Natural Products to Counteract the Epidemic of Cardiovascular and Metabolic Disorders

Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an “opening” of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease.


Introduction
It is well known that natural products have been a valuable source of therapeutic agents for millenia and even today, many medicines are natural products or their derivatives [1]. Although natural products have played an important role in lead discovery [1], nowadays the pharmaceutical industry tends to not prioritize natural product research anymore [2]. Instead, common strategies in industry are high throughput screening (HTS) of synthetic compound databases and structural modifications of existing leads. However, the HTS and combinatorial chemistry approaches followed by many pharmaceutical companies have not been very successful. Furthermore, even stakeholders in industry still see a high potential in natural products as drug leads [3]. In line with this view, the number of scientific studies in the area of natural products research is increasing rapidly [1]. The 2015 Nobel Prize in Physiology or Medicine, which was awarded to Youyou Tu, William C. Campbell, and Satoshī Omura for the discovery of natural products for the treatment of tropical parasitic diseases [4,5], might

Increasing Scientific Interest in Natural Products with Potential Application in Cardiovascular and Metabolic Disorders
Considering the huge morbidity and mortality burden related to cardiometabolic disorders with no end in sight, there is a high interest in the discovery of novel compounds as well as novel pharmacological targets that might be effective in the treatment or prevention of cardiovascular and/or metabolic disorders. Although natural product drug discovery often requires more effort compared to HTS and combinatorial chemistry, nature is still considered as the most productive source of potential drug leads for new medicines [3].
In recent decades, herbal remedies and natural products have undisputedly attracted much research attention in the context of prevention or treatment of cardiovascular and metabolic disease [17][18][19]. Thus, when searching Scopus using the keywords "cardiovascular disease" and "natural products" (CVD+NP) or "metabolic disease" and "natural products" (MD+NP) it becomes evident that the scientific interest in these areas increased exponentially in the period 2004-2014 ( Figure 1).

Figure 1.
Annual number of publications resulting from the search with the keywords "cardiovascular disease" and "natural products" (CVD + NP) (a) and "metabolic disease" and "natural products" (MD + NP) (b), (Scopus, January 2016).

Plants Traditionally Used in the Context of Cardiovascular and Metabolic Disorders
Millenary civilizations rely on plants or other natural resources to sustain or restore health, and in various situations they still represent interesting therapeutic alternatives to synthetic drugs. According to the WHO, over 100 million Europeans and many more people in Africa, Asia, Australia, and North America are users of traditional and complementary medicine. Especially in Africa and some developing countries, traditional medicine is often the primary source of health care [20].
Along with herbal extracts and natural products with validated efficacy and safety proven by randomized controlled clinical trials (further discussed in chapter 5), many other medicinal plants are used world-wide to alleviate cardiovascular and metabolic complaints. Table 1 provides an overview of selected traditionally used plants and their targeted indications.
There is no doubt that medicinal plants and natural products are used for the treatment or prevention of cardiovascular and metabolic disorders, also with rising popularity in western societies. However, in most cases the expected health benefits are not scientifically proven by rigorous clinical trials. Hence, it is vital to provide robust scientific evidence for clinical efficacy and safety. Annual number of publications resulting from the search with the keywords "cardiovascular disease" and "natural products" (CVD + NP) (a) and "metabolic disease" and "natural products" (MD + NP) (b), (Scopus, January 2016).

Plants Traditionally Used in the Context of Cardiovascular and Metabolic Disorders
Millenary civilizations rely on plants or other natural resources to sustain or restore health, and in various situations they still represent interesting therapeutic alternatives to synthetic drugs. According to the WHO, over 100 million Europeans and many more people in Africa, Asia, Australia, and North America are users of traditional and complementary medicine. Especially in Africa and some developing countries, traditional medicine is often the primary source of health care [20].
Along with herbal extracts and natural products with validated efficacy and safety proven by randomized controlled clinical trials (further discussed in chapter 5), many other medicinal plants are used world-wide to alleviate cardiovascular and metabolic complaints. Table 1 provides an overview of selected traditionally used plants and their targeted indications.
There is no doubt that medicinal plants and natural products are used for the treatment or prevention of cardiovascular and metabolic disorders, also with rising popularity in western societies. However, in most cases the expected health benefits are not scientifically proven by rigorous clinical trials. Hence, it is vital to provide robust scientific evidence for clinical efficacy and safety.

Herbal Products in Recruiting Clinical Trials Targeting Indications Related to Cardiovascular and Metabolic Disorders
Many medicinal plants and natural products are considered by the public as a safe, natural, and cost-effective alternative to synthetic drugs without unambiguous proof by randomized controlled clinical trials. On this background, there is an increased interest in the development of products with validated efficacy and safety, similar to the recently FDA-approved botanical drugs Veregen ® (sinecatechins; green tea (Camellia sinensis (L.) Kuntze) leaf extract), Fulyzaq ® (crofelemer; extract from the red latex of the Dragon's blood tree (Croton lechleri Müll.Arg.)), and Grastek ® (Timothy grass (Phleum pretense L.) pollen allergen extract) [177,178]. Some herbal extracts and pure compounds are currently undergoing clinical trials for cardiometabolic indications; an overview is presented in Table 2.

Dietary Constituents with Potential Benefits in the Context of Cardiovascular and Metabolic Disorders
Ample evidence demonstrates that dietary patterns can affect the development of cardiovascular and metabolic disorders [179,180]. The reduced intake of highly processed foods by replacing them with fruits, nuts, seeds, vegetables, and legumes [181] is considered health promoting. The latter dietary constituents are free of food additives, low in salt content, and rich in phenolics, carotenoids, fibers, minerals, and unsaturated fats. They possess antioxidant effects, lower glycemic indices, and normalize levels of cholesterol in blood. The traditional Mediterranean diet is one example, which is associated with longer life expectancy, lower rates of cardiovascular and metabolic disorders, and even lower rates of certain cancers [182]. This diet is characterized by an abundance of seasonally fresh plant foods (fruits, vegetables, beans, nuts, seeds, etc.), minimal food processing, olive oil, and wine consumed in low to moderate amounts, normally with meals [19,182,183].
Another example for a presumably health promoting dietary constituent is coffee, one of the most popular beverages worldwide. It exhibits a range of bioactivities and potential health benefits. Since coffee drinking is very common in Western societies, its bioactivities and in particular its impact on cardiovascular and metabolic parameters have been widely investigated [184][185][186][187][188][189][190]. Compared to non-drinkers, coffee consumption of one to five cups/day was associated with lower risk of mortality, while coffee consumption of more than five cups/day did not affect mortality risk. Additionally, coffee consumption (with or without caffeine) was associated with significantly lower death risk due to cardiovascular disease, neurological disorders, and suicide [191]. It was also linked to a lower risk of diabetes mellitus type 2, independent of race, geographic distribution and gender of the studied populations [192]. Major bioactive ingredients in coffee include phenolics (chlorogenic acid and its isomers), diterpenes (cafestol and kahweol), and caffeine ( Figure 2). Coffee is considered to be a very prominent source of phenolic compounds, and it appears that it is the number one source of dietary antioxidants in the US [193,194]. The total phenolic content per cup of coffee ranges between 200 and 550 mg, with chlorogenic acid being the main phenolic compound [192]. dietary constituents are free of food additives, low in salt content, and rich in phenolics, carotenoids, fibers, minerals, and unsaturated fats. They possess antioxidant effects, lower glycemic indices, and normalize levels of cholesterol in blood. The traditional Mediterranean diet is one example, which is associated with longer life expectancy, lower rates of cardiovascular and metabolic disorders, and even lower rates of certain cancers [182]. This diet is characterized by an abundance of seasonally fresh plant foods (fruits, vegetables, beans, nuts, seeds, etc.), minimal food processing, olive oil, and wine consumed in low to moderate amounts, normally with meals [19,182,183].
Another example for a presumably health promoting dietary constituent is coffee, one of the most popular beverages worldwide. It exhibits a range of bioactivities and potential health benefits. Since coffee drinking is very common in Western societies, its bioactivities and in particular its impact on cardiovascular and metabolic parameters have been widely investigated [184][185][186][187][188][189][190]. Compared to non-drinkers, coffee consumption of one to five cups/day was associated with lower risk of mortality, while coffee consumption of more than five cups/day did not affect mortality risk. Additionally, coffee consumption (with or without caffeine) was associated with significantly lower death risk due to cardiovascular disease, neurological disorders, and suicide [191]. It was also linked to a lower risk of diabetes mellitus type 2, independent of race, geographic distribution and gender of the studied populations [192]. Major bioactive ingredients in coffee include phenolics (chlorogenic acid and its isomers), diterpenes (cafestol and kahweol), and caffeine ( Figure 2). Coffee is considered to be a very prominent source of phenolic compounds, and it appears that it is the number one source of dietary antioxidants in the US [193,194]. The total phenolic content per cup of coffee ranges between 200 and 550 mg, with chlorogenic acid being the main phenolic compound [192]. Chlorogenic acid intake leads to lower blood glucose and insulin concentrations 15 minutes after ingestion [195]. In streptozocin-nicotinamide induced diabetic rats, a dose of 5 mg chlorogenic acid/kg body weight exerts antidiabetic effects [195,196]. Additionally, coffee phenolics can intensify energy metabolism and decrease lipogenesis by down-regulation of SREBP-1c and related molecules [197]. Moreover, coffee phenolics are able to modulate whole-body substrate oxidation by suppressing postprandial hyperglycemia and hyperinsulinemia [198].
Another commonly consumed beverage is tea (Camellia sinensis (L.) Kuntze). Infusions from tea are enormously rich in phenolic substances, and also contain considerable amounts of caffeine [199][200][201]. Consumption of tea was found to correlate with several health benefits including beneficial effects on the cardiovascular system [202]. Several studies showed that regular consumption of this polyphenol-rich beverage may exert cardio-protective effects in humans and reduce the risk of cardiovascular disease [203][204][205]. The phenolics of tea are represented particularly by epicatechin (EC), epigallocatechin (EGC), Chlorogenic acid intake leads to lower blood glucose and insulin concentrations 15 minutes after ingestion [195]. In streptozocin-nicotinamide induced diabetic rats, a dose of 5 mg chlorogenic acid/kg body weight exerts antidiabetic effects [195,196]. Additionally, coffee phenolics can intensify energy metabolism and decrease lipogenesis by down-regulation of SREBP-1c and related molecules [197]. Moreover, coffee phenolics are able to modulate whole-body substrate oxidation by suppressing postprandial hyperglycemia and hyperinsulinemia [198].
Another commonly consumed beverage is tea (Camellia sinensis (L.) Kuntze). Infusions from tea are enormously rich in phenolic substances, and also contain considerable amounts of caffeine [199][200][201]. Consumption of tea was found to correlate with several health benefits including beneficial effects on the cardiovascular system [202]. Several studies showed that regular consumption of this polyphenol-rich beverage may exert cardio-protective effects in humans and reduce the risk of cardiovascular disease [203][204][205]. The phenolics of tea are represented particularly by epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG) [206]. The effects of EGCG (Figure 3) are multifaceted and include among others the inhibition of the activator protein 1 (AP-1), the nuclear factor kappa B (NF-κB), the tumor necrosis factor α (TNFα) signaling, the inhibition of the vascular endothelial growth factor (VEGF) signaling, the insulin-like growth factor (IGF-1) signaling, and the activation of peroxisome proliferator-activated receptor (PPAR) [207]. the vascular endothelial growth factor (VEGF) signaling, the insulin-like growth factor (IGF-1) signaling, and the activation of peroxisome proliferator-activated receptor (PPAR) [207]. The significance of dietary constituents in the context of metabolic and cardiovascular diseases is also evident in Table 2, which among herbal extracts also lists several prominent dietary constituents (e.g., curcumin and resveratrol).
Detailed studies on the efficacy of dietary constituents and the mechanisms by which they exert beneficial effects on cardiovascular and metabolic diseases are of critical importance in order to better rationalize dietary recommendations, and might also allow the development of novel effective nutraceuticals and functional foods [208][209][210][211][212]. Metabolism, bioavailability, and interaction with the intestinal microbiome will be important aspects to consider in this endeavor and also need to be taken into account for any natural product which is taken up orally.

Common Molecular Targets Affected by Natural Compounds in the Context of Cardiovascular and Metabolic Disorders
Diverse natural compounds have been shown to affect cardiovascular and metabolic disorders via different mechanisms, such as anti-inflammatory activity, improvement of blood lipid profiles, improvement of insulin sensitivity, or normalization of blood glucose levels [72,[213][214][215][216][217]. Often the underlying molecular targets mediating these beneficial effects are not well understood. However, there are several molecular targets or pathways that are already well established to mediate the beneficial effects of natural compounds in the context of cardiovascular and metabolic disorders. Of those, selected examples, i.e., the AMP-activated protein kinase (AMPK), cyclooxygenase (COX)-1 and -2, the dipeptidyl peptidase-4 (DPP-4), the endothelial nitric oxide synthase (eNOS), the transcription factors NF-κB, nuclear factor-erythroid 2-related factor 2 (Nrf2), and PPARγ, the protein-tyrosine phosphatase 1B (PTP1B), and 5-lipoxygenase (5-LO), are listed in Table 3, together with their major physiological consequences and some examples of compound classes of interacting natural products. The significance of dietary constituents in the context of metabolic and cardiovascular diseases is also evident in Table 2, which among herbal extracts also lists several prominent dietary constituents (e.g., curcumin and resveratrol).
Detailed studies on the efficacy of dietary constituents and the mechanisms by which they exert beneficial effects on cardiovascular and metabolic diseases are of critical importance in order to better rationalize dietary recommendations, and might also allow the development of novel effective nutraceuticals and functional foods [208][209][210][211][212]. Metabolism, bioavailability, and interaction with the intestinal microbiome will be important aspects to consider in this endeavor and also need to be taken into account for any natural product which is taken up orally.

Common Molecular Targets Affected by Natural Compounds in the Context of Cardiovascular and Metabolic Disorders
Diverse natural compounds have been shown to affect cardiovascular and metabolic disorders via different mechanisms, such as anti-inflammatory activity, improvement of blood lipid profiles, improvement of insulin sensitivity, or normalization of blood glucose levels [72,[213][214][215][216][217]. Often the underlying molecular targets mediating these beneficial effects are not well understood. However, there are several molecular targets or pathways that are already well established to mediate the beneficial effects of natural compounds in the context of cardiovascular and metabolic disorders. Of those, selected examples, i.e., the AMP-activated protein kinase (AMPK), cyclooxygenase (COX)-1 and -2, the dipeptidyl peptidase-4 (DPP-4), the endothelial nitric oxide synthase (eNOS), the transcription factors NF-κB, nuclear factor-erythroid 2-related factor 2 (Nrf2), and PPARγ, the protein-tyrosine phosphatase 1B (PTP1B), and 5-lipoxygenase (5-LO), are listed in Table 3, together with their major physiological consequences and some examples of compound classes of interacting natural products.

Natural Products (or Their Derivatives) Developed as Drugs for the Treatment of Cardiovascular and Metabolic Disorders
Other than providing a direct remedy, natural products also represent an excellent pool of inspiring lead structures for the development of successful pharmaceuticals to combat cardiovascular and metabolic disorders. This could be demonstrated with historical views on the development of the statins and the biguanides.
Aberrantly high cholesterol is causally connected to atherosclerosis and coronary heart disease. Therefore, in the 1950s and 1960s, companies were searching for compounds which block one of the 30 enzymatic reactions involved in cholesterol biosynthesis. However, none of the developed synthetic inhibitors of cholesterol biosynthesis had an ideal efficacy and safety profile [259]. In the early 1970s, the natural product citrinin (Figure 4) was isolated from fungi and identified as a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [260], the rate-controlling enzyme in the cholesterol biosynthesis. Citrinin also displayed serum cholesterol lowering effects in rats [261]. Shortly after that, mevastatin (compactin; Figure 4), the first statin, was isolated from Penicillium citrinum [262]. It was found to be a strong HMG-CoA reductase inhibitor [263] with great structural similarity with HMG-CoA, the substrate of HMG-CoA reductase [259]. Mevastatin potently inhibited cholesterol biosynthesis in vitro and in vivo [262,264]. Clinical studies started in 1978 but it never came on the market due to side effects in dogs at a dosage of about 200 times the dosage used in human patients [259]. In the 1980s, clinical studies and long-term toxicity studies showed that lovastatin (Figure 4), a natural product isolated from Aspergillus terreus [265] and Monascus ruber [266], effectively lowered blood cholesterol levels and was well tolerated [259]. In 1987, lovastatin was approved by the FDA and became the first commercial statin. After lovastatin, several synthetic and semi-synthetic statins were also introduced to the market [259,267]. Today, statins represent the first-line pharmacologic intervention for dyslipidemia patients with failed treatment with diet and exercise alone [268] and are one of the most widely prescribed class of drugs worldwide.

Natural Products (or Their Derivatives) Developed as Drugs for the Treatment of Cardiovascular and Metabolic Disorders
Other than providing a direct remedy, natural products also represent an excellent pool of inspiring lead structures for the development of successful pharmaceuticals to combat cardiovascular and metabolic disorders. This could be demonstrated with historical views on the development of the statins and the biguanides.
Aberrantly high cholesterol is causally connected to atherosclerosis and coronary heart disease. Therefore, in the 1950s and 1960s, companies were searching for compounds which block one of the 30 enzymatic reactions involved in cholesterol biosynthesis. However, none of the developed synthetic inhibitors of cholesterol biosynthesis had an ideal efficacy and safety profile [259]. In the early 1970s, the natural product citrinin (Figure 4) was isolated from fungi and identified as a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [260], the rate-controlling enzyme in the cholesterol biosynthesis. Citrinin also displayed serum cholesterol lowering effects in rats [261]. Shortly after that, mevastatin (compactin; Figure 4), the first statin, was isolated from Penicillium citrinum [262]. It was found to be a strong HMG-CoA reductase inhibitor [263] with great structural similarity with HMG-CoA, the substrate of HMG-CoA reductase [259]. Mevastatin potently inhibited cholesterol biosynthesis in vitro and in vivo [262,264]. Clinical studies started in 1978 but it never came on the market due to side effects in dogs at a dosage of about 200 times the dosage used in human patients [259]. In the 1980s, clinical studies and long-term toxicity studies showed that lovastatin (Figure 4), a natural product isolated from Aspergillus terreus [265] and Monascus ruber [266], effectively lowered blood cholesterol levels and was well tolerated [259]. In 1987, lovastatin was approved by the FDA and became the first commercial statin. After lovastatin, several synthetic and semi-synthetic statins were also introduced to the market [259,267]. Today, statins represent the first-line pharmacologic intervention for dyslipidemia patients with failed treatment with diet and exercise alone [268] and are one of the most widely prescribed class of drugs worldwide. Since the Middle Ages, Galega officinalis (also known as French lilac, Italian fitch, goat's rue) has been known to relieve symptoms (the intense urination) of a disease now described as diabetes mellitus type 2 [98,269]. Galegine ( Figure 5), a guanidine derivative which lowers blood glucose levels [270], turned out to be the bioactive constituent in G. officinalis [271,272]. Guanidine itself also decreases blood glucose levels [273], but is too toxic for clinical application. Galegine from G. officinalis is less toxic, nevertheless, clinical trials conducted with diabetic patients in the 1920s and 1930s, were not successful. However, the identification of the antidiabetic natural product galegine led to the development of the biguanide compound metformin, which is now one of the most important therapeutic agents for the treatment of diabetes mellitus type 2 [98,274,275].  Since the Middle Ages, Galega officinalis (also known as French lilac, Italian fitch, goat's rue) has been known to relieve symptoms (the intense urination) of a disease now described as diabetes mellitus type 2 [98,269]. Galegine ( Figure 5), a guanidine derivative which lowers blood glucose levels [270], turned out to be the bioactive constituent in G. officinalis [271,272]. Guanidine itself also decreases blood glucose levels [273], but is too toxic for clinical application. Galegine from G. officinalis is less toxic, nevertheless, clinical trials conducted with diabetic patients in the 1920s and 1930s, were not successful. However, the identification of the antidiabetic natural product galegine led to the development of the biguanide compound metformin, which is now one of the most important therapeutic agents for the treatment of diabetes mellitus type 2 [98,274,275].

Natural Products (or Their Derivatives) Developed as Drugs for the Treatment of Cardiovascular and Metabolic Disorders
Other than providing a direct remedy, natural products also represent an excellent pool of inspiring lead structures for the development of successful pharmaceuticals to combat cardiovascular and metabolic disorders. This could be demonstrated with historical views on the development of the statins and the biguanides.
Aberrantly high cholesterol is causally connected to atherosclerosis and coronary heart disease. Therefore, in the 1950s and 1960s, companies were searching for compounds which block one of the 30 enzymatic reactions involved in cholesterol biosynthesis. However, none of the developed synthetic inhibitors of cholesterol biosynthesis had an ideal efficacy and safety profile [259]. In the early 1970s, the natural product citrinin (Figure 4) was isolated from fungi and identified as a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [260], the rate-controlling enzyme in the cholesterol biosynthesis. Citrinin also displayed serum cholesterol lowering effects in rats [261]. Shortly after that, mevastatin (compactin; Figure 4), the first statin, was isolated from Penicillium citrinum [262]. It was found to be a strong HMG-CoA reductase inhibitor [263] with great structural similarity with HMG-CoA, the substrate of HMG-CoA reductase [259]. Mevastatin potently inhibited cholesterol biosynthesis in vitro and in vivo [262,264]. Clinical studies started in 1978 but it never came on the market due to side effects in dogs at a dosage of about 200 times the dosage used in human patients [259]. In the 1980s, clinical studies and long-term toxicity studies showed that lovastatin (Figure 4), a natural product isolated from Aspergillus terreus [265] and Monascus ruber [266], effectively lowered blood cholesterol levels and was well tolerated [259]. In 1987, lovastatin was approved by the FDA and became the first commercial statin. After lovastatin, several synthetic and semi-synthetic statins were also introduced to the market [259,267]. Today, statins represent the first-line pharmacologic intervention for dyslipidemia patients with failed treatment with diet and exercise alone [268] and are one of the most widely prescribed class of drugs worldwide. Since the Middle Ages, Galega officinalis (also known as French lilac, Italian fitch, goat's rue) has been known to relieve symptoms (the intense urination) of a disease now described as diabetes mellitus type 2 [98,269]. Galegine ( Figure 5), a guanidine derivative which lowers blood glucose levels [270], turned out to be the bioactive constituent in G. officinalis [271,272]. Guanidine itself also decreases blood glucose levels [273], but is too toxic for clinical application. Galegine from G. officinalis is less toxic, nevertheless, clinical trials conducted with diabetic patients in the 1920s and 1930s, were not successful. However, the identification of the antidiabetic natural product galegine led to the development of the biguanide compound metformin, which is now one of the most important therapeutic agents for the treatment of diabetes mellitus type 2 [98,274,275]. Figure 5. Chemical structure of the natural blood glucose lowering agent galegine. Figure 5. Chemical structure of the natural blood glucose lowering agent galegine.

Conclusions and Future Perspectives
The reviewed key examples and recent developments clearly demonstrate the great potential and the future promise of natural products for the treatment or prevention of cardiovascular and metabolic disorders. This work should provide an inspiration for authors who consider preparing further submissions to the special issue "Effects of Natural Products in the Context of Cardiometabolic Disease". With the present review as well as with the expected valuable contributions to this special issue we do hope to further boost the scientific interest and knowledge on the efficacy of natural products with regard to the prevention and the therapy of cardiovascular and metabolic disease.

Conflicts of Interest:
The authors declare no conflict of interest.

Abbreviations
The following abbreviations are used in this manuscript: