Cardiovascular Effects of Cydonia oblonga Miller (Quince)

Cydonia oblonga Miller (quince) is a monotypic genus in the Rosaceae family which used to treat or prevent many medical conditions such as diabetes, cancer, infections, and ulcer. This review will summarize the current state of knowledge available on botany, phytochemistry, and pharmacology of this plant with a focus on its effect on some cardiovascular risk factors such as diabetes, blood pressure, lipid profile, and body weight. Databases of Google Scholar, Web of Science, PubMed, Scopus, and SID were searched systematically for English published articles with no date limitation. There were no human studies found, and all of the studies were conducted on animals or in vitro models. Reviewing of all 12 included articles showed that different types of quince extract have positive effects on cardiovascular-related factors such as blood pressure, diabetes, glucose metabolism, lipid profile, ROS, body weight, liver dysfunction, and thrombosis. An antihypertensive effect of quince showed to be a magnitude that is comparable to captopril and the lipid-lowering effect of quince showed to be a magnitude that is comparable to simvastatin. However, two studies evaluated the effect of quince fruit extract on insulin levels; one of them reported no positive effect, and the other one reported a significant positive effect. It can be concluded that different parts of quince including leaf, seed, and fruit could be used for improving cardiovascular-related factors including blood pressure, glucose metabolism and diabetes, obesity, and lipid-adjusting purposes. Quince was also found to have strong anti-inflammatory and antioxidant capacity. This study paves the way for further studies on the cardiovascular effect of quince consumption as a beneficial nutraceutical in humans.


Introduction
Dr. Stephen DeFelice coined the term "Nutraceutical" from "Nutrition" and "Pharmaceutical" in 1989 [1]. Nutraceuticals, in contrast to pharmaceuticals, are substances, which usually have no patent protection. Both pharmaceutical and nutraceutical compounds might be used to cure or prevent diseases, but only pharmaceutical compounds have the governmental sanction. Consumers are turning increasingly toward food supplements to improve well-being when pharmaceuticals fail [2,3]. Nowadays, nutraceuticals have received considerable interest due to their potential nutritional, safety, and therapeutic effects [4,5]. According to previous studies, many medicinal plants such as fenugreek, sumac, dill, ginger, grape, and green tea improve the lipid profile significantly [6][7][8][9][10].
Quince is one of the herbal nutraceuticals that has been used throughout olden times [11]. Cydonia oblonga Miller (COM) leaves are used in traditional medicines for cardiovascular disease (CVD) treatment or prevention [12]. Its fruit is employed in the food sector as a source of pectin, which defends the colon from damage in IBS and peptic ulcers [13][14][15]. (e plant's seeds have long been used to cure cough, diarrhea, dysentery, constipation, sore throat, and bronchitis [16][17][18]. Quince extract has been proven to have cancer-fighting, antihemolytic, and antidiabetic properties [19][20][21][22]. It is also found to have an anti-inflammatory and antioxidant capacity [23], antiallergic [24], antidepressant, and antistress effect [25,26]. In addition, the plant contains phenol peroxidase, an enzyme that decolorizes hazardous aromatic colors in industrial wastewater [27,28]. Quince's widespread therapeutic use and valuable phytochemical composition prompted us to write a review on it, with a focus on its cardiovascular effects.

General Characteristics.
(e quince (Cydonia oblonga), is a nondrought-tolerant small deciduous tree with fruits that look like pears and a superficial and fasciculate root [11]. When exposed to air, the white-yellow pulp becomes hard, or sour, bitter, and acidic, making it unfit for consumption as a fresh product (just a few cultivars are), but when mature, the quince has a pleasant, durable, and powerful flavor. (e existence of essential oil in quince fruit, whose odor-active components are considered to be monoterpene lactones and oxides, is responsible for the fruit's strong and distinctive odor [29].

Distribution.
(e quince fruit is a native of Western Asia and Southwest Europe and has been originated from Armenia, Iran, Azerbaijan, Turkmenistan, and southwest Russia [29]. Turkey produces the most quinces worldwide, ahead of China, Uzbekistan, Morocco, Iran, Azerbaijan, Argentina, and Spain (FAO, 2013).

Methodology
Databases of Google Scholar, Web of Science, PubMed, Scopus, and SID were searched systematically with no date limitation for English published articles.

Discussion
In 2016, an evaluation of quince's possible bioactive components and nutritional applications was published. We discuss and update the cardiovascular effects of quince, as well as its botany, phytochemistry, and pharmacology, in this review. Reviewing of all 13 included articles on this topic showed that different types of quince extract have positive and beneficial effects on cardiovascular-related factors such as blood pressure [50,52,53], diabetes, and glucose metabolism but not on the insulin level [22,47,48], lipid profile [12,[43][44][45][46]49], serum biomarkers of liver function [12,43,44,46], body weight [45], and thrombosis [51]. (e quince leaf extract's effect on lipid profile, liver enzymes, and atherosclerotic plaque formation in the coronary artery was not significantly different from effects reported in the atorvastatin group [43]. (e antihypertensive effect of 320 mg/kg per day of quince leaf extract reported to be not very different from using captopril [52]. None of the studies reported a negative or no positive effect of quince consumption on cardiac-related factors.

Lipid Profile and Body Weight.
Of six studies that reported outcomes related to the effect of quince on the lipid profile, all reported significant positive improvement [12,[43][44][45][46]49]. Umar et al. showed that total flavonoids of quince fruit and leaves could adjust the lipid profile in hyperlipidemic rats significantly [49]. In their study high dose of COM total leave flavonoids (160 mg/kg), had lipidlowering effect almost same as 5 mg/day of simvastatin [49]. According to Khademi et al., the quince group had significantly decreased TC, TG, and LDL_C levels compared to the high-cholesterol diet group (P < 0.05), and it was more similar to the normal diet group. (eir results showed that quince leaf extract, such as atorvastatin, can successfully adjust the lipid profile; however, both cannot improve atherosclerosis caused on by a high-fat diet significantly [43]. Another study also reported that the aqueous extract of quince fruit significantly reduced serum TG, TC, and LDL-C levels while increasing HDL-C levels in diabetic rats [46]. Abliz et al. found that in hyperlipidemia rats, COM lowered TC, TG, and LDL-C while increasing HDL-C, which was significant at high and medium doses [12]. Lee et al. reported that COM has lipid-adjusting and antiobesity effects, and it can reduce fat mass and adipose tissue weight [45].

Diabetes, Glucose Metabolism, and the Insulin Level.
Of five studies that reported outcomes related to the effect of quince on glucose metabolism and diabetes, all reported significant positive improvement [22,40,41,47,48]. Tang et al. using the in vitro model showed that by stimulating the PI3K/AKT signaling pathway, COM prompted glucose metabolism [48]. However, in terms of the insulin level, results were inconsistent, and procyanidin-rich extract of Chinese quince fruit showed no positive effect on the insulin level, while elevation of adiponectin in obese mice resulted in insulin level elevation [45].

Blood Pressure.
Of two studies that investigated the effect of COM on blood pressure, both reported significant positive results [50,52]. It has been shown that extracts of COM leaves (80, 160, and 320 mg/kg) at the highest doses have an antihypertensive effect comparable to captopril [52,53]. Another study using aqueous-methanolic extract from seeds of quince (200, 400, and 600 mg/kg doses) showed that extract in 600 mg/kg dose produced the most effect and avoided a rise in blood pressure [50].

Oxidative Stress.
Oxidative stress is defined as increased intracellular levels of reactive oxygen species (ROS). ROS plays a role in the onset and development of coronary artery disease [54]. ROS is involved in the development of oxidized LDL, which is the first stage in the pathogenesis of atherosclerosis. Furthermore, ROS may activate matrix metalloproteinases, leading to plaque rupture. However, ROS appears to have a significant function in the setting of acute MI and after reperfusion treatment [55]. ROS may oxidize myofibrillar proteins, causing contractile dysfunction in heart failure patients [56]. An in vitro study on a polyphenolic extract of Japanese quince fruit showed that it can reduce ROS intracellular [40]. HPLC analysis of the phenolic profile of COM showed that chlorogenic acid was the major phenolic compound in quince leaf extract [19,45]. Chlorogenic acid is a bioactive polyphenol with potent antioxidant properties which have a heart-protective capacity [57]. Quince fruit had a lot of quinic acid and shikimic derivatives which can protect against cardiovascular disease and cancer [58], as well as procyanidins and flavonoids in it.
(e presence of 4-caffeoyl shik, which has antioxidative activity, in quince is significantly higher than that of an apple [57].
Quince leaves had a much stronger lowering power than green tea in a comparison research study [19]. In a similar   HDL was significantly increased.

Evidence-Based Complementary and Alternative Medicine
ALT, AST and ALP were significantly reduced.
Aslan et al. [22] Healthy and diabetic rats way to green tea, the methanolic extract of quince leaves strongly protected the erythrocyte membrane against hemolysis [19]. (e phenolic fraction of quince has been found to have stronger antioxidant activity than the entire methanolic extract [59]. According to Silva et al., organic acid extracts consistently had the lowest antiradical activity, showing that the phenolic component of quince fruit contributes significantly to its antioxidant ability [59]; however, Khademi et al. mentioned that the antioxidant properties of the quince leaf are most likely to be responsible for its antiatherosclerotic effects [43]. In study by Silva et al., methanolic extracts were tested for the antioxidant capacity, and peel extract was shown to have the highest antioxidant activity [59].
A study by Magalhães et al. reported that the DPPH free radical scavenging capabilities of pulp and peel extracts were comparable, whereas seed extract had a substantially lower antioxidant capacity. Pulp and peel extracts significantly protected the erythrocyte membrane from hemolysis under the oxidative action of AAPH in a time-dependent and concentration-dependent manner. Seed extracts alone caused significant hemolysis [60]. (ese findings imply that the quince leaf or fruit could be employed as a prophylactic or therapeutic agent in free radical-related diseases such as CVD. Doxorubicin is one of the most regularly used medications to treat a wide range of cancers, and its most common adverse effects include anemia and cardiovascular toxicity. Doxorubicin increases malondialdehyde (MDA) while decreasing glutathione (GSH) and catalase activity in rat heart tissue. Two weeks of treatment with Cydonia hydroalcoholic extract significantly reduced MDA levels while raising GSH, demonstrating that Cydonia can relieve oxidative stress and minimize cardiac toxicity [61].

Inflammation. Zhou et al. in their study besides
showing the significant antihypertensive effect of quince leaf extract also reported a considerable decrease in the contents of IL-6, IL-1β, TNF-α, and CRP levels in total flavonoids of COM leaves [53]. It has been documented that chronic inflammation is a hallmark of atherosclerosis [23]. According to a study on a polyphenolic extract from Tunisian COM, it can prevent high levels of the proinflammatory cytokine TNF-, chemokine IL-8, and LPS-mediated activation of three main cellular proinflammatory effectors; p38MAPK, nuclear factor-kappa B, and Akt [23]. Reduced antiinflammatory cytokine levels, such as CRP, together with lower LDL-C and TC levels, inhibited the development of atherosclerosis [62].

Other Factors.
In a study on male rabbits, Khademi et al. discovered that high-cholesterol diet significantly elevated alkaline phosphatase (ALP), ALT, AST, Cr, and BUN. Biochemical markers; AST, ALT, and Cr levels were dramatically reduced when quince leaf extract (50 mg/kg) and atorvastatin 0.5 mg/kg were used in comparison to the control group; however, the difference was not significant [43]. Other studies also proved the positive effect of Cydonia on liver function biomarkers (ALP, AST, and ALT) and kidney function biomarkers (Cr and BUN) [44,46,49]. However, histological analysis in their study revealed that atorvastatin and COM leaf extract were unable to prevent plaque accumulation in the coronary artery following plaque formation for 12 weeks.
Zhou et al. found that in comparison to aspirin (2.58), extract from Cydonia (20, 40, 80 mg/kg/day) prolonged bleeding times by 2.17, 2.78, and 3.63 and the clotting time by 1.44, 2.47, and 2.48 times, respectively [51]. Cydonia extract also reduced pulmonary emboli mortality, increased thrombolysis, decreased euglobulin lysis time, and increased the length of venous occlusion in rats compared to the aspirin group [51].

Conclusion
It can be concluded that Cydonia oblonga Miller (quince) has cardiovascular preventive properties. In animal studies, it regulates blood lipids, lowers blood pressure and glucose levels, and protects the liver and kidneys. It also helps with thrombosis and body weight and has anti-inflammatory and antioxidant properties.

Data Availability
No data were used to support the findings of the study.

Ethical Approval
(is article does not feature any of the authors' human subject research.

Conflicts of Interest
All the authors declare that they have no conflicts of interest.