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Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide
Abstract
Pomegranate juice (PJ), which is a rich source of potent flavonoid antioxidants, was tested for its capacity to protect nitric oxide (NO) against oxidative destruction and enhance the biological actions of NO. Employing chemiluminescence headspace analysis, PJ was found to be a potent inhibitor of superoxide anion-mediated disappearance of NO. PJ was much more potent than Concord grape juice, blueberry juice, red wine, ascorbic acid, and DL-alpha-tocopherol. As little as 3 microl of a 6-fold dilution of PJ, in a reaction volume of 5000 microl, produced a marked antioxidant effect, whereas 300 microl of undiluted blueberry juice or nearly 1000 microl of undiluted Concord grape juice were required to produce similar effects. PJ and other antioxidant-containing products were found to augment the anti-proliferative action of NO (DETA/NO) on vascular smooth muscle cell (rat aorta) proliferation. PJ was much more effective than the other products tested and elicited no effects when tested alone in the absence of added NO. Similarly, neither PJ nor the other products enhanced the anti-proliferative action of alpha-difluoromethylornithine, a stable substance that inhibits cell growth by NO-independent mechanisms. In order to determine whether PJ is capable of increasing the production of NO by vascular endothelial cells, PJ was tested for its capacity to upregulate and/or activate endothelial NO synthase (eNOS) in bovine pulmonary artery endothelial cells. PJ elicited no effects on eNOS protein expression or catalytic activity. Moreover, PJ did not enhance promoter activity in the eNOS gene (COS-7 cells transfected with eNOS). These observations indicate that PJ possesses potent antioxidant activity that results in marked protection of NO against oxidative destruction, thereby resulting in augmentation of the biological actions of NO.
... Pomegranate is purported to confer antioxidant effects (21) which could augment the synthesis, bioavailability, and physiological effects of NO (22). In addition, pomegranate has been suggested to be a rich source of NO 3 − (23), but to date, only two studies have examined the effects of pomegranate supplementation on NO bioavailability (24,25). ...
... The main novel findings of the present study were that: (1) ] were similar following the co-ingestion of NO 3 − and N-acetylcysteine (34,48), as well as NO 3 − and ascorbic acid (50) compared to NO 3 − supplementation alone. Given that POM has been previously shown to contain high antioxidant and polyphenolic content (22), in aggregate, current evidence indicates that the administration of NO 3 − concomitant with antioxidant-based supplements may not have an appreciable impact on NO biomarkers, despite the potential for the antioxidant supplements, to preserve NO bioavailability by quenching ROS (19). Due to the limited available data, and that the present study did not measure antioxidant properties of POM, caution is required in the interpretation of data and further research is required. ...
This study tested the hypothesis that co-ingesting nitrate (NO3⁻)-rich beetroot juice (BR) and pomegranate powder (POM) would enhance neuromuscular performance during vertical countermovement jumps, explosive kneeling countermovement push-ups, and back squats compared to BR ingestion alone. Fifteen recreationally-active males were assigned in a double-blind, randomized, crossover design, to supplement in 3 conditions: (1) NO3⁻-depleted beetroot juice (PL; 0.10 mmol NO3⁻) with two empty gelatin capsules; (2) NO3⁻-rich beetroot juice (BR; 11.8 mmol NO3⁻) with two empty gelatin capsules, and (3) BR with 1,000 mg of POM powder in two capsules (BR + POM). Participants completed 5 countermovement jumps and 5 kneeling countermovement push-ups interspersed by 1 min of recovery. Subsequently, participants performed 2 sets of 2 × 70% one-repetition maximum back squats, interspersed by 2 min of recovery. Plasma [NO3⁻] and nitrite ([NO2⁻]) were elevated following BR and BR + POM compared with PL and POM (p < 0.001) with no differences between BR and BR + POM (p > 0.05) or PL and POM (p > 0.05). Peak power during countermovement jumps increased by 3% following BR compared to BR + POM (88.50 ± 11.46 vs. 85.80 ± 10.14 W/Kg0.67, p = 0.009) but not PL (88.50 ± 11.46 vs. 85.58 ± 10.05 W/Kg0.67, p = 0.07). Neuromuscular performance was not different between conditions during explosive kneeling push-ups and back squats (p > 0.05). These data provide insight into the efficacy of NO3⁻ to modulate explosive resistance exercise performance and indicate that supplementing with BR alone or combined with POM has limited ergogenic potential on resistance exercise. Furthermore, caution is required when combining BR with POM, as this could compromise aspects of resistance exercise performance, at least when compared to BR ingested independently.
... However, eNOS activity is reduced at sites of perturbed shear stress with OSS (Wang et al., 2019). There was a study showing that pomegranate juice enhances the biological actions of NO (Ignarro et al., 2006). Therefore, we investigated the effects of PPP and PU on the vascular reactivity. ...
... Previous studies showed that PE ameliorates perturbed shear stress-related atherosclerosis by regulating the expression of eNOS and oxidation-related genes in ECs (de Nigris et al., 2005;de Nigris et al., 2007). In addition, pomegranate juice was shown to enhance the biological actions of NO (Ignarro et al., 2006). Our results advanced the new notion to demonstrate that the vasoprotective effects of PPP and PU are endothelium-dependent. ...
Background
Pathophysiological vascular remodeling in response to disturbed flow with low and oscillatory shear stress (OSS) plays important roles in atherosclerosis progression. Pomegranate extraction (PE) was reported having anti-atherogenic effects. However, whether it can exert a beneficial effect against disturbed flow-induced pathophysiological vascular remodeling to inhibit atherosclerosis remains unclear. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms.Methods
The anti-atherogenic effects of PPP/PU were examined on low-density lipoprotein receptor knockout mice fed with a high fat diet. The vaso-protective effects of PPP/PU were examined in rat aortas using myograph assay. A combination of in vivo experiments on rats and in vitro flow system with human endothelial cells (ECs) was used to investigate the pharmacological actions of PPP/PU on EC dysfunction induced by disturbed flow. In addition, the effects of PPP/PU on vascular smooth muscle cell (VSMC) dysfunction were also examined.ResultsPU is the effective component in PPP against atherosclerosis. PPP/PU evoked endothelium-dependent relaxation in rat aortas. PPP/PU inhibited the activation of Smad1/5 in the EC layers at post-stenotic regions of rat aortas exposed to disturbed flow with OSS. PPP/PU suppressed OSS-induced expression of cell cycle regulatory and pro-inflammatory genes in ECs. Moreover, PPP/PU inhibited inflammation-induced VSMC dysfunction.ConclusionPPP/PU protect against OSS-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects.
... Its production depends on nitric oxide synthetase (NOS), including nNOS, eNOS, and iNOS [41]. nNOS and eNOS produce low levels of NO and protect the gastric mucosa to a certain extent [14,42,43]. It was found that the occurrence of gastric ulcers was related to the over-inhibition of eNOS and nNOS levels [42]. ...
... nNOS and eNOS produce low levels of NO and protect the gastric mucosa to a certain extent [14,42,43]. It was found that the occurrence of gastric ulcers was related to the over-inhibition of eNOS and nNOS levels [42]. In addition, we also measured the expression mediators of related inflammatory factors in gastric tissue, such as iNOS and COX-2, which inhibit the production of inflammatory cytokines (such as IL-6). ...
The aim of this study was to investigate the effect of Lactobacillus plantarum HFY09 on gastric injury induced by HCl/ethanol in Kunming mice. The results showed that HFY09-H inhibited any increases in gastric juice volume, maintained the normal pH value of gastric acid, and reduced the damage caused to the gastric mucosa and gastric wall, the inhibition rate on the injury area reaches 63.70%. Compared with the negative control group, HFY09 increased the levels of serum somatostatin (SS) and vasoactive intestinal peptide (VIP), and also decreased the levels of substance P (SP), endothelin-1 (ET-1), interleukin-6 (IL-6), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). In addition, real time fluorescent quantitative PCR (Q-PCR) also confirmed that high-dose HFY09 (109 CFU/kg/day) upregulated the mRNA expression of copper/zinc superoxide dismutase (Cu/Zn-SOD), manganese superoxide dismutase (Mn-SOD), catalase (CAT), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS), and downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). At the same time, the results of the HFY09 treatment group were similar to those of the ranitidine treatment group. These results indicate that HFY09 can prevent gastric injury induced by HCl/ethanol in vivo. Therefore, HFY09 may play a potential role in the treatment of gastric diseases.
... PE is a rich source of potent polyphenolic and flavonoid antioxidants. These polyphenolic flavonoid antioxidants enhance the biological actions of naturally produced nitric oxide (NO) in vivo, stabilize NO and prolong cellular concentration of NO by protecting it against free radical destruction, e.g. by reactive oxygen species (Ignarro et al., 2006). ...
... Also, presence of polyphenols that pharmacological known as antioxidant properties as it responsible for antioxidants, anti-inflammatory, anti-mutagenic, anti-carcinogenic and antimicrobial effects (Ismail et al., 2012). ...
... 123,124 It increases the bioavailability of NO and precipitate smooth muscle relaxation by its antioxidant property due to presence of polyphenolic flavonoids. So it can be used in ED. 125 In a double-blind, randomized, placebo-controlled trial involving 53 individuals with mild to moderate erectile dysfunction, consuming 8 ounces of pomegranate juice daily for 28 days significantly improved erectile dysfunction scores The side effect of pomegranate juice are diarrhoea, flatulence, hyperlipidaemia, nasal congestion and hypertension. 126 Studies indicated that, pomegranate juice inhibits the intestinal CYP2C9 and CYP2A4 isoenzymes which may cause interactions with drugs which are metabolized by these enzymes. ...
Nutraceuticals are the food supplements that play a vital role to maintain healthy body and provide essential supplements required by the body in order to regulate body's metabolic process as well as to prevent from diseases. Nature provides us a vast diversified flora and fauna which are used tremendously from a long time by different civilizations for their health promoting effects. Unlike modern day synthetic drugs, nutraceuticals have the ability to provide both preventive action as well as nutritive action without exerting any adverse effects. Nutraceuticals have gained interest worldwide due to their nutritional and therapeutic effects without any toxic issues. The substances derived from foods and dietary supplements have shown different metabolic and biological actions on reproductive system in both human as well as animals. The present review discusses the use of nutraceuticals in different reproductive health anomalies. Articles were gathered using search engines such as Scopus, PubMed, Google Scholar, ResearchGate, and ScienceDirect.
... Improved endothelial function and increasing nitric oxide availability have been suggested as potential pathways. Notably, ellagitannins in PE have been reported to enhance endothelial function by reducing oxidative stress and promoting endothelial nitric oxide synthase (eNOS) activity, leading to better vasodilation and lower blood pressure [33,34]. ...
Background: Chronic inflammation increases morbidity in older adults and significantly impacts healthy ageing. Pomegranate extract (PE), rich in polyphenols, has been suggested to reduce inflammation and could prevent cardiovascular disease. However, there is limited research examining the potential of PE in disease prevention in ageing. Methods: A two-arm double-blind parallel trial was conducted, in which participants received either placebo capsules (maltodextrin) or pomegranate extract (740 mg) daily for 12 weeks. At baseline, week 6, and week 12, anthropometric measurements, blood pressure, and blood samples were collected. Serum inflammatory markers (IL-6, IL-1-α, IL1-β, IL-2, TNF-α, CRP and PAI-1), fasting blood glucose, and lipid levels were also measured. Results: A total of 86 participants met the eligibility criteria, with 76 completing the trial. A significant interaction between treatment and time was observed for the IL-6 (p = 0.02) and IL1-β (p = 0.05) levels, with both parameters significantly decreasing in the PE group. CRP and TNF-α showed a downward trend in the PE group, but it was not statistically significant (p > 0.05). Systolic blood pressure significantly decreased in the PE group (by 5.22 ± 1.26 mmHg (SE), p = 0.04), indicating potential clinical relevance, with diastolic blood pressure showing a similar downward trend (2.94 ± 1.08 mmHg (SE), p = 0.3). Despite being apparently healthy with no diagnosed diseases, a substantial number of participants exhibited elevated levels of inflammatory markers and systolic blood pressure. Conclusions: PE can lower inflammatory markers and blood pressure, which can be high in both normal-weight and overweight older adults, making it a cost-effective measure to promote healthy ageing. Further long-term studies are needed to address the limitations of this 3-month study, including the overrepresentation of normal-weight participants, and to gain a better understanding of the impact of weight on the above-mentioned outcomes.
... Several studies, including those on oxidative stress in HUVECs, have shown that rutin can enhance the production of nitric oxide (NO) (Ugusman et al., 2014). Additionally, antioxidants are known to enhance the biological effects of NO by protecting against cell or tissue damage induced by reactive oxygen species (ROS) through oxidation (Ignarro et al., 2006). Researchers have observed strong and positive correlations between the ABTS radical scavenging activity and the polyphenol levels in SM. ...
Sugarcane molasses (SM) is a viscous syrup produced during sugar processing. Its main
composition consists of carbohydrates, followed by moisture, ash, and bioactive compounds. SM has
the potential to be utilized to provide health benefits. This study aims to determine the effect of SM on
vasodilation in the rat thoracic aorta using an isolated tissue model (ex vivo). A healthy male Wistar rat
was isolated, and the tracing was recorded using Power Lab. The result of phenylephrine (PE) induced
maximal contraction at 10-4 mol/L in the tissue bath, and PE to induce vasoconstriction. The result of
acetylcholine (ACh) as a positive control was presented. The linea vasodilation of the rat thoracic
aorta at concentrations of 10-5 and 10-4 mol/L of thoracic aorta vasodilation was significantly different
(p < 0.05) compared with the control group. In addition, SM can reduce PE-induced vasoconstriction
with 25.22±1.46% of vasodilation at a concentration of 10 mg/ml. In the future, sugarcane molasses
(SM) may be studied in vivo for its potential anti-hypertensive effects, and it could also be used in the
creation of nutritionally alternative foods.
... The beneficial effects from plant sources might be due to vegetable components, such as phenols and ascorbic acid, tocopherols, carotenoids, and flavonoids that prevent the toxic effects of nitrites (79,80). Furthermore, certain dietary compounds like vitamin C and polyphenols enhance the conversion of nitrites into NO and protect NO from oxidative degradation (81,82). Two studies reported that plant-based diets with a high intake of vegetable and fruit juices (including beetroot) could increase fecal Bacteroidetes and decrease Firmicutes, a phenotype linked to lower obesity (83,84). ...
Background
Metabolic syndrome (MetS) prevalence has increased globally.The evidence shows thatdiet and gut microbial metabolites includingtrimethylamine N-oxide (TMAO) and kynurenine (KYN) play an important role in developing MetS. However, there is a lack of evidence on associations between between diet and these metabolites. This study aimed to investigate the interaction between dietary nitrate/nitrite and gut microbial metabolites (TMAO, KYN) on MetS and its components.
Methods
This cross-sectional study included 250 adults aged 20–50 years. Dietary intake was assessed using food frequency questionnaires (FFQ), and serum TMAO and KYN levels were measured. MetS was defined usingthe National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) criteria.
Result
The ATPIII index revealed an 11% prevalence of metabolic syndrome among the study participants. After adjusting for confounders, significant positive interactions were found: High animal-source nitrate intake and high TMAO levels with elevated triglycerides (TG) (p interaction = 0.07) and abdominal obesity (p interaction = 0.08). High animal-source nitrate intake and high KYN levels with increased TG (p interaction = 0.01) and decreased high-density lipoprotein cholesterol (HDL) (p interaction = 0.01).Individuals with high animal-source nitrite intake and high TMAO levels showed increased risk of hypertriglyceridemia (OR: 1.57, 95%CI: 0.35–2.87, p = 0.05), hypertension (OR: 1.53, 95%CI: 0.33–2.58, p = 0.06), and lower HDL (OR: 1.96, 95%CI: 0.42–2.03, p = 0.04). Similarly, high animal-source nitrite intake with high KYN levels showed lower HDL (OR: 2.44, 95%CI: 1.92–3.89, p = 0.07) and increased risk of hypertension (OR: 2.17,95%CI: 1.69–3.40, p = 0.05). Conversely, Negative interactions were found between high plant-source nitrate/nitrite intake with high KYN and TMAO levels on MetS and some components.
Conclusion
There is an interaction between dietary nitrate/nitrite source (animal vs. plant) and gut microbial metabolites (TMAO and KYN) on the risk of of MetS and its components. These findings highlight the importance of considering diet, gut microbiome metabolites, and their interactions in MetS risk assessment.
... T A B L E 4 GRADE profile of pomegranate intake for blood pressure in adults. pomegranate have been suggested to be due to its potent antioxidant activity that results in the protection of nitric oxide against oxidative destruction (Ignarro et al., 2006), hindering coronary endothelial dysfunction by upregulating expression and activity of endothelial nitric oxide synthase favoring reduced vascular inflammation and oxidative damage (Vilahur et al., 2015) and promoting vasorelaxation through inhibiting the angiotensin-converting enzyme (ACE) (Aviram & Dornfeld, 2001;Stowe, 2011). Indeed, a preclinical study showed that pomegranate juice consumption could decrease angiotensin II-induced hypertension in diabetic hypertensive rats (Mohan et al., 2010). ...
Considering the main component of cardiovascular disease and due to the high prevalence of hypertension, controlling blood pressure is required in individuals with various health conditions. Randomized clinical trials (RCTs) which studied the effects of pomegranate consumption on blood pressure have shown inconsistent findings. As a result, we intended to assess the effects of pomegranate consumption on systolic (SBP) and diastolic (DBP) blood pressure in adults. Systematic literature searches up to January 2024 were carried out using electronic databases, including PubMed, Web of Science, and Scopus, to identify eligible RCTs assessing the effects of pomegranate on blood pressure as an outcome. All the individuals who took part in our research were adults who consumed pomegranate in different forms as part of the study intervention. Heterogeneity tests of the selected trials were performed using the I2 statistic. Random effects models were assessed based on the heterogeneity tests, and pooled data were determined as the weighted mean difference (WMD) with a 95% confidence interval (CI). Of 2315 records, 22 eligible RCTs were included in the current study. Our meta-analysis of the pooled findings showed that pomegranate consumption significantly reduced SBP (WMD: −7.87 mmHg; 95% CI: −10.34 to −5.39; p < 0.001) and DBP (WMD: −3.23 mmHg; 95% CI: −5.37 to −1.09; p = 0.003). Individuals with baseline SBP > 130 mmHg had a significantly greater reduction in SBP compared to individuals with baseline SBP < 130 mmHg. Also, there was a high level of heterogeneity among studies (SBP: I2 = 90.0% and DBP: I2 = 91.8%). Overall, the results demonstrated that pomegranate consumption lowered SBP and DBP in adults. Although our results suggest that pomegranate juice may be effective in reducing blood pressure in the pooled data, further high-quality studies are needed to demonstrate the clinical efficacy of pomegranate consumption.
... However, according to the current literature available, amaranth does not appear to be the best dietary source of nitrates, but studies are needed where doses are administered in the ergogenic range [27][28][29][30]. In contrast, beet is rich in vitamin C and phenolic compounds (especially flavonoids), which are a great help to avoid oxidative stress and protect NO, increasing its biological actions in the organism [19,31]. Recently, beet consumption has been found to trivially improve endurance exercise performance; no significant effects were observed after consumption of other nitrate-rich vegetables such as amaranth, chard or rhubarb [32]. ...
Soccer players make frequent use of dietary supplements to improve performance. One of the most widely used strategies to optimize performance is to increase the bioavailability of nitric oxide through nitrates, as it could delay fatigue during physical exertion, among other benefits. This may be positive for performance in soccer, although there is almost no research in professional soccer. The aim of the study was to evaluate the use of nitrates and behaviours related to their consumption in Spanish elite soccer clubs. Dietitian-nutritionist representatives from 45 teams from the most important Span-ish soccer leagues completed an online survey to determine if, when, how and why nitrates are prescribed to soccer players. Of the total sample, 55.6% indicated providing nitrates, always before matches, but only 36% in training. There was a wide variation and lack of consistency in the timing, dosage and form of administration of nitrates. The use of mouthwashes or the protocol of chronic nitrate intake was not taken into account in most cases. The present study indicates a lack of interpretation between scientific knowledge and its application in practice, highlighting the need for future research to better understand how to optimize the use of nitrates in professional soccer.
... Flavonoids, polyphenols, pectin, and ascorbic acid form 1.5% of the weight of pomegranate juice (PJ). The soluble polyphenol content is between 0.2% and 1% depending on variety, and includes mainly anthocyanins (Ignarro et al., 2006;Darwish et al., 2009). The total content of anthocyanins was found to be higher in pomegranate than in any other fruit juice tested for antioxidant activity. ...
... Flavonoids, polyphenols, pectin, and ascorbic acid form 1.5% of the weight of pomegranate juice (PJ). The soluble polyphenol content is between 0.2% and 1% depending on variety, and includes mainly anthocyanins (Ignarro et al., 2006;Darwish et al., 2009). The total content of anthocyanins was found to be higher in pomegranate than in any other fruit juice tested for antioxidant activity. ...
Background: Pomegranate granatum (molasses and peels) and its constituents showed protective effects against natural toxins such as phenylhydrazine (PHZ) as well as chemical toxicants such as arsenic, diazinon, and carbon tetrachloride. Aim: The current study aimed to assess the effect of pomegranate molasses (PM), white peel extract, and red peel extract on nephrotoxicity induced by PHZ. Methods: 80 male rats were divided into eight equal groups; a control group, PM pure group, white peel pomegranate pure group, red peel pomegranate pure group, PHZ group, PM + PHZ group, white peel pomegranate + PHZ group and red peel pomegranate + PHZ group. Kidney function, inflammation markers, antioxidant activities, and renal tissue histopathology were investigated. Results: The results revealed that PHZ group showed a significant increase in lactate Dehydrogenase (LDH), malondialdehyde (MDA), creatinine, uric acid, BUNBUN, C-reactive protein (CRP), tumor necrosis factor, thiobarbituric acid reactive substances (TBARSs), and total antioxidant capacity (TAC) with a significant decrease of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as compared with a control group. Other pomegranate-treated and PHZ co-treated groups with pomegranate showed a significant decrease of LDH, MDA, creatinine, uric acid, BUN, tumor necrosis factor, TBARSs, and TAC with a significant increase of CAT, GPx, and SOD as compared with PHZ group. Conclusion: Collectively, our data suggest that red, white peels, and molasses have anti-toxic and anti-inflammatory effects on renal function and tissues.
... Pomegranate juice was used in present study as the antioxidant of choice, as it is very rich in polyphenol and demonstrates high capability to scavenge free radicals and to inhibit LDL oxidation in vitro and in vivo (20,21,22,23), have been shown to increase serum antioxidant capacity or decrease oxidative damage of biomolecules (24,25). Pomegranate juice has shown significant antiatherosclerotic, antihypertensive, antioxidant, and anti-inflammatory effects in human subjects and rabbits models, Pomegranate juice has also been shown to prevent oxidative destruction of nitric oxide and enhance its antioxidant and anti-inflammatory functions (26). ...
In present study, aminoglycosides as amikacin, was proved to induce alterations in the liver of experimental animals. The aim present study is to investigate the effect of amikacin on rabbit liver which is commonly used in infections resistant to other antibiotics and study treated and protective effect of Pomegranate juice(Punica granatum L.), which antibiotic inhibit & decrease liver toxic formed by amikacin in males and females white rabbits by measuring some of the criteria for biochemical variations, such as, blood serum cholesterol (Ch), triglyceride concentration (TG), blood serum high density lipoprotein-cholesterol (HDL-C),Low density lipoprotein-cholesterol (LDL-C) concentration. In those were given (amikacin80mg/kg) by injection in muscle for period of 15 days, caused a significant increase at the level (p≤0.05) in cholesterol(Ch), triglyceride(TG) concentration, Low density lipoprotein-cholesterol concentration(LDL-C) as compared with a control group, while decreased concentration of high density lipoprotein-cholesterol(HDL-C) significantly as compared with the control group. The rabbits treated with Pomegranate juice 100ml the concentration of 40% for a period of 15 days has recorded a significant decrease in the concentrations of cholesterol, triglyceride concentration and low density lipoprotein-cholesterol concentration as compared with a group Rabbits treated with amikacin only, and increased significantly in high density lipoprotein-cholesterol compared to the group treated with amikacin only
... Phytochemicals such as tannins found in P. sarmentosum leaves, is an active antioxidants that decreases the blood glucose level. It contains an enzyme related to the benzoic acid molecule which inhibit insulinase preventing insulin degradation and promoting insulin secretion (19). ...
Introduction: Diabetes mellitus (DM) is an endocrine, metabolic syndrome and has reached pandemic proportions worldwide. The multifactorial pathology results in the patient to including lifelong drug therapy for treatment. Alternative medicines such as traditional remedies using plant herbs to treat various diseases are common in most countries. Piper sarmentosum extracts have been as a traditional medicine to treat various diseases. The plant has abundant phytochemical properties such as alkaloids and flavonoids exhibiting pharmacological activities such as antidiabetic effects, antioxidant, anti-inflammatory, and anticancer. This paper aims to appraise the data into a comprehensive systematic review on the antidiabetic effect of P. sarmentosum and it’s potential in managing DM. Methods: This systematic review used the PRISMA method with searches in three electronic databases such as SCOPUS, PUBMED and WEB OF SCIENCE in November 2021. Six articles were included based on the inclusion criteria. Results: The results showed a hypoglycaemic effect in induced diabetic models. Piper sarmentosum extracts significantly reduces fasting blood glucose and reduces the risk of diabetes complications related to renal and cardiovascular system. In summary, a promising result regarding antidiabetic activity was found. Conclusion: This finding suggests that this plant has the potential to be used as an alternative therapy or pair along with other medications to treat DM.
... Its prolonged use for 3-15 days prior to sports practice may also be useful, since highly trained athletes are less responsive to the ergogenic effect of nitrates (AIS, 2021;Jones et al. 2021). Due to the multitude of factors capable of affecting the bioavailability and utilization of nitrates from whole foods (AESAN, 2021; Roumeliotis, Siomos, and Gerasopoulos 2021; Ignarro et al. 2006;Dewhurst-Trigg et al. 2018), the use of concentrates and/or extracts with a known nitrate concentration is more efficient. There is also evidence of improvement in endurance performance through the consumption of beet juice, but not through the consumption of other food sources that contain nitrates such as amaranth, Swiss chard, or rhubarb (d' Unienville et al. 2021). ...
Endurance athletes are defined as those who take part in competitive events and workouts that last more than 30 minutes. The high physical demand in this type of event, as well as the possibility that any small gain obtained may provide a real improvement in sports performance, encourages athletes to consider the use of various tools and/or strategies, among which we find the use of sports supplements. Sports supplements are defined as a food, food component, nutrient, or non-food compound that is purposefully ingested in addition to the habitually consumed diet, to obtain a specific health and/or performance benefit. It is important to know and compare the benefits of consuming sports supplements in specific sports situations using evidence-based protocols. As part of dietary-nutritional planning for training and competition, a nutritional chronology should be established for ingesting food, liquids and/or sports supplements for each hour of physical exercise, considering the sports equipment of the athlete, characteristics of the training or competition, and nutritional needs. This chapter describes potentially beneficial sports supplements for endurance athletes, and their possible use, through examples according to best practice protocols.
... Polyphenol containing AO capsules (pomegranate extract, green tea extract, vitamin C) showed several positive additional effects (increase in antioxidant molecules (glutathione levels)/capacity, reduction in oxidative stress (MDA levels), improvements in lipid profiles post-training). In addition to antioxidant vitamin C, pomegranates and tea have potent antioxidant properties due to their phenolic compounds (45). It is generally accepted that oxidative stress promotes T2DM and its complications (46). ...
Introduction
Physical training can improve several health variables in patients with type 2 diabetes mellitus (T2DM). A growing body of studies also finds a positive influence of dietary supplement (DS) intake. The aim of this review is to shed light on the possible effects of training interventions combined with DS intake in T2DM patients.
Methods
A systematic search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed and BISp Surf databases. Inclusion criteria were defined using the Patient-Intervention-Comparison-Outcome (PICO) scheme. The Physiotherapy Evidence Database (PEDro) scale was used for quality assessment and risk of bias analysis.
Results
Ten controlled interventional studies with a total number of 643 subjects met the inclusion criteria. These studies investigated the effects of (a) vitamin D (VD), (b) VD + whey protein, (c) polyphenol containing antioxidant capsules, (d) creatine, (e) L-arginine, (f) leucine-rich amino acids, and (g) broccoli sprouts powder. Eight studies investigated effects on one or more of the following health outcomes: body mass index, fat mass, insulin resistance, glycemic control, lipid profile, oxidative stress/antioxidative capacity and/or inflammatory markers/molecules. Five of the studies show clear superior effects of physical training combined with DS intake (supplements a, b, c, e) on some of these variables compared with training only. However, one study indicates that VD intake might attenuate the training effects on triglyceride levels. Another study found that training + VD + whey protein intake increased tumor necrosis factor-α levels in T2DM patients. The effects of training combined with DS intake on renal function (supplement d) or incretin metabolism (supplement a) were investigated in two further studies. These studies do not show any additional effects of DS intake. The quality of the majority of the studies was high.
Conclusion
DS intake can potentially increase the benefits of physical training for specific health outcomes in T2DM patients. However, negative effects can also be observed. Possible cellular and molecular mechanisms behind potential synergistic or divergent effects of exercise training and DS use in T2DM should be explored in detail in future studies for the development of safe recommendations.
... However, the total content of anthocyanins in pomegranate juice was reported to be higher than any other fruit juice tested for antioxidant activity. Pomegranate juice increased the biological actions of NO by protecting NO against oxidative destruction but reversed proatherogenic effects induced by perturbed shear stress (de Nigris et al., 2007;Ignarro et al., 2006). ...
The term “superfruit” usually refers to certain fruits, which are rich in antioxidant components, therefore, are beneficial to human health. In China, there has been the concept of health preservation and dietary therapy through food intake in a long history. However, some other superfruits growing mainly in China have not attracted extensive attention, such as Cili, Goji berry, and sea buckthorn. Many studies suggested all of these superfruits showed strong antioxidant effects and anti-inflammatory activity in common. However, there are various other advantages and functions in different fruits. This article reviewed the research findings from the existing literature published about major antioxidant bioactive compounds and the potential health benefits of these fruits. The phytochemicals from superfruits are bioaccessible and bioavailable in humans with promising health benefits. More studies are needed to validate the health benefits of these superfruits. It would provide essential information for further research and functional food development.
... More importantly, pomegranate juice halts atherosclerosis progression (de Nigris et al. 2005(de Nigris et al. , 2007b. Current evidence suggest that punicalaginweakly affect eNOS expression/activity under basal conditions (Ignarro et al. 2006), but could possibly increase eNOS expression and activity under pathological conditions, such as high fat feeding (de Nigris et al. 2005), obese (de Nigris et al. 2007a) and disturbed shear stress (de Nigris et al. 2005). Also, punicalagin derivative 1-alpha-O-galloylpunicalagin potentiates calcium-dependent activation of eNOS through PI3K/Akt pathway in endothelial cells (Chen et al. 2008).These evidences imply punicalaginas an effective therapeutic agent in preventing or treating atherosclerosis and its complications. ...
Vascular diseases arise due to vascular endothelium dysfunction in response to several pro-inflammatory stimuli and invading pathogens. Thickening of the vessel wall, formation of atherosclerotic plaques consisting of proliferating smooth muscle cells, macrophages and lymphocytes are the major consequences of impaired endothelium resulting in atherosclerosis, hypercholesterolemia, hypertension, type 2 diabetes mellitus, chronic renal failure and many others. Decreased nitric oxide (NO) bioavailability was found to be associated with anomalous endothelial function because of either its reduced production level by endothelial NO synthase (eNOS) which synthesize this potent endogenous vasodilator from L-arginine or its enhanced breakdown due to severe oxidative stress and eNOS uncoupling. Polyphenols are a group of bioactive compounds having more than 7000 chemical entities present in different cereals, fruits and vegetables. These natural compounds possess many OH groups which are largely responsible for their strong antioxidative, anti-inflammatory antithrombotic and anti-hypersensitive properties. Several flavonoid-derived polyphenols like flavones, isoflavones, flavanones, flavonols and anthocyanidins and non-flavonoid polyphenols like tannins, curcumins and resveratrol have attracted scientific interest for their beneficial effects in preventing endothelial dysfunction. This article will focus on in vitro as well as in vivo and clinical studies evidences of the polyphenols with eNOS modulating activity against vascular disease condition while their molecular mechanism will also be discussed.
... AA was taken as a standard while conducting quantitative spectrophotometric analysis. 0.25 mL of 10 mM sodium nitroprusside solution was added to 1 mL of the test samples (APO, NPs, and APO-NPs) at different concentrations (10-50 μg/mL) and incubated for 3 h at 37 °C with 500 μL of Griess reagent and to this purple-colored chromophore (Griess Reagent) coupled with dihydrochloride, ethylenediamine, naphthyl was added for measuring absorbance at 546 nm [47]. Formation of this complex also acts as an indicator because reaction occurs due to diazotization of nitrite with sulphanilamide and to calculate percentage inhibition, using (4): ...
Apocynin (APO) is a known multi-enzymatic complexed compound, employed as a viable NADPH oxidase (NOX) inhibitor, extensively used in both traditional and modern-day therapeutic strategies to combat neuronal disorders. However, its therapeutic efficacy is limited by lower solubility and lesser bioavailability; thus, a suitable nanocarrier system to overcome such limitations is needed. The present study is designed to fabricate APO-loaded polymeric nanoparticles (APO-NPs) to enhance its therapeutic efficacy and sustainability in the biological system. The optimized APO NPs in the study exhibited 103.6 ± 6.8 nm and −13.7 ± 0.43 mV of particle size and zeta potential, respectively, along with further confirmation by TEM. In addition, the antioxidant (AO) abilities quantified by DPPH and nitric oxide scavenging assays exhibited comparatively higher AO potential of APO-NPs than APO alone. An in-vitro release profile displayed a linear diffusion pattern of zero order kinetics for APO from the NPs, followed by its cytotoxicity evaluation on the PC12 cell line, which revealed minimal toxicity with higher cell viability, even after treatment with a stress inducer (H2O2). The stability of APO-NPs after six months showed minimal AO decline in comparison to APO only, indicating that the designed nano-formulation enhanced therapeutic efficacy for modulating NOX-mediated ROS generation.
... The seeds also contain sugars, protein, crude fibers, minerals, vitamins, pectin, polyphenols, isoflavones (mainly genistein), and phytoestrogen coumestrol (El-Nemr et al., 1990;Syed et al., 2007). Many studies noted that main compounds include calcium is 50% of its ash content, and the main amino acids are glutamic and aspartic acids and organic acids, sterols, triteryenoids and α-tocopherol (Ignarro et al., 2006;Lansky & Newman, 2007;Mousavinejad et al., 2009;Jaiswal et al., 2010;Krueger, 2012). Minerals in the pomegranate juice and seed include iron, but not in so high concentrations as in watermelon, and other minerals such as calcium, copper, potassium, magnesium, manganese, chlorine, sodium, selenium, and zinc (Waheed et al., 2004). ...
The main purpose of phase one was the determination of the antioxidant activity, phenolic contents, as well as antioxidant vitamin composition of pomegranate seed (PS), juice (PJ), and mixture of fruit (PSJ), to compare the most effective edible part of the fruit. The total antioxidant activity (TAA) was determined based on FRAP assay. Total phenolic content (TPC) was determined by using Folin-Ciocalteu (FC) method based on colorimetric reduction. The antioxidant vitamins compositions were determined according to the modified method using high performance liquid chromatography (HPLC) assay. The amount of vitamin A, C, and E were 22.8 µg/100 g, 57.8 mg/100 g, and 0.07 mg/100 g respectively. The TAA value of PJ, PS, and PSJ were 32 ± 5.1, 20 ± 2.8, 47 ± 5.5 (mmol/L Fe+2), and also for the TPC were 2502 ± 54, 165 ± 9, and 2696 ± 49 mg GAE/L (GAE:Gallic Acid Equivalent) respectively.
In the phase two, study was carried out on antioxidant effect of pomegranate on plasma oxidative markers, and antioxidant defense system in streptozotocin-Nicotinamide induced diabetic rats. Forty-eight male Sprague-Dawley rats weight between 250-280 g were used. All rats were randomly divided into six groups, that consisted of two control groups, and four treatment groups. Rats were administrated a single intraperitoneal (i.p) injection of 60 mg/kg of STZ, and NA (120 mg/kg, i.p) 15 min before STZ. For treatment, 1 mL of pomegranate juice to PJ, and 100 mg pomegranate seed powder to PS, and combination of 100 mg PS with 1 mL PJ for PSJ group.
After 21 days of forced-feeding period, the results from the experiment revealed that the treatment with pomegranate showed a significant increase in the level of biomarkers of oxidative stress (MDA and GGT), that treatment with 1 mL of PSJ significantly reduced the level of both markers of oxidative stress. However, there were significant reductions in the levels of antioxidant status (SOD, CAT, and TAS), after treatment with 1 mL of PSJ significantly increased.
In the phase three, biochemical observations were supplemented with histological examination of kidney and liver. Rats were fasted 12 hours before sacrificing by using chloroform anesthesia. The paraffin sections were dyed with Hematoxylin and Eosin (H&E) for histopathological study, and surveyed under light microscope. The depletion of exogenous antioxidant store can permit that the reactive intermediates react to destroy the hepatic and renal cells such pathological changes can be seen in the diabetic rats.
Apparently, the treatment with pomegranate is able to increase antioxidant enzyme; which has ability to ameliorate oxidative stress, and protects the hepatic and renal tissues in diabetic rats. Oral treatment with pomegranate for a period of three weeks showed significant ameliorative effects on all the biochemical and histological parameters.
... These effects may be attributed to their diverse bioactive phytochemicals as ellagitannins, ellagic acid, or anthocyanins [7], which may be attributed to its antioxidant capacity. The effect of pomegranate antioxidant compounds on pain modulation is related to the elimination of free radicals [21], decreases macrophage oxidative stress [22], and enhances the biological actions of naturally produced nitric oxide (NO) [23][24][25]. There is also evidence that shows that the NO acts as a modulator in the spinal cord and dorsal root ganglia through the nociceptive pathway [26]. ...
Objective: The aim of this study was to explore the analgesic activity of lyophilized juice of Punica granatum L., obtained from Hidalgo, Mexico, in theformalin test.Methods: We extracted the juice manually, filtered it and then dried down in a lyophilizer machine. We evaluated the antinociceptive effect oflyophilized juice from pomegranate in the formalin test (2%) in male Wistar rats (180–200 g body weight). Thirty minutes before the test, a dose of316 mg/kg (lyophilized juice) and acetylsalicylic acid as reference drug (100 mg/kg) both were administered intragastrically (i.g.).Results: The oral administration of lyophilized juice of pomegranate showed a significant decrease in the number of flinches in the temporal courseand a significant antinociceptive effect in nociceptive and inflammatory pain compared with the vehicle. In the same way, this effect appeared with thedrug of reference (acetylsalicylic acid 100 mg/kg i.g). Furthermore, it was shown that juice had a 34% of antinociception on overall effect versus vehicle.Conclusion: The results suggest that lyophilized juice of pomegranate has antinociceptive effect in nociceptive and inflammatory pain. Therefore, thisstudy supports the possible use of this lyophilized juice of pomegranate in the treatment of pain.
... Antiantioxidant properties of pomegranate juice on rat aortic smooth muscle cells have been reported under in vitro conditions, and the results indicated that pomegranate juice promoted the biological actions of NO and protected against oxidative damage inflicted by reactive oxygen species. Activation of NO led to inhibition of vascular smooth muscle cell proliferation and progression of atherosclerosis (Ignarro et al., 2006). However, this meta-analysis found that there was no significant effect of pomegranate juice on the endothelial parameters, such as ICAM-1, VCAM1 and E-selectin. ...
Background
Cardiovascular diseases, obesity, and insulin resistance demonstrate elements of functional impairment of the endothelium. Treatment of endothelial dysfunction with natural products, such as pomegranate, can open new ways in the treatment of cardiovascular diseases.
Purpose
The present meta-analysis provides information in highlighting the role of pomegranate in endothelial dysfunction.
Methods
Various databases, such as PubMed, Scopus, Web of Science, Cochrane, and Google Scholar, were searched up to July 2020 using relevant keywords. We have selected the studies that investigated the effects of pomegranate on vascular adhesion factors, including intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, and interleukin-6 (IL-6). MD with 95% CrI with 100,000 iterations by using Markov chain Monte Carlo code were used.
Results
Pooled effect size of articles in human studies indicated that pomegranate juice was not significantly effective on ICAM-1 [MD: −0.42; CrI: (−1.01, 0.17)], VCAM-1 [MD: −0.20; CrI: (−1.95, 1.40)], and E-selectin [MD: −0.21; CrI: (−1.62, 1.21)] compared to the control group. But it can significantly reduce IL-6 [MD: −1.07; CrI: (−1.90, -0.19)].
Conclusion
Generally, present study showed that pomegranate juice has no significant effect on vascular adhesion factors, ICAM-1, VCAM-1, and E-selectin, but can reduce IL-6 significantly. Future prospective randomized clinical trials with longer intervention duration are warranted to obtain a precise conclusion.
... The beneficial effects of (poly)phenols on cognitive performance may be due to their positive impact on limiting nitric oxide (NO) scavenging by ROS, thereby enhancing NO bioavailability and activating NO synthesis (NOS) pathways [15,16,60], which are important contributors to flow-mediated dilation [61,62] and neurotransmission [63]. As NOS is responsible for vasodilation [64], promoting NOS via (poly)phenols-rich supplementation will increase regional perfusion, brain activity, and may contribute to improved cognitive performance [15,16,51]. ...
Background:
Recent anti-aging interventions have shown contradictory impacts of (poly)phenols regarding the prevention of cognitive decline and maintenance of brain function. These discrepancies have been linked to between-study differences in supplementation protocols. This subgroup analysis and meta-regression aimed to (i) examine differential effects of moderator variables related to participant characteristics and supplementation protocols and (ii) identify practical recommendations to design effective (poly)phenol supplementation protocols for future anti-aging interventions.
Methods:
Multiple electronic databases (Web of Science; PubMed) searched for relevant intervention published from inception to July 2019. Using the PICOS criteria, a total of 4303 records were screened. Only high-quality studies (n = 15) were included in the final analyses. Random-effects meta-analysis was used, and we calculated standard differences in means (SDM), effect size (ES), and 95% confidence intervals (CI) for two sufficiently comparable items (i.e., psychomotor function and brain-derived neurotrophic factor (BDNF)). When significant heterogeneity was computed (I2 > 50%), a subgroup and meta-regression analysis were performed to examine the moderation effects of participant characteristics and supplementation protocols.
Results:
The reviewed studies support the beneficial effect of (poly)phenols-rich supplementation on psychomotor functions (ES = -0.677, p = 0.001) and brain plasticity (ES = 1.168, p = 0.028). Subgroup analysis revealed higher beneficial impacts of (poly)phenols (i) in younger populations compared to older (SDM = -0.89 vs. -0.47 for psychomotor performance, and 2.41 vs. 0.07 for BDNF, respectively), (ii) following an acute compared to chronic supplementation (SDM = -1.02 vs. -0.43 for psychomotor performance), and (iii) using a phenolic compound with medium compared to low bioavailability rates (SDM = -0.76 vs. -0.68 for psychomotor performance and 3.57 vs. 0.07 for DBNF, respectively). Meta-regressions revealed greater improvement in BDNF levels with lower percentages of female participants (Q = 40.15, df = 6, p < 0.001) and a skewed scatter plot toward a greater impact using higher (poly)phenols doses.
Conclusion:
This review suggests that age group, gender, the used phenolic compounds, their human bioavailability rate, and the supplementation dose as the primary moderator variables relating to the beneficial effects of (poly)phenol consumption on cognitive and brain function in humans. Therefore, it seems more advantageous to start anti-aging (poly)phenol interventions in adults earlier in life using medium (≈500 mg) to high doses (≈1000 mg) of phenolic compounds, with at least medium bioavailability rate (≥9%).
... Some of the major chemical constituents present in the PG aregallic acid, anthocyanins, ellagitannins, flavones, flavonoids, antocyanidins, sterols, quercitin, rutin, and other fatty acids [173]. The plant is of high value due to its anti-inflammatory [175], anti-carcinogenic [176,177], antioxidant [178,179], hypotensive [180], hypolipidaemic [181], anti-artheroseclerotic [182], and anti-diabetic activities [183]. PG is also used in the treatment of myocardial ischemia [184], prostrate cancer [185,186], dental plaques [187], denture stomatitis [188], bacterial infections [189,190], erectile dysfunctions [191], male infertility [192], alzheimer's disease [193], and ischemic brain injury [194,195]. ...
Ethno Pharmacological Relevance: Traditional medicinal plants are practiced worldwide for treatment of
arthritis especially in developing countries where resources are meager. This review presents the plants
profiles inhabiting throughout the world regarding their traditional usage by various tribes/ethnic groups for
treatment of arthritis. Materials and Methods: Bibliographic investigation was carried out by analyzing classical
text books and peer reviewed papers, consulting worldwide accepted scientific databases from the last six
decades. Plants/their parts/extracts/polyherbal formulations, toxicity studies for arthritis have been included
in the review article. The profiles presented also include information about the scientific name, family, dose,
methodology along with mechanism of action and toxicity profile. Research status of 20 potential plant species
has been discussed. Further, geographical distribution of research, plants distribution according to families has
been given in graphical form. Results: 485 plant species belonging to 100 families, traditionally used in arthritis
are used. Among 100 plant families, malvaceae constitute 16, leguminasae 7, fabaceae 13, euphorbiaceae
7, compositae 20, araceae 7, solanaceae 12, liliaceae 9, apocynaceae, lauraceae, and rubiaceae 10, and
remaining in lesser proportion. It was observed in our study that majority of researches are carried mainly in
developing countries like India, China, Korea and Nigeria. Conclusion: This review clearly indicates that list of
medicinal plants presented in this review might be useful to researchers as well as practioners. This review
can be useful for preliminary screening of potential anti-arthritis plan
... On the other hand, iNOS is an isoform of nitric oxide synthase (NO), which mainly contributes to mucosal damage. 55 These findings are in line with previous findings. 24,56 Pretreatment of rats with Antodine or the two doses of the DCM-L fraction of Murcott mandarin ameliorated the gastric ulcer by increasing the PGE 2 levels and decreasing the iNOS levels. ...
Stem (S), leaf (L) and fruits peel (P) of Murcott mandarins were separately extracted using 80% ethanol and then fractionated to dichloromethane (DCM) and ethyl acetate (ET) fractions. Their metabolomics profiling by HPLC-PDA-ESI-MS/MS was studied and afforded a tentative characterization of 98 compounds regarding to free organic acids, phenolic acid derivatives, flavonoid aglycones, flavonoid glycosides, flavonoids containing 3-hydroxyl-3-methylglutaroyl (HMG) units, coumarin derivatives and limonoids. Column chromatography resulted in isolation of six metabolites for the first time that identified as 4՝- demethylnobiletin, nobiletin, isosinensetin, limonin, stigmasterol-O-glucoside and hesperidin, respectively. In vitro anti-inflammatory activity against cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX) enzymes revealed that DCM- L showed a higher activity than other tested fractions. In vivo gastroprotective effect of that fraction using alcohol induced gastric ulcer in rats was evaluated. Where, the obtained finding validated the gastroprotective and anti-ulcerogenic activity of DCM-L through its anxiolytic, anti-inflammatory, antioxidant and anti-apoptotic effects. So, we recommended the use of Murcott mandarin leaves as a part of protection strategy for gastric ulcer.
Dietary supplements are widely used among individuals exposed to hot environments, but whether their consumption confers any thermoregulatory effect is unclear. Therefore, we systematically evaluated the effect of dietary supplementation on key aspects of thermoregulation (core temperature [T core ] and sweating responses) in the heat. Three databases were searched in April 2024. After screening, 124 peer-reviewed articles were identified for inclusion within three separate meta-analyses: (1) peak T core ; (2) whole-body sweat rate (WBSR); (3) local sweat rate (LSR). The moderating effect of several variables (e.g. training and heat acclimation status), known to influence thermoregulatory function, were assessed via sub-analysis and meta-regression. There was no overall effect of the differing supplement types on WBSR ( p = 0.405) and LSR ( p = 0.769), despite taurine significantly increasing WBSR ( n = 3, Hedges’ g = 0.79, p = 0.006). Peak T core was significantly affected by supplement type ( p = 0.011), primarily due to caffeine’s small significant positive effect ( n = 30; Hedges’ g = 0.44, p < 0.001) and taurine’s ( n = 3, Hedges’ g = −0.66, p = 0.043) and oligonol’s ( n = 3; Hedges’ g = −0.50, p = 0.014) medium significant negative effects. Dietary supplements, such as amino acids (e.g. taurine), some anti-oxidants and anti-inflammatories (e.g. oligonol) conferred the greatest thermoregulatory benefits during heat exposure. Taurine ingestion in such conditions may lower heat strain, which is likely through its augmentation of thermal sweating. Conversely, caffeine intake may potentially pose the greatest risk in the heat due to its effect on T core .
Pomegranate (Punica granatum), commonly known as "Anar", is an ancient fruit. It is preferably consumed due to its pleasing taste and high nutritious value along with some other associated health benefits. These benefits are not only meant for human beings, however, also for the fish. In recent times, scientific interest in pomegranate and its consumption has increased due to its numerous health benefits. Therefore, the current study aimed to review the most recent literature on different properties of the pomegranate. These properties include antimicrobial and antioxidant activities, its effect on hematological and growth parameters along with the role of pomegranate as a preservative in fish and fish products. The current study evaluated previously conducted studies to determine the effect of pomegranate on different systems of fish. Results showed that the intake of pomegranate effectively increased the growth of juvenile fish and dietary value of fish, boosted the hematological and immune responses, as well as feed efficiency and antioxidant activity. Moreover, it also showed antioxidant properties and proved effective for the preservation of fish fillets by reducing lipid oxidation, chemical degradation, and microbial growth in stored fish. Therefore, the incorporation of pomegranate in fish food has numerous applications. However, additional research is required to ascertain the safe limits.
Interest in the role of dietary nitrate in human health and disease has grown exponentially in recent years. However, consensus is yet to be reached as to whether consuming nitrate from various food sources is beneficial or harmful to health. Global authorities continue to recommend an acceptable daily intake (ADI) of nitrate of 3.7 mg/kg-bw/day due to concerns over its carcinogenicity. This is despite evidence showing that nitrate consumption from vegetable sources, exceeding the ADI, is associated with decreased cancer prevalence and improvements in cardiovascular, oral, metabolic and neurocognitive health. This review examines the paradox between dietary nitrate and health and disease and highlights the key role of the dietary source and food matrix in moderating this interaction. We present mechanistic and epidemiological evidence to support the notion that consuming vegetable-derived nitrate promotes a beneficial increase in nitric oxide generation and limits toxic N-nitroso compound formation seen with high intakes of nitrate added during food processing or present in contaminated water. We demonstrate the need for a more pragmatic approach to nitrate-related nutritional research and guidelines. Ultimately, we provide an overview of our knowledge in this field to facilitate the various therapeutic applications of dietary nitrate, whilst maintaining population safety.
Pomegranate juice (PJ) has a possible anti‐inflammatory effect because of its polyphenol content and antioxidants. However, the anti‐inflammatory effect of PJ in randomized controlled trials (RCTs) has not been consistent. A previous meta‐analysis conducted in 2016 reported a nonsignificant lowering effect of PJ on C‐reactive protein (CRP) levels. This systematic review and meta‐analysis aim to update the pooled effect size of PJ supplementation on CRP levels in RCT studies. PubMed, Scopus, and Web of Science databases were comprehensively searched until July 2023. Eligible studies were found by screening, their relevant data was extracted, and a risk of bias assessment was performed. The pooled effect size was calculated using a random effect model as the weighted mean difference (WMD) with a 95% confidence interval. This systematic review included 11 studies with 13 effect sizes and 696 participants. Meta‐analysis showed that PJ supplementation led to a significant decrease in CRP levels compared to control groups (WMD: −2.55 mg/L; 95%CI: −3.44 to −1.66; p < 0.001). Subgroup analysis demonstrated the significant reduction effect of PJ on CRP levels in studies conducted on the both sexes or only females as well as Iranian population, individuals with 40 years≤, type 2 diabetes, polycystic ovary syndrome, or trials that intervened with PJ dosage of <250 ml/day. Meta‐regression and dose–response analysis reported a nonsignificant linear and nonlinear relationship between intervention characteristics (duration and dose of PJ) and CRP changes. The current meta‐analysis revealed that PJ supplemantation has a beneficial effect in improving CRP levels. It is recommended to understand this effect better, and find the optimal dose and duration of PJ supplementation to reduce CRP levels in the blood, and repeat meta‐analysis after related RCTs are available. For the final proof of these effects, more detailed human studies are needed.
Approximately one in twenty men have sperm counts low enough to impair fertility but little progress has been made in answering fundamental questions in andrology or in developing new diagnostic tools or management strategies in infertile men. Many of these problems increase with age, leading to a growing population of men seeking help. To address this, there is a strong movement towards integrating male reproductive and sexual healthcare involving clinicians such as andrologists, urologists, endocrinologists and counselors. This book will emphasize this integrated approach to male reproductive and sexual health throughout the lifespan. Practical advice on how to perform both clinical and laboratory evaluations of infertile men is given, as well as a variety of methods for medically and surgically managing common issues. This text ties together the three major pillars of clinical andrology: clinical care, the andrology laboratory, and translational research.
This study was designed to investigate the probable role of pomegranate seed oil as
antioxidant in ameliorating the harmful effects of methionine overload on
cardiovascular function of adult female rabbits. Thirty-two female rabbits were
randomly assigned into four equal groups (eight animals each) and treated for 42 days
daily as follows: the first group was drenched drinking corn oil, serving as control (group
C), the second group (G1) was intubated orally with methionine 100mg/kg. B.W, while
the third group (G2) was intubated orally with methionine 100mg/kg. B.W and
pomegranate seed oil (PSO)30 mg /Kg. B.W, while the animals in the group(G3) were
intubated orally with pomegranate seed oil 30 mg /Kg. B.W. After fasting the animal's
blood samples were collected at 0, 21and 42 days of the experiment to assess: serum
troponin I and calcium concentrations .The electrocardiographs (ECG) were recorded for
rabbits in all experimental groups at the same interval of the experiment .The results
showed a significant increase in concentrations of serum troponin-I and calcium ions in
group G1 after 42 days of the experiment. The analysis of ECG in rabbits treated with
methionine (groupG1) showed a significant decrease in p wave, QRS wave, and T wave
amplitude, as well as a significant increase in QRS and T wave interval as well as significant
prolongation in P-Q and Q-T interval. PSO maintains the normal shape of QRS
waves and prevents the prolongation of Q-T interval in group G3 and it was less effective in
group G2 where the oil failed to restore the normal level of P, P-Q, and Q-T waves. In conclusion,
the deleterious effects of methionine overload on heart function are represented by
the abnormality of the ECG component and documented the cardioprotective role of PSO.
KEYWORDS: Pomegranate seed oil, ECG, Troponin-I, Heart rate, Calcium.
Patients undergoing maintenance dialysis have a significantly higher incidence of cardiovascular disease (CVD) compared with the general population. CVD is the most common cause of morbidity and mortality among hemodialysis patients, and has been attributed, among other causes, to increased oxidative stress, inflammation, hypertension and dyslipidemia. Pomegranate, a popular fruit worldwide, has demonstrated health benefits such as antioxidative, antidiabetic, antihypertensive, antihyperlipidemic and anti-inflammatory effects. In this systematic review of clinical trials, we aim to summarize the effect of different parts of pomegranate and the effects of its use on CVD risk factors in hemodialysis patients. PubMed/MEDLINE, EMBASE, Scopus, and Web of Science were searched to identify eligible clinical trials up to December 2021. Ultimately, seven clinical trials were included in this study. Different parts of pomegranate used in these trials were pomegranate juice, pomegranate extract and pomegranate peel extract. The duration of the studies varied from one dialysis session to 1 year. Our results showed that different parts of pomegranate may have anti-hypertensive, antioxidant, anti-inflammatory effects and improve lipid profile by decreasing TG (triglycerides) and increasing HDL-C (high-density lipoprotein cholesterol) in hemodialysis patients. However, due to limited number of studies, more clinical trials need to be performed.
Pomegranate (Punica granatum L.) is associated with numerous health benefits due to its high levels of antioxidant polyphenolic substances. Since pomegranate extract has been shown to inhibit angiotensin-converting enzyme (ACE), the potential inhibitory effect of most of its main constituents against ACE is unknown. Therefore, we tested the activities of 24 major compounds, the majority of which significantly inhibited ACE. Notably, pedunculagin, punicalin, and gallagic acid were the most effective ACE inhibitors with IC50 values of 0.91, 1.12, and 1.77 μM, respectively. As demonstrated in molecular docking studies, compounds block ACE by forming multiple hydrogen bonds and hydrophobic interactions with catalytic residues and zinc ions in ACE's C- and N-domains, consequently inhibiting ACE's catalytic activity. Also, the most active pedunculagin stimulated nitric oxide (NO) production, activated the endothelial nitric oxide synthase enzyme (eNOS), and significantly increased eNOS protein expression levels up to 5.3-fold in EA.hy926 cells. Furthermore, pedunculagin increased in cellular calcium (Ca2+) concentration promoted eNOS enzyme activation and reduced the production of reactive oxygen species (ROS). In addition, the active compounds improved glucose uptake in insulin-resistant C2C12 skeletal muscle cells in a dose-dependent manner. The results of these computational, in vitro, and cellular experiments provide further evidence to the traditional medicine that involves using pomegranates to treat cardiovascular diseases like hypertension.
Pomegranate (Punica granatum L.) is a useful fruit which mostly consumed as fresh fruit and can also be used as a various of processed products. Reports proved pomegranate were beneficial to health. Polyphenolic compounds in pomegranate especially ellagitannin (hydrolyzed), anthocyanins, gallotannin,and ellagic acid can maintain oral hygiene, healthy skin from the effects of free radicals caused by UV radiation, has the ability to synthesize cholesterol, destroying free radicals in the human vascular system and can prevent prostate cancer. In vitro and in vivo test has shown the fruit is acting as anti diabetic drug, and hypolipidemic, anticarcinogenic, antibacterial, anti inflamation, and antiviral. This review presenting an overview about the bioactive compound contents, physiological and health function of the fruit.
A sedentary lifestyle has evoked a high risk of cardiovascular (CV) disease, diabetes, and obesity, all of them with high morbimortality rates and with a common denominator, hypertension. Numerous pharmacological drugs have been used for the treatment of hypertension. However, the side effects associated with the use of existing pharmacological therapies have triggered a demand for plant-based medications. In this connection, the aim of this review was to provide an in-depth analysis of the use of plant-derived bioactives for the effective management of hypertension. Phytoconstituents from leaves, bark, stem, roots, seeds, and fruits of medicinal plants grown in our different regions of the globe have been highly searched. Among them, polyphenols (e.g., flavonoids as quercetin, anthocyanins as cyanidin, tannins as ellagic acid, stilbenes as resveratrol, lignans as honokiol and others as hydroxytyrosol or curcumin), organosulfur compounds (e.g. s-allyl cysteine and allicin), fatty acids (e.g. α-lipoic acid, DHA and oleic acid), alkaloids (e.g. berberine or tetrandrine) and some terpenes have been intensively investigated for the management of hypertension, with effective ability being stated in controlling high blood pressure and related health problems both in vivo and in vitro studies. Some of the activities presented by these bioactive compounds are reducing oxidative stress, renin-angiotensin system control, SIRT1 activation, regulating platelet aggregation and COX activity, anti-atherogenic effects, anti-inflammatory properties, vasorelaxation and other results that translate into the prevention or control of hypertension. The knowledge of these bioactive compounds is important in developing countries where traditional medicine is the majority, but it can also give rise to new approaches in hypertension therapy.
Punicacae ailesinin bir üyesi olan nar, Punica granatum L., tıpkı diğer pek çok bitki gibi antik çağdan günümüze kadar ulaşan, tıbbi amaçlı olarak kullanıldığı bilinen, yenilebilir bir meyvedir. Narın kökleri, çiçeği, meyvesi, kabuğu, aril (çekirdek) ve diğer kısımları sağlık sektöründe aktif olarak kullanılmaktadır. Bu güncel çalışmanın amacı geçmişten günümüze fonksiyonel besin olarak tüketilebilen narın sağlığa olan etkilerinin farklı alt başlıklarda değerlendirilmesidir. Nar ve yan ürünleri anti-bakteriyel, anti-oksidan, anti-kanser, anti-obezite, anti-nörodejeneratif, anti-aterosklerotik, yara iyileşmesi gibi pek çok alanda kullanılmakta ve her geçen gün narın tıbbi kullanımına olan ilgi artmaktadır. Nar meyvesine bu fonksiyonelliği veren içindeki flavonoidler, polifenoller, ellajitaninler (gallik asit, ellajik asit, punikalin, punikalagin, luteolin, kuersetin, kamferol, glikosid, pedunkulagin) gibi fenolik maddelerdir. Bu maddeler sayesinde nar, kan glikoz düzeyini azaltma, kanser hücrelerinde apoptozisi arttırma, LDL ve total kolesterol gibi bazı kan yağları düzeylerini ve bel çevresini azaltma, nöroinflamasyonu azaltma ve oksidatif stresi azaltarak antioksidan etkiyi arttırma gibi etkilere sahiptir. Narda bulunan aktif maddelerin ilaç etkileşimlerine neden olup olmadığı halen tartışmalıdır. Nar ve türevlerinin özellikle anjiyotensin dönüştürücü enzimi (ACE) inhibe eden ilaçlar, antihipertansifler, karbamazepin, CYP 2D6 substratları, varfarin, rosuvastatin ve tolbutamit ile etkileşime girebileceği bilinmeli ve dikkatli olunmalıdır. Narın farklı kısımlarının içinde bulunan punikalagin ve punikalin başta olmak üzere bazı biyoaktif maddeler narın bu denli eşsiz olmasını sağlayan temel faktörlerdir.
Punica granatum (Family Lythraceae) comprises considerable content of phenolic components and it proves the antioxidant activity of pomegranate. Some clinical trial investigations display that consumption of pomegranate is able to boost the antioxidant status. This systematic review assessed the efficacy of pomegranate extract to reduce oxidative stress. Pomegranate was used in some studies as capsules (between 250 mg and 250 g) and some in liquid form (between 10 and 500 ml), and the follow-up duration varied from 3 weeks to 12 months. Standardized mean difference and its corresponding 95% confidence interval (CI) was used as the effect size of pomegranate supplementation on oxidative stress biomarkers. Based on the results, pomegranate decreased but it was not statistically significant and the same result was obtained for ox-LDL and POX 1. In addition, the results showed that pomegranate consumption can significantly increase GPX and TAC. Result of combination of on TBRAS showed significantly effect of pomegranate use on reduction of TBRAS. Since this study has evaluated mostly Eastern countries’ studies it could be concluded that pomegranate supplements are effective in modifying oxidative stress in Eastern countries. The evidence to support this study is low, therefore, needs the future studies to confirm the results.
انسان از دو بعد جسم و روح تشکیل یافته است و لازمه سعادت وی آن است که در هر دو بعد به کمال برسد . خداوند در قرآن کریم علاوه براینکه به بعد روحانی و معنوی آدمی برای هدایت اشاره نموده است؛ راهکارهایی نیز در جهت سلامتی و کمال جسم بیان داشته است. یکی از این راهکارها استفاده از میوه هایی است خداوند در قرآن کریم بدان اشاره کرده است. انار یکی از میوه های قرآنی است که خداوند در سه آیه از قرآن کریم به ذکر آن پرداخته و از سوی دیگر در احادیث و روایات اسلامی نیز خواص مفید و بسیاری از سوی معصومین (ع) برای این میوه بیان شده است. با پیشرفت علوم پزشکی و آزمایشگاهی یکی از زمینه های بررسی، نشان دادن خواص و فواید میوه ها بود و آزمایشات و بررسی های عدیده ای در این زمینه، به خصوص میوه انار انجام گرفت و نشان داد که انار یکی از میوه های مغذی در بهبود عملکرد بدن و پیشگیری کننده از بسیاری از بیماری ها می باشد. در این تحقیق سعی بر این است که با روش مروری و استفاده از منابع کتابخانه ای ابتدا آشنایی با انار و ویژگی های آن صورت گیرد و در ادامه به بررسی ذکر آن در قرآن کریم و خواص آن با توجه به احادیث و روایات و شواهد علمی و پزشکی بپردازیم. توصیه به استفاده از انار از سوی قرآن کریم و از سوی دیگر ذکر خواص و فواید آن از سوی معصومین(ع) که علوم پزشکی و تجربی با آزمایشات بسیار و مکرر توانست آنها را اثبات کند یکی از جنبه های اعجاز آور قرآن کریم و شأن والا و عظیم احادیث و روایات اسلامی است.
Erectile dysfunction (ED) is defined as an inability to achieve or maintain penile erection sufficiently enough for sexual performance. Sexual function involves an interplay between psychological, vascular, neurological, endocrine functions; thus the various etiologies of ED can be divided into psychosocial or organic causes. Current mainstays of treatment for ED are centered around enhancing levels of nitric oxide at the nerve terminal with pharmacologic agents such as phosphodiesterase inhibitors, followed by more invasive therapies such as intracavernosal injections and penile prosthesis. The market for supplements for ED has been growing in popularity and has warranted further investigation into mechanisms of action and efficacy. This chapter discusses several supplements that have been marketed as therapies for ED, their efficacies in clinical trials, as well as their mechanism of action on the biochemical level, safety profiles, and adverse effects.
The role of pomegranate on folk medicine has been largely established and in recent years a notable increase of scientific support has occurred. However, what is real? Evidence suggests that phenolic phytochemicals of pomegranate fruit, mainly anthocyanins and ellagitannins, could exert multiple therapeutic properties on health management as playing an essential role in oxidative stress balance, preventing important cardiovascular diseases, and fighting as chemoprotective agent against several kinds of cancer. In addition, pomegranate antioxidant bioactives also could possess a role as neuroprotectors in some neurological disorders just as broad antimicrobial activities among other beneficial implications. Regarding promising prospects of pomegranate phenolics, this review summarizes the available scientific information related to health promotion features of pomegranate-derived products and underlines the influence of multiple constituents on the observed biological actions, pointing out pomegranate juice as an interesting source to obtain health benefits.
Ethnopharmacological relevance
Pomegranate, Punica granatum L., has been used in traditional medicine in China and several regions of the world including Ayurveda, Islamic, and Persian for the treatment of atherosclerosis, diabetes, hypertension, hyperlipidemia, and several types of cancer, as well as for peptic ulcer and oral diseases for hundreds of years. Presently, pomegranate is treated as both a “medicine food homology” herbal medicine and a healthy food supplemental product.
Aim of the study
The aim of this work is to develop an overview of pomegranate in the context of the status of its traditional medicine theories, the spread along the Silk Road, ethnopharmacological uses, chemical compositions, pharmacological activities, toxicology, and the involved pathways.
Materials and Methods
Information on P. granatum L. was acquired from published materials, including monographs on medicinal plants, ancient and modern recorded classical texts; and pharmacopoeias and electronic databases (PubMed, Science Direct, Web of Science, Google Scholar, CNKI, and Wanfang Data).
Results
Pomegranate has been used in many traditional medical systems throughout history. It is widely cultivated in Central Asia and spread throughout China along the Silk Road. Many phytochemicals, such as tannins, organic acids, flavonoids, alkaloids, and volatile oils have been identified from different parts of pomegranate, these compounds have a wide range of activities, including antioxidant, antimicrobial, and anti-oncogenic properties, as well as conferring resistance to cerebrovascular disease. Furthermore, A summary of the four promising pharmacological pathways is provided.
Conclusions
The traditional uses, chemical compositions, pharmacological activities, and signaling pathways of pomegranate are summarized comprehensively in the review. It can be treated as a guidance for the future clinical and basic research. The information provided in this review will be very useful for further studies to develop novel therapeutic directions for application of pomegranate.
Bu çalışmada, karbon tetraklorür (CCl4) ile kronik karaciğer hasarı oluşturulan ratlarda nar çekirdeği yağının (NÇY) karaciğer dokusunda oluşabilecek lezyonlar üzerine koruyucu etkisi ve biyokimyasal değerleri araştırılmıştır.Çalışmada 32 adet, her grupta 8 rat olmak üzere 4 gruba ayrıldı. İlk grup kontrol olarak belirlendi. İkinci gruba 12 hafta her gün 2 ml/kg dozunda NÇY gavaj ile verildi. Üçüncü gruba dilüe edilen 0.2 ml/kg iki doz CCl4 her hafta 3 gün ara ile intraperitoneal olarak enjekte edildi. Dördüncü gruba 2 ml/kg dozunda NÇY 12 hafta her gün, gavaj ile verilirken her hafta 3 gün ara ile 2 doz CCl4 uygulandı.Kontrol gruplarında normal karaciğer doku yapısı gözlenirken; CCl4+NÇY grubu hepatositlerde CCl4 grubuna göre daha az yoğunlukta makro ve mikroveziküler yağ vakuolleri görüldü. NÇY uygulamalarında histopatolojik değişiklikler kısmen CCl4 grubuna göre kısmen azalırken, kaspaz 3 ve 9 aktivitesi de sınırlı sayıda azaldı. Kronik olarak CCl4 uygulanan gruplarda serum ALT aktivitesi ve karaciğer MDA düzeyleri önemli düzeyde artış gösterirken, NÇY uygulamaları istatistiki önemde etkilenmedi.Kronik CCl4 ile NÇY verilen deney gruplarında karaciğer hasarı üzerinde biyokimyasal veriler ve histopatolojik lezyonlar üzerine iyileştirici yönden anlamlı bir etkisi gözlenmedi.
The purpose of this study was to determine if chronic administration of L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), normalizes endothelium-dependent relaxation and decreases atherosclerosis in hypercholesterolemic animals. Male rabbits were fed (a) normal rabbit chow; (b) 1% cholesterol diet; or (c) 1% cholesterol diet supplemented by 2.25% L-arginine HCl in drinking water. Arginine supplementation doubled plasma arginine levels without affecting serum cholesterol values. After 10 wk, the thoracic aorta was harvested for studies of vascular reactivity and histomorphometry. Endothelium-dependent relaxations (to acetylcholine and calcium ionophore A23187) were significantly impaired in thoracic aortae from animals fed a 1% cholesterol diet. By contrast, vessels from hypercholesterolemic animals receiving L-arginine supplementation exhibited significantly improved endothelium-dependent relaxations. Responses to norepinephrine or nitroglycerin were not affected by either dietary intervention. Histomorphometric analysis revealed a reduction in lesion surface area and intimal thickness in thoracic aortae from arginine-supplemented animals compared to those from untreated hypercholesterolemic rabbits. This is the first study to demonstrate that supplementation of dietary L-arginine, the EDRF precursor, improves endothelium-dependent vasorelaxation. More importantly, we have shown that this improvement in EDRF activity is associated with a reduction in atherogenesis.
This study was designed to test the hypothesis that long-term oral supplementation of dietary L-arginine (to provide a sustained elevation of nitric oxide activity) would inhibit atherogenesis in hypercholesterolemic rabbits, as assessed by histomorphometric measurements.
Endothelium-derived nitric oxide inhibits a number of processes that are critical in atherogenesis. Hypercholesterolemia reduces endothelial nitric oxide activity, and we postulate that this may promote atherogenesis. This reduction in nitric oxide activity can be reversed acutely by intravenous infusion of L-arginine, the precursor of nitric oxide. We show that dietary supplementation of L-arginine abrogates the development of coronary atheroma in hypercholesterolemic rabbits.
Male New Zealand White rabbits were fed normal rabbit chow, 1% cholesterol chow or 1% cholesterol chow with dietary arginine or methionine supplementation to increase their intake of these amino acids sixfold. After 1 or 10 weeks of dietary intervention, the left main and left anterior descending coronary arteries were harvested for histologic study. Plasma cholesterol measurements were elevated to the same degree in all groups of rabbits receiving the 1% cholesterol diet, whereas plasma arginine levels were doubled in the arginine-treated group. High density lipoprotein (HDL) cholesterol values were not affected by arginine treatment.
In rabbits receiving the 1% cholesterol diet, with or without methionine supplementation, light and electron microscopy revealed a marked increase from 1 to 10 weeks in the intimal accumulation of macrophages, associated with an increase in the intimal area of the left main coronary artery. By contrast, in arginine-treated hypercholesterolemic rabbits, there was a near absence of adherent monocytes and tissue macrophages and no progression of intimal thickness from 1 to 10 weeks.
Dietary supplements of L-arginine prevent intimal thickening in the coronary arteries of hypercholesterolemic rabbits. This antiatherogenic effect is not due to an alteration in plasma total cholesterol, HDL cholesterol or caloric or nitrogen balance. The data are consistent with the hypothesis that nitric oxide has antiatherogenic properties.
The antioxidant activity of pomegranate juices was evaluated by four different methods (ABTS, DPPH, DMPD, and FRAP) and compared to those of red wine and a green tea infusion. Commercial pomegranate juices showed an antioxidant activity (18-20 TEAC) three times higher than those of red wine and green tea (6-8 TEAC). The activity was higher in commercial juices extracted from whole pomegranates than in experimental juices obtained from the arils only (12-14 TEAC). HPLC-DAD and HPLC-MS analyses of the juices revealed that commercial juices contained the pomegranate tannin punicalagin (1500-1900 mg/L) while only traces of this compound were detected in the experimental juice obtained from arils in the laboratory. This shows that pomegranate industrial processing extracts some of the hydrolyzable tannins present in the fruit rind. This could account for the higher antioxidant activity of commercial juices compared to the experimental ones. In addition, anthocyanins, ellagic acid derivatives, and hydrolyzable tannins were detected and quantified in the pomegranate juices.
Ornithine decarboxylase is the initial and rate-limiting enzyme in the polyamine biosynthetic pathway. Polyamines are found
in all mammalian cells and are required for cell growth. We previously demonstrated that N-hydroxyarginine and nitric oxide inhibit tumor cell proliferation by inhibiting arginase and ornithine decarboxylase, respectively,
and, therefore, polyamine synthesis. In addition, we showed that nitric oxide inhibits purified ornithine decarboxylase by
S-nitrosylation. Herein we provide evidence for the chemical mechanism by which nitric oxide and S-nitrosothiols react with cysteine residues in ornithine decarboxylase to form an S-nitrosothiol(s) on the protein. The diazeniumdiolate nitric oxide donor agent 1-diethyl-2-hydroxy-2-nitroso-hydrazine acts
through an oxygen-dependent mechanism leading to formation of the nitrosating agents N2O3 and/or N2O4. S-Nitrosoglutathione inhibits ornithine decarboxylase by an oxygen-independent mechanism likely byS-transnitrosation. In addition, we provide evidence for the S-nitrosylation of 4 cysteine residues per ornithine decarboxylase monomer including cysteine 360, which is critical for enzyme
activity. Finally S-nitrosylated ornithine decarboxylase was isolated from intact cells treated with nitric oxide, suggesting that nitric oxide
may regulate ornithine decarboxylase activity by S-nitrosylation in vivo.
Arginase, which exists as the isoforms arginase I and II, catalyzes the hydrolysis of arginine to ornithine and urea. Ornithine is the principal precursor for production of polyamines, which are required for cell proliferation. Rat aortic smooth muscle cells (RASMC) contain constitutive arginase I, and arginase inhibitors cause inhibition of cell proliferation. The objective of this study was to determine whether the elevated expression of arginase I in RASMC causes increased cell proliferation. RASMC were stably transfected with either rat arginase I cDNA or a beta-galactosidase control expression plasmid. Western blots and arginase enzymatic assays revealed high-level expression of cytosolic arginase I in arginase I-transfected RASMC. Moreover, this observation was associated with the increased production of urea and polyamines and higher rates of RASMC proliferation. The two selective inhibitors of arginase, N(G)-hydroxy-l-arginine and S-(2-boronoethyl)-l-cysteine, inhibited arginase and decreased the production of urea and polyamines in arginase I-transfected RASMC, all of which were associated with the inhibition of cell proliferation. This study demonstrates that elevated arginase I expression increases RASMC proliferation by mechanisms involving increased production of polyamines. These observations suggest that arginase I plays a potentially important role in controlling RASMC proliferation.
The effects of chronic treatment with nitric oxide-containing aspirin (NO-aspirin, NCX-4016) in comparison with regular aspirin or placebo on the development of a chronic disease such as atherosclerosis were investigated in hypercholesterolemic low-density lipoprotein (LDL)-receptor-deficient mice. Male mice were assigned randomly to receive in a volume of 10 ml/kg either placebo (n = 10), 30 mg/kg/day NO-aspirin (n = 10), or 18 mg/kg/day of regular aspirin (n = 10). After 12 weeks of treatment, the computer-assisted imaging analysis revealed that NO-aspirin reduced the aortic cumulative lesion area by 39.8 +/- 12.3% compared with that of the placebo (P < 0.001). Regular aspirin did not reduce significantly aortic lesions (-5.1 +/- 2.3%) compared with the placebo [P = 0.867, not significant (NS)]. Furthermore, NO-aspirin reduced significantly plasma LDL oxidation compared with aspirin and placebo, as shown by the significant reduction of malondialdehyde content (P < 0.001) as well as by the prolongation of lag-time (P < 0.01). Similarly, systemic oxidative stress, measured by plasma isoprostanes, was significantly reduced by treatment with NCX-4016 (P < 0.05). More importantly, mice treated with NO-aspirin revealed by immunohistochemical analysis of aortic serial sections a significant decrease in the intimal presence of oxidation-specific epitopes of oxLDL (E06 monoclonal antibody, P < 0.01), and macrophages-derived foam cells (F4/80 monoclonal antibody, P < 0.05), compared with placebo or aspirin. These data indicate that enhanced NO release by chronic treatment with the NO-containing aspirin has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic mice.
Atherogenesis is enhanced in arterial segments exposed to disturbed blood flow, indicating the active participation of the hemodynamic environment in lesion formation. Turbulent shear stress selectively regulates responsive genes in the endothelium and increases the damage induced by free radicals. The purpose of the present study was to evaluate the effects of intervention with antioxidants and l-arginine on endothelial NO synthase (eNOS) and oxidation-sensitive gene perturbation induced by disturbed flow in vitro and in vivo. Both human endothelial cells exposed to shear stress and high atherosclerosis-prone areas of hypercholesterolemic low-density lipoprotein receptor knockout (LDLR(-/-)) mice showed increased activities of redox-transcription factors (ELK-1, p-Jun, and p-CREB) and decreased expression of eNOS. Intervention with antioxidants and l-arginine reduced the activation of redox-transcription factors and increased eNOS expression in cells and in vivo. These results demonstrate that atherogenic effects induced by turbulent shear stress can be prevented by cotreatment with antioxidants and l-arginine. The therapeutic possibility to modulate shear stress-response genes may have important implications for the prevention of atherosclerosis and its clinical manifestations.
Atherosclerosis is the major cause of death and disability in the United States, Europe, and much of Asia. The lesions of atherosclerosis have a nonuniform distribution in the vasculature and are prone to develop at bends, branches, and bifurcations of the aorta and its conduit arteries. At these sites in the vasculature laminar flow is disturbed by recirculation, which resembles an eddy at a river branch. Here the endothelium of the blood vessel is exposed to reduced and oscillating flow, a hemodynamic condition that produces physicochemical and biological alterations predisposing to atherogenesis (Fig. 1). Recirculation causes an increase in particle residence time, so that lipoproteins and monocytes (the anlagen of atherosclerosis) have greater contact with the endothelium in these regions (1). The endothelium itself is morphologically altered. In relatively straight segments of a conduit vessel, endothelial cells are regularly aligned, each cell with its longitudinal axis oriented in the direction of flow. By contrast, in areas of disturbed flow, the usual orientation of endothelial cells is lost, and the cells become more polygonal in appearance. Intriguingly, endothelial cells at branch points appear to age faster. Endothelial cells exposed to disturbed flow in vitro turn over more rapidly (2). In human iliac arteries, endothelial cells at the bifurcation have shorter telomeres, consistent with a focal acceleration of senescence (3). Senescent human endothelial cells produce less nitric oxide (NO⋅), generate more superoxide anion (O), and are more adhesive for monocytes, effects that can be reversed by transfection with the gene encoding telomerase (4).
The pathogenic mechanisms by which physical exercise influences atherosclerotic lesion formation remain poorly understood. Because vigorous physical training increases oxidative stress, this study tested the hypothesis that graduated and moderate physical exercise together with metabolic intervention (l-arginine and antioxidants) may contribute to increased vascular protection. Exercise training in mice was induced by graduated swimming. In hypercholesterolemic male mice on an atherogenic high-cholesterol diet, graduated and moderate exercise lowered plasma cholesterol and decreased atherosclerotic lesions compared with sedentary control mice. Antioxidants (1.0% vitamin E added to the chow and 0.05% vitamin C added to the drinking water) and l-arginine (6% in drinking water) supplementation to exercising hypercholesterolemic mice further and synergistically reduced atherosclerosis compared with untreated exercised mice. Arterial oxidation-specific epitopes and systemic oxidative stress were reduced by metabolic intervention. Graduated chronic exercise elicited an increase in production of nitric oxide through increased endothelial nitric oxide synthase expression and ameliorated scavenger activities. Thus, metabolic intervention with l-arginine and antioxidants together with graduated and moderate exercise training reduce atherosclerotic lesion formation.
• catalase
• nitric oxide synthase
• vitamin E
• oxidative stress
• low-density lipoprotein
This chapter provides an overview of the basic principles involved in the field of nitric oxide (NO) research. It is one of the smallest and simplest of biologically active molecules in nature. As one of the most widespread signaling molecules in the mammal, it is a major player in controlling nearly every cellular and organ function in the body. NO is the only endogenous molecule that functions as a neurotransmitter, autacoid, constitutive mediator, inducible mediator, cytoprotective molecule, and cytotoxic molecule. Certain physiological functions, such as vasodilation and smooth muscle relaxation, are mediated by multiple mechanisms of NO release and action. Furthermore, NO can promote biological actions by cyclic GMP-dependent and independent molecular mechanisms. Because it plays multiple physiological roles in regulating numerous and diverse organ functions, defects in the pathway lead to the development of many different pathophysiological states. These disorders include hypertension, atherosclerosis, coronary artery disease, cardiac failure, pulmonary hypertension, stroke, impotence, vascular complications in diabetes mellitus, gastrointestinal ulcers, asthma, and other central nervous system and systemic disorders. Nearly all small and large pharmaceutical companies have established research and development programs for discovery of novel therapeutic strategies for NO-based disorders.
Objective:
To determine whether flavonoid intake explains differences in mortality rates from chronic diseases between populations.Design:
Cross-cultural correlation study.Setting/Participants:
Sixteen cohorts of the Seven Countries Study in whom flavonoid intake at baseline around 1960 was estimated by flavonoid analysis of equivalent food composites that represented the average diet in the cohorts.Main Outcome Measures:
Mortality from coronary heart disease, cancer (various sites), and all causes in the 16 cohorts after 25 years of follow-up.Results:
Average intake of antioxidant flavonoids was inversely associated with mortality from coronary heart disease and explained about 25% of the variance in coronary heart disease rates in the 16 cohorts. In multivariate analysis, intake of saturated fat (73%; P=.0001), flavonoid intake (8%; P=.01), and percentage of smokers per cohort (9%; P=.03) explained together, independent of intake of alcohol and antioxidant vitamins, 90% of the variance in coronary heart disease rates. Flavonoid intake was not independently associated with mortality from other causes.Conclusions:
Average flavonoid intake may partly contribute to differences in coronary heart disease mortality across populations, but it does not seem to be an important determinant of cancer mortality.(Arch Intern Med. 1995;155:381-386)
Estrone was isolated from pomegranate seeds and its identity was confirmed by thin-layer chromatography in three solvent systems and by four color reactions. Three derivatives were prepared and had the same chromatographic characteristics in three solvent systems as the corresponding derivatives from authentic estrone. The biological potency of this material was also comparable to that of estrone. Pomegranate seeds are the richest plant source of steroidal estrogens yet found.
The advanced lesions of atherosclerosis represent the culmination of a specialized form of chronic inflammation followed by a fibroproliferative process that takes place within the intima of the affected artery. Proliferation of smooth muscle cells and generation of connective tissue occur. Proliferation results from interactions between arterial smooth muscle, monocyte-derived macrophages, T lymphocytes, and endothelium. The initial lesion of atherosclerosis, the fatty streak, begins as an accumulation of monocytederived macrophages and T lymphocytes, which adhere and migrate into the intima of the affected artery. Smooth muscle cells, which are present in the intima or which migrate into the intima from the media, then replicate. Monocyte-derived macrophages and T cells also replicate during lesion formation and progression due to the production of cytokines and growth-regulatory molecules. These molecules determine whether there is proliferation and lesion progression or inhibition of proliferation and lesion regression. Several growthregulatory molecules may play critical roles in this process, including platelet-derived growth factor (PGDF), transforming growth factor beta, fibroblast growth factor, heparinbinding epidermal growth factor-like growth factor, and others. PDGF may be one of the principal components in this process because protein containing the PDGF B-chain has been demonstrated within activated lesion macrophages during every phase of atherogenesis. The presence of this growth factor and its receptors on lesion smooth muscle cells creates opportunities for smooth muscle chemotaxis and replication. Smooth muscle proliferation depends upon a series of complex signals based upon cellular interactions in the local microenvironment of the artery. The intracellular signalling pathways for mitogenesis versus chemotaxis are being investigated for smooth muscle. The roles of the cytokines and growth-regulatory peptides involved in these cellular interactions represent critical points of departure for intervention and the development of new diagnostic methods. In addition, magnetic resonance imaging has been developed to demonstrate the fine structure of lesions of atherosclerosis in peripheral arteries not subject to cardiac motion. This noninvasive methodology holds great promise for the future of these approaches.
To determine whether flavonoid intake explains differences in mortality rates from chronic diseases between populations.
Cross-cultural correlation study.
Sixteen cohorts of the Seven Countries Study in whom flavonoid intake at baseline around 1960 was estimated by flavonoid analysis of equivalent food composites that represented the average diet in the cohorts.
Mortality from coronary heart disease, cancer (various sites), and all causes in the 16 cohorts after 25 years of follow-up.
Average intake of antioxidant flavonoids was inversely associated with mortality from coronary heart disease and explained about 25% of the variance in coronary heart disease rates in the 16 cohorts. In multivariate analysis, intake of saturated fat (73%; P = 0.0001), flavonoid intake (8%, P = .01), and percentage of smokers per cohort (9%; P = .03) explained together, independent of intake of alcohol and antioxidant vitamins, 90% of the variance in coronary heart disease rates. Flavonoid intake was not independently associated with mortality from other causes.
Average flavonoid intake may partly contribute to differences in coronary heart disease mortality across populations, but it does not seem to be an important determinant of cancer mortality.
The antioxidant activity of pomegranate juices was evaluated by four different methods (ABTS, DPPH, DMPD, and FRAP) and compared to those of red wine and a green tea infusion. Commercial pomegranate juices showed an antioxidant activity (18−20 TEAC) three times higher than those of red wine and green tea (6−8 TEAC). The activity was higher in commercial juices extracted from whole pomegranates than in experimental juices obtained from the arils only (12−14 TEAC). HPLC-DAD and HPLC-MS analyses of the juices revealed that commercial juices contained the pomegranate tannin punicalagin (1500−1900 mg/L) while only traces of this compound were detected in the experimental juice obtained from arils in the laboratory. This shows that pomegranate industrial processing extracts some of the hydrolyzable tannins present in the fruit rind. This could account for the higher antioxidant activity of commercial juices compared to the experimental ones. In addition, anthocyanins, ellagic acid derivatives, and hydrolyzable tannins were detected and quantified in the pomegranate juices. Keywords: Pomegranate; Punica granatum; Punicaceae; juice; phenolics; anthocyanins; ellagic acid; punicalagin; tannins; antioxidant activity; ABTS; DPPH; DMPD; FRAP
L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce the progression of atherosclerosis in cholesterol-fed rabbits. In the present study, we investigated whether myointimal cell proliferation is enhanced in hypercholesterolaemic rabbit aorta and whether chronic treatment of the rabbits with L-arginine or with the NO synthase inhibitor L-NAME influences this proliferative response and vascular monocyte accumulation. Rabbits were fed 1% cholesterol or normal rabbit chow for 12 weeks. Subgroups of cholesterol-fed rabbits were treated with oral L-arginine (2.25%) or L-NAME (3 mg/dl) in drinking water. Myointimal cell proliferation was quantified in aortic segments by immunohistochemical detection of bromodeoxyuridine (BrdU) incorporation into nuclear DNA; vascular monocyte accumulation was assessed by immunohistochemistry using a monoclonal anti-macrophage/monocyte antibody (RAM-11). Plasma levels of L-arginine and the endogenous NO synthase inhibitor, ADMA, were quantified by high-performance liquid chromatography (HPLC). Cholesterol feeding increased the aortic intima/media (I/M) ratio, which was not measurable in the control group, to 1.9 +/- 0.3. This was paralleled by enhanced cell proliferation (cholesterol, 2.4 +/- 0.2%; P < 0.05; control, 0.02 +/- 0.001% BrdU-positive cells per 72 h) and vascular monocyte accumulation. Double immunostaining for BrdU and alpha-actin showed that about two thirds of the proliferating cells were smooth muscle cells. ADMA levels increased from 0.8 +/- 0.1 micromol/l to 2.2 +/- 0.2 micromol/l in cholesterol-fed rabbits, but were unchanged by L-arginine or L-NAME treatment. Myointimal proliferation and intima/media ratios were correlated with ADMA plasma levels. Dietary L-arginine reduced monocyte accumulation by 85 +/- 2% (P < 0.05 vs cholesterol), myointimal cell proliferation (1.8 +/- 0.3% per 72 h; P < 0.05) and intimal thickening (I/M ratio: 0.7 +/- 0.2), whereas the inhibitor of NO synthase, L-NAME, further increased cell proliferation to 3.1 +/- 0.4% per 72 h (P < 0.05). No significant difference was observed in vascular monocyte infiltration between the cholesterol and L-NAME groups. We conclude that cell proliferation and vascular monocyte accumulation are enhanced in hypercholesterolaemic rabbit aorta. These atherogenic effects can be attenuated by dietary L-arginine. Decreased NO formation might underlie the enhanced monocyte accumulation and cell proliferation in hypercholesterolaemic rabbit aorta. The observed inhibition of cell proliferation adds to our understanding of the antiatherosclerotic effects of L-arginine in vivo.
Increased generation of oxidants, resulting from disruption of aerobic metabolism and from respiratory burst, is an essential defense mechanism against pathogens and aberrant cells. However, oxidative stress can also trigger and enhance deregulated apoptosis or programmed cell death, characteristic of atherosclerotic lesions. Oxidation-sensitive mechanisms also modulate cellular signaling pathways that regulate vascular expression of cytokines and growth factors, and influence atherogenesis, in particular when increased levels of plasma lipoproteins provide ample substrate for lipid peroxidation and lead to increased formation of adducts with lipoprotein amino acids. In some cases, increased oxidation and apoptosis in a group of cells might be beneficial for survival and function of other groups of arterial cells. However, overall, oxidation and apoptosis appear to promote the progression of diseased arteries towards a lesion that is vulnerable to rupture, and to give rise to myocardial infarction and ischemic stroke. Recent rapid advances in our understanding of the interactions between oxidative stress, apoptosis and arterial gene regulation suggest that selective interventions targeting these biological functions have great therapeutic potential.
This study examined whether constitutive nitric oxide (NO) synthase from rat cerebellum catalyzes the formation of equimolar amounts of NO plus citrulline from L-arginine under various conditions. Citrulline was determined by monitoring the formation of 3H-citrulline from 3H-L-arginine. NO was determined by monitoring the formation of total NOx (NO+nitrite [NO2-] + nitrate [NO3-]) by chemiluminescence after reduction of NOx to NO by acidic vanadium (III). Equal quantities of NO plus citrulline were generated from L-arginine and the formation of both products was linear for about 20 min at 37 degrees C provided L-arginine was present in excess to maintain a zero order reaction rate. Deletion of NADPH, addition of the calmodulin antagonist calmidazolium, or addition of NO synthase inhibitors (NG-methyl-L-arginine, NG-amino-L-arginine) abolished or markedly inhibited the formation of both NO and citrulline. The Km for L-arginine (14 microM; 18 microM) and the Vmax of the reaction (0.74 nmol/min/mg protein; 0.67 nmol/min/mg protein) were the same whether NO or citrulline formation, respectively, was monitored. These observations indicate clearly that NO and citrulline are formed in equimolar quantities from L-arginine by the constitutive isoform of NO synthase from rat cerebellum.
We evaluated the effect of a low level of hyperlipidemia and the effects of in vitro exposure to atherogenic lipoproteins (LDL, VLDL) on the vascular responsiveness of isolated porcine coronary arteries. Firstly we studied the change in vascular responsiveness induced by feeding a cholesterol-rich diet to pigs for 4 and 9 weeks (C4 and C9 pigs). The serum cholesterol level in pigs fed a cholesterol-rich diet reached 218.5 +/- 32.9 mg/dl compared with 85.5 +/- 8.4 mg/dl in the controls. Segments of the left descending coronary artery were examined. The contraction induced by KCl or prostaglandin F2 alpha was not altered significantly by hypercholesterolemia nor was the relaxation induced by the Ca2+ ionophore, A23187, or by nitroglycerin. Endothelium-dependent relaxation (EDR) evoked by high, but not low, concentrations of bradykinin was reduced in the C4 pigs as compared with those in normal animals. EDRs evoked by bradykinin, substance P, and serotonin were significantly reduced in C9 pigs. Histologically, as observed by light and electron microscopy, fatty changes or intimal thickenings were not seen in the coronary arteries of the C4 pigs. Minimal changes (intimal thickening and fragmentation of internal elastic lamina) were observed only in parts of arteries of the C9 pigs. Secondly, the direct effects of LDL and VLDL on vascular responsiveness were studied. Although preincubation with LDL inhibited the EDR caused by exposure to bradykinin and A23187 in the coronary arteries of normal and cholesterol-fed pigs, preincubation with LDL inhibited the arterial relaxation induced by exposure to substance P or serotonin in both the C4 and the C9 pigs, but not in the control animals. The degree of inhibition was especially marked in the C9 pigs. The inhibitory effect of VLDL on EDR was weaker than that of LDL. Indomethacin (5 microM) did not alter this inhibitory effect of lipoproteins. Neither LDL nor VLDL had any effect on the vascular relaxation induced by nitroglycerin. These results are consistent with the idea that endothelium-dependent arterial relaxation is attenuated even at the very early stage of cholesterol-induced atherosclerosis. Atherogenic lipoproteins may further impair the decreased EDR in the arteries of hyperlipidemic pigs by two factors: one released on stimulation with bradykinin and the calcium ionophore A23187, the other released on stimulation with substance P and serotonin.
Although nitric oxide (NO) appears to be one of the oxidation products of L-arginine catalyzed by NO synthase (NOS; EC 1.14.13.39), past studies on the measurement of NO in cell-free enzymatic assays have not been based on the direct detection of the free NO molecule. Instead, assays have relied on indirect measurements of the stable NO oxidation products nitrite and nitrate and on indirect actions of NO such as guanylate cyclase activation and oxyhemoglobin oxidation. Utilizing a specific chemiluminescence assay, we report here that the gaseous product of L-arginine oxidation, catalyzed by both inducible macrophage and constitutive neuronal NOS, is indistinguishable from authentic NO on the basis of their physicochemical properties. NO gas formation by NOS was dependent on L-arginine, NADPH, and oxygen and inhibited by NG-methyl-L-arginine and cyanide anion. Superoxide dismutase (SOD) caused a marked, concentration-dependent increase in the production of free NO by mechanisms that were unrelated to the dismutation of superoxide anion or activation of NOS. These observations indicate that free NO is formed as a result of NOS-catalyzed L-arginine oxidation and that SOD enhances the generation of NO without directly affecting NO itself. SOD appears to elicit a novel biological action, perhaps accelerating the conversion of an intermediate in the L-arginine-NO pathway such as nitroxyl (HNO) to NO.
The relative antioxidant activities, against radicals generated in the aqueous phase, of a range of plant-derived polyphenolic flavonoids, constituents of fruit, vegetables, tea and wine, have been assessed. The results show that compounds such as quercetin and cyanidin, with 3',4' dihydroxy substituents in the B ring and conjugation between the A and B rings, have antioxidant potentials four times that of Trolox, the vitamin E analogue. Removing the ortho-dihydroxy substitution, as in kaempferol, or the potential for electron delocalisation by reducing the 2,3 double bond in the C ring, as in catechin and epicatechin, decreases the antioxidant activity by more than 50%, but these structures are still more effective than alpha-tocopherol or ascorbate. The relative significance of the positions and extents of hydroxylation of the A and B rings to the total antioxidant activity of these plant polyphenolics is demonstrated.
Intimal hyperplasia that results from therapeutic revascularization is an important etiologic factor in the failure of these procedures (i.e., restenosis). Drugs which donate nitric oxide have been shown to inhibit the proliferation of vascular smooth muscle cells in vitro. We tested the hypothesis that administration of L-arginine (0.5 g/kg/day), the precursor of nitric oxide, would inhibit development of intimal hyperplasia following balloon catheter-induced injury. L-arginine administration from 2 days prior to and 2 weeks following catheter-induced injury to the rabbit thoracic aorta attenuated the development of intimal hyperplasia by 39% as compared with untreated controls. This effect was due to decreased intimal area. The effect of L-arginine was inhibited by co-administration of an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl ester (0.5 g/kg/day). These data demonstrate that L-arginine attenuates intimal hyperplasia and suggest that the mechanism for this effect is the conversion of L-arginine to nitric oxide.
Flavonoids, a group of naturally occurring antioxidants and iron chelators, might be used as cardioprotective agents in doxorubicin-induced cardiotoxicity, which is believed to be caused by the formation of oxygen free radicals. To investigate the underlying molecular mechanism, we tested a large group of flavonoids from all major structural subclasses on their ability to inhibit doxorubicin (enzymatically)-induced and Fe2+/ascorbate (nonenzymatically)-induced microsomal lipid peroxidation (LPO) and to chelate Fe2+. In addition, we measured half peak oxidation potentials (Ep/2). LPO inhibition data gave a good qualitative correlation with the oxidation potentials. Most flavonoids tested chelated Fe2+, but there were large differences in the chelating capacity. For good scavenging activity, a catechol moiety on ring B is required. The 3-OH moiety can function as a chelation site and can also be oxidized. The 3-OH group in combination with a C2 C3 double bond, increases the scavenging activity. Fe2+ chelation only plays a role in the LPO inhibition by less active scavengers. Chelation can then raise the activity to the level of the most active scavengers, possibly by site-specific scavenging. It can be concluded that Ep/2 values and iron chelating activity can almost completely describe the LPO inhibiting behaviour of the flavonoids.
The recent explosion of interest in the bioactivity of the flavonoids of higher plants is due, at least in part, to the potential health benefits of these polyphenolic components of major dietary constituents. This review article discusses the biological properties of the flavonoids and focuses on the relationship between their antioxidant activity, as hydrogen donating free radical scavengers, and their chemical structures. This culminates in a proposed hierarchy of antioxidant activity in the aqueous phase. The cumulative findings concerning structure-antioxidant activity relationships in the lipophilic phase derive from studies on fatty acids, liposomes, and low-density lipoproteins; the factors underlying the influence of the different classes of polyphenols in enhancing their resistance to oxidation are discussed and support the contention that the partition coefficients of the flavonoids as well as their rates of reaction with the relevant radicals define the antioxidant activities in the lipophilic phase.
1-Substituted diazen-1-ium-1,2-diolates have proved useful as tools in enzymology and other pharmacological research applications in which spontaneous generation of nitric oxide according to a reasonably well-defined time course is required. This chapter summarizes relevant physicochemical data, including the NO release rates and product profiles, for a selection of these compounds. Guidelines for quality control and a systematic nomenclature scheme are also presented. It is hoped that, in summarizing this information here, our chapter will help those contemplating new applications of diazeniumdiolate technology as they seek to capitalize on what we believe are the inherent advantages of this compound type in research on the pharmacological properties of nitric oxide.
L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce intimal plaque area in cholesterol (Chol)-fed rabbits. We have studied endogenous NO production in such animals in vitro (endothelium-dependent relaxations) and in vivo (assessed by urinary NO3- excretion) before and during chronic oral administration of L-arginine and inhibitor of NO synthesis, L-NAME. Vascular superoxide anion (O2-) production of aortic rings was measured under basal conditions and following exposure to phorbol-myristate-acetate (PMA). Cholesterol feeding reduced endothelium-dependent relaxations and decreased urinary NO3- excretion. These effects were potentiated by administration of L-NAME. L-arginine partly restored endothelium-dependent relaxations and increased NO3- excretion. PMA-stimulated O2- production was increased in aortic rings from rabbits given cholesterol ( +159 +/- 28%; mean +/- S.E.M.) or cholesterol + L-NAME ( +149 +/- 37%) as compared with controls ( -22 +/- 7%). In rabbits given cholesterol + L-arginine, O2- production was decreased to control levels ( +14 +/- 17%; P < 0.05). We conclude that the systemic synthesis of NO is impaired in cholesterol-fed rabbits, as indicated by the decreased urinary excretion of NO3-. Enhanced O2- production may further contribute to the decreased biological activity of NO in hypercholesterolaemia. L-arginine restores endothelial function in hypercholesterolaemia by enhancing NO production and by protecting NO from early breakdown by O2-.
Epidemiologic studies have provided evidence of an inverse relation between coronary artery disease and antioxidant intake, and vitamin E supplementation in particular. The oxidative-modification hypothesis implies that reduced atherosclerosis is a result of the production of LDL that is resistant to oxidation, but linking the reduced oxidation of LDL to a reduction in atherosclerosis has been problematic. Several important additional mechanisms may underlie the role of antioxidants in preventing the clinical manifestations of coronary artery disease (Fig. 2). Specifically, there is evidence that plaque stability, vasomotor function, and the tendency to thrombosis are subject to modification by specific antioxidants. For example, cellular antioxidants inhibit monocyte adhesion, protect against the cytotoxic effects of oxidized LDL, and inhibit platelet activation. Furthermore, cellular antioxidants protect against the endothelial dysfunction associated with atherosclerosis by preserving endothelium-derived nitric oxide activity. We speculate that these mechanisms have an important role in the benefits of antioxidants.
To conclude, an impairment of the NO synthase pathway may be one of the earliest events in atherogenesis. A reduction in NO synthesis and/or activity may contribute to the initiation and progressive of atherosclerosis. Derangement of the NO synthase pathway may occur by several mechanisms, including lipoproptein-induced alterations in signal transduction; increases in superoxide anion elaboration (and degradation of NO); reduced affinity of NOS for L-arginine; and/or elevated levels of circulating antagonists. NO is a potent vasodilator, a regulator of vascular structure, and an inhibitor of endothelial interactions and circulating blood elements. A loss of endothelial NO activity may contribute to the abnormal vasomotion observed in coronary artery disease, as well as the progression of atherosclerosis. Strategies to enhance NO synthesis and/or activity may be useful in maintaining cardiovascular health.
Administration of L-arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients.
We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endothelium-independent vasodilator prostaglandin E1, and control patients.
Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L-arginine/day, or 2 x 40 microg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3', 5'-monophosphate (GMP) were assessed as indices of endogenous NO production.
L-Arginine improved the pain-free walking distance by 230+/-63% and the absolute walking distance by 155+/-48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209+/-63% and 144+/-28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine (ADMA) ratio and the pain-free walking distance at baseline (r=0.359, p < 0.03). L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51+/-0.18 to 83+/-0.4 (L-arginine) and 7.0+/-0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3+/-0.4).
Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.
Vascular oxidative stress brought about by superoxide radicals and oxidized low-density lipoproteins (oxLDL) is a major factor contributing to decreased NO-dependent vasodilator function in hypercholesterolemia and atherosclerosis. We investigated whether chronic administration of L-arginine (2% in drinking water) or of alpha-tocopherol (300 mg/day) improves endothelium-dependent vasodilator function and systemic NO production, reduces vascular oxidative stress, and reduces the progression of atherosclerosis in cholesterol-fed rabbits with pre-existing hypercholesterolemia. Systemic NO production was assessed as urinary nitrate excretion; oxidative stress was measured by urinary 8-iso-PGF2alpha excretion in vivo, by lucigenin-enhanced chemiluminescence of isolated aortic rings ex vivo, and by copper-mediated LDL oxidation in vitro. Endothelium-dependent relaxation was almost completely abrogated in cholesterol-fed rabbits. Urinary nitrate excretion was reduced by 46+/-10%, and 8-iso-PGF2alpha excretion was increased by 61+/-18% as compared to controls (each P <0.05). Vascular superoxide radical release stimulated by PMA ex vivo was increased by 273+/-93% in this group, and the lag time of LDL oxidation was reduced by 35+/-6% (each P <0.05). Treatment with L-arginine and alpha-tocopherol reduced intimal lesion formation (by 68+/-6 and 4+/-11%, respectively; P <0.05) and improved endothelium-dependent relaxation. Both treatments also normalized urinary 8-iso-PGF2alpha excretion. L-Arginine increased urinary nitrate excretion by 43+/-13% (P <0.05) and reduced superoxide radical release by isolated aortic rings to control levels, which was unaffected by vitamin E treatment. By contrast, vitamin E dramatically increased the resistance of isolated LDL to copper-mediated oxidation in vitro by 178+/-7% (P <0.05), which was only marginally prolonged by L-arginine. Intimal thickening was reduced by both treatments. We conclude that both L-arginine and alpha-tocopherol reduce the progression of atherosclerotic plaques in cholesterol-fed rabbits. However, while L-arginine increases NO formation and reduces superoxide release, alpha-tocopherol antagonizes mainly oxLDL-related events in atherogenesis. Thus, both treatments reduce urinary isoprostane excretion and improve endothelium-dependent vasodilation via different mechanisms.
Thus the lesions of atherosclerosis represent a protective, inflammatory-fibroproliferative response against the different agents that can cause the disease. If the injury continues over a long period of time, it may become excessive, and in its excess it becomes the disease itself. It has been shown that this excessive, inflammatory, fibroproliferative response can be reversed given sufficient opportunity for the injurious factors to be modified. Approaches to modifying specific cellular interactions, growth- regulatory molecules, or intracellular signaling molecules may afford opportunities to modify these processes and lead to lesion prevention or regression.
In retrospect, basic research in the fields of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) during the past two decades appears to have followed a logical course, beginning with the findings that NO and cGMP are vascular smooth muscle relaxants, that nitroglycerin relaxes smooth muscle by metabolism to NO, progressing to the discovery that mammalian cells synthesize NO, and finally the revelation that NO is a neurotransmitter mediating vasodilation in specialized vascular beds. A great deal of basic and clinical research on the physiologic and pathophysiologic roles of NO in cardiovascular function has been conducted since the discovery that endothelium-derived relaxing factor (EDRF) is NO. The new knowledge on NO should enable investigators in this field to develop novel and more effective therapeutic strategies for the prevention, diagnosis, and treatment of numerous cardiovascular disorders. The goal of this review was to highlight the early research that led to our current understanding of the pathophysiologic role of NO in cardiovascular medicine. Furthermore, we discussed the possible mechanism of some drugs interfering with NO signaling cascade.
This study investigated the role of endogenous nitric oxide (NO) in the progression of atherosclerosis in apolipoprotein E-deficient [apoE-knockout (KO)] mice. Mice were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) an inhibitor of nitric oxide synthase (NOS) or with the NOS substrate L-arginine for 8 wk. L-NAME treatment resulted in a significant inhibition of NO-mediated vascular responses and a significant increase in the atherosclerotic plaque/surface area in the aorta of apoE-KO mice. L-arginine treatment had no influence on endothelial function and did not alter lesion size. Mean arterial blood pressure and serum lipid levels were not altered by the treatments. At the beginning of the study impairment in endothelial function was only apparent in the case of N(G)-nitro-L-arginine-induced, NO-mediated contraction, whereas ACh-induced, NO-mediated relaxation was not different between age-matched apoE-KO and C57Bl/6J mice. After the 8-wk treatment with the NOS inhibitor, both NO-mediated responses were significantly inhibited. The acceleration in lesion size concomitant to the severely impaired NO-mediated responses indicates that lack of endogenous NO is an important progression factor of atherosclerosis in the apoE-KO mouse.
The pomegranate was chosen as the logo for the Millennium Festival of Medicine from a shortlist that included DNA, the human body, and a heart beat. Not only has the pomegranate been revered through the ages for its medicinal properties but it also features in the heraldic crests of several medical institutions involved in the organisation of the festival.
#### Summary points
The pomegranate has been held sacred by many of the world's major religions
It has been revered through the ages for its medicinal properties
Preparations of different parts of the plant have been used to treat a variety of conditions
It features in the coat of arms of several medical associations
Before its medicinal properties were described the pomegranate was held sacred by many of the world's major religions.
In the Greek myth of Persephone's abduction by Hades, lord of the underworld, the pomegranate represents life, regeneration, and marriage.1 One day while out gathering flowers, Persephone noticed a narcissus of exquisite beauty. As she bent down to pick it, the earth opened and Hades seized her and dragged her down to his kingdom. By eating a few pomegranate seeds, Persephone tied herself to Hades—the pomegranate being a symbol of the indissolubility of …
The objective of this study was to elucidate the mechanisms by which nitric oxide (NO) inhibits rat aortic smooth muscle cell (RASMC) proliferation. Two products of the arginine-NO pathway interfere with cell growth by distinct mechanisms. N(G)-hydroxyarginine and NO appear to interfere with cell proliferation by inhibiting arginase and ornithine decarboxylase (ODC), respectively. S-nitroso-N-acetylpenicillamine, (Z)-1-[N-(2-aminoethyl)-N-(2-aminoethyl)-amino]-diazen-1-ium-1,2-diolate, and a nitroaspirin derivative (NCX 4016), each of which is a NO donor agent, inhibited RASMC growth at concentrations of 1-3 microM by cGMP-independent mechanisms. The cytostatic action of the NO donor agents as well as alpha-difluoromethylornithine (DFMO), a known ODC inhibitor, was prevented by addition of putrescine but not ornithine. These observations suggested that NO, like DFMO, may directly inhibit ODC. Experiments with purified, recombinant mammalian ODC revealed that NO inhibits ODC possibly by S-nitrosylation of the active site cysteine in ODC. DFMO, as well as the NO donor agents, interfered with cellular polyamine (putrescine, spermidine, spermine) production. Conversely, increasing the expression and catalytic activity of arginase I in RASMC either by transfection of cells with the arginase I gene or by induction of arginase I mRNA with IL-4 resulted in increased urea and polyamine production as well as cell proliferation. Finally, coculture of rat aortic endothelial cells, which had been pretreated with lipopolysaccharide plus a cytokine mixture to induce NO synthase and promote NO production, caused NO-dependent inhibition of target RASMC proliferation. This study confirms the inhibitory role of the arginine-NO pathway in vascular smooth muscle proliferation and indicates that one mechanism of action of NO is cGMP-independent and attributed to its capacity to inhibit ODC.
L-Arginine (2-amino-5-guanidinovaleric acid) is the precursor of nitric oxide, an endogenous messenger molecule involved in a variety of endothelium-mediated physiological effects in the vascular system. Acute and chronic administration of L-arginine has been shown to improve endothelial function in animal models of hypercholesterolemia and atherosclerosis. L-Arginine also improves endothelium-dependent vasodilation in humans with hypercholesterolemia and atherosclerosis. The responsiveness to L-arginine depends on the specific cardiovascular disease studied, the vessel segment, and morphology of the artery. The pharmacokinetics of L-arginine have recently been investigated. Side effects are rare and mostly mild and dose dependent. The mechanism of action of L-arginine may involve nitric oxide synthase substrate provision, especially in patients with elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine. Endocrine effects and unspecific reactions may contribute to L-arginine-induced vasodilation after higher doses. Several long-term studies have been performed that show that chronic oral administration of L-arginine or intermittent infusion therapy with L-arginine can improve clinical symptoms of cardiovascular disease in man.
Endothelial dysfunction has been shown in a wide range of vascular disorders including atherosclerosis and related diseases. Here, we examine and address the complex relationship among nitric oxide (NO)-mediated pathways and atherogenesis. In view of the numerous pathophysiological actions of NO, abnormalities could potentially occur at many sites: (a) impairment of membrane receptors in the arterial wall that interact with agonists or physiological stimuli capable of generating NO; (b) reduced concentrations or impaired utilization of l-arginine; (c) reduction in concentration or activity both of inducible and endothelial NO synthase; (d) impaired release of NO from the atherosclerotic damaged endothelium; (e) impaired NO diffusion from endothelium to vascular smooth muscle cells followed by decreased sensitivity to its vasodilator action; (f) local enhanced degradation of NO by increased generation of free radicals and/or oxidation-sensitive mechanisms; and (g) impaired interaction of NO with guanylate cyclase and consequent limitation of cyclic GMP production. Therefore, one target for new drugs should be the preservation or restoration of NO-mediated signaling pathways in arteries. Such novel therapeutic strategies may include administration of l-arginine/antioxidants and gene-transfer approaches.
Consumption of pomegranate juice which is rich in tannins, possess anti-atherosclerotic properties which could be related to its potent anti-oxidative characteristics. As some antioxidants were recently shown to reduce blood pressure, we studied the effect of pomegranate juice consumption (50 ml, 1.5mmol of total polyphenols per day, for 2 weeks) by hypertensive patients on their blood pressure and on serum angiotensin converting enzyme (ACE) activity. A 36% decrement in serum ACE activity and a 5% reduction in systolic blood pressure were noted. Similar dose-dependent inhibitory effect (31%) of pomegranate juice on serum ACE activity was observed also in vitro. As reduction in serum ACE activity, even with no decrement in blood pressure, was previously shown to attenuate atherosclerosis, pomegranate juice can offer a wide protection against cardiovascular diseases which could be related to its inhibitory effect on oxidative stress and on serum ACE activity.
The purpose of this study was to determine the involvement of the p42/p44 mitogen-activated protein kinase (MAPK) pathway and induction of p21(waf1/cip1) in the antiproliferative effects of nitric oxide (NO) on rat aortic smooth muscle cells (RASMC). NO, like alpha-difluoromethylornithine (DFMO), interferes with cell proliferation by inhibiting ornithine decarboxylase (ODC) and, therefore, polyamine synthesis. S-nitroso-N-acetylpenicillamine or (Z)-1-[N-(2-aminoethyl)-N-(2-aminoethyl)-amino]-diazen-1-ium-1,2-diolate inhibited RASMC growth at concentrations as low as 3 microM, and DFMO elicited effects at concentrations of 100 microM or greater. The cytostatic effect of NO and DFMO was prevented by the MAPK kinase 1/2 inhibitors PD 098,059 or U0126. This finding suggests that the p42/p44 MAPK pathway is involved in the inhibition of RASMC proliferation by NO. Western blot analysis revealed that treatment of RASMC with NO or DFMO leads to activation of p42/p44 MAPK and induction of p21(waf1/cip1). This effect was prevented by MAPK kinase 1/2 inhibitors, suggesting that induction of p21(waf1/cip1) depended on activation of p42/p44. Moreover, activation of p42/p44 and induction of p21(waf1/cip1) were prevented by exogenous putrescine but not ornithine, suggesting this effect was due to the inhibition of ODC by NO or DFMO. Finally, activation of p42/p44 MAPK and induction of p21(waf1/cip1) were cGMP-independent. Neither 1H-(1,2,4)oxadiazolo[4,3-alpha]quinoxalin-1-one nor zaprinast influenced the cytostatic effect of NO or DFMO or their ability to activate these signal transduction pathways. These observations suggest that inhibition of ODC and accompanying putrescine production are the underlying mechanisms by which NO and DFMO activate the MAPK pathway to promote induction of p21(waf1/cip1) and consequent inhibition of cell proliferation.
The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation.
The effect of red wine and wine polyphenol resveratrol on endothelial function was investigated in experimental hypercholesterolemic rabbits. Endothelial function as measured by flow-mediated dilation (FMD) in the femoral artery was 19.28+/-2.81% in control animals fed a regular diet. In contrast, rabbits fed a high-cholesterol (1.5%) diet showed a reduced endothelial function, as revealed by a 25% reduction in the measured FMD. Intragastric feeding of resveratrol (3 mg/kg/day), red wine (4 ml/kg/day), dealcoholized red wine (4 ml/kg/day), for 12 weeks in hypercholesterolemic rabbits significantly mitigated the reduction in endothelial function, and resulted in FMD values of 14.52+/-0.60, 18.95+/-2.30, 17.58+/-1.43, and 18.80+/-3.94%, respectively. Measurement of plasma endothelin 1 (ET-1) and nitric oxide (NO) levels showed that feeding a high-cholesterol diet significantly increased plasma ET-1 levels (from 51.4+/-17.6 to 96.9+/-24.3 pg/ml), and decreased plasma NO concentration (from 104.6+/-18.5 to 67.7+/-16.1 pg/ml). With administration of resveratrol, red wine, or dealcoholized red wine, plasma ET-1 levels statistically decreased, in parallel with a significant elevation in NO levels. These results provide in vivo evidence suggesting that resveratrol and red wine improve endothelial function, which may be one of the mechanisms by which this red wine polyphenol exerts its alcohol-independent cardioprotective effects.
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In view of the widespread use of pomegranate seeds for therapeutic purposes it was decided to study the oestrogenic activity of pomegranate seed oil, which has not been investigated previously.
The oestrogenic effect of the oil was tested in immature rabbits by the uterine weight method and in ovariectomized mice by the vaginal smear technique. The results were evaluated by the method of Robson (1938). Immature rabbits were injected with the pomegranate seed oil daily for 10 days, killed without anaesthesia and their uteri weighed. Mature albino mice, weighing about 35g. were ovariectomized, injected with the oil in the morning and evening of two consecutive days. Four smears were taken: the first in the evening of the day after the last injection, the second and third in the morning and evening of the day after, and the 4th in the morning of the following day. Smears were regarded as positive
There is a complex pathophysiologic scenario involving nitric oxide (NO), endothelial nitric oxide synthase (eNOS), and the development of atherosclerosis and unstable atheroma. Endothelial damage induced by atherosclerosis leads to the reduction in bioactivity of eNOS with subsequent impaired release of NO. An important mechanism is local enhanced degradation of NO by increased generation of reactive oxygen species and other free radicals, with subsequent cascade of oxidation-sensitive mechanisms in the arterial wall. Novel molecular approaches have resulted in the development of new strains of mice lacking eNOS. These experimental models will help to understand how to implement NO-based therapies against atherosclerosis. L-arginine, the precursor of NO, has demonstrated beneficial effects in atherosclerosis and disturbed shear stress. The target or goal for new drugs should be the complete restoration of NO-mediated signaling pathways in atherosclerotic arteries.
A high intake of polyphenolic compounds is likely to have beneficial effects on the cardiovascular system. Especially red wine is a rich source of polyphenols, and we have previously shown that French red wine upregulates eNOS, a protective enzyme in the cardiovascular system. The current study tested (poly)phenolic constituents of red wine for their ability to enhance eNOS expression (and the activity of a 3.5-kb human eNOS promoter) in human EA.hy 926 endothelial cells. Of the compounds tested, we found 3,4',5-trihydroxy-trans-stilbene (trans-resveratrol) to be the most efficacious stimulator of eNOS expression (and eNOS transcription), but this compound alone could not explain the total stimulatory effect of red wine. The flavanols catechin and epicatechin, the flavonols fisetin, myricetin, isoquercitrin and hyperoside, the anthocyanins delphinidin, malvidin, and paeonidin, gallic acid, and the hydroxycinnamic acids ferulic acid and sinapinic acid did not change eNOS expression or eNOS promoter activity in any substantial way. The flavonol quercetin inhibited eNOS expression (with no effect on eNOS promoter activity). Cinnamic acid was a rather potent enhancer of eNOS expression, however with an efficacy of only 170%. Surprisingly, it reduced eNOS promoter activity. The anthocyanins cyanidin, the hydroxycinnamic acids p-coumaric acid and caffeic acid, and the phenolic acids benzoic acid and vanillic acid also enhanced eNOS expression moderately (with no effect on eNOS promoter activity). Thus, the increase in eNOS in response to red wine involves several polyphenolic compounds with a major contribution from trans-resveratrol and lesser contributions from cinnamic and hydroxycinnamic acids, cyanidin, and some phenolic acids.