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Cardiovascular disease (CVD), particularly atherosclerosis, is a major cause of morbidity and mortality worldwide; it places a great burden on families and caregivers and results in significant financial costs. Hawthorn has a long history of medicinal use in many countries. In China, the use of hawthorn for the treatment of CVD dates back to 659 AD. In addition, according to the theory of traditional Chinese medicine, it acts to tonify the spleen to improve digestion and activate blood circulation to eliminate blood stasis. This review revealed that hawthorn extract has serum lipid protective, anti-oxidative, and cardiovascular properties, thus gaining popularity, especially for its anti-atherosclerotic effects. We summarize the four main mechanisms, including blood lipid, anti-oxidative, anti-inflammatory, and vascular endothelial protection, thus providing a theoretical basis for the further use of hawthorn.
Hawthorn Berries For Bph
Cardiovascular disease (CVD), particularly atherosclerosis, is a major cause of morbidity and mortality worldwide. CVD imposes a significant burden on families and primary caregivers, as well as high financial costs to society. During the past decade in China, ischemic heart disease and stroke were the two leading causes of death ( Yang et al., 2013 ). With a rapidly aging population, the total number of deaths due to CVD has increased by 46% in China, four and three times higher than in the United States and Western Europe, respectively (Du et al., 2019). Beyond conventional medical treatment, herbal plants have several natural compounds to prevent and treat various diseases. Herbal medicines, such as adjuvants, have also become popular around the world. According to the World Health Organization, in developing countries, almost four billion people consume herbal medicines as the main source of health (Bodeker and Ong, 2005). Therefore, the use of herbal medicine in complementary and alternative medicine has been widely adopted in many countries (Ekor, 2014).
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Crataegus sp., commonly known as hawthorn, or hawberry, is a genus of thorny shrubs and large trees of the Rosaceae family, which includes approximately 280 species, native to temperate zones in Europe, East Asia, and North America ( Hobbs). and Foster, 1994). Hawthorn has been used for centuries around the world as a food and folk medicine. Hawthorn is one of the medicinal plants recognized in European medicine, because Dioscorides mainly described its cardiovascular action in the first century (Petrovska, 2012). Currently, countries such as China, Germany, and France have officially listed some species in their pharmacopoeia (Chang et al., 2002).
In China, the bright red berries of hawthorn, also called Shanzha (Figure 1), have been widely used to treat various diseases due to their medicinal properties. It was first mentioned to “treat dysentery” in the Tang Materia Medica (Tang Ben Cao) from 659 AD, the first official pharmacopoeia known in the world. As described in the Compendium of Materia Medica (Bencao Gangmu), which is considered to be the most complete and comprehensive herbal monograph, the dried berry of Crataegus pinnatifida is described as having healing properties for thoracalgia, hernia, indigestion, blood stagnation, and hematochezia (Liu). et al., 2011). Currently, many efforts are being made to identify the bioactive components of various plant parts and reveal the potential mechanisms of pharmaceutical action.
Figure 1 Crataegus pinnatifida tree and fruits (left). Traditional Chinese Herb Shanzha (Fructus Crataegus, prepared from pieces of Crataegus pinnatifida var. main) fruit pieces (right).
Currently, in traditional Chinese medicine (TCM), the fruits of C. pinnatifida Bge. var. N.E.Br main and C. pinnatifida Bge are the only two medicinal species documented in the Chinese pharmacopoeia, which are used to improve digestion and improve blood circulation. Other species, such as Crataegus monogyna and C. azarolus, are also used as focal medicine in other countries. Different plant parts, such as flowers, leaves, seeds, and berries, have long been recorded for traditional medical use in the form of decoction or powder as folk medicine in many countries, such as Serbia, France, Chile, Turkey , and China, for the treatment of various diseases (eg, antispasmodic, cardiotonic, diuretic, hypotensive, and anti-atherosclerotic) (Cloud et al., 2019; Dehghani et al., 2019).
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In the past 20 years, more than 150 chemical compounds, including flavonoids, triterpenoids, oligomeric proanthocyanidins, and organic acids, were isolated and characterized in the berries, leaves, and flowers of C. pinnatifida (Özcan et al., 2005; Wu et al. al., 2014) (Figures 2–4). In addition, pectin in fresh hawthorn fruit was reported to be up to 20.5% (Wang et al., 2007). Pectin oligosaccharides with 2-11 polymers show antioxidant, hypolipidemic, antiglycation, and antibiotic properties (Li et al., 2010; Li et al., 2013a; Li et al., 2014; Zhu et al., 2019). Interestingly, one study showed the contribution of total polyphenols, rather than total flavonoids or anthocyanins to the antioxidant capacity of hawthorn liquor (made from C. pinnatifida) (Liu et al., 2016). In addition, exposure to heat and microwaves can increase the level of anthocyanins, such as cyanidin-3-galactoside (Liu et al., 2016). In other species such as C. monogyna and C. azarolus, the same type of phenolic compounds are present and categorized into four subclasses: phenolic acids including hydroxycinnamic acid and hydroxybenzoic acid, flavonoids, which are the most abundant components, including flavones and glucosylated flavonols, anthocyanins, such as cyanidin glycosides, the most abundant of which is cyanidin-3-O-glucoside (Mraihi et al., 2015). Another study identified seven neolignans in the ethanol extract of C. pinnatifida seeds, which produced antioxidant and anti-inflammatory effects (Peng et al., 2016).
These results suggest that hawthorn fruit may be a promising health supplement and also a potential source of antioxidants and cardiotonic phenolic substances. One study identified phenolic compounds in the fruit of Crataegus pubescens, and the most abundant substances are (+)-catechin, (-)-epicatechin, and chlorogenic acid, which can be used as nutraceutical and functional foods (González-Jiménez et al. , 2018) .
With global interest expanding, modern research validates the presence of various biological and pharmacological activities in extracts of hawthorn fruit, leaves, and flowers, including cardioprotective ability, hypolipidemic activity, and anti-oxidative capacity (Pittler et al., 2003; Wang H. et al., 2011; Zhang et al., 2014). WS
1442 is the most studied compound consisting of 20% oligomeric procyanidins extracted from leaves and flowers (45% ethanol extract) of C. monogyna and Crataegus laevigata ( Holubarsch et al., 2008 ). In the United States and European countries, WS
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1442 has been recommended for the treatment of congestive heart failure stage I-III based on the New York Heart Association (NYHA) classification (Tauchert, 2002; Pittler et al., 2003).
Crataegus sp. has a long history of cardioprotective ability, which is added to first-line clinical practice. Due to its popularity and efficacy, the extract of Crataegus sp. assessed in several clinical trials. In addition to its well-known cardiotonic properties, Crataegus oxyacantha has also been reported to exert various other pharmacological activities such as anxiolytic, hypotensive, hypolipidemic, antioxidant, hypoglycemic, immunomodulatory, and antimutagenic activities. This article focuses mainly on the anti-atherosclerotic effects of hawthorn and summarizes the mechanisms involved in these effects.
Although no side effects have been reported in current clinical use, C. oxyacantha extract shows genotoxic and mutagenic effects in different cultured cell lines (de Quadros et al., 2017), as well as mild genotoxicity in mice (Yonekubo et al., 2018) . ). Interestingly, several studies have shown the protective effect of C. microphylla extract against various genotoxic insults in cells of the lymphoid lineage (Hosseinimehr et al., 2006; Hosseinimehr et al., 2008; Hosseinimehr et al., 2009; Hosseinimehr et al., 2011). These results suggest caution regarding prolonged use or high doses.
CVD has been a leading cause of global mortality and morbidity for decades. The main pathogenesis of CVD is atherosclerosis, which can lead to dramatic clinical events, such as unstable angina or myocardial infarction ( Reiner et al., 2011 ). The pathophysiological mechanisms of atherosclerosis are oxidative stress damage, lipid deposition, inflammatory response, and vascular endothelial dysfunction (Libby et al., 2002; Weber and Noels, 2011). Various risk factors associated with the development of atherosclerotic plaques are diabetes mellitus, dyslipidemia, hypertension, obesity, and smoking (Folsom et al., 1997; Hackam and Anand, 2003; Mannarino and Pirro, 2008). Among the risk factors identified in epidemiological studies, only apolipoprotein (apo)-B containing lipoproteins, including low-density lipoprotein (LDL) and very high-density lipoprotein (VLDL), causes atherosclerosis in humans and experimental animals (Skålén et al). ., 2002).
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After LDL passes through the sub-endothelium, it will bind to the sites of chondroitin sulfate (CS) and dermatan sulfate (DS) of the matrix proteoglycan, further leading to entrapment and phagocytosis by macrophages and other cells, finally forming foam cells and lipids. core to initiate a local inflammatory response (Little et al., 2007). Lipid retention is an important and critical initial step in the atherosclerotic cascade, and without it, atherosclerosis cannot be induced in animal models (Olofsson and Boren, 2005).
A 6-month clinical observation of 64 patients with carotid artery atherosclerosis showed that consumption of hawthorn extract at a dose of 5.0 mg/kg reduced serum lipid levels and improved plaque stability (Liu et al., 2014). C. pinnatifida extract which mainly contains flavonoids showed promising hypolipidemic activity in different experimental animals. Flavonoid extract from C. pinnatifida leaves reduced serum lipid levels, such as total cholesterol (TC) and triglyceride (TG) in mice, rats, and rabbits ( Zhang et al., 2002b ; Luo et al., 2009 Zhang et al., 2013 ). At