Potential of Cydonia oblonga leaves in cardiovascular disease

HJ356-1

Nowadays plant-based medicine or herbal medicine research is becoming more prevalent all over the world, presumably due to natural accessibility and fewer adverse effects. Quince (Cydonia oblonga Miller), a plant in the Rosaceae family, is considered to be a good and cheap natural source for potent antioxidants including phenolic acids and flavonoids. There have been limited investigations on the efficacy of quince leaves in heart function. The potential for prophylactic and therapeutic effects of quince leaves in reducing cardiovascular disease is discussed based on its beneficial constituents. The review covers the findings from traditional medicines and various actions of effective constituents demonstrated in other investigations including antioxidant, antiatherogenic, anti-inflammation, antihypertensive and vasodilatory effects, which all are in accordance with the hypothesis of a beneficial role of quince in cardiovascular health. 

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Introduction
Quince (Cydonia oblonga Miller), the sole member of the genus Cydonia of the Rosaceae family, is a small, deciduous tree, 5–8 m tall and 4–6 m wide, with bright yellow pome-like fruits 7–12 cm long and 6–9 cm broad. The leaves are simple, elliptical, 6–11 cm long with fine white hairs. The white or pink flowers 5 cm across are produced in spring (1). It is cultivated from prehistoric periods in countries extending from Iran to India (2). Quince is considered a safe plant and toxicity is only proposed for seeds if they are eaten in large quantities because of their nitrile content. Nitrile is a common agent in seeds of Rosaceae and when hydrolyzed, produces hydrogen cyanide in the body (3). For the other parts of this plant, especially the leaves, which are our targeted segment, toxicity is not claimed. In various studies the quince fruit is recognized as a source of health-promoting natural compounds, due to its antioxidant, antimicrobial (antibacterial and anti-influenza virus) and anti-ulcerative properties, which are mainly attributed to phenolic compounds (4-9).

Traditional drugs have an important role in drug research, resulting in the discovery of novel agents. In folk medicine, the decoction of quince leaves is used as a treatment for cough, cold, bronchitis, abdominal pain, diarrhea, nervousness, insomnia and dysuria for its sedative, anti-pyretic, anti-diarrheal and antitussive properties and for the treatment of various skin diseases (10,11). Also, anti-hemolytic, anti-diabetic and anti-lipoperoxidative effects and the ability to reduce lipid levels have been attributed to quince leaf (12). The extract of quince leaf also possesses concentration-dependent antiproliferative effects on colon (Caco-2) cancer cell lines (13). The sugar lowering potency of quince leaves is revealed to be the same as that of standard antidiabetic drugs (10). In addition, in hypercholesterolemia-induced renal injury, the quince leaf decoction showed probable protective effects which are attributed to both its antioxidants and lipid-lowering characteristics (12). Recently, an anti-inflammation role of quince extract was reported in a study of colitis and inflammatory bowel disease1 (4).

The Hypothesis

Cardiovascular disease Cardiovascular diseases (CVD) contribute a major and increasing health burden in developed countries. Despite huge advances in treatment, traditional medicine is used all over the world and this points to the importance of research in natural compounds used in folk medicine.

Oxidative stress has a central role in the pathogenesis of CVDs and is associated with several pathological states, including atherosclerosis, hypertension, heart failure, stroke, diabetes and inflammation (15-18). Among the cardiovascular risk factors, it is recognized that high blood pressure, arterial stiffness, atherosclerosis, easy blood clotting and heart inflammation can lead to catastrophic events such as heart attack and stroke. Oxidative stress plays a key role in all of these different pathophysiological processes. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen and highly reactive due to the presence of unpaired electrons. An increased generation of ROS along with reduction of nitric oxide (NO) amounts causes vascular wall damage and shifting of the cell towards oxidation of DNA, lipids and proteins associated with cell death and cardiac injury (19,20). In different studies the relation of oxidative stress and various cardiovascular risk factors has been demonstrated (summarized in Table 1). In addition, in Table 2 a list of important cardiovascular diseases related to ROS and oxidative stress is presented briefly.

 

Table 1 |  Existing evidence of association of oxidative stress and cardiovascular risk factors

(click below for larger view)

Table 1 |  Existing evidence of association of oxidative stress and cardiovascular risk factors

It has been demonstrated that by means of specific antioxidants, mitochondrial respiration and ROS production can be modulated in a way to protect mitochondria against oxidative stress in CVDs (108). Antioxidants, by potentiating endothelial nitric oxide levels as well as inhibiting vascular inflammation, lipid peroxidation, platelet aggregation and oxidation of LDL, can also contribute to preventing endothelial dysfunction. Fruits and vegetables are one of the main sources of antioxidants in our diets (109,110). Various studies have recognized that there is a clear affiliation between intake of these beneficial agents and reduced rate of heart disease, different cancers and other degenerative diseases (5). This affiliation is often attributed to the antioxidant compounds present in these natural agents, primarily to phenolic compounds such as phenolic acids and flavonoids (6). With antioxidant properties of these agents, the cells would be capable of scavenging free radicals and surviving destructive injuries.

 

Table 2 |  Existing evidence of association of oxidative stress and cardiovascular disease

(click below for larger view)

Table 2 |  Existing evidence of association of oxidative stress and cardiovascular disease

Costa et al. (111) studied the phenolic profile of quince and compared the antioxidant potential of quince leaf with that of green tea (Camellia sinensis). Their results point out that quince leaf may have applications as a preventive or therapeutic agent in diseases in which free radicals are involved and according to this point, the antihemolytic activities of the quince leaf also have been confirmed (111,112). Among different parts of the plant C. oblonga, the total phenolic content of leaves was reported as much higher than that found in pulps, peels and seeds, which may indicate that the leaves of the tree can be much more interesting in terms of health-promoting constituents (113).

Constituents and bioactivity As a source of phenolic compounds, especially flavonoids, which are considered potent antioxidants, Cydonia species are excellent low-cost natural health promoting compounds(6,11,113,114). Various studies were performed to evaluate phenolic compounds and organic acids of quince (115-117). For example, the influence of jam processing upon the contents of these constituents of quince fruit was assessed and the antioxidant activity of the methanolic extracts of quince jam was reported (6,118).

The most abundant compound in quince leaves is 5-O-caffeoylquinic acid (neochlorogenic acid or 5-CQA), followed by quercetin-3-O-rutinoside119. 5-CQA, a major antioxidant in quince leaves, is an isomer of chlorogenic acid, which refers to a family of esters of hydroxycinnamic acids (caffeic acid, ferulic acid and p-coumaric acid) with quinic acid. These agents are classified in phenol groups with the property of inhibiting excessive production of ROS in vessels and thereby decreasing oxidative stress and improving nitric oxide bioavailability, leading to attenuation of endothelial dysfunction, hypertension and vascular hypertrophy (120,121). As well as antioxidant activity, strong anti-inflammatory effects which can inhibit edema, inflammation, neutrophil migration and TNF-α expression are reported (122). In a study of the effects of coffee consumption, it is documented that biological effects such as antioxidation, antimutation, anticarcinogenesis, antibiotic, antihypercholesterolemia, antihypertension and anti-inflammatory actions are due to relatively large amounts of chlorogenic acid in this useful beverage (123). Therefore, it is possible that all or at least some of these beneficial effects of chlorogenic acid can also be demonstrated in quince.

Astragalin (kaempferol-3-O-glucoside) and quercetin, which belong to flavonoid groups, are the other beneficial constituents of quince leaf. In comparison with other parts of quince, the leaves presented the highest relative contents of kaempferol derivatives, especially of kaempferol-3-O-rutinoside, which represented 12.5% of the total phenolic content (119). But these contents are variable according to geographical origin and collection month, especially the 3-O-caffeoylquinic and 3,5-O-dicaffeoylquinic acid contents, which indicates a possible use of them as markers of samples with different geographical origins and/or physiological maturities (113).

In various studies of flavonoids, antiallergic, anti-inflammatory (124), anti-microbial (125,126), anti-cancer (127), anti-diarrheal (128) and antioxidant activities (129) of this major class of phytochemicals were demonstrated (130). Several epidemiological studies have examined the relationship between flavonoids and heart disease (131,132). An inverse correlation between dietary flavonoid intake and the incidence of coronary artery disease (CAD) in elderly men has been shown by Hertog et al. (133). Dietary flavonoids, mainly quercetin, were inversely associated with stroke incidence and the claimed reasons for this effect were the possibility of storing certain flavonoids in blood vessels and exertion of their antiatherogenic effects (133). In a study of the mechanism of antiatherogenic effects of quercetin and phenolic compounds of red wine, impairing of copper ion-catalyzed oxidation of LDL was demonstrated (134). Vasodilatory effects of flavonoids also have been shown (135). The potential utility of flavonoids as a means of enhancing myocardial ischemic tolerance or resistance to reperfusion injury by diminishing detrimental ROS production was also reported (136). Flavonoids constitute a more stable form of free radicals with lower toxicity. Besides, they can chelate Fe2+ and prohibit the effects of free radicals (130). A protective effect of quercetin by its preventive effect on the decrease of xanthine dehydrogenase/oxidase ratio was observed during ischemia-reperfusion in the rat (137). The enzyme xanthine oxidase is formed from dehydrogenase and is a source of ROS in oxidative tissue injury (138). The inhibition of xanthine oxidase activity by flavonoids has been described (139). By antioxidant activity, flavonoids could be important in protecting LDL from oxidation, thus reducing their atherogenicity. In a Japanese study an inverse correlation between flavonoid intake and total plasma cholesterol concentration was reported (140). Thereby, flavonoids could potentially influence disease states in which lipid peroxidation products are involved, especially vascular disorders and coronary artery disease. Considering the relevance of inflammatory process and cardiovascular disease, the ability of flavonoids in modulation of inflammation by inhibitory effect on mast cells, T cells, B cells, interferons, NK cells, basophils and neutrophils provides protective evidence in cardiovascular disease treatment (141,142).

 

Table 3 | Antioxidant profile of Cydonia oblonga

ORGANIC ACID PROFILE PHENOLIC PROFILE
Oxalic acid
Citric acid*
Malic acid
Quinic acid*
Shikimic acid
Fumaric acids
3-O-caffeoylquinic acid
4-O-caffeoylquinic acid
5-O-caffeoylquinic acid*
3,5-O-dicaffeoylquinic acid
quercetin-3-O-galactoside
quercetin-3-O-rutinoside*
kaempferol-3-O-glycoside
kaempferol-3-O-glucoside
kaempferol-3-O-rutinoside
*Quinic acid was the major compound (72.2%), followed by citric acid (13.6%). *5-O-caffeoylquinic acid was the major phenolic compound (36.2%), followed by quercetin-3-O-rutinoside (21.1%).

 

The organic acids, which are primary compounds found in great amounts in all plants, may also have a protective role against various diseases due to their antioxidant properties (Table 3). Citric, malic and tartaric acids are commonly found in fruits, while oxalic acid is present in higher amounts in green leaves. Quince leaves contain an organic acid profile composed of six constituents: oxalic, citric, malic, quinic, shikimic and fumaric acids. These structures behave as antioxidants because they also have the ability to chelate metals (6,11,143).

Conclusion

In conclusion, the possible efficacy of phenols, flavonoids and other constituents of quince as protective agents in CVD is described. This protective ability could arise by influencing several processes, such as 1) antioxidant action and inhibitory effect on xanthine oxidase and ability to chelate metals, 2) enhancing myocardial ischemic tolerance to reperfusion injury, 3) decrease in LDL oxidation by antioxidant property and increase in HDL levels, mainly due to flavonoids, 4) antiatherogenic effects in vessels, 5) improving nitric oxide bioavailability and attenuation of endothelial dysfunction, hypertension and vascular hypertrophy by vasodilatory effects and 6) reduction of cardiac mast cell mediator release and decrease in cardiovascular inflammation. Traditional natural compounds have an important role in drug research, and may result in the discovery of novel molecules. Therefore more study is needed in this context to demonstrate each possible effective pathway in quince. In other natural compounds like honey and grape seed, the cardioprotective effects were attributed to various available polyphenols and flavonoids in these agents (144,145). These findings suggest a novel path in quince research to study these compounds further. To evaluate the validity of our hypothesis, we propose the use of isolated rat hearts to assess cardiac function in the presence of different doses of the extract. Finally, this study suggests that leaves from C. oblonga can be used as a great natural and cheap source of bioactive compounds with primary antioxidative properties along with other mechanisms of action. By modulating various cardiovascular risk factors such as atherosclerosis, smoking, endothelial dysfunction,
hypertension, diabetes and hyperhomocysteinaemia, quince leaf extract may have relevance in the prevention and treatment of different pathological states of ischemic, inflammatory and hypertrophic heart disease. H

Acknowledgements

The authors thank the Faculty of Pharmacy of Tabriz University of Medical Sciences, Tabriz, Iran.

Authors declare no conflicts of interest.

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About the authors

Haleh Vaez is a pharmacist who received a PharmD degree in 2011 from Tabriz Medical University and now is educating in pharmacology at the PhD level and studying different natural extractions’ effects on the heart using an isolated heart system.

Samin Hamidi is studying medicinal chemistry at the PhD level and concentrates on the chemistry of various constituents of natural extracts.

Sanam Arami is a pharmacist and received a PharmD degree in 2009 from Tabriz Medical University and now is educating in biotechnology at the PhD level and studying the development of new drugs.

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