patients. Therefore, more trials are needed to confirm or reject the antihypertensive impact of artichoke.
... Among them cynaropicrin and grosheimin showed weak cytotoxicity while others didn't. 69 Milk clotting properties This property of artichoke has been used for the preparation of cheese. In the experiment, the artichoke flower extract showed the milk clotting property useful for cheese preparation. ...
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Cynara scolymus Linn. (Asteraceae) is used medicinally in Europe and in USA. It is also known as “Garden artichoke” and has been subject of several chemical, pharmacological and biological studies. It is used in traditional medicine in all over the world for treatment of rheumatism, gout, jaundice and especially for dropsies. The chemical studies have underlined the presence of various classes of compounds, the main being Flavonoids, Terpenoids, Acids, Enzymes, Anthocynins and others. The extract of this plant as well as pure isolated compounds, showed multiple pharmacological activities such as Hypocholesterolaemic, Hypolipidemic, Choleretic, Antioxidant, Hepatoprotective, Antistress, Hypoglycemic, Antispasmodic activity and others. In this review we have explored phytochemistry, pharmacological, biological activities, side effects and contraindications of C. scolymus in order to comprehend and synthesize its potential image as multipurpose medicinal agent. The plant is widely cultivated to world and its importance, as a medicinal plant, is growing substantially with increasing and stronger reports in support of its multifarious therapeutic use.
... responsible for health-promoting properties. In fact, artichoke flavonoids luteolin and cynaroside were considered responsible for antithrombotic and anti-atherosclerotic activities as they increased the expression of the endothelial nitric-oxide synthase (eNOS) and the resulting vasodilator response, while the cynarin and chlorogenic acid did not show this effect (Li, Xia, Brausch, Yao, & Forstermann, 2004). In this regard, Rossoni, Grande, Galli and Visioli (2005) also demonstrated that luteolin and apigenin improved aortic relaxation of isolated rat aortic rings and that an artichoke extract restored the appropriate vasomotor function in aged rats. ...
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The performance of probiotic bacterial strains is influenced by the carrier food and its functional components which while buffering the probiotic through the gastro-intestinal tract, contribute to an efficient implantation of bacterial cells and regulate probiotic features. Particularly, plant-based matrices are eligible substrate for hosting and delivering microbial populations because of their richness in nutrients, fibers, vitamins, minerals and dietary bioactive phytochemicals. The available data indicate that the intrinsic health-promoting properties of diverse plant-based matrices can be successfully exploited and improved developing effective association with probiotics, whose beneficial activity could be in turn improved and modulated by components of the plant-based carrier. In this review, the health-promoting properties of solid plant-based matrices (particularly artichokes, table olives, apple and cabbage) and their association with probiotic bacteria are also described indicating the role of the food matrix in sustaining probiotic cells during product processing, digestive process, gut implantation, and finally in exerting beneficial effects.
... Dietary fl avonoids improve endothelial dysfunction by stimulating NO synthesis through up-regulation of endothelial NO synthase (eNOS) expression, and/ or enhancing its activity (35,36). For instance, luteolin and cynaroside from artichoke (Cynara scolymus L.) upregulate eNOS in human umbilical vein endothelial cells (EA.hy 926 and HUVECs) and potentiate the vasorelaxant response to acetylcholine in rat aortic rings (37). Similarly, the red wine polyphenol cyanidin and the tea catechins epicatechin gallate and epigallocatechin gallate stimulate eNOS expression in EA.hy926 endothelial cells (38). ...
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Several modifiable and non-modifiable risk factors are associated with incidence of cardiovascular diseases, the leading cause of death worldwide. A healthy diet, such as the Mediterranean diet, lowers the incidence of cardiovascular disease. Intake of flavonoids, a class of plant-derived polyphenols widely distributed in fruits, vegetables, tea, coffee, and wine, is the hallmark of the Mediterranean diet that has been associated with reduced cardiovascular risk factors. Several mechanisms underpin this beneficial activity: a direct vasodilatory effect, prevention of endothelial dysfunction, inhibition of platelet aggregation, and smooth muscle cell proliferation along with an anti-oxidant, anti-inflammatory, anti-obesity, anti-diabetic, and anti-atherosclerotic effects. This review provides an updated overview of the mechanisms by which flavonoids ameliorate cardiovascular risk factors, thus retarding cardiovascular disease progression.
... Li et al. discovered the enhanced endothelium-dependent vasodilation of rat aorta ex vivo incubated with artichoke leaf extract. 45 Nonetheless, the specific mechanism of the antihypertensive effect of ABE remains unknown. As such, we evaluated the effect of ABE on heart tissue metabolomics of SHR, relative to age-matched WKY rats and explored the antihypertensive mechanism of ABE. ...
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Hypertension adversely affects the quality of life in humans across modern society. Studies have attributed increased reactive oxygen species production to the pathophysiology of hypertension. So far, a specific drug to control the disease perfectly has not been developed. However, artichoke, an edible vegetable, plays an essential role in treating many diseases due to its potent antioxidant activities. The objective of this study is to evaluate the effect of artichoke bud extract (ABE) on heart tissue metabolomics of hypertensive rats. Spontaneously hypertensive rats and Wistar–Kyoto (WKY) rats were divided into six groups, then exposed to different doses comprising ABE, Enalapril Maleate, or 1% carboxylmethyl cellulose for 4 weeks. Their blood pressures were recorded at 0, 2, 3, and 4 weeks after the start of the test period. Thereafter, all rats were anesthetized, and blood was collected from their cardiac apexes. Then, we measured the levels for 15 kinds of serum biochemical parameters. An established orthogonal partial least square-discriminant analysis model completed the metabolomic analysis. Hypertensive rats in the ABE group exhibited well-controlled blood pressure, relative to those in the model group. Specifically, artichoke significantly lowered serum levels for total protein (TP), albumin (ALB), and uric acid (UA) in the hypertensive rats. This effect involved the action of eight metabolites, including guanine, 1-methylnicotinamide, p-aminobenzoic acid, NAD, NADH, uridine 5′-monophosphate, adenosine monophosphate, and methylmalonic acid. Collectively, these findings suggest that ABE may play a role in affecting oxidative stress and purine, nicotinate, and nicotinamide metabolism.
... Lut upregulated eNOS expression by increasing eNOS promoter activity and eNOS mRNA expression in human endothelial cells [41]. In a diabetic rat model, lut was revealed to have a protective effect on the diabetic heart against myocardial ischemia/reperfusion injury by upregulating the myocardial eNOS pathway, Nrf2 and the Nrf2-related antioxidative signaling pathway, the enhancement of manganese superoxide dismutase (MnSOD) activity, and inhibition of the mitochondrial permeability transition pore (mPTP) [42,43]. ...
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The vascular nitric oxide (NO) system has a protective effect in atherosclerosis. NO is generated from the conversion of L-arginine to L-citrulline by the enzymatic action of endothelial NO synthase (eNOS). Compounds with the effect of enhancing eNOS expression are considered to be candidates for the prevention of atherosclerosis. In this study, extracts from the aerial, root, and whole plant of Glossogyne tenuifolia (GT) were obtained with ethanol, n-hexane, ethyl acetate (EA), and methanol extraction, respectively. The effects of these GT extracts on the synthesis of NO and the expression of eNOS in human umbilical vein endothelial cells (HUVECs) were investigated. NO production was determined as nitrite by colorimetry, following the Griess reaction. The treatment of HUVECs with EA extract from the root of GT and n-hexane, methanol, and ethanol extract from the aerial, root, and whole plant of GT increased NO production in a dose-dependent manner. When at a dose of 160 μg/mL, NO production increased from 0.9 to 18.4-fold. Among these extracts, the methanol extract from the root of GT (R/M GTE) exhibited the most potent effect on NO production (increased by 18.4-fold). Furthermore, using Western blot and RT–PCR analysis, treatment of HUVECs with the R/M GTE increased both eNOS protein and mRNA expression. In addition, Western blot analysis revealed that the R/M GTE increased eNOS phosphorylation at serine1177 as early as 15 min after treatment. The chemical composition for the main ingredients was also performed by HPLC analysis. In conclusion, the present study demonstrated that GT extracts increased NO production in HUVECs and that the R/M GTE increased NO production via increasing eNOS expression and activation by phosphorylation of eNOS at serine1177.
... Based on such results, it can be stated that ALE and AFE are potent antioxidants against ROS and this may be due to artichoke which is rich in phytochemical compounds that have a powerful antioxidant activity (Padmashree et al. 2018;Vijayakumari and Raj 2019). Also, ALE is rich in caffeoylquinic acids and flavonoids that are powerful antioxidants compounds (Li et al. 2004). Globe artichoke is also rich in flavonoids, which has a high antioxidant effect by reducing ROS (Lombardo et al. 2015). ...
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The study examines the prophylactic action of artichoke leaf hydroethanolic extract (ALE) and artichoke flower head hydroethanolic extract (AFE) against diethylnitrosamine (DEN)/acetylaminofluorene (AAF)-induced lung cancer in Wistar rats. To chemically induce lung cancer, DEN was injected intraperitoneally twice a week for a fortnight at a dose of 150 mg/kg body weight (b.w.), followed by oral supplementation of AAF four times a week for 3 weeks at a dose of 20 mg/kg b.w. The DEN/AAF-administered rats were orally supplemented with ALE or AFE at a dose of 100 mg/kg b.w. for 17 weeks starting from the 1st week of DEN injection to the 17th week of the experiment. The lung cancerous injuries resulting from DEN/AAF-administration were significantly improved by the treatment with ALE and AFE as observed in histological examination. In addition, there was a significant reduction in lung lipid peroxidation, with resultant elevation in antioxidant enzymatic activity of glutathione-S-transferase, glutathione peroxidase, glutathione reductase, and superoxide dismutase as well as glutathione content in DEN/AAF-supplemented rats treated with ALE and AFE as compared to DEN/AAF-administered control. The lung tumor suppressor protein (p53) and B-cell lymphoma-2 (Bcl-2) mRNA expression significantly increased in the rats treated with ALE and AFE. In conclusion, the finding showed that ALE and AFE produced anti-cancer prophylactic effects against DEN/AAF-induced lung cancer in rats via suppression of oxidative stress and improved apoptotic signal induction.
... In this study, we observed that the expression levels of eNOS were upregulated when supplemented at a higher concentration of phenolic-rich BSE demonstrating the cytoprotective effect of BSE on human endothelial cells under oxidative stress. Consistent with results from our study, flavonoids from artichoke (Cyanara scolymus L.) have been shown to upregulate the expression of eNOS in human endothelial cells [29]. Similarly, extracts from the leaves of Ribes nigrum L. stimulated the expression of eNOS and thereby increased the production of NO in cultured endothelial cells [30]. ...
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Oxidative stress is one of the primary factors leading to endothelial dysfunction, a major underlying cause of vascular disorders. This study aims to understand the key signalling pathways regulated by sorghum (Shawaya short black 1 variety; characterised to be very high in its antioxidant activity) under oxidative stress in endothelial cells. Human umbilical vein endothelial cells (HUVECs) were pre-treated with non-cytotoxic concentrations of phenolic-rich black sorghum extract (BSE) prior to induction of oxidative stress using hydrogen peroxide (H2O2). Treatment with BSE upregulated the expression of heme oxygenase 1 (HO1) and endothelial nitric oxide synthase (eNOS) and downregulated the levels of NADPH oxidase 4 (NOX4). BSE treatment significantly reduced the expression of pro-inflammatory mediators such as monocyte chemoattractant protein 1 (MCP1) and intracellular adhesion molecule 1 (ICAM1). Results from this study suggest that phenolic-rich BSE may reduce oxidative stress by regulating pro- and antioxidant signalling pathways and the expression of inflammatory mediators linked to endothelial dysfunction under oxidative stress.
... The plants are summarized in Table 1, the vasodilation effects of which are mediated via the NO-cGMP pathway. As examples, Cynara scolymus L. [27], Panax ginseng C. A. Meyer [28], and Theobroma cacao L. [29] can be mentioned. ...
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According to the World Health Organization, cardiovascular diseases are the main cause of death worldwide. They may be caused by various factors or combinations of factors. Frequently, endothelial dysfunction is involved in either development of the disorder or results from it. On the other hand, the endothelium may be disordered for other reasons, e.g., due to infection, such as COVID-19. The understanding of the role and significance of the endothelium in the body has changed significantly over time—from a simple physical barrier to a complex system encompassing local and systemic regulation of numerous processes in the body. Endothelium disorders may arise from impairment of one or more signaling pathways affecting dilator or constrictor activity, including nitric oxide–cyclic guanosine monophosphate activation, prostacyclin–cyclic adenosine monophosphate activation, phosphodiesterase inhibition, and potassium channel activation or intracellular calcium level inhibition. In this review, plants are summarized as sources of biologically active substances affecting the endothelium. This paper compares individual substances and mechanisms that are known to affect the endothelium, and which subsequently may cause the development of cardiovascular disorders.
... Recent data suggested also that this flavonoid reduces hepatic steatosis and insulin resistance (El-Bassossy et al., 2013;Xu et al., 2014;Kwon et al., 2015), inhibits cholesterol biosynthesis (Gebhardt, 2002) and increases endothelial NO synthase (eNOS) gene expression (Li et al., 2004). However, the effects of luteolin on obesity-related endothelial dysfunction have not been clarified yet. ...
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Purpose: Luteolin exerts beneficial effects against obesity-associated comorbidities, although its influence on vascular dysfunction remains undetermined. We examined the effects of luteolin on endothelial dysfunction in a mouse model of diet-induced obesity. Methods: Standard diet (SD) or high-fat diet (HFD)-fed mice were treated daily with luteolin intragastrically. After 8 weeks, body and epididymal fat weight, as well as blood cholesterol, glucose, and triglycerides were evaluated. Endothelium-dependent relaxations of resistance mesenteric vessels was assessed by a concentration-response curve to acetylcholine, repeated upon N w-nitro-L-arginine methylester (L-NAME) or ascorbic acid infusion to investigate the influence of nitric oxide (NO) availability and reactive oxygen species (ROS) on endothelial function, respectively. Intravascular ROS production and TNF levels were measured by dihydroethidium dye and ELISA, respectively. Endothelial NO synthase (eNOS) and superoxide dismutase 1 (SOD1), as well as microRNA-214-3p expression were examined by Western blot and RT-PCR assays, respectively. Results: HFD animals displayed elevated body weight, epididymal fat weight and metabolic indexes. Endothelium-dependent relaxation was resistant to L-NAME and enhanced by ascorbic acid, which restored also the inhibitory effect of L-NAME, suggesting a ROS-dependent reduction of NO availability in HFD vessels. Moreover, media-lumen ratio, intravascular superoxide anion and TNF levels were increased, while vascular eNOS, SOD1, and microRNA-214-3p expression were decreased. In HFD mice, luteolin counteracted the increase in body and epididymal fat weight, and metabolic alterations. Luteolin restored vascular endothelial NO availability, normalized the media-lumen ratio, decreased ROS and TNF levels, and normalized eNOS, SOD1 and microRNA-214-3p expression. Conclusion: Luteolin prevents systemic metabolic alterations and vascular dysfunction associated with obesity, likely through antioxidant and anti-inflammatory mechanisms.
... While previous reviews have not considered the efficacy of artichoke on BP, the role of artichoke in the improvement of lipid profiles has been previously reviewed 35 Additionally, luteolin and cymaroside have been shown to increase eNOS promoter activity as well as eNOS mRNA expression, which resulted in a subsequent increase in NO production 42 . ...
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Purpose Clinical trials considering the effects of artichoke supplementation on blood pressure have yielded different and contradictory outcomes. Thus, a systematic review and meta-analysis were performed to assess effects of artichoke administration on blood pressure. Methods Related studies were detected by searching the Cochrane Library, PubMed, Embase and Scopus databases up to 15 March 2020. Weighted Mean Differences (WMD) were pooled using a random-effects model. Heterogeneity, sensitivity analyses, and publication bias were evaluated using standard methods. Results Pooled analysis of eight randomized controlled trials revealed that artichoke supplementation did not have an effect on systolic blood pressure (SBP), (WMD: -0.77 mmHg, 95% CI: -2.76 to 1.22) or diastolic blood pressure (DBP) (WMD: -0.11 mmHg, 95% CI: -1.72 to 1.50) when compared to the placebo group. However, subgroup analyses based on health status suggested that artichoke administration among hypertensive patients may significantly reduce SBP (WMD: -3.19 mmHg, 95% CI: -3.32 to -3.06) and DBP (WMD: -2.33 mmHg, 95% CI: -2.23 to -2.43), but no such reduction was found in NAFLD patients. Furthermore, our results indicated that artichoke supplementation for 12 weeks led to a significantly decreased DBP (WMD: -2.33 mmHg, 95% CI: -2.43 to -2.23), but 8 weeks of intervention did not (WMD: 0.80 mmHg, 95% CI: -1.06 to 2.66). Conclusion Artichoke supplementation may potentially lead to SBP and DBP reduction in hypertensive patients. In addition, artichoke supplementation for 12 weeks may significantly improve DBP.
... The nutritional benefits of artichokes include high levels of potassium, an excellent source of fiber and vitamin C, and a good source of folate and magnesium. Thus, in addition to the lipid lowering and antioxidant properties of artichoke and an increase in endothelial nitric-oxide synthase (eNOS) gene transcription may also contribute to its beneficial cardiovascular diseases ( Li et al., 2004). Meanwhile, flowers of artichoke have been used since ancient times as a source of milk -clotting enzymes. ...
... Intake of anthocyanins seems to have positive effects on the cardiovascular system by also reducing arterial stiffness [278]. In another study, it was observed that artichoke leaf extracts and artichoke flavonoids up-regulate the gene expression of endothelial-type nitric oxide synthase (eNOS, a vasoprotective molecule) in human endothelial cells [279]. While in a follow-up study Xia et al. [280] observed that treatment of human coronary artery smooth muscle cells (HCASMC) with artichoke leaf extracts and particularly with cynarin and cyanidin induced a down-regulation of inducible nitrous oxide synthase (iNOS, a pro-inflammatory molecule that can cause vascular dysfunctions), suggesting that artichoke flavonoid compounds may have great therapeutic potential. ...
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The current trend for substituting synthetic compounds with natural ones in the design and production of functional and healthy foods has increased the research interest about natural colorants. Although coloring agents from plant origin are already used in the food and beverage industry, the market and consumer demands for novel and diverse food products are increasing and new plant sources are explored. Fresh vegetables are considered a good source of such compounds, especially when considering the great color diversity that exists among the various species or even the cultivars within the same species. In the present review we aim to present the most common species of colored vegetables, focusing on leafy and fruit vegetables, as well as on vegetables where other plant parts are commercially used, with special attention to blue color. The compounds that are responsible for the uncommon colors will be also presented and their beneficial health effects and antioxidant properties will be unraveled.
... Moreover Skarpañska-Stejnborn et al. reported that Artichoke (Cynara scolymus L.), as a natural vegetable preparation of high antioxidant potential, significantly increased total antioxidant capacity in competitive rowers subjected to strenuous training [39]. Li et al. also reported that flavonoids from artichoke (Cynara scolymus L.) up-regulate endothelial-type nitric-oxide (NO) synthase gene expression in human endothelial cells [40], and interestingly it has been proposed that, NO can protect against oxidative damage by intercepting reactive species, which converting them to less damaging and more easily detoxified products [41]. While in contrast to our results these researches also indicated that supplementation with Artichoke did not influence the level of free radicaldamage markers. ...
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Background: Strenuous acute exercise induces oxidative stress in the active muscles and circulation, However, consumption of products rich in antioxidants may potentially ameliorate these effects. Objective: The present investigation was conducted to determine the effect of Artichoke (Cynara scolymus L.) extract on oxidative stress and antioxidant defense after aerobic exercise in young athletes. Method: Twenty two subjects received 2400 ml/kg/day Artichoke-leaf extract or placebo capsule for a period of 14 days. All subjects of both groups underwent in acute aerobic exercise before and after 14 days supplementation. Blood samples were collected at pre supplementation, pre exercise, post exercise and 24 hours after exercise. Malondiadehyde (MDA), plasma total antioxidant capacity (FRAP), superoxide dismutase (SOD), and 8-iso-prostaglandin-F2α (8-iso-PGF2α) were measured. Results: The results showed that concentration of MDA and Serum 8-iso-PG F2α, SOD, and plasma total antioxidant significantly increased at immediately and 24 hrs after aerobic exercise (P0.05), but after 24-h of exercise, 8-iso-PG F2α concentration in the group supplement was significantly lower in comparison to placebo group (P=0.002). Conclusion: The results of this study indicated that a single session of strenuous aerobic exercise induces oxidative stress production and increase of antioxidant indices in young athletes. However, further studies are necessary to clarify the exact antioxidant effects of Artichoke extract in athletes.
... This achievement can be explained by the antihypertensive effect exerted by artichoke, Centella asiatica L., and Capsicum annuum L. extracts. Precedent in vitro studies have demonstrated how artichoke leaf extracts can increase genetic expression of endothelial nitric oxide synthase (eNOS) and induce nitric oxide (NO) production in human vascular endothelial cells [64]. The results are consistent with a randomized placebo-controlled trial conducted on 107 mildly hypertensive or healthy male subjects, which demonstrated a drop in systolic and diastolic blood pressure after 12 weeks oral administration of concentrate artichoke leaf juice [65]. ...
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Nephropathic patients show elevated cardiovascular morbidity and mortality compared to the general population. In order to delve deeper into the understanding of this phenomenon, it is necessary to recognize risk factors that are distinctive to the uremic state, such as oxidative stress and chronic low-grade inflammation. Moreover, gender differences have been reported in nephrology, as it has been observed that chronic kidney disease has higher prevalence in males than in females. The use of an oral food supplement (OFS) containing natural active compounds from Capsicum annuum L., Garcinia cambogia, Centella asiatica L., artichoke, and Aesculus hippocastanum L. which are virtually devoid from side effects, but rich in antioxidant and antiradical properties, could represent a valid therapeutic adjunct in the clinical management of nephropathic patients. Moreover, quantitative analysis performed in vitro on such compounds showed that they expressed good total antioxidant (7.28 gallic acid equivalents) and antiradical activity (above 80%). In this study, 23 male nephropathic patients and 10 age and body composition parameter matched healthy males (control group) were enrolled and took 3 cps/day of OFS for 5 weeks. At the end of the study, the nephropathic patient group showed a statistically significant reduction in the following laboratory parameters: total cholesterol (TC) (), atherogenic index TC/high-density lipoprotein cholesterol (), inflammatory parameters (C-reactive protein, , and erythrocyte sedimentation rate, ), systolic (), and diastolic arterial blood pressure (). Regarding body composition, there was an increase in total body water % () with redistribution of extracellular water % () and intracellular water % (). In the control group, there was a reduction in fat mass % () and extracellular water % (). Therefore, this OFS may represent a valid adjunct therapy to counteract comorbidities related to uremia. 1. Introduction During the last century, a substantial increase in the incidence of chronic noncommunicable diseases (NCDs), such as cardiovascular diseases (CVD), chronic kidney disease (CKD), diabetes mellitus (DM), and cancer, has been observed [1, 2]. Up to this day, NCDs represent the primary cause of death in both developed and developing countries [3]. In this context, prevention, especially through following a healthy diet and leading an active lifestyle, becomes of paramount importance [4, 5]. Amongst NCDs, CKD represents a health problem with significant worldwide impact, its global prevalence being estimated between 7 and 12% [6]. Its increase in prevalence, especially during recent years, is related to different factors. Firstly, it is linked not only to the global ageing of the population [7] but also to the concomitant increase in prevalence of other risk factors such as arterial hypertension (AH), DM, and metabolic syndrome, and thanks to more attentive diagnosis performed by clinicians [8]. Patients affected by CKD frequently present a series of comorbidities, prevalently at the cardiovascular (CV) level; therefore, a new clinical entity has been defined as “type IV cardiorenal syndrome,” characterized by the presence of chronic renal failure which induces a reduction in cardiac function, left ventricular hypertrophy, and increased risk to develop CV complications [9]. Amongst factors related to cardiac dysfunction in CKD patients [10], volume overload and blood pressure increase must be considered as they contribute in producing left ventricular hypertrophy [11]. In fact, CKD patients show an elevated prevalence of AH, principally correlated with extracellular volume expansion [12]; in turn, this induces a decline in cardiac function [13]. A study has highlighted how, in these patients, systolic blood pressure values positively correlate with the expansion of extracellular fluid whilst the latter is inversely correlated with the glomerular filtration rate (GFR) [14]. Other CV risk factors typical of the uremic state are chronic low-grade inflammation, hyperhomocysteinemia [15, 16], insulin resistance, and malnutrition-inflammation-atherosclerosis syndrome [17, 18], which contribute to accelerate the atherosclerotic process. Moreover, the gradual accumulation of uremic toxins in the organism, which increases as GFR decreases, plays a key role in CV alterations [19–21] . Uremic toxins can precipitate in the progression of CKD, through various mechanisms such as renal fibrosis, loss of antioxidant defenses, dysfunction, and apoptosis of renal tubular cells and endothelial cells, contributing to the generation and propagation of the chronic low-grade inflammatory state which characterizes this pathology [22–24]. Regarding the increment in oxidative stress (OS), which can be observed in CKD patients [25], it is important to consider that the kidney represents one of the most metabolically active organs, which renders it particularly vulnerable to oxidative damage [26–29]. Interestingly, gender differences have been documented in the field of nephrology and in this regard women seem to be protected from developing end-stage renal disease (ESRD) [30, 31]. A screening study has highlighted how the cumulative incidence of ESRD is lower in women during reproductive age and starts increasing 10 years later than in men [31]. This has been confirmed in a Japanese population study, which pointed out that the incidence and the prevalence of ESRD was higher in men compared to women and that the average age at the beginning of renal replacement therapy was higher [30, 31]. In recent years, numerous in vitro and in vivo studies have focused on researching natural bioactive compounds, which would be ideally free from side effects and would increase the therapeutic potential of standard treatments, as well as having a preventive role in the development of CKD comorbidities [32]. Up to this day, more than 5000 phytocompounds are known, and it is estimated that a large number of these are yet to be discovered [33]. Amongst these, there are vitamins, minerals, flavonoids, phenolic acids, alkaloids, and carotenoids [34–36]. Different classes of phytocompounds act on the organism through various mechanisms and, depending on their polyphenol and antiradical content, perform different antioxidant, cardioprotective, antiproliferative, anti-inflammatory, and hepatoprotective roles. In particular, the oral food supplement (OFS) used in the present study contains a number of plant dry extracts, listed as follows: Capsicum annuum L., which stimulates metabolism; Garcinia cambogia, as a potential antiobesogenic agent [37, 38]; Centella asiatica L., which improves microcirculatory parameters [39, 40]; Cynara scolymus L. or artichoke, which has an antioxidant and depurative function; and Aesculus hippocastanum L. bark extract, which improves the regularity of bowel movements and digestive system functionality. The present study sets out to evaluate the potential therapeutic effect of this OFS on CV risk and body composition, in male CKD patients versus healthy controls. 2. Material and Methods The study was structured into two phases: (1)In vitro phase: qualitative and quantitative HPLC-DAD characterization of the active compounds present in the selected OFS, followed by the evaluation of its antioxidant and free-radical scavenger properties.(2)In vivo phase: administration of the characterized OFS to CKD patients and healthy subjects (control group). 2.1. Oral Food Supplement, Polyphenol Total Content, and Antioxidant Capacity In Vitro The OFS used in the present study contains a number of plant dry extracts: Capsicum annuum L. present in 60 mg, Garcinia cambogia present in 60 mg, Centella asiatica L. present in 100 mg, Cynara scolymus L. or artichoke present in 60 mg, and Aesculus hippocastanum L. bark extract present in 80 mg. The OFS is formulated in capsules, produced under carefully controlled conditions. Controls are performed continuously throughout the process and guarantee that the capsules conform to the highest quality standards. The excipients used are titanium dioxide (2.0000%) and gelatin (qsp 100%). This OFS has been registered with the Italian Ministry of Health with the number 79086. The extraction of 400 mg of OFS powder was made in 4.0 ml H2O adjusted to pH 2.4 by the addition of HCOOH. The extract was stirred at room temperature for 30 min, centrifuged at 14.000 rpm for 5 min, and analyzed. 2.1.1. HPLC-DAD Analysis Analyses of flavonols, hydroxycinnamic acids, and coumarins were carried out using an HP 1100 L liquid chromatograph equipped with a DAD detector and managed by an HP 9000 workstation (Agilent Technologies, Palo Alto, CA, USA). Compounds were separated by using a i.d. 5 μm LUNA C18 column (Phenomenex, USA). UV/Vis spectra were recorded in the 190-600 nm range, and the chromatograms were acquired at 250, 280, 330, and 350 nm. The samples were analyzed by gradient elution at a flow rate of 0.8 ml/min. The mobile phase was a multistep linear solvent gradient system, starting from 95% H2O (adjusted to pH 2 by HCOOH) up to 100% CH3CN in 53 minutes. The chemical reagents used were HPLC grade, acetonitrile (CH3CN) HPLC grade, ethanol (EtOH) HPLC grade, Folin-Ciocalteu reagent, and sodium carbonate (Na2CO3); all were purchased from Sigma-Aldrich (St. Louis, Mo, USA). 2.1.2. Identification and Quantification of Individual Compounds The identity of polyphenols was acquired using data from HPLC-DAD analysis, by comparison with bibliographic data, combination of retention times, and UV/Vis spectra with those of authentic standards. The quantification of individual polyphenolic compounds was performed directly by HPLC-DAD using a five-point regression curve () in the range of 0-30 μg. In particular, flavonols like the quercetin derivatives were determined at 350 nm using rutin as a reference compound, and hydroxycinnamic acid derivatives were determined at 330 nm using ferulic acid as a reference compound, while coumarins were determined at 330 nm using aesculin as a reference compound. In all cases, actual concentrations of the derivatives were calculated after applying corrections for differences in molecular weight. Each sample was analyzed in triplicate, in order to express the analytical results as an average. 2.1.3. Total Phenolic Content and Total Antioxidant Capacity The total phenolic content was determined using the Folin-Ciocalteu method, described by Singleton et al. [41] and slightly modified according to Dewanto et al. [42]. To 125 μl of the suitably diluted sample extract, 0.5 ml of deionized water and 125 μl of the Folin-Ciocalteu reagent were added. The mixture was kept in the darkness for 6 minutes, and then 1.25 ml of a 7% aqueous Na2CO3 solution was added. The final volume was adjusted to 3 ml with water. After 90 minutes, the absorption was measured at 760 nm against water as a blank. The total amount of phenols was expressed as gallic acid equivalents (GAE, mg gallic acid/100 g sample) through the calibration curve of gallic acid. The calibration curve ranged from 20 to 500 μg/ml (). The phenol content was correlated with the in vitro antioxidant activity, as previously confirmed by comparisons with different electron transfer reaction assays and in vitro human low-density lipoprotein (LDL) assays [43–45]. 2.1.4. Antiradical Activity Free radical scavenging activity was evaluated with the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH⋅) assay. The antiradical capacity of the sample extracts was estimated according to a slightly modified procedure reported by Brand-Williams et al. [46]. Two ml of the sample solution, suitably diluted with ethanol, was added to 2 ml of an ethanol solution of DPPH⋅ (0.0025 g/100 ml), and the mixture was kept at room temperature. After 20 minutes, the absorption was measured at 517 nm with a Lambda 25 spectrophotometer (PerkinElmer) versus ethanol as a blank. Successively, the absorption of the DPPH⋅ solution was checked. The antiradical activity is calculated by plotting the ratio , where is the absorption of the DPPH⋅ solution and is the absorption of the DPPH⋅ solution after addition of the sample, against the concentration of the sample. 2.2. CKD Patients and Control Group Men affected by CKD and healthy subjects (control group), aged 18-80 years, were considered suitable for the study. The study protocol complied with the declaration of Helsinki and was appointed by the Ethical Committee of Fondazione Policlinico Tor Vergata (PTV) of Rome. The flow chart of the study is summarized in Figure 1.
... The phenolic contents in leaf and seed of Cynara cardunculus were similar and two times higher than those in flower heads [16]. The organic subfraction of artichoke is rich in polyphenolic compounds, with caffeoylquinic acids and flavonoids as the major chemical constituent [32]. In commercially available artichoke (C. ...
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It has been previously shown that besides synthesizing nitric oxide (NO), neuronal and inducible NO synthase (NOS) generates superoxide (O⨪2) under conditions ofl-arginine depletion. However, there is controversy regarding whether endothelial NOS (eNOS) can also produce O⨪2. Moreover, the mechanism and control of this process are not fully understood. Therefore, we performed electron paramagnetic resonance spin-trapping experiments to directly measure and characterize the O⨪2 generation from purified eNOS. With the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), prominent signals of O⨪2 adduct, DMPO-OOH, were detected from eNOS in the absence of added tetrahydrobiopterin (BH4), and these were quenched by superoxide dismutase. This O⨪2formation required Ca2+/calmodulin and was blocked by the specific NOS inhibitor N-nitro-l-arginine methyl ester (l-NAME) but not its non-inhibitory enantiomerd-NAME. A parallel process of Ca2+/calmodulin-dependent NADPH oxidation was observed which was also inhibited by l-NAME but notd-NAME. Pretreatment of the enzyme with the heme blockers cyanide or imidazole also prevented O⨪2 generation. BH4 exerted dose-dependent inhibition of the O⨪2 signals generated by eNOS. Conversely, in the absence of BH4 l-arginine did not decrease this O⨪2 generation. Thus, eNOS can also catalyze O⨪2formation, and this appears to occur primarily at the heme center of its oxygenase domain. O⨪2 synthesis from eNOS requires Ca2+/calmodulin and is primarily regulated by BH4 rather than l-arginine.
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In human umbilical vein endothelial cells and in human umbilical vein endothelial cell-derived EA.hy 926 cells, staurosporine (Stsp) and its glycosidic indolocarbazole analogs 7-hydroxystaurosporine (UCN-01) and 4'-N-benzoyl staurosporine (CGP 41251) enhanced nitric-oxide synthase (NOS) III mRNA expression (analyzed by RNase protection assay), protein expression (determined by Western blot), and activity [measured by rat fetal lung fibroblast (RFL-6) reporter cell assay] in a concentration- and time-dependent manner. In contrast, the bisindolylmaleimide analogs GF 109203X, Ro 31-8220 and Gö 6983 had no effect on NOS III expression, and Gö 6976, a methyl- and cyanoalkyl-substituted nonglycosidic indolocarbazole derivative of Stsp, even reduced NOS III expression in a concentration-dependent fashion. The up-regulation of NOS III expression by Stsp and analogs appears to be a transcriptional event because Stsp, 7-hydroxystaurosporine, and CGP 41251 enhanced the activity of a 1.6-kb human NOS III promoter fragment transiently transfected into EA.hy 926 endothelial cells. Stsp and analogs did not affect the stability of the NOS III mRNA. Stsp is known as a potent protein kinase (PK) inhibitor. Data obtained with other kinase inhibitors (and stimulators) indicated, however, that the effect of Stsp and analogs on NOS III expression was unrelated to the activities of PKC, PKA, PKG, or tyrosine kinase(s). Stsp analogs such as CGP 41251 also counteracted the NOS III mRNA-decreasing effect of tumor necrosis factor-alpha. These findings demonstrate that Stsp analogs represent a new class of compounds positively interacting with the transcription of the endothelial NOS III gene. Such compounds may prove useful in the prophylaxis and therapy of vascular disease.
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Four conclusions derive from the studies exploring NOS-generated O 2.- and the kinetic data outlined here. 1) When sufficient L-arginine and H4B are present, NOS dimers secrete small amounts of O2.- or H2O2 and instead couple their heme and O2 reduction to NO. synthesis. 2) Significant O2.- production may occur when concentrations of H4B (≤2 μM) or L-arginine (≤100 μM) fall below levels required to saturate the enzyme. In these circumstances, O2.- forms by heme-catalyzed O2 reduction. 3) NOS reductase domain flavins are protected from autooxidation and do not secrete large amounts of O2.- unless certain redox-active xenobiotics are present. These cause O2.- production by catalyzing electron transfer from the NOS reductase domain to O2. One recent example suggests that NOS-derived O2.- participates in tissue injury associated with the xenobiotic (54). 4) NOS may generate both NO. and O2.- when concentrations of L-arginine or H4B are low (41-45, 51, 59). When the steady-state flux of O 2.- was high there was evidence for ONOO- formation (57, 58). Indeed, certain pathologic states might promote formation of ONOO- such as ischemia/reperfusion injury (67). Formation of HO., either through metal ion-catalyzed H2O2 decomposition (68) or from decomposition of ONOO- (69-71), at sensitive cellular sites may also contribute to cytotoxicity. Finally, it is worth noting that sequential formation of NO. and O2.- can result in differing cell signaling pathways (15, 16), few of which have been well defined. Therefore, under different conditions a variety of oxidants may derive from NOS that can impact cell function in ways that are significant.
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Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase activity has been implicated in the inflammatory processes contributing to the pathogenesis of atherosclerosis. However, reports of stimulatory effects of ceramide on endothelial NO production in animal models suggest antiatherosclerotic effects of the molecule. Therefore, we investigated long-term effects of ceramide on NO generation in human endothelial cells. In human umbilical vein endothelial cells (HUVECs) and in HUVEC-derived EA.hy 926 endothelial cells, C6-ceramide (N-hexanoyl-D-erythro-sphingosine) reduced the generation of bioactive NO (RFL-6 reporter-cell assay). At the same time, the signaling molecule increased endothelial NO synthase (eNOS) mRNA (RNase protection assay) and protein expression (Western blot). C6-ceramide stimulated eNOS transcription by a signaling mechanism involving protein phosphatase PP2A but did not modify the stability of the eNOS mRNA. Endothelial generation of reactive oxygen species (ROS) was increased by C6-ceramide [5-(and-6)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA) oxidation-based fluorescence assay], and this effect was partially reversed by the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). On the other hand, (6R)-5,6,7,8-tetrahydro-L-biopterin (BH(4)) normalized in part the ceramide-induced reduction in bioactive NO. Ceramide produces oxidative stress in human endothelial cells, thereby reducing bioactive NO. The partial reversal of this reduction by BH(4) and the diminution of ROS generation by L-NAME suggest that ceramide promotes NADPH oxidase activity of eNOS, leading to ROS formation at the expense of NO synthesis. The ceramide-induced upregulation of eNOS gene transcription can be considered an ineffective compensatory mechanism. The decreased bioavailability of NO is likely to favor a proatherogenic role of ceramide.
In primary human umbilical vein endothelial cells (HUVECs), incubation with phorbol-12-myristate-13-acetate (PMA) enhanced basal and bradykinin-stimulated nitric oxide production. In the HUVEC-derived cell line EA.hy 926, PMA and phorbol-12,1 3-dibutyrate stimulated endothelial nitric oxide synthase (NOS III) mRNA expression in a concentration- and time-dependent manner. Maximal mRNA expression (3.3-fold increase) was observed after 18 hr. NOS III protein and activity were increased to a similar extent. The specific protein kinase C (PKC) inhibitors bisindolylmaleimide I (1 mu M), Go 6976 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo-[2,3-a]pyrrolo-[3,4-c]carbazole] (1 mu M), Ro-31-8220 [3-[1-[3-(amidinothio)propyl-1H-inoyl-3-yl]3-(1-methyl-1H-indoyl-3-yl) maleimide methane sulfonate] (1 mu M), and chelerythrine (3 mu M) did not change NOS III expression when applied alone, but they all prevented the up-regulation of NOS III mRNA produced by PMA. Of the PKC isoforms expressed in EA.hy 926 cells (alpha, beta I, delta, epsilon, eta, zeta, lambda, and mu), only PKC alpha and PKC epsilon showed changes in protein expression after PMA treatment. Incubation of EA.hy 926 cells with PMA for 2-6 hr resulted in a translocation of PKC alpha and PKC epsilon from the cytosol to the cell membrane, indicating activation of these isoforms. After 24 hr of PMA incubation, both isoforms were down-regulated. The time course of activation and down-regulation of these two PKC isoforms correlated well with the PMA-stimulated increase in NOS III expression. When human endothelial cells (ECV 304 or EA.hy 926) were transiently or stably transfected with a 3.5-kb fragment of the human NOS III promoter driving a luciferase reporter gene, PMA stimulated promoter activity up to 2.5-fold. On the other hand, PMA did not change the stability of the NOS III mRNA. These data indicate that stimulation of PKC alpha, PKC epsilon, or both by active phorbol esters represents an efficacious pathway activating the human NOS III promoter in human endothelium.
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The treatment of ischemic strokes is limited to prophylactic agents that block the coagulation cascade. Here, we show that cholesterol-lowering agents, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, protect against cerebral injury by a previously unidentified mechanism involving the selective up-regulation of endothelial NO synthase (eNOS). Prophylactic treatment with HMG-CoA reductase inhibitors augments cerebral blood flow, reduces cerebral infarct size, and improves neurological function in normocholesterolemic mice. The up-regulation of eNOS by HMG-CoA reductase inhibitors is not associated with changes in serum cholesterol levels, but is reversed by cotreatment with L-mevalonate and by the downstream isoprenoid, geranylgeranyl pyrophosphate and not by farnesyl pyrophosphate. The blood flow and neuroprotective effects of HMG-CoA reductase inhibitors are completely absent in eNOS-deficient mice, indicating that enhanced eNOS activity by HMG-CoA reductase inhibitors is the predominant if not the only mechanism by which these agents protect against cerebral injury. Our results suggest that HMG-CoA reductase inhibitors provide a prophylactic treatment strategy for increasing blood flow and reducing brain injury during cerebral ischemia.
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Background: Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase activity has been implicated in the inflammatory processes contributing to the pathogenesis of atherosclerosis. However, reports of stimulatory effects of ceramide on endothelial NO production in animal models suggest antiatherosclerotic effects of the molecule. Therefore, we investigated long-term effects of ceramide on NO generation in human endothelial cells. Methods and results: In human umbilical vein endothelial cells (HUVECs) and in HUVEC-derived EA.hy 926 endothelial cells, C6-ceramide (N-hexanoyl-D-erythro-sphingosine) reduced the generation of bioactive NO (RFL-6 reporter-cell assay). At the same time, the signaling molecule increased endothelial NO synthase (eNOS) mRNA (RNase protection assay) and protein expression (Western blot). C6-ceramide stimulated eNOS transcription by a signaling mechanism involving protein phosphatase PP2A but did not modify the stability of the eNOS mRNA. Endothelial generation of reactive oxygen species (ROS) was increased by C6-ceramide [5-(and-6)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA) oxidation-based fluorescence assay], and this effect was partially reversed by the NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). On the other hand, (6R)-5,6,7,8-tetrahydro-L-biopterin (BH(4)) normalized in part the ceramide-induced reduction in bioactive NO. Conclusions: Ceramide produces oxidative stress in human endothelial cells, thereby reducing bioactive NO. The partial reversal of this reduction by BH(4) and the diminution of ROS generation by L-NAME suggest that ceramide promotes NADPH oxidase activity of eNOS, leading to ROS formation at the expense of NO synthesis. The ceramide-induced upregulation of eNOS gene transcription can be considered an ineffective compensatory mechanism. The decreased bioavailability of NO is likely to favor a proatherogenic role of ceramide.
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We have recently demonstrated that hydrogen peroxide (H2O2) is an extremely potent stimulus of endothelial NO synthase (eNOS) gene expression. The present study was designed to identify the signaling mechanisms mediating this response. Induction of eNOS expression by H2O2 was found to be Ca²⁺ dependent, inasmuch as it was blocked by BAPTA-AM. Further studies have indicated that Ca²⁺/calmodulin-dependent protein kinase II (CaM kinase II) plays a critical role in mediating this response. Immunocytochemical staining with an anti-CaM kinase II antibody confirmed the expression of CaM kinase II in cultured bovine aortic endothelial cells. H2O2 induced autophosphorylation of CaM kinase II and increased the activity of the enzyme, as assessed by an in-gel kinase assay. A specific inhibitor for CaM kinase II, KN93, and a calmodulin antagonist, W-7, attenuated eNOS induction by H2O2. Further studies have indicated that janus kinase 2 is important in mediating increased eNOS expression in response to H2O2 and likely is downstream from CaM kinase II. In conclusion, these data provide the first evidence that CaM kinase II plays a critical role in endothelial redox signaling. Regulation of eNOS via this pathway may represent an important vascular adaptation to oxidant stress.
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Objectives The study tested the effect of red wine on endothelial-type nitric oxide synthase (eNOS) expression and eNOS activity in human endothelial cells.
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The choleretic action of artichoke extract [main ingredient: cynarin (1.5-di-caffeoyl-D-quinc acid)] was investigated in a randomised placebo-controlled double-blind cross-over study (pilot study) [n = 20]. The effect of the standardized, artichoke extract: Hepar SL forte (administered as a single dose: 1.92 g, by the intraduodenal route in a solution of 50 ml of water) was studied by measuring intra-duodenal bile secretion using multi-channel probes. Thirty minutes after the test-substance was administered, a 127.3% increase in bile secretion was recorded, after 60 minutes, 151.5%, and after another 60 minutes, 94.3%, each in relation to the initial value. The relevant differences for the placebo were significant to the extent of p < 0.01 and were clinically relevant. The highest increase in the case of the placebo (139.5%) was seen after 30 minutes. At 120 and 150 minutes the volume of bile secreted under the active treatment was also significantly higher than under the placebo (p < 0.05). In the placebo group, bile secretion fell below the initial level after 3 hours. An effective period of about 120-150 minutes was regarded as satisfactory to influence enzymatic digestion and the motor function of the intestine when the test substance was given postprandially. No side effects nor changes in the laboratory parameters in connection with the experiment were observed. Results indicate that artichoke extract can be recommended for the treatment of dyspepsia, especially when the cause may be attributed to dyskinesia of the bile ducts or disorder in the assimilation of fat.
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A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
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To determine if endogenous local levels of nitric oxide (NO) modulate atherogenesis, we studied the effect of inhibiting NO with NG-nitro-L-arginine methyl ester (L-NAME) on early neointima formation in cholesterol-fed rabbits. Male rabbits were fed for 5 weeks with a 0.5% cholesterol diet alone or treated in addition during the last 4 weeks with L-NAME (12 mg/kg per day SC) via osmotic minipump. Endothelial cell function was assessed in isolated aortic rings by vascular reactivity and levels of cyclic GMP. In L-NAME-treated rabbits there was inhibition of endothelium-dependent relaxations to acetylcholine and the calcium ionophore A23187 as well as impaired cyclic GMP accumulation in response to acetylcholine. Neointima formation in the ascending thoracic aorta was assessed by determining media and intima cross-sectional areas with computerized image analysis. Compared with rabbits that consumed the cholesterol diet alone, L-NAME-treated rabbits had significant increases in lesion area (0.29 +/- 0.04 versus 0.15 +/- 0.03 mm2) and in lesion/media ratio (0.06 +/- 0.01 versus 0.03 +/- 0.01). Plasma levels of cholesterol and fluorescent lipid peroxide products were unchanged, suggesting no difference in cholesterol metabolism or oxidation. Because arterial blood pressure was not altered by L-NAME treatment, the increased atherogenesis could not be attributed to an increase in blood pressure. These results indicated that local inhibition of NO accelerates early neointima formation possibly because of modulating monocyte recruitment or foam cell lipid accumulation.
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Primary rat hepatocyte cultures exposed to tert-butylhydroperoxide (t-BHP) or cumene hydroperoxide were used to assess the antioxidative and protective potential of water-soluble extracts of artichoke leaves. Both hydroperoxides stimulated the production of malondialdehyde (MDA), particularly when the cells were pretreated with diethylmaleate (DEM) in order to diminish the level of cellular glutathione (GSH). Addition of artichoke extracts did not affect basal MDA production, but prevented the hydroperoxide-induced increase of MDA formation in a concentration-dependent manner when presented simultaneously or prior to the peroxides. The effective concentrations (down to 0.001 mg/ml) were well below the cytotoxic levels of the extracts which started above 1 mg/ml. The protective potential assessed by the LDH leakage assay and the MTT assay closely paralleled the reduction in MDA production and largely prevented hepatocyte necrosis induced by the hydroperoxides. The artichoke extracts did not affect the cellular level of glutathione (GSH), but diminished the loss of total GSH and the cellular leakage of GSSG resulting from exposure to t-BHP. Chlorogenic acid and cynarin accounted for only part of the antioxidative principle of the extracts which was resistant against tryptic digestion, boiling, acidification, and other treatments, but was slightly sensitive to alkalinization. These results demonstrate that artichoke extracts have a marked antioxidative and protective potential. Primary hepatocyte cultures seem suitable for identifying the constituents responsible for these effects and for elucidating their possible mode of action.
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In primary human umbilical vein endothelial cells (HUVECs), incubation with phorbol-12-myristate-13-acetate (PMA) enhanced basal and bradykinin-stimulated nitric oxide production. In the HUVEC-derived cell line EA.hy 926, PMA and phorbol-12,13-dibutyrate stimulated endothelial nitric oxide synthase (NOS III) mRNA expression in a concentration- and time-dependent manner. Maximal mRNA expression (3.3-fold increase) was observed after 18 hr. NOS III protein and activity were increased to a similar extent. The specific protein kinase C (PKC) inhibitors bisindolylmaleimide I (1 microM), Gö 6976 [12-(2 cyanoethyl)-6,7,12, 13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo-[3, 4-c]carbazole] (1 microM), Ro-31-8220 [3-[1-[3(amidinothio)propyl-1H-inoyl-3-yl]3-(1-methyl-1H- indoyl-3-yl) maleimide methane sulfonate] (1 microM), and chelerythrine (3 microM) did not change NOS III expression when applied alone, but they all prevented the up-regulation of NOS III mRNA produced by PMA. Of the PKC isoforms expressed in EA.hy 926 cells (alpha, beta I, delta, epsilon, eta, zeta, lambda, and mu), only PKC alpha and PKC epsilon showed changes in protein expression after PMA treatment. Incubation of EA.hy 926 cells with PMA for 2-6 hr resulted in a translocation of PKC alpha and PKC epsilon from the cytosol to the cell membrane, indicating activation of these isoforms. After 24 hr of PMA incubation, both isoforms were down-regulated. The time course of activation and down-regulation of these two PKC isoforms correlated well with the PMA-stimulated increase in NOS III expression. When human endothelial cells (ECV 304 or EA.hy 926) were transiently or stably transfected with a 3.5-kb fragment of the human NOS III promoter driving a luciferase reporter gene, PMA stimulated promoter activity up to 2.5-fold. On the other hand, PMA did not change the stability of the NOS III mRNA. These data indicate that stimulation of PKC alpha, PKC epsilon, or both by active phorbol esters represents an efficacious pathway activating the human NOS III promoter in human endothelium.
Article
High-dose aqueous extracts from artichoke leaves were found to inhibit cholesterol biosynthesis from 14C-acetate in primary cultured rat hepatocytes in a concentration-dependent biphasic manner with moderate inhibition (approximately 20%) between 0.007 and 0.1 mg/ml and more strong inhibition at 1 mg/ml. Cytotoxic effects detected by lactate dehydrogenase leakage and the 3-[4, 5-dimethylthiazol-2-yl]-2,5-dephenyl tetrazolium bromide-assay were restricted to higher concentrations. Replacement of 14C-acetate by 14C-mevalonate largely omitted the inhibiting effect of artichoke extracts indicating an inhibition at the level of hydroxymethylglutaryl-CoA-reductase. However, no direct inhibition of this enzyme could be detected and no other enzymic steps later in the biosynthetic pathway for cholesterol seemed to be affected. Instead, inhibition was found to occur in a time-dependent manner, to last for several hours even after washing out the extracts by fresh medium and to be fully reversible within 20 hr after removal of the extracts. In addition, the stimulation of HMGCoA-reductase activity by insulin was efficiently blocked by the extracts, although other insulin-dependent phenomena, such as increased lactate production, were not influenced. These results suggest an indirect modulation of hydroxymethylglutaryl-CoA-reductase activity as the most likely inhibitory mechanism of the artichoke extracts. Screening of several known constituents of artichoke extracts revealed that cynaroside and particularly its aglycone luteolin were mainly responsible for inhibition, whereas chlorogenic acid was much less effective and caffeic acid, cynarin and other dicaffeoylquinic acids were without significant influence. Indeed, luteolin also efficiently blocked the insulin effect on cholesterol biosynthesis. In conclusion, these results demonstrate that artichoke extracts may inhibit hepatic cholesterol biosynthesis in an indirect but efficient manner and, thus, may contribute via this action to the recently confirmed hypolipidemic influence of this phytopharmacon in man.
Article
Flavonoids represent a diverse group of phytochemicals which possess the capacity to act as antioxidants in vitro. This study examined the free radical scavenging properties of a luteolin-rich artichoke extract and some of its pure flavonoid constituents by assessing their ability to prevent Cu2+-mediated LDL oxidation. Artichoke extract retarded LDL oxidation in a dose-dependent manner as measured by a prolongation of the lag phase to conjugated diene formation, a decrease in the rate of propagation and a sparing of endogenous LDL alpha-tocopherol during oxidation. The pure aglycone, luteolin (1 microM), demonstrated an efficacy similar to that of 20 microg/ml artichoke extract in inhibiting lipid peroxidation. Luteolin-7-O-glucoside, one of the glycosylated forms in the diet, also demonstrated a dose-dependent reduction of LDL oxidation that was less effective than that of luteolin. Studies of the copper-chelating properties of luteolin-7-O-glucoside and luteolin suggest a potential role for chelation in the antioxidative effects of artichoke extract. Overall, the results demonstrate that the antioxidant activity of the artichoke extract relates in part to its constituent flavonoids which act as hydrogen donors and metal ion chelators, and the effectiveness is further influenced by their partitioning between aqueous and lipophilic phases.
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Nitric oxide (NO) is synthesized by at least three distinct isoforms of NO synthase (NOS). Their substrate and cofactor requirements are very similar. All three isoforms have some implications, physiological or pathophysiological, in the cardiovascular system. The endothelial NOS III is physiologically important for vascular homeostasis, keeping the vasculature dilated, protecting the intima from platelet aggregates and leukocyte adhesion, and preventing smooth muscle proliferation. Central and peripheral neuronal NOS I may also contribute to blood pressure regulation. Vascular disease associated with hypercholesterolaemia, diabetes, and hypertension is characterized by endothelial dysfunction and reduced endothelium-mediated vasodilation. Oxidative stress and the inactivation of NO by superoxide anions play an important role in these disease states. Supplementation of the NOS substrate L-arginine can improve endothelial dysfunction in animals and man. Also, the addition of the NOS cofactor (6R)-5,6,7, 8-tetrahydrobiopterin improves endothelium-mediated vasodilation in certain disease states. In cerebrovascular stroke, neuronal NOS I and cytokine-inducible NOS II play a key role in neurodegeneration, whereas endothelial NOS III is important for maintaining cerebral blood flow and preventing neuronal injury. In sepsis, NOS II is induced in the vascular wall by bacterial endotoxin and/or cytokines. NOS II produces large amounts of NO, which is an important mediator of endotoxin-induced arteriolar vasodilatation, hypotension, and shock.
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Wirksamkeit von Artischocken-Trockenextrakt bei Hyperlipoproteinämie Wirksamkeit und Verträglichkeit eines Artischocken-Trockenextraktes (Droge/Extrakt-Verhältnis 25-35 : 1, Extraktionsmittel: Wasser, CY450) als Filmtablette mit 450 mg Trockenextrakt aus frischen Artischockenblättern (Handelsname: Valverde Artischocke bei Verdauungsbeschwerden) wurden bei der Behandlung der Hyperlipoproteinämie in einer Studie untersucht und mit Plazebo verglichen. 143 erwachsene Patienten mit einem Ausgangswert für Gesamtcholesterin von > 7,3 mmol/l (> 280 mg/dl) wurden in eine doppel-blinde, randomi-sierte, plazebokontrollierte Multizenterstudie aufgenommen. Die Teilnehmer erhielten für 6 Wochen täglich 1.800 mg Artischocken-Trockenextrakt oder Plazebo. Veränderungen von Gesamtcholesterin und LDL-Cholesterin vom Ausgangswert bis zum Ende der sechswöchigen Behandlung zeigten eine statistisch signifikante Überlegenheit (p = 0,0001) für den Artischok-ken-Trockenextrakt gegenüber Plazebo. Die Abnahme von Gesamtcholesterin war in der CY450-Gruppe 18,5%, verglichen mit 8,6% in der Plazebo-Gruppe. LDL-Cholesterin nahm in der CY450-Gruppe um 22,9% ab, in der Plazebo-Gruppe um 6,3%. Das LDL/HDL-Verhältnis sank um 20,2% in der CY450-Gruppe und um 7,2% in der Plazebo-Gruppe. Es traten keine arzneimittelbedingten unerwünschten Ereignisse auf, was auf die sehr gute Verträglichkeit des eingsetzten Artischocken-Trockenextraktes hinweist. Diese prospektive Studie dokumentiert, daß der Artischocken-Trockenextrakt CY450 für die Behandlung der Hyperlipopro-teinämie und damit Prävention von Arteriosklerose und koronarer Herzkrankheit zu empfehlen ist.
Article
Thrombosis superimposed on atherosclerosis causes approximately two thirds of all brain infarctions. We previously demonstrated that statins protect from cerebral ischemia by upregulation of endothelial type III nitric oxide synthase (eNOS), but the downstream mechanisms have not been determined. Therefore, we investigated whether antithrombotic effects contribute to stroke protection by statins. 129/SV wild-type and eNOS knockout mice were treated with atorvastatin for 14 days (0.5, 1, and 10 mg/kg). eNOS mRNA from aortas and platelets was measured by reverse-transcriptase polymerase chain reaction. Platelet factor 4 (PF 4) and beta-thromboglobulin (beta-TG) in the plasma were quantified by ELISA. Transient cerebral ischemia was induced by filamentous occlusion of the middle cerebral artery followed by reperfusion. Stroke volume after 1-hour middle cerebral artery occlusion/23-hour reperfusion was significantly reduced by 38% in atorvastatin-treated animals (10 mg/kg) compared with controls. Serum cholesterol levels were not affected by the treatment. eNOS mRNA was significantly upregulated in a dose-dependent manner in aortas and in thrombocytes of statin-treated mice compared with controls. Moreover, indices of platelet activation in vivo, ie, plasma levels of PF 4 and beta-TG, were dose-dependently downregulated in the treatment group. Surprisingly, atorvastatin-treatment did not influence PF 4 and beta-TG levels in eNOS knockout mice. The synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin upregulates eNOS in thrombocytes, decreases platelet activation in vivo, and protects from cerebral ischemia in normocholesterolemic mice. Antithrombotic and stroke-protective effects of statins are mediated in part by eNOS upregulation. Our results suggest that statins may provide a novel prophylactic treatment strategy independent of serum cholesterol levels.
Article
Recent evidence suggests that some benefit from the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may occur independent of lipid lowering. We aimed to determine the effect of simvastatin on coronary endothelial function, endothelial NO synthase (eNOS) expression, and oxidative stress in experimental hypercholesterolemia (HC) in the absence of cholesterol lowering. Pigs were randomized to 3 experimental groups: normal diet (N group), high cholesterol diet (HC group), and HC diet with simvastatin (HC+S group) for 12 weeks. Low density lipoprotein cholesterol was similarly increased in the HC and HC+S groups compared with the N group. In vitro analysis of coronary large- and small-vessel endothelium-dependent vasorelaxation was performed. The mean vasorelaxation of epicardial vessels to bradykinin was significantly attenuated in the HC group compared with the N group (32.3+/-1.2% versus 42.9+/-1.6%, respectively; P<0.0001). This attenuation was significantly reversed in the HC+S group (38.7+/-1.5%, P<0.005 versus HC group). The maximal vasorelaxation to substance P was significantly attenuated in the HC group compared with the N group (50.5+/-11.9% versus 79.3+/-5.3%, respectively; P<0.05). This attenuated response was normalized in the HC+S group (74.9+/-4.1%, P<0.05 versus HC group). The maximal arteriolar vasorelaxation to bradykinin was also significantly attenuated in the HC group compared with the N group (71.9+/-4.9% versus 96.8+/-1.34%, respectively; P<0.005). This was reversed in the HC+S group (98.4+/-0.6%, P<0.0001 versus HC group). Western blotting of coronary tissue homogenates for eNOS demonstrated a decrease in protein levels in the HC group compared with the N group, with normalization in the HC+S group. Elevation of plasma F(2)-isoprostanes and thiobarbituric acid-reactive substances, markers of oxidative stress, occurred in the HC compared with the N group. These changes were reversed in the HC+S group. In summary, simvastatin preserves endothelial function in coronary epicardial vessels and arterioles in experimental HC (in the absence of cholesterol lowering) in association with an increase in coronary eNOS levels and a decrease in oxidative stress. These alterations may play a role in the reduction in cardiac events after treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.